What is the pathophysiology of cardiomyopathies?

Pathophysiology of Cardiomyopathies

Cardiomyopathies represent genetically-driven structural and functional myocardial disorders characterized by distinct molecular mechanisms: sarcomeric protein dysfunction causing hypertrophic cardiomyopathy (HCM), cytoskeletal and desmosomal protein defects leading to dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM), with each resulting in progressive ventricular dysfunction, arrhythmias, and heart failure through impaired force generation, transmission, or cellular integrity. 1

Hypertrophic Cardiomyopathy (HCM)

Genetic Basis and Molecular Mechanisms

• Sarcomeric gene mutations are the primary cause, with MYH7 (beta-myosin heavy chain) and MYBPC3 (myosin-binding protein C) accounting for 70% of genetically-identified cases 1
• Additional sarcomeric genes (TNNI3, TNNT2, TPM1, MYL2, MYL3, ACTC1) each contribute 1-5% of cases, with over 1,500 variants identified, most being "private" (family-specific) 1
• Mutant sarcomere genes trigger myocardial hypertrophy and fibrosis, resulting in a small, stiff ventricle with impaired systolic and diastolic performance despite preserved left ventricular ejection fraction 1
• Approximately 40% of HCM patients have no identifiable genetic etiology or affected family members, suggesting oligogenic or multifactorial inheritance 1

Core Pathophysiologic Mechanisms

Dynamic Left Ventricular Outflow Tract Obstruction (LVOTO):

• Present in a significant proportion of patients, caused by septal hypertrophy narrowing the LVOT and creating abnormal blood flow vectors that dynamically displace mitral valve leaflets anteriorly 1
• Systolic anterior motion (SAM) of the mitral valve results from anatomic alterations including longer leaflets and anterior displacement of papillary muscles 1
• LVOTO increases LV systolic pressure, exacerbating left ventricular hypertrophy, myocardial ischemia, and prolonging ventricular relaxation 1
• Obstruction is considered present if peak LVOT gradient ≥30 mm Hg, with gradients ≥50 mm Hg capable of causing symptoms 1

Diastolic Dysfunction:

• Results from altered ventricular load with high intracavitary pressures, impaired LV compliance from hypertrophy and fibrosis, altered energetics, microvascular ischemia, and delayed inactivation from abnormal intracellular calcium reuptake 1, 2
• Impaired relaxation creates greater dependency on atrial systole for ventricular filling, leading to poor tolerance of atrial fibrillation 1
• Severe hypertrophy increases chamber stiffness, further contributing to elevated filling pressures 2

Mitral Regurgitation:

• Occurs secondarily from LVOTO when SAM leads to loss of leaflet coaptation, or from primary leaflet abnormalities 1
• Contributes significantly to dyspnea symptoms 1

Myocardial Ischemia:

• Results from abnormal intramural coronary arteries responsible for small vessel ischemia, which appear to have no direct association with sarcomere variants 1

Metabolic and Energetic Abnormalities:

• Impaired force production associated with inefficient ATP utilization is a crucial disease mechanism 1, 3

Dilated Cardiomyopathy (DCM)

Genetic Architecture

• Familial inheritance occurs in 30-50% of cases, with autosomal dominant being the predominant pattern; X-linked, autosomal recessive, and mitochondrial inheritance are less common 1
• Genetic testing identifies a causative mutation in approximately 30-40% of patients 1

Molecular Mechanisms by Gene Category

Dystrophin-Associated Proteins (X-linked):

• Dystrophin gene mutations cause X-linked cardiomyopathy (XLCM), Duchenne and Becker muscular dystrophy 1, 4
• Dystrophin binds actin at the N-terminus and α-dystroglycan at the C-terminus, forming the dystrophin-associated protein complex (including β-dystroglycan, sarcoglycans, syntrophins, dystrobrevins) 1
• This complex interacts with α-laminin and the extracellular matrix; mechanical stress plays a significant role in age-dependent dysfunction 1
• Tafazzin gene mutations cause Barth syndrome, presenting with LV dysfunction, neutropenia, 3-methylglutaconic aciduria, and cardiolipin deficiency with mitochondrial dysfunction 1

Cytoskeletal and Nuclear Proteins (Autosomal Dominant):

• LMNA gene mutations (encoding A-type nuclear lamins) cause DCM associated with conduction system disease, typically presenting in the third decade with progressive conduction abnormalities and late-onset DCM out of proportion to conduction disease 1
• Mutated cytoskeletal and nuclear transporter proteins alter force transmission or disrupt nuclear function, resulting in cell death 3

Sarcomeric Proteins:

• Pathogenic desmosomal variants are identified in 3.5% of DCM cases, indicating overlap with ACM genetics 1
• Different defects in the same sarcomeric protein can result in either HCM or DCM, depending on the specific mutation 3

Pathophysiologic Consequences

• Defective force transmission from cytoskeletal protein mutations leads to progressive ventricular dilatation 5, 3
• Myocardial energy deficits occur from mutations in ATP regulatory protein genes 5
• Abnormal calcium homeostasis results from altered calcium availability and myofibrillar calcium sensitivity 5

Arrhythmogenic Cardiomyopathy (ACM)

Genetic Basis

Desmosomal Genes (Majority):

• Approximately 50% of ACM patients have one or more desmosomal pathogenic variants 1
• Heterozygous truncating variants in PKP2 (plakophilin-2) are most common, particularly in arrhythmogenic right ventricular cardiomyopathy (ARVC) 1
• Cohorts including arrhythmogenic left ventricular cardiomyopathy (ALVC) are enriched for DSP (desmoplakin) and DSG2 (desmoglein-2) variants 1
• Loss-of-function variants are prevalent with strongest evidence for pathogenicity based on significant over-representation in ACM cases versus population databases 1

Non-Desmosomal Genes (Minority):

• TMEM43 p.S358L founder variant common in Newfoundland 1
• PLN p.R14del (phospholamban) predominantly found in the Netherlands 1
• Area composita genes: CDH2 (cadherin-2) and CTNNA3 (α-T-catenin) reported in several families 1
• FLNC (Filamin C) truncating variants cause highly arrhythmogenic ALVC 1
• Novel genes: TJP1 (tight junction protein 1), ANK2 (ankyrin-B) 1

Pathologic Features and Clinical Manifestations

• Fibrofatty myocardial replacement, apoptosis, and inflammation are hallmark pathologic features 1
• Prevalence of 1/5000 with frequent sustained ventricular arrhythmias (average 10.6%/year) 1
• Progressive ventricular dysfunction with deterioration in right ventricular fractional area change averaging 0.7%/year 1
• High risk of sudden cardiac death, with typical presentation between ages 12-50 years with arrhythmia-associated symptoms 1
• Desmosomal protein defects disrupt cell-junction integrity, altering force transmission and leading to cell death with fibrofatty replacement 3

Common Pathophysiologic Themes Across Cardiomyopathies

Progressive Heart Failure

• All cardiomyopathies lead to progressive heart failure with significant morbidity and mortality through distinct but converging mechanisms 6
• Environmental factors (obesity, hypertension, sleep apnea, diabetes) interact with genetic predisposition, particularly in HCM, to worsen prognosis 1

Arrhythmogenic Substrate

• Structural abnormalities (hypertrophy, fibrosis, fibrofatty replacement) create substrate for both atrial and ventricular arrhythmias across all cardiomyopathy types 1, 4
• Sudden cardiac death risk varies by cardiomyopathy type but represents a major concern requiring risk stratification 1

Modifier Genes and Environmental Factors

• Genetic background, modifier genes of the renin-angiotensin, adrenergic, and endothelin systems contribute to wide clinical variability 3
• Gene-environment interactions determine age of onset, severity, and clinical course 1