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CARDIOMYOPATHY

CARDIOMYOPATHY. Athena Poppas, MD Associate Professor of Medicine, Brown Medical School Director, Echocardiography Laboratory Rhode Island Hospital. Cardiomyopathies. Definition: diseases of heart muscle 1980 WHO: unknown causes Not clinically relevant

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CARDIOMYOPATHY

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  1. CARDIOMYOPATHY Athena Poppas, MD Associate Professor of Medicine, Brown Medical School Director, Echocardiography Laboratory Rhode Island Hospital

  2. Cardiomyopathies Definition: diseases of heart muscle • 1980 WHO: unknown causes • Not clinically relevant • 1995 WHO: “diseases of the myocardium associated with cardiac dysfunction “ • pathophysiology • each with multiple etiologies

  3. Cardiomyopathy • WHO Classification • anatomy & physiology of the LV • Dilated • Enlarged • Systolic dysfunction • Hypertrophic • Thickened • Diastolic dysfunction • Restrictive • Diastolic dysfunction • Arrhythmogenic RV dysplasia • Fibrofatty replacement • Unclassified • Fibroelastosis • LV noncompaction Circ 93:841, 1996

  4. CM: Specific Etiologies • Ischemic • Valvular • Hypertensive • Inflammatory • Metabolic • Inherited • Toxic reactions • Peripartum Ischemic: thinned, scarred tissue

  5. Dilated Cardiomyopathy • Dilation and impaired contraction of ventricles: • Reduced systolic function with or without heart failure • Characterized by myocyte damage • Multiple etiologies with similar resultant pathophysiology • Majority of cases are idiopathic • incidence of idiopathic dilated CM 5-8/100,000 • incidence likely higher due to mild, asymptomatic cases • 3X more prevalent among males and African-Americans

  6. DCM: Etiology Ischemic Valvular Hypertensive Familial Idiopathic Inflammatory Infectious Viral – picornovirus, Cox B, CMV, HIV Ricketsial - Lyme Disease Parasitic - Chagas’ Disease, Toxoplasmosis Non-infectious Collagen Vascular Disease (SLE, RA) Peripartum Toxic Alcohol, Anthracyclins (adriamycin), Cocaine Metabolic Endocrine –thyroid dz, pheochromocytoma, DM, acromegaly, Nutritional Thiamine, selenium, carnitine Neuromuscular (Duchene’s Muscular Dystrophy--x-linked)

  7. Prognosis depends on Etiology 1230 pts. referred for unexplained CM. Felker GM. NEJM 2000;342:1077

  8. DCM: Infectious Acute viral myocarditis • Coxasackie B or echovirus • Self-limited infection in young people • Mechanism?: • Myocyte cell death and fibrosis • Immune mediated injury • BUT: • No change with immunosuppressive drugs

  9. DCM: toxic Alcoholic cardiomyopathy • Chronic use • Reversible with abstinence • Mechanism?: • Myocyte cell death and fibrosis • Directly inhibits: • mitochondrial oxidative phosphorylation • Fatty acid oxidation

  10. DCM: inherited Familial cardiomyopathy • 30% of ‘idiopathic’ • Inheritance patterns • Autosommal dom/rec, x-linked, mitochondrial • Associated phenotypes: • Skeletal muscle abn, neurologic, auditory • Mechanism: • Abnormalities in: • Energy production • Contractile force generation • Specific genes coding for: • Myosin, actin, dystophin…

  11. DCM: Peripartum Diagnostic Criteria • 1 mo pre, 5 mos post • Echo: LV dysfunction • LVEF < 45% • LVEDD > 2.7 cm/m2 • Epidemiology/Etiology • 1:4000 women • JAMA 2000;283:1183 • Proposed mechanisms: • Inflammatory Cytokines: • TNFa, IL6, Fas/AP01 • JACC 2000 35(3):701.

  12. PPCM: Prognosis • Death from CM: ’91-97 • 245 CM deaths in US, 0.88/100,000 live births, 70% peripartum • Increased risk with: • Maternal age • AA 6.4x greater • Whitehead SJ. ObGyn2003;102:1326. • Risk of recurrent pregnancy • Retrospective survey : 44 women (16 vs 28) • Reduced EF, CHF 44% vs 21%, mortality 0 vs. 19% • Elkyam U. NEJM.2001;344:1567. • DSE:contractile reserve reduced in patients • 7 women: change in Vcfc σES relationship • Lampert MB. AJOG.1997.176.189.

  13. Dilated Cardiomyopathy

  14. MECHANISMS IN HEART FAILURE Neurohormones Cytokines Oxidative stress Ischemic injury Myocardial disease Genetics Altered molecular expression Ultrastructural changes Myocyte hypertrophy Myocyte contractile dysfunction Apoptosis Fibroblast proliferation Collagen deposition Ventricular remodeling Hemodynamic Derangement Clinical Heart Failure Arrhythmia

  15. Pathophysiology • Initial Compensation for impaired myocyte contractility: • Frank-Starling mechanism • Neurohumoral activation •  intravascular volume • Eventual decompensation • ventricular remodeling • myocyte death/apoptosis • valvular regurgitation

  16. Pathophysiology: Starling Curve

  17. Pathophysiology: Neurohumoral • Adrenergic nervous system • Renin-angiotensin-aldosterone axis • Vasopressin • Natriuretic peptides • Endothelin

  18. Reduced Response to Adrenergic Stimulation

  19. Renin-Angiotensin-Aldosterone Pathways Angiotensinogen Renin ACE-inhibitor Angiotensin-I Chymase ACE Angiotensin-II Angiotensin receptor blocker Bradykinin degradation AT-1 Receptor Spironolactone Aldosterone

  20. Vasoconstriction Aldosterone production Myocyte hypertrophy Fibroblast proliferation Collagen deposition Apoptosis Pro-thrombotic Pro-oxidant Adrenergic stimulation Endothelial dysfunction Angiotensin-II Effects

  21. The Kidney in Heart Failure • Reduced renal blood flow • Reduced glomerular filtration rate • Increased renin production • Increased tubular sodium reabsorption • Increased free water retention (vasopressin)

  22. Ventricular Remodeling in Heart Failure

  23. Extracellular Stimuli of Myocyte Hypertrophy

  24. Clinical Findings Biventricular Congestive Heart Failure -Low forward Cardiac Output -fatigue, lightheadedness, hypotension -Pulmonary Congestion -Dyspnea, -orthopnea, & PND -Systemic Congestion -Edema -Ascites -Weight gain

  25. Physical Exam Decreased C.O. Tachycardia  BP and pulse pressure cool extremities (vasoconstriction) Pulsus Alternans (end-stage) Pulmonary venous congestion: rales pleural effusions Cardiac: laterally displaced PMI S3 (acutely) mitral regurgitation murmur Systemic congestion  JVD hepatosplenomegaly ascites peripheral edema

  26. Diagnostic Studies CXR -enlarged cardiac silhouette, vascular redistribution interstitial edema, pleural effusions EKG –normal tachycardia, atrial and ventricular enlargement, LBBB, RBBB, Q-waves Blood Tests (ANA,RF, Fe2+, TFT’s,ferritin,) Echocardiography LV size, wall thickness function valve dz, pressures Cardiac Catheterization hemodynamics LVEF angiography Endomyocardial Biopsy

  27. Echo in dilated CM

  28. Influence of EF on Survival in Patients with Heart Failure Vasan RS et al. J Am Coll Cardiol. 1999;33:1948-55

  29. Criteria for NYHA Functional Classification Class 1: No limitation of physical activity. Ordinary physical activity w/o fatigue, palpitation, or dyspnea. Class 2: Slight limitation of physical activity. Comfortable at rest, but symptoms w/ ordinary physical activity Class 3: Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class 4: Unable to carry out any physical activity without discomfort. Symptoms include cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased. J Cardiac Failure 1999;5:357-382

  30. Aim of Treatment • Preload reduction • Diuretics • venodilators • Vasodilators • ACEI • Inotropes • Acutely • Chronically • mortality

  31. Vasodilator Agents in Heart Failure *Hydralazine and a long-nitrate shown to reduce mortality long-term # Other actions (aside from vasodilation) likely to be important

  32. Dobutamine and Milrinone Effects

  33. Electrical and Mechanical Ventricular Dyssynchrony • Experimentallyinduced LBBB has effect on: • expressionof regional stress kinases • calcium-handling proteins. • Expression of p38-MAPK(a stress kinase) is elevated in the endocardiumof the late-activated region, whereas phospholamban is decreased. • Sarcoplasmatic reticulum Ca2+-ATPaseis decreased in the region of early activation.

  34. Deleterious Hemodynamic Effects of LV Dyssynchrony Diminished SV & CO due: • Reduced diastolic filling time1 • Weakened contractility 2 • Protracted MV regurgitation 2 • Post systolic regional contraction 3 Atrio-ventricular Intra-V Inter-V 1. Grines CL, Circulation 1989;79: 845-853 2. Xiao HB, Br Heart J 1991;66: 443-447 3. Søgaard P, JACC 2002;40:723–730 Cazeau, et al. PACE 2003; 26[Pt. II]: 137–143

  35. CRT: Cardiac Resynchronization Therapy 1. Improved hemodynamics • Increased CO • Reduced LV filling pressures • Reduced sympathetic activity • Increased systolic function w/o MVO2 2. Reverse LV remodeling/architecture • Decreased LVES/ED volumes • Increased LVEF • Circ ’02, JACC ’02, JACC ’02, NEJM’02

  36. Risk of Sudden Death c/w EF 1.00 1.00 0.98 0.98 p log-rank 0.002 0.96 0.96 0.94 0.94 Survival Survival 0.92 0.92 p log-rank 0.0001 0.90 0.90 0.88 0.88 A B Patients withoutLV Dysfunction (LVEF >35%) 0.86 0.86 0 30 60 90 120 150 180 0 30 60 90 120 150 180 Days Days Patients withLV Dysfunction (LVEF < 35%) No PVBs1-10 PVBs/h> 10 PVBs/h Maggioni AP. GISSI-2 TrialCirculation. 1993;87:312-322.

  37. Anti-arrhythmic drugs, ICD placebo and Death

  38. What are the two characteristic findings in DCM?

  39. Hypertensive Hypertrophic Cardiomyopathy

  40. Women and Hypertension Prevalence of HTN in Women from NHANES-III. Burt VL. Hypertension ‘95

  41. Diastolic Dysfunction • 40-50% of pts w/ CHF have nml LVEF • Vasan JACC ’99 • Grossman Circ ‘00 • Prevalence: • increases with age • higher in women • Etiology: HTN & LVH • Diagnosis: • MV& PV Doppler • TDI, Color m-mode

  42. Echo Doppler Parameters Zile MR. Circ;105:1387

  43. Diastolic Dysfunction Kawaguchi M. Circ 2003.107:714

  44. Isolated Diastolic HF Isolated Systolic HF Systolic & Diastolic HF Zile MR. Circ;105:1387

  45. What is the difference between systolic and diastolic LV dysfunction?

  46. Hypertrophic Cardiomyopathy Left ventricular hypertrophy not due to pressure overload Hypertrpohy is variable in both severity and location: -asymmetric septal hypertrophy -symmetric (non-obstructive) -apical hypertrophy Vigorous systolic function, but impaired diastolic function impaired relaxation of ventricles elevated diastolic pressures prevalence as high as 1/500 in general population mortality in selected populations 4-6% (institutional) probably more favorable (1%)

  47. Etiology Familial in ~ 55% of cases with autosomal dominant transmission Mutations in one of 4 genes encoding proteins of cardiac sarcomere account for majority of familial cases -MHC cardiac troponin T myosin binding protein C -tropomyosin Remainder are spontaneous mutations.

  48. Hypertrophic Cardiomyopathy

  49. Hypertrophic Cardiomyopathy

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