Restrictive Cardiomyopathy

Genetic MONDO:0005201 Pathograph 15 Show in embeddings browser Cardiovascular Disease Genetic Disorder

Restrictive cardiomyopathy (RCM) is the least common of the three classic cardiomyopathy patterns, defined by restrictive ventricular filling — a stiff, non-compliant ventricle with impaired diastolic relaxation but preserved (or only mildly reduced) systolic function and non-dilated, non-hypertrophied chambers, producing marked biatrial enlargement and elevated filling pressures. This entry is scoped to the primary/heritable form, in which the restrictive physiology is the final common pathway of a sarcomeric or cytoskeletal defect: pathogenic variants in thin-filament and myosin genes — most characteristically the troponins (TNNI3, TNNT2), alpha-cardiac actin (ACTC1), beta-myosin heavy chain (MYH7), and the myosin light chains (MYL3), as well as the Z-disc and intermediate-filament proteins desmin (DES), filamin C (FLNC) and myopalladin (MYPN) — increase myofilament tension and resting myocardial stiffness. More than half of patients carry no sarcomere variant at all, and in those the cardiac fibroblast is itself mechanically abnormal, so the entry models a fibroblast arm running parallel to the sarcomeric one. RCM overlaps genetically and mechanistically with hypertrophic cardiomyopathy (the same genes and often the same alleles can produce either pattern), and thin-filament HCM shades into restrictive physiology. Infiltrative causes of a restrictive phenotype (cardiac amyloidosis, storage disease) are curated under their own entries; this entry models the primary sarcomeric/cytoskeletal mechanism.

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1
Mappings
1
Inheritance
6
Pathophys.
9
Phenotypes
2
Gaps
15
Pathograph
8
Genes
5
Medical Actions
2
Subtypes
4
Differentials
2
Trials
1
Models
1
Deep Research
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Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
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Mappings

MONDO
MONDO:0016340 familial restrictive cardiomyopathy Not Yet Curated
skos:narrowMatch dismech curation MONDO: CONSISTENT
MONDO:0016340 is_a the MONDO:0005201 anchor of this entry and denotes the inherited subset of restrictive cardiomyopathy. It is narrower than the anchor - which by its own MONDO definition also covers scarring, infiltrative and deposition causes - but it is precisely the scope this entry curates: the primary/heritable sarcomeric and cytoskeletal disease. The anchor is retained as `disease_term` because MONDO:0005201 carries "familial restrictive cardiomyopathy" as a synonym, so the two labels are not cleanly separable at the term level, and because the acquired causes have to be nameable here to be excluded. No Grouping was created for MONDO:0016340 - unlike the sibling MONDO classes behind `Familial_Hypertrophic_Cardiomyopathy` and `Familial_Dilated_Cardiomyopathy`, none of its numbered members (RCM1-RCM6) is a curated DisMech Disease entry, so a union over them would have no members to unite.
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Inheritance

1
Autosomal dominant HP:0000006
Familial RCM is most often inherited as an autosomal dominant trait caused by a sarcomeric or cytoskeletal gene variant, frequently the same genes implicated in hypertrophic cardiomyopathy; de novo variants and recessive/desmin-related forms also occur. Penetrance and the hypertrophic-versus-restrictive expression of a given allele are variable.
Autosomal dominant inheritance Penetrance: INCOMPLETE
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Subtypes

2
Cardiomyopathy, familial restrictive, 1 (TNNI3) MONDO:0007270
TNNI3 hgnc:11947 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TNNI3 (hgnc:11947). hgnc:11947 is a gene from the HUGO Gene Nomenclature Committee.
The prototype and by far the most common molecularly defined familial RCM: heterozygous missense variants in cardiac troponin I, in conserved and functionally important domains of the gene. It was the locus at which idiopathic RCM was first shown to be a sarcomeric disease, in a family segregating both RCM and hypertrophic cardiomyopathy, and TNNI3 remains the single gene most often returned by pediatric RCM sequencing. De novo variants occur, so an absent family history does not exclude it.
Show evidence (2 references)
PMID:12531876 SUPPORT Human Clinical
"TNNI3 mutations were identified in six of these nine RCM patients"
Establishes TNNI3 as a cause of idiopathic restrictive cardiomyopathy in unrelated patients selected on restrictive physiology, which is the gene-disease relationship this subtype names.
PMID:12531876 SUPPORT Human Clinical
"Two of the mutations identified in young individuals were de novo mutations."
Records the de novo occurrence noted in this subtype's description, which is why an absent family history does not exclude TNNI3 disease.
Cardiomyopathy, familial restrictive, 3 (TNNT2) MONDO:0012900
TNNT2 hgnc:11949 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in TNNT2 (hgnc:11949). hgnc:11949 is a gene from the HUGO Gene Nomenclature Committee.
Familial restrictive cardiomyopathy caused by variants in cardiac troponin T, the other thin-filament regulatory subunit. Curated as a distinct numbered entity because MONDO and OMIM separate it from RCM1, but the clinical presentation is not separable from TNNI3 disease at the bedside; the pediatric series that established sarcomeric causation found TNNT2 and TNNI3 variants side by side in the same cohort.
Show evidence (1 reference)
PMID:18467357 SUPPORT Human Clinical
"Sarcomere protein gene mutations were identified in four patients (33%): 2 in the cardiac troponin I gene (TNNI3) and 1 each in the troponin T (TNNT2) and alpha-cardiac actin (ACTC) genes."
Human evidence for a TNNT2 variant in a patient ascertained as idiopathic restrictive cardiomyopathy, alongside TNNI3 and ACTC1 in the same cohort.
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Discussions and Knowledge Gaps

2
Does the Drosophila upheld/troponin-T and mouse MYL3 E143K mechanism — increased myofilament tension producing elevated resting stiffness and restrictive filling — hold in human restrictive cardiomyopathy myocardium, where it has not been functionally confirmed?
HUMAN MODEL MISMATCH OPEN rcm_mechanism_is_model_organism_weighted
Attached to
pathophysiology#Sarcomeric or Cytoskeletal Variant with Increased Myofilament Tension pathophysiology#Increased Resting Myocardial Stiffness and Impaired Relaxation pathophysiology#Restrictive Filling Physiology
The animal-derived core of this chain is unchanged: the tension, fibrosis, filling, and heart-failure nodes still rest on a Drosophila troponin-T model and a transgenic mouse carrying the myosin essential light chain E143K substitution. Two human-cell measurements have since been added and narrow the question without closing it. Patient-derived engineered cardiac tissue carrying an FLNC in-frame deletion shows increased passive tension and impaired relaxation against a CRISPR-corrected isogenic control (PMID:36921598), and cardiac fibroblasts explanted from children with idiopathic RCM are themselves stiffer and more viscous than control fibroblasts (PMID:36174041). Both are human cells, and the isogenic comparison in the first removes genetic background as an explanation - so the mechanism is no longer purely a cross-species inference. But neither is a measurement in human myocardium: engineered tissue is immature and lacks the vascular and neurohormonal context of the ventricle, the fibroblast work is a single non-myocyte cell type in culture, and the FLNC result is one patient and one allele. The question the proposed experiment below asks - do genotyped human RCM myocardial fibres show raised passive tension and stiffness - is therefore still open, and it is still a question of translational validity rather than absent evidence, which is why it is a HUMAN_MODEL_MISMATCH and not a KNOWLEDGE_GAP. The fidelity concern is specific rather than generic: Drosophila indirect flight muscle differs from mammalian myocardium in sarcomere regulation and has no comparable neurohormonal or fibrotic context, and the mouse line reports a supraphysiological single-allele substitution whose duty-ratio effect need not scale to the human ventricle. If the mechanism does not transfer, the direction of therapy implied by this pathograph — lowering myofilament tension rather than treating congestion — would be wrong for patients.
Proposed experiments
Human RCM myocardial mechanics in genotyped explants
exp_rcm_human_myocardium_tension_and_stiffness
In skinned myocardial fibres from explanted or biopsy tissue of genotyped sarcomeric RCM patients, measure active and passive tension, calcium sensitivity, and passive stiffness against non-failing donor myocardium matched for age and region. A human increase in resting tension and passive stiffness tracking genotype would carry the model result into human disease; equivalence with donor myocardium would show the restrictive physiology is driven by something other than the myofilament step this pathograph asserts.
Would support
pathophysiology#Increased Resting Myocardial Stiffness and Impaired Relaxation
Would refute
pathophysiology#Sarcomeric or Cytoskeletal Variant with Increased Myofilament Tension
Supporting outcome
  • Genotype-positive human RCM myocardium shows significantly higher passive stiffness and resting tension than matched non-failing donor myocardium.
Refuting outcome
  • Human RCM myocardium shows passive stiffness and resting tension indistinguishable from matched donor myocardium.
Show evidence (2 references)
PMID:28371863 SUPPORT Model Organism
"E143K-myosin had increased duty ratio and binding affinity to actin compared with WT-myosin"
The core tension mechanism curated here is a mouse transgenic measurement, which is the model-side half of the mismatch.
PMID:24221941 SUPPORT Model Organism
"Elevated resting myocardial stiffness, consistent with upheld(101) diastolic dysfunction, was confirmed by an atomic force microscopy-based nanoindentation approach"
The stiffness node's only quantitative support is a Drosophila nanoindentation measurement, not a human one.
Is there direct human evidence that MYH7 variants cause the restrictive pattern specifically, as opposed to the hypertrophic pattern with restrictive physiology already curated in the sibling HCM entries?
KNOWLEDGE GAP OPEN rcm_tnni3_myh7_restrictive_evidence_absent
Attached to
genetic#MYH7
MYH7 is named in this entry's trigger node and carried in its genetic section, but the record still carries no evidence item, because nothing quoted in this file speaks to MYH7 in restrictive cardiomyopathy specifically. The MYH7 relationships evidenced elsewhere in this repository are hypertrophic (Hypertrophic Cardiomyopathy 1) and dilated (Dilated Cardiomyopathy 1S), and neither can be carried across to this pattern. This is a KNOWLEDGE_GAP rather than a HUMAN_MODEL_MISMATCH because the evidence is absent rather than model-bound - a distinct problem from the model-organism weighting of the pathophysiology chain, and one closed by a human cohort rather than by a better model. Until it is closed, this gene record should not be treated as independently established for the restrictive pattern.
The TNNI3 and TNNT2 halves of this gap are now closed and the discussion has been narrowed accordingly rather than retitled: TNNI3 carries the Mogensen linkage and mutation-screening result (PMID:12531876) plus a pediatric case fraction (PMID:41219744), and TNNT2 carries a proband from the Kaski series (PMID:18467357). The discussion_id is deliberately left unchanged so that references to it from outside this file still resolve.
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Pathophysiology

6
Sarcomeric or Cytoskeletal Variant with Increased Myofilament Tension
The initiating lesion in primary RCM is a variant in a sarcomeric thin-filament or myosin gene, or in a cytoskeletal/Z-disc protein (desmin, filamin C, myopalladin), that raises myofilament tension or destabilises the apparatus that anchors it. Two evidenced archetypes illustrate the myofilament route: a cardiac troponin-T variant that increases the number of actively cycling myosin cross-bridges, and a myosin essential light chain variant (MYL3 E143K) that produces myosin hypercontractility (increased duty ratio, actin-binding affinity, and actin-activated ATPase). The mutant protein is incorporated into the sarcomere and shifts the myocyte toward a hypercontractile, poorly relaxing state. The cytoskeletal route reaches the same node by a different lesion in kind - failure of intermediate-filament assembly for desmin, disturbed myofibrillogenesis for the restrictive myopalladin allele - which is why the node is named for the sarcomeric *or* cytoskeletal variant rather than for the sarcomere alone.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
TNNI3 hgnc:11947 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TNNI3 (hgnc:11947). hgnc:11947 is a gene from the HUGO Gene Nomenclature Committee. TNNT2 hgnc:11949 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TNNT2 (hgnc:11949). hgnc:11949 is a gene from the HUGO Gene Nomenclature Committee. MYH7 hgnc:7577 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYH7 (hgnc:7577). hgnc:7577 is a gene from the HUGO Gene Nomenclature Committee. MYL3 hgnc:7584 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYL3 (hgnc:7584). hgnc:7584 is a gene from the HUGO Gene Nomenclature Committee. ACTC1 hgnc:143 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ACTC1 (hgnc:143). hgnc:143 is a gene from the HUGO Gene Nomenclature Committee. DES hgnc:2770 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DES (hgnc:2770). hgnc:2770 is a gene from the HUGO Gene Nomenclature Committee. FLNC hgnc:3756 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FLNC (hgnc:3756). hgnc:3756 is a gene from the HUGO Gene Nomenclature Committee.
Sarcomere Organization GO:0045214 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Sarcomere Organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Increased Resting Myocardial Stiffness and Impaired Relaxation Hypercontractility and increased passive tension raise resting myocardial stiffness and impair diastolic relaxation.
Myocardial Fibrosis and Ventricular Remodeling Chronic sarcomeric stress drives fibrotic remodeling of the myocardium.
Show evidence (3 references)
PMID:28371863 SUPPORT Model Organism
"the myosin essential light chain has been associated with restrictive cardiomyopathy (RCM) in humans"
Establishes a sarcomeric myosin light chain (MYL3 E143K) variant as a human cause of restrictive cardiomyopathy, modeled in transgenic mice.
PMID:28371863 SUPPORT Model Organism
"E143K-myosin had increased duty ratio and binding affinity to actin compared with WT-myosin"
Identifies myosin hypercontractility (increased duty ratio and actin-binding affinity) as the molecular consequence of the RCM light-chain variant.
PMID:24221941 SUPPORT Model Organism
"prolongs systole and restricts diastolic dimensions of the heart"
A troponin-T RCM model showing that the thin-filament variant increases cross-bridge cycling, prolonging systole and restricting diastolic filling.
Increased Resting Myocardial Stiffness and Impaired Relaxation
The hypercontractile, tension-loaded sarcomere raises the resting (passive) tension of the myocyte and impairs relaxation. In an RCM troponin-T model, elevated resting myocardial stiffness was measured directly; in the MYL3 RCM model, both active and passive tension of papillary muscle were augmented. The same pair of quantities has since been measured in human cells: engineered cardiac tissue built from the cardiomyocytes of an FLNC restrictive cardiomyopathy patient shows increased passive tension and impaired relaxation velocity against a CRISPR-corrected isogenic control. Increased resting stiffness is the cellular basis of the restrictive filling that defines the disease.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Regulation of Cardiac Muscle Contraction GO:0055117 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Regulation of Cardiac Muscle Contraction (GO:0055117). GO:0055117 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Experimental models
FLNC RCM patient iPSC-derived cardiomyocytes and 3D engineered cardiac tissue IPSC DERIVED MODEL Mutant engineered tissues reproduce both halves of the node - raised passive tension and slowed relaxation - in human cells, against an isogenic control.
Downstream
Restrictive Filling Physiology A stiff, poorly relaxing ventricle cannot fill normally in diastole.
Show evidence (3 references)
PMID:24221941 SUPPORT Model Organism
"Elevated resting myocardial stiffness, consistent with upheld(101) diastolic dysfunction, was confirmed by an atomic force microscopy-based nanoindentation approach"
Direct measurement of elevated resting myocardial stiffness in a troponin-T RCM model, the cellular correlate of diastolic dysfunction.
PMID:28371863 SUPPORT Model Organism
"augmented active and passive tension measured in skinned papillary muscle fibres compared with wild-type (WT)-generated force"
Shows augmented passive (resting) tension in an RCM myosin light chain model, the mechanical basis of increased myocardial stiffness.
PMID:36921598 SUPPORT In Vitro
"mutant engineered cardiac tissues (ECTs) demonstrate increased passive tension and impaired relaxation velocity compared with isogenic controls"
The same two quantities - increased passive tension and impaired relaxation - measured in human patient-derived tissue rather than in an animal, against a CRISPR-corrected isogenic control. This is the closest thing this entry carries to a human measurement of the node, and is why the HUMAN_MODEL_MISMATCH discussion is narrowed rather than left as first written.
Cardiac Fibroblast Stiffening and Fibroblast-Cardiomyocyte Crosstalk
A second, non-myocyte contribution to the stiff ventricle, and the arm that matters for the sizeable fraction of patients in whom no sarcomere variant is found - a third of genotyped children in a national pediatric cohort, and more than half in the series behind the fibroblast work. Cardiac fibroblasts explanted from children with idiopathic RCM are themselves mechanically abnormal - measured by atomic force microscopy they are stiffer and more viscous, and less fluid, than control fibroblasts - with a transcriptional signature of altered cytoskeletal signalling (cytoskeletal actin-associated genes up, several tubulin genes down). Because fibroblasts restrain cardiomyocyte relaxation through humoral factors and direct cell-cell contact, a stiffened fibroblast population acts on diastolic function independently of the myofilament, which is why this node is curated as a parallel amplifier of myocardial stiffness rather than as a step downstream of the sarcomeric lesion.
Cardiac Fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac Fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology.
Actin Cytoskeleton Organization GO:0030036 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Actin Cytoskeleton Organization (GO:0030036). GO:0030036 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Increased Resting Myocardial Stiffness and Impaired Relaxation Mechanically abnormal fibroblasts contribute to the stiffness of the myocardium as a tissue and restrain cardiomyocyte relaxation.
Myocardial Fibrosis and Ventricular Remodeling An activated, cytoskeletally altered fibroblast population is the cell that lays down the interstitial matrix of the remodelled ventricle.
Show evidence (4 references)
PMID:36174041 SUPPORT In Vitro
"RCM-derived CFs showed significantly higher stiffness and viscosity and lower fluidity compared to healthy control CFs."
The direct measurement behind this node, made on fibroblasts from human RCM patients rather than on an animal model.
PMID:36174041 SUPPORT In Vitro
"RNA-sequencing revealed that the signaling pathways associated with cytoskeleton elements were affected in RCM CFs; specifically, cytoskeletal actin-associated genes (ACTN1, ACTA2, and PALLD) were highly expressed in RCM CFs, whereas several tubulin genes (TUBB3, TUBB, TUBA1C, and TUBA1B) were..."
The transcriptional result behind this node's abnormal actin-cytoskeleton-organization annotation, measured in the same patient fibroblasts as the rheology.
PMID:36174041 SUPPORT In Vitro
"These results implies that the signaling pathways associated with cytoskeletal elements alter the rheological properties of RCM CFs, particularly those related to CF-cardiomyocyte interactions, thereby leading to diastolic cardiac dysfunction in RCM."
The authors' conclusion from their own measurements, supplying the crosstalk step by which a fibroblast-intrinsic mechanical change reaches cardiomyocyte relaxation.
+ 1 more reference
Myocardial Fibrosis and Ventricular Remodeling
Chronic sarcomeric stress drives interstitial fibrosis and ventricular remodeling. In the MYL3 RCM model, hearts developed ultrastructural defects and fibrosis that progressively worsened with age, with upregulation of stress-response and collagen genes. Unlike dilated or hypertrophic remodeling, the chambers remain non-dilated and non-hypertrophied, but the fibrotic, stiffened wall is the structural substrate of restrictive physiology.
Cardiac Fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac Fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology. Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Extracellular Matrix Organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Extracellular Matrix Organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ↑ INCREASED
Left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Left ventricle, annotated with heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Restrictive Filling Physiology
Show evidence (2 references)
PMID:28371863 SUPPORT Model Organism
"ultrastructural defects and fibrosis that progressively worsened in senescent animals"
Documents progressive myocardial fibrosis and ultrastructural remodeling in an RCM model.
PMID:24221941 SUPPORT Model Organism
"cardiac dysfunction and remodeling comparable to that observed during human restrictive cardiomyopathy"
Establishes that the sarcomeric lesion produces cardiac dysfunction and remodeling matching human RCM.
Restrictive Filling Physiology
The stiff, fibrotic, poorly relaxing ventricle produces the hemodynamic signature of RCM: severely impaired diastolic filling with preserved systolic function and non-dilated ventricles, so that atrial pressures rise and the atria enlarge markedly to maintain filling. This restrictive filling pattern is the defining physiology that separates RCM from the dilated and hypertrophic patterns.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Heart Contraction GO:0060047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Heart Contraction (GO:0060047). GO:0060047 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Diastolic Heart Failure and Arrhythmic Risk
Show evidence (1 reference)
PMID:24221941 SUPPORT Model Organism
"prolongs systole and restricts diastolic dimensions of the heart"
Demonstrates restriction of diastolic filling — the defining physiology of RCM — in a sarcomeric model.
Diastolic Heart Failure and Arrhythmic Risk
Restrictive filling with elevated atrial and pulmonary pressures produces heart failure with preserved ejection fraction — dyspnea, congestion, and exercise intolerance — together with a high burden of atrial arrhythmia and thromboembolism from the dilated atria, and a risk of sudden death. RCM carries a poor prognosis and is frequently an indication for heart transplantation, including in patients whose systolic function is preserved.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Heart Contraction GO:0060047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Heart Contraction (GO:0060047). GO:0060047 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (1 reference)
PMID:28371863 SUPPORT Model Organism
"the hearts of RCM mice model exhibited cardiac dysfunction, stiff ventricles"
Ties the stiff-ventricle restrictive remodeling to overt cardiac dysfunction, the clinical endpoint of the disease.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Restrictive Cardiomyopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

9
Cardiovascular 2
Left Ventricular Diastolic Dysfunction HP:0025168 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular diastolic dysfunction (HP:0025168). HP:0025168 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24221941 SUPPORT Model Organism
"Elevated resting myocardial stiffness, consistent with upheld(101) diastolic dysfunction, was confirmed by an atomic force microscopy-based nanoindentation approach"
Links elevated myocardial stiffness to diastolic dysfunction in an RCM model.
PMID:41219744 SUPPORT Human Clinical
"Pediatric RCM is characterized by echocardiographic findings of ventricular diastolic dysfunction"
The echocardiographic diagnostic criterion applied to all 185 children in this national cohort, establishing diastolic dysfunction as a human finding rather than a model-organism inference.
Congestive Heart Failure FREQUENT HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28371863 SUPPORT Model Organism
"the hearts of RCM mice model exhibited cardiac dysfunction, stiff ventricles"
Supports the progression from stiff ventricles to overt cardiac dysfunction and heart failure.
PMID:41219744 SUPPORT Human Clinical
"Approximately 40% of patients showed congestive heart failure, with 43% classified as NYHA/Ross FC III-IV, comparable to the 37% in the Registry study"
Quantifies congestive heart failure in a 185-patient national pediatric cohort and replicates the Pediatric Cardiomyopathy Registry figure, placing the phenotype in the FREQUENT (30-79%) band on human data.
Digestive 1
Hepatomegaly FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41219744 SUPPORT Human Clinical
"Children diagnosed with RCM showed significant heart failure symptoms, most commonly fatigue and hepatomegaly, along with markedly elevated BNP or NT-proBNP levels"
Names hepatomegaly as one of the two most common presenting heart-failure signs in a 185-patient national pediatric cohort.
PMID:41219744 SUPPORT Human Clinical
"Hepatomegaly, No. (%)124 (67)44 (80)75 (63)"
Table 1 reports hepatomegaly in 124 of 185 patients (67%), placing the phenotype in the FREQUENT (30-79%) band; the split columns also show it is commoner in those who went on to a major adverse cardiovascular event (80% vs 63%).
Metabolism 1
Peripheral Edema FREQUENT HP:0012398 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral edema (HP:0012398). HP:0012398 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41219744 SUPPORT Human Clinical
"Edema, No. (%)76 (41)26 (47)47 (39)"
Table 1 reports edema in 76 of 185 patients (41%) at diagnosis, placing the phenotype in the FREQUENT (30-79%) band on human cohort data.
Respiratory 1
Dyspnea FREQUENT HP:0002094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyspnea (HP:0002094). HP:0002094 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41219744 SUPPORT Human Clinical
"Dyspnea, No. (%)75 (41)24 (44)47 (39)"
Table 1 reports dyspnea in 75 of 185 patients (41%) at diagnosis, placing the phenotype in the FREQUENT (30-79%) band on human cohort data.
Constitutional 1
Fatigue FREQUENT HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41219744 SUPPORT Human Clinical
"Fatigue, No. (%)125 (68)38 (69)82 (68)"
Table 1 reports fatigue in 125 of 185 patients (68%) at diagnosis, placing the phenotype in the FREQUENT (30-79%) band on human cohort data.
Other 3
Restrictive Cardiomyopathy OBLIGATE HP:0001723 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Restrictive cardiomyopathy (HP:0001723). HP:0001723 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28371863 SUPPORT Model Organism
"the myosin essential light chain has been associated with restrictive cardiomyopathy (RCM) in humans"
Establishes the restrictive cardiomyopathy phenotype as the disease entity caused by the sarcomeric variant.
PMID:12531876 SUPPORT Human Clinical
"an additional nine unrelated RCM patients with restrictive filling patterns, bi-atrial dilatation, normal systolic function, and normal wall thickness"
Human ascertainment criteria for idiopathic RCM, stating the composite restrictive phenotype directly in patients rather than in a model system.
Left Atrial Enlargement VERY_FREQUENT HP:0031295 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left atrial enlargement (HP:0031295). HP:0031295 is a phenotype from the Human Phenotype Ontology.
HPO has no single biatrial-enlargement term, so the biatrial finding is curated as the two atrium-specific terms rather than forced onto one side.
Show evidence (2 references)
PMID:41219744 SUPPORT Human Clinical
"Baseline echocardiographic characteristics were similar, with atrial enlargement but normal left ventricular dimensions and systolic function"
Reports atrial enlargement alongside normal ventricular dimensions as the baseline echocardiographic finding in a 185-patient national pediatric cohort, replicating the Pediatric Cardiomyopathy Registry.
PMID:41219744 SUPPORT Human Clinical
"LA4CH LAX Z-score, median (IQR)4.8"
Table 1 reports a median left-atrial four-chamber long-axis Z-score of 4.8 (IQR 3.4-6.3) for the whole cohort. The lower quartile alone puts at least three quarters of patients above the Z >= 2 enlargement threshold the same paper uses diagnostically, and the threshold sits well below that quartile, so the VERY_FREQUENT (80-99%) band follows from the distribution rather than from the median alone. Banded at VERY_FREQUENT rather than OBLIGATE because atrial enlargement is itself part of the pediatric diagnostic criteria, which would make any within-cohort rate circular.
Right Atrial Enlargement VERY_FREQUENT HP:0030718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Right atrial enlargement (HP:0030718). HP:0030718 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12531876 SUPPORT Human Clinical
"an additional nine unrelated RCM patients with restrictive filling patterns, bi-atrial dilatation, normal systolic function, and normal wall thickness"
Bi-atrial dilatation, which includes the right atrium, is stated as a defining feature of the human RCM patients ascertained in this study.
PMID:41219744 SUPPORT Human Clinical
"RA4CH LAX Z-score, mean (SD)4.7"
Table 1 reports a mean right-atrial four-chamber long-axis Z-score of 4.7 (SD 1.9) in the 185-patient cohort. The Z >= 2 enlargement threshold lies about 1.4 standard deviations below that mean, which places roughly 90% of patients above it and supports the VERY_FREQUENT (80-99%) band; banded short of OBLIGATE for the same circularity reason as the left atrium.
🧬

Genetic Associations

8
MYL3
Gene: MYL3 hgnc:7584 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYL3 (hgnc:7584). hgnc:7584 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:28371863 SUPPORT Model Organism
"the myosin essential light chain has been associated with restrictive cardiomyopathy (RCM) in humans"
The only gene in this entry for which a human restrictive-cardiomyopathy association is quoted at all, which is why it is curated first among the four. Tagged MODEL_ORGANISM because the publication is a transgenic-mouse study and the quoted sentence is its framing of prior human reports rather than a human result of its own; the human gene-disease relationship still needs a primary clinical citation.
PMID:28371863 SUPPORT Model Organism
"E143K-myosin had increased duty ratio and binding affinity to actin compared with WT-myosin"
Gives the functional consequence of the E143K allele - increased duty ratio and actin affinity - which is the increased-myofilament-tension mechanism this entry's trigger node asserts. Tagged MODEL_ORGANISM to match this entry's existing use of the same quote: the myosin was purified from the transgenic mouse, so the assay is inseparable from the animal model that supplied it.
TNNT2
Gene: TNNT2 hgnc:11949 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TNNT2 (hgnc:11949). hgnc:11949 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:18467357 SUPPORT Human Clinical
"Sarcomere protein gene mutations were identified in four patients (33%): 2 in the cardiac troponin I gene (TNNI3) and 1 each in the troponin T (TNNT2) and alpha-cardiac actin (ACTC) genes."
Human evidence that a TNNT2 variant was found in a child ascertained as idiopathic restrictive cardiomyopathy, which is the gene-disease relationship this record asserts.
PMID:24221941 SUPPORT Model Organism
"prolongs systole and restricts diastolic dimensions of the heart"
Model-organism evidence for the troponin-T restrictive mechanism. Kept PARTIAL: the measurement is in Drosophila, so it supports the mechanism rather than the human gene-disease relationship, which the Kaski cohort quote above now supplies.
TNNI3
Gene: TNNI3 hgnc:11947 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TNNI3 (hgnc:11947). hgnc:11947 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:12531876 SUPPORT Human Clinical
"TNNI3 mutations were identified in six of these nine RCM patients"
Direct human evidence that TNNI3 variants cause the restrictive pattern specifically: the nine patients were ascertained on restrictive filling, biatrial dilatation, normal systolic function and normal wall thickness, not on hypertrophy.
PMID:12531876 SUPPORT Human Clinical
"Linkage analysis to selected sarcomeric contractile protein genes identified cardiac troponin I"
The linkage result in the index family that first tied idiopathic restrictive cardiomyopathy to a sarcomeric gene.
MYH7
Gene: MYH7 hgnc:7577 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYH7 (hgnc:7577). hgnc:7577 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
ACTC1
Gene: ACTC1 hgnc:143 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ACTC1 (hgnc:143). hgnc:143 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:18467357 SUPPORT Human Clinical
"We describe the first mutation in ACTC in familial RCM."
Establishes ACTC1 as a cause of the familial restrictive pattern, which is why the thin-filament arm of this entry's trigger node is not limited to the troponins.
DES
Gene: DES hgnc:2770 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DES (hgnc:2770). hgnc:2770 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:31718026 SUPPORT Human Clinical
"the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block"
The human presentation curated here: restrictive cardiomyopathy with atrioventricular block, the conduction-disease accompaniment that distinguishes the desmin route from the thin-filament routes.
PMID:31718026 SUPPORT In Vitro
"Confocal microscopy revealed a severe filament assembly defect of mutant desmin"
The molecular consequence of the variant - failure of intermediate filament assembly - which is a different lesion in kind from the increased-myofilament-tension mechanism of the sarcomeric genes. Tagged IN_VITRO because the measurement is in transfected iPSC-derived cardiomyocytes and HT-1080 cells.
FLNC
Gene: FLNC hgnc:3756 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FLNC (hgnc:3756). hgnc:3756 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (4 references)
PMID:26666891 SUPPORT Human Clinical
"we identified two novel missense variants (p.S1624L; p.I2160F) in filamin-C (FLNC), an actin-cross-linking protein mainly expressed in heart and skeletal muscle, segregating in two families with autosomal-dominant RCM"
The report that added FLNC to the familial restrictive gene set: two novel missense variants segregating with autosomal-dominant RCM in two families, in a Z-disc actin cross-linker rather than a sarcomere protein.
PMID:26666891 SUPPORT Human Clinical
"Thus, FLNC is a disease gene for autosomal-dominant RCM and broadens the phenotype spectrum of filaminopathies."
The authors' own conclusion, establishing FLNC as a causative gene for the autosomal-dominant familial restrictive phenotype curated here.
PMID:39472949 SUPPORT Human Clinical
"In a cohort of 58 patients, novel heterozygous FLNC variants, c.3962A > T (p.Glu1321Val) and c.7543C > T (p.Leu2515Phe), were identified in patients presenting with dilated and mixed restrictive/hypertrophic cardiomyopathies, respectively"
Independent pediatric ascertainment of an FLNC missense variant in a child with a restrictive phenotype. Curated PARTIAL because that child's phenotype is mixed restrictive/hypertrophic rather than pure RCM, which is itself the point: FLNC is a cross-phenotype cardiomyopathy gene and the restrictive presentation is one pole of its spectrum.
+ 1 more reference
MYPN
Gene: MYPN hgnc:23246 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYPN (hgnc:23246). hgnc:23246 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:22286171 SUPPORT Human Clinical
"Q529X-MYPN was found in familial RCM"
Human evidence tying a specific MYPN nonsense allele to the familial restrictive pattern, within a 900-patient cardiomyopathy screen.
PMID:22286171 SUPPORT In Vitro
"Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X)"
The proposed mechanism of the restrictive MYPN allele - disturbed myofibrillogenesis - which is distinct from the hypertrophic/dilated Y20C allele's nuclear-shuttling defect in the same paper. Tagged IN_VITRO because the measurement is in transfected neonatal rat cardiomyocytes.
💊

Medical Actions

5
Heart Failure Pharmacotherapy and Supportive Care
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: diuretic NCIT:C448 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses diuretic (NCIT:C448). NCIT:C448 is a therapeutic agent from the NCI Thesaurus.
Management targets congestion and filling pressures; because output is filling-limited, therapy is largely supportive (diuretics for congestion, rate and rhythm control, anticoagulation for atrial arrhythmia).
Heart Transplantation
Action: organ transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is organ transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. Ontology label: Organ Transplantation NCIT:C15289
RCM has a poor prognosis and is frequently an indication for heart transplantation, including in patients with preserved systolic function.
Implantable Cardioverter-Defibrillator
Action: implantable cardioverter-defibrillator placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is implantable cardioverter-defibrillator placement (NCIT:C80435). NCIT:C80435 is a clinical intervention from the NCI Thesaurus. Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435
Considered for prevention of sudden cardiac death in selected high-risk patients.
Antithrombotic Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: antiplatelet agent NCIT:C1327 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses antiplatelet agent (NCIT:C1327). NCIT:C1327 is a therapeutic agent from the NCI Thesaurus. anticoagulant agent NCIT:C263 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anticoagulant agent (NCIT:C263). NCIT:C263 is a therapeutic agent from the NCI Thesaurus.
Blood stasis in the dilated, poorly emptying atria of a restrictively filled heart carries a thromboembolic risk, and antithrombotic cover is part of routine RCM management rather than a disease-modifying therapy. In the Chinese national pediatric cohort a third of children were on an antiplatelet agent at baseline while thrombosis was recorded in 3%, so the practice is common and prophylactic rather than reactive. Agent choice (antiplatelet versus anticoagulant) is not settled by that cohort, which reports only antiplatelet use; anticoagulation is conventionally added for atrial fibrillation or documented thrombus, and this record does not assert a preference between them.
Show evidence (2 references)
PMID:41219744 SUPPORT Human Clinical
"Antiplatelet, No. (%)62 (34)20 (36)39 (33)"
Table 1 records antiplatelet therapy in 62 of 185 children (34%) at baseline, establishing antithrombotic cover as routine practice in this cohort.
PMID:41219744 SUPPORT Human Clinical
"Thrombosis, No. (%)6 (3)3 (5)3 (3)"
Table 1 records thrombosis in 6 of 185 children (3%), the event this therapy is directed against; the low rate is under prevailing antiplatelet use and should not be read as an untreated baseline risk.
PDE3 Inhibition (Trequinsin) - preclinical lead only
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: trequinsin CHEBI:748124 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses trequinsin (CHEBI:748124). CHEBI:748124 is a therapeutic agent from Chemical Entities of Biological Interest.
NOT a treatment for this disease. Recorded because it is the only mechanism-directed therapeutic lead this entry has, and because the absence of any disease-modifying therapy is itself a curated fact: management is otherwise entirely congestion control and transplantation. Trequinsin emerged from a high-throughput screen of small molecules run on the FLNC patient-derived engineered cardiac tissue system described under `experimental_models`, where it improved cardiomyocyte relaxation. The evidence is a single in vitro screen in one genotype; there is no animal efficacy study, no trial, and no human exposure in restrictive cardiomyopathy. Do not read this record as a clinical recommendation. A class-level safety caveat also applies and is recorded in this record's own evidence: chronic oral PDE3 inhibition raised mortality in severe chronic heart failure, so a relaxation benefit measured in engineered tissue is not on its own a reason to expect net benefit from sustained dosing.
Mechanism Target:
INHIBITS Increased Resting Myocardial Stiffness and Impaired Relaxation — The screen was scored on cardiomyocyte relaxation, so the node this lead addresses is the impaired-relaxation half of the stiffness node rather than the upstream sarcomeric lesion or the downstream fibrosis.
Show evidence (1 reference)
PMID:36921598 SUPPORT In Vitro
"High-throughput small-molecule screening identifies phosphodiesterase 3 (PDE3) inhibition by trequinsin as a potential therapy to improve cardiomyocyte relaxation in this genotype."
Curated PARTIAL, and deliberately: the authors themselves say "potential therapy" and "in this genotype". The quote supports a screening hit against the relaxation node, not efficacy in patients.
Show evidence (1 reference)
PMID:1944425 REFUTE Human Clinical
"long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure"
The class-level counterweight to the screening hit. A randomized trial of chronic oral PDE3 inhibition found excess mortality despite favourable haemodynamics, so an improvement in cardiomyocyte relaxation in vitro does not establish that sustained PDE3 inhibition would help. Curated REFUTE against the therapeutic proposition rather than against the mechanism, and the extrapolation is explicit: the trial studied milrinone in severe systolic heart failure, not trequinsin in restrictive cardiomyopathy.
📈

Progression

1
Progressive diastolic heart failure to transplantation or death
RCM does not plateau. In the largest reported pediatric cohort the median time from diagnosis to a major adverse cardiovascular event - cardiac death, transplantation, or equivalent - was about two years, and roughly five in eight children reached such an event during follow-up. Reported transplant-free survival at five years is about 30%. Significant heart failure is the presenting feature rather than a late complication, which is why listing decisions are made early and why risk models for this disease are built around timing of transplantation rather than around drug therapy.
Show evidence (2 references)
PMID:41219744 SUPPORT Human Clinical
"During the follow-up period, 114 patients (62%) experienced MACE, with the median MACE-free survival time for the entire cohort being 2.1 years post-diagnosis"
Quantifies the event rate and the time course this progression record asserts, in a 185-child multicentre cohort.
PMID:41219744 SUPPORT Human Clinical
"often resulting in heart failure, arrhythmias, and sudden cardiac death, with a 5-year transplant-free survival rate of about 30%"
Source for the five-year transplant-free survival figure and for the three endpoints named in this record.
📊

Prevalence

1
Worldwide
Unknown Rare
RCM is the rarest of the three classic cardiomyopathy patterns; no precise population rate is established for the primary/genetic form.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Restrictive Cardiomyopathy:

Cardiac amyloidosis (ATTR and AL)
Overlapping Features The most important acquired mimic, and the reason this entry's boundary has to be stated rather than assumed. Amyloid infiltration produces the same restrictive filling, biatrial enlargement and preserved ejection fraction, but by extracellular deposition of a misfolded precursor rather than by a heritable defect of the contractile apparatus - so it is curated on its own entries and conforms to `amyloidogenesis`, not here. Hereditary ATTR is itself inherited, which means "familial" does not separate the two; the separating question is whether the myocardium is infiltrated. No `disease_term` is bound here because MONDO has no single class covering both the transthyretin and the light-chain routes to cardiac amyloidosis; the two are curated as `ATTR_Amyloidosis` and `AL_Amyloidosis`.
Distinguishing Features
  • Increased wall thickness on echocardiography, whereas primary RCM has normal or near-normal wall thickness.
  • Bone-avid tracer uptake on scintigraphy (ATTR) or a monoclonal protein on serum/urine immunofixation and free light chains (AL).
  • Extracardiac features - polyneuropathy, carpal tunnel syndrome, macroglossia, nephrotic-range proteinuria - that a sarcomeric cardiomyopathy does not produce.
  • Congo red-positive, apple-green birefringent deposits on endomyocardial biopsy.
Show evidence (1 reference)
PMID:12531876 SUPPORT Human Clinical
"Restrictive cardiomyopathy (RCM) is an uncommon heart muscle disorder characterized by impaired filling of the ventricles with reduced volume in the presence of normal or near normal wall thickness and systolic function"
Supplies the case definition the first distinguishing feature below turns on: primary RCM is defined by normal or near-normal wall thickness, which is what an amyloid-infiltrated ventricle does not show.
Storage and infiltrative cardiomyopathies other than amyloid
Overlapping Features Lysosomal storage disease (Fabry, Gaucher, glycogen storage disease II), haemochromatosis and sarcoidosis all reach restrictive physiology by loading or replacing the myocardium. MONDO asserts several of these under MONDO:0016340 because they are both inherited and restrictive; this entry keeps them out because the mechanism is deposition, not myofilament tension, and each has its own mechanism module.
Distinguishing Features
  • Extracardiac storage phenotype (organomegaly, renal, ophthalmological, or neurological involvement).
  • Enzyme assay or genotype for the specific storage disorder.
  • A disease-modifying therapy directed at the stored substrate exists, which is not true of primary sarcomeric RCM.
Endomyocardial fibrosis MONDO:0006746
Overlapping Features Obliterative fibrosis of the ventricular apex and subvalvular apparatus, endemic in parts of the tropics and elsewhere associated with hypereosinophilia. Restrictive physiology arises from an obliterated ventricular cavity rather than from a stiff myocardium, and it is curated separately.
Distinguishing Features
  • Apical cavity obliteration and thrombus on imaging.
  • Eosinophilia, or residence in an endemic region.
  • Atrioventricular valve regurgitation from involvement of the subvalvular apparatus.
Constrictive pericarditis Not Yet Curated MONDO:0006711
Overlapping Features Not a cardiomyopathy at all, but the classic haemodynamic imitator: a thickened, non-compliant pericardium limits filling with a normal myocardium underneath. It matters because it is surgically curable, so the distinction changes management more than any other on this list.
Distinguishing Features
  • Ventricular interdependence with respirophasic septal shift on echocardiography and at catheterisation.
  • Pericardial thickening or calcification on CT or CMR.
  • Normal or increased mitral annular e-prime (annulus reversus), whereas RCM reduces it.
🔬

Clinical Trials

2
NCT01873963 NOT_APPLICABLE COMPLETED
PCM GENES - a completed observational genotype-phenotype study of pediatric cardiomyopathy that enrolled restrictive cardiomyopathy alongside the dilated and hypertrophic phenotypes. Recorded because it is one of the few studies of any design to have enrolled pediatric RCM at scale; it is observational, so it establishes no therapy.
Target Phenotypes: Restrictive cardiomyopathy HP:0001723 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Restrictive cardiomyopathy (HP:0001723). HP:0001723 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT01873963 SUPPORT Human Clinical
"the purpose of this study is to identify genes that cause cardiomyopathy or that influence how people with cardiomyopathy do over time"
States the genotype-phenotype aim; the registry lists restrictive cardiomyopathy among the enrolled conditions.
NCT02432092 NOT_APPLICABLE RECRUITING
Ongoing observational mutation-analysis protocol in pediatric cardiomyopathy families, listing restrictive cardiomyopathy among its conditions. Again a genetics study rather than an intervention.
Target Phenotypes: Restrictive cardiomyopathy HP:0001723 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Restrictive cardiomyopathy (HP:0001723). HP:0001723 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT02432092 SUPPORT Human Clinical
"The goal of this protocol is to obtain information from individuals with cardiomyopathy and from their families in order to elucidate the molecular genetics of this disorder"
States the study aim; restrictive cardiomyopathy is one of the registered conditions.
🧫

Experimental Models

1
FLNC RCM patient iPSC-derived cardiomyocytes and 3D engineered cardiac tissue IPSC_DERIVED_MODEL
Induced pluripotent stem cells reprogrammed from a patient carrying the FLNC in-frame deletion c.7416_7418delGAA, differentiated to cardiomyocytes and assembled into three-dimensional engineered cardiac tissues, each compared against a CRISPR-Cas9-corrected isogenic line. The isogenic correction is what makes this model informative: it removes genetic background as an explanation for the mechanical difference. The 3D format exists because the defining property of RCM - passive tension and relaxation of a contracting tissue - cannot be measured in cells attached to a plastic substrate, which the authors give as the reason no iPSC model of RCM existed before.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Patient-derived iPSC, with a CRISPR-Cas9-corrected isogenic control line
Culture
Two-dimensional iPSC-cardiomyocyte monolayer and three-dimensional engineered cardiac tissue
Publication
PMID:36921598
Pathograph links
Increased Resting Myocardial Stiffness and Impaired Relaxation recapitulates fidelity: moderate Mutant engineered tissues reproduce both halves of the node - raised passive tension and slowed relaxation - in human cells, against an isogenic control.
Limitations: Engineered cardiac tissue is immature relative to adult ventricular myocardium, lacks the fibroblast, vascular and neurohormonal context in which the human ventricle stiffens, and here represents a single patient and a single FLNC allele. It is a human-cell surrogate for the mechanism, not a measurement made in human myocardium.
Readouts
Passive tension of engineered cardiac tissue
Direction: INCREASED
Interpretation: The mechanical correlate of increased resting myocardial stiffness, measured in mutant versus isogenic-control tissue.
Show evidence (1 reference)
PMID:36921598 SUPPORT In Vitro
"mutant engineered cardiac tissues (ECTs) demonstrate increased passive tension and impaired relaxation velocity compared with isogenic controls"
Reports the passive-tension measurement behind this readout.
Cardiomyocyte relaxation and calcium kinetics in 2D culture
Direction: DECREASED
Interpretation: Impaired relaxation and reduced calcium kinetics in the monolayer format, showing the defect is present at the cardiomyocyte level and not only a property of the assembled tissue.
Show evidence (1 reference)
PMID:36921598 SUPPORT In Vitro
"Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with this variant display impaired relaxation and reduced calcium kinetics in 2D culture when compared with a CRISPR-Cas9-corrected isogenic control line."
Reports the monolayer relaxation and calcium measurements behind this readout.
Show evidence (1 reference)
PMID:36921598 SUPPORT In Vitro
"Together, these data demonstrate an engineered cardiac tissue model of RCM and establish the translational potential of this precision medicine approach to identify therapeutics targeting myocardial relaxation."
The authors' own statement of what the system is for, which is the claim this model entry makes: a human-cell platform for the relaxation defect.
{ }

Source YAML

click to show 
name: Restrictive Cardiomyopathy
creation_date: "2026-08-22T00:00:00Z"
synonyms:
- RCM
- restrictive cardiomyopathy
- familial restrictive cardiomyopathy
- primary restrictive cardiomyopathy
description: >-
  Restrictive cardiomyopathy (RCM) is the least common of the three classic
  cardiomyopathy patterns, defined by restrictive ventricular filling — a stiff,
  non-compliant ventricle with impaired diastolic relaxation but preserved (or only
  mildly reduced) systolic function and non-dilated, non-hypertrophied chambers,
  producing marked biatrial enlargement and elevated filling pressures. This entry
  is scoped to the primary/heritable form, in which the restrictive physiology is
  the final common pathway of a sarcomeric or cytoskeletal defect: pathogenic
  variants in thin-filament and myosin genes — most characteristically the
  troponins (TNNI3, TNNT2), alpha-cardiac actin (ACTC1), beta-myosin heavy chain
  (MYH7), and the myosin light chains (MYL3), as well as the Z-disc and
  intermediate-filament proteins desmin (DES), filamin C (FLNC) and myopalladin
  (MYPN) — increase myofilament tension and resting myocardial
  stiffness. More than half of patients carry no sarcomere variant at all, and in
  those the cardiac fibroblast is itself mechanically abnormal, so the entry
  models a fibroblast arm running parallel to the sarcomeric one. RCM overlaps
  genetically and mechanistically with
  hypertrophic cardiomyopathy (the same genes and often the same alleles can produce
  either pattern), and thin-filament HCM shades into restrictive physiology.
  Infiltrative causes of a restrictive phenotype (cardiac amyloidosis, storage
  disease) are curated under their own entries; this entry models the primary
  sarcomeric/cytoskeletal mechanism.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: restrictive cardiomyopathy
  term:
    id: MONDO:0005201
    label: restrictive cardiomyopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0016340
      label: familial restrictive cardiomyopathy
    mapping_predicate: skos:narrowMatch
    mapping_source: dismech curation
    mapping_justification: >-
      MONDO:0016340 is_a the MONDO:0005201 anchor of this entry and denotes the
      inherited subset of restrictive cardiomyopathy. It is narrower than the
      anchor - which by its own MONDO definition also covers scarring,
      infiltrative and deposition causes - but it is precisely the scope this
      entry curates: the primary/heritable sarcomeric and cytoskeletal disease.
      The anchor is retained as `disease_term` because MONDO:0005201 carries
      "familial restrictive cardiomyopathy" as a synonym, so the two labels are
      not cleanly separable at the term level, and because the acquired causes
      have to be nameable here to be excluded. No Grouping was created for
      MONDO:0016340 - unlike the sibling MONDO classes behind
      `Familial_Hypertrophic_Cardiomyopathy` and `Familial_Dilated_Cardiomyopathy`,
      none of its numbered members (RCM1-RCM6) is a curated DisMech Disease
      entry, so a union over them would have no members to unite.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        MONDO's asserted descendant set for MONDO:0016340 mixes the numbered
        RCM series with systemic diseases that reach a restrictive phenotype by
        deposition or infiltration (Gaucher disease type I, glycogen storage
        disease II, ATTRV122I amyloidosis) and with atrial standstill. This
        entry follows the mechanistic boundary rather than that descendant set:
        the infiltrative and storage routes are curated on their own entries
        (`ATTR_Amyloidosis`, `AL_Amyloidosis`, `Endomyocardial_Fibrosis`) and
        recorded here as differential diagnoses, not as members of this concept.
parents:
- Cardiovascular Disease
- Genetic Disorder
has_subtypes:
- name: RCM1
  display_name: Cardiomyopathy, familial restrictive, 1 (TNNI3)
  description: >-
    The prototype and by far the most common molecularly defined familial RCM:
    heterozygous missense variants in cardiac troponin I, in conserved and
    functionally important domains of the gene. It was the locus at which
    idiopathic RCM was first shown to be a sarcomeric disease, in a family
    segregating both RCM and hypertrophic cardiomyopathy, and TNNI3 remains the
    single gene most often returned by pediatric RCM sequencing. De novo
    variants occur, so an absent family history does not exclude it.
  subtype_term:
    preferred_term: cardiomyopathy, familial restrictive, 1
    term:
      id: MONDO:0007270
      label: cardiomyopathy, familial restrictive, 1
  genes:
  - preferred_term: TNNI3
    term:
      id: hgnc:11947
      label: TNNI3
  evidence:
  - reference: PMID:12531876
    reference_title: Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TNNI3 mutations were identified in six of these nine RCM patients
    explanation: >-
      Establishes TNNI3 as a cause of idiopathic restrictive cardiomyopathy in
      unrelated patients selected on restrictive physiology, which is the
      gene-disease relationship this subtype names.
  - reference: PMID:12531876
    reference_title: Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two of the mutations identified in young individuals were de novo mutations.
    explanation: >-
      Records the de novo occurrence noted in this subtype's description, which
      is why an absent family history does not exclude TNNI3 disease.
- name: RCM3
  display_name: Cardiomyopathy, familial restrictive, 3 (TNNT2)
  description: >-
    Familial restrictive cardiomyopathy caused by variants in cardiac troponin
    T, the other thin-filament regulatory subunit. Curated as a distinct
    numbered entity because MONDO and OMIM separate it from RCM1, but the
    clinical presentation is not separable from TNNI3 disease at the bedside;
    the pediatric series that established sarcomeric causation found TNNT2 and
    TNNI3 variants side by side in the same cohort.
  subtype_term:
    preferred_term: cardiomyopathy, familial restrictive, 3
    term:
      id: MONDO:0012900
      label: cardiomyopathy, familial restrictive, 3
  genes:
  - preferred_term: TNNT2
    term:
      id: hgnc:11949
      label: TNNT2
  evidence:
  - reference: PMID:18467357
    reference_title: Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sarcomere protein gene mutations were identified in four patients (33%): 2 in the cardiac troponin I gene (TNNI3) and 1 each in the troponin T (TNNT2) and alpha-cardiac actin (ACTC) genes.
    explanation: >-
      Human evidence for a TNNT2 variant in a patient ascertained as idiopathic
      restrictive cardiomyopathy, alongside TNNI3 and ACTC1 in the same cohort.
inheritance:
- name: Autosomal dominant
  description: >-
    Familial RCM is most often inherited as an autosomal dominant trait caused by
    a sarcomeric or cytoskeletal gene variant, frequently the same genes implicated
    in hypertrophic cardiomyopathy; de novo variants and recessive/desmin-related
    forms also occur. Penetrance and the hypertrophic-versus-restrictive expression
    of a given allele are variable.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    RCM is the rarest of the three classic cardiomyopathy patterns; no precise
    population rate is established for the primary/genetic form.
pathophysiology:
- name: Sarcomeric or Cytoskeletal Variant with Increased Myofilament Tension
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion in primary RCM is a variant in a sarcomeric thin-filament
    or myosin gene, or in a cytoskeletal/Z-disc protein (desmin, filamin C,
    myopalladin), that raises myofilament tension or destabilises the apparatus
    that anchors it. Two evidenced archetypes illustrate the myofilament route: a
    cardiac troponin-T variant that increases the number of actively cycling myosin
    cross-bridges, and a myosin essential light chain variant (MYL3 E143K) that
    produces myosin hypercontractility (increased duty ratio, actin-binding
    affinity, and actin-activated ATPase). The mutant protein is incorporated into
    the sarcomere and shifts the myocyte toward a hypercontractile, poorly relaxing
    state. The cytoskeletal route reaches the same node by a different lesion in
    kind - failure of intermediate-filament assembly for desmin, disturbed
    myofibrillogenesis for the restrictive myopalladin allele - which is why the
    node is named for the sarcomeric *or* cytoskeletal variant rather than for the
    sarcomere alone.
  genes:
  - preferred_term: TNNI3
    term:
      id: hgnc:11947
      label: TNNI3
  - preferred_term: TNNT2
    term:
      id: hgnc:11949
      label: TNNT2
  - preferred_term: MYH7
    term:
      id: hgnc:7577
      label: MYH7
  - preferred_term: MYL3
    term:
      id: hgnc:7584
      label: MYL3
  - preferred_term: ACTC1
    term:
      id: hgnc:143
      label: ACTC1
  - preferred_term: DES
    term:
      id: hgnc:2770
      label: DES
  - preferred_term: FLNC
    term:
      id: hgnc:3756
      label: FLNC
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Sarcomere Organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the myosin essential light chain has been associated with restrictive cardiomyopathy (RCM) in humans"
    explanation: >-
      Establishes a sarcomeric myosin light chain (MYL3 E143K) variant as a human
      cause of restrictive cardiomyopathy, modeled in transgenic mice.
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "E143K-myosin had increased duty ratio and binding affinity to actin compared with WT-myosin"
    explanation: >-
      Identifies myosin hypercontractility (increased duty ratio and actin-binding
      affinity) as the molecular consequence of the RCM light-chain variant.
  - reference: PMID:24221941
    reference_title: "A Drosophila melanogaster model of diastolic dysfunction and cardiomyopathy based on impaired troponin-T function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "prolongs systole and restricts diastolic dimensions of the heart"
    explanation: >-
      A troponin-T RCM model showing that the thin-filament variant increases
      cross-bridge cycling, prolonging systole and restricting diastolic filling.
  downstream:
  - target: Increased Resting Myocardial Stiffness and Impaired Relaxation
    causal_link_type: DIRECT
    description: >-
      Hypercontractility and increased passive tension raise resting myocardial
      stiffness and impair diastolic relaxation.
  - target: Myocardial Fibrosis and Ventricular Remodeling
    causal_link_type: DIRECT
    description: >-
      Chronic sarcomeric stress drives fibrotic remodeling of the myocardium.
- name: Increased Resting Myocardial Stiffness and Impaired Relaxation
  biological_scale: CELLULAR
  role: effector
  description: >-
    The hypercontractile, tension-loaded sarcomere raises the resting (passive)
    tension of the myocyte and impairs relaxation. In an RCM troponin-T model,
    elevated resting myocardial stiffness was measured directly; in the MYL3 RCM
    model, both active and passive tension of papillary muscle were augmented. The
    same pair of quantities has since been measured in human cells: engineered
    cardiac tissue built from the cardiomyocytes of an FLNC restrictive
    cardiomyopathy patient shows increased passive tension and impaired relaxation
    velocity against a CRISPR-corrected isogenic control. Increased resting
    stiffness is the cellular basis of the restrictive filling that defines the
    disease.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Regulation of Cardiac Muscle Contraction
    term:
      id: GO:0055117
      label: regulation of cardiac muscle contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24221941
    reference_title: "A Drosophila melanogaster model of diastolic dysfunction and cardiomyopathy based on impaired troponin-T function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Elevated resting myocardial stiffness, consistent with upheld(101) diastolic dysfunction, was confirmed by an atomic force microscopy-based nanoindentation approach"
    explanation: >-
      Direct measurement of elevated resting myocardial stiffness in a
      troponin-T RCM model, the cellular correlate of diastolic dysfunction.
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "augmented active and passive tension measured in skinned papillary muscle fibres compared with wild-type (WT)-generated force"
    explanation: >-
      Shows augmented passive (resting) tension in an RCM myosin light chain model,
      the mechanical basis of increased myocardial stiffness.
  - reference: PMID:36921598
    reference_title: "Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      mutant engineered cardiac tissues (ECTs) demonstrate increased passive tension and impaired relaxation velocity compared with isogenic controls
    explanation: >-
      The same two quantities - increased passive tension and impaired relaxation
      - measured in human patient-derived tissue rather than in an animal, against
      a CRISPR-corrected isogenic control. This is the closest thing this entry
      carries to a human measurement of the node, and is why the
      HUMAN_MODEL_MISMATCH discussion is narrowed rather than left as first
      written.
  downstream:
  - target: Restrictive Filling Physiology
    causal_link_type: DIRECT
    description: >-
      A stiff, poorly relaxing ventricle cannot fill normally in diastole.
- name: Cardiac Fibroblast Stiffening and Fibroblast-Cardiomyocyte Crosstalk
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    A second, non-myocyte contribution to the stiff ventricle, and the arm that
    matters for the sizeable fraction of patients in whom no sarcomere variant is
    found - a third of genotyped children in a national pediatric cohort, and
    more than half in the series behind the fibroblast work. Cardiac fibroblasts explanted from children with idiopathic RCM are
    themselves mechanically abnormal - measured by atomic force microscopy they
    are stiffer and more viscous, and less fluid, than control fibroblasts -
    with a transcriptional signature of altered cytoskeletal signalling
    (cytoskeletal actin-associated genes up, several tubulin genes down). Because
    fibroblasts restrain cardiomyocyte relaxation through humoral factors and
    direct cell-cell contact, a stiffened fibroblast population acts on diastolic
    function independently of the myofilament, which is why this node is curated
    as a parallel amplifier of myocardial stiffness rather than as a step
    downstream of the sarcomeric lesion.
  cell_types:
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: Actin Cytoskeleton Organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36174041
    reference_title: Atomic force microscopy identifies the alteration of rheological properties of the cardiac fibroblasts in idiopathic restrictive cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      RCM-derived CFs showed significantly higher stiffness and viscosity and lower fluidity compared to healthy control CFs.
    explanation: >-
      The direct measurement behind this node, made on fibroblasts from human
      RCM patients rather than on an animal model.
  - reference: PMID:36174041
    reference_title: Atomic force microscopy identifies the alteration of rheological properties of the cardiac fibroblasts in idiopathic restrictive cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      RNA-sequencing revealed that the signaling pathways associated with cytoskeleton elements were affected in RCM CFs; specifically, cytoskeletal actin-associated genes (ACTN1, ACTA2, and PALLD) were highly expressed in RCM CFs, whereas several tubulin genes (TUBB3, TUBB, TUBA1C, and TUBA1B) were down-regulated.
    explanation: >-
      The transcriptional result behind this node's abnormal
      actin-cytoskeleton-organization annotation, measured in the same patient
      fibroblasts as the rheology.
  - reference: PMID:36174041
    reference_title: Atomic force microscopy identifies the alteration of rheological properties of the cardiac fibroblasts in idiopathic restrictive cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These results implies that the signaling pathways associated with cytoskeletal elements alter the rheological properties of RCM CFs, particularly those related to CF-cardiomyocyte interactions, thereby leading to diastolic cardiac dysfunction in RCM.
    explanation: >-
      The authors' conclusion from their own measurements, supplying the
      crosstalk step by which a fibroblast-intrinsic mechanical change reaches
      cardiomyocyte relaxation.
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 123 subjects (66%) who underwent genetic testing, 81 (66%) had a
      positive genotype: 70 had variants in sarcomeric genes
    explanation: >-
      Quantifies, on human cohort data rather than as review background, the
      genotype-negative fraction this node exists to explain: a third of
      genotyped children in a 185-patient national cohort had no pathogenic
      variant, so a genotype-independent route to myocardial stiffness is needed.
  downstream:
  - target: Increased Resting Myocardial Stiffness and Impaired Relaxation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - >-
      Fibroblast-derived humoral factors restraining cardiomyocyte relaxation
    - >-
      Direct fibroblast-cardiomyocyte contact
    description: >-
      Mechanically abnormal fibroblasts contribute to the stiffness of the
      myocardium as a tissue and restrain cardiomyocyte relaxation.
  - target: Myocardial Fibrosis and Ventricular Remodeling
    causal_link_type: DIRECT
    description: >-
      An activated, cytoskeletally altered fibroblast population is the cell
      that lays down the interstitial matrix of the remodelled ventricle.
- name: Myocardial Fibrosis and Ventricular Remodeling
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    Chronic sarcomeric stress drives interstitial fibrosis and ventricular
    remodeling. In the MYL3 RCM model, hearts developed ultrastructural defects and
    fibrosis that progressively worsened with age, with upregulation of
    stress-response and collagen genes. Unlike dilated or hypertrophic remodeling,
    the chambers remain non-dilated and non-hypertrophied, but the fibrotic,
    stiffened wall is the structural substrate of restrictive physiology.
  cell_types:
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Extracellular Matrix Organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  locations:
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "ultrastructural defects and fibrosis that progressively worsened in senescent animals"
    explanation: >-
      Documents progressive myocardial fibrosis and ultrastructural remodeling in
      an RCM model.
  - reference: PMID:24221941
    reference_title: "A Drosophila melanogaster model of diastolic dysfunction and cardiomyopathy based on impaired troponin-T function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "cardiac dysfunction and remodeling comparable to that observed during human restrictive cardiomyopathy"
    explanation: >-
      Establishes that the sarcomeric lesion produces cardiac dysfunction and
      remodeling matching human RCM.
  downstream:
  - target: Restrictive Filling Physiology
    causal_link_type: DIRECT
- name: Restrictive Filling Physiology
  biological_scale: ORGANISM
  role: effector
  description: >-
    The stiff, fibrotic, poorly relaxing ventricle produces the hemodynamic
    signature of RCM: severely impaired diastolic filling with preserved systolic
    function and non-dilated ventricles, so that atrial pressures rise and the
    atria enlarge markedly to maintain filling. This restrictive filling pattern is
    the defining physiology that separates RCM from the dilated and hypertrophic
    patterns.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Heart Contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24221941
    reference_title: "A Drosophila melanogaster model of diastolic dysfunction and cardiomyopathy based on impaired troponin-T function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "prolongs systole and restricts diastolic dimensions of the heart"
    explanation: >-
      Demonstrates restriction of diastolic filling — the defining physiology of
      RCM — in a sarcomeric model.
  downstream:
  - target: Diastolic Heart Failure and Arrhythmic Risk
    causal_link_type: DIRECT
- name: Diastolic Heart Failure and Arrhythmic Risk
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    Restrictive filling with elevated atrial and pulmonary pressures produces heart
    failure with preserved ejection fraction — dyspnea, congestion, and exercise
    intolerance — together with a high burden of atrial arrhythmia and
    thromboembolism from the dilated atria, and a risk of sudden death. RCM carries
    a poor prognosis and is frequently an indication for heart transplantation,
    including in patients whose systolic function is preserved.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Heart Contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the hearts of RCM mice model exhibited cardiac dysfunction, stiff ventricles"
    explanation: >-
      Ties the stiff-ventricle restrictive remodeling to overt cardiac
      dysfunction, the clinical endpoint of the disease.
phenotypes:
- name: Restrictive Cardiomyopathy
  category: Cardiovascular
  description: >-
    The defining feature: restrictive ventricular filling with a stiff,
    non-compliant, non-dilated ventricle and preserved systolic function.
  phenotype_term:
    preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  frequency: OBLIGATE
  evidence:
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the myosin essential light chain has been associated with restrictive cardiomyopathy (RCM) in humans"
    explanation: >-
      Establishes the restrictive cardiomyopathy phenotype as the disease entity
      caused by the sarcomeric variant.
  - reference: PMID:12531876
    reference_title: "Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an additional nine unrelated RCM patients with restrictive filling patterns,
      bi-atrial dilatation, normal systolic function, and normal wall thickness
    explanation: >-
      Human ascertainment criteria for idiopathic RCM, stating the composite
      restrictive phenotype directly in patients rather than in a model system.
- name: Left Ventricular Diastolic Dysfunction
  category: Cardiovascular
  description: >-
    Impaired ventricular relaxation and increased stiffness are the functional
    hallmark of RCM.
  phenotype_term:
    preferred_term: Left ventricular diastolic dysfunction
    term:
      id: HP:0025168
      label: Left ventricular diastolic dysfunction
  evidence:
  - reference: PMID:24221941
    reference_title: "A Drosophila melanogaster model of diastolic dysfunction and cardiomyopathy based on impaired troponin-T function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Elevated resting myocardial stiffness, consistent with upheld(101) diastolic dysfunction, was confirmed by an atomic force microscopy-based nanoindentation approach"
    explanation: >-
      Links elevated myocardial stiffness to diastolic dysfunction in an RCM model.
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pediatric RCM is characterized by echocardiographic findings of ventricular
      diastolic dysfunction
    explanation: >-
      The echocardiographic diagnostic criterion applied to all 185 children in
      this national cohort, establishing diastolic dysfunction as a human finding
      rather than a model-organism inference.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Restrictive filling with elevated filling pressures produces heart failure with
    preserved ejection fraction, often progressive and transplant-requiring.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  frequency: FREQUENT
  evidence:
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the hearts of RCM mice model exhibited cardiac dysfunction, stiff ventricles"
    explanation: >-
      Supports the progression from stiff ventricles to overt cardiac dysfunction
      and heart failure.
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 40% of patients showed congestive heart failure, with 43%
      classified as NYHA/Ross FC III-IV, comparable to the 37% in the Registry study
    explanation: >-
      Quantifies congestive heart failure in a 185-patient national pediatric
      cohort and replicates the Pediatric Cardiomyopathy Registry figure, placing
      the phenotype in the FREQUENT (30-79%) band on human data.
- name: Left Atrial Enlargement
  category: Cardiovascular
  description: >-
    Chronic elevation of left-sided filling pressures across a stiff, non-compliant
    ventricle dilates the left atrium. Together with right atrial enlargement this
    forms the biatrial enlargement that is the cardinal morphological sign of RCM
    on echocardiography, and in pediatric series it is part of the diagnostic
    definition.
  phenotype_term:
    preferred_term: Left atrial enlargement
    term:
      id: HP:0031295
      label: Left atrial enlargement
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Baseline echocardiographic characteristics were similar, with atrial
      enlargement but normal left ventricular dimensions and systolic function
    explanation: >-
      Reports atrial enlargement alongside normal ventricular dimensions as the
      baseline echocardiographic finding in a 185-patient national pediatric
      cohort, replicating the Pediatric Cardiomyopathy Registry.
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LA4CH LAX Z-score, median (IQR)4.8
    explanation: >-
      Table 1 reports a median left-atrial four-chamber long-axis Z-score of 4.8
      (IQR 3.4-6.3) for the whole cohort. The lower quartile alone puts at least
      three quarters of patients above the Z >= 2 enlargement threshold the same
      paper uses diagnostically, and the threshold sits well below that quartile,
      so the VERY_FREQUENT (80-99%) band follows from the distribution rather
      than from the median alone. Banded at VERY_FREQUENT rather than OBLIGATE
      because atrial enlargement is itself part of the pediatric diagnostic
      criteria, which would make any within-cohort rate circular.
  notes: >-
    HPO has no single biatrial-enlargement term, so the biatrial finding is
    curated as the two atrium-specific terms rather than forced onto one side.
- name: Right Atrial Enlargement
  category: Cardiovascular
  description: >-
    The right atrium dilates in parallel with the left as restrictive physiology
    raises filling pressures in both circuits; the combined appearance is the
    biatrial enlargement characteristic of RCM.
  phenotype_term:
    preferred_term: Right atrial enlargement
    term:
      id: HP:0030718
      label: Right atrial enlargement
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:12531876
    reference_title: "Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an additional nine unrelated RCM patients with restrictive filling patterns,
      bi-atrial dilatation, normal systolic function, and normal wall thickness
    explanation: >-
      Bi-atrial dilatation, which includes the right atrium, is stated as a
      defining feature of the human RCM patients ascertained in this study.
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RA4CH LAX Z-score, mean (SD)4.7
    explanation: >-
      Table 1 reports a mean right-atrial four-chamber long-axis Z-score of 4.7
      (SD 1.9) in the 185-patient cohort. The Z >= 2 enlargement threshold lies
      about 1.4 standard deviations below that mean, which places roughly 90% of
      patients above it and supports the VERY_FREQUENT (80-99%) band; banded
      short of OBLIGATE for the same circularity reason as the left atrium.
- name: Hepatomegaly
  category: Gastrointestinal
  description: >-
    Systemic venous congestion behind the restrictive right ventricle enlarges the
    liver; with fatigue it is the most common presenting sign in childhood RCM and
    is associated with adverse outcome.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  frequency: FREQUENT
  evidence:
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children diagnosed with RCM showed significant heart failure symptoms, most
      commonly fatigue and hepatomegaly, along with markedly elevated BNP or
      NT-proBNP levels
    explanation: >-
      Names hepatomegaly as one of the two most common presenting heart-failure
      signs in a 185-patient national pediatric cohort.
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatomegaly, No. (%)124 (67)44 (80)75 (63)"
    explanation: >-
      Table 1 reports hepatomegaly in 124 of 185 patients (67%), placing the
      phenotype in the FREQUENT (30-79%) band; the split columns also show it is
      commoner in those who went on to a major adverse cardiovascular event
      (80% vs 63%).
- name: Fatigue
  category: Constitutional
  description: >-
    Reduced cardiac output across a fixed, restrictively filled ventricle presents
    as exertional fatigue, the single most frequent symptom at diagnosis in
    childhood RCM.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  frequency: FREQUENT
  evidence:
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fatigue, No. (%)125 (68)38 (69)82 (68)"
    explanation: >-
      Table 1 reports fatigue in 125 of 185 patients (68%) at diagnosis, placing
      the phenotype in the FREQUENT (30-79%) band on human cohort data.
- name: Peripheral Edema
  category: Cardiovascular
  description: >-
    Elevated systemic venous pressure from restrictive right-heart filling produces
    dependent peripheral edema, part of the congestive presentation of RCM.
  phenotype_term:
    preferred_term: Peripheral edema
    term:
      id: HP:0012398
      label: Peripheral edema
  frequency: FREQUENT
  evidence:
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Edema, No. (%)76 (41)26 (47)47 (39)"
    explanation: >-
      Table 1 reports edema in 76 of 185 patients (41%) at diagnosis, placing the
      phenotype in the FREQUENT (30-79%) band on human cohort data.
- name: Dyspnea
  category: Respiratory
  description: >-
    Pulmonary venous congestion behind the stiff left ventricle causes exertional
    breathlessness, one of the presenting complaints in childhood RCM.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  frequency: FREQUENT
  evidence:
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dyspnea, No. (%)75 (41)24 (44)47 (39)"
    explanation: >-
      Table 1 reports dyspnea in 75 of 185 patients (41%) at diagnosis, placing
      the phenotype in the FREQUENT (30-79%) band on human cohort data.
genetic:
- name: MYL3
  gene_term:
    preferred_term: MYL3
    term:
      id: hgnc:7584
      label: MYL3
  relationship_type: CAUSATIVE
  frequency: >-
    Rare. One of the sarcomeric genes reported in primary restrictive
    cardiomyopathy; no case fraction has been reported in a screened cohort.
  evidence:
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the myosin essential light chain has been associated with restrictive
      cardiomyopathy (RCM) in humans
    explanation: >-
      The only gene in this entry for which a human
      restrictive-cardiomyopathy association is quoted at all, which is why it
      is curated first among the four. Tagged MODEL_ORGANISM because the
      publication is a transgenic-mouse study and the quoted sentence is its
      framing of prior human reports rather than a human result of its own; the
      human gene-disease relationship still needs a primary clinical citation.
  - reference: PMID:28371863
    reference_title: "Hypercontractile mutant of ventricular myosin essential light chain leads to disruption of sarcomeric structure and function and results in restrictive cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      E143K-myosin had increased duty ratio and binding affinity to actin
      compared with WT-myosin
    explanation: >-
      Gives the functional consequence of the E143K allele - increased duty
      ratio and actin affinity - which is the increased-myofilament-tension
      mechanism this entry's trigger node asserts. Tagged MODEL_ORGANISM to
      match this entry's existing use of the same quote: the myosin was
      purified from the transgenic mouse, so the assay is inseparable from the
      animal model that supplied it.
- name: TNNT2
  gene_term:
    preferred_term: TNNT2
    term:
      id: hgnc:11949
      label: TNNT2
  relationship_type: CAUSATIVE
  frequency: >-
    Rare. A thin-filament gene shared with hypertrophic cardiomyopathy, where
    the same alleles can produce either pattern; no restrictive-cardiomyopathy
    case fraction has been reported.
  evidence:
  - reference: PMID:18467357
    reference_title: Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sarcomere protein gene mutations were identified in four patients (33%): 2 in the cardiac troponin I gene (TNNI3) and 1 each in the troponin T (TNNT2) and alpha-cardiac actin (ACTC) genes.
    explanation: >-
      Human evidence that a TNNT2 variant was found in a child ascertained as
      idiopathic restrictive cardiomyopathy, which is the gene-disease
      relationship this record asserts.
  - reference: PMID:24221941
    reference_title: "A Drosophila melanogaster model of diastolic dysfunction and cardiomyopathy based on impaired troponin-T function."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      prolongs systole and restricts diastolic dimensions of the heart
    explanation: >-
      Model-organism evidence for the troponin-T restrictive mechanism. Kept
      PARTIAL: the measurement is in Drosophila, so it supports the mechanism
      rather than the human gene-disease relationship, which the Kaski cohort
      quote above now supplies.
  notes: >-
    The human evidence carried here is a single TNNT2 proband within a
    twelve-patient pediatric series, so the gene-disease relationship is
    established for the restrictive pattern but not quantified; no
    restrictive-cardiomyopathy case fraction for TNNT2 has been reported.
- name: TNNI3
  gene_term:
    preferred_term: TNNI3
    term:
      id: hgnc:11947
      label: TNNI3
  relationship_type: CAUSATIVE
  frequency: >-
    The thin-filament gene most often associated with a restrictive
    presentation, and the commonest molecular cause of pediatric RCM.
  case_fractions:
  - population: >-
      Chinese national pediatric RCM cohort, 185 children from 14 centres,
      2013-2022
    case_fraction_percent: 61.0
    cohort_size: 185
    notes: >-
      Share of children with restrictive cardiomyopathy carrying a TNNI3
      variant in the largest reported pediatric RCM cohort. Ascertainment is
      pediatric and single-country, so it should not be read as the adult or
      worldwide share.
    evidence:
    - reference: PMID:41219744
      reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        TNNI3 mutations were present in 61% of cases, the most common in pediatric RCM.
      explanation: >-
        Quantifies the TNNI3 share of pediatric restrictive cardiomyopathy in a
        185-patient multicentre cohort.
  evidence:
  - reference: PMID:12531876
    reference_title: Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TNNI3 mutations were identified in six of these nine RCM patients
    explanation: >-
      Direct human evidence that TNNI3 variants cause the restrictive pattern
      specifically: the nine patients were ascertained on restrictive filling,
      biatrial dilatation, normal systolic function and normal wall thickness,
      not on hypertrophy.
  - reference: PMID:12531876
    reference_title: Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Linkage analysis to selected sarcomeric contractile protein genes identified cardiac troponin I
    explanation: >-
      The linkage result in the index family that first tied idiopathic
      restrictive cardiomyopathy to a sarcomeric gene.
- name: MYH7
  gene_term:
    preferred_term: MYH7
    term:
      id: hgnc:7577
      label: MYH7
  relationship_type: CAUSATIVE
  frequency: >-
    Rare. A thick-filament gene shared with hypertrophic and dilated
    cardiomyopathy; no restrictive-cardiomyopathy case fraction has been
    reported.
  notes: >-
    Deliberately carries no evidence item, on the same basis as TNNI3 above:
    MYH7 is named in this entry's trigger node, but no source quoted in this
    file speaks to MYH7 in restrictive cardiomyopathy specifically. The MYH7
    gene-disease relationships that are evidenced in this repository are
    against hypertrophic cardiomyopathy (Hypertrophic Cardiomyopathy 1) and
    dilated cardiomyopathy (Dilated Cardiomyopathy 1S), and neither can be
    carried across to this pattern.
- name: ACTC1
  gene_term:
    preferred_term: ACTC1
    term:
      id: hgnc:143
      label: ACTC1
  relationship_type: CAUSATIVE
  frequency: >-
    Rare. Alpha-cardiac actin, the thin filament's structural core; a single
    proband in the founding pediatric series, reported there as the first ACTC1
    variant in familial restrictive cardiomyopathy.
  evidence:
  - reference: PMID:18467357
    reference_title: Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe the first mutation in ACTC in familial RCM.
    explanation: >-
      Establishes ACTC1 as a cause of the familial restrictive pattern, which
      is why the thin-filament arm of this entry's trigger node is not limited
      to the troponins.
- name: DES
  gene_term:
    preferred_term: DES
    term:
      id: hgnc:2770
      label: DES
  relationship_type: CAUSATIVE
  frequency: >-
    Rare. The cytoskeletal rather than sarcomeric route to the restrictive
    pattern, and the reason this entry's trigger node is titled sarcomeric *or
    cytoskeletal*. Desmin variants more often produce dilated, arrhythmogenic
    or hypertrophic disease; restrictive presentations are the uncommon end of
    that spectrum and are characteristically accompanied by conduction disease
    and, in much of the spectrum, a skeletal myopathy.
  evidence:
  - reference: PMID:31718026
    reference_title: "Restrictive Cardiomyopathy is Caused by a Novel Homozygous Desmin (DES) Mutation p.Y122H Leading to a Severe Filament Assembly Defect."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block
    explanation: >-
      The human presentation curated here: restrictive cardiomyopathy with
      atrioventricular block, the conduction-disease accompaniment that
      distinguishes the desmin route from the thin-filament routes.
  - reference: PMID:31718026
    reference_title: "Restrictive Cardiomyopathy is Caused by a Novel Homozygous Desmin (DES) Mutation p.Y122H Leading to a Severe Filament Assembly Defect."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Confocal microscopy revealed a severe filament assembly defect of mutant desmin
    explanation: >-
      The molecular consequence of the variant - failure of intermediate
      filament assembly - which is a different lesion in kind from the
      increased-myofilament-tension mechanism of the sarcomeric genes. Tagged
      IN_VITRO because the measurement is in transfected iPSC-derived
      cardiomyocytes and HT-1080 cells.
  notes: >-
    The cited family is consanguineous and the variant is homozygous, which the
    authors read as pointing to recessive inheritance for this allele. That does
    not generalise: most pathogenic DES alleles are heterozygous missense or
    small in-frame deletions acting through a poison-protein mechanism, so this
    record should not be taken as evidence that desmin RCM is recessive in
    general.
- name: FLNC
  gene_term:
    preferred_term: FLNC
    term:
      id: hgnc:3756
      label: FLNC
  relationship_type: CAUSATIVE
  frequency: >-
    Rare. Filamin C, the Z-disc actin cross-linker; the second cytoskeletal route
    to the restrictive pattern alongside desmin, and the gene behind the numbered
    entity RCM5.
  evidence:
  - reference: PMID:26666891
    reference_title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified two novel missense variants (p.S1624L; p.I2160F) in filamin-C
      (FLNC), an actin-cross-linking protein mainly expressed in heart and skeletal
      muscle, segregating in two families with autosomal-dominant RCM
    explanation: >-
      The report that added FLNC to the familial restrictive gene set: two novel
      missense variants segregating with autosomal-dominant RCM in two families,
      in a Z-disc actin cross-linker rather than a sarcomere protein.
  - reference: PMID:26666891
    reference_title: Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, FLNC is a disease gene for autosomal-dominant RCM and broadens the
      phenotype spectrum of filaminopathies.
    explanation: >-
      The authors' own conclusion, establishing FLNC as a causative gene for the
      autosomal-dominant familial restrictive phenotype curated here.
  - reference: PMID:39472949
    reference_title: "Novel FLNC variants in pediatric cardiomyopathy: an insight into disease mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a cohort of 58 patients, novel heterozygous FLNC variants, c.3962A > T
      (p.Glu1321Val) and c.7543C > T (p.Leu2515Phe), were identified in patients
      presenting with dilated and mixed restrictive/hypertrophic cardiomyopathies,
      respectively
    explanation: >-
      Independent pediatric ascertainment of an FLNC missense variant in a child
      with a restrictive phenotype. Curated PARTIAL because that child's
      phenotype is mixed restrictive/hypertrophic rather than pure RCM, which is
      itself the point: FLNC is a cross-phenotype cardiomyopathy gene and the
      restrictive presentation is one pole of its spectrum.
  - reference: PMID:36921598
    reference_title: "Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Human variants in filamin C (FLNC) are linked to a variety of cardiomyopathies, and in this study, we investigate an in-frame deletion (c.7416_7418delGAA, p.Glu2472_Asn2473delinAsp) in a patient with RCM.
    explanation: >-
      Identifies a specific FLNC in-frame deletion in a patient ascertained with
      restrictive cardiomyopathy, the allele modeled in this entry's engineered
      cardiac tissue system.
  notes: >-
    MONDO carries "restrictive cardiomyopathy 5" as a synonym of the FLNC
    hypertrophic entity CMH26, and the FLNC hypertrophic/restrictive spectrum is
    curated in full in `Hypertrophic_Cardiomyopathy_26`. FLNC is listed here as a
    gene reaching the restrictive pattern, not as a duplicate of that entry; the
    hypertrophic-versus-restrictive label for a given FLNC family is partly
    nosological rather than biological.
- name: MYPN
  gene_term:
    preferred_term: MYPN
    term:
      id: hgnc:23246
      label: MYPN
  relationship_type: CAUSATIVE
  frequency: >-
    Rare. Myopalladin, a Z-disc protein - the sarcomere's anchoring apparatus
    rather than its contractile stroke. MONDO codes the MYPN entity as
    dilated cardiomyopathy 1KK (MONDO:0014100) while carrying
    "cardiomyopathy, familial restrictive, 4" as one of its synonyms, so the
    restrictive presentation is allelic within a gene that more commonly
    produces dilated or hypertrophic disease.
  evidence:
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Q529X-MYPN was found in familial RCM
    explanation: >-
      Human evidence tying a specific MYPN nonsense allele to the familial
      restrictive pattern, within a 900-patient cardiomyopathy screen.
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X)
    explanation: >-
      The proposed mechanism of the restrictive MYPN allele - disturbed
      myofibrillogenesis - which is distinct from the hypertrophic/dilated
      Y20C allele's nuclear-shuttling defect in the same paper. Tagged IN_VITRO
      because the measurement is in transfected neonatal rat cardiomyocytes.
  notes: >-
    Not curated as a `has_subtypes` entry. MONDO:0014100 is an open item in
    `stubs/Dilated_Cardiomyopathy_1KK.yaml`, where it is nominated as a dilated
    cardiomyopathy; claiming it here as a restrictive subtype would pre-empt
    that decision on the strength of one allele.
progression:
- phase: Progressive diastolic heart failure to transplantation or death
  notes: >-
    RCM does not plateau. In the largest reported pediatric cohort the median
    time from diagnosis to a major adverse cardiovascular event - cardiac death,
    transplantation, or equivalent - was about two years, and roughly five in
    eight children reached such an event during follow-up. Reported
    transplant-free survival at five years is about 30%. Significant heart
    failure is the presenting feature rather than a late complication, which is
    why listing decisions are made early and why risk models for this disease
    are built around timing of transplantation rather than around drug therapy.
  evidence:
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During the follow-up period, 114 patients (62%) experienced MACE, with the median MACE-free survival time for the entire cohort being 2.1 years post-diagnosis
    explanation: >-
      Quantifies the event rate and the time course this progression record
      asserts, in a 185-child multicentre cohort.
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      often resulting in heart failure, arrhythmias, and sudden cardiac death, with a 5-year transplant-free survival rate of about 30%
    explanation: >-
      Source for the five-year transplant-free survival figure and for the
      three endpoints named in this record.
differential_diagnoses:
- name: Cardiac amyloidosis (ATTR and AL)
  description: >-
    The most important acquired mimic, and the reason this entry's boundary has
    to be stated rather than assumed. Amyloid infiltration produces the same
    restrictive filling, biatrial enlargement and preserved ejection fraction,
    but by extracellular deposition of a misfolded precursor rather than by a
    heritable defect of the contractile apparatus - so it is curated on its own
    entries and conforms to `amyloidogenesis`, not here. Hereditary ATTR is
    itself inherited, which means "familial" does not separate the two; the
    separating question is whether the myocardium is infiltrated. No
    `disease_term` is bound here because MONDO has no single class covering both
    the transthyretin and the light-chain routes to cardiac amyloidosis; the two
    are curated as `ATTR_Amyloidosis` and `AL_Amyloidosis`.
  distinguishing_features:
  - Increased wall thickness on echocardiography, whereas primary RCM has normal or near-normal wall thickness.
  - Bone-avid tracer uptake on scintigraphy (ATTR) or a monoclonal protein on serum/urine immunofixation and free light chains (AL).
  - Extracardiac features - polyneuropathy, carpal tunnel syndrome, macroglossia, nephrotic-range proteinuria - that a sarcomeric cardiomyopathy does not produce.
  - Congo red-positive, apple-green birefringent deposits on endomyocardial biopsy.
  evidence:
  - reference: PMID:12531876
    reference_title: Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Restrictive cardiomyopathy (RCM) is an uncommon heart muscle disorder
      characterized by impaired filling of the ventricles with reduced volume in
      the presence of normal or near normal wall thickness and systolic function
    explanation: >-
      Supplies the case definition the first distinguishing feature below turns
      on: primary RCM is defined by normal or near-normal wall thickness, which
      is what an amyloid-infiltrated ventricle does not show.
- name: Storage and infiltrative cardiomyopathies other than amyloid
  description: >-
    Lysosomal storage disease (Fabry, Gaucher, glycogen storage disease II),
    haemochromatosis and sarcoidosis all reach restrictive physiology by loading
    or replacing the myocardium. MONDO asserts several of these under
    MONDO:0016340 because they are both inherited and restrictive; this entry
    keeps them out because the mechanism is deposition, not myofilament tension,
    and each has its own mechanism module.
  distinguishing_features:
  - Extracardiac storage phenotype (organomegaly, renal, ophthalmological, or neurological involvement).
  - Enzyme assay or genotype for the specific storage disorder.
  - A disease-modifying therapy directed at the stored substrate exists, which is not true of primary sarcomeric RCM.
- name: Endomyocardial fibrosis
  description: >-
    Obliterative fibrosis of the ventricular apex and subvalvular apparatus,
    endemic in parts of the tropics and elsewhere associated with
    hypereosinophilia. Restrictive physiology arises from an obliterated
    ventricular cavity rather than from a stiff myocardium, and it is curated
    separately.
  distinguishing_features:
  - Apical cavity obliteration and thrombus on imaging.
  - Eosinophilia, or residence in an endemic region.
  - Atrioventricular valve regurgitation from involvement of the subvalvular apparatus.
  disease_term:
    preferred_term: endomyocardial fibrosis
    term:
      id: MONDO:0006746
      label: endomyocardial fibrosis
- name: Constrictive pericarditis
  description: >-
    Not a cardiomyopathy at all, but the classic haemodynamic imitator: a
    thickened, non-compliant pericardium limits filling with a normal
    myocardium underneath. It matters because it is surgically curable, so the
    distinction changes management more than any other on this list.
  distinguishing_features:
  - Ventricular interdependence with respirophasic septal shift on echocardiography and at catheterisation.
  - Pericardial thickening or calcification on CT or CMR.
  - Normal or increased mitral annular e-prime (annulus reversus), whereas RCM reduces it.
  disease_term:
    preferred_term: constrictive pericarditis
    term:
      id: MONDO:0006711
      label: constrictive pericarditis
treatments:
- name: Heart Failure Pharmacotherapy and Supportive Care
  description: >-
    Management targets congestion and filling pressures; because output is
    filling-limited, therapy is largely supportive (diuretics for congestion, rate
    and rhythm control, anticoagulation for atrial arrhythmia).
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: diuretic
      term:
        id: NCIT:C448
        label: Diuretic
- name: Heart Transplantation
  description: >-
    RCM has a poor prognosis and is frequently an indication for heart
    transplantation, including in patients with preserved systolic function.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
- name: Implantable Cardioverter-Defibrillator
  description: >-
    Considered for prevention of sudden cardiac death in selected high-risk
    patients.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
- name: Antithrombotic Therapy
  description: >-
    Blood stasis in the dilated, poorly emptying atria of a restrictively filled
    heart carries a thromboembolic risk, and antithrombotic cover is part of
    routine RCM management rather than a disease-modifying therapy. In the
    Chinese national pediatric cohort a third of children were on an antiplatelet
    agent at baseline while thrombosis was recorded in 3%, so the practice is
    common and prophylactic rather than reactive. Agent choice (antiplatelet
    versus anticoagulant) is not settled by that cohort, which reports only
    antiplatelet use; anticoagulation is conventionally added for atrial
    fibrillation or documented thrombus, and this record does not assert a
    preference between them.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antiplatelet agent
      term:
        id: NCIT:C1327
        label: Antiplatelet Agent
    - preferred_term: anticoagulant agent
      term:
        id: NCIT:C263
        label: Anticoagulant Agent
  evidence:
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antiplatelet, No. (%)62 (34)20 (36)39 (33)"
    explanation: >-
      Table 1 records antiplatelet therapy in 62 of 185 children (34%) at
      baseline, establishing antithrombotic cover as routine practice in this
      cohort.
  - reference: PMID:41219744
    reference_title: "Clinical-genetic profiles and risk prediction model in childhood restrictive cardiomyopathy: a national cohort study of China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thrombosis, No. (%)6 (3)3 (5)3 (3)"
    explanation: >-
      Table 1 records thrombosis in 6 of 185 children (3%), the event this
      therapy is directed against; the low rate is under prevailing antiplatelet
      use and should not be read as an untreated baseline risk.
- name: PDE3 Inhibition (Trequinsin) - preclinical lead only
  description: >-
    NOT a treatment for this disease. Recorded because it is the only
    mechanism-directed therapeutic lead this entry has, and because the absence
    of any disease-modifying therapy is itself a curated fact: management is
    otherwise entirely congestion control and transplantation. Trequinsin
    emerged from a high-throughput screen of small molecules run on the FLNC
    patient-derived engineered cardiac tissue system described under
    `experimental_models`, where it improved cardiomyocyte relaxation. The
    evidence is a single in vitro screen in one genotype; there is no animal
    efficacy study, no trial, and no human exposure in restrictive
    cardiomyopathy. Do not read this record as a clinical recommendation.
    A class-level safety caveat also applies and is recorded in this record's
    own evidence: chronic oral PDE3 inhibition raised mortality in severe chronic
    heart failure, so a relaxation benefit measured in engineered tissue is not
    on its own a reason to expect net benefit from sustained dosing.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: trequinsin
      term:
        id: CHEBI:748124
        label: trequinsin
  target_mechanisms:
  - target: Increased Resting Myocardial Stiffness and Impaired Relaxation
    treatment_effect: INHIBITS
    description: >-
      The screen was scored on cardiomyocyte relaxation, so the node this lead
      addresses is the impaired-relaxation half of the stiffness node rather
      than the upstream sarcomeric lesion or the downstream fibrosis.
    evidence:
    - reference: PMID:36921598
      reference_title: "Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        High-throughput small-molecule screening identifies phosphodiesterase 3 (PDE3) inhibition by trequinsin as a potential therapy to improve cardiomyocyte relaxation in this genotype.
      explanation: >-
        Curated PARTIAL, and deliberately: the authors themselves say "potential
        therapy" and "in this genotype". The quote supports a screening hit
        against the relaxation node, not efficacy in patients.
  evidence:
  - reference: PMID:1944425
    reference_title: Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      long-term therapy with oral milrinone increases the morbidity and mortality
      of patients with severe chronic heart failure
    explanation: >-
      The class-level counterweight to the screening hit. A randomized trial of
      chronic oral PDE3 inhibition found excess mortality despite favourable
      haemodynamics, so an improvement in cardiomyocyte relaxation in vitro does
      not establish that sustained PDE3 inhibition would help. Curated REFUTE
      against the therapeutic proposition rather than against the mechanism, and
      the extrapolation is explicit: the trial studied milrinone in severe
      systolic heart failure, not trequinsin in restrictive cardiomyopathy.
clinical_trials:
- name: NCT01873963
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    PCM GENES - a completed observational genotype-phenotype study of pediatric
    cardiomyopathy that enrolled restrictive cardiomyopathy alongside the dilated
    and hypertrophic phenotypes. Recorded because it is one of the few studies of
    any design to have enrolled pediatric RCM at scale; it is observational, so
    it establishes no therapy.
  target_phenotypes:
  - preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  evidence:
  - reference: clinicaltrials:NCT01873963
    reference_title: Genotype-Phenotype Associations in Pediatric Cardiomyopathy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the purpose of this study is to identify genes that cause cardiomyopathy or
      that influence how people with cardiomyopathy do over time
    explanation: >-
      States the genotype-phenotype aim; the registry lists restrictive
      cardiomyopathy among the enrolled conditions.
- name: NCT02432092
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    Ongoing observational mutation-analysis protocol in pediatric cardiomyopathy
    families, listing restrictive cardiomyopathy among its conditions. Again a
    genetics study rather than an intervention.
  target_phenotypes:
  - preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  evidence:
  - reference: clinicaltrials:NCT02432092
    reference_title: Pediatric Cardiomyopathy Mutation Analysis
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The goal of this protocol is to obtain information from individuals with
      cardiomyopathy and from their families in order to elucidate the molecular
      genetics of this disorder
    explanation: >-
      States the study aim; restrictive cardiomyopathy is one of the registered
      conditions.
  notes: >-
    A third candidate surfaced by deep research, NCT06794710, is not curated
    here: it is registered NOT_YET_RECRUITING, which this schema's status enum
    cannot express without overstating how far along it is.
experimental_models:
- name: FLNC RCM patient iPSC-derived cardiomyocytes and 3D engineered cardiac tissue
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Induced pluripotent stem cells reprogrammed from a patient carrying the FLNC
    in-frame deletion c.7416_7418delGAA, differentiated to cardiomyocytes and
    assembled into three-dimensional engineered cardiac tissues, each compared
    against a CRISPR-Cas9-corrected isogenic line. The isogenic correction is
    what makes this model informative: it removes genetic background as an
    explanation for the mechanical difference. The 3D format exists because the
    defining property of RCM - passive tension and relaxation of a contracting
    tissue - cannot be measured in cells attached to a plastic substrate, which
    the authors give as the reason no iPSC model of RCM existed before.
  cell_source: Patient-derived iPSC, with a CRISPR-Cas9-corrected isogenic control line
  culture_system: Two-dimensional iPSC-cardiomyocyte monolayer and three-dimensional engineered cardiac tissue
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  publication: PMID:36921598
  evidence:
  - reference: PMID:36921598
    reference_title: "Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Together, these data demonstrate an engineered cardiac tissue model of RCM and establish the translational potential of this precision medicine approach to identify therapeutics targeting myocardial relaxation.
    explanation: >-
      The authors' own statement of what the system is for, which is the claim
      this model entry makes: a human-cell platform for the relaxation defect.
  modeled_mechanisms:
  - target: Increased Resting Myocardial Stiffness and Impaired Relaxation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Mutant engineered tissues reproduce both halves of the node - raised
      passive tension and slowed relaxation - in human cells, against an
      isogenic control.
    limitations: >-
      Engineered cardiac tissue is immature relative to adult ventricular
      myocardium, lacks the fibroblast, vascular and neurohormonal context in
      which the human ventricle stiffens, and here represents a single patient
      and a single FLNC allele. It is a human-cell surrogate for the mechanism,
      not a measurement made in human myocardium.
    readouts:
    - name: Passive tension of engineered cardiac tissue
      target: Increased Resting Myocardial Stiffness and Impaired Relaxation
      direction: INCREASED
      interpretation: >-
        The mechanical correlate of increased resting myocardial stiffness,
        measured in mutant versus isogenic-control tissue.
      evidence:
      - reference: PMID:36921598
        reference_title: "Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          mutant engineered cardiac tissues (ECTs) demonstrate increased passive tension and impaired relaxation velocity compared with isogenic controls
        explanation: >-
          Reports the passive-tension measurement behind this readout.
    - name: Cardiomyocyte relaxation and calcium kinetics in 2D culture
      target: Increased Resting Myocardial Stiffness and Impaired Relaxation
      direction: DECREASED
      interpretation: >-
        Impaired relaxation and reduced calcium kinetics in the monolayer
        format, showing the defect is present at the cardiomyocyte level and not
        only a property of the assembled tissue.
      evidence:
      - reference: PMID:36921598
        reference_title: "Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with this variant display impaired relaxation and reduced calcium kinetics in 2D culture when compared with a CRISPR-Cas9-corrected isogenic control line.
        explanation: >-
          Reports the monolayer relaxation and calcium measurements behind this
          readout.
discussions:
- discussion_id: rcm_mechanism_is_model_organism_weighted
  prompt: >-
    Does the Drosophila upheld/troponin-T and mouse MYL3 E143K mechanism — increased
    myofilament tension producing elevated resting stiffness and restrictive filling —
    hold in human restrictive cardiomyopathy myocardium, where it has not been
    functionally confirmed?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Sarcomeric or Cytoskeletal Variant with Increased Myofilament Tension
  - pathophysiology#Increased Resting Myocardial Stiffness and Impaired Relaxation
  - pathophysiology#Restrictive Filling Physiology
  rationale: >-
    The animal-derived core of this chain is unchanged: the tension, fibrosis,
    filling, and heart-failure nodes still rest on a Drosophila troponin-T model
    and a transgenic mouse carrying the myosin essential light chain E143K
    substitution. Two human-cell measurements have since been added and narrow the
    question without closing it. Patient-derived engineered cardiac tissue carrying
    an FLNC in-frame deletion shows increased passive tension and impaired
    relaxation against a CRISPR-corrected isogenic control (PMID:36921598), and
    cardiac fibroblasts explanted from children with idiopathic RCM are themselves
    stiffer and more viscous than control fibroblasts (PMID:36174041). Both are
    human cells, and the isogenic comparison in the first removes genetic
    background as an explanation - so the mechanism is no longer purely a
    cross-species inference. But neither is a measurement in human myocardium:
    engineered tissue is immature and lacks the vascular and neurohormonal context
    of the ventricle, the fibroblast work is a single non-myocyte cell type in
    culture, and the FLNC result is one patient and one allele. The question the
    proposed experiment below asks - do genotyped human RCM myocardial fibres show
    raised passive tension and stiffness - is therefore still open, and it is still
    a question of translational validity rather than absent evidence,
    which is why it is a HUMAN_MODEL_MISMATCH and not a KNOWLEDGE_GAP. The fidelity
    concern is specific rather than generic: Drosophila indirect flight muscle differs
    from mammalian myocardium in sarcomere regulation and has no comparable
    neurohormonal or fibrotic context, and the mouse line reports a supraphysiological
    single-allele substitution whose duty-ratio effect need not scale to the human
    ventricle. If the mechanism does not transfer, the direction of therapy implied by
    this pathograph — lowering myofilament tension rather than treating congestion —
    would be wrong for patients.
  evidence:
  - reference: PMID:28371863
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      E143K-myosin had increased duty ratio and binding affinity to actin compared with
      WT-myosin
    explanation: >-
      The core tension mechanism curated here is a mouse transgenic measurement, which
      is the model-side half of the mismatch.
  - reference: PMID:24221941
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Elevated resting myocardial stiffness, consistent with upheld(101) diastolic
      dysfunction, was confirmed by an atomic force microscopy-based nanoindentation
      approach
    explanation: >-
      The stiffness node's only quantitative support is a Drosophila nanoindentation
      measurement, not a human one.
  proposed_experiments:
  - experiment_id: exp_rcm_human_myocardium_tension_and_stiffness
    name: Human RCM myocardial mechanics in genotyped explants
    description: >-
      In skinned myocardial fibres from explanted or biopsy tissue of genotyped
      sarcomeric RCM patients, measure active and passive tension, calcium sensitivity,
      and passive stiffness against non-failing donor myocardium matched for age and
      region. A human increase in resting tension and passive stiffness tracking
      genotype would carry the model result into human disease; equivalence with donor
      myocardium would show the restrictive physiology is driven by something other
      than the myofilament step this pathograph asserts.
    would_support:
    - pathophysiology#Increased Resting Myocardial Stiffness and Impaired Relaxation
    supporting_outcome:
    - >-
      Genotype-positive human RCM myocardium shows significantly higher passive
      stiffness and resting tension than matched non-failing donor myocardium.
    would_refute:
    - pathophysiology#Sarcomeric or Cytoskeletal Variant with Increased Myofilament Tension
    refuting_outcome:
    - >-
      Human RCM myocardium shows passive stiffness and resting tension
      indistinguishable from matched donor myocardium.
- discussion_id: rcm_tnni3_myh7_restrictive_evidence_absent
  prompt: >-
    Is there direct human evidence that MYH7 variants cause the restrictive pattern
    specifically, as opposed to the hypertrophic pattern with restrictive physiology
    already curated in the sibling HCM entries?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#MYH7
  rationale: >-
    MYH7 is named in this entry's trigger node and carried in its genetic section,
    but the record still carries no evidence item, because nothing quoted in this
    file speaks to MYH7 in restrictive cardiomyopathy specifically. The MYH7
    relationships evidenced elsewhere in this repository are hypertrophic
    (Hypertrophic Cardiomyopathy 1) and dilated (Dilated Cardiomyopathy 1S), and
    neither can be carried across to this pattern. This is a KNOWLEDGE_GAP rather
    than a HUMAN_MODEL_MISMATCH because the evidence is absent rather than
    model-bound - a distinct problem from the model-organism weighting of the
    pathophysiology chain, and one closed by a human cohort rather than by a better
    model. Until it is closed, this gene record should not be treated as
    independently established for the restrictive pattern.
  notes: >-
    The TNNI3 and TNNT2 halves of this gap are now closed and the discussion has
    been narrowed accordingly rather than retitled: TNNI3 carries the Mogensen
    linkage and mutation-screening result (PMID:12531876) plus a pediatric case
    fraction (PMID:41219744), and TNNT2 carries a proband from the Kaski series
    (PMID:18467357). The discussion_id is deliberately left unchanged so that
    references to it from outside this file still resolve.
notes: >-
  Scope. This entry fills the gap of a dedicated restrictive cardiomyopathy entity
  (the third classic cardiomyopathy pattern, previously represented in the KB only
  as restrictive physiology noted inside HCM7/TNNI3). It is curated as the
  primary/heritable sarcomeric-cytoskeletal RCM, whose restrictive filling is the
  final common pathway of increased myofilament tension and myocardial stiffness,
  and it conforms to the shared cardiomyopathy_maladaptive_remodeling module.
  RCM overlaps genetically with hypertrophic cardiomyopathy — the same sarcomere
  genes (TNNI3, TNNT2, MYH7, ACTC1, MYL3) and often the same alleles can produce
  either pattern — which is why several thin-filament HCM entries (notably
  HCM7/TNNI3) carry restrictive features. Infiltrative causes of a restrictive
  phenotype (cardiac amyloidosis, storage diseases such as Fabry) are curated under
  their own entries and are deliberately out of scope here, and are named in
  `differential_diagnoses` so the boundary is stated rather than assumed.

  Familial restrictive cardiomyopathy (MONDO:0016340). The heritable subset is
  curated here rather than as a separate entry or a Grouping, and is recorded as a
  `skos:narrowMatch` in `mappings.mondo_mappings` with its reasoning; the two
  molecularly defined members that this entry evidences, RCM1 (TNNI3) and RCM3
  (TNNT2), are carried as `has_subtypes`. The remaining gene arms are curated in
  `genetic:` rather than as further subtypes, each for a stated reason: FLNC's
  numbered entity RCM5 is a MONDO synonym of CMH26 and is already curated in full
  as `Hypertrophic_Cardiomyopathy_26`; MYPN's RCM4 is a synonym of MONDO:0014100,
  which is an open nomination as a *dilated* cardiomyopathy in
  `stubs/Dilated_Cardiomyopathy_1KK.yaml`; ACTC1 and DES have no numbered MONDO
  entity to bind a `subtype_term` to; and RCM2 and RCM6 are left uncurated because
  nothing cached in this repository names their causal genes, which is a better
  outcome than guessing one. MONDO:0016340 is a `disease_grouping`
  term whose asserted descendants mix the numbered RCM series with deposition and
  infiltration diseases (Gaucher disease type I, glycogen storage disease II,
  ATTRV122I amyloidosis) and with atrial standstill; this entry follows the
  mechanistic boundary rather than that descendant set.

  Evidence weighting. The phenotype layer is human: every entry in `phenotypes:`
  now carries human clinical evidence, principally the 185-patient Chinese
  national pediatric cohort (PMID:41219744) and the troponin-I RCM series
  (PMID:12531876), with the model-organism items retained alongside rather than
  as sole support. The remaining model weighting is in the *mechanism* chain,
  which is what the HUMAN_MODEL_MISMATCH discussion is about: it remains weighted
  towards model organisms (Drosophila troponin-T and mouse MYL3 E143K), but two
  human-cell measurements now sit alongside them — patient-derived engineered cardiac tissue
  against a CRISPR-corrected isogenic control (PMID:36921598) and atomic-force
  rheology of patient cardiac fibroblasts (PMID:36174041) — so the
  HUMAN_MODEL_MISMATCH discussion `rcm_mechanism_is_model_organism_weighted` is
  narrowed rather than closed: neither is a measurement in human myocardium. The
  companion KNOWLEDGE_GAP `rcm_tnni3_myh7_restrictive_evidence_absent` is likewise
  narrowed; its TNNI3 and TNNT2 halves are closed by human cohort evidence and
  only the MYH7 half remains open.

  GeneReviews scope. No GeneReviews chapter covering this entity is cached in
  this repository, so none is tagged in `references`; the two cardiomyopathy
  overviews used elsewhere in this series (PMID:20301725, PMID:20301486) address
  the hypertrophic and dilated phenotypes rather than this one. The
  clinical-characteristics baseline for this entry is therefore built entirely
  from the primary literature cited throughout, principally the 185-patient
  Chinese national pediatric cohort PMID:41219744 and the troponin-I RCM series
  PMID:12531876 for the clinical picture, and PMID:28371863, PMID:24221941 for
  the mechanism.
📚

References & Deep Research

Deep Research

1
Falcon ▸
Restrictive Cardiomyopathy: Disease-Characteristics Research Report
Edison Scientific Literature 25 citations 2026-08-27T11:46:56.406696

Restrictive Cardiomyopathy: Disease-Characteristics Research Report

Scope. This report treats restrictive cardiomyopathy (RCM) as a phenotype, while emphasizing primary/familial genetic RCM. Amyloidosis, storage disease, iron overload, eosinophilic disease, radiation injury, and other acquired disorders can produce the same physiology but are etiologically distinct. Evidence is labeled as human, database, animal, in-vitro, or trial-registry evidence. Literature was prioritized through 2024; robust RCM-specific data remain limited because the disease is rare.

Executive summary

RCM is myocardial stiffness and impaired ventricular relaxation causing high filling pressures, usually with nondilated, nonhypertrophied ventricles, preserved ejection fraction early, and marked biatrial enlargement. Pediatric RCM represents approximately 2.5–5% of childhood cardiomyopathy, about 30% of pediatric patients have a positive family history, and nearly half reportedly die or undergo transplantation within three years. Familial primary RCM is usually autosomal dominant and is most convincingly associated with TNNI3, TNNT2, FLNC, MYH7, and MYPN, although phenotype overlap and variable expressivity are substantial. A 2023 patient-specific FLNC iPSC/engineered-tissue study and a 2024 pediatric FLNC study are the most notable recent mechanistic advances. There is no approved molecular therapy for primary genetic RCM; management remains careful congestion control, arrhythmia/thromboembolism management, cause-specific therapy for phenocopies, and early transplant evaluation for progressive disease. (kim2021geneticsofcardiomyopathy pages 22-23, schubert2018theuseof pages 17-21, dong2024novelflncvariants pages 1-2, wang2023engineeredcardiactissue pages 1-3)

domain key finding/statistic evidence type (human clinical/database/in vitro/mouse/trial registry) key gene/variant or intervention source year/DOI or NCT
Disease identifier Restrictive cardiomyopathy mapped to MONDO_0005201; pediatric mutation-analysis registry also indexed MeSH term D002313 database MONDO_0005201 / MeSH D002313 Open Targets disease mapping; ClinicalTrials.gov-derived browse term (OpenTargets Search: restrictive cardiomyopathy, NCT02432092 chunk 1)
Definition/phenotype RCM is defined by increased myocardial stiffness, impaired diastolic relaxation, elevated filling pressures, preserved or near-preserved systolic function early, and biatrial enlargement human clinical / in vitro disease-model paper Phenotypic definition 2023; DOI: 10.1016/j.xcrm.2023.100976 (wang2023engineeredcardiactissue pages 1-3)
Pediatric frequency In children, RCM accounts for approximately 2.5–5% of all cardiomyopathies human clinical review Pediatric RCM 2018 review summarizing pediatric literature (schubert2018theuseof pages 17-21)
Pediatric prognosis Nearly half of pediatric patients die or require heart transplantation within 3 years of diagnosis human clinical review Pediatric RCM natural history 2018 review summarizing pediatric literature (schubert2018theuseof pages 17-21)
Adult/combined outcome burden In an RCM cohort with TNNI3-linked disease spectrum, composite outcome of mortality, cardiac transplantation, or ICD discharge was 56% human clinical TNNI3 / MYH7-associated RCM 2021; DOI: 10.4070/kcj.2021.0154 (kim2021geneticsofcardiomyopathy pages 4-5)
Core genes Highest-confidence recurrent genes include TNNI3, TNNT2, FLNC, MYPN; additional evidence for TTN and CRYAB; disease databases also capture secondary/metabolic phenocopy genes such as GAA, GBA1, TTR database / human genetic literature TNNI3, TNNT2, FLNC, MYPN, TTN, CRYAB, GAA, GBA1, TTR Open Targets association evidence and cardiomyopathy genetics reviews (OpenTargets Search: restrictive cardiomyopathy, kim2021geneticsofcardiomyopathy pages 22-23)
Inheritance Familial primary RCM is usually autosomal dominant; de novo sarcomeric variants are associated with severe pediatric disease and premature death/transplant human clinical/genetic review Sarcomeric and cytoskeletal variants 2021; DOI: 10.4070/kcj.2021.0154 (kim2021geneticsofcardiomyopathy pages 22-23)
2024 variant report In 58 pediatric cardiovascular cases, novel heterozygous FLNC variants c.3962A>T (p.Glu1321Val) and c.7543C>T (p.Leu2515Phe) were identified; mixed restrictive/hypertrophic phenotype seen with p.Leu2515Phe human clinical/genetic FLNC c.3962A>T; FLNC c.7543C>T 2024; DOI: 10.1186/s40246-024-00683-9 (dong2024novelflncvariants pages 1-2, dong2024novelflncvariants pages 4-6)
2024 functional interpretation FLNC c.3962A>T disrupted canonical splicing in a minigene assay, producing c.3961_3964del / p.Glu1321Alafs*23; both reported variants were de novo, absent from gnomAD, and classified likely pathogenic human genetic / in vitro FLNC c.3962A>T splicing defect 2024; DOI: 10.1186/s40246-024-00683-9 (dong2024novelflncvariants pages 1-2, dong2024novelflncvariants pages 4-6)
2023 disease model A de novo FLNC in-frame deletion c.7416_7418delGAA (p.Glu2472_Asn2473delinsAsp) in a child with RCM was modeled in patient-specific iPSC-cardiomyocytes and 3D engineered cardiac tissue; mutant tissues showed increased passive tension and impaired relaxation velocity in vitro FLNC c.7416_7418delGAA 2023; DOI: 10.1016/j.xcrm.2023.100976 (wang2023engineeredcardiactissue pages 3-4, wang2023engineeredcardiactissue pages 1-3)
2023 therapeutic screen High-throughput screening of 2,185 compounds identified PDE3 inhibition (trequinsin) as a lead; trequinsin reduced calcium-relaxation tau by ~50% and improved passive tension/relaxation without detected arrhythmic signal at tested conditions in vitro Trequinsin / PDE3 inhibition 2023; DOI: 10.1016/j.xcrm.2023.100976 (wang2023engineeredcardiactissue pages 4-7, wang2023engineeredcardiactissue pages 3-4)
Troponin mechanism Troponin I C-terminal RCM mutations cause impaired relaxation via marked myofibril Ca2+ hypersensitivity; severe variants include K178E and R192H mouse / in vitro / human genetic literature TNNI3 mutations (e.g., R145W, K178E, R192H) 2016; DOI: 10.3389/fphys.2016.00629 (liu2016restrictivecardiomyopathycaused pages 2-3, liu2016restrictivecardiomyopathycaused pages 1-2)
Mouse rescue evidence In transgenic mouse models, crossing cTnI193His RCM mice with cTnI-ND mice induced calcium desensitization and rescued diastolic dysfunction/RCM phenotype mouse TNNI3 (cTnI193His) rescue via cTnI-ND 2016; DOI: 10.3389/fphys.2016.00629 (liu2016restrictivecardiomyopathycaused pages 2-3)
Trial/registry PCM GENES enrolled 544 participants to study genotype-phenotype associations in pediatric dilated, hypertrophic, and restrictive cardiomyopathy with exome-based tiered testing trial registry Observational genomics cohort NCT01873963 (NCT01873963 chunk 1)
Trial/registry Pediatric Cardiomyopathy Mutation Analysis is a recruiting family-based observational cohort estimating 300 participants, including restrictive cardiomyopathy trial registry Molecular genetics / family study NCT02432092 (NCT02432092 chunk 1)
Trial/registry EARLY-MYO-RARE is a multimodal imaging-guided interventional rare-cardiomyopathy cohort (estimated n=300) including restrictive cardiomyopathy, using biomarker/imaging risk stratification and optimized HF care trial registry Multimodal imaging, HF pharmacotherapy, rehabilitation guidance NCT06794710 (NCT06794710 chunk 1)

Table: This table summarizes the most decision-relevant evidence for restrictive cardiomyopathy across identifiers, epidemiology, genetics, mechanisms, models, and active clinical studies. It prioritizes human clinical and 2023-2024 translational findings while separating preclinical and registry evidence.

1. Disease information

Definition and classification

RCM is defined physiologically by increased myocardial stiffness and impaired diastolic relaxation leading to elevated ventricular filling pressures. The classic phenotype comprises normal or reduced ventricular volumes, normal or near-normal wall thickness, severe diastolic dysfunction, biatrial enlargement, and initially preserved systolic ejection fraction. Doppler commonly shows rapid early filling and a high E/A ratio. A frequently used genetic-RCM “gray-zone” definition is maximum LV wall thickness ≤13 mm plus severe diastolic dysfunction. (kim2021geneticsofcardiomyopathy pages 22-23, kim2021geneticsofcardiomyopathy pages 4-5, wang2023engineeredcardiactissue pages 1-3)

Exact abstract-level wording from Wang et al. (published 21 March 2023) is: “Restrictive cardiomyopathy (RCM) is defined as increased myocardial stiffness and impaired diastolic relaxation leading to elevated ventricular filling pressures.” DOI: 10.1016/j.xcrm.2023.100976. (wang2023engineeredcardiactissue pages 1-3)

Identifiers and synonyms

  • MONDO: MONDO:0005201, restrictive cardiomyopathy. Familial RCM is separately represented as MONDO:0016340; TNNI3-associated familial RCM1 as MONDO:0007270; TNNT2-associated familial RCM3 as MONDO:0012900. (OpenTargets Search: restrictive cardiomyopathy)
  • MeSH: D002313, Cardiomyopathy, Restrictive. (NCT02432092 chunk 1)
  • ICD-10-CM: I42.5, Other restrictive cardiomyopathy. ICD coding does not reliably separate primary genetic RCM from amyloid, endomyocardial, or other restrictive phenocopies.
  • Common names: restrictive cardiomyopathy, primary restrictive cardiomyopathy, idiopathic restrictive cardiomyopathy, familial restrictive cardiomyopathy, and familial isolated restrictive cardiomyopathy.
  • OMIM uses gene-specific familial RCM entities rather than one etiologically uniform disorder; current OMIM cross-references should be checked during database ingestion because phenotype-series mappings change.

The information summarized here is aggregated disease-level evidence from publications, curated associations, and trial registries. Individual case data are used only where explicitly described; no EHR-derived patient-level dataset was accessed.

2. Etiology

Causal factors

Primary genetic RCM most often arises from germline variants affecting sarcomere calcium regulation or cytoskeletal/Z-disc integrity. Established or repeatedly implicated genes include TNNI3, TNNT2, FLNC, MYH7, MYPN, and less consistently ACTC1, MYBPC3, MYL2, MYL3, TTN, CRYAB, DES, and BAG3. Curated Open Targets evidence particularly supports TNNI3 (PMID 12531876), TNNT2 (PMID 16651346), MYPN (PMIDs 22286171, 25541130), and FLNC (including PMIDs 26666891, 27908349, 29858533, 31924696, 33060286). (OpenTargets Search: restrictive cardiomyopathy, kim2021geneticsofcardiomyopathy pages 22-23)

Secondary genetic/systemic causes include hereditary transthyretin amyloidosis (TTR), Fabry disease (GLA), Pompe disease (GAA), Gaucher disease (GBA1), and hereditary hemochromatosis (HFE). Acquired causes include AL amyloidosis, sarcoidosis, hypereosinophilic/Löffler endocardial disease, iron overload, radiation, drug toxicity, and endomyocardial fibrosis. These should be encoded as etiologic diseases causing an RCM phenotype, not collapsed into familial isolated RCM. (OpenTargets Search: restrictive cardiomyopathy, kim2021geneticsofcardiomyopathy pages 22-23, wang2023engineeredcardiactissue pages 1-3)

Risk, protective factors, and gene–environment interaction

  • Strongest risk factors: a pathogenic familial variant, an affected first-degree relative, or a de novo pathogenic variant. De novo sarcomeric variants are associated with severe childhood disease and premature death or transplantation. (kim2021geneticsofcardiomyopathy pages 22-23)
  • Environmental contributors: radiation, iron overload, cardiotoxic drugs, eosinophilic inflammation, and systemic infiltrative disease can independently create restrictive physiology. Ordinary diet, smoking, obesity, and exercise are not established causes of monogenic primary RCM.
  • A 2024 FLNC series noted infectious contexts in both pediatric cases and considered myocarditis a possible contributor; improvement after infection treatment in one child suggested a potentially reversible inflammatory component superimposed on persistent genetically mediated structural disease. This is hypothesis-generating, not proof of a reproducible FLNC–infection interaction. (dong2024novelflncvariants pages 4-6)
  • Protective variants or validated environmental protective factors: none established. Calcium desensitization is protective in experimental TNNI3 models but is not a proven human preventive factor. (liu2016restrictivecardiomyopathycaused pages 2-3)
  • Modifiers: variable RCM/HCM/near-normal expression within the same TNNI3 genotype strongly implies genetic or environmental modifiers, but no reproducible modifier gene is ready for clinical annotation. (kim2021geneticsofcardiomyopathy pages 4-5)

3. Phenotypes

Phenotype Typical characteristics Suggested HPO term
Restrictive ventricular filling Defining sign; chronic/progressive; may precede systolic failure HP:0011663, Restrictive cardiomyopathy
Diastolic dysfunction Severe; elevated end-diastolic pressures, impaired relaxation HP:0005117, Elevated left ventricular end-diastolic pressure; verify current HPO label/version
Biatrial enlargement Frequent/classic; consequence of chronically high filling pressure HP:0005120, Abnormality of cardiac atrium; use specific left/right atrial enlargement children where available
Dyspnea/exercise intolerance Common symptoms; progressive and quality-of-life limiting HP:0002094, Dyspnea; HP:0003546, Exercise intolerance
Congestive heart failure Advanced manifestation; right-, left-, or biventricular HP:0001635, Congestive heart failure
Pulmonary hypertension Secondary to high left-sided filling pressure; severity variable HP:0002092, Pulmonary arterial hypertension
Hepatomegaly/peripheral edema/ascites Systemic venous congestion HP:0002240, Hepatomegaly; HP:0012398, Peripheral edema; HP:0001541, Ascites
Atrial/ventricular arrhythmia Variable; can cause syncope, ICD therapy, or sudden death HP:0011675, Arrhythmia; HP:0001645, Sudden cardiac death
Preserved EF early Systolic function initially normal despite severe filling abnormality Encode as clinical measurement rather than disease-defining HPO abnormality
Later systolic dysfunction Progressive subset HP:0001723, Restrictive cardiomyopathy may be paired with reduced EF measurement

Onset ranges from infancy to late adulthood. Primary sarcomeric/FLNC disease often presents in childhood or early adulthood; TTR amyloidosis is generally later onset. Severity and progression are highly variable, but childhood-onset disease is frequently severe. A 2024 FLNC report documented preserved EF, dilated atria, pulmonary hypertension, valvular regurgitation, congestion/hepatomegaly, elevated BNP, and reduced activity tolerance in an affected child. (schubert2018theuseof pages 17-21, dong2024novelflncvariants pages 4-6)

RCM reduces exertional capacity and daily functioning through dyspnea, fatigue, edema, repeated hospitalization, arrhythmia surveillance, and transplant evaluation. No validated RCM-specific patient-reported outcome instrument or robust EQ-5D/SF-36 reference distribution was identified.

4. Genetic and molecular information

Principal genes and variant mechanisms

  • TNNI3—cardiac troponin I; classic RCM variants include p.Leu144Gln, p.Arg145Trp, p.Ala171Thr, p.Lys178Glu, p.Asp190Gly, and p.Arg192His. Most are heterozygous missense variants with dominant inheritance; increased myofilament Ca²⁺ sensitivity and impaired relaxation are central effects. PMID 12531876 is the landmark human association. (OpenTargets Search: restrictive cardiomyopathy, liu2016restrictivecardiomyopathycaused pages 2-3, kim2021geneticsofcardiomyopathy pages 4-5)
  • TNNT2—cardiac troponin T; heterozygous sarcomeric variants can cause familial isolated RCM or overlapping HCM/RCM. PMID 16651346 supports association. (OpenTargets Search: restrictive cardiomyopathy)
  • FLNC—filamin C, localized to Z-discs/intercalated discs and involved in actin cross-linking, structural integrity, and mechanotransduction. Missense/in-frame variants, especially in ROD2, occur in HCM/RCM; truncating variants more often cause dilated/arrhythmogenic disease through haploinsufficiency and are associated with fibrosis and arrhythmia. (dong2024novelflncvariants pages 1-2, wang2023engineeredcardiactissue pages 1-3)
  • MYH7/MYPN—thick-filament/Z-disc genes with RCM and overlap phenotypes. MYH7 or TNNI3 pathogenic variants were found in approximately half of probands in one RCM series summarized in a 2021 review. (kim2021geneticsofcardiomyopathy pages 4-5)

Recent variant-level findings

Dong et al. (October 2024) studied 58 pediatric cardiovascular patients and found two de novo heterozygous FLNC variants: c.3962A>T (p.Glu1321Val) and c.7543C>T (p.Leu2515Phe); the latter occurred with mixed restrictive/hypertrophic cardiomyopathy. Both were absent from gnomAD and classified likely pathogenic using ACMG evidence PS2 + PM2-supporting + PP3. The c.3962A>T substitution disrupted canonical splicing in a minigene assay, producing c.3961_3964del, p.Glu1321Alafs*23 and a predicted 1,342-aa truncated protein. DOI: 10.1186/s40246-024-00683-9. (dong2024novelflncvariants pages 1-2, dong2024novelflncvariants pages 4-6)

Exact abstract quote: “The c.3962A > T variant disrupted normal splicing, as demonstrated through the splicing prediction tool and minigene studies.” (dong2024novelflncvariants pages 1-2)

Wang et al. identified de novo FLNC c.7416_7418delGAA, p.Glu2472_Asn2473delinsAsp, a pathogenic in-frame ROD2 deletion in a three-year-old with RCM. Patient iPSC cardiomyocytes and CRISPR-corrected controls established functional pathogenicity. (wang2023engineeredcardiactissue pages 3-4, wang2023engineeredcardiactissue pages 1-3)

Primary RCM variants are generally germline. Somatic variants are not an established causal class. Large chromosomal abnormalities, recurrent copy-number changes, repeat expansions, and disease-specific epigenetic signatures have not been established. Pathogenic alleles are expected to be absent or extremely rare in population databases; variant-specific gnomAD frequency and ClinVar status must be recorded rather than assigning one disease-wide frequency.

5. Environmental information

No infectious organism is a recognized direct cause of familial RCM. Infection or myocarditis may unmask genetically susceptible myocardium, but evidence is preliminary. Relevant acquired exposures include mediastinal radiation, cardiotoxic drugs, heavy metals/iron overload, and inflammatory or eosinophilic injury. Lifestyle changes support general cardiovascular health but have not been shown to prevent penetrance of a pathogenic sarcomeric/FLNC allele. Excessive preload depletion may worsen output after disease develops; this is a management issue, not an etiologic risk factor. (dong2024novelflncvariants pages 4-6, wang2023engineeredcardiactissue pages 1-3)

6. Mechanism and pathophysiology

Causal chains

  1. Troponin pathway: TNNI3/TNNT2 variant → altered troponin–actin–tropomyosin regulation → excessive myofilament Ca²⁺ sensitivity → persistent tension during diastole → impaired relaxation and elevated end-diastolic pressure → atrial dilation, pulmonary venous hypertension, congestion, arrhythmia, and heart failure. Strong Ca²⁺ sensitization tends toward HCM/RCM, whereas reduced sensitivity can produce DCM. (kim2021geneticsofcardiomyopathy pages 4-5, liu2016restrictivecardiomyopathycaused pages 1-2)
  2. FLNC pathway: altered filamin-C structure/splicing → defective Z-disc/intercalated-disc mechanotransduction and sarcomere organization, sometimes impaired autophagic/lysosomal flux → contractile-relaxation uncoupling and increased passive tension → restrictive filling. Patient-specific tissue showed increased calcium-transient decay time, reduced active force, increased passive tension, and slower relaxation. (wang2023engineeredcardiactissue pages 4-7, wang2023engineeredcardiactissue pages 3-4)
  3. Downstream remodeling: persistent pressure and mechanical stress → fibroblast/ECM remodeling and fibrosis → still lower compliance. FLNC is also expressed in fibroblasts; the 2023 cardiomyocyte-only system could not model this non-myocyte contribution. (wang2023engineeredcardiactissue pages 8-9)
  4. Infiltrative/storage phenocopies: extracellular amyloid, intracellular storage, iron, granulomas, or endomyocardial fibrosis → myocardial/endocardial stiffening → the same hemodynamic syndrome through a different upstream mechanism. (kim2021geneticsofcardiomyopathy pages 22-23)

Suggested ontology annotations include GO:0006936 muscle contraction, GO:0060048 cardiac muscle contraction, GO:0055001 muscle-cell development, GO:0007015 actin-filament organization, GO:0006874 intracellular calcium-ion homeostasis, GO:0030198 extracellular-matrix organization, and GO:0048771 tissue remodeling. Principal cells are cardiac muscle cell/cardiomyocyte (CL:0000746) and fibroblast (CL:0000057); endothelial, conduction-system, and immune cells are secondary/context-dependent.

No reproducible RCM-specific bulk transcriptomic, proteomic, metabolomic, lipidomic, single-cell, or spatial signature is clinically validated. The most advanced disease-specific platform is patient-derived iPSC cardiomyocytes combined with CRISPR isogenic controls and 3D engineered cardiac tissue. (wang2023engineeredcardiactissue pages 3-4, wang2023engineeredcardiactissue pages 1-3)

7. Anatomical structures affected

The primary organ is the heart (UBERON:0000948), particularly myocardium (UBERON:0002349) of both ventricles. The left and right atria enlarge secondarily; pulmonary vasculature develops post-capillary hypertension, and liver, kidneys, and peripheral tissues can be affected by congestion or reduced output. Disease is generally bilateral/biventricular rather than lateralized. Relevant subcellular structures include sarcomere (GO:0030017), Z disc (GO:0030018), myofibril (GO:0030016), actin cytoskeleton (GO:0015629), intercalated disc, sarcoplasmic reticulum, lysosome, and autophagosome. (dong2024novelflncvariants pages 1-2, wang2023engineeredcardiactissue pages 3-4)

8. Temporal development

Onset is usually insidious and chronic but ranges from congenital/infantile to late adult. Early disease may show isolated diastolic dysfunction and atrial enlargement with preserved EF. Intermediate disease adds exertional symptoms, congestion, pulmonary hypertension, atrial arrhythmia, and thromboembolic risk. Advanced disease includes low output, progressive systolic dysfunction, ventricular arrhythmia, transplant, or death. Spontaneous durable remission of primary genetic RCM is not established; temporary improvement may follow treatment of a superimposed infection or reversible secondary cause. Childhood onset, severe pulmonary hypertension, and de novo variants warrant early specialist/transplant assessment. (schubert2018theuseof pages 17-21, dong2024novelflncvariants pages 4-6)

9. Inheritance and population

Primary familial RCM is usually autosomal dominant, with age-dependent/incomplete penetrance and markedly variable expressivity. Recessive disease can occur in syndromic/metabolic conditions and rare biallelic cardiomyopathy genotypes. Germline mosaicism is biologically possible after an apparently de novo result but is not quantitatively defined; anticipation is not established. No robust founder allele, carrier-frequency estimate, sex bias, or ancestry-specific prevalence is established for primary RCM. (kim2021geneticsofcardiomyopathy pages 22-23, kim2021geneticsofcardiomyopathy pages 4-5)

RCM constitutes approximately 2.5–5% of pediatric cardiomyopathies, and around 30% of affected children reportedly have a positive family history. Population prevalence and incidence per 100,000 remain undefined. Typical RCM physiology was found in 1.5% of more than 1,200 familial HCM patients, illustrating phenotype overlap rather than general-population prevalence. (schubert2018theuseof pages 17-21, kim2021geneticsofcardiomyopathy pages 4-5)

10. Diagnostics

Clinical workflow

  1. Phenotype: history, three-generation pedigree, examination, ECG/Holter, BNP or NT-proBNP, troponin when injury is suspected, renal/hepatic indices, and echocardiography.
  2. Echocardiography: nondilated ventricles, little/no hypertrophy, severe restrictive filling, low tissue-Doppler velocities, biatrial enlargement, valve regurgitation, pulmonary-pressure estimates, and initially preserved EF. (wang2023engineeredcardiactissue pages 3-4, liu2016restrictivecardiomyopathycaused pages 2-3)
  3. CMR: ventricular volumes/function, atrial size, edema, late gadolinium enhancement, T1/T2 mapping and extracellular volume; especially valuable for amyloid, iron, inflammation, endomyocardial disease, and fibrosis.
  4. Catheterization: confirms elevated filling pressures, restrictive pressure contours, pulmonary vascular resistance, and low output when noninvasive findings are uncertain or transplant assessment requires it.
  5. Biopsy: not routine for every familial case; use when amyloid, myocarditis, storage disease, sarcoid, eosinophilic disease, or another tissue diagnosis would change treatment. Sarcomeric RCM may show myofibrillar disarray but this is not gene-specific. (kim2021geneticsofcardiomyopathy pages 4-5)

The principal differential is constrictive pericarditis, distinguished using tissue Doppler, respiratory ventricular interdependence, CT/CMR pericardial assessment, and catheterization. Other differentials include HCM with restrictive physiology, pulmonary hypertension, valvular disease, congenital heart disease, amyloidosis, Fabry/storage disease, hemochromatosis, sarcoidosis, and endomyocardial fibrosis.

Genetic testing

Use a curated cardiomyopathy panel including at minimum TNNI3, TNNT2, FLNC, MYH7, MYPN, ACTC1, MYBPC3, MYL2, MYL3, TTN, DES, CRYAB, and BAG3, plus phenotype-driven phenocopy genes such as TTR, GLA, GAA, GBA1, and HFE. Trio testing is particularly useful in severe pediatric cases. CNV analysis should accompany sequencing. WES/WGS is reasonable after a negative panel, syndromic presentation, or suspected novel gene; RNA/minigene studies can resolve splice effects, as shown for FLNC c.3962A>T. CMA, karyotype, FISH, repeat-expansion testing, and mtDNA sequencing are phenotype-driven rather than routine. A VUS is not diagnostic and should not direct predictive testing. (dong2024novelflncvariants pages 1-2, dong2024novelflncvariants pages 4-6)

Screen first-degree relatives with history, examination, ECG, and echocardiography; offer cascade testing only after identifying a pathogenic/likely pathogenic familial variant. The completed PCM GENES prospective cohort enrolled 544 participants and used tiered exome analysis to correlate genotype with death/transplant outcomes. (NCT01873963 chunk 1)

11. Outcome and prognosis

RCM has one of the poorest cardiomyopathy prognoses. Nearly 50% of pediatric patients reportedly die or require transplantation within three years. One genetic/overlap cohort had a 56% composite outcome of death, transplantation, or appropriate ICD discharge. Sudden cardiac death, progressive heart failure, atrial and ventricular arrhythmias, thromboembolism, pulmonary hypertension, hepatic congestion, and multiorgan dysfunction are major complications. (schubert2018theuseof pages 17-21, kim2021geneticsofcardiomyopathy pages 4-5)

Adverse prognostic features include early onset, de novo pathogenic variants, worsening symptoms, pulmonary hypertension/high pulmonary vascular resistance, declining EF, fibrosis, arrhythmias, syncope, rising natriuretic peptides, and end-organ dysfunction. Reliable disease-wide 5- or 10-year survival, life expectancy, and standardized quality-of-life statistics are unavailable because cohorts are small and etiologically mixed.

12. Treatment

Current real-world management

  • Congestion: cautious loop diuretics, sometimes mineralocorticoid-receptor antagonists; avoid excessive preload reduction because the stiff ventricle is filling-dependent.
  • Arrhythmias: rhythm/rate management, cardioversion or ablation when appropriate; pacemaker for clinically important conduction disease. ICD decisions are individualized because RCM-specific primary-prevention evidence is sparse.
  • Thromboembolism: anticoagulation for atrial fibrillation, intracardiac thrombus, or other standard indications.
  • Heart-failure drugs: ACE inhibitor/ARB/ARNI, beta blocker, MRA, and SGLT2 inhibitor may be used for conventional indications, hypertension, or systolic dysfunction, but none has proven disease-modifying efficacy in primary RCM with preserved EF.
  • Cause-directed treatment: treat AL/ATTR amyloidosis, Fabry disease, iron overload, sarcoid/eosinophilic inflammation, or storage disease according to the underlying disorder.
  • Transplantation: definitive therapy for refractory primary RCM. Early referral is important; severe pulmonary vascular disease can preclude isolated heart transplant and occasionally necessitate heart–lung transplantation. (schubert2018theuseof pages 17-21, wang2023engineeredcardiactissue pages 1-3)

Suggested NCIT concepts include Diuretic Therapy, Antiarrhythmic Therapy, Anticoagulation Therapy, Pacemaker Implantation, Implantable Cardioverter-Defibrillator Placement, Cardiac Transplantation, Genetic Counseling, and Cardiac Rehabilitation; terminology IDs should be version-validated at ingestion.

Experimental therapy and recent development

Wang et al. screened 2,185 compounds in FLNC-mutant iPSC cardiomyocytes. The PDE3 inhibitor trequinsin reduced calcium-relaxation tau by approximately 50%, reduced passive tension, and improved relaxation/contraction kinetics in engineered tissue; no increased after-depolarization or LDH cytotoxicity was detected under the tested conditions. This is preclinical genotype-specific evidence, not justification for clinical PDE3 therapy; chronic PDE3 inhibition has recognized arrhythmic and mortality concerns. (wang2023engineeredcardiactissue pages 4-7, wang2023engineeredcardiactissue pages 3-4)

Relevant studies

  • NCT01873963, PCM GENES: completed, prospective observational cohort, actual enrollment 544; pediatric DCM/HCM/RCM genotype–phenotype analysis. ClinicalTrials.gov. (NCT01873963 chunk 1)
  • NCT02432092: recruiting family-based Pediatric Cardiomyopathy Mutation Analysis, estimated 300 participants. ClinicalTrials.gov. (NCT02432092 chunk 1)
  • NCT06794710, EARLY-MYO-RARE: posted 27 January 2025, not yet recruiting in the retrieved record; randomized multimodal-imaging/risk-guided management study, estimated 300, including RCM. It is not a genotype-specific RCM drug trial. ClinicalTrials.gov. (NCT06794710 chunk 1)

No approved gene, cell, RNA, or CRISPR therapy for primary RCM was identified, and no RCM-specific pharmacogenomic guideline is established.

13. Prevention

Primary prevention of a de novo or inherited allele is not currently possible. Secondary prevention consists of genetic counseling, cascade testing, serial ECG/echo surveillance, early evaluation of symptoms, and reproductive options such as preimplantation genetic testing or prenatal diagnosis after a familial pathogenic variant is established. Tertiary prevention includes congestion control, arrhythmia and thromboembolism surveillance, avoiding cardiotoxic exposures, vaccination/general infection prevention appropriate to heart-failure patients, and timely transplant referral. There is no RCM-specific vaccine, newborn-screening program, prophylactic drug, or population screening recommendation. (kim2021geneticsofcardiomyopathy pages 22-23, NCT01873963 chunk 1)

14. Other species and natural disease

RCM-like disease occurs clinically in companion animals, but the retrieved evidence did not establish a well-validated naturally occurring breed-specific orthologous genetic RCM suitable for confident VBO/OMIA annotation. There is no zoonotic or transmissible component. Orthologous sarcomeric and FLNC pathways are deeply conserved, which supports engineered mouse models, but experimental models should not be mislabeled as natural veterinary disease.

15. Model organisms and experimental systems

Mouse models

Transgenic mice expressing human-equivalent TNNI3 p.Arg192His (mouse cTnI p.Arg193His) or p.Lys178Glu (mouse p.Lys179Glu) reproduce impaired relaxation and biatrial enlargement without ventricular hypertrophy. The causal mechanism is marked myofibrillar Ca²⁺ hypersensitivity. Crossing p.Arg193His mice with an N-terminally deleted cTnI line that lowers Ca²⁺ sensitivity rescued diastolic dysfunction and the restrictive phenotype, providing target-validation evidence for calcium desensitization. DOI: 10.3389/fphys.2016.00629, published 19 December 2016. (liu2016restrictivecardiomyopathycaused pages 2-3, liu2016restrictivecardiomyopathycaused pages 1-2)

Exact abstract quote: “the deficiency of cTnI or mutations in cTnI … results in diastolic dysfunction (impaired relaxation) due to an increased myofibril sensitivity to calcium.” (liu2016restrictivecardiomyopathycaused pages 1-2)

Human cellular and engineered-tissue model

Patient-derived FLNC c.7416_7418delGAA iPSCs, a CRISPR-corrected isogenic control, a CRISPR knock-in reporter line, and fibrin-based 3D engineered cardiac tissues reproduced reduced active force, sarcomere disorganization, increased passive tension, slowed contraction/relaxation, and abnormal calcium decay. The platform enabled the trequinsin screen and is currently the clearest precision-model implementation for primary RCM. Limitations include immature iPSC cardiomyocytes, short experimental times, a single genotype, and failure to model fibroblast, vascular, immune, neurohumoral, and whole-organ hemodynamic contributions. (wang2023engineeredcardiactissue pages 8-9, wang2023engineeredcardiactissue pages 4-7, wang2023engineeredcardiactissue pages 3-4, wang2023engineeredcardiactissue pages 1-3)

Evidence-quality assessment and knowledge gaps

The strongest evidence consists of human familial segregation/de novo data, functional assays with isogenic controls, and consistent RCM physiology in TNNI3 mice. Most clinical statistics derive from small pediatric or genetically enriched cohorts, not population surveillance. Disease databases may mix primary RCM with metabolic/infiltrative causes; therefore, gene–disease validity should be assessed at the specific etiologic-entity level. Major gaps are population prevalence/incidence, ancestry-specific penetrance, validated modifiers, RCM-specific patient-reported outcomes, prospective risk models, and controlled disease-specific therapy trials. The 2023–2024 FLNC studies materially advance mechanism and variant interpretation but do not yet alter standard treatment. (OpenTargets Search: restrictive cardiomyopathy, dong2024novelflncvariants pages 1-2, wang2023engineeredcardiactissue pages 4-7)

References

  1. (kim2021geneticsofcardiomyopathy pages 22-23): Kyung-Hee Kim and Naveen L. Pereira. Genetics of cardiomyopathy: clinical and mechanistic implications for heart failure. Korean Circulation Journal, 51:797-836, Jul 2021. URL: https://doi.org/10.4070/kcj.2021.0154, doi:10.4070/kcj.2021.0154. This article has 66 citations and is from a peer-reviewed journal.

  2. (schubert2018theuseof pages 17-21): JA Schubert. The use of genetic analyses and functional assays for the interpretation of rare variants in pediatric heart disease. Unknown journal, 2018.

  3. (dong2024novelflncvariants pages 1-2): Rui Dong, Xin Zhou, Haiyan Zhang, Bingyi Shi, Guohua Liu, and Yi Liu. Novel flnc variants in pediatric cardiomyopathy: an insight into disease mechanisms. Human Genomics, Oct 2024. URL: https://doi.org/10.1186/s40246-024-00683-9, doi:10.1186/s40246-024-00683-9. This article has 3 citations and is from a peer-reviewed journal.

  4. (wang2023engineeredcardiactissue pages 1-3): Bryan Z. Wang, Trevor R. Nash, Xiaokan Zhang, Jenny Rao, Laura Abriola, Youngbin Kim, Sergey Zakharov, Michael Kim, Lori J. Luo, Margaretha Morsink, Bohao Liu, Roberta I. Lock, Sharon Fleischer, Manuel A. Tamargo, Michael Bohnen, Carrie L. Welch, Wendy K. Chung, Steven O. Marx, Yulia V. Surovtseva, Gordana Vunjak-Novakovic, and Barry M. Fine. Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery. Cell Reports Medicine, 4:100976, Mar 2023. URL: https://doi.org/10.1016/j.xcrm.2023.100976, doi:10.1016/j.xcrm.2023.100976. This article has 35 citations and is from a peer-reviewed journal.

  5. (OpenTargets Search: restrictive cardiomyopathy): Open Targets Query (restrictive cardiomyopathy, 28 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  6. (NCT02432092 chunk 1): Stephanie Ware. Pediatric Cardiomyopathy Mutation Analysis. Indiana University. 2014. ClinicalTrials.gov Identifier: NCT02432092

  7. (kim2021geneticsofcardiomyopathy pages 4-5): Kyung-Hee Kim and Naveen L. Pereira. Genetics of cardiomyopathy: clinical and mechanistic implications for heart failure. Korean Circulation Journal, 51:797-836, Jul 2021. URL: https://doi.org/10.4070/kcj.2021.0154, doi:10.4070/kcj.2021.0154. This article has 66 citations and is from a peer-reviewed journal.

  8. (dong2024novelflncvariants pages 4-6): Rui Dong, Xin Zhou, Haiyan Zhang, Bingyi Shi, Guohua Liu, and Yi Liu. Novel flnc variants in pediatric cardiomyopathy: an insight into disease mechanisms. Human Genomics, Oct 2024. URL: https://doi.org/10.1186/s40246-024-00683-9, doi:10.1186/s40246-024-00683-9. This article has 3 citations and is from a peer-reviewed journal.

  9. (wang2023engineeredcardiactissue pages 3-4): Bryan Z. Wang, Trevor R. Nash, Xiaokan Zhang, Jenny Rao, Laura Abriola, Youngbin Kim, Sergey Zakharov, Michael Kim, Lori J. Luo, Margaretha Morsink, Bohao Liu, Roberta I. Lock, Sharon Fleischer, Manuel A. Tamargo, Michael Bohnen, Carrie L. Welch, Wendy K. Chung, Steven O. Marx, Yulia V. Surovtseva, Gordana Vunjak-Novakovic, and Barry M. Fine. Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery. Cell Reports Medicine, 4:100976, Mar 2023. URL: https://doi.org/10.1016/j.xcrm.2023.100976, doi:10.1016/j.xcrm.2023.100976. This article has 35 citations and is from a peer-reviewed journal.

  10. (wang2023engineeredcardiactissue pages 4-7): Bryan Z. Wang, Trevor R. Nash, Xiaokan Zhang, Jenny Rao, Laura Abriola, Youngbin Kim, Sergey Zakharov, Michael Kim, Lori J. Luo, Margaretha Morsink, Bohao Liu, Roberta I. Lock, Sharon Fleischer, Manuel A. Tamargo, Michael Bohnen, Carrie L. Welch, Wendy K. Chung, Steven O. Marx, Yulia V. Surovtseva, Gordana Vunjak-Novakovic, and Barry M. Fine. Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery. Cell Reports Medicine, 4:100976, Mar 2023. URL: https://doi.org/10.1016/j.xcrm.2023.100976, doi:10.1016/j.xcrm.2023.100976. This article has 35 citations and is from a peer-reviewed journal.

  11. (liu2016restrictivecardiomyopathycaused pages 2-3): Xiaoyan Liu, Lei Zhang, Daniel Pacciulli, Jianquan Zhao, Changlong Nan, Wen Shen, Junjun Quan, Jie Tian, and Xupei Huang. Restrictive cardiomyopathy caused by troponin mutations: application of disease animal models in translational studies. Frontiers in Physiology, Dec 2016. URL: https://doi.org/10.3389/fphys.2016.00629, doi:10.3389/fphys.2016.00629. This article has 26 citations.

  12. (liu2016restrictivecardiomyopathycaused pages 1-2): Xiaoyan Liu, Lei Zhang, Daniel Pacciulli, Jianquan Zhao, Changlong Nan, Wen Shen, Junjun Quan, Jie Tian, and Xupei Huang. Restrictive cardiomyopathy caused by troponin mutations: application of disease animal models in translational studies. Frontiers in Physiology, Dec 2016. URL: https://doi.org/10.3389/fphys.2016.00629, doi:10.3389/fphys.2016.00629. This article has 26 citations.

  13. (NCT01873963 chunk 1): Steve Lipshultz. Genotype-Phenotype Associations in Pediatric Cardiomyopathy (PCM GENES). Wayne State University. 2013. ClinicalTrials.gov Identifier: NCT01873963

  14. (NCT06794710 chunk 1): Early Identification and Treatment of Rare Cardiomyopathy Cohorts. RenJi Hospital. 2025. ClinicalTrials.gov Identifier: NCT06794710

  15. (wang2023engineeredcardiactissue pages 8-9): Bryan Z. Wang, Trevor R. Nash, Xiaokan Zhang, Jenny Rao, Laura Abriola, Youngbin Kim, Sergey Zakharov, Michael Kim, Lori J. Luo, Margaretha Morsink, Bohao Liu, Roberta I. Lock, Sharon Fleischer, Manuel A. Tamargo, Michael Bohnen, Carrie L. Welch, Wendy K. Chung, Steven O. Marx, Yulia V. Surovtseva, Gordana Vunjak-Novakovic, and Barry M. Fine. Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery. Cell Reports Medicine, 4:100976, Mar 2023. URL: https://doi.org/10.1016/j.xcrm.2023.100976, doi:10.1016/j.xcrm.2023.100976. This article has 35 citations and is from a peer-reviewed journal.

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