Cardiomyopathy Maladaptive Remodeling Module

Toxicology Module cardiomyopathy_maladaptive_remodeling 76 disorders Pathograph 5

A conserved cardiac pathophysiology module representing the maladaptive remodeling pathway that underlies structural and contractile cardiomyopathy (HP:0001638, MONDO:0004994) across dilated, hypertrophic, and secondary forms. A primary cardiomyocyte insult — an inherited sarcomere or cytoskeletal protein defect, or an acquired hemodynamic, metabolic, toxic, or inflammatory stress — impairs contractile performance. The failing myocardium activates neurohormonal axes (renin-angiotensin-aldosterone and sympathetic) that initially compensate but chronically drive myocyte hypertrophy, cardiomyocyte loss, cardiac fibroblast activation, interstitial fibrosis, and chamber dilation or wall thickening. This adverse ventricular remodeling produces progressive systolic and/or diastolic contractile dysfunction, culminating in structural cardiac impairment and heart failure. This module is distinct from electrical/channelopathy disease (covered by cardiac_ion_channel_repolarization); it captures the structural/contractile final common pathway. Individual disorder entries declare conformance via conforms_to, substituting disorder-specific primary lesions (e.g., MYH7/MYBPC3 sarcomere variants in hypertrophic cardiomyopathy, TTN truncations or LMNA/desmosomal defects in dilated cardiomyopathy, infiltrative or toxic injury in secondary cardiomyopathy) while preserving the conserved chain.

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Pathophysiology Nodes

5 shared nodes are defined in this module.

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Cell Types

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Biological Processes

Sarcomere Organization GO:0045214 ⚠ ABNORMAL Muscle Contraction GO:0006936 ⚠ ABNORMAL Response to Angiotensin GO:1990776 ↑ INCREASED Cardiac Muscle Hypertrophy GO:0003300 ↑ INCREASED Cardiac Muscle Hypertrophy in Response to Stress GO:0014898 ↑ INCREASED Extracellular Matrix Organization GO:0030198 ↑ INCREASED Cardiomyocyte Apoptosis GO:0010659 ↑ INCREASED Heart Contraction GO:0060047 ↓ DECREASED Heart Contraction GO:0060047 ⚠ ABNORMAL

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should include the corresponding cell types, biological processes, and causal edges, specialized to their etiologic context. Key disorder-specific substitutions: the trigger node substitutes the disorder's primary lesion (e.g., MYH7/MYBPC3/TNNT2 sarcomere variants in HCM, TTN/LMNA/desmosomal variants in DCM, amyloid infiltration in cardiac amyloidosis, anthracycline or alcohol toxicity in secondary cardiomyopathy). This module covers the structural/contractile remodeling pathway and is deliberately kept distinct from the electrical/arrhythmia mechanism captured by the cardiac_ion_channel_repolarization module.

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Used By Disorder Entries

ALPK3-Related Hypertrophic Cardiomyopathy via ALPK3 Loss of Function → Primary Cardiomyocyte Insult , Ventricular Hypertrophy → Ventricular Remodeling

Anthracycline-Induced Cardiomyopathy via Anthracycline-TOP2B-DNA Complex Formation → Primary Cardiomyocyte Insult , Ventricular Remodeling , Reduced Ventricular Contractile Function → Progressive Contractile Dysfunction

arrhythmogenic right ventricular cardiomyopathy via Fibrofatty myocardial replacement → Ventricular Remodeling

Becker Muscular Dystrophy via Dystrophin-Deficient Cardiomyocyte Injury → Primary Cardiomyocyte Insult , Left Ventricular Impairment and Dilated Cardiomyopathy → Structural Cardiac Impairment and Heart Failure

Cardiac Sarcoidosis via Progressive Ventricular Dysfunction and Heart Failure → Structural Cardiac Impairment and Heart Failure

Cardiomyopathy Dilated 100 via Left Ventricular Dilation and Systolic Dysfunction → Structural Cardiac Impairment and Heart Failure

Cardiomyopathy-Hypotonia-Lactic Acidosis Syndrome via Cardiomyocyte and Skeletal Muscle Bioenergetic Stress → Primary Cardiomyocyte Insult , Cardiomyocyte Hypertrophic Remodeling → Ventricular Remodeling

Carvajal Syndrome via Contractile and Electrical Dysfunction → Progressive Contractile Dysfunction

Chagas disease via Ventricular remodeling and dilated cardiomyopathy → Ventricular Remodeling

Dilated Cardiomyopathy via Myocardial Fibrosis → Ventricular Remodeling

Dilated Cardiomyopathy 1A via LMNA Variant and Nuclear Lamina Assembly Defect → Primary Cardiomyocyte Insult , Cardiomyocyte Loss and Myocardial Fibrosis → Ventricular Remodeling , Left Ventricular Dilation and Systolic Dysfunction → Progressive Contractile Dysfunction , Progressive Heart Failure and End-Stage Disease → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1AA via Alpha-Actinin-2 Z-Disc Dysfunction → Primary Cardiomyocyte Insult , Neurohormonal Activation , Adverse Ventricular Remodeling → Ventricular Remodeling , Left Ventricular Dilation and Systolic Dysfunction → Progressive Contractile Dysfunction , Heart Failure and Sudden Cardiac Death → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1B via Impaired Myocardial Contractility → Progressive Contractile Dysfunction , Left Ventricular Dilation and Systolic Dysfunction → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1BB via Biventricular Remodeling and Chamber Dilation → Ventricular Remodeling , Progressive Contractile Dysfunction and Heart Failure → Progressive Contractile Dysfunction

Dilated Cardiomyopathy 1C via LDB3 Heterozygous Missense Variant → Primary Cardiomyocyte Insult , Left Ventricular Dilation and Systolic Dysfunction → Ventricular Remodeling

Dilated Cardiomyopathy 1CC via Nexilin Loss of Function → Primary Cardiomyocyte Insult , Impaired Cardiomyocyte Force Generation → Progressive Contractile Dysfunction , Left Ventricular Dilation and Systolic Dysfunction → Ventricular Remodeling , Heart Failure → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1D via TNNT2 Variant in Cardiac Troponin T → Primary Cardiomyocyte Insult , Ventricular Dilation and Systolic Dysfunction → Ventricular Remodeling , Heart Failure → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1DD via RBM20 Loss-of-Function Variant in the RS Domain → Primary Cardiomyocyte Insult , Ventricular Dilation and Systolic Dysfunction → Ventricular Remodeling , Heart Failure and Malignant Ventricular Arrhythmia → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1E via SCN5A Missense Variant in the Cardiac Sodium Channel → Primary Cardiomyocyte Insult , Ventricular Dilation and Systolic Dysfunction → Ventricular Remodeling , Heart Failure and Atrial Fibrillation → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1FF via Heterozygous TNNI3 Variant Altering Cardiac Troponin I → Primary Cardiomyocyte Insult , Reduced Cardiomyocyte Contractility and Systolic Calcium Transient → Progressive Contractile Dysfunction , Adverse Ventricular Remodeling → Ventricular Remodeling , Left Ventricular Dilation and Systolic Failure → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1G via TTN Truncating Variant in the A-Band → Primary Cardiomyocyte Insult , Ventricular Dilation and Systolic Dysfunction → Ventricular Remodeling , Heart Failure and Arrhythmic Risk → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1HH via BAG3 Loss-of-Function Variant → Primary Cardiomyocyte Insult , Ventricular Dilation and Systolic Dysfunction → Ventricular Remodeling , Heart Failure → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1I via DES Variant in the Desmin Intermediate Filament → Primary Cardiomyocyte Insult , Ventricular Dilation and Systolic Dysfunction → Ventricular Remodeling , Heart Failure → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1II via Cardiomyocyte Sarcomeric Stress-Protection Deficit → Primary Cardiomyocyte Insult , Adverse Ventricular Remodeling and Myocardial Fibrosis → Ventricular Remodeling , Left Ventricular Dilation and Systolic Dysfunction → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1J via EYA4 Heterozygous Truncating Variant → Primary Cardiomyocyte Insult , Adverse Ventricular Remodeling → Ventricular Remodeling , Progressive Systolic Dysfunction → Progressive Contractile Dysfunction

Dilated Cardiomyopathy 1JJ via Loss of Laminin-Integrin Binding at the Cardiac Basement Membrane → Primary Cardiomyocyte Insult , Neurohormonal Activation , Adverse Ventricular Remodeling → Ventricular Remodeling , Left Ventricular Dilation and Systolic Dysfunction → Progressive Contractile Dysfunction , Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1M via Heterozygous CSRP3 Missense Variant → Primary Cardiomyocyte Insult , Left Ventricular Dilation and Systolic Dysfunction → Ventricular Remodeling , Heart Failure → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1NN via RAF1 Variant Altering Kinase Activity → Primary Cardiomyocyte Insult , Ventricular Dilation and Systolic Dysfunction → Ventricular Remodeling , Heart Failure → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1O via Failure of Metabolic-Electrical Adaptation Under Cardiac Stress → Primary Cardiomyocyte Insult , Calcineurin-Dependent Maladaptive Remodeling → Ventricular Remodeling , Left Ventricular Dilation and Systolic Dysfunction → Progressive Contractile Dysfunction , Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1P via Ventricular Dilatation and Pump Failure → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1R via ACTC1 Missense Variant in Cardiac Alpha-Actin → Primary Cardiomyocyte Insult , Left Ventricular Dilation and Systolic Dysfunction → Progressive Contractile Dysfunction

Dilated Cardiomyopathy 1S via MYH7 Missense Variant Causing Diminished Contractile Function → Primary Cardiomyocyte Insult , Ventricular Dilation and Systolic Dysfunction → Ventricular Remodeling , Heart Failure → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1U via PSEN1 Asp333Gly Missense Variant in Cardiomyocytes → Primary Cardiomyocyte Insult , Ventricular Remodeling and Chamber Dilatation → Ventricular Remodeling , Progressive Systolic Dysfunction and Heart Failure → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1V via PSEN2 Ser130Leu Missense Variant in Cardiomyocytes → Primary Cardiomyocyte Insult , Ventricular Remodeling and Chamber Dilatation → Ventricular Remodeling , Systolic Dysfunction and Heart Failure → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1W via Metavinculin Tail Variant Altering Actin Cross-Linking → Primary Cardiomyocyte Insult , VCL Predicted Loss-of-Function Allele → Primary Cardiomyocyte Insult , Ventricular Dilation and Systolic Dysfunction → Ventricular Remodeling , Heart Failure with Reduced Ejection Fraction → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1X via Weakened Sarcolemma-to-Basement-Membrane Linkage in Cardiomyocytes → Primary Cardiomyocyte Insult , Ventricular Remodeling and Myocardial Fibrosis → Ventricular Remodeling , Dilated Cardiomyopathy with Systolic Failure → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 1Z via Cardiac Troponin C Variant and Thin-Filament Regulatory Defect → Primary Cardiomyocyte Insult , Neurohormonal Activation , Adverse Ventricular Remodeling → Ventricular Remodeling , Left Ventricular Dilation and Systolic Dysfunction → Progressive Contractile Dysfunction , Heart Failure, Ventricular Arrhythmia and Sudden Cardiac Death → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 2A via Biallelic TNNI3 Loss of Function → Primary Cardiomyocyte Insult , Left Ventricular Dilation and Systolic Failure → Progressive Contractile Dysfunction

Dilated Cardiomyopathy 2B via Left Ventricular Dilation and Remodeling → Ventricular Remodeling , Chronic Systolic Heart Failure → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy 2G via Biallelic LMOD2 Loss-of-Function Variant → Primary Cardiomyocyte Insult , Ventricular Dilation → Ventricular Remodeling , Heart Failure → Structural Cardiac Impairment and Heart Failure

Dilated Cardiomyopathy with Woolly Hair, Keratoderma, and Tooth Agenesis via Progressive Ventricular Dilation and Systolic Dysfunction → Progressive Contractile Dysfunction

DSP Cardiomyopathy via Desmoplakin Haploinsufficiency — Desmosomal Disruption → Primary Cardiomyocyte Insult , Fibrofatty Myocardial Replacement → Ventricular Remodeling

FLNC-Related Dilated Cardiomyopathy via FLNC Truncating Variant Causing Filamin C Haploinsufficiency → Primary Cardiomyocyte Insult , Myocardial Fibrosis and Ventricular Dilation → Ventricular Remodeling , Sudden Cardiac Death and End-Stage Heart Failure → Structural Cardiac Impairment and Heart Failure

Hypertensive Heart Disease via Left Ventricular Hypertrophy → Ventricular Remodeling , Cardiac Fibrosis → Ventricular Remodeling

Hypertrophic Cardiomyopathy 1 via MYH7 Missense Variant in Beta-Cardiac Myosin Heavy Chain → Primary Cardiomyocyte Insult , Ventricular Hypertrophy, Myocyte Disarray and Fibrosis → Ventricular Remodeling , Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk → Structural Cardiac Impairment and Heart Failure

Hypertrophic Cardiomyopathy 10 via MYL2 Variant in Ventricular Regulatory Myosin Light Chain → Primary Cardiomyocyte Insult , Ventricular Hypertrophy, Myocyte Disarray and Fibrosis → Ventricular Remodeling , Diastolic Dysfunction, Heart Failure and Arrhythmic Risk → Structural Cardiac Impairment and Heart Failure

Hypertrophic Cardiomyopathy 11 via ACTC1 Missense Variant in Alpha-Cardiac Actin → Primary Cardiomyocyte Insult , Ventricular Hypertrophy, Myocyte Disarray and Fibrosis → Ventricular Remodeling , Diastolic Dysfunction, Heart Failure and Arrhythmic Risk → Structural Cardiac Impairment and Heart Failure

Hypertrophic Cardiomyopathy 12 via CSRP3 Germline Variant → Primary Cardiomyocyte Insult , Maladaptive Hypertrophic Remodeling → Ventricular Remodeling

Hypertrophic Cardiomyopathy 13 via TNNC1 Missense Variant in Cardiac Troponin C → Primary Cardiomyocyte Insult , Ventricular Hypertrophy, Myocyte Disarray and Fibrosis → Ventricular Remodeling , Diastolic Dysfunction, Heart Failure and Arrhythmic Risk → Structural Cardiac Impairment and Heart Failure

Hypertrophic Cardiomyopathy 14 via MYH6 Missense Variant in Alpha-Myosin Heavy Chain → Primary Cardiomyocyte Insult , Maladaptive Ventricular Remodeling → Ventricular Remodeling , Progressive Contractile Dysfunction and Progression to Dilation → Progressive Contractile Dysfunction

Hypertrophic Cardiomyopathy 18 via Cardiomyocyte Hypertrophic Remodeling → Ventricular Remodeling

Hypertrophic Cardiomyopathy 2 via Cardiac Troponin T Thin Filament Regulatory Defect → Primary Cardiomyocyte Insult , Cardiomyocyte Hypertrophy with Disarray and Fibrosis, Often Disproportionately Mild → Ventricular Remodeling , Diastolic Dysfunction → Progressive Contractile Dysfunction , Progressive Heart Failure → Structural Cardiac Impairment and Heart Failure

Hypertrophic Cardiomyopathy 20 via Cardiac Z-Disc Destabilization Under Mechanical Load → Primary Cardiomyocyte Insult , Cardiomyocyte Hypertrophy, Sarcomeric Disarray, and Myocardial Fibrosis → Ventricular Remodeling

Hypertrophic Cardiomyopathy 21 via Ventricular Dilation and End-Stage Heart Failure → Structural Cardiac Impairment and Heart Failure

Hypertrophic Cardiomyopathy 25 via Telethonin Z-Disc Titin-Capping and Stretch-Sensor Perturbation → Primary Cardiomyocyte Insult , Ventricular Remodeling with Sigmoidal Septal Geometry → Ventricular Remodeling , Left Ventricular Hypertrophy with Diastolic Dysfunction → Progressive Contractile Dysfunction , Progressive Heart Failure → Structural Cardiac Impairment and Heart Failure

Hypertrophic Cardiomyopathy 26 via Filamin C Z-Disc Cross-Linking Defect → Primary Cardiomyocyte Insult , Cardiomyocyte Hypertrophy and Adverse Ventricular Remodeling → Ventricular Remodeling , Impaired Diastolic Relaxation and Myocardial Stiffening → Progressive Contractile Dysfunction , Heart Failure and Sudden Cardiac Death → Structural Cardiac Impairment and Heart Failure

Hypertrophic Cardiomyopathy 28 via Sarcomere Disorganization and Impaired Myofibril Maintenance → Primary Cardiomyocyte Insult , Maladaptive Hypertrophic Remodeling → Ventricular Remodeling

Hypertrophic Cardiomyopathy 3 via Alpha-Tropomyosin Thin Filament Regulatory Defect → Primary Cardiomyocyte Insult , Cardiomyocyte Hypertrophy with Myofiber Disarray and Interstitial Fibrosis → Ventricular Remodeling , Diastolic Dysfunction and Left Ventricular Outflow Tract Obstruction → Progressive Contractile Dysfunction , Progressive Heart Failure → Structural Cardiac Impairment and Heart Failure

Hypertrophic Cardiomyopathy 4 via MYBPC3 Truncating Variant and Premature Termination Codon Generation → Primary Cardiomyocyte Insult , Ventricular Hypertrophy, Disarray and Fibrosis → Ventricular Remodeling , Diastolic Dysfunction, Heart Failure and Arrhythmic Risk → Structural Cardiac Impairment and Heart Failure

Hypertrophic Cardiomyopathy 7 via Cardiac Troponin I Inhibitory Dysfunction → Primary Cardiomyocyte Insult , Cardiomyocyte Hypertrophy, Myocyte Disarray and Interstitial Fibrosis → Ventricular Remodeling , Left Ventricular Hypertrophy with Diastolic Dysfunction → Progressive Contractile Dysfunction , Heart Failure and Sudden Cardiac Death → Structural Cardiac Impairment and Heart Failure

Hypertrophic Cardiomyopathy 8 via MYL3 Essential Light Chain Variant — Altered Lever-Arm and Actin Contact → Primary Cardiomyocyte Insult , Cardiomyocyte Hypertrophy, Myocardial Stiffness and Fibrosis → Ventricular Remodeling , Diastolic Dysfunction and Restrictive Physiology → Progressive Contractile Dysfunction

Hypomyelinating Leukodystrophy 23 via Cardiac and Hepatic Involvement → Structural Cardiac Impairment and Heart Failure

Left Ventricular Noncompaction 10 via MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion → Primary Cardiomyocyte Insult , Neonatal Structural Cardiac Failure → Structural Cardiac Impairment and Heart Failure

Left Ventricular Noncompaction 8 via Left Ventricular Dilation and Systolic Dysfunction → Ventricular Remodeling , Congestive Heart Failure → Structural Cardiac Impairment and Heart Failure

Long-Olsen-Distelmaier Syndrome via Ventricular Dilation and Systolic Failure → Progressive Contractile Dysfunction

Malonic Aciduria via Cardiomyocyte Energy Substrate Deficit → Primary Cardiomyocyte Insult , Cardiomyopathy and Ventricular Dysfunction → Structural Cardiac Impairment and Heart Failure

MRPL44 Deficiency via Cardiomyocyte Contractile Element Loss → Primary Cardiomyocyte Insult

Myocardial Infarction via Cardiac Fibrosis and Ventricular Remodeling → Ventricular Remodeling

Myocarditis via Cardiomyocyte Necrosis and Contractile Failure → Primary Cardiomyocyte Insult , Post-Inflammatory Ventricular Remodeling → Ventricular Remodeling , Inflammatory Dilated Cardiomyopathy → Structural Cardiac Impairment and Heart Failure

Myofibrillar Myopathy via Cardiomyocyte Z-Disc Aggregate Pathology → Primary Cardiomyocyte Insult

MYPN-Related Cardiomyopathy via MYPN Variant Altering Myopalladin → Primary Cardiomyocyte Insult , Impaired Contractile and Passive Mechanics → Progressive Contractile Dysfunction , Neurohormonal Activation , Ventricular Remodeling , Structural Cardiac Impairment and Heart Failure

Naxos disease via Fibrofatty myocardial replacement → Ventricular Remodeling

PRKAG2 Cardiac Syndrome via Progressive Contractile Dysfunction , Advanced Heart Failure and End-Stage Cardiomyopathy → Structural Cardiac Impairment and Heart Failure

Restrictive Cardiomyopathy via Sarcomeric or Cytoskeletal Variant with Increased Myofilament Tension → Primary Cardiomyocyte Insult , Myocardial Fibrosis and Ventricular Remodeling → Ventricular Remodeling , Diastolic Heart Failure and Arrhythmic Risk → Structural Cardiac Impairment and Heart Failure

Taurine transporter deficiency via Cardiomyocyte Atrophy and Ventricular Remodeling → Ventricular Remodeling

X-linked Dilated Cardiomyopathy via Sarcolemmal Fragility and Contraction-Induced Cardiomyocyte Injury → Primary Cardiomyocyte Insult , Left Ventricular Dilation and Systolic Heart Failure → Structural Cardiac Impairment and Heart Failure

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.

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Pathophysiology

Primary Cardiomyocyte Insult

trigger

The cascade is initiated by an insult to cardiomyocyte contractile function. In inherited cardiomyopathies this is a variant in a sarcomeric or cytoskeletal protein gene that perturbs sarcomere assembly and force generation; in acquired and secondary cardiomyopathies it is a hemodynamic (pressure or volume overload), metabolic, toxic, or inflammatory stress that impairs myocyte contraction. The specific lesion varies, but the downstream response converges on impaired contractile performance that the myocardium must compensate for.

Cardiomyocyte CL:0000746

Sarcomere Organization GO:0045214 ⚠ ABNORMAL Muscle Contraction GO:0006936 ⚠ ABNORMAL

Used by disorders

ALPK3-Related Hypertrophic Cardiomyopathy as ALPK3 Loss of Function

Anthracycline-Induced Cardiomyopathy as Anthracycline-TOP2B-DNA Complex Formation

Becker Muscular Dystrophy as Dystrophin-Deficient Cardiomyocyte Injury

Cardiomyopathy-Hypotonia-Lactic Acidosis Syndrome as Cardiomyocyte and Skeletal Muscle Bioenergetic Stress

Dilated Cardiomyopathy 1A as LMNA Variant and Nuclear Lamina Assembly Defect

Dilated Cardiomyopathy 1AA as Alpha-Actinin-2 Z-Disc Dysfunction

Dilated Cardiomyopathy 1C as LDB3 Heterozygous Missense Variant

Dilated Cardiomyopathy 1CC as Nexilin Loss of Function

Dilated Cardiomyopathy 1D as TNNT2 Variant in Cardiac Troponin T

Dilated Cardiomyopathy 1DD as RBM20 Loss-of-Function Variant in the RS Domain

Dilated Cardiomyopathy 1E as SCN5A Missense Variant in the Cardiac Sodium Channel

Dilated Cardiomyopathy 1FF as Heterozygous TNNI3 Variant Altering Cardiac Troponin I

Dilated Cardiomyopathy 1G as TTN Truncating Variant in the A-Band

Dilated Cardiomyopathy 1HH as BAG3 Loss-of-Function Variant

Dilated Cardiomyopathy 1I as DES Variant in the Desmin Intermediate Filament

Dilated Cardiomyopathy 1II as Cardiomyocyte Sarcomeric Stress-Protection Deficit

Dilated Cardiomyopathy 1J as EYA4 Heterozygous Truncating Variant

Dilated Cardiomyopathy 1JJ as Loss of Laminin-Integrin Binding at the Cardiac Basement Membrane

Dilated Cardiomyopathy 1M as Heterozygous CSRP3 Missense Variant

Dilated Cardiomyopathy 1NN as RAF1 Variant Altering Kinase Activity

Dilated Cardiomyopathy 1O as Failure of Metabolic-Electrical Adaptation Under Cardiac Stress

Dilated Cardiomyopathy 1R as ACTC1 Missense Variant in Cardiac Alpha-Actin

Dilated Cardiomyopathy 1S as MYH7 Missense Variant Causing Diminished Contractile Function

Dilated Cardiomyopathy 1U as PSEN1 Asp333Gly Missense Variant in Cardiomyocytes

Dilated Cardiomyopathy 1V as PSEN2 Ser130Leu Missense Variant in Cardiomyocytes

Dilated Cardiomyopathy 1W as Metavinculin Tail Variant Altering Actin Cross-Linking

Dilated Cardiomyopathy 1W as VCL Predicted Loss-of-Function Allele

Dilated Cardiomyopathy 1X as Weakened Sarcolemma-to-Basement-Membrane Linkage in Cardiomyocytes

Dilated Cardiomyopathy 1Z as Cardiac Troponin C Variant and Thin-Filament Regulatory Defect

Dilated Cardiomyopathy 2A as Biallelic TNNI3 Loss of Function

Dilated Cardiomyopathy 2G as Biallelic LMOD2 Loss-of-Function Variant

DSP Cardiomyopathy as Desmoplakin Haploinsufficiency — Desmosomal Disruption

FLNC-Related Dilated Cardiomyopathy as FLNC Truncating Variant Causing Filamin C Haploinsufficiency

Hypertrophic Cardiomyopathy 1 as MYH7 Missense Variant in Beta-Cardiac Myosin Heavy Chain

Hypertrophic Cardiomyopathy 10 as MYL2 Variant in Ventricular Regulatory Myosin Light Chain

Hypertrophic Cardiomyopathy 11 as ACTC1 Missense Variant in Alpha-Cardiac Actin

Hypertrophic Cardiomyopathy 12 as CSRP3 Germline Variant

Hypertrophic Cardiomyopathy 13 as TNNC1 Missense Variant in Cardiac Troponin C

Hypertrophic Cardiomyopathy 14 as MYH6 Missense Variant in Alpha-Myosin Heavy Chain

Hypertrophic Cardiomyopathy 2 as Cardiac Troponin T Thin Filament Regulatory Defect

Hypertrophic Cardiomyopathy 20 as Cardiac Z-Disc Destabilization Under Mechanical Load

Hypertrophic Cardiomyopathy 25 as Telethonin Z-Disc Titin-Capping and Stretch-Sensor Perturbation

Hypertrophic Cardiomyopathy 26 as Filamin C Z-Disc Cross-Linking Defect

Hypertrophic Cardiomyopathy 28 as Sarcomere Disorganization and Impaired Myofibril Maintenance

Hypertrophic Cardiomyopathy 3 as Alpha-Tropomyosin Thin Filament Regulatory Defect

Hypertrophic Cardiomyopathy 4 as MYBPC3 Truncating Variant and Premature Termination Codon Generation

Hypertrophic Cardiomyopathy 7 as Cardiac Troponin I Inhibitory Dysfunction

Hypertrophic Cardiomyopathy 8 as MYL3 Essential Light Chain Variant — Altered Lever-Arm and Actin Contact

Left Ventricular Noncompaction 10 as MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion

Malonic Aciduria as Cardiomyocyte Energy Substrate Deficit

MRPL44 Deficiency as Cardiomyocyte Contractile Element Loss

Myocarditis as Cardiomyocyte Necrosis and Contractile Failure

Myofibrillar Myopathy as Cardiomyocyte Z-Disc Aggregate Pathology

MYPN-Related Cardiomyopathy as MYPN Variant Altering Myopalladin

Restrictive Cardiomyopathy as Sarcomeric or Cytoskeletal Variant with Increased Myofilament Tension

X-linked Dilated Cardiomyopathy as Sarcolemmal Fragility and Contraction-Induced Cardiomyocyte Injury

Downstream

Neurohormonal Activation

Show evidence (2 references)

PMID:37060436 SUPPORT Other

"The genomics era has identified and validated many genetic causes of hypertrophic and dilated cardiomyopathies."

Establishes that genetic defects in sarcomere proteins are validated primary causes of the two major cardiomyopathy phenotypes, supporting the sarcomere/contractile lesion as the initiating insult. Evidence source is OTHER because this is a review synthesizing genomic and mechanistic data.

PMID:31073128 SUPPORT Other

"Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or..."

Documents the diversity of primary insults — genetic sarcomere/desmosome defects and acquired inflammatory, toxic, endocrine, and autoimmune injuries — that converge on the same cardiomyopathy phenotype. Evidence source is OTHER because this is a Nature Reviews Disease Primers review.

Neurohormonal Activation

amplifier

Impaired contractile performance and the resulting fall in cardiac output trigger compensatory activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system. While initially adaptive, chronic neurohormonal activation becomes maladaptive, directly stimulating cardiomyocyte hypertrophy and promoting fibrosis and apoptosis. This axis is the principal amplifier that converts an initial contractile deficit into progressive structural remodeling, and it is the target of the foundational heart-failure pharmacotherapies (ACE inhibitors, angiotensin receptor blockers, beta-blockers, mineralocorticoid receptor antagonists).

Response to Angiotensin GO:1990776 ↑ INCREASED Cardiac Muscle Hypertrophy GO:0003300 ↑ INCREASED

Used by disorders

Dilated Cardiomyopathy 1AA

Dilated Cardiomyopathy 1JJ

Dilated Cardiomyopathy 1Z

MYPN-Related Cardiomyopathy

Downstream

Ventricular Remodeling

Show evidence (1 reference)

PMID:25445411 SUPPORT Other

"The systemic as well as the tissue RAAS are also dedicated to promote tissue remodeling, particularly relevant after damage, when chronic activation may configure as a maladaptive response, leading to fibrosis, hypertrophy and apoptosis, and organ dysfunction."

Directly states that chronic renin-angiotensin-aldosterone system activation is a maladaptive response driving cardiac fibrosis, hypertrophy, apoptosis, and organ dysfunction, defining the amplifier role of neurohormonal activation. Evidence source is OTHER because this is a review synthesizing clinical and mechanistic data.

Ventricular Remodeling

central effector

Sustained insult and neurohormonal drive produce adverse structural remodeling of the ventricle. This central effector step combines cardiomyocyte hypertrophy and progressive cardiomyocyte loss (necrosis and apoptosis) with activation of resident cardiac fibroblasts into myofibroblasts that deposit excess collagen, producing interstitial fibrosis. The net geometric result is chamber dilation with wall thinning (dilated pattern) or wall thickening with reduced cavity size (hypertrophic pattern). Although the dominant geometry differs across disorders, expansion of the cardiac fibroblast population and interstitial matrix deposition are conserved features of the remodeling myocardium.

Cardiac Fibroblast CL:0002548

Cardiac Muscle Hypertrophy in Response to Stress GO:0014898 ↑ INCREASED Extracellular Matrix Organization GO:0030198 ↑ INCREASED Cardiomyocyte Apoptosis GO:0010659 ↑ INCREASED

Used by disorders

ALPK3-Related Hypertrophic Cardiomyopathy as Ventricular Hypertrophy

Anthracycline-Induced Cardiomyopathy

arrhythmogenic right ventricular cardiomyopathy as Fibrofatty myocardial replacement

Cardiomyopathy-Hypotonia-Lactic Acidosis Syndrome as Cardiomyocyte Hypertrophic Remodeling

Chagas disease as Ventricular remodeling and dilated cardiomyopathy

Dilated Cardiomyopathy as Myocardial Fibrosis

Dilated Cardiomyopathy 1A as Cardiomyocyte Loss and Myocardial Fibrosis

Dilated Cardiomyopathy 1AA as Adverse Ventricular Remodeling

Dilated Cardiomyopathy 1BB as Biventricular Remodeling and Chamber Dilation

Dilated Cardiomyopathy 1C as Left Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1CC as Left Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1D as Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1DD as Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1E as Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1FF as Adverse Ventricular Remodeling

Dilated Cardiomyopathy 1G as Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1HH as Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1I as Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1II as Adverse Ventricular Remodeling and Myocardial Fibrosis

Dilated Cardiomyopathy 1J as Adverse Ventricular Remodeling

Dilated Cardiomyopathy 1JJ as Adverse Ventricular Remodeling

Dilated Cardiomyopathy 1M as Left Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1NN as Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1O as Calcineurin-Dependent Maladaptive Remodeling

Dilated Cardiomyopathy 1S as Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1U as Ventricular Remodeling and Chamber Dilatation

Dilated Cardiomyopathy 1V as Ventricular Remodeling and Chamber Dilatation

Dilated Cardiomyopathy 1W as Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1X as Ventricular Remodeling and Myocardial Fibrosis

Dilated Cardiomyopathy 1Z as Adverse Ventricular Remodeling

Dilated Cardiomyopathy 2B as Left Ventricular Dilation and Remodeling

Dilated Cardiomyopathy 2G as Ventricular Dilation

DSP Cardiomyopathy as Fibrofatty Myocardial Replacement

FLNC-Related Dilated Cardiomyopathy as Myocardial Fibrosis and Ventricular Dilation

Hypertensive Heart Disease as Cardiac Fibrosis

Hypertensive Heart Disease as Left Ventricular Hypertrophy

Hypertrophic Cardiomyopathy 1 as Ventricular Hypertrophy, Myocyte Disarray and Fibrosis

Hypertrophic Cardiomyopathy 10 as Ventricular Hypertrophy, Myocyte Disarray and Fibrosis

Hypertrophic Cardiomyopathy 11 as Ventricular Hypertrophy, Myocyte Disarray and Fibrosis

Hypertrophic Cardiomyopathy 12 as Maladaptive Hypertrophic Remodeling

Hypertrophic Cardiomyopathy 13 as Ventricular Hypertrophy, Myocyte Disarray and Fibrosis

Hypertrophic Cardiomyopathy 14 as Maladaptive Ventricular Remodeling

Hypertrophic Cardiomyopathy 18 as Cardiomyocyte Hypertrophic Remodeling

Hypertrophic Cardiomyopathy 2 as Cardiomyocyte Hypertrophy with Disarray and Fibrosis, Often Disproportionately Mild

Hypertrophic Cardiomyopathy 20 as Cardiomyocyte Hypertrophy, Sarcomeric Disarray, and Myocardial Fibrosis

Hypertrophic Cardiomyopathy 25 as Ventricular Remodeling with Sigmoidal Septal Geometry

Hypertrophic Cardiomyopathy 26 as Cardiomyocyte Hypertrophy and Adverse Ventricular Remodeling

Hypertrophic Cardiomyopathy 28 as Maladaptive Hypertrophic Remodeling

Hypertrophic Cardiomyopathy 3 as Cardiomyocyte Hypertrophy with Myofiber Disarray and Interstitial Fibrosis

Hypertrophic Cardiomyopathy 4 as Ventricular Hypertrophy, Disarray and Fibrosis

Hypertrophic Cardiomyopathy 7 as Cardiomyocyte Hypertrophy, Myocyte Disarray and Interstitial Fibrosis

Hypertrophic Cardiomyopathy 8 as Cardiomyocyte Hypertrophy, Myocardial Stiffness and Fibrosis

Left Ventricular Noncompaction 8 as Left Ventricular Dilation and Systolic Dysfunction

Myocardial Infarction as Cardiac Fibrosis and Ventricular Remodeling

Myocarditis as Post-Inflammatory Ventricular Remodeling

MYPN-Related Cardiomyopathy

Naxos disease as Fibrofatty myocardial replacement

Restrictive Cardiomyopathy as Myocardial Fibrosis and Ventricular Remodeling

Taurine transporter deficiency as Cardiomyocyte Atrophy and Ventricular Remodeling

Downstream

Progressive Contractile Dysfunction

Show evidence (2 references)

PMID:22752727 SUPPORT Other

"The pathophysiological basis of heart failure is cardiac remodeling, a process that comprises structural and functional changes including cardiomyocyte proliferation, hypertrophy, necrosis, apoptosis, autophagy, interstitial fibrosis, contractile dysfunction and ventricular dilatation."

Defines cardiac remodeling as the pathophysiological basis of heart failure and enumerates its conserved components — hypertrophy, cardiomyocyte loss, interstitial fibrosis, contractile dysfunction, and ventricular dilatation — which are the substance of this node. Evidence source is OTHER because this is a mechanistic review.

PMID:28957531 SUPPORT Other

"Right ventricular pressure overload in PH is associated with the expansion of the fibroblast population, myofibroblast activation, and secretion of extracellular matrix proteins."

Establishes cardiac fibroblast expansion, myofibroblast activation, and extracellular matrix secretion as the cellular machinery of interstitial remodeling in the stressed ventricle, supporting the cardiac fibroblast and ECM organization assignments. Evidence source is OTHER because this is a review synthesizing multiple study types.

Progressive Contractile Dysfunction

effector

Adverse remodeling degrades pump function. Myocyte loss, fibrosis, and altered chamber geometry impair systolic shortening (reduced ejection fraction in dilated and end-stage disease) and/or diastolic relaxation and filling (stiffened, hypertrophied, or infiltrated myocardium). Increased wall stress further depresses contractile properties of surviving myocardium, creating a self-reinforcing cycle of declining performance that underlies the clinical progression of cardiomyopathy.

Cardiomyocyte CL:0000746

Heart Contraction GO:0060047 ↓ DECREASED

Used by disorders

Anthracycline-Induced Cardiomyopathy as Reduced Ventricular Contractile Function

Carvajal Syndrome as Contractile and Electrical Dysfunction

Dilated Cardiomyopathy 1A as Left Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1AA as Left Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1B as Impaired Myocardial Contractility

Dilated Cardiomyopathy 1BB as Progressive Contractile Dysfunction and Heart Failure

Dilated Cardiomyopathy 1CC as Impaired Cardiomyocyte Force Generation

Dilated Cardiomyopathy 1FF as Reduced Cardiomyocyte Contractility and Systolic Calcium Transient

Dilated Cardiomyopathy 1J as Progressive Systolic Dysfunction

Dilated Cardiomyopathy 1JJ as Left Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1O as Left Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1R as Left Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1Z as Left Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 2A as Left Ventricular Dilation and Systolic Failure

Dilated Cardiomyopathy with Woolly Hair, Keratoderma, and Tooth Agenesis as Progressive Ventricular Dilation and Systolic Dysfunction

Hypertrophic Cardiomyopathy 14 as Progressive Contractile Dysfunction and Progression to Dilation

Hypertrophic Cardiomyopathy 2 as Diastolic Dysfunction

Hypertrophic Cardiomyopathy 25 as Left Ventricular Hypertrophy with Diastolic Dysfunction

Hypertrophic Cardiomyopathy 26 as Impaired Diastolic Relaxation and Myocardial Stiffening

Hypertrophic Cardiomyopathy 3 as Diastolic Dysfunction and Left Ventricular Outflow Tract Obstruction

Hypertrophic Cardiomyopathy 7 as Left Ventricular Hypertrophy with Diastolic Dysfunction

Hypertrophic Cardiomyopathy 8 as Diastolic Dysfunction and Restrictive Physiology

Long-Olsen-Distelmaier Syndrome as Ventricular Dilation and Systolic Failure

MYPN-Related Cardiomyopathy as Impaired Contractile and Passive Mechanics

PRKAG2 Cardiac Syndrome

Downstream

Structural Cardiac Impairment and Heart Failure

Show evidence (2 references)

PMID:8829958 SUPPORT Other

"Left ventricular remodelling after acute myocardial infarction, through long-term left ventricular chamber dilatation and increased wall stress can result in alteration of the contractile properties of the non-infarct zone, impairment of the systolic and diastolic performances of the left..."

Directly links ventricular remodeling and increased wall stress to impairment of both systolic and diastolic performance progressing to heart failure, supporting the progressive contractile dysfunction step. Evidence source is OTHER because this is a review.

PMID:31073128 SUPPORT Other

"As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM."

Confirms that the cardiomyopathy process culminates in impaired contractility for which heart-failure management is the standard treatment. Evidence source is OTHER because this is a review.

Structural Cardiac Impairment and Heart Failure

consequence

The end state is cardiomyopathy: a structurally and functionally abnormal myocardium that can no longer meet circulatory demand, manifesting as heart failure with its attendant morbidity and mortality and risk of progression to end-stage disease requiring mechanical support or transplantation. While the dominant geometry (dilated, hypertrophic, restrictive) and the triggering lesion differ across disorders, the convergence on maladaptive structural remodeling and impaired pump function defines the shared cardiomyopathy phenotype.

Heart Contraction GO:0060047 ⚠ ABNORMAL

Used by disorders

Becker Muscular Dystrophy as Left Ventricular Impairment and Dilated Cardiomyopathy

Cardiac Sarcoidosis as Progressive Ventricular Dysfunction and Heart Failure

Cardiomyopathy Dilated 100 as Left Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1A as Progressive Heart Failure and End-Stage Disease

Dilated Cardiomyopathy 1AA as Heart Failure and Sudden Cardiac Death

Dilated Cardiomyopathy 1B as Left Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1CC as Heart Failure

Dilated Cardiomyopathy 1D as Heart Failure

Dilated Cardiomyopathy 1DD as Heart Failure and Malignant Ventricular Arrhythmia

Dilated Cardiomyopathy 1E as Heart Failure and Atrial Fibrillation

Dilated Cardiomyopathy 1FF as Left Ventricular Dilation and Systolic Failure

Dilated Cardiomyopathy 1G as Heart Failure and Arrhythmic Risk

Dilated Cardiomyopathy 1HH as Heart Failure

Dilated Cardiomyopathy 1I as Heart Failure

Dilated Cardiomyopathy 1II as Left Ventricular Dilation and Systolic Dysfunction

Dilated Cardiomyopathy 1JJ

Dilated Cardiomyopathy 1M as Heart Failure

Dilated Cardiomyopathy 1NN as Heart Failure

Dilated Cardiomyopathy 1O

Dilated Cardiomyopathy 1P as Ventricular Dilatation and Pump Failure

Dilated Cardiomyopathy 1S as Heart Failure

Dilated Cardiomyopathy 1U as Progressive Systolic Dysfunction and Heart Failure

Dilated Cardiomyopathy 1V as Systolic Dysfunction and Heart Failure

Dilated Cardiomyopathy 1W as Heart Failure with Reduced Ejection Fraction

Dilated Cardiomyopathy 1X as Dilated Cardiomyopathy with Systolic Failure

Dilated Cardiomyopathy 1Z as Heart Failure, Ventricular Arrhythmia and Sudden Cardiac Death

Dilated Cardiomyopathy 2B as Chronic Systolic Heart Failure

Dilated Cardiomyopathy 2G as Heart Failure

FLNC-Related Dilated Cardiomyopathy as Sudden Cardiac Death and End-Stage Heart Failure

Hypertrophic Cardiomyopathy 1 as Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk

Hypertrophic Cardiomyopathy 10 as Diastolic Dysfunction, Heart Failure and Arrhythmic Risk

Hypertrophic Cardiomyopathy 11 as Diastolic Dysfunction, Heart Failure and Arrhythmic Risk

Hypertrophic Cardiomyopathy 13 as Diastolic Dysfunction, Heart Failure and Arrhythmic Risk

Hypertrophic Cardiomyopathy 2 as Progressive Heart Failure

Hypertrophic Cardiomyopathy 21 as Ventricular Dilation and End-Stage Heart Failure

Hypertrophic Cardiomyopathy 25 as Progressive Heart Failure

Hypertrophic Cardiomyopathy 26 as Heart Failure and Sudden Cardiac Death

Hypertrophic Cardiomyopathy 3 as Progressive Heart Failure

Hypertrophic Cardiomyopathy 4 as Diastolic Dysfunction, Heart Failure and Arrhythmic Risk

Hypertrophic Cardiomyopathy 7 as Heart Failure and Sudden Cardiac Death

Hypomyelinating Leukodystrophy 23 as Cardiac and Hepatic Involvement

Left Ventricular Noncompaction 10 as Neonatal Structural Cardiac Failure

Left Ventricular Noncompaction 8 as Congestive Heart Failure

Malonic Aciduria as Cardiomyopathy and Ventricular Dysfunction

Myocarditis as Inflammatory Dilated Cardiomyopathy

MYPN-Related Cardiomyopathy

PRKAG2 Cardiac Syndrome as Advanced Heart Failure and End-Stage Cardiomyopathy

Restrictive Cardiomyopathy as Diastolic Heart Failure and Arrhythmic Risk

X-linked Dilated Cardiomyopathy as Left Ventricular Dilation and Systolic Heart Failure

Show evidence (2 references)

PMID:22752727 SUPPORT Other

Anchors the consequence node by identifying cardiac remodeling as the pathophysiological basis of heart failure, the clinical endpoint of the module. Evidence source is OTHER because this is a mechanistic review.

PMID:8829958 SUPPORT Other

"Recent observations of changes in left ventricular chamber dilatation and left ventricular wall hypertrophy occurring over the course of time after acute myocardial infarction allow better definition of the subset of patients who are at risk of progressive left ventricular dysfunction and..."

Describes chamber dilatation and wall hypertrophy as the structural changes underlying progressive ventricular dysfunction and congestive heart failure, the defining structural-functional impairment of this consequence node. Evidence source is OTHER because this is a review.