5 MID Study 5 Year Mortality in Patients with Left Ventricular Diastolic Dysfunction and Preserved Ejection Fraction Catholic Health System, Buffalo, NY Salim H Memon M.B.B.S. Yuji Saito M.D., Ph.D., F.A.C.C.

Background Epidemiological Importance Olmsted County, Minnesota 2042 randomly selected residents (mean age 63) 5.6% had moderate or severe diastolic dysfunction with normal EF Cleveland Clinic study 36,261 adults (mean age 58) with LVEF ≥55% 65.2 % had diastolic dysfunction 5 MID Study

Background 5 MID Study Clinical Importance Asymptomatic Risk factor for DHF / HFpEF Heart failure Prevalence of more than 5 million 50% have DHF / HFpEF

Background Prognostic Importance Limited Studies available Increased Mortality with DD (3 significant studies) No increased Mortality with Mild/Grade 1 DD No mortality reducing drugs up to date 5 MID Study

Background Types of LV Dysfunction Systolic - Impaired cardiac contractility Diastolic - Abnormal cardiac relaxation, stiffness or filling Distinct disorders Not a continuous spectrum of disorders Can co-exist 5 MID Study

Background Terminology Diastolic Dysfunction Diastolic Heart Failure Heart Failure with Preserved Ejection Fraction (HFpEF) Characteristics: Normal LVEF Normal LV end-diastolic volume Abnormal diastolic function 5 MID Study

Normal Diastolic Function 5 MID Study Video from:

Abnormal Diastolic Function 5 MID Study Video from:

Diagnosis and Grading Requires Comprehensive assessment using Echocardiography Transmitral Doppler inflow velocity patterns Pulmonary venous Doppler flow patterns Tissue Doppler velocities Color M-mode flow propagation velocity 5 MID Study

Trans Mitral Doppler Inflow pattern 5 MID Study

Trans Mitral Doppler Inflow pattern 5 MID Study

Tissue Doppler (Septal) 5 MID Study e΄e΄ a΄a΄

Measuring IVRT from CW Doppler 5 MID Study

Grading Diastolic Dysfunction 5 MID Study

Study Design Study Flow Diagram Outcome Measures Methods Statistical Analyses used Results Conclusions Strengths and Limitations Future Considerations References Acknowledgements

Study Design Case Control Retrospective Analysis Comparison of patients with normal and abnormal diastolic function in terms of all cause mortality over 60 months from the date of 2- Dimensional Echocardiogram Institutional Review Board Approval Sisters of Charity Hospital 5 MID Study

Study Design Inclusion Criteria: Age ≥ 18 2-D Echocardiogram between Dec’07 – Dec’08 Preserved Ejection Fraction (≥50%) 5 MID Study

Study Design Exclusion Criteria: LV Ejection Fraction < 50% Atrial Fibrillation Unable to assess Diastolic function Unavailable Mortality Data Severe Mitral Valve Disease History of Mitral Valve Surgery Two 2D-Echocardiograms (2 nd Echo excluded) 5 MID Study

3018 Patients who has 2-Dimensional Echocardiograms from Dec’07 to Dec’08 were assessed for eligibility for the study Study Flow Diagram 5 MID Study 2107 Patients were excluded LV Ejection Fraction < 50% Atrial Fibrillation Unable to assess Diastolic function Unavailable Mortality Data Severe Mitral Valve Disease History of Mitral Valve Surgery 911 Patients included 250 Had normal diastolic function 661 Had diastolic dysfunction (abnormal diastolic dysfunction) Followed for 60 months for all cause mortality

Grading of Diastolic Dysfunction 5 MID Study

Outcome Measure All Cause Mortality 5 MID Study

Statistical Analyses IBM Statistical Package for Social Sciences (SPSS) software V.20 Continuous data expressed as Mean with 1 SD Categorical – Number (%) Analyze Group Differences: Continuous Variables: ANOVA Categorical Variables: χ ² tests Kaplin – Meier Curves – Unadjusted Survival Cox Regression Survival Analyses for adjusted survival 5 MID Study

Baseline Demographic and Clinical Characteristics 5 MID Study Characteristic No DD (N = 250) Grade 1 DD (N = 340) Grade 2 DD (N = 308) Grade 3 DD (N = 13) Total (N = 911) p-value Age – yr62.6 ± ± ± ± 15.4<0.001 Male – No. (%)76 (30.4%)111 (32.6%)116 (37.7%)2 (15.4%)321 (33.5%)0.139 CAD – No. (%)48 (19.2%)83 (26.1%)78 (27.4%)3 (25.0%)212 (24.5%)0.138 HTN – No. (%)179 (71.6%)249 (78.3%)228 (80.0%)11 (91.7%)667 (77.1%)0.062 Hypercholestrolemia – No. (%) 115 (46.0%)190 (59.7%)154 (54.0%)6 (50.0%)465 (53.8%)0.013 Diabetes Mellitus -NIDDM – No. (%) -IDDM – No. (%) 43 (17.2%) 27 (10.8%) 48 (15.1%) 41 (12.9%) 52 (18.2%) 38 (13.3%) 3 (25.0%) 146 (16.9%) 109 (12.6%) Total no. of Coronary Risk Factors 1.65 ± ± ± ± Race -Caucasian -African American -Other 163 (65.2%) 77 (30.8%) 10 (4%) 305 (89.7%) 24 (7.1%) 11 (3.2%) 258 (83.8%) 35 (11.4%) 15 (4.9%) 11 (84.6%) 1 (7.7%) 737 (80.9%) 137 (15.0%) 37 (4.0%) <0.001

Baseline Demographic and Clinical Characteristics 5 MID Study Characteristic No DD (N = 250) Grade 1 DD (N = 340) Grade 2 DD (N = 308) Grade 3 DD (N = 13) Total (N = 911) p-value Age – yr62.6 ± ± ± ± 15.4<0.001 Male – No. (%)76 (30.4%)111 (32.6%)116 (37.7%)2 (15.4%)321 (33.5%)0.139 CAD – No. (%)48 (19.2%)83 (26.1%)78 (27.4%)3 (25.0%)212 (24.5%)0.138 HTN – No. (%)179 (71.6%)249 (78.3%)228 (80.0%)11 (91.7%)667 (77.1%)0.062 Hypercholestrolemia – No. (%) 115 (46.0%)190 (59.7%)154 (54.0%)6 (50.0%)465 (53.8%)0.013 Diabetes Mellitus -NIDDM – No. (%) -IDDM – No. (%) 43 (17.2%) 27 (10.8%) 48 (15.1%) 41 (12.9%) 52 (18.2%) 38 (13.3%) 3 (25.0%) 146 (16.9%) 109 (12.6%) Total no. of Coronary Risk Factors 1.65 ± ± ± ± Race -Caucasian -African American -Other 163 (65.2%) 77 (30.8%) 10 (4%) 305 (89.7%) 24 (7.1%) 11 (3.2%) 258 (83.8%) 35 (11.4%) 15 (4.9%) 11 (84.6%) 1 (7.7%) 737 (80.9%) 137 (15.0%) 37 (4.0%) <0.001

Echocardiograhic Characteristics Degree of Diastolic Dysfunction → Grade 1Grade 2Grade 3p Value Echocardiograhic Characteristics ↓ E-wave velocity (cm/s)68 ± 1687 ± ± 25<0.001 A-wave velocity (cm/s)101 ± 2397 ± 2945 ± 14<0.001 E/A Velocity Ratio0.68 ± ± ± 0.59<0.001 Medial e' wave velocity (cm/s)9.8 ± ± ± E/e' (medial) Velocity Ratio8.12 ± ± ± 5.34<0.001 IVRT (ms)99 ± 2585 ± 2261 ± 19<0.001 Deceleration Time (ms)293 ± ± ± 39<0.001 Left Atrial Size (cm)3.7 ± ± ± 0.7<0.001 Inter Ventricular Septum Size (cm)1.15 ± ± ± Posterior Wall Size (cm)1.11 ± ± ± 0.35<0.001 LV Diameter - End Diastolic (cm)4.4 ± ± ± 0.7<0.001 LV Ejection Fraction (%)61 ± 6 62 ± RVSP (mm Hg)35 ± 1040 ± 1347 ± 13< MID Study

Outcome: Normal Function vs DD 5 MID Study

Outcome: Normal Function vs DD 5 MID Study Vital Status → AliveDeceasedTotal Diastolic Dysfunction ↓ Present – No. (%)445 (67.3)216 (32.7)661 (100) Absent – No. (%)181 (72.4)69 (27.6)250 (100) Total – No. (%)626 (68.7)285 (31.3)911 (100)

Outcome: Normal Function vs DD 5 MID Study Vital Status → AliveDeceasedTotal Diastolic Dysfunction ↓ Present – No. (%)445 (67.3)216 (32.7)661 (100) Absent – No. (%)181 (72.4)69 (27.6)250 (100) Total – No. (%)626 (68.7)285 (31.3)911 (100) Diastolic Dysfunction as Risk for all cause mortality: Hazard Ratio = (1.005 – 1.748) p-value = 0.046

Outcome: Normal Function vs different grades of DD 5 MID Study

Outcome: Normal Function vs different grades of DD Vital Status → AliveDeceasedTotal Grade of DD ↓ None – No. (%)181 (72.4)69 (27.6)250 (100) Grade 1 – No. (%)235 (69.1)105 (30.9)340 (100) Grade 2 – No. (%)204 (66.2)104 (33.8)308 (100) Grade 3 – No. (%)6 (46.2)7 (53.8)13 (100) Total – No. (%)626 (68.7)285 (31.3)911 (100)

Outcome: Normal Function vs different grades of DD Vital Status → AliveDeceasedTotal Grade of DD ↓ None – No. (%)181 (72.4)69 (27.6)250 (100) Grade 1 – No. (%)235 (69.1)105 (30.9)340 (100) Grade 2 – No. (%)204 (66.2)104 (33.8)308 (100) Grade 3 – No. (%)6 (46.2)7 (53.8)13 (100) Total – No. (%)626 (68.7)285 (31.3)911 (100) 5 MID Study

Outcome: Normal Function vs different grades of DD Grade of Diastolic Dysfunction Hazard Ratio (95% CI)p value Grade 1 / Mild1.177 (0.859 – 1.612)0.309 Grade 2 / Moderate1.363 (1.001 – 1.857)0.049 Grade 3 / Severe2.416 (1.075 – 5.434)0.033

5 MID Study Outcome: Normal Function vs different grades of DD Grade of Diastolic Dysfunction Hazard Ratio (95% CI)p value Grade 1 / Mild1.177 (0.859 – 1.612)0.309 Grade 2 / Moderate1.363 (1.001 – 1.857)0.049 Grade 3 / Severe2.416 (1.075 – 5.434)0.033

Conclusions Moderate and severe Left Ventricular DD with preserved ejection fraction was associated with worsened 5-year all-cause mortality. Mortality was worse when DD was more severe. Mild DD had no significant impact on survival. 5 MID Study

Strengths and Limitations Strengths: Long follow up One of the very few mortality studies based on grades of Left Ventricular Diastolic Dysfunction Good number of subjects in the cohort Limitations: Retrospective nature Single Geographical Location Unequal representation of both genders 5 MID Study

Future Considerations Can Diastolic Dysfunction be defined a significant precursor for development of DHF? As Impaired Fasting Glucose or Impaired Glucose Tolerance is for Diabetes Mellitus As Prehypertension is for Hypertension Can aggressive control of DD risk factors prevent progression to DHF? 5 MID Study

References Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic; Redfield MM et al; JAMA. 2003;289(2):194. Mortality rate in patients with diastolic dysfunction and normal systolic function; Halley CM et al; Arch Intern Med. 2011;171(12):1082. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355: [PMID: ] Lam CS, Donal E, Kraigher-Krainer E, Vasan RS. Epidemiology and clinical course of heart failure with preserved ejection fraction. Eur J Heart Fail. 2011;13: [PMID: ] Mitral ratio of peak early to late diastolic filling velocity as a predictor of mortality in middle-aged and elderly adults: the Strong Heart Study; Bella JN et al; Circulation. 2002;105(16): MID Study

Acknowledgements Continuous support and mentoring Dr. Khalid QaziDr. Khalid Qazi Dr. Henri WoodmanDr. Henri Woodman Dr. Azhar SupariwalaDr. Azhar Supariwala Institutional Review Board Dr. Sateesh SatchidanandDr. Sateesh Satchidanand Danielle CasucciDanielle Casucci Catholic Health System – IRBCatholic Health System – IRB Echo Lab Staff at Sisters of Charity Hospital 5 MID Study

Methods