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
Clinical Importance
Asymptomatic
Risk factor for DHF / HFpEF
Heart failure
Prevalence of more than 5 million
50% have DHF / HFpEF
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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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Video from:
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)
e΄
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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
5 MID Study
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 2Dimensional 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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Study Flow Diagram
3018 Patients who has 2-Dimensional Echocardiograms from
Dec’07 to Dec’08 were assessed for eligibility for the 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
250 Had normal diastolic
function
911 Patients included
661 Had diastolic dysfunction
(abnormal diastolic dysfunction)
Followed for 60 months for all cause mortality
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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
survival
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Baseline Demographic and Clinical Characteristics
No DD
(N = 250)
Grade 1 DD
(N = 340)
Grade 2 DD
(N = 308)
Grade 3 DD
(N = 13)
Age – yr
62.6 ± 15.4
73.7 ± 11.1
69.7 ± 13.1
75.7 ± 15.4
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
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%)
0.641
0.462
1.65 ± 1.16
1.92 ± 1.08
1.93 ± 1.16
2.17 ± 1.11
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%)
Characteristic
Diabetes Mellitus
-NIDDM – No. (%)
-IDDM – No. (%)
Total no. of Coronary
Risk Factors
Race
-Caucasian
-African American
-Other
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Total
(N = 911)
p-value
<0.001
0.012
737 (80.9%)
137 (15.0%)
37 (4.0%)
<0.001
Baseline Demographic and Clinical Characteristics
No DD
(N = 250)
Grade 1 DD
(N = 340)
Grade 2 DD
(N = 308)
Grade 3 DD
(N = 13)
Age – yr
62.6 ± 15.4
73.7 ± 11.1
69.7 ± 13.1
75.7 ± 15.4
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
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%)
0.641
0.462
1.65 ± 1.16
1.92 ± 1.08
1.93 ± 1.16
2.17 ± 1.11
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%)
Characteristic
Diabetes Mellitus
-NIDDM – No. (%)
-IDDM – No. (%)
Total no. of Coronary
Risk Factors
Race
-Caucasian
-African American
-Other
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Total
(N = 911)
p-value
<0.001
0.012
737 (80.9%)
137 (15.0%)
37 (4.0%)
<0.001
Echocardiograhic Characteristics
Degree of Diastolic Dysfunction →
Grade 1
Grade 2
Grade 3
p Value
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
Echocardiograhic Characteristics ↓
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Outcome: Normal Function vs DD
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Outcome: Normal Function vs DD
Vital Status →
Diastolic Dysfunction ↓
Alive
Deceased
Total
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)
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Outcome: Normal Function vs DD
Vital Status →
Diastolic Dysfunction ↓
Alive
Deceased
Total
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
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Outcome:
Normal Function vs different grades of DD
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Outcome:
Normal Function vs different grades of DD
Vital Status →
Grade of DD ↓
Alive
Deceased
Total
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
Vital Status →
Grade of DD ↓
Alive
Deceased
Total
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
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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.html
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Acknowledgements
Continuous 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