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

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Background

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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

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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

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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

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Normal Diastolic Function

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Abnormal Diastolic Function

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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

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Trans Mitral Doppler Inflow pattern

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Trans Mitral Doppler Inflow pattern

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Tissue Doppler (Septal)

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e΄a΄

Measuring IVRT from CW Doppler

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Grading Diastolic Dysfunction

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• 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

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Study Design

Inclusion Criteria:• Age ≥ 18

• 2-D Echocardiogram between Dec’07 – Dec’08

• Preserved Ejection Fraction (≥50%)

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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 (2nd Echo excluded)

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3018 Patients who has 2-Dimensional Echocardiograms from Dec’07 to Dec’08 were assessed for eligibility for the study

Study Flow Diagram

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2107 Patients were excluded LV Ejection Fraction < 50%Atrial FibrillationUnable to assess Diastolic function Unavailable Mortality DataSevere Mitral Valve DiseaseHistory 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

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Outcome Measure

All Cause Mortality

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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: χ² tests

• Kaplin – Meier Curves – Unadjusted Survival• Cox Regression Survival Analyses for adjusted

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Baseline Demographic and Clinical Characteristics

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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 – yr 62.6 ± 15.4 73.7 ± 11.1 69.7 ± 13.1 75.7 ± 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%)3 (25.0%)

146 (16.9%)109 (12.6%)

0.6410.462

Total no. of Coronary Risk Factors

1.65 ± 1.16 1.92 ± 1.08 1.93 ± 1.16 2.17 ± 1.11 0.012

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%)1 (7.7%)

737 (80.9%)137 (15.0%)

37 (4.0%)

<0.001

Baseline Demographic and Clinical Characteristics

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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 – yr 62.6 ± 15.4 73.7 ± 11.1 69.7 ± 13.1 75.7 ± 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%)3 (25.0%)

146 (16.9%)109 (12.6%)

0.6410.462

Total no. of Coronary Risk Factors

1.65 ± 1.16 1.92 ± 1.08 1.93 ± 1.16 2.17 ± 1.11 0.012

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%)1 (7.7%)

737 (80.9%)137 (15.0%)

37 (4.0%)

<0.001

Echocardiograhic Characteristics Degree of Diastolic Dysfunction →

Grade 1 Grade 2 Grade 3 p ValueEchocardiograhic Characteristics ↓

E-wave velocity (cm/s) 68 ± 16 87 ± 26 114 ± 25 <0.001

A-wave velocity (cm/s) 101 ± 23 97 ± 29 45 ± 14 <0.001

E/A Velocity Ratio 0.68 ± 0.18 0.92 ± 0.19 2.6 ± 0.59 <0.001

Medial e' wave velocity (cm/s) 9.8 ± 3.8 9.6 ± 3.9 8.2 ± 2.5 0.405

E/e' (medial) Velocity Ratio 8.12 ± 4.54 10.78 ± 5.96 15.53 ± 5.34 <0.001

IVRT (ms) 99 ± 25 85 ± 22 61 ± 19 <0.001

Deceleration Time (ms) 293 ± 75 247 ± 63 178 ± 39 <0.001

Left Atrial Size (cm) 3.7 ± 0.8 4.1 ± 0.6 4.7 ± 0.7 <0.001

Inter Ventricular Septum Size (cm) 1.15 ± 0.36 1.12 ± 0.24 1.22 ± 0.35 0.026

Posterior Wall Size (cm) 1.11 ± 0.25 1.09 ± 0.22 1.22 ± 0.35 <0.001

LV Diameter - End Diastolic (cm) 4.4 ± 0.7 4.6 ± 0.7 5.0 ± 0.7 <0.001

LV Ejection Fraction (%) 61 ± 6 61± 6 62 ± 6 0.027

RVSP (mm Hg) 35 ± 10 40 ± 13 47 ± 13 <0.001

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Outcome: Normal Function vs DD

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Outcome: Normal Function vs DD

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Vital Status →

Alive Deceased TotalDiastolic 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

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Vital Status →

Alive Deceased TotalDiastolic 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 = 1.325 (1.005 – 1.748) p-value = 0.046

Outcome:Normal Function vs different grades of DD

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Outcome:Normal Function vs different grades of DD

Vital Status →

Alive Deceased TotalGrade 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 →

Alive Deceased TotalGrade 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)

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Outcome:Normal Function vs different grades of DD

Grade of Diastolic Dysfunction

Hazard Ratio (95% CI) p value

Grade 1 / Mild 1.177 (0.859 – 1.612) 0.309

Grade 2 / Moderate 1.363 (1.001 – 1.857) 0.049

Grade 3 / Severe 2.416 (1.075 – 5.434) 0.033

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Outcome:Normal Function vs different grades of DD

Grade of Diastolic Dysfunction

Hazard Ratio (95% CI) p value

Grade 1 / Mild 1.177 (0.859 – 1.612) 0.309

Grade 2 / Moderate 1.363 (1.001 – 1.857) 0.049

Grade 3 / Severe 2.416 (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.

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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

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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?

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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;355:251-9. [PMID: 16855265]

• 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;13:18-28. [PMID: 20685685]

• 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):1928

• www.biodigital.com• http://www.learntheheart.com/GADD-echoClassification.html5 MID Study

AcknowledgementsContinuous support and mentoring• Dr. Khalid Qazi• Dr. Henri Woodman• Dr. Azhar Supariwala

Institutional Review Board• Dr. Sateesh Satchidanand• Danielle Casucci• Catholic Health System – IRB

Echo Lab Staff at Sisters of Charity Hospital

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Methods