cardiomyopathy 2

8/22/2019 Cardiomyopathy 2

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CARDIOMYOPATHY

Athena Poppas, MD

Associate Professor of Medicine,

Brown Medical School

Director, Echocardiography Laboratory

Rhode Island Hospital


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Cardiomyopathies

Definition: diseases of heart muscle

1980 WHO: unknown causes

Not clinically relevant

1995 WHO: diseases of themyocardium associated with cardiac

dysfunction pathophysiology each with multiple etiologies


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Cardiomyopathy

WHO Classificationanatomy & physiology of the LV

1. Dilated

Enlarged

Systolic dysfunction

2. Hypertrophic Thickened

Diastolic dysfunction

3. Restrictive


4. Arrhythmogenic RV dysplasia Fibrofatty replacement

5. Unclassified

Fibroelastosis

LV noncompaction

Circ 93:841, 1996


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CM: Specific Etiologies

Ischemic

Valvular

Hypertensive Inflammatory

Metabolic

Inherited Toxic reactions

Peripartum

Ischemic: thinned, scarred tissue


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Dilated Cardiomyopathy

Dilation andimpaired contraction of ventricles:

Reducedsystolic 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 cases3X more prevalent among males and African-Americans


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DCM: Etiology

Ischemic

Valvular

Hypertensive

Familial

Idiopathic

Inflammatory

Infectious

Viralpicornovirus, Cox B, CMV, HIVRicketsial - Lyme Disease

Parasitic - Chagas Disease, Toxoplasmosis

Non-infectious

Collagen Vascular Disease (SLE, RA)

Peripartum

ToxicAlcohol, Anthracyclins (adriamycin), Cocaine

Metabolic

Endocrinethyroid dz, pheochromocytoma, DM, acromegaly,

Nutritional

Thiamine, selenium, carnitine

Neuromuscular (Duchenes Muscular Dystrophy--x-linked)


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Prognosis depends on Etiology

1230 pts. referred for unexplained CM. Felker GM. NEJM 2000;342:1077


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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


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DCM: toxic

Alcoholic cardiomyopathy

Chronic use

Reversible with abstinence Mechanism?:

Myocyte cell death and fibrosis

Directly inhibits: mitochondrial oxidative phosphorylation

Fatty acid oxidation


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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


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DCM: PeripartumDiagnostic 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.


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PPCM: Prognosis

Death from CM: 91-97 245 CM deaths in US, 0.88/100,000 live births,

70% peripartum

Increased risk with:

Maternal ageAA 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 ES relationship

Lampert MB. AJOG.1997.176.189.


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Dilated Cardiomyopathy


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MECHANISMS IN HEART FAILURE

Hemodynamic Derangement

Clinical Heart Failure

Arrhythmia

Neurohormones

Cytokines

Oxidative stress

Ischemic injury

Myocardial disease

GeneticsAltered molecular expression

Ultrastructural changes

Myocyte hypertrophy

Myocyte contractiledysfunction

Apoptosis

Fibroblast proliferation

Collagen deposition

Ventricular remodeling


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Pathophysiology

Initial Compensation for impaired myocyte contractility:

Frank-Starling mechanism

Neurohumoral activation

intravascular volume

Eventual decompensation

ventricular remodeling

myocyte death/apoptosisvalvular regurgitation


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Pathophysiology: Starling Curve


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Pathophysiology: Neurohumoral

Adrenergic nervoussystem

Renin-angiotensin-aldosterone axis

Vasopressin

Natriuretic peptides

Endothelin


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Reduced Response to Adrenergic Stimulation


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Renin-Angiotensin-Aldosterone Pathways

Angiotensinogen

Angiotensin-I

Angiotensin-II

Renin

ACE

AT-1 Receptor

Chymase

Bradykinindegradation

ACE-inhibitor

Angiotensinreceptor

blocker

Aldosterone

Spironolactone


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Angiotensin-II Effects

Vasoconstriction

Aldosterone

production Myocyte hypertrophy

Fibroblast proliferation

Collagen deposition

Apoptosis

Pro-thrombotic

Pro-oxidant Adrenergic stimulation

Endothelial dysfunction


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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)


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Ventricular

Remodeling in HeartFailure


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Ventricular Remodeling following MI


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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-


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Clinical Findings

Biventricular Congestive Heart Failure

-Low forward Cardiac Output-fatigue, lightheadedness, hypotension

-Pulmonary Congestion-Dyspnea,-orthopnea, & PND

-Systemic Congestion

-Edema-Ascites

-Weight gain


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Physical Exam

Decreased C.O.

Tachycardia

BP and pulse pressurecool extremities (vasoconstriction)

Pulsus Alternans (end-stage)

Pulmonary venous congestion:

ralespleural effusions

Cardiac:

laterally displaced PMI

S3 (acutely)

mitral regurgitation murmurSystemic congestion

JVDhepatosplenomegaly

ascites

peripheral edema


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Diagnostic Studies

CXR-enlarged cardiac silhouette,

vascular redistribution interstitial edema,

pleural effusions

EKGnormal

tachycardia, atrial and ventricular

enlargement, LBBB, RBBB, Q-waves

Blood Tests(ANA,RF, Fe2+, TFTs,ferritin,)

Echocardiography

LV size, wall thickness function

valve dz, pressures

Cardiac Catheterizationhemodynamics

LVEF

angiography

Endomyocardial Biopsy


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Echo in dilated CM


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Influence of EF on Survival inPatients with Heart Failure

Vasan RS et al. J Am Coll Cardiol. 1999;33:1948-55


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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, butsymptoms 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 Fai lure1999;5:357-382

Criteria for NYHA Functional Classification


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Aim of Treatment

Preload reduction

Diuretics

venodilators

Vasodilators

ACEI

Inotropes

Acutely

Chronically

mortality


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Vasodilator Agents in Heart Failure

Drug Mechanism Action Use

Nitroglycerinand long-

acting nitrates*

Direct via nitricoxide

Veno /arterioloar

Hemodynamic;anti-ischemic;

long term

Nitroprusside Direct via nitricoxide

Arteriolar >venodilation

Hemodynamic

Hydralazine* Direct Arteriolar ?long term*

ACEinhibitors#

Reduced A-IIIncr. bradykinin

Veno /arterioloar

Long-term

*Hydralazine and a long-nitrate shown to reduce mortality long-term

# Other actions (aside from vasodilation) likely to be important


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Dobutamine and Milrinone Effects


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Electrical and Mechanical

Ventricular Dyssynchrony Experimentallyinduced LBBB has effect on:

expressionof regional stress kinases

calcium-handling proteins.

Expression of p38-MAPK(a stress kinase) iselevated in the endocardiumof the late-activated region, whereas phospholamban is

decreased. Sarcoplasmatic reticulum Ca2+-ATPaseis

decreased in the region of early activation.

D l t i H d i


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Deleterious HemodynamicEffects of LV Dyssynchrony

Diminished SV & CO due:

Reduced diastolic filling

time1

Weakened contractility 2

Protracted MVregurgitation 2

Post systolic regionalcontraction 3

Atrio-

ventricular

Inter-V

Intra-V

Cazeau, et al. PACE2003; 26[Pt. II]: 137143

1. Grines CL, Circulation1989;79: 845-853

2. Xiao HB, Br Heart J1991;66: 443-447

3. Sgaard P, JACC 2002;40:723730


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CRT: CardiacResynchronization Therapy

1. Improved hemodynamics Increased CO Reduced LV filling

pressures

Reduced sympatheticactivity Increased systolic function

w/o MVO2

2. Reverse LVremodeling/architecture Decreased LVES/ED

volumes Increased LVEF

Circ 02, JACC 02, JACC02, NEJM02


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Risk of Sudden Death c/w EF

Patients withoutLV Dysfunction

(LVEF >35%)

Maggioni AP. GISSI-2 TrialCirculation. 1993;87:312-322.

Patients with

LV Dysfunction

(LVEF < 35%)

No PVBs

1-10 PVBs/h

> 10 PVBs/h

0.86

A

0.88

0.90

0.92

0.94

0.96

0.98

1.00

0 30 60 90 120 150 180

Days

Survival

p log-rank 0.002

0.88

0.90

0.92

0.94

0.96

0.98

1.00

0 30 60 90 120 150 180

Days

Survival

B

p log-rank

0.0001

0.86

A ti h th i d ICD


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Anti-arrhythmic drugs, ICDplacebo and Death


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What are the two characteristicfindings in DCM?

H t i H t hi


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Hypertensive HypertrophicCardiomyopathy


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Women and Hypertension

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


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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


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Zile MR. Circ;105:1387

Echo Doppler Parameters


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Diastolic Dysfunction

Kawaguchi M. Circ 2003.107:714


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Zile MR. Circ;105:1387

Isolated Diastolic HF

Isolated Systolic HF

Systolic & Diastolic HF

What is the difference


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What is the differencebetween systolic and

diastolic LV dysfunction?


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Hypertrophic Cardiomyopathy

Left ventricular hypertrophy not due to pressure overloadHypertrpohy 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%)


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Etiology

Familial in ~ 55% of cases with autosomal dominant transmission

Mutations in one of 4 genes encoding proteins of cardiac sarcomereaccount for majority of familial cases

-MHCcardiac troponin T

myosin binding protein C-tropomyosin

Remainder are

spontaneous

mutations.

H t hi C di th


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H t hi C di th


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Hypertrophiccardiomyopathy


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Apical HypertrophicCardiomopathy


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Pathophysiology

HCM ith tfl b t ti


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

SAM (systolic anterior motion of mitral valve)

LVOT Obstruction LVOT gradientwall 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 diastolicdysfunction than to outflow tract obstruction

Syncope: LVOT obstruction (failure to increase CO during exercise

or after vasodilatory stress) or arrhythmia.

h l


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Physical Exam

Bisferiens pulse (spike and dome)S4 gallop

Crescendo/Descrescendo systolic ejection murmur

HOCM vs. Valvular AS Intensity of murmurHOCM AS

Valsalva (preload, afterload) Squatting ( preload, afterload) Standing (preload, afterload)

Holosystolic apical blowing murmur of mitral regurgitation


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Diagnostic Studies

EKG NSR

LVH

septal Q waves

2D-Echocardiography LVH; septum >1.4x free wall

LVOT gradient by Doppler

Systolic anterior motion ofthe mitral valeregurgitation

Cardiac Catheterization LVOT gradient and pullback

provocative maneuvers

Brockenbrough phenHCM-ASH using contrast

Cardiac Catheterization


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LV pullback

Brockenbrough-Braunwald Signfailure of aortic pulse pressure to rise post PVC

Provocative maneuvers:Valsalva

amyl nitrate inhalation

Atrial Fibrillation


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Atrial FibrillationAcute A. Fib is poorly tolerated -Acute Pulmonary Edema and Shock

Chronic a fib - Fatigue, dyspnea and angina

Rapid HR - decreased time for diastolic filling and LV relaxation

Loss of atrial Kick decreased LV filling

- decreased SV and increased outflow tract obstruction

Rate slowing with -blockers and Ca2+ channel blockersDigitalis is relatively contra-indicated- positive inotrope

DC Cardioversion

No p wave P wave present


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TreatmentFor symptomatic benefit

-blockers mvO2 gradient (exercise)

arrythmias

Calcium Channel blockersAnti-arrhythmics

afib

amiodorone

Disopyramide

AICD for sudden death

antibiotic prophylaxis for endocarditis

No therapy has been shown to improve mortality

HCM: Surgical Treatment


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HCM: Surgical Treatment

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

Myomyectomy

removal of small portion of upper IV septum

+/- mitral valve replacement5 year symptomatic benefit in ~ 70% of patients

Dual Camber (DDD pacemaker) pacing

decreases LVOT gradient (by~25%)

randomized trials have shown little longterm benefitpossible favorable morphologic changes

ETOH septal ablation

AICD to prevent sudden death


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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 nosymptoms 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.

W ll Thi k d


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Wall Thickness andSudden Death in HCM

Spirito P. N Engl J Med. 2000;342:1778-1785.

0

2

4

6

810

12

14

16

18

20

< 15 16-19 20-24 25-29 > 30

Maximum Left-Ventricular-Wall Thickness (mm)

IncidenceofSudden

Death

(per1,0

00

person/yr)

0

2.6

7.4

11.0

18.2

Prognosis


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Prognosis

Sudden Death 2-4%/year in adults

4-6% in children/adolescentsAICD for: survivors of SCD with Vfib

episodes of Sustained VT

pts with family hx of SCD in young family members

High risk mutation (TnT, Arg403Gln)

Predictors of adverse prognosis:

early age of diagnosis

familial form with SCD in 1st degree relative

history of syncope

ischemiapresence of ventricular arrhythmias on Holter (EPS)

EPS

Amiodorone (low dose)

Prophylactic AICD?


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HCM vs Athletes Heart

Endurance training:

Physiologic increase in LV mass

Wall thickness and cavity size

Early HCM vs Athletes heart

DEFINITION: Symmetric,


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Why do patients with HCMdevelop heart failure?


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Restrictive Cardiomyopathy

Characterized by:

impaired ventricular filling due to an abnormally stiff (rigid) ventricle

normal systolic function (early on in disease)

intraventricular pressure rises precipitously with small increases in volume

Pressure

Volume

Causes : infiltration of myocardium by abnormal substance

fibrosis or scarring of endocardium

normal

restriction


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Amyloid infiltrative CM

Amyloidosis


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Amyloidosis

Primary Amyloidosis

immunoglobulin light chains -- multiple myeloma

Secondary Amyloidosis

deposition of protein other than immunoglobulin

senile

familialchronic inflammatory process

restriction caused by replacement of normal myocardial contractile

elements by infiltrative interstitial deposits


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Amyloidosis


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Amyloid Cardiomyopathy


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Sarcoidosis

Restriction

Conduction System Disease

Ventricular Arrhythmias

(Sudden Cardiac Death)

Endomyocardial Fibrosis


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Endomyocardial Fibrosis

Endemic in parts of Africa, India, South and Central America, Asia

15-25% of cardiac deaths in equatorial Africahypereosinophilic syndrome (Lofflers endocarditis)

Thickening of basal inferior wall

endocardial deposition of thrombus

apical obliteration

mitral regurgitation

80-90% die within 1-2 years


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Pathophysiology of Restriction

Elevated systemic and pulmonary venous pressures

right and left sided congestion

reduced ventricular cavity size with SV and CO

Clinical Findings


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Clinical Findings

Right > Left heart failure

Dyspnea

Orthopnea/PND

Peripheral edema

Ascites/Hepatomegaly

Fatigue/ exercise tolerance

Clinically mimics constrictive Pericarditis

Diagnostic Studies


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Diagnostic Studies

2D-Echo/Doppler-mitral in-flow velocity

rapid early diastolic filling

Catheterization

diastolic pressure equilibrationrestrictive vs constrictive

hemodynamics

Endomyocardial biopsy-definite Dx of restrictive pathology


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Prominent y descent dip and plateau

rapid atrial emptying rapid ventricular filling

then abrupt cessation of blood flow due to non-compliant myocardium

Constriction vs Restrictive CM


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Constriction vs. Restrictive CM

T t t


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Treatment

Treat underlying cause

r/o constriction which is treatable (restriction poor prognosis)

amyloid (melphalan/prednisone/colchicine)

Endomyocardial Fibrosis (steroids, cytotoxic drugs, MVR)

Hemochromatosis (chelation, phlebotomy)

Sarcoidosis (steroids)

Diuretics

For congestive symptoms, but LV/RV filling CODigoxin (avoid in amyloidosis)

Antiarrhythmics for afib

amiodoronePacemaker for conduction system disease

Anticoagulation for thrombus (esp in atrial appendages)

What is the hemodynamic


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What is the hemodynamicproblem in RCM?


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Arrhythmogenic RV Dysplasia

Myocardium of RV free wall replaced:

Fibrofatty tissue

Regional wall motion/function is reducedVentricular arrhythmias

SCD in young

MRI: RV Dysplasia


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MRI: RV Dysplasia

i


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LV Noncompaction

Diagnostic Criteria

Prominent trabeculations, deep recesses in LVapex

Thin compact epicardium, thickened endocardium Stollberger C, JASE 04

Other phenotypic findings

Prognosis and Treatment

Increased risk of CHF, VT/SCD, thrombosis

Oechslin EN, JACC 00 Hereditary risk

Screening of offspring

Pregnancy: case report


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Echo: LV Noncompaction

Cardiomyopathy


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Cardiomyopathy

WHO Classificationanatomy & physiology of the LV1. Dilated

Enlarged

Systolic dysfunction

2. Hypertrophic

Thickened


3. Restrictive

Myocardial stiffness


4. Arrhythmogenic RV dysplasia Fibrofatty replacement

5. Unclassified

Fibroelastosis

cardiomyopathy 2

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