1. Showkat Hamid Mentor: Dr. Mrinalini Meesala MD, FACC. University at Buffalo; State University of New York; Sisters Hospital IMTP June 12 th 2013

2. Disclosures: None

3. Topic: Evaluation of electrogenic properties of myocardium in patients with HFpEF with Tp-e/QT ratio as marker of ventricular repolarization.

4. Introduction: 1 Nearly one-half of patients presenting with heart failure have preserved left ventricular ejection fraction 1. Patients with low ejection fraction are known to be susceptible to arrhythmias and device therapy (ICD/CRT) is a basic tenet to decrease sudden death 2. Ref: 1. Yancy CW, Lopatin M, Stevenson LW, et al. Clinical presentation, management,and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from ADHERE) Database. J Am Coll Cardiol 2006; 47:76–84. 2. Smith GL, Masoudi FA, Vaccarino V, et al. Outcomes in heart failure patients with preserved ejection fraction: mortality, readmission, and functional decline. J Am Coll Cardiol 2003; 41:1510–1518.

5. Mortality of patients with HFpEF is not markedly different from patients with decreased ejection fraction. Ref: 1. Yancy CW, Lopatin M, Stevenson LW, et al. Clinical presentation, management,and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from ADHERE) Database. J Am Coll Cardiol 2006; 47:76–84.

6. Background: T-wave: a manifestation of ventricular repolarazation. Tp-e interval corresponds to the dispersion of ventricular repolarization. Amplification of dispersion of ventricular repolarization is a substrate for ventricular arrhythmias Ref: Antzelevitch C. T peak-Tend interval as an index of transmural dispersion of repolarization. Eur J Clin Invest 2001;31:555. Antzelevitch C. The role of spatial dispersion of repolarization in inherited and acquired sudden cardiac death syndromes. Am J Physiol Heart Circ Physiol 2007. Antzelevitch C. Heterogeneity and cardiac arrhythmias: an overview. Heart Rhythm 2007;4:964.

8. Ventricular myocardium is comprised of 3 distinct myocardial cell types— Epicardial, Endocardial, and Masonic Midmyocardial Moe cells - M cells. Cellular basis of T wave and Tp-e Interval: Ref: Antzelevitch C, Sicouri S, Litovsky SH, et al. Heterogeneity within the ventricular wall: electrophysiology and pharmacology of epicardial, endocardial and M cells. Circ Res 1991;69:1427.

9. M-cells Histologically similar; Electrophysiologically different. Located in sub-endocardial layer Longest action potential (APD) than epicardial or endocardial cell at lower rate or in response to action potential prolonging agents. Ref: Antzelevitch C, Sicouri S, Litovsky SH, et al. Heterogeneity within the ventricular wall: electrophysiology and pharmacology of epicardial, endocardial and M cells. Circ Res 1991;69:1427

10. Heterogeneity persists but is less pronounced in intact ventricular wall due to well coupled adjacent myocytes. Ref: Antzelevitch C, Sicouri S, Litovsky SH, et al. Heterogeneity within the ventricular wall: electrophysiology and pharmacology of epicardial, endocardial and M cells. Circ Res 1991;69:1427

11. Ref : Circulation 1998;98:1928, PACE 2006;29:1130, and Heart Rhythm 2008;5:585.

12. QT interval is specific to species, so-called normal QT interval for that species. QT interval and Tp-e interval increase linearly with increase in body weight. Ref: Guo D, Zhou J, Zhao X, et al. Calcium channel recovery kinetics versusventricular repolarization: preserved membrane-stabilizing mechanism across species. Heart Rhythm 2008;5:271

13. Adapted from Heart Rhythm 2008;5:271.

15. Tp-e/QT ratio is an index of ventricular repolarization that remains constant within a very narrow range of value despite dynamic physiological changes in HR and also evolutionary changes across species. Ref: Guo D, Zhou J, Zhao X, et al. Calcium channel recovery kinetics versusventricular repolarization: preserved membrane-stabilizing mechanism across species. Heart Rhythm 2008;5:271

16. Tp-e interval serves as an index of total dispersion of repolarization (transmural, apicobasal, or global)in vivo. Changes in this parameter from the baseline value may forecast the risk of arrhythmia. Ref : Prasad Gupta,Gan-Xin Yan, MD, PhDa, Tp-e/QT ratio as an index of arrhythmogenesis Journal of Electrocardiology 41 (2008) 567–574

17. Rationale of the study: Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio are prolonged in patients with moderate and severe obstructive sleep apnea. Tp-e interval and Tp-e/QT ratio is increased in patiests with ankylosing spondylitis Ref : Kilicaslan F, Cebeci BS. Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio are prolonged in patients with moderate and severe OSA patients. (PACE 2012; 35:966–972) Acar G, Bozoglan O. Evaluation of Tp-e interval and Tp-e/QT ratio in patients with ankylosing spondylitis. Mod Rheumatol. 2013 Apr 12. [Epub ahead of print] Acar GBozoglan O Mod Rheumatol.

18. Left ventricular hypertrophy amplifies the QT, and Tp-e intervals and the Tp-e/QT ratio of left chest ECG Tp-e/QT ratio may serve as a prognostic predictor of adverse outcomes after successful pPCI treatment in STEMI patients. Ref : Zhao Z, Yuan Z, Ji Y, Wu Y, Qi Y. Left ventricular hypertrophy amplifies the QT, and Tp-e intervals and the Tp-e/ QT ratio of left chest ECG J Biomed Res. 2010 Jan;24(1):69-72. doi: 10.1016/S1674-8301(10)60011-5. Zhao ZYuan ZJi YWu YQi YJ Biomed Res.

19. Big Question What happens to Tp-e/QT ratio in HFpEF ???

20. Research Hypothesis: “In patients with HFpEF cellular and metabolic changes in myocytes are associated with changes in electrogenic properties of the ventricular myocardium reflected as prolongation of Tp-e/QT intervals suggesting increased risk of ventricular arrhythmias ”.

21. Research Design and Methods: Retrospective Study

22. Patient Population Cases: Patients admitted to Catholic Health System from January 2009 onwards with a diagnosis of HFpEF Controls: Patients who had echo done for different reasons and found to have normal systolic and diastolic functon, and have none of the following(exclusion criterias): Primary/secondary diagnosis of A.Fib. IVCD. Anti-arrhythmic drugs Intracardiac device. Poor quality echo images. Recent CABG/or structural heart disease. Acute MI Severe MR Severe COPD Flat T waves or T wave obscured by U wave Inclusion Criteria: Discharge diagnositic code for HFpEF EF ≥50% Clinical and Biochemical evidence of HFpEF within 1 year. Exclusion Criteria: Primary/secondary diagnosis of A.Fib. IVCD. Anti-arrhythmic drugs Intracardiac device. Poor quality echo images. Recent CABG/or structural heart disease. Acute MI Severe MR Severe COPD Flat T waves or T wave obscured by U wave Randomization and Blinding: None

23. Total (967) Excluded (828) Unclassified (999 group) (16) Controls (49) Patients (90) Included (139) Grade III (7) E/A>2 DT <160ms Av. E/e’>13 Grade II (42) E/A 0.8-<1.5 DT 160-200ms Av. E/e’ 9-12 Grade I (25) E/A<0.8 DT >200ms Av. E/e’≤8

24. Methodology: Naugeh SF, Appleton CP, Evangelista A. Recommendations for the evaluation of left ventricular diastolic function by echocardiography. J. Am Soc Echocardiogr. 2009 Feb;22(2):107-33. doi: 10.1016/j.echo.2008.11.023

25. Methodology cont: EKGs were analyzed for T wave morphology. T peak and T end interval (Tp-e) were measured by (Standard Tangential Method) identifying two points on isoelectric line: 1) Perpendicular to the isoelectric line from crest of T wave 2) The point at which the tangent to the down curve of T wave intersects the isoelectric line.

27. Results:

30. Tp-e/QT

33. Conclusion: There is no significant prolongation of Tp-e/QT to demonstrate increased risk of ventricular arrhythmias hence sudden death in patients with HFpEF in this study. A decreasing trend in Tp-e/QT ratio with increasing grade of diastolic dysfunction was observed which did not achieve statistical significant due to small cohort of subjects.

34. Strengths Of the Study: Echo and EKG parameters collected in different times to avoid observer bias. Internal as well as external comparison were attempted Patients with EF>/= 50% strictly were taken for study. Patients with clinical syndrome of HF along with biochemical evidence of HF taken.

35. Limitations of Study: Retrospective Study Small population size Extrapolation of results of Wedge Electro-gram to chest ECGs. Tp-e/QT ratio is a relatively new parameter and not much is known about its significance in HFpEF.

36. Questions?

37. Acknowledgements: Dr. K.J.Qazi, MD (Program Director) Dr. Mrinalini Meesala, MD (Research Mentor) Dr. Micheal Banas, MD (Advisor) Dr. Salim Memon, MBBS Dr. Sachitanand MD (Chair IRB) Ms Danielle Casucci (IRB) Staff of Echo Lab Sisters Hospital

38. Thank you !