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)

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

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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