Predictors of Incident Heart Failure with Preserved Ejection Fraction

Predictors of Incident Heart Predictors of Incident Heart Failure with Preserved with Preserved Ejection Ejection Fraction: The The Multi Multi- -Ethnic Study of Atherosclerosis Ethnic Study of Atherosclerosis Failure Fraction: Michael G. Silverman, MD1 Birju S. Patel, MD MPH2 Ron Blankstein, MD 1 Jo o A.C. Lima, MD 3 Roger S. Blumenthal, MD 3,4 Khurram Nasir, MD MPH 3,4 Michael J. Blaha, MD MPH 3,4 1 University of Texas Southwestern 2 Brigham and Women s Hospital 3 Johns Hopkins University School of Medicine 4Johns Hopkins Ciccarone Center for the Prevention of Heart Disease

Background Background Nearly 50% of all patients with congestive heart failure (CHF) have preserved Ejection Fraction (EF) Prevalence of Heart Failure with preserved EF (HFpEF) has increased over time, now estimated at 1 5% Associated with significant morbidity and mortality No specific therapy for HFpEF Lam C, et al. Epidemiology and clinical course of heart failure with preserved ejection fraction. Eur J Heart Failure 2011; 13:18-28 2

Background Background HFpEF is a heterogeneous condition Need to understand pathophysiology of HFpEF there is no animal model Better phenotypic characterization is needed Important to identify and characterize risk factors for incident HFpEF 3 Shah A, Pfeffer M. The many faces of heart failure with preserved ejection fraction. Nat. Rev. Cardiol 2012; 9:555-556

Background Background Several prior studies have characterized patients already diagnosed with HFpEF (ex: ARIC) Only 1 study has evaluated risk factors associated with developing incident HFpEF Limited to a single center ethnically homogeneous population (Framingham Heart Study) 4 Ho JE et al. Predictors of New-Onset Heart Failure Differences in Preserved Versus Reduced Ejection Fraction. Circ Heart Fail 2013;6:279-86.

Study Objectives Study Objectives Study Aim: Characterize the risk factors including ethnicity associated with incident HFpEF in a multi-ethnic cohort. Hypotheses 1) The risk factor profile for HFpEF will be different from the risk factor profile for HF reduced EF (HFrEF) 2) Incidence of HFpEF will differ by race/ethnicity 5

Primary Outcome Primary Outcome HFpEF clinical diagnosis of HF with EF 45% HFrEF clinical diagnosis of HF with EF < 45% (First) Incident CHF is an adjudicated endpoint requiring the following criteria: Symptoms of pulmonary congestion or edema Physician diagnosis and medical treatment for HF Evidence from chest x-ray or echocardiography EF is a clinical outcome collected from hospital records at time of CHF diagnosis 6

Analysis Analysis Evaluate association of race/ethnicity with incident HFpEF/HFrEF using Cox proportional hazards models Forward selection of risk factors Demographic Clinical history Laboratory Imaging 7

Study Population Study Population 6814 in baseline cohort -Excluded for missing information (n=35) - Developed CHF, unable to classify EF (n=35) 6744 in final cohort - 5540 in NT-proBNP subset - 4956 in MRI subset Individuals were followed for median 10.2 (9.7-10.7) years 103 individuals developed incident HFpEF 95 individuals developed incident HFrEF 8

Baseline Characteristics by Outcome Baseline Characteristics by Outcome Demographic Information Variable HFpEF n = 103 HFrEF n = 95 No HF n = 6546 Age 70 ( 9) 67 ( 9) 62 ( 10) Male 50% 72% 47% Race/ethnicity White 45% 39% 38% Chinese 11% 0 12% Black 23% 43% 28% Hispanic 21% 18% 22% 9

Baseline Characteristics by Outcome Baseline Characteristics by Outcome Clinical History Variable HFpEF n = 103 HFrEF n = 95 No HF n = 6546 Hypertension 73% 72% 44% BMI (kg/m2) 30 ( 6) 29 ( 5) 28 ( 5) Diabetes 32% 29% 12% Current Smoker 13% 21% 13% LVH by EKG 5% 5% 1% Incident MI 13% 12% 2% 10

Baseline Characteristics by Outcome Baseline Characteristics by Outcome Laboratory and Imaging Data Variable HFpEF n = 103 HFrEF n = 95 No HF n = 6546 Total cholesterol (mg/dL) 188 ( 34) 187 ( 35) 194 ( 36) HDL cholesterol (mg/dL) 49 ( 15) 47 ( 13) 51 ( 15) eGFR (ml/min/1.73 m2 BSA) 71 ( 18) 70 ( 20) 78 ( 16) hs-CRP (mg/L) 2.7 (1.1 6.4) 3.3 (1.2 6.3) 1.9 (0.8 4.2) NT-proBNP (pg/mL) 139 (77 254) 181 (81 375) 53 (23 108) EF by MRI 70 ( 8) 58 ( 12) 69 ( 7) CAC > 0 69% 73% 49% 11

Incident HF Incident HF Distribution of Ejection Fraction 15 10 Frequency (%) 5 20 40 60 80 12 Ejection fraction (%)

Incident HF Incident HF Cumulative CHF Incidence 2 HFpEF n = 103 (1.5%) Cumulative CHF incidence (%) HFrEF n = 95 (1.4%) 1 3 6 9 Follow-up year 13

Incident HF Incident HF Incidence rates of HFpEF by race/ethnicity 4 CHF incidence / 1,000 person-years 3 2 1 1.8 1.6 1.4 1.4 0 White Chinese Black Hispanic HFPEF n = 46 (1.8%) 11 (1.4%) 24 (1.3%) 22 (1.5%) 14

Multivariable adjusted HR Multivariable adjusted HR Demographic Information Variable HFpEF HFrEF HR* 95% CI, p value HR* 95% CI Age 2.5 1.9 3.3 p < 0.001 1.5 1.1 1.9 p = 0.008 Male 1.1 0.7 1.7 p = 0.68 2.6 1.6 4.2 p < 0.001 Race/ethnicity White ref -- -- Ref -- -- Chinese 1.4 0.6 3.3 p = 0.4 ** Black 0.6 0.3 1.1 p = 0.08 1.7 1.0 2.9 p = 0.045 Hispanic 0.8 0.4 1.5 p = 0.5 0.8 0.4 1.6 p = 0.5 p < 0.05 highlighted in bold if significant for both HFpEF and HFrEF, green text if HFpEF only, blue text if HFrEF only *Adjusted for age, gender, race/ethnicity, MESA site, socioeconomic status, smoking, diabetes, hypertension, LVH by EKG, obesity, eGFR, coronary artery calcium, total cholesterol, abnormal HDL cholesterol, and incident MI. ** no Chinese individuals developed incident HFrEF 15

Multivariable adjusted HR Multivariable adjusted HR Clinical History Variable HFpEF HFrEF HR* 95% CI, p value HR* 95% CI Hypertension 1.8 1.1 2.8 p = 0.02 1.8 1.1 2.9 p = 0.02 BMI (per SD) 1.4 1.2 1.8 p = 0.001 1.1 0.9 1.4 p = 0.4 Diabetes 2.7 1.8 4.3 p < 0.001 2.5 1.5 4.0 p < 0.001 Current Smoker 2.0 1.1 3.7 p = 0.03 2.5 1.5 4.2 p = 0.001 LVH by EKG 4.3 1.7 10.7 p = 0.002 4.4 1.8 11.2 p = 0.002 Incident MI 4.9 2.7 9.0 p < 0.001 3.8 2.0 7.3 p < 0.001 p < 0.05 highlighted in bold if significant for both HFpEF and HFrEF, green text if HFpEF only, blue text if HFrEF only *Adjusted for age, gender, race/ethnicity, MESA site, socioeconomic status, smoking, diabetes, hypertension, LVH by EKG, obesity, eGFR, coronary artery calcium, total cholesterol, abnormal HDL cholesterol, and incident MI. 16

Multivariable adjusted HR Multivariable adjusted HR Laboratory and Imaging Data Variable HFpEF HFrEF HR* 95% CI, p value HR* 95% CI p value Total cholesterol (per SD) 0.9 0.8 1.2 p = 0.6 0.9 0.8 1.2 p = 0.06 Low HDL-Cholesterol 1.1 0.7 1.7 p = 0.6 0.8 0.5 1.3 p = 0.4 eGFR (per SD decrease) 1.0 0.8 1.2 p = 0.95 1.3 1.1 1.6 p 0.004 CAC > 0 0.9 0.6 1.5 p = 0.8 1.3 0.8 2.2 p = 0.3 NT-proBNP > 75th % ile 3.6 2.2 6.0 p < 0.001 5.6 3.2 9.6 p < 0.001 LV mass index (per SD) 1.4 1.1 1.8 p = 0.004 2.0 1.8 2.4 p < 0.001 p < 0.05 highlighted in bold if significant for both HFpEF and HFrEF, green text if HFpEF only, blue text if HFrEF only *Adjusted for age, gender, race/ethnicity, MESA site, socioeconomic status, smoking, diabetes, hypertension, LVH by EKG, obesity, eGFR, coronary artery calcium, total cholesterol, abnormal HDL cholesterol, and incident MI. 17

Limitations Limitations EF was obtained from chart review of hospitalizations, not via centralized core lab reviewing echo images no set protocol for EF evaluation when diagnosis made There were non-classifiable CHF events due to varying EF reporting in the hospital documentation Small number of events, limited sample size for formal interaction testing within ethnicities 18

Conclusions Conclusions There are significant risk factors for HFpEF, most of which overlap with HFrEF Older Age Hypertension Diabetes Current smoking LVH by EKG Incident MI Higher NT-proBNP Higher LV mass index by MRI BMI was associated with increased risk for incident HFpEF but not HFrEF 19

Conclusions Conclusions Non-significant univariate predictors: gender race/ethnicity socioeconomic status (level of education) elevated hs-CRP (> 2mg/L) Elevated triglycerides, Increased heart rate Significant univariate but non-significant multivariate predictors: pulse pressure total cholesterol CAC > 0 20

Conclusions Conclusions There is overlap with risk factors identified for incident HFpEF in prior analysis from Framingham Heart Study (FHS) Older Age, Diabetes, BMI, Smoking Gender was not a significant predictor of HFpEF in FHS either Race/Ethnicity was not a significant predictor of HFpEF Formal interaction testing between race/ethnicity and HFpEF was negative 21 Ho JE et al. Predictors of New-Onset Heart Failure Differences in Preserved Versus Reduced Ejection Fraction. Circ Heart Fail 2013;6:279-86.

Conclusions Conclusions Future Directions Goal of this study is find the standard risks factors for HFpEF, guide future analyses in MESA Evaluate additional predictors for HFpEF to better characterize pathophysiology Metabolic and lifestyle parameters Serologic markers Imaging parameters Need for larger sample size for increased power to better characterize difference in risk factors by ethnicity 22

Acknowledgements Acknowledgements The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. We wish to thank all the MESA volunteer research participants who made this study possible This research was supported by contracts R01 HL071739, N01-HC-95159 through N01-HC-95165, and N01-HC- 95169 from the National Heart, Lung, and Blood Institute. 23

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