Cardiomyopathy

1. Cardiomyopathy Dr. Jamal Dabbas Interventional cardiologist & internist

2. Definition:A 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. Cardiomyopathies either are confined to the heart or are part of generalized systemic disorders, often leading to cardiovascular death or progressive heart failure-related disability. Ref: American Heart Association, Clinical Cardiology Current Practice Guidelines by OXFORD 2016, page:427

4. Dilatedcardiomyopathy Definition: Dilatedcardiomyopathy(DCM)ischaracterizedbyleftventriculardilatationandsystolicdysfunctionintheabsenceofhypertension,coronaryarterydisease,valvedisease,congenitalheartdisease,andotheroverloadingconditions.Leftventriculardiastolicdysfunctionmaycoexist,andatrialdilationaswellasrightventriculardilationanddysfunctioncanalsodevelop.

6. MAJORCAUSESOFDILATEDCARDIOMYOPATHY: Inflammatory Myocarditis: Infective Viral (coxsackie, a adenovirus, a HIV, hepatitis C) Parasitic (T. cruzi—Chagas’ disease, trypanosomiasis, toxoplasmosis) Bacterial (diphtheria) Spirochetal (Borrelia burgdorferi—Lyme disease) Rickettsial (Q ever) Fungal (with systemic infection) Noninfective Granulomatous inflammatory disease Sarcoidosis Giant cell myocarditis Eosinophilic myocarditis Polymyositis, dermatomyositis Collagen vascular disease Peripartum cardiomyopathy Transplant rejection

7. Toxic: Alcohol Catecholamines: amphetamines, cocaine Chemotherapeutic agents (anthracyclines, trastuzumab) Interferon Other therapeutic agents (hydroxychloroquine, chloroquine) Drugs of misuse (emetine, anabolic steroids) Heavy metals: lead, mercury Occupational exposure: hydrocarbons, arsenicals Metabolic: Nutritional deficiencies: thiamine, selenium, carnitine Electrolyte deficiencies: calcium, phosphate, magnesium Endocrinopathy Thyroid disease Pheochromocytoma Diabetes Obesity Hemochromatosis Inherited Metabolic Pathway Defects

8. Familial: Skeletal and cardiac myopathy Dystrophin-related dystrophy (Duchenne’s, Becker’s) Mitochondrial myopathies (e.g., Kearns-Sayre syndrome) Arrhythmogenic ventricular dysplasia Hemochromatosis Associated with other systemic diseases Susceptibility to immune-mediated myocarditis Overlap with Nondilated Cardiomyopathy:“Minimally dilated cardiomyopathy” Hemochromatosis Amyloidosis Hypertrophic cardiomyopathy (“burned-out”) “Idiopathic”

9. Pathology • Cardiac dilatation • ? Adaptive – due to increased loading conditions • Idiopathic DCM – maladaptive.. • Myocellular hypertrophy and cell death • Cardiac hypertrophy – adaptive response • increase in collagen content • preserves myocardial performance • Cumulative loss of myofibrils and cardiac • myocytes • apoptosis, cellular necrosis decrease in the wall thickness

10. Extracellularmatrixremodeling • Cardiac fibroblast proliferate • Mechanically stable cross linked collagen is degraded by metalloproteinases • Excess of poorly cross-linked collagen is deposited into interstitium • Increase myocardial mass, intersitial fibrosis, • ventricular dilatation

11. IDIOPATHICDILATEDCARDIOMYOPATHY PATHOLOGICFINDINGS

12. MOLECULARDEFECTSINDILATED CARDIOMYOPATHY GENES LaminA/C δ-sarcoglycan DystrophinDesminVinculinTitinTroponin-T α-tropomyosin ß-myosinheavychainActin MitochondrialDNAmutations FatkinD,etal.NEJM1999;341

13. Clinical features • Highest incidence in middle age • Symptoms may be gradual in onset • Acute presentation • Misdiagnosed as viral URTI in young adults • Symptoms/Signs of heart failure • Pulmonary congestion (left heart failure) dyspnea (rest, exertional, nocturnal), orthopnea • Systemic congestion (right heart failure) edema, nausea, abdominal pain, nocturia • Low cardiac output • Hypotension, tachycardia, tachypnea • Fatigue and weakness • Arrhythmia • Atrial fibrillation, conduction delays,,sudden death

14. Incidenceof symptoms • Heartfailuresymptoms • Anginalchestpain • Emboli(systemicorpulmonary) • Syncope • Suddencardiacdeath 75%-85% 8%-20% 1%-4% <1% <1%

15. DCM-IncidenceandPrognosis • Prevalence is36per100,000population • Thirdmostcommoncauseofheartfailure • Mostfrequentcauseofhearttransplantation • Completerecoveryis rare • 50%diewithin2yrsand25%survive longerthan 5yrs

16. ECG • Sinus tachycardiainpresenceof heartfailure. • Atrialand ventriculartachyarryhthmias • Poor r waveprogression • Anterior q waves • Intaventricularconductiondefects–mostlyLBBB • Leftatrialabnormality • Hypertensivechangesby voltagecriterianot • evident

17. Echocardiography • Dilated chambers • Left atrium is usually enlarged • Left ventricle is enlarged. Normal 3.8—5.0cm • Mitral and tricuspid regurgitation on doppler • flow. • Stress testing -- tachyarryhthmias • Dobutamine stress echo helpful in assessing the clinical prognosis.

18. DILATEDCARDIOMYOPATHY PROVENTHERAPEUTICOPTIONS TREATMENTINDICATIONS ACEInhibitors Symptomaticheartfailureand asymptomaticLVdysfunction ACEintoleranceACEintoleranceVolumeoverload Diuretic-induceddepletionSymptomaticheartfailureinadditiontoACEinhibitor Persistentheartfailuredespite diuretics,ACEinhibitor ChronicorparoxysmalatrialfibrillationLVthrombusorprioremboliceventCardiacarrest;uncontrolledVT ARBs Hydralazine-nitratesDiuretics Potassium/MagnesiumBeta-blockers Digoxin Warfarin ICD

19. Peripartumcardiomyopathy • definition---fourcriteria:threeclinicalandoneechocardiographic– • Developmentofheartfailureduringlasttrimesterofpregnancyorfirstsixmonthspostpartum. • Absenceofanyidentifiablecauseforcardiacfailure. • Absenceofanyrecognizableheartdiseasepriortolasttrimesterofpregnancy. • Echocardiographiccriteria-Demonstrableechocardiographicproofofleftventricularsystolicdysfunction.Ejectionfractionlessthan45%,leftventricularfractionalshorteninglessthan30%orleftventricularend-diastolicdimension>2.7cm/msquareofbodysurfacearea.

20. Hypertrophiccardiomyopathy This is the most common form of cardiomyopathy, with a prevalence of approximately 100 per 100 000. It is characterized by inappropriate and elaborate left ventricular hypertrophy with mal-alignment of the myocardial fibres and myocardial fibrosis caused by mutation of genes encoding sarcomeric proteins. The hypertrophy may be generalized or confined largely to the interventricular septum or other regions .

21. Pathogenesis • Autosomal dominant with variable penetrance. • Remaining are sporadic. • Mutations are mostly missense. • Mutations causing HCM found in genes encoding β MHC,cardiac TnT,α tropomyosin,myosin binding protein C.

22. ThemajorabnormalityoftheheartinHCM--excessivethickeningofthemuscle.Thickeningusuallybeginsduringearlyadolescenceandstopswhengrowthhasfinished.uncommonforthickeningtoprogressafterthisageThemajorabnormalityoftheheartinHCM--excessivethickeningofthemuscle.Thickeningusuallybeginsduringearlyadolescenceandstopswhengrowthhasfinished.uncommonforthickeningtoprogressafterthisage • leftventriclealmostalwaysaffected • Hypertrophyisusuallygreatestintheseptum,associatedwithobstructiontotheflowofbloodintotheaorta

23. Asymmetricseptalhypertrophywithobstructiontotheoutflowofbloodfromtheheartmayoccur.Themitralvalvetouchestheseptum,blockingtheoutflowtract.SomebloodisleakingbackthroughthemitralvalvecausingmitralregurgitationAsymmetricseptalhypertrophywithobstructiontotheoutflowofbloodfromtheheartmayoccur.Themitralvalvetouchestheseptum,blockingtheoutflowtract.Somebloodisleakingbackthroughthemitralvalvecausingmitralregurgitation

24. Extensivemyocytehypertrophy • Myofiberdisarray • Interstitialandreplacementfibrosis

25. Pathophysiology • Impaireddiastolicfilling-----reducedstrokevolume • ReducedCOandincreaseinpulmonaryvenouspressure---exertionaldyspneoa • Diastolicdysfunction • – Impaireddiastolicfilling,fillingpressure • Myocardialischemia • • • • MitralregurgitationArrhythmias

26. Clinical features • Asymptomatic • Echocardiographicfindingonly • Symptomatic • Dyspneain90% • Harshsystolicejectionmurmur • Anginapectorisin75% • Fatigue,pre-syncope,syncope,riskofSCD • Palpitation,paroxysmalnocturnaldyspnea,CHF,dizziness • Atrialfibrillation,thromboembolism

27. Physical Findings • With outflow obstructionArterialpulsesrapidrise-withbisferienscontourDoubleortripleapicalimpulsesmaybepalpable • Outwardsystolicthrust-ventricularcontraction • Presystolicaccentuatedatrialcontraction. • Medium-pitchESMatthelowerleftsternalborderandapex • Loudmurmurs-LVoutflowgradients>30mmHg • Without subaortic gradientsSubtle-withnoorsoftsystolicmurmurForcefulapicalimpulse

28. ECG Abnormal->90%ofpts&>75%ofasymptomaticrelatives • IncreasedvoltagesconsistentwithLVhypertrophy • ST-Tchanges-markedTwaveinversioninthelateralprecordialleads • Leftatrialenlargement • DeepandnarrowQwaves • DiminishedRwavesinthelateralprecordialleads. • NormalECG-5%ofpts • Lessseverephenotypeandfavorablecourse • Notpredictiveoffuturesuddendeath • Increasedvoltages • WeaklycorrelatedwiththemagnitudeofLVhypertrophy • Donotdistinguishtheobstructiveandnonobstructiveforms

29. Holter • Supraventriculartachycardia(46percent) • Prematureventricularcontractions(43percent) • Nonsustainedventriculartachycardia(26percent) • Atrialfibrillation(25to30percent) • PreexcitationhasalsobeenassociatedwithHCM

30. Serum C-terminal propeptide of type Iprocollagen (PICP) ElevatedlevelsPICPindicatedincreasedmyocardialcollagensynthesisinsarcomere-mutationcarrierswithoutovertdisease. ProfibroticstateprecededleftventricularhypertrophyorfibrosisvisibleonMRI.

31. ECHOCARDIOGRAPHY • Diffusehypertrophyoftheventricularseptumandanterolateralfreewall(70%to75%) • Basalseptalhypertrophy(10%to15%) • Concentrichypertrophy(5%) • Apicalhypertrophy(<5%) • Hypertrophyofthelateralwall(1%to2%). • Mitralannulusvelocity,Ea-statusofmyocardialrelaxation-reducedinmostpatientswithHCM

32. MimickingHypertrophicCardiomyopathy • Chronichypertension • RVhypertrophy • cardiacamyloidosis • Athlete'sheart • Phaeochromocytoma • Long-termhaemodialysis • Fabrydisease • Friedreichataxia. • Apicalhypertrophy-apicalcavityobliterationcausedbyhypereosinophilicsyndromeornoncompaction.

33. Athlete'sHeartVsHypertrophic Cardiomyopathy • Athleticheart • Concentric&regresses • • <15mm • • <40mm • • >45mm • Normal • HCM • Canbeasymmetric • Wallthickness:>15mm • • • • • • LA: LVEDD: >40mm <45mm Diastolicfunction:alwaysabnormal

34. CMR(Cardiovascular magneticresonance imaging ) • Moreaccuratethanecho • Candetect6%morehypertrophy • Accuratemeasurementofthickness • Shouldbedonein • --Poorechowindow • --DiscrepancybetweenClinicalfindings/ECG/Echo

35. CMR IncreasedLVmassindex– notsensitive–20%HCMnormal Betterdifferentiationbetweenphysiological&pathologicalLVH End-diastolicwallthickness–to–cavityvolumeratio<0.15mm/mL/m2 LackofLGE(lategadoliniumenhancement)oftheventricular myocardium

36. CMR-PoorPrognostic factors • MarkedlyelevatedLVmassindex(men>91g/m2;women>69g/m2)wassensitive(100%) • Maximalwallthicknessofmorethan30mmwasspecific(91%)forcardiacdeaths • Rightventricular(RV)hypertrophy • MyocardialedemabyT2-weightedimaging • LGE(Lategadoliniumenhancement)hasbeenassociatedwith • Ventriculararrhythmias • Progressiveventriculardilation

37. MANAGEMENT

38. Generalguidelines • Screeningallfirst-degreerelativesisrecommended • Echocardiography • Children&participatingincompetitiveathleticsEvery12to18months • Adultsnocompetitiveathletics-every5years • Counseledagainstengagingincompetitiveathletics • Maintainhydration

39. SuddenDeath&Riskstratification • Primaryventriculartachycardiaandventricularfibrillation • Adolescentsandyoungadults<30to35yearsofage • MostcommoncauseofAthleticfielddeaths • Deathmostcommonlyoccuratrest

40. HighRisk Primary prevention oneormoreofthefollowing FamilyhistoryofoneormoreprematureHCM-relateddeaths,particularlyifsuddenandmultiple Unexplainedsyncope,especiallyifrecentandintheyoung Hypotensiveorattenuatedbloodpressureresponsetoexercise Multiple,repetitive(orprolonged)NSVTonHolter Massive LVH (wall thickness, ≥30 mm),particularlyinyoungpatients Secondary prevention Priorcardiacarrest Sustainedventriculartachycardia

41. Potentialarbitrators • Whenlevelofriskjudged-ambiguousonthebasisofconventionalmarkers • CMR-delayedenhancement • Thin-walledakineticLVapicalaneurysms • End-stagephase • Percutaneousalcoholseptalablation • Verylimitedprognosticsignificancecanbeattributedto • specificHCM-causingmutations

42. PreventionofSCD • ICDimplantation–asprimaryprevention • followingcardiacarrest. • -assecondarypreventionif • oneormorehighriskfactors. • Empiricalpharmacologicaltherapywith • amiodaroneisnowobsolete.

43. MedicalTreatment • Empirical&highlyvariable • Beta blockers • Slowingheartrate • ReducingforceofLVcontraction • Augmentingventricularfillingandrelaxation • Decreasingmyocardialoxygenconsumption • Long-actingpreparations-propranolol,atenolol,metoprololornadolol • BluntLVoutflowgradienttriggeredbyphysiologicexercise. • Targetrestingheartrate-60beats/min • Mayrequireupto400mgequivalentofmetoprolol

44. Verapamil • Improvessymptomsandexercisecapacity(patientswithout • markedobstructiontoLVoutflow) • Beneficialeffectonventricularrelaxationandfilling • Betteranginacontrolthanbetablocker • HemodynamicdeteriorationwithCCBagents-loweringoftheafterloadinthepresenceofsevereoutflowtractgradientsandhighdiastolicfillingpressures

45. Disopyramide(sodium channel blocker) Negativeinotropiceffectdecreasesthegradientandimprovesymptoms. Concomitantbetablockademaybeimportanttopreventrapid atrioventricularnodeconduction Between300and600mg/d ThecorrectedQTintervalmustbemonitored Anticholinergicsideeffectsinolderpatients Diureticagentsmaybejudiciouslyadministered Eitherbetablockersorverapamilinitially NoadvantagebycombinationsofBB&CCBDisopyramidemaybecombinedwithBBorCCB

47. Surgicalmyectomy • Drug-refractoryheartfailuresymptoms • NYHAClassesIII(Markedlimitationofphysicalactivity.Comfortableatrest.Lessthanordinaryactivitycausesfatigue,palpitation,ordyspnea)&IV(Unabletocarryonanyphysicalactivitywithoutdiscomfort.Symptomsofheartfailureatrest.Ifanyphysicalactivityisundertaken,discomfortincreases). • LVoutflowobstruction • Rest-gradient ≥ 30 mmHg • Physiologicexercise-gradient ≥ 50 mmHg • Transaorticresectionofmusclefromtheproximaltomidseptalregion.Operativemortality<1percent • Maintainlong-lastingimprovementinsymptomsandexercisecapacityMortalitymaybeimprovedafterseptalmyectomy

48. DDDPacing(dual-chamberedpacing) • Objectivemeasurementsofexercisecapacitydidnotdiffersignificantly. • Overalldecreaseinoutflowtractgradient(25to40percentofbaseline) • Roleofdual-chamberpacing-patientsathighriskforothertherapeuticmodalities. • Candidatesfordual-chamberpacing • Significantbradycardiainwhichpacingmayallowan • increaseddosageofmedication • PatientswhoneedICDasaprimarytreatment

49. AlcoholSeptalAblation • Outflowtractgradientisreducedfromameanof60to70mmofmercuryoftento<20mmofmercury • 80–85%symptomaticimprovement • Complications • completeheartblock<10% • coronarydissections • largemyocardialinfarctions • ventricularseptaldefects • myocardialperforations • ventricularfibrillation

50. Restrictivecardiomyopathy In this rare condition, ventricular filling is impaired because the ventricles are ‘stiff’ .This leads to high atrial pressures with atrial hypertrophy, dilatation and later, atrial fibrillation.