Lecture #102. W. Zaloga D.O. (PPT) PDF

CARDIOMYOPATHIES Part 1 – DILATED AND HYPERTROPHIC CARDIOMYOPATHIES CARDIOVASCULAR SYSTEM/PPOM 2 William Zaloga, D.O. Department of Clinical Medicine Wilson Hall Room #424F Arkansas State University Jonesboro, Arkansas Session Objectives 1. Discuss, describe, and illustrate the gen...

CARDIOMYOPATHIES Part 1 – DILATED AND HYPERTROPHIC CARDIOMYOPATHIES CARDIOVASCULAR SYSTEM/PPOM 2 William Zaloga, D.O. Department of Clinical Medicine Wilson Hall Room #424F Arkansas State University Jonesboro, Arkansas Session Objectives 1. Discuss, describe, and illustrate the general characteristics of Dilated Cardiomyopathy as well as its gross and histological features. 2. Explain the varied pathogenesis along with clinical manifestations, genetic characteristics, and pathophysiology of Dilated Cardiomyopathy. 3. Discuss the general characteristics along with clinical manifestations, genetic characteristics, and pathophysiology of Arrhythmogenic Right Ventricular Cardiomyopathy. 4. Describe, and illustrate the general characteristics along with clinical manifestations and pathophysiology of Hypertrophic Cardiomyopathy as well as its gross and histological features. 5. Explain the pathogenesis, genetic characteristics, etiology, and pathophysiology of Hypertrophic Cardiomyopathy. 6. Compare Dilated to Hypertrophic Cardiomyopathy. Cardiomyopathies (heart muscle diseases) are generally structural cardiac abnormalities manifesting as failure of myocardial performance Distinct from impairment resulting from defined cardiovascular diseases such as hypertension, valvular disorders, and coronary artery disease. Symptoms of heart failure (etiology is often unknown (idiopathic)) Robbins and Cotran, Pathological Basis of Disease, 10th ed. , 2020, Ch. 12 Primary and secondary cardiomyopathies Primary cardiomyopathies involve mainly the heart and can be genetic or acquired (examples of acquired diseases are viral cardiomyocarditis, or anthracycline chemotherapy) – Genetic causes include mutations in myocardial proteins involved in contraction, or cell-cell contacts, or the cytoskeleton (example, leads to abnormal contraction/relaxation or dysregulated of ion transport across the cell membrane that can cause dysrhythmias) Secondary cardiomyopathies are a component of a systemic or multi-organ disease process, such as hemochromatosis or amyloidosis Robbins and Cotran, Pathologic Basis of Disease, 10th ed., 2020, Ch. 12 Cardiomyopathy types Dilated Cardiomyopathy (DCM) 90% of cases Abnormality = Enlarged chambers Leads to systolic contraction dysfunction Includes Arrhythmogenic Cardiomyopathy Hypertrophic Cardiomyopathy (HCM) Abnormality = Thickened ventricular wall Leads to diastolic relaxation dysfunction Restrictive Cardiomyopathy (RCM, next lecture) Least frequent Abnormality = Stiff myocardium Leads to diastolic relaxation dysfunction Robbins and Cotran, Pathological Basis of Disease, 10th ed., 2020, Ch. 12  DCM DCM Eccentric hypertrophy with Globoid, flabby, poorly progressive dilation and contractile contractile dysfunction (does not mean asymmetric when discussing ventricular hypertrophy): Commonly Normal seen in volume overload (ex. valve regurgitation) with new sarcomeres added in series, vs in parallel to existing sarcomeres (concentric hypertrophy) seen in pressure overload like hypertension Commonly at diagnosis, end-stage disease (suggested by left ventricular ejection fraction (LVEF) = Loeffler/salamat > Flashcards > PATH 404 Study Guide (2012-13 Loeffler/salamat) | StudyBlue http://www.dra-amo.com/draamoen/styled-10/index.html DCM pathology Overview - heavy, large, flabby heart with marked dilation of all chambers, can be limited to just one side of the heart – Dilation leads to thinning of the walls, may be some increase in ventricular wall thickness, but dilation out of proportion to hypertrophy – Heart increases 2-3x normal wt. – bi-ventricular heart failure results Nonspecific histology– severity does not correlate with degree of dysfunction/prognosis; may indicate etiology – Myocyte – Enlarged nuclei, irregular hypertrophy of myocytes present, but other myocytes may be attenuated, stretched, irregular, degenerated, atrophic – Interstitial, endocardial, perivascular fibrosis Robbins and Cotran, Pathologic Basis of Disease, 10th ed., 2020, Ch. 12 DCM Pathophysiology due to ventricular SV and CO decline because of impaired myocyte contractility, three compensatory effects occur: Enlarged Ventricles systolic Impaired myocyte contractility dysfunction Compensatory mechanisms decreased SV and CO Frank-Starling Neurohormonal Activation RAAS activation Increased end Decreased CO decreased renal perfusion diastolic increased renin release volume sympathetic Increased stimulation Angiotensin II Aldosterone myofiber stretch increased heart increased rate and contractility increased increased contractile force intravascular SVR volume increased CO increased SV Compensatory mechanisms gone wrong. Due to this, patient may be asymptomatic early on, but eventually heart failure develops Angiotensin II  increased SVR afterload becomes too high for the impaired LV to pump against Aldosterone  increased intravascular/EDV fluid backs up pulmonary and systemic congestion Chronic elevations in aldosterone and angiotensin II cardiac remodeling and fibrosis With heart enlargement, mitral/tricuspid regurgitation may occur causing:  Increased volume and pressure loads in atria causing them to dilate; possible atrial fibrillation  Regurgitation of blood into the LA further decreases forward stroke volume into the aorta and systemic circulation  Regurgitant volume returns to the LV during each diastole resulting in greater volume load for LV to pump out DCM clinical Features Slow, progressive signs/symptoms of CHF – Cool extremities, low arterial pressure, tachycardia – Pulmonary venous congestion leads to auscultatory crackles – Left and upward displacement of PMI, enlarged heart – Third heart sound (S3) Complications: Mitral/Tricuspid Regurgitation, atrial fibrillation, mural thrombus/thromboembolism – Annual mortality high: 10-50% die usually from progressive cardiac failure or arrhythmia Robbins and Cotran, Pathologic Basis of Disease, 10th ed., 2020, Ch. 12  DCM etiology general categories examples Idiopathic (most common) Toxic* Familial/Genetic – Chronic alcohol ingestion Inflammatory – Chronic cocaine use – Infectious (Viral) – Chemotherapeutic agents (eg. Coxsackievirus A & B Doxorubicin) Adenovirus Metabolic* Chagas’ disease – Hypothyroidism – Noninfectious – Chronic hypocalcemia or Connective tissue diseases* hypophosphatemia Peripartum cardiomyopathy* – Beriberi Sarcoidosis* Neuromuscular Hemochromatosis – Muscular or myotonic dystrophy * Possibly reversible DCM Pathogenesis Genetic Causes: Familial in 30-50% of cases - AD inheritance is most common – Caused by mutations in diverse group of genes, > 20, encoding proteins involved in the cytoskeleton, sarcolemma, and nuclear envelope - mutation in TTN gene encoding titan may account for nearly 20% of cases – Leading to impairments in generation of contractile force, transmission of contractile force, energy production, myocyte signaling, myocyte viability Less commonly X-linked, AR, or mitochondrial inheritance – X-linked DCM linked to gene for dystrophin (links cytoskeleton to extracellular matrix) – muscular dystrophy sign after puberty to early adult – Deletions in mitochondrial genes  problems with FA oxidation or oxidative phosphorylation; typically pediatric manifestation Supraphysiologic Stress - persistent tachycardia, hyperthyroidism, or even during development (fetuses of insulin-dependent diabetic mothers), catecholamines toxicity may cause multifocal myocardial contraction band necrosis leading to DCM – Includes pheochromocytomas (epinephrine), cocaine or vasopressor agents such as dopamine – Also, intense autonomic stimulation due to intracranial lesion or emotional duress Takotsubo (“octopus pot”) cardiomyopathy - left ventricular contractile dysfunction following extreme psychological stress; affected myocardium may be stunned or show multi-focal contraction band necrosis. Left ventricular apex is most often affected leading to “apical ballooning” Mechanism uncertain – maybe calcium overload or focal vasoconstriction in coronary arteries with increased heart rate Robbins and Cotran, Pathologic Basis of Disease, 10th ed., 2020, Ch. 12 DCM: Pathogenesis Myocarditis Heart may grossly appear normal or dilated; in advanced stages mural thrombi may be present Viral – most common (common causes- coxsackievirus A & B, parvovirus B19, adenovirus, ECHO, HIV, CMV, influenza) – Lymphocytic infiltrate in myocardium with injury by direct cytopathic effect, destructive immune response, inflammatory cytokines cause myocardial dysfunction, possible http://www.pathologyatlas.ro/acute-viral-myocarditis.php fibrosis when healing- some fully recover or develop DCM, HF or death Nonviral causes - Trypanasoma cruzi (Chagas Disease) - 10% die during attack, others have chronic immune-mediated myocarditis leading to cardiac insufficiency 10-20 years later; trypanasomes present – Trichinella spiralis (Trichinosis) - most common helminthic myocarditis – Toxoplasma gondii (Toxoplasmosis), Borrelia burgdorferi (Lyme Disease), Corynebacterium diphtheriae (Diptheria) Noninfectious causes – Hypersensitivity myocarditis - perIvascular interstitial infiltrates: lymphocytes, macrophages, and a high proportion of eosinophils – Giant cell myocarditis - widespread inflammatory infiltrate: multinucleate giant cells, lymphocytes, eosinophils, plasma cells, and macrophages. Necrosis is present. Poor prognosis.  DCM pathogenesis Toxin-Induced Strong association with chronic excessive alcohol use – Ethanol (acetylaldehyde)  inhibition of mitochondrial oxidative phosphorylation and fatty acid oxidation cell function declines – Alcohol metabolite acetaldehyde = direct toxin to myocardium – Chronic alcoholism thiamine deficiency beriberi (beriberi heart disease indistinguishable from DCM) – Can be reversible: ventricular function improves with cessation of alcohol Other toxins: Adriamycin chemotherapy agents (Doxorubicin/Daunorubicin), cobalt, chronic cocaine use, iron overload - hemochromatosis (genetic or exogenous, ex. via transfusions) Peripartum Associated Can occur late in pregnancy or up to 6 months postpartum Probably multi-factorial - poorly understood immune response/cytokine release, pregnancy associated hypertension, volume overload, nutritional deficiencies – Recent work suggests primary defect is microvascular angiogenic imbalance in the myocardium leading to functional ischemic injury 50% regain normal ventricular function Risks include advanced maternal age, African American race, multiple pregnancies/gestations May have recurrence in future pregnancies DCM: Treatment Goals: Treat early, treat underlying cause, symptom relief, decrease backward vascular congestion, increase forward CO, prevent complications, prevent thromboembolic events, prevent and treat ensuing arrythmias, improve long term survival Standard CHF meds: Na+ restriction, ACEI/ARBs, beta blockers, diuretics, digoxin In those with poor LV function, anti-arrythmic drugs may worsen rhythm and lead to arrythmias - amiodarone safest Anticoagulation therapy may be for those prone to thrombus formation Implantable cardioverter-defibrillator (ICD) Cardiac transplant may be the only definitive treatment 1/3 patients spontaneously improve after diagnosis With no transplantation, 5 yr survival =74%; 10 yr = 55% DCM: Summary Lilly, L. (2011). Cardiomyopathies. In Pathophysiology of heart disease: A collaborative project of medical students and faculty (5th ed.). Baltimore, MD: Wolters Kluwer/Lippincott Williams & Wilkins. Case A 58-year-old man presents with dyspnea on exertion and fatigue. PE shows evidence of congestive heart failure and an echocardiogram discloses a dilated left ventricle with a left ventricular ejection fraction of 20%. The liver appears fatty by MRI. Cardiac catherization demonstrates minimal coronary artery atherosclerosis. Which of the following is the most likely cause of these signs and symptoms? A. Duchenne muscular dystrophy B. Restrictive cardiomyopathy C. Hypertrophic cardiomyopathy D. Alcoholic cardiomyopathy E. Peripartum associated cardiomyopathy Hypertrophic Cardiomyopathy (HCM) Hypertrophic obstructive cardiomyopathy aka idiopathic hypertrophic subaortic stenosis incidence 1 in 500 births worldwide Poorly compliant left ventricular myocardium leading to abnormal diastolic filling; 25-33% have intermittent ventricular outflow obstruction - diastolic dysfunction; systolic function is usually preserved Mechanisms of HCM: Left ventricular hypertrophy, which leads to increased muscle mass that the existing vasculature cannot support, decreased compliance and outflow obstruction, coronary arteries also narrows due to wall hardening, leads to myocardial ischemia Disease of sarcomere proteins, causing massive primary myocardial hypertrophy of ventricular wall without dilation – Unexplained LVH in absence of external stimuli (e.g., HTN or aortic stenosis) Heart is thick-walled, heavy, and hypercontracting (vs flabby, hypocontracting heart of DCM Most common cardiac abnormality in young athletes who die suddenly during exertion (ventricular arrhythmia) Robbins and Cotran, Pathologic Basis of Disease, 10th ed., 2020, Ch. 12  Asymmetric (not concentric) hypertrophy; HCM gross pathology, histology septum to free wall thickness ratio ≥ 3:1 - subaortic septum most commonly affected Normal LV HCM Hypertrophy symmetric or asymmetric; asymmetric is more commonly seen and is found at the septum LV lumen has a “banana like” shape due to protrusion of septum The LVOT often has a fibrous endocardial plaque due to thickening of anterior mitral leaflet Chaotic arrangement of myocardial fibers makes the tissue stiff and leads to diastolic failure Source: The failing heart. J. A. Towbin and N. E. Bowles, Nature 415, 227-233(10 January 2002) Heart cross section shows ventricular cavity with a “banana-like” configuration because of bulging ventricular septum into the lumen Septum in a case of hypertrophic obstructive CM. Note myofiber disarray with bundles running in all directions. Interstitial fibrosis is also present HCM pathophysiology Without Obstruction Reduced LV chamber size Decreased LV compliance: SV and CO decline; diastolic pressures rise and transmit backwards to LA and pulmonary vessels With Obstruction = DYNAMIC obstruction Systolic contraction: Thickened septum narrows LV outflow track  more rapid ejection of blood creates a force that draws the anterior leaflet of mitral valve towards septum transient obstruction of LV outflow tract HCM pathophysiology Subaortic hypertrophy of septum leads to functional aortic stenosis below the aortic valve Leads to dyspnea, possible syncope, atrial fibrillation Hypertrophic obstructive cardiomyopathy shows asymmetric septal hypertrophy (ASH), systolic anterior motion of the mitral valve leaflet (SAM) and obstruction of the left ventricular outflow tract Mitral regurgitation may also be present Ulrich Sigwart, MD, FRCP, FACC, FESC; Rod Stables, MD, MRCP,Department of Interventional Cardiology, Royal Brompton & Harefield NHS Trust, London, United Kingdom HCM pathophysiology Pressure gradient increases wall stress & myocardial O2 consumption, which can result in angina & focal ischemia Mitral regurgitation further elevates LA and pulmonary venous pressures Things that decrease LV cavity will bring anterior mitral leaflet and septum closer together – Reduced venous return – Volume depletion – Positive inotropic drugs increase force of contraction so promote obstruction Things that increase LV cavity will bring anterior mitral leaflet & septum apart – Increased venous return – Volume increase – Negative inotropic drugs decrease force of contraction so reduce obstruction HCM pathophysiology massive LV Hypertrophy decreased ventricular compliance impaired diastolic relaxation heart can’t fill + small LV chamber size +/- LV outflow obstruction heart failure symptoms HCM histology Hallmarks of histological diagnosis include myocyte hypertrophy, fibrosis and disarray Haphazard arrangement of bundles of extremely hypertrophied myocytes, and contractile elements in sarcomeres within myocytes (regional myofibril disarray) – HTN shows uniform enlargement of myocytes with order maintained Interstitial and replacement fibrosis Aberrant myofibers present in conduction system may lead to fatal arrhythmias Robbins and Cotran, Pathologic Basis of Disease, 10th ed., 2020, Ch. 12 HCM etiology 70-80% familial with AD inheritance; variable expression 100’s of known mutations, encoding for sarcomere proteins Most missense point mutations in 9 genes – beta-myosin heavy chain (most common) – cardiac troponins – myosin binding protein C – alpha-tropomyosin Prognosis varies widely, correlates with specific mutations – Sequence of events from mutations to disease poorly understood May be associated with Friedreich Ataxia HCM pathogenesis Normal Sarcomere Disease Contraction Mutated protein within sarcomere Ca2+ binds to troponin C, I, and T and alpha- contractile impairments tropomyosinmyosin-actin interaction increased myocyte stress Actin stimulates ATPase activity in myosin head  force generation Compensatory Hypertrophy Growth factor Fibroblast release proliferation Myofiber Interstitial disarray Fibrosis Illustration of the sarcomere (Kamisago, M. et al. N Engl J Med. 2000; 343:1688-96. Copyright 2000 Massachusetts Medical Society. (All rights reserved.) HCM clinical features Varies from no to extensive limitations on physical activity Most do NOT have severe outflow obstruction, and MOST symptoms result from hypertrophy-induced impairment in diastolic filling Major clinical problems/complications: Mitral regurgitation, atrial fibrillation with mural thrombus, cardiac failure, ventricular arrhythmias, syncope and sudden death – One of the most common causes of sudden, unexplained death in young athletes is hypertrophic cardiomyopathy - cause = v.fib on strenuous exertion – Risks = History of syncope, family history of sudden death, high risk mutations, extreme hypertrophy (LV wall thickness correlates with risk) HCM: Clinical Features Hypertrophy Obstruction Mechanism Dyspnea diastolic impairment  increased increased systolic LV pressures during LV, LA, PCW pressures obstruction + possible MR Angina hypertrophy inc. muscle mass Plus: increased LV pressure during systole inc. O2 demand increased wall stress  increased hypertrophy squeezes down on myocardial O2 demand small coronary branches in ventricular wall impaired myocardial perfusion Light standing blood pools in legs decreased Headedness preload decreased LV return decreased LV chamber size increased obstruction  transient decrease in CO and cerebral perfusion Syncope/ Aberrant myocytes within Increased physical exertion increased force of Arrythmias conduction system abnormal contraction worsens obstruction transient Arrhythmias can worse HCM conduction and development of symptoms like a. fib. causing loss outflow block CO drops  syncope arrhythmias which can lead to of atrial kick so diastolic filling is syncope further impaired and pulmonary congestion is worsened HCM clinical features Physical Exam S4 heart sound (LA contraction into stiffened LV) Outflow obstruction: Harsh systolic ejection murmur, crescendo, de-crescendo, caused by turbulent flow through the narrowed outflow tract; best heard at left lower sternal border Screening Screening of first degree relatives Serial echocardiograms to note increases in hypertrophy during growth All HCM patients, even if asymptomatic, should evaluate (at risk for sudden death) Treatment Most do well with medications that relax the heart Obstruction: Avoid strenuous exercise/competitive sports and drugs that decreases preload or increase force of contraction Standard therapy = beta blockers Non-dihydropyridine Ca2+ channel blockers (verapamil) Antiarrhythmic drugs such as amiodarone Implantable Cardioverter Defibrillator (ICD): life saving for patients at high risk of SCD Surgery: Myomectomy (more proven to hold) or septal ablation with alcohol HCM pathophysiology summary MVO2 (myocardial oxygen consumption) = coronary blood flow x arteriovenous difference in O2 content  Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) AKA Arrhythmogenic RV Dysplasia Rare, progressive, mostly sporadic Some familial forms occur: AD with variable penetrance - deletions of cell membrane desmosomal junctional proteins lose cell to cell adhesions between cardiac myocytes fibrosis or aberrant signaling between cells can result Leads to RV failure + rhythm disturbances, esp. ventricular tachycardia and fibrillation with sudden death - associated with reentrant VT originating from the RV – Left sided involvement may occur Can see abnormal RV morphology with non-invasive imaging Treatment usually involves ICD (implantable cardioverter defibrillator) Naxos syndrome: ARVC + hyperkeratosis of plantar/palmar surfaces associated with mutations in plakoglobin (desmosome-associated protein) Can pick this up on routine EKG – Inverted T waves in V1-V3 – Possible epsilon wave = terminal QRS notch in V1 Indicates abnormal RV activation  ARVC morphology Loss of myocytes and myocyte replacement with massive fatty infiltration + fibrosis +/- inflammation of RV severe thinning of RV wall Robbins and Cotran, Pathologic Basis of Disease, 10th ed., 2020, Ch. 12 DCM: Summary GENETIC (30 – 50%) NON-GENETIC DEFECT IN FORCE GENERATION, MYOCARDITIS, FORCE TRANSMISSION, PERIPARTUM, ALCOHOL, OR MYOCYTE SIGNALING ETC. DILATED CARDIOMYOPATHY PHENOTYPE CLINICAL – HEART FAILURE, A-FIB, STROKE, SLOW PROGRESSIVE SIGNS AND SYMPTOMS OF CHF HCM summary Most commonly genetic SARCOMERIC PROTEIN MUTATION DEFECT IN ENERGY TRANSFER FROM MITOCHONDRIA TO SARCOMERE AND/OR DIRECT SARCOMERIC DYSFUNCTION (versus defect in force generation and/or transmission in DCM) HYPERTROPHIC CARDIOMYOPATHY PHENOTYPE CLINICAL: HEART FAILURE, A-FIB, STROKE, SUDDEN DEATH A 19-year-old college basketball player suddenly collapses on the court. A cardiac monitor shows ventricular tachycardia and then ventricular fibrillation. He is successfully resuscitated and hospitalized. His history reveals that his father died suddenly at the age of 35 years. The boy’s echocardiogram reveals a thickened left ventricular wall, with a small slit-like chamber. The IVS is also markedly thickened. Three years later the patient expires suddenly. A mutation in which of the following proteins is most likely? Alpha-tropomyosin Beta-myosin heavy chain Dystrophin Myosin binding protein C Cardiac troponins Summary Slide Introduction – types of cardiomyopathies Dilated cardiomyopathy Definition, etiology Pathogenesis – including viral, toxins (inc. alcohol), peripartum, genetic Pathological (gross) features Pathophysiology Histology Diagnosis and treatment pearls Hypertrophic cardiomyopathy Definition, etiology (genetic) Pathogenesis Histology, Gross features Pathophysiology Clinical Arrhythmogenic right ventricular cardiomyopathy Dilated v. Hypertrophic Cardiomyopathy  References Kumar, V. (2014). The Heart. In Robbins basic pathology (9th ed, ch. 12). Philadelphia, PA: Saunders/Elsevier. Lilly, L. (2011). Cardiomyopathies. In Pathophysiology of heart disease: A collaborative project of medical students and faculty (5th ed.). Baltimore, MD: Wolters Kluwer/Lippincott Williams & Wilkins. First Aid for the USMLE Step 1, 2016 USMLERx Question Bank Robbins and Cotran, Pathologic Basis of Disease, 10th ed., 2020, Ch. 12 Lecture Feedback Form https://comresearchdata.nyit.edu/redcap/surveys/?s=HRCY448FWYXREL4R