Cardiomyopathies: overview

Article written and reviewed by Dr Luca Moretti

Cardiomyopathies are a heterogeneous group of diseases in which the myocardium develops structural or functional abnormalities that cannot be fully explained by coronary artery disease, pressure or volume overload, valvular disease or congenital heart disease of sufficient severity. This definition does not imply that the heart is the only organ involved, nor that every disease originates exclusively in the cardiomyocyte. Some forms arise from genetic variants that alter the sarcomere, cytoskeleton, desmosome, nuclear envelope or energy metabolism; others represent the cardiac manifestation of infiltrative, inflammatory, toxic, endocrine, nutritional or neuromuscular processes. The term therefore identifies a clinical myocardial problem from which a systematic etiologic investigation should begin.

The same cause can produce different phenotypes and, conversely, the same phenotype can be the common outcome of many causes. A variant in a desmosomal gene may present as predominantly right-sided, left-sided or biventricular disease, whereas a hypertrophied left ventricle may reflect sarcomeric cardiomyopathy, Fabry disease, amyloidosis, a glycogen storage disease or a response to loading conditions. This heterogeneity prevents morphological classification from being converted into a final diagnosis. The phenotype describes what the heart shows at a given time; the etiology clarifies, when possible, which process produced it and what consequences follow for prognosis, treatment and the family.

Clinical expression ranges from complete absence of symptoms to advanced heart failure, and from incidental discovery of an electrocardiographic abnormality to sudden cardiac death. Between these extremes are preclinical phases in which abnormalities of rhythm, myocardial deformation or tissue characterization appear before conventional criteria for an overt phenotype are met. Assessment therefore cannot be limited to an anatomical snapshot: it must integrate function, tissue, electrical features, family history and evolution over time. The possibility that disease precedes visible dilation or hypertrophy is particularly important in arrhythmogenic forms and in certain genotypes associated with early scar.

The classification of cardiomyopathies provides the language used to describe this spectrum, but clinical practice requires a further step: reconstructing the pathway linking finding, mechanism, cause and risk. This pathway includes personal and family history, electrocardiography, multimodality imaging, rhythm monitoring, functional testing, laboratory investigations and, when indicated, genetics, nuclear medicine, biopsy or other targeted investigations. The useful result is not an isolated label, but a diagnosis precise enough to guide concrete decisions.

Contemporary management is therefore longitudinal and family-centered. An apparently stable patient may develop ventricular dysfunction, atrial fibrillation, ventricular arrhythmias or extracardiac progression over time; a relative with initially normal tests may express disease years later because of age-dependent penetrance. Surveillance should be proportionate to the phenotype, genotype, disease stage and modifiable exposures. In this setting, centers with integrated expertise in imaging, cardiovascular genetics, electrophysiology and heart failure help avoid both premature reassurance and excessive diagnosis and restriction.

Cardiac phenotypes and major disease groups

Hypertrophic cardiomyopathy is recognized when ventricular wall thickness exceeds what can be explained by loading conditions. Hypertrophy may be asymmetric septal, apical, concentric or midventricular and may or may not be associated with dynamic outflow tract obstruction. Clinical significance does not depend only on wall thickness in millimeters: sarcomeric disarray, microvascular ischemia, fibrosis, impaired diastolic function and abnormalities of the mitral apparatus contribute in different proportions to symptoms and risk. The presence of hypertrophy also requires distinction between sarcomeric disease and potentially treatable phenocopies.

Dilated cardiomyopathy combines left ventricular, and sometimes biventricular, dilation with systolic dysfunction not explained by sufficient loading conditions or coronary artery disease. Dilation, however, represents a stage rather than a universal requirement throughout the disease course: some diseases begin with hypokinesia, conduction disturbances or arrhythmias and only later remodel the cavity. The phenotype may arise from variants in TTN, LMNA, FLNC, DSP and many other genes, but also from myocarditis, alcohol, drugs, tachyarrhythmias, pregnancy or nutritional abnormalities. Distinguishing genetic, acquired and multifactorial forms affects both prognosis and the extent of family assessment.

Non-dilated left ventricular cardiomyopathy includes non-ischemic scar or fatty replacement of the left ventricle, or isolated global hypokinesia, in the absence of dilation. Introduction of this phenotype recognizes that the older dilated cardiomyopathy category did not adequately describe early stages and predominantly arrhythmic forms. Cardiac magnetic resonance has a central role because it can reveal tissue injury that may precede global loss of function. The term does not automatically assign a cause and must be completed by integrating scar distribution, electrocardiography, arrhythmias, family history and genetics.

Arrhythmogenic cardiomyopathy identifies a spectrum in which fibrous or fibrofatty replacement and electrical instability may involve mainly the right ventricle, the left ventricle or both. Classic right-dominant forms show regional or global dilation, dyskinesia and ventricular tachycardias with morphology consistent with a right-sided origin; left-sided forms may instead show lateral T-wave inversion, low voltages, ectopy of left ventricular origin and subepicardial or mid-wall late gadolinium enhancement. In some genotypes, intense exercise accelerates penetrance and progression, making exercise prescription a therapeutic component rather than a generic recommendation.

Restrictive cardiomyopathy is characterized by restrictive filling physiology in the presence of normal or reduced ventricular volumes, atrial dilation and normal wall thickness. The latter feature distinguishes the ESC morphological phenotype from infiltrative diseases with increased wall thickness, which can produce restrictive physiology but are described according to the observed cardiac phenotype and specific etiology. Restriction results from reduced distensibility and causes a rapid rise in diastolic pressures with small increases in volume. Right ventricular involvement, pulmonary hypertension and systemic congestion may dominate the clinical picture even when left ventricular ejection fraction is preserved.

Alongside the major phenotypes, ventricular hypertrabeculation is described as a morphological trait, whereas isolated right ventricular dysfunction is a functional trait; both require contextual interpretation. Prominent trabeculation may occur in healthy individuals, athletes, pregnancy, anemia or other states of increased preload and does not automatically equal noncompaction cardiomyopathy. Conversely, when associated with dysfunction, scar, arrhythmias, neuromuscular disease or familial segregation, it may be part of a broader pathological process. This distinction prevents highly sensitive imaging criteria from turning an anatomical variant into a diagnosis without adequate clinical significance.

Etiology, genetics and mechanisms of myocardial injury

Genetic cardiomyopathies do not depend on a single type of cellular abnormality. Variants in sarcomeric genes alter force generation, energy consumption and calcium regulation; desmosomal variants impair adhesion between cardiomyocytes exposed to mechanical stress; defects of the cytoskeleton and nuclear envelope alter force transmission and nuclear responses; lysosomal, mitochondrial and glycogen disorders interfere with degradation, energy production or substrate accumulation. These mechanisms do not remain confined to the initially affected protein, but activate secondary pathways of inflammation, cell death, fibrosis and remodeling that ultimately converge in partially overlapping clinical phenotypes.

Inheritance is often autosomal dominant, but autosomal recessive, X-linked, mitochondrial and de novo forms are also possible. A pathogenic variant does not predict age at onset, severity or a specific trajectory with certainty, because penetrance and expressivity depend on age, biological sex, polygenic background, comorbidities and exposures. Even within the same family, an older carrier with a mild phenotype and a young relative with arrhythmias or heart failure may coexist. Genetic counseling must therefore distinguish the risk of transmission from the probability and severity of clinical expression.

Genetic testing is most informative when it arises from accurate phenotypic characterization and uses genes with a robust association with the suspected disease. Identification of a pathogenic or likely pathogenic variant can confirm the etiology, guide surveillance, modify risk stratification in specific genotypes and enable cascade testing in relatives. A variant of uncertain significance, by contrast, should not be used for predictive diagnosis or to exclude a relative from follow-up. Variant classification is dynamic and requires periodic reassessment in light of new clinical, functional and population evidence.

Acquired causes include myocarditis, chronic alcohol exposure, anthracyclines and other cardiotoxins, persistent tachycardias, endocrine diseases, nutritional deficiencies and peripartum conditions. Causality must be demonstrated cautiously, because the mere presence of an exposure does not prove that it explains the entire phenotype. In many patients the environmental insult acts on a genetic predisposition, lowering the threshold required for clinically overt disease. This model is particularly plausible in cardiomyopathies associated with pregnancy, alcohol, chemotherapy and myocarditis, in which a proportion of patients carry variants in genes already implicated in inherited forms.

Infiltrative cardiomyopathies result from deposition or infiltration of myocardial tissue and require distinct diagnostic pathways. In amyloidosis, extracellular fibril deposition alters mechanics, microcirculation and conduction; in sarcoidosis, granulomas and scar create an inflammatory and arrhythmic substrate; in iron overload, intracellular accumulation damages membranes, mitochondria and electrical function. Identifying the cause is essential because therapy is not the same as nonspecific heart failure treatment and may modify the natural history of the systemic disease.

Metabolic and storage forms and neuromuscular cardiomyopathies show particularly clearly that the cardiac phenotype is only part of the diagnosis. Neuropathy, muscle weakness, hearing loss, renal abnormalities, angiokeratomas, conduction disturbances or a childhood history of hypotonia may provide decisive clues. Extracardiac assessment is not an optional addition, but the means by which diseases with specific therapies, anesthetic implications or a need for multiorgan surveillance are recognized.

Clinical manifestations and modes of presentation

Dyspnea is a common but pathophysiologically heterogeneous manifestation. It may reflect reduced cardiac output during exercise, elevated filling pressures, mitral or tricuspid regurgitation, dynamic obstruction, chronotropic incompetence, pulmonary hypertension or deconditioning. Its severity does not necessarily track ejection fraction, because a small hypertrophied ventricle may retain apparently normal global systolic function despite severe hemodynamic limitation. Defining the mechanism of dyspnea is essential to avoid indiscriminate treatment and to interpret echocardiography, exercise testing and biomarkers correctly.

Palpitations, presyncope and syncope require rhythm-oriented assessment but should not automatically be attributed to an arrhythmia. Ectopy, nonsustained ventricular tachycardia, atrial fibrillation, atrioventricular block and sinus node dysfunction can all occur in cardiomyopathies; however, exertional hypotension, dynamic obstruction, reduced output reserve and neurally mediated mechanisms are frequent alternatives. The temporal relationship between symptom and tracing is often decisive and may require prolonged monitoring. Unexplained syncope also carries different prognostic weight according to phenotype, age and the context in which it occurs.

Chest pain may result from microvascular ischemia, increased myocardial mass, wall stress, outflow tract obstruction or inflammation. Coexisting epicardial coronary artery disease remains possible and should be evaluated according to age, risk profile and symptom characteristics, without assuming that cardiomyopathy always explains it. In inflammatory forms, pain may accompany increased troponin and subepicardial abnormalities on magnetic resonance; in hypertrophic forms it may occur during exertion even in the absence of coronary stenoses. Correct attribution changes both therapy and prognostic interpretation.

Heart failure may present with left-sided, right-sided or biventricular congestion and with reduced, mildly reduced or preserved ejection fraction. Orthopnea, edema, ascites, jugular venous distension and reduced perfusion identify a clinical stage but do not clarify the underlying etiology. In restrictive and infiltrative forms, congestion may be disproportionate to ventricular size; in dilated forms, functional mitral regurgitation and low output often predominate; in hypertrophic cardiomyopathy, diastolic stiffness and obstruction may precede any systolic dysfunction by many years. The hemodynamic phenotype should therefore be interpreted together with the morphological and tissue phenotype.

The first manifestation may be extracardiac or familial. An early conduction disturbance, elevated creatine kinase, neuropathy, unexplained renal failure or a history of sudden death during exercise may point toward diagnoses that echocardiography alone does not suggest. Apparent seizures, single-vehicle crashes and unexplained drownings also deserve attention in the family history because they may conceal arrhythmic syncope. A pedigree extending through at least three generations can reveal clustering of different phenotypes that a generic question about "family heart disease" would miss.

Age modifies both the probability of different causes and the way disease is expressed. In neonates and children, inborn errors of metabolism, syndromes, neuromuscular diseases and severe sarcomeric forms are more prominent; in adults, genetic phenotypes with late penetrance, exposures and comorbidities emerge more often; in older adults, ATTR amyloidosis and overlap with hypertension, valvular disease and coronary artery disease become more common. Interpretation should avoid two opposite errors: considering every finding in an older person a consequence of age, or considering genetic disease impossible simply because diagnosis is late.

Diagnostic pathway and multiparametric characterization

Diagnosis begins by defining the phenotype and verifying that more common conditions do not fully explain it. History, physical examination, electrocardiography and echocardiography constitute the first level, but none of these elements is self-sufficient. The electrocardiogram may reveal involvement disproportionate to imaging through conduction block, low voltages, deep T waves or ectopy; echocardiography defines dimensions, wall thickness, global and regional function, valves, gradients and pressures. Discordance among findings should not be eliminated by choosing the apparently most convincing test, because it often represents an etiologic clue.

Cardiac magnetic resonance complements anatomical assessment with tissue characterization that distinguishes ischemic from non-ischemic scar, edema, infiltration and expansion of extracellular volume. The distribution and amount of late gadolinium enhancement may suggest specific etiologies and provide prognostic information, but they are not equivalent to histologic findings and do not have identical meaning in every disease. Native T1 and T2 sequences, mapping and iron assessment broaden diagnostic capability, while technical quality and clinical context remain essential to avoid overinterpretation. In device carriers and patients with renal impairment, the protocol should be individualized.

Electrocardiographic monitoring documents the frequency and complexity of arrhythmias, but the required duration depends on the clinical question. A one- or two-day Holter may be adequate to quantify frequent ectopy, whereas rare symptoms require prolonged patches, external monitors or implantable loop recorders. Exercise testing assesses functional capacity, blood pressure response, arrhythmias and provoked gradients; cardiopulmonary exercise testing adds integrated measurements of oxygen consumption, ventilatory efficiency and circulatory reserve. These data contribute to risk stratification, exercise prescription and assessment of advanced disease.

Laboratory investigations should be guided by the phenotype rather than reduced to an invariant panel. Troponin and natriuretic peptides quantify components of injury and hemodynamic stress, while electrolytes, renal, hepatic and thyroid function, blood count and iron studies identify aggravating factors or alternative diagnoses. Serum and urine immunofixation with free light chains is essential when amyloidosis is suspected; alpha-galactosidase A and lyso-Gb3, iron studies, metabolic tests, autoimmunity and serologies are selected according to clinical clues. An isolated biomarker rarely establishes the diagnosis, but it may reveal a discrepancy that directs the correct pathway.

Endomyocardial biopsy is reserved for scenarios in which histologic diagnosis can change a therapeutic decision and cannot be obtained by less invasive means. Fulminant or rapidly progressive myocarditis, suspected giant cell myocarditis, selected sarcoidosis, undefined storage diseases and some cardiotoxicities are possible settings to be assessed in expert centers. Yield depends on disease distribution, the number and location of samples, and the use of appropriate histology, immunohistochemistry, electron microscopy and molecular analyses. A negative sample does not exclude a focal process and should not be interpreted without comparison with imaging and the clinical picture.

The final diagnosis should be expressed in layers: phenotype, etiology when known, functional stage, extracardiac involvement and risk profile. This formulation is more useful than a single label because it allows only the layer that changes over time to be updated. A patient may carry the same genotype while progressing from a preclinical phase to non-dilated scar and later to dysfunction; another may retain the same phenotype while genetic reclassification clarifies the cause. Periodic reassessment is therefore not repetition, but an integral part of the diagnostic process.

Family, follow-up and prevention of complications

When the phenotype or history suggests inherited disease, the proband should undergo genetic counseling before and after testing. The pre-test phase clarifies possible results, limitations, implications for relatives and the risk of uncertain findings; the post-test phase translates variant classification into a clinical plan. If a causal variant is identified, cascade testing can distinguish relatives who carry it from those who did not inherit that specific variant. Non-carriers can generally be released from surveillance related to that variant, provided that the proband's molecular diagnosis is robust and there are no other independent clinical findings.

In the absence of an identified variant, first-degree relatives are followed clinically at intervals adapted to age, familial phenotype and development of symptoms. A normal examination does not eliminate future risk when penetrance is age dependent. Electrocardiography and echocardiography form the basis, while magnetic resonance and rhythm monitoring are added when the family genotype, borderline findings or symptoms require them. In children, frequency should account for possible acceleration during growth and puberty while avoiding unnecessarily invasive testing.

Follow-up of the affected patient assesses symptoms, biventricular function, valves, pressures, rhythm and new risk markers. Intervals cannot be uniform: stable low-risk disease requires a different cadence from an arrhythmogenic genotype, recent scar progression or a phase of heart failure. Intercurrent events such as pregnancy, chemotherapy, infections, increased sports activity or onset of tachyarrhythmias may justify earlier reassessment. Surveillance is effective only when linked to predefined decisions and not when reduced to ritual repetition of tests.

Physical activity should be prescribed through shared risk assessment, avoiding both indiscriminate prohibition and generic reassurance. Regular aerobic exercise of appropriate intensity improves functional capacity and general health in many patients, whereas high-intensity competition or large volumes of endurance exercise may be unfavorable in specific arrhythmogenic phenotypes. Symptoms, arrhythmias, ventricular function, obstruction, history of syncope, genotype and type of sport all contribute to the decision. The prescription should be reassessed when disease, training or the patient's goals change.

Prevention of sudden cardiac death requires phenotype-specific tools. Relevant data include previous cardiac arrest, sustained ventricular tachycardia, suspicious syncope, ventricular function, scar, aneurysms, nonsustained ventricular tachycardia burden, family history and certain genotypes. No single minor finding automatically justifies a defibrillator, while the combination of factors should not be reduced to an intuitive judgment. The ICD decision must balance expected benefit against infection, inappropriate shocks, lead complications and the impact of decades of treatment, particularly in young people.

Reproductive planning includes maternal risk, transmission, medications, hemodynamic status and the possibility of preimplantation or prenatal genetic diagnosis when legally and clinically appropriate. Most women with stable cardiomyopathy can undergo pregnancy within a specialist pathway, but severe obstruction, ventricular dysfunction, pulmonary hypertension or uncontrolled arrhythmias increase risk. Counseling should not promise a phenotypic prediction that genetics often cannot provide. The aim is to enable an informed choice and arrange monitoring, therapy and place of delivery consistent with the individual profile.

Principles of treatment, prognosis and specialist care

Therapy is built on three levels: treatment of the cause, control of the phenotype and prevention of complications. Etiologic therapies include, in specific settings, transthyretin stabilizers or silencers, chemotherapy for AL amyloidosis, enzyme replacement or chaperones in Fabry disease, chelation or phlebotomy in iron overload, and immunosuppression in selected inflammatory diseases. Benefit depends on early diagnosis because removing the cause does not always reverse established scar or advanced dysfunction. Specific therapy therefore does not eliminate the need to manage heart failure, rhythm and thromboembolic risk.

In the phenotype with reduced ejection fraction, principles of neurohormonal heart failure therapy are applied and adapted to blood pressure, renal function and etiologic features. Renin-angiotensin system inhibition with ARNI or appropriate agents, beta-blockers, mineralocorticoid receptor antagonists and SGLT2 inhibitors reduce morbidity and mortality in populations supported by evidence. Normalization of ejection fraction does not prove that the substrate has healed and, in dilated forms, complete withdrawal of therapy exposes a substantial proportion of patients to relapse. Diuretics and congestion management improve symptoms but should be titrated without excessively compromising preload and perfusion.

In obstructive hypertrophic cardiomyopathy, treatment aims to reduce gradient and symptoms through drugs that modulate heart rate, contractility and filling, myosin inhibitors in appropriate patients, and septal reduction when obstruction remains severely symptomatic. In non-obstructive forms, rate control, congestion management and treatment of comorbidities predominate, avoiding automatic transfer of strategies validated for obstruction. In arrhythmogenic cardiomyopathies, reduction of exposure to intense exercise, antiarrhythmic drugs, ablation and ICD therapy are combined according to risk. Therapy is therefore phenotype specific and can become harmful if applied without recognizing the dominant mechanism.

Atrial fibrillation and thromboembolism require particular attention because atrial dilation, stasis and endocardial injury may increase risk beyond that suggested by general tools. In hypertrophic cardiomyopathy, clinical atrial fibrillation itself constitutes a strong indication for anticoagulation in the absence of contraindications, without relying solely on CHA2DS2-VASc. In dilated or restrictive phenotypes, the decision integrates general rules and specific factors, while ventricular thrombi and aneurysms require dedicated assessment. Rhythm control may improve symptoms and hemodynamics, especially when loss of atrial contraction is poorly tolerated.

Devices and procedures are used when risk or dysfunction exceeds what drugs can modify. Pacemakers, cardiac resynchronization and defibrillators are indicated according to conduction disturbances, dyssynchrony, ventricular function and arrhythmic risk, taking genetic features into account. Ablation may reduce recurrence of ventricular tachycardia but does not eliminate a progressive substrate; similarly, a septal reduction procedure treats obstruction rather than the sarcomeric disease as a whole. In patients with refractory heart failure, ventricular assistance and transplantation should be evaluated before right ventricular dysfunction, fixed pulmonary hypertension or organ damage make risk prohibitive.

Prognosis has improved through earlier diagnosis, heart failure therapy, arrhythmic prevention and etiologic treatments, but it is not uniform among cardiomyopathies. Etiology, ventricular function, fibrosis, arrhythmias, systemic involvement, therapeutic response and access to expert care determine very different trajectories even within the same phenotype. Risk communication requires absolute values and time horizons, avoiding both catastrophic scenarios derived from old referral cohorts and reassurance based on a single favorable check. Quality of care ultimately depends on the ability to coordinate the patient, family and different specialties throughout the entire disease course.