HOPKINS AND HYPERTROPHIC CARDIOMYOPATHY

Xiaoping LinTongji university

Johns Hopkins University

Johns Hopkins, the Quaker merchant, banker and businessman, left $7 million in 1873 to create The Johns Hopkins University and The Johns Hopkins Hospital

Introduction-JHMI

Over $6.5 billion in operating revenues

More than 34,000 combined full-time equivalent employees; among largest private employers in Maryland

Annual outpatient visits: over 2.6 million

Annual Emergency Department visits: over 294,000

Annual hospital admissions: over 114,000

Annually ranked #1 in NIH funding for U.S. medical schools ($439 million)  

•Medical and doctoral students: over 1,400  

•Full-time faculty: over 2,550 •Part-time faculty: over 1,290

Johns Hopkins Medicine (2012 projected)

The Johns Hopkins Johns Hopkins Children’s Center Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Bayview Medical Center All Children's Hospital (St. Petersburg, FL)Howard County General Hospital (Columbia, MD) Sibley Memorial Hospital (Northwest Washington D.C.)Suburban Hospital (Bethesda, MD)

Achievements Achievements

Pioneered surgery for breast cancer (1889)  •First major medical school in the United States to admit women (1893)  •First to develop renal dialysis (1912)  •First direct heart surgery (blue baby operation,1944) u  •Developed cardiopulmonary resuscitation – CPR (1958)  •Invented first implantable, rechargeable pacemaker for cardiac disorders (1972)  •Pioneered complex surgeries for separating twins joined at the head (1987)  •Among the first to isolate and cultivate human embryonic stem cells (1998)  •Discovered that in-vitro fertilization (IVF) appears to be associated with a rare combination of birth defects characterized by excessive growth of various tissues (2002)  •Developed the first biologic pacemaker for the heart, paving the way for a genetically engineered alternative to implanted electronic pacemakers (2002)

“Telomere” Expert Carol Greider Shares 2009 Nobel Prize in Physiology or Medicine

“Aquaporin Protein” Expert Peter C. Agre Shares 2003 Nobel Prize in Chemistry

Hypertrophic cardiomyopathy(HCM)

Hopkins & HCM…over the years

Hopkins HCM Clinic Evolution

2005Launch

2007COE

2010Consortium

Echo Nurses & Sonograp

hers

Grap/

Access

Team

Referring

The HCM Enterprise

HCM Clinic

Echo

Surgery

Genetics

EPPEDS

CMR/CT

Nuclear

HCM Clinic

Clinical/Echo

Basic Science

Hydro-dynamics

GeneticsInformatics

Mechanics

CMR

Nuclear

Clinical

Research

52 M Hx of long standing hypertension Occasional episodes of dizziness Single syncopal episode while standing

44 M Competitive cyclist Borderline hypertension Worsening fatigue; exertional dyspnea x 2

years Echo – severe ventricular hypertrophy

A Tale of Two Hypertrophs

Physiologic hypertrophy – Athlete’s

Heart

Hypertension related hypertrophy

Hypertrophic cardiomyopathy

Infiltrative cardiomyopathy

Cardiac amyloid

Differential Diagnosis

Inherited cardiomyopathy

Mutation in genes encoding sarcomeric proteins

Diverse clinical presentation

Common (1:500)

Spirito: NEJM, 1999Spirito: NEJM, 1999

Hypertrophic Cardiomyopathy (HCM)

Hypertrophy (>1.5 cm) Any distribution

▪ Concentric vs. asymmetric▪ Basal vs. mid vs. apical vs. diffuse

Severity▪ Normal to severe ▪ (6.0 cm- largest reported)

Systolic anterior motion of mitral valve Outflow tract gradient

Present vs. absent Rest vs. provocation Day to day variation

Ommen, Circ, 2003

Typical Features of HCM

Any or all features could be ABSENT

Hypertrophic cardiomyopathy

Challenges:

1. Distinguish HCM from other causes of hypertrophy (hypertensive heart disease, athlete’s heart)

2. Risk stratification of sudden death

3. Preclinical diagnosis

Needed:

Non-invasive diagnostic tools (EP, imaging, genomic, proteomic computational) to reliably diagnose HCM and distinguish it from other pathologies

Goals of HCM program at JHU

Detailed characterization of phenotype using advanced imaging (2D echo strain, MRI) and EKG

Discovery of causal or modifier genes in HCM (miRNA genes)

Improved understanding of HCM pathophysiology using transgenic mouse models

Generation of computational models to assess sudden death risk and understand arrhythmias

Design metabolism-based therapies and imaging for preclinical diagnosis/treatment of HCM

EKG and Echo/Mechanics

Aurelio PinheiroXiaoping LinLea DimaanoHsin-Yueh LiangLars SorensenFatih YalcinNagis Kucukler

Cyclic changes

muscle length

wall thickness

Changes are

quantifiable

Rate of change

(strain rate)

Extent of change

(strain)

The Heart is a Mechanical Organ

New techniques: Strain and strain rate echocardiography

Accepted by 2011 AHA (American heart association) scientific session

MRI

Miguel SantaulariaStefan ZimmermanJens-Vogel ClaussenDavid Bluemke

Miguel SantaulariaJens-Vogel Claussen

Prevalence and Clinical Attributes of T2-weighted edema in HCM Tissue injury alters T2 relaxation CMR-based T2 imaging sensitive to regional and global myocardial water content Myocardial edema an important determinant

Variable Mild LVH

Severe LVH

p-value

Edema 34% 80% 0.001

DE 45% 86% 0.001

Perfusion Abn

8% 33% 0.006

Nuclear Imaging

Paco Bravo ValenzuelaFrank Bengel

N-13Ammonia PET/CT

STRESS

REST

STRESS

REST

Tc-99m Tetrofosmin SPECT

Paco Bravo Valenzuela

23 F with severe angina and HCM…..sent to psychiatry

Basic Science

Roselle AbrahamXiaoping LinBrian FosterMiguel AonSonia CortasaBrian O’Rourke

Xiaoping LinRoselle AbrahamBrian O’Rourke

How does exercise influence phenotype in normal thickness HCM Examine mitochondrial physiology Reactive oxygen speciesPatch clamp2-photon imaging

Informatics/Computational Medicine

Rai WinslowSteve GraniteHagit ShatkayLaurent YounesSiamak ArdekaniMatt ToerperMike ShipwayBlaid Mbiyangandu (HCM – CVRG liaison)Junaid AfzalXun Zhou

HCM consortium – CVRG infrastructure

Electrophysiology and Genetics

Roselle AbrahamLarisa TereschenkoXiaoping LinBlaid MbiyanganduGarry CuttingSteven SteinbergDan Arking

Results: Step1 bioinformatics analysis

Potential causative or modifier miRNAs for HCM were identified

Fig2. Literature search was performed in two steps: 1) miRNAs regulation dysfunction were observed in human heart (hypertrophy, failing or cardiomyopathy) and In vitro/vivo experiments confirmed their role in cardiac pathological process: hypertrophy, fibrosis and apoptosis 2)Confirm their role in other phenotype secondary to HCM, like metabolic deficiency and electrophysiological dysfunction

Results: step 2 Sequencing results

Subjects:HCM Patients 199111 familial 88 sporadic (?)Hispanic:1; African American: 11; Asian: 1; Caucasian: 176; Others:10

miRNAs studied miRNAs (positive) FindingsmiR1-1 miR-1-1 SNPmiR1-2 miR-1-2 SNP

miR133a-1 miR133a-2 MIR133a-2 SNPmiR30C-1 miR30C-2 miR29a

miR29b-1 MIR29b-1 SNP, deletion (4 bp)miR29b-2 MIR29b-2 deletion (1 bp)

miR29c MIR29c SNPmiR23a miR21 MIR21 insertion ( 1 bp)

miR208a miR208b miR195 miR590 MIR590 SNPmiR15a miR16-1 MIR16-1 SNP

Results overview

The more you know (image) …..the better decision you will make

Thank you