Hopkins and Hypertrophic cardiomyopathy

1. Xiaoping Lin Tongji university Johns Hopkins University Hopkins and Hypertrophic cardiomyopathy

2. 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

3. 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

5. 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)

6. “Telomere” Expert Carol Greider Shares 2009 Nobel Prize in Physiology or Medicine “Aquaporin Protein” Expert Peter C. Agre Shares 2003 Nobel Prize in Chemistry

7. Hypertrophic cardiomyopathy(HCM)

8. Hopkins & HCM…over the years

9. Hopkins HCM Clinic Evolution

10. Research The HCM Enterprise Clinical

11. 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

12. Differential Diagnosis • Physiologic hypertrophy – Athlete’s Heart • Hypertension related hypertrophy • Hypertrophic cardiomyopathy • Infiltrative cardiomyopathy • Cardiac amyloid

13. Hypertrophic Cardiomyopathy (HCM) • Inherited cardiomyopathy • Mutation in genes encoding sarcomeric proteins • Diverse clinical presentation • Common (1:500) Spirito: NEJM, 1999

14. 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

15. 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

16. 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

17. Aurelio Pinheiro Xiaoping Lin Lea Dimaano Hsin-Yueh Liang Lars Sorensen FatihYalcin NagisKucukler EKG and Echo/Mechanics

18. 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)

19. Accepted by 2011 AHA (American heart association) scientific session

20. Miguel Santaularia Stefan Zimmerman Jens-Vogel Claussen David Bluemke MRI

21. 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

22. Paco Bravo Valenzuela Frank Bengel Nuclear Imaging

23. 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

24. Roselle Abraham Xiaoping Lin Brian Foster Miguel Aon Sonia Cortasa Brian O’Rourke Basic Science

25. 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

26. 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

27. Roselle Abraham Larisa Tereschenko Xiaoping Lin BlaidMbiyangandu Garry Cutting Steven Steinberg Dan Arking Electrophysiology and Genetics

28. 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

29. 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

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

31. Thank you