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Xiaoping Lin Tongji university Johns Hopkins University. Hopkins and Hypertrophic cardiomyopathy. Introduction-JHMI. Johns Hopkins, the Quaker merchant, banker and businessman, left $7 million in 1873 to create The Johns Hopkins University and The Johns Hopkins Hospital.

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xiaoping lin tongji university johns hopkins university
Xiaoping Lin

Tongji university

Johns Hopkins University

Hopkins and Hypertrophic cardiomyopathy

slide2

Introduction-JHMI

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

slide3

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
slide5

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)

slide6

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

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

a tale of two hypertrophs
A Tale of Two Hypertrophs
  • 52 M
    • Hx of long standing hypertension
    • Occasional episodes of dizziness
    • Single syncopal episode while standing
  • 44 M
    • Competitive cyclist
    • Borderline hypertension
    • Worsening fatigue; exertionaldyspnea x 2 years
  • Echo – severe ventricular hypertrophy
differential diagnosis
Differential Diagnosis
  • Physiologic hypertrophy – Athlete’s Heart
  • Hypertension related hypertrophy
  • Hypertrophic cardiomyopathy
  • Infiltrative cardiomyopathy
    • Cardiac amyloid
hypertrophic cardiomyopathy hcm1
Hypertrophic Cardiomyopathy (HCM)
  • Inherited cardiomyopathy
  • Mutation in genes encoding sarcomeric proteins
  • Diverse clinical presentation
  • Common (1:500)

Spirito: NEJM, 1999

typical features of hcm
Typical Features of 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

Any or all features could be ABSENT

hypertrophic cardiomyopathy

Challenges:

  • Distinguish HCM from other causes of hypertrophy (hypertensive heart disease, athlete’s heart)
  • Risk stratification of sudden death
  • Preclinical diagnosis
  • Needed:
  • Non-invasive diagnostic tools (EP, imaging, genomic, proteomic computational) to reliably diagnose HCM and distinguish it from other pathologies

Hypertrophic cardiomyopathy

goals of hcm program at jhu
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
aurelio pinheiro xiaoping lin lea dimaano hsin yueh liang lars sorensen fatih yalcin nagis kucukler
Aurelio Pinheiro

Xiaoping Lin

Lea Dimaano

Hsin-Yueh Liang

Lars Sorensen

FatihYalcin

NagisKucukler

EKG and Echo/Mechanics

slide18

New techniques: Strain and strain rate echocardiography

The Heart is a Mechanical Organ

Cyclic changes

muscle length

wall thickness

Changes are quantifiable

Rate of change (strain rate)

Extent of change (strain)

miguel santaularia stefan zimmerman jens vogel claussen david bluemke
Miguel Santaularia

Stefan Zimmerman

Jens-Vogel Claussen

David Bluemke

MRI

miguel santaularia jens 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

Miguel SantaulariaJens-Vogel Claussen

23 f with severe angina and hcm sent to psychiatry

N-13

Ammonia

PET/CT

STRESS

STRESS

REST

REST

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

Tc-99m Tetrofosmin

SPECT

Paco Bravo Valenzuela

roselle abraham xiaoping lin brian foster miguel aon sonia cortasa brian o rourke
Roselle Abraham

Xiaoping Lin

Brian Foster

Miguel Aon

Sonia Cortasa

Brian O’Rourke

Basic Science

xiaoping lin roselle abraham brian o rourke

How does exercise influence phenotype in normal thickness HCM

Examine mitochondrial physiology

Reactive oxygen species

Patch clamp

2-photon imaging

Xiaoping LinRoselle AbrahamBrian O’Rourke

informatics computational medicine

HCM consortium – CVRG infrastructure

Rai Winslow

Steve Granite

Hagit Shatkay

Laurent Younes

Siamak Ardekani

Matt Toerper

Mike Shipway

Blaid Mbiyangandu (HCM – CVRG liaison)

Junaid Afzal

Xun Zhou

Informatics/Computational Medicine

slide27
Roselle Abraham

Larisa Tereschenko

Xiaoping Lin

BlaidMbiyangandu

Garry Cutting

Steven Steinberg

Dan Arking

Electrophysiology and Genetics

slide28

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 humanheart (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

Results overview

Results: step 2 Sequencing results

Subjects:

HCM Patients 199

111 familial 88 sporadic (?)

Hispanic:1; African American: 11; Asian: 1; Caucasian: 176; Others:10