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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