CARDIOMYOPATHYAthena Poppas, MDAssociate Professor of Medicine,Brown Medical SchoolDirector, Echocardiography LaboratoryRhode Island Hospital

CardiomyopathiesDefinition: diseases of heart muscle1980 WHO: unknown causesNot clinically relevant1995 WHO: diseases of the myocardium associated with cardiac dysfunction pathophysiologyeach with multiple etiologies

CardiomyopathyWHO Classificationanatomy & physiology of the LVDilatedEnlarged Systolic dysfunctionHypertrophicThickenedDiastolic dysfunctionRestrictiveDiastolic dysfunction Arrhythmogenic RV dysplasiaFibrofatty replacement UnclassifiedFibroelastosisLV noncompactionCirc 93:841, 1996

CM: Specific EtiologiesIschemicValvularHypertensiveInflammatoryMetabolicInheritedToxic reactionsPeripartum

Ischemic: thinned, scarred tissue

Dilated CardiomyopathyDilation and impaired contraction of ventricles:Reduced systolic function with or without heart failureCharacterized by myocyte damage Multiple etiologies with similar resultant pathophysiology

Majority of cases are idiopathicincidence of idiopathic dilated CM 5-8/100,000incidence likely higher due to mild, asymptomatic cases3X more prevalent among males and African-Americans

DCM: EtiologyIschemicValvularHypertensiveFamilial Idiopathic InflammatoryInfectiousViral picornovirus, Cox B, CMV, HIVRicketsial - Lyme DiseaseParasitic - Chagas Disease, ToxoplasmosisNon-infectiousCollagen Vascular Disease (SLE, RA)PeripartumToxicAlcohol, Anthracyclins (adriamycin), CocaineMetabolicEndocrine thyroid dz, pheochromocytoma, DM, acromegaly, NutritionalThiamine, selenium, carnitine Neuromuscular (Duchenes Muscular Dystrophy--x-linked)

Prognosis depends on Etiology1230 pts. referred for unexplained CM. Felker GM. NEJM 2000;342:1077

DCM: InfectiousAcute viral myocarditisCoxasackie B or echovirusSelf-limited infection in young peopleMechanism?:Myocyte cell death and fibrosisImmune mediated injuryBUT:No change with immunosuppressive drugs

DCM: toxicAlcoholic cardiomyopathyChronic useReversible with abstinenceMechanism?:Myocyte cell death and fibrosisDirectly inhibits: mitochondrial oxidative phosphorylationFatty acid oxidation

DCM: inheritedFamilial cardiomyopathy30% of idiopathicInheritance patternsAutosommal dom/rec, x-linked, mitochondrialAssociated phenotypes:Skeletal muscle abn, neurologic, auditoryMechanism:Abnormalities in:Energy productionContractile force generationSpecific genes coding for:Myosin, actin, dystophin

DCM: PeripartumDiagnostic Criteria 1 mo pre, 5 mos postEcho: LV dysfunction LVEF < 45% LVEDD > 2.7 cm/m2 Epidemiology/Etiology1:4000 womenJAMA 2000;283:1183Proposed mechanisms: Inflammatory Cytokines: TNFa, IL6, Fas/AP01JACC 2000 35(3):701.

PPCM: Prognosis Death from CM: 91-97245 CM deaths in US, 0.88/100,000 live births, 70% peripartumIncreased risk with:Maternal ageAA 6.4x greaterWhitehead SJ. ObGyn2003;102:1326.Risk of recurrent pregnancyRetrospective 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 ES relationshipLampert MB. AJOG.1997.176.189.

Dilated Cardiomyopathy

MECHANISMS IN HEART FAILUREHemodynamic DerangementClinical Heart FailureArrhythmiaNeurohormonesCytokinesOxidative stressIschemic injuryMyocardial diseaseGeneticsAltered molecular expressionUltrastructural changesMyocyte hypertrophyMyocyte contractile dysfunctionApoptosisFibroblast proliferationCollagen depositionVentricular remodeling

PathophysiologyInitial Compensation for impaired myocyte contractility:Frank-Starling mechanismNeurohumoral activation intravascular volume

Eventual decompensationventricular remodelingmyocyte death/apoptosisvalvular regurgitation

Pathophysiology: Starling Curve

Pathophysiology: NeurohumoralAdrenergic nervous systemRenin-angiotensin-aldosterone axisVasopressinNatriuretic peptidesEndothelin

Reduced Response to Adrenergic Stimulation

Renin-Angiotensin-Aldosterone PathwaysAngiotensinogenAngiotensin-IAngiotensin-IIReninACEAT-1 ReceptorChymaseBradykinindegradationACE-inhibitorAngiotensinreceptorblockerAldosteroneSpironolactone

Angiotensin-II EffectsVasoconstrictionAldosterone productionMyocyte hypertrophyFibroblast proliferationCollagen deposition

ApoptosisPro-thromboticPro-oxidantAdrenergic stimulationEndothelial dysfunction

The Kidney in Heart FailureReduced renal blood flowReduced glomerular filtration rateIncreased renin production Increased tubular sodium reabsorptionIncreased free water retention (vasopressin)

Ventricular Remodeling in Heart Failure

Ventricular Remodeling following MI

Extracellular Stimuli of Myocyte Hypertrophy

Type

Examples

Mechanical

Stretch

Vasoactive peptides

Angiotensin-II

Endothelin-1

adrenergic agonists

Norepinephrine

Peptide growth factors

Fibroblast GF

Insulin-like GF

Cytokines

TNF-

Clinical FindingsBiventricular Congestive Heart Failure

-Low forward Cardiac Output-fatigue, lightheadedness, hypotension

-Pulmonary Congestion-Dyspnea, -orthopnea, & PND

-Systemic Congestion-Edema-Ascites-Weight gain

Physical ExamDecreased C.O.Tachycardia BP and pulse pressurecool extremities (vasoconstriction)Pulsus Alternans (end-stage)Pulmonary venous congestion:ralespleural effusionsCardiac:laterally displaced PMIS3 (acutely)mitral regurgitation murmurSystemic congestion JVDhepatosplenomegalyascitesperipheral edema

Diagnostic StudiesCXR -enlarged cardiac silhouette, vascular redistribution interstitial edema, pleural effusionsEKG normaltachycardia, atrial and ventricular enlargement, LBBB, RBBB, Q-wavesBlood Tests (ANA,RF, Fe2+, TFTs,ferritin,)Echocardiography LV size, wall thickness functionvalve dz, pressuresCardiac CatheterizationhemodynamicsLVEFangiographyEndomyocardial Biopsy

Echo in dilated CM

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

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;5:357-382Criteria for NYHA Functional Classification

Aim of TreatmentPreload reductionDiureticsvenodilators

Vasodilators ACEIInotropesAcutelyChronicallymortality

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

Drug

Mechanism

Action

Use

Nitroglycerin and long-acting nitrates*

Direct via nitric oxide

Veno / arterioloar

Hemodynamic; anti-ischemic; long term

Nitroprusside

Direct via nitric oxide

Arteriolar >

venodilation

Hemodynamic

Hydralazine*

Direct

Arteriolar

?long term*

ACE inhibitors#

Reduced A-II

Incr. bradykinin

Veno / arterioloar

Long-term

Dobutamine and Milrinone Effects

Electrical and Mechanical Ventricular Dyssynchrony

Experimentally induced LBBB has effect on:expression of regional stress kinasescalcium-handling proteins.Expression of p38-MAPK (a stress kinase) is elevated in the endocardium of the late-activated region, whereas phospholamban is decreased.Sarcoplasmatic reticulum Ca2+-ATPase is decreased in the region of early activation.

Deleterious Hemodynamic Effects of LV DyssynchronyDiminished SV & CO due:Reduced diastolic filling time1Weakened contractility 2Protracted MV regurgitation 2Post systolic regional contraction 3

Atrio-ventricularInter-VIntra-VCazeau, et al. PACE 2003; 26[Pt. II]: 137143 1. Grines CL, Circulation 1989;79: 845-853 2. Xiao HB, Br Heart J 1991;66: 443-447 3. Sgaard P, JACC 2002;40:723730

CRT: Cardiac Resynchronization Therapy1. Improved hemodynamicsIncreased COReduced LV filling pressuresReduced sympathetic activityIncreased systolic function w/o MVO22. Reverse LV remodeling/architectureDecreased LVES/ED volumesIncreased LVEFCirc 02, JACC 02, JACC 02, NEJM02

Risk of Sudden Death c/w EFPatients without LV Dysfunction(LVEF >35%)Maggioni AP. GISSI-2 Trial Circulation. 1993;87:312-322.Patients with LV Dysfunction(LVEF < 35%)No PVBs 1-10 PVBs/h > 10 PVBs/h0.86A0.880.900.920.940.960.981.000306090120150180DaysSurvivalp log-rank 0.0020.880.900.920.940.960.981.000306090120150180DaysSurvivalBp log-rank 0.00010.86

Anti-arrhythmic drugs, ICD placebo and Death

What are the two characteristic findings in DCM?

Hypertensive Hypertrophic Cardiomyopathy

Women and HypertensionPrevalence of HTN in Women from NHANES-III. Burt VL. Hypertension 95

Diastolic Dysfunction40-50% of pts w/ CHF have nml LVEFVasan JACC 99Grossman Circ 00Prevalence:increases with agehigher in womenEtiology: HTN & LVHDiagnosis:MV& PV DopplerTDI, Color m-mode

Zile MR. Circ;105:1387Echo Doppler Parameters

Diastolic DysfunctionKawaguchi M. Circ 2003.107:714

Zile MR. Circ;105:1387Isolated Diastolic HF

Isolated Systolic HF

Systolic & Diastolic HF

What is the difference between systolic and diastolic LV dysfunction?

Hypertrophic CardiomyopathyLeft ventricular hypertrophy not due to pressure overload Hypertrpohy is variable in both severity and location:-asymmetric septal hypertrophy-symmetric (non-obstructive)-apical hypertrophyVigorous systolic function, but impaired diastolic functionimpaired relaxation of ventricleselevated diastolic pressures

prevalence as high as 1/500 in general populationmortality in selected populations 4-6% (institutional)probably more favorable (1%)

EtiologyFamilial in ~ 55% of cases with autosomal dominant transmissionMutations in one of 4 genes encoding proteins of cardiac sarcomereaccount for majority of familial cases

-MHCcardiac troponin T myosin binding protein C -tropomyosinRemainder are spontaneous mutations.

Hypertrophic Cardiomyopathy

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy

Apical Hypertrophic Cardiomopathy

Pathophysiology

HCM with outflow obstructionDynamic LVOT obstruction (may not be present at rest)

SAM (systolic anterior motion of mitral valve)

LVOT Obstruction LVOT gradient wall stress MVO2 ischemia/angina

LVOT gradient: HR (DFP), preload (LVEDV), afterload(BP). LVOT gradient: BP (Afterload), LVEDV(preload)

Symptoms of dyspnea and angina more related to diastolic dysfunction than to outflow tract obstructionSyncope: LVOT obstruction (failure to increase CO during exercise or after vasodilatory stress) or arrhythmia.

Physical ExamBisferiens pulse (spike and dome)S4 gallop Crescendo/Descrescendo systolic ejection murmur

HOCM vs. Valvular AS Intensity of murmurHOCMASValsalva (preload, afterload) Squatting ( preload, afterload) Standing (preload, afterload)

Holosystolic apical blowing murmur of mitral regurgitation

Diagnostic StudiesEKGNSRLVHseptal Q waves2D-EchocardiographyLVH; septum >1.4x free wallLVOT gradient by DopplerSystolic anterior motion of the mitral valeregurgitationCardiac CatheterizationLVOT gradient and pullbackprovocative maneuversBrockenbrough phen

HCM-ASH using contrast

Cardiac CatheterizationLV pullbackBrockenbrough-Braunwald Signfailure of aortic pulse pressure to rise post PVC Provocative maneuvers:Valsalvaamyl nitrate inhalation

Atrial FibrillationAcute A. Fib is poorly tolerated -Acute Pulmonary Edema and ShockChronic a fib - Fatigue, dyspnea and angina

Rapid HR - decreased time for diastolic filling and LV relaxationLoss of atrial Kick decreased LV filling - decreased SV and increased outflow tract obstruction

Rate slowing with -blockers and Ca2+ channel blockers Digitalis is relatively contra-indicated- positive inotropeDC CardioversionNo p waveP wave present

TreatmentFor symptomatic benefit-blockers mvO2 gradient (exercise)arrythmiasCalcium Channel blockersAnti-arrhythmicsafibamiodoroneDisopyramideAICD for sudden death

antibiotic prophylaxis for endocarditisNo therapy has been shown to improve mortality

HCM: Surgical Treatment

For severe symptoms with large outflow gradient (>50mmHg)Does not prevent Sudden Cardiac Death

Myomyectomyremoval of small portion of upper IV septum +/- mitral valve replacement5 year symptomatic benefit in ~ 70% of patients

Dual Camber (DDD pacemaker) pacingdecreases LVOT gradient (by~25%)randomized trials have shown little longterm benefitpossible favorable morphologic changes

ETOH septal ablation

AICD to prevent sudden death

Hypertrophic CM

Most common cause of death in young people. The magnitude of left ventricular hypertrophy is directly correlated to the risk of SCD.

Young pts with extreme hypertrophy and few or no symptoms are at substantial long-term risk of SCD..Spirito P. N Engl J Med. 1997;336:775-785. Maron BJ. N Engl J Med. 2000;342:365-373.

Wall Thickness and Sudden Death in HCMSpirito P. N Engl J Med. 2000;342:1778-1785.Maximum Left-Ventricular-Wall Thickness (mm)Incidence of Sudden Death(per 1,000 person/yr)02.67.411.018.2

PrognosisSudden Death 2-4%/year in adults4-6% in children/adolescentsAICD for:survivors of SCD with Vfibepisodes of Sustained VTpts with family hx of SCD in young family membersHigh risk mutation (TnT, Arg403Gln)Predictors of adverse prognosis:early age of diagnosisfamilial form with SCD in 1st degree relativehistory of syncopeischemiapresence of ventricular arrhythmias on Holter (EPS)EPSAmiodorone (low dose)Prophylactic AICD?

HCM vs Athletes HeartEndurance training:Physiologic increase in LV massWall thickness and cavity sizeEarly HCM vs Athletes heartDEFINITION: Symmetric,

Why do patients with HCM develop heart failure?

Restrictive CardiomyopathyCharacterized by: impaired ventricular filling due to an abnormally stiff (rigid) ventriclenormal systolic function (early on in disease)intraventricular pressure rises precipitously with small increases in volumePressureVolumeCauses :infiltration of myocardium by abnormal substancefibrosis or scarring of endocardiumnormalrestriction

Amyloid infiltrative CM

AmyloidosisPrimary Amyloidosisimmunoglobulin light chains -- multiple myelomaSecondary Amyloidosisdeposition of protein other than immunoglobulinsenilefamilialchronic inflammatory process

restriction caused by replacement of normal myocardial contractile elements by infiltrative interstitial deposits

Amyloidosis

Amyloid Cardiomyopathy

SarcoidosisRestrictionConduction System DiseaseVentricular Arrhythmias (Sudden Cardiac Death)

Endomyocardial FibrosisEndemic in parts of Africa, India, South and Central America, Asia15-25% of cardiac deaths in equatorial Africahypereosinophilic syndrome (Lofflers endocarditis)Thickening of basal inferior wallendocardial deposition of thrombusapical obliterationmitral regurgitation80-90% die within 1-2 years

Pathophysiology of RestrictionElevated systemic and pulmonary venous pressuresright and left sided congestionreduced ventricular cavity size with SV and CO

Clinical FindingsRight > Left heart failureDyspneaOrthopnea/PNDPeripheral edemaAscites/Hepatomegaly

Fatigue/ exercise tolerance

Clinically mimics constrictive Pericarditis

Diagnostic Studies2D-Echo/Doppler-mitral in-flow velocityrapid early diastolic filling

Catheterization diastolic pressure equilibration restrictive vs constrictivehemodynamics

Endomyocardial biopsy- definite Dx of restrictive pathology

Cardiac Catheterization Prominent y descent dip and plateau rapid atrial emptying rapid ventricular fillingthen abrupt cessation of blood flow due to non-compliant myocardium

Constriction vs. Restrictive CM

TreatmentTreat underlying causer/o constriction which is treatable (restriction poor prognosis)amyloid (melphalan/prednisone/colchicine)Endomyocardial Fibrosis (steroids, cytotoxic drugs, MVR)Hemochromatosis (chelation, phlebotomy)Sarcoidosis (steroids)DiureticsFor congestive symptoms, but LV/RV filling CODigoxin (avoid in amyloidosis)Antiarrhythmics for afibamiodoronePacemaker for conduction system diseaseAnticoagulation for thrombus (esp in atrial appendages)

What is the hemodynamic problem in RCM?

Arrhythmogenic RV DysplasiaMyocardium of RV free wall replaced:Fibrofatty tissue Regional wall motion/function is reducedVentricular arrhythmiasSCD in young

MRI: RV Dysplasia

LV NoncompactionDiagnostic Criteria Prominent trabeculations, deep recesses in LV apexThin compact epicardium, thickened endocardiumStollberger C, JASE 04Other phenotypic findingsPrognosis and Treatment Increased risk of CHF, VT/SCD, thrombosisOechslin EN, JACC 00Hereditary riskScreening of offspringPregnancy: case report

Echo: LV Noncompaction

CardiomyopathyWHO Classificationanatomy & physiology of the LVDilatedEnlarged Systolic dysfunctionHypertrophicThickenedDiastolic dysfunctionRestrictiveMyocardial stiffnessDiastolic dysfunction Arrhythmogenic RV dysplasiaFibrofatty replacement UnclassifiedFibroelastosisLV noncompaction

*The threshold of left ventricular enlargement and dysfunction necessary to diagnose peripartum cardiomyopathy has not been precisely defined. The following definition, based upon a 1992 NHLBI workshop definition for idiopathic dilated cardiomyopathy, has been proposed [34,35]: Left ventricular ejection fraction (LVEF) less than 45 percent AND/OR M-mode fractional shortening less than 30 percent PLUS Left ventricular end-diastolic dimension greater than 2.7 cm/m2

*Fas signaling receptor for apoptosis: All of these are increased in other DCM/CHF cause or marker? JACC ABST:OBJECTIVES: 1) To evaluate the outcome of patients with peripartum cardiomyopathy (PPC) on current treatment for heart failure, 2) to assess the circulating plasma levels of cytokines and Fas receptors and 3) to identify predictors of prognosis. BACKGROUND: Previous studies in patients with PPC were done when angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blocking agents were not routinely used in heart failure. Inflammatory cytokines play an important role in the pathogenesis and progression of heart failure of other etiologies. However, there is a paucity of data regarding cytokine expression in patients with PPC. Plasma concentrations of Fas receptors (an apoptosis-signalling receptor) have not been reported in this population. METHODS: We followed prospectively 29 consecutive black women with PPC. All patients were treated with diuretics, digoxin, enalapril and carvedilol. Echocardiograms were performed at baseline and after six months of treatment. Cytokine and soluble Fas/APO-1 plasma levels were measured at baseline. RESULTS: Tumor necrosis factor-alpha, interleukin-6 and Fas/APO-1 levels were significantly elevated in the study patients compared with 20 healthy volunteers. Eight patients died. sFas/APO-1 levels were significantly higher in patients who died compared with survivors (8.98 +/- 4.5 vs. 5.33 +/- 3 U/ml, respectively, p = 0.02). At six months, ejection fraction improved from 26.7 +/- 10 to 42.7 +/- 16%, p = 0.00003, with an increment of more than 10 U in 10 patients (28.1 +/- 4 to 51.9 +/- 8%, p = 0.000008). CONCLUSIONS: Cytokine and sFas levels are elevated in patients with PPC. Despite treatment with ACE inhibitors and beta-blockers, mortality remains high. However, in 34% of the patients, left ventricular function almost completely normalized. *Initial Compensation for impaired myocyte contractility includes:Frank-Starling mechanismEDV (ventricular dilation) to stroke workNeurohumoral ( sympathetic activation) HR x SV (contractility) to maintain C.O.renal blood flow renin: Angiotensin II PVR Aldosterone & intravascular volume

Eventual decompensation PVR and intravascular volume overburden ventriclespulmonary and systemic congestionTricuspid and mitral regurgitation from annular dilatation**Similar to the previous analysis by Dr. Bigger, we see that EF by itself predicts increased mortality. Next, at low ejection fractions (those less than 35%), we see that the presence of ventricular premature beats (PVBs) provides additional risk-stratification. At greater than 10 PVBs/hour and a low ejection fraction, there is a very high rate of mortality. **Hypertrophy may involve any portion of ventricle:ASH in > 90%symmetric hypertrophyapical hypertrophy

Myocardial fiber disarray -diastolic dysfunction, withimpaired LV relaxation and decreased LV compliance.

Coronary Arteriesintramyocardial arteries with intimal and medial hypertrophydecreased luminal area ischemia

*60-70% reduction in gradientSymptomatic improvement in all patientsCHB in 10-20%Long-term and randomized data not available*Sudden cardiac deaths among young adults and children are most often caused by these genetic disorders. *In HCM the magnitude of hypertrophy is directly related to the risk of sudden death and is strong independent predictor of prognosis. Over a mean follow-up of 6.5 years, 65 of 480 patients (15%) died, 23 suddenly. As shown the risk of sudden death increased progressively and in direct relation to wall thickness (p=.001).*benign and transient ?Persistent diastolic abnormalities