Hypertrophic Cardiomyopathy

Stephen Heitner, MDD

A Little Backround

Some Diagnostic Testing

Clinical Considerations

Tratment Considerations

14 y/o playing at school

25 y/owalking

home from work

25 y/owalking

home from work

21 y/o Running to catch a bus

21 y/ocycling in a home in a

storm

45 y/oafter mitral

valve surgery

28 y/o collapse in the street

33 y/o walking to work

Teare D. Asymmetrical hypertrophy of the heart in young adults. British heart journal 1958;20:1-8.

Morrow AG, Braunwald E. Functional aortic stenosis; a malformation characterized by resistance to left ventricular outflow without anatomic obstruction. Circulation 1959;20:181-9.

27 y/o Murmur

20 y/oDyspnea and chest

pain

16 y/o Murmur and angina

1956

Braunw

ald

1959

Hollman

1958

Teare

1960

Morrow

Brocke

nbro

ugh

1961

1964

Harriso

nBrau

nwald

Sigwart

1995

1990

Seidm

an

1990

idman

Maron

2000

1979

Echo

2006

MRI

Courtesy of Barry Maron

Perspective

HCMPossible HCMCoronary AnomaliesMyocarditisChannelopathiesRuptured AAARVCCommotio CordisOther

Maron, B.J., Sudden death in young athletes. N Engl J Med, 2003. 349(11): p. 1064-75.

New Disease

Scary Disease

Rare Disease

Discovery Phase

Less Scary Disease

Unusual Disease

Treatment Phase

Treatable Disease

Common Disease

A rose by any other name would smell as sweet

Courtesy of Barry Maron

>15mm (adult)> 2 SD (ped)

Elevated wall stressAthletic conditioning

Thick walls Non-dilated LV

No cause for LVH

Definition

Morphologic diagnosis

Normal Architecture

Myocyte Disarray

Histopathologic diagnosis

Interstitial Fibrosis

Histopathologic diagnosis

β-myosin Heavy Chain 25-30%

Myosin-binding protein C 20-30%

Trop T - 3-5%Trop I - < 5%

Tropomysin 1αReg. myosin light chain 2 - <5%

Ess. myosin L-chain 3α-Cardiac actin 1

TitinTroponin C

α-Myosin heavy chainMuscle LIM protein

Myosin light chain kinase 2LIM binding domain 3

TelethoninVinculin/metavinculin

α-Actinin 2Phospholamban

Myozenin 2Junctophilin 2

Sigmoidal40-50%

Reverse Curve30-40%

Neutral10%

Apical10%

The Mitral Valve in HCM

• SAM

• MAC

• Elongation of leaflets

• Decreased mobility of the posterior leaflet

• Abnormal papillary muscle

LVOTO

Kwon, D. H., R. M. Setser, et al. (2008). "Abnormal papillary muscle morphology is independently associated with increased left ventricular outflow tract obstruction in hypertrophic cardiomyopathy." Heart 94(10): 1295-1301.

Fabry’s Disease

Danon’s disease - LAMP2 Deficiency

PRKAγ2 Mutation

Pompe’s diseaseFabry’s disease

Not all hypertrophy is HCM

Pompe’s Disease

Hypertrophy and WPW

SCD

•< 35 yrs•Asymptomatic

AF

•CHF•CVA

CHF

•Exertional•Progressive

Presentation Benign

Maron MS, Rowin EJ, Olivotto I, et al. Contemporary Natural History and Management of Nonobstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2016;67(12):1399-1409. doi:10.1016/j.jacc.2016.01.023.

Maron MS, Rowin EJ, Olivotto I, et al. Contemporary Natural History and Management of Nonobstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2016;67(12):1399-1409. doi:10.1016/j.jacc.2016.01.023.

Heterogenous

Unpredictable

0.2%

Quintessintial Phenotype

Clinical Features

Clinical Features

Physical Findings

Physical Findings

Obstruction to LV outflow is dynamic, varying with loading conditions and

contractility of the ventricle

•Valsava•Inotropic agents•Dehydration•Decrease afterload

•Hand-grip•Negative inotropes•Increased afterload

LV Cavity Volume or

Contractility

Increased Murmur

LV Cavity Volume or

Contractility

Decreased Murmur

CHF LVOTO

Systolic HF

Diastolic HF

LVOTO

+

LVOTO

Not all HCM has LVOTO

Septal Hypertrophy

DragDrag

Suction

LVOTO

Posteriorly directed MR

Valsalva

LVOTO

Kwon, D. H., R. M. Setser, et al. (2008). "Abnormal papillary muscle morphology is independently associated with increased left ventricular outflow tract obstruction in hypertrophic cardiomyopathy." Heart 94(10): 1295-1301.

Physical Findings

Valvular Aortic Stenosis IHSS

Brockenbrough’s Sign

EDWIN C. BROCKENBROUGH, EUGENE BRAUNWALD and ANDREW G.A Hemodynamic Technic for the Detection of Hypertrophic Subaortic Stenosis, Circulation. 1961;23:189-194

LVOTO

Maron, M. S., I. Olivotto, et al. (2003). "Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy." The New England journal of medicine 348(4): 295-303.

LVOTOTreatment of LVOTO

β-blockerCa++-blockerDysopirimide

Medical Septal Reduction Pacemaker

Induction of Septal Dyssynchrony

Mitral Valve Plication

ETOH Septal Ablation

Pap Realignment

Surgical Myectomy

LVOTOMedical Therapies

β-blockers 1

Non-dihydropyridine Ca++-blockers

VerapamilDiltiazem

2

Disopyrimide3

LVOTO

Sherrid, M. V., I. Barac, et al. (2005). "Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy." Journal of the American College of Cardiology 45(8): 1251-1258.

Morrow Procedure

Ommen, S. R., B. J. Maron, et al. (2005). "Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy." Journal of the American College of Cardiology 46(3): 470-476.

Ball, W., J. Ivanov, et al. (2011). "Long-term survival in patients with resting obstructive hypertrophic cardiomyopathy comparison of conservative versus invasive treatment." Journal of the American College of Cardiology 58(22): 2313-2321.

LVOTO

Alcohol Septal Ablation

Infarct

Sorajja, P., U. Valeti, et al. (2008). "Outcome of alcohol septal ablation for obstructive hypertrophic cardiomyopathy." Circulation 118(2): 131-139.

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Nagueh, S. F., B. M. Groves, et al. (2011). "Alcohol septal ablation for the treatment of hypertrophic obstructive cardiomyopathy a multicenter north american registry." Journal of the American College of Cardiology 58(22): 2322-2328.

98%

96%

83%

Ommen, S. R., B. J. Maron, et al. (2005). "Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy." Journal of the American College of Cardiology 46(3): 470-476.

LVOTO

98%

95%

88%

1st Septal Perforator

LAD

PDA

Acute Marginal

AV-Nodal Artery

RCA

SA-Nodal ArteryS

LVOTO

LVOTO

LVOTO

Fananapazir, L., et al., Impact of dual-chamber permanent pacing in patients with obstructive hypertrophic cardiomyopathy with symptoms refractory to verapamil and beta-adrenergic blocker therapy. Circulation, 1992. 85(6): p. 2149-61.

Maron, B.J., et al., Assessment of permanent dual-chamber pacing as a treatment for drug-refractory symptomatic patients with obstructive hypertrophic cardiomyopathy. A randomized, double-blind, crossover study (M-PATHY). Circulation, 1999. 99(22): p. 2927-33.

LVOTO

Systolic HF β-blockerACE-I or ARBAldosterone

BlockerDiuretic

ICD +\- CRT

Transplantation

Diastolic HF

Careful Diuresis

Transplantation

SCD

•Paucity of data•Relative infrequency of HCM and SCD•Cumulative Morbidity of living with an ICD

ICD

ICD for 1o Prevention

•Personal Hx of SCD/VT/VF•Documented NSVT•Family Hx of SCD•Unexplained Syncope•Wall thickness >30mm•Abnormal exercise BP response

Established Risk Markers

O'Mahony, C., et al., A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM risk-SCD). Eur Heart J, 2014. 35(30): p. 2010-20.

http://www.doc2do.com/hcm/webHCM.html

SCDSCDSCD

SCDSCDSCD

AF

2/3 patients are symptomatic

All patients should be anti-coagulated unless contraindicated

Common - about 1/4 patients will develop AF

Associated with a worse survival

AF

Olivotto, I., F. Cecchi, et al. (2001). "Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy." Circulation 104(21): 2517-2524.

Clinical Trials at OHSUEleclazine

PerherhexilineexilineB-myosin HC inhibitor

Exercise in HCMNovel predictors HCM

Thank You

heitner@ohsu.edu

DAM that SAM

Genotype Guided Therapy

40 mmHg

Effect of Isoproterenol Effect of Propranolol

Harrison DC, Braunwald E, Glick G, Mason DT, Chidsey CA, Ross J, Jr. Effects of Beta Adrenergic Blockade on the Circulation with Particular Reference to Observations in Patients with Hypertrophic Subaortic Stenosis. Circulation 1964;29:84-98.

Mitten, M. J., B. J. Maron, et al. (2005). "Task Force 12: legal aspects of the 36th Bethesda Conference recommendations." Journal of the American College of Cardiology 45(8): 1373-1375.

Phenotypic Heterogeneity

Lack of Consistent Biological Effect of Current Therapies

Need for Individualized/Targeted Therapies

Biomechanical Stress Sensing Altered Calcium Trafficking

Energy Homeostasis Fibrosis

Structural MechanicalBiochemicalMetabolic

Sarcomeric Mutation +

Stress

Potential Therapeutic Targets

Calcium Trafficking

Myocardial Energetics

Fibrosis

BioMechanical Stress

Oxidative Stress

Diltiazem

Perhexiline

RAAS Modulation

M-band and Z-disc

Atorvastatin, NAC