Lecture 11.0 - Cardiomyopathy Notes_2024.pdf

Cardiomyopathy Dr Adam Botha Division of Anatomical Pathology University of the Witwatersrand / National Health Laboratory Service Learning objectives 1. By the end of the session, the student will be able to define cardiomyopathy 2. By...

Cardiomyopathy Dr Adam Botha Division of Anatomical Pathology University of the Witwatersrand / National Health Laboratory Service Learning objectives 1. By the end of the session, the student will be able to define cardiomyopathy 2. By the end of the session, the student will be able to describe the clinical, pathophysiological and pathological features of dilated, hypertrophic and restrictive cardiomyopathy Definitions Cardiomyopathy: Literally: disease of the cardiac myocytes More nuanced definition: heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of causes that frequently are genetic Cardiomyopathy Cardiomyopathies present as failure of myocardial performance: This can be mechanical (diastolic or systolic dysfunction) leading to congestive cardiac failure Or result in life-threatening arrhythmias Underlying causes can either be Primary - genetic or acquired diseases of myocardium Secondary – myocardial involvement as a component of a systemic or multiorgan disorder Pathogenesis A major advance in our understanding of cardiomyopathies stems from the frequent identification of underlying genetic causes Mutations in myocardial proteins involved in contraction, cell-cell contacts and the cytoskeleton These lead to abnormal contraction or relaxation or to dysregulated ion transport across cell membranes Pathophysiological patterns Three identifiable patterns Dilated cardiomyopathy (most common) Hypertrophic cardiomyopathy Restrictive cardiomyopathy (least common) Robbins and Cotran Pathologic Basis of Disease, 9th Ed. Mitchell RN, Kumar, V et al. Eds. Elsevier Saunders, Philadelphia, 2017 Dilated cardiomyopathy Characterized morphologically and functionally by progressive cardiac dilation and contractile (systolic) dysfunction (ineffective contraction) Dilated cardiomyopathy - Pathogenesis Genetic causes (20-50%): Mutation of dystrophin most frequently Infection Viral myocarditis Alcohol or other toxic exposure Alcohol and metabolites have a toxic effect on myocardium Peripartum cardiomyopathy Late gestation and few months post partum (multifactorial, contributing factors - hypertension, volume overload, nutritional deficiency, metabolic derangements) Iron overload Dilated cardiomyopathy - Pathology Macroscopy: The heart is enlarged, heavy (2-3x normal) and flabby due to dilation of all chambers Mural thrombi are common and may be a source of thromboemboli There are no primary valvular alterations Microscopy: Non-specific - usually do not point to a specific etiology Most muscle cells are hypertrophied, but some are attenuated, stretched and irregular Interstitial and endocardial fibrosis of variable degree is present Robbins and Cotran Pathologic Basis of Disease, 9th Ed. Mitchell RN, Kumar, V et al. Eds. Elsevier Saunders, Philadelphia, 2017 Clinical significance End-stage - the cardiac ejection fraction typically is less than 25% (n= 50-65%) Manifests with slowly progressive congestive heart failure Half of the patients die within 2 years Cardiac transplant only definite treatment Hypertrophic cardiomyopathy Specific clinical and pathological entity – primary disease of the myocardium (not to be confused with the general term “myocardial hypertrophy”) Characterised by myocardial hypertrophy, poorly compliant left ventricular myocardium and defective diastolic filling Systolic function usually is preserved but the myocardium does not relax and therefore exhibits primary diastolic dysfunction Hypertrophic cardiomyopathy - Pathogenesis 100% genetic causes Mutations in one of several genes encoding proteins that form the contractile apparatus The pattern of transmission is autosomal dominant with variable penetrance. Mutations in genes that encode sarcomeric proteins (more than 400 different known mutations in nine different genes) The prognosis varies widely and correlates strongly with specific mutations Hypertrophic cardiomyopathy - Pathology Classic macroscopic pattern: Disproportionate thickening of the ventricular septum relative to the left ventricle free wall Microscopy: Myocyte hypertrophy Haphazard disarray of bundles of myocytes, individual myocytes and contractile elements in sarcomeres within cells = myofiber disarray Interstitial and replacement fibrosis Robbins and Cotran Pathologic Basis of Disease, 9th Ed. Mitchell RN, Kumar, V et al. Eds. Elsevier Saunders, Philadelphia, 2017 Clinical significance Reduced stroke volume due to impaired diastolic filling - consequence of a reduced chamber size, as well as reduced compliance of the massively hypertrophied left ventricle In addition, approximately 25% of patients with HCM have dynamic obstruction to the left ventricular outflow Important mimics to exclude include hypertensive heart disease and deposition diseases Clinical significance Complications: Atrial fibrillation - mural thrombus formation leading to embolization and possible stroke Cardiac failure Ventricular arrhythmias and sudden death One of the most common causes of sudden, unexplained death in young athletes Most patients can be helped by pharmacologic intervention (e.g., β-adrenergic blockade) to decrease heart rate and contractility Robbins and Cotran Pathologic Basis of Disease, 9th Ed. Mitchell RN, Kumar, V et al. Eds. Elsevier Saunders, Philadelphia, 2017 Restrictive cardiomyopathy Characterised by primary decrease in ventricular compliance, resulting in impaired ventricular filling during diastole Potential to be confused with hypertrophic cardiomyopathy and restrictive pericarditis Restrictive cardiomyopathy - causes Systemic disorders: Amyloidosis Sarcoidosis Metastatic tumours Inborn errors of metabolism → deposition of metabolites Myeloproliferative disorder → Loeffler endomyocarditis Restrictive cardiomyopathy - causes Iatrogenic: Radiation-induced fibrosis Multifactorial: Endocardial fibroelastosis Idiopathic: Endomyocardial fibrosis Restrictive cardiomyopathy- pathology The ventricles are of approximately normal size or slightly enlarged, the cavities are not dilated Myocardium is firm and non-compliant Bi-atrial dilation is commonly observed Robbins and Cotran Pathologic Basis of Disease, 9th Ed. Mitchell RN, Kumar, V et al. Eds. Elsevier Saunders, Philadelphia, 2017 Restrictive cardiomyopathy- pathology Microscopy: May be non-specific – fibrosis One of above specific causes may be identified microscopically e.g. amyloidosis – endomyocardial biopsy may be important Robbins and Cotran Pathologic Basis of Disease, 9th Ed. Mitchell RN, Kumar, V et al. Eds. Elsevier Saunders, Philadelphia, 2017 Restrictive cardiomyopathy – specific entities Endomyocardial fibrosis: Affects childhood and young adults in tropical areas Fibrosis of the ventricular endocardium and subendocardium - extends from the apex upward, often involving the tricuspid and mitral valves Aetiology unknown Loeffler endocarditis Similar to above, but associated peripheral eosinophilia and microscopic eosinophilic infiltrate Associated with myeloproliferative disease with mutations causing constitutively activated tyrosine kinase – important to diagnose as treatment with tyrosine kinase inhibitor - which reverses an otherwise fatal condition Restrictive cardiomyopathy – specific entities Endocardial fibroelastosis: Characterized by fibroelastic thickening that typically involves the left ventricular endocardium Common in first two years of life – often associated with other congenital cardiac abnormalities May be end-point of various insults including viral infections and genetic mutations Summary points Cardiomyopathies are specific disease entities that result in myocardial dysfunction Three important pathological patterns – dilated cardiomyopathy, hypertrophic cardiomyopathy and restrictive cardiomyopathy, with different underlying aetiologies and treatments An understanding of the underlying pathophysiology assists in differentiated these three groups and recognising clinically important features / entities Thank you