Risk Of Heart Failure With Preserved Ejection Fraction Research Articles

Invited Commentary: Searching for the Perfect Measure of Diastolic Dysfunction-A Futile Exercise?

Heart failure with preserved ejection fraction (HFpEF) is common, recalcitrant to treatment, and associated with poor outcomes. Diastolic dysfunction (DD) is an independent predictor of HFpEF risk, associated clinical manifestations, and long-term outcomes. However, the usefulness of diastolic function assessment is limited by the heterogeneity in the existing definitions of DD. In this issue of the Journal, Rasmussen-Torvik et al. (Am J Epidemiol. 2017;185(12):1221-1227) have highlighted this problem by evaluating the prevalence and concordance of 4 established definitions of DD in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. The authors demonstrate significant variability in prevalence of DD and its association with established risk factors across the different definitions. These findings suggest that the current 1-dimensional approach to HFpEF risk prediction based on noninvasive measures of diastolic function may not be optimal. Perhaps the future of HFpEF risk assessment lies in a multimodality approach that combines the relevant echocardiographic measures of diastolic function with blood-based biomarkers (such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP)) and a measure of functional status (such as exercise capacity).

Association Between HIV Infection and the Risk of Heart Failure With Reduced Ejection Fraction and Preserved Ejection Fraction in the Antiretroviral Therapy Era

With improved survival, heart failure (HF) has become a major complication for individuals with human immunodeficiency virus (HIV) infection. It is unclear if this risk extends to different types of HF in the antiretroviral therapy (ART) era. Determining whether HIV infection is associated with HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), or both is critical because HF types differ with respect to underlying mechanism, treatment, and prognosis. To investigate whether HIV infection increases the risk of future HFrEF and HFpEF and to assess if this risk varies by sociodemographic and HIV-specific factors. This study evaluated 98 015 participants without baseline cardiovascular disease from the Veterans Aging Cohort Study, an observational cohort of HIV-infected veterans and uninfected veterans matched by age, sex, race/ethnicity, and clinical site, enrolled on or after April 1, 2003, and followed up through September 30, 2012. The dates of the analysis were October 2015 to November 2016. Human immunodeficiency virus infection. Outcomes included HFpEF (EF≥50%), borderline HFpEF (EF 40%-49%), HFrEF (EF<40%), and HF of unknown type (EF missing). Among 98 015 participants, the mean (SD) age at enrollment in the study was 48.3 (9.8) years, 97.0% were male, and 32.2% had HIV infection. During a median follow-up of 7.1 years, there were 2636 total HF events (34.6% were HFpEF, 15.5% were borderline HFpEF, 37.1% were HFrEF, and 12.8% were HF of unknown type). Compared with uninfected veterans, HIV-infected veterans had an increased risk of HFpEF (hazard ratio [HR], 1.21; 95% CI, 1.03-1.41), borderline HFpEF (HR, 1.37; 95% CI, 1.09-1.72), and HFrEF (HR, 1.61; 95% CI, 1.40-1.86). The risk of HFrEF was pronounced in veterans younger than 40 years at baseline (HR, 3.59; 95% CI, 1.95-6.58). Among HIV-infected veterans, time-updated HIV-1 RNA viral load of at least 500 copies/mL compared with less than 500 copies/mL was associated with an increased risk of HFrEF, and time-updated CD4 cell count less than 200 cells/mm3 compared with at least 500 cells/mm3 was associated with an increased risk of HFrEF and HFpEF. Individuals who are infected with HIV have an increased risk of HFpEF, borderline HFpEF, and HFrEF compared with uninfected individuals. The increased risk of HFrEF can manifest decades earlier than would be expected in a typical uninfected population. Future research should focus on prevention, risk stratification, and identification of the mechanisms for HFrEF and HFpEF in the HIV-infected population.

Abstract MP082: Sex Hormone Levels and Change in Left Ventricular Structure Among Men and Women With Preserved Ejection Fraction The Multi Ethnic Study of Atherosclerosis

Background: Heart failure with preserved ejection fraction (HFpEF) is more common in older women than men. Differences in sex hormone (SH) levels may contribute to sex differences in HFpEF risk. Left ventricular (LV) hypertrophy and concentric remodeling [increased Mass (M): Volume (V) ratio] are risk markers of HFpEF. In a multi-ethnic cohort of men and women with preserved EF, we examined whether SH levels were associated with LV structure. We hypothesized that a more androgenic pattern would predict adverse concentric remodeling in women but not men. Methods: We studied 4279 MESA participants (49% women) aged 45-84 yrs with serum SH levels and cardiac MRI performed at baseline (2000-2002) and baseline EF ≥50%. Among these, 2957 participants underwentMRI at Exam 5 (2010-2012). Stratified by sex, we used linear regression for cross-sectional analyses and mixed model effect methods for longitudinal analyses to test the associations of SH and binding globulin (SHBG) levels [per 1 SD greater log(SH)] with baseline levels and changes in LV mass (LVM), end diastolic volume (LVEDV) and M:V ratio. Models were adjusted for age, ethnicity, center, height, weight, education, physical activity and smoking, and for hormone use and menopause in women. Results: The mean (SD) age was 64 (9) for women and 62 (10) yrs for men. Cross-sectionally, among women, higher Testosterone (T) and Dehydroepiandrosterone (DHEA) levels were associated with greater LVM ( Table ). Among both men and women, higher free T and lower SHBG were associated lower LVEDV and greater M:V ratio. In men, greater estradiol levels were associated with lower LVEDV and greater M:V ratio. After a mean followup of 10 yrs, higher free T and lower SHBG were associated with an increase in LVM in both sexes. Findings were generally consistent after adjustment for possible mediators of these associations such as blood pressure and other CV risk factors. Conclusion: A more androgenic profile of higher free T and lower SHBG is associated with greater increase in LVM over 10 yrs in both men and women.

Abstract P170: High Intake of Dietary Protein is Associated With Increased Risk of Heart Failure With Preserved Ejection Fraction

Background: Heart Failure with preserved ejection fraction(HFpEF) is growing and common problem in elderly women with high morbidity and mortality. The role of diet in its prevention is under-researched. Objective: To evaluate calibrated and uncalibrated dietary protein, energy adjusted animal and vegetable protein and their association with incident HFpEF. Methods: Study participants in Women’s Health Initiatve (n=14,184) with valid FFQ data, free of baseline HF or missing covariates had urinary nitrogen calibrated total protein, energy calibrated using doubly labelled water animal and vegetable protein determined. Cox models adjusted for age, education, race/ethnicity, CHD, diabetes,waist to hip ration,hypertension, physical activity, systolic blood pressure, anemia, atrial fibrillation evaluated prospective association with HFpEF. HFpEF was defined as ejection fraction &gt;45%. Results: Over 13.2 years of follow-up, there were 513 cases of HF, 268 cases of HFpEF, 162 of HFrEF and 83 of undetermined ejection fraction. Increasing levels of calibrated total protein showed a linear dose response relationship with an increased risk of HFpEF whereas uncalibrated total protein did not. Higher intake of animal protein demonstrated an increased risk , while vegetable protein showed a trend towards and inverse relationship. (see table) Conclusion: HIgher levels of calibrated total protein are associated with increased risk of HFpEF with animal protein appearing to be the most deleterious. Plant based diets with high levels of vegetable protein may be protective. Further studies should evaluate this.

Relationship Between Physical Activity, Body Mass Index, and Risk of Heart Failure

BackgroundLower leisure-time physical activity (LTPA) and higher body mass index (BMI) are independently associated with risk of heart failure (HF). However, it is unclear if this relationship is consistent for both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). ObjectivesThis study sought to quantify dose–response associations between LTPA, BMI, and the risk of different HF subtypes. MethodsIndividual-level data from 3 cohort studies (WHI [Women’s Health Initiative], MESA [Multi-Ethnic Study of Atherosclerosis], and CHS [Cardiovascular Health Study]) were pooled and participants were stratified into guideline-recommended categories of LTPA and BMI. Associations between LTPA, BMI, and risk of overall HF, HFpEF (ejection fraction ≥45%), and HFrEF (ejection fraction <45%) were assessed by using multivariable adjusted Cox models and restricted cubic splines. ResultsThe study included 51,451 participants with 3,180 HF events (1,252 HFpEF, 914 HFrEF, and 1,014 unclassified HF). In the adjusted analysis, there was a dose-dependent association between higher LTPA levels, lower BMI, and overall HF risk. Among HF subtypes, LTPA in any dose range was not associated with HFrEF risk. In contrast, lower levels of LTPA (<500 MET-min/week) were not associated with HFpEF risk, and dose-dependent associations with lower HFpEF risk were observed at higher levels. Compared with no LTPA, higher than twice the guideline-recommended minimum LTPA levels (>1,000 MET-min/week) were associated with an 19% lower risk of HFpEF (hazard ratio: 0.81; 95% confidence interval: 0.68 to 0.97). The dose–response relationship for BMI with HFpEF risk was also more consistent than with HFrEF risk, such that increasing BMI above the normal range (≥25 kg/m2) was associated with a greater increase in risk of HFpEF than HFrEF. ConclusionsOur study findings show strong, dose–dependent associations between LTPA levels, BMI, and risk of overall HF. Among HF subtypes, higher LTPA levels and lower BMI were more consistently associated with lower risk of HFpEF compared with HFrEF.

Arterial Stiffness and Risk of Overall Heart Failure, Heart Failure With Preserved Ejection Fraction, and Heart Failure With Reduced Ejection Fraction: The Health ABC Study (Health, Aging, and Body Composition).

Higher arterial stiffness is associated with increased risk of atherosclerotic events. However, its contribution toward risk of heart failure (HF) and its subtypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), independent of other risk factors is not well established. In this study, we included Health ABC study (Health, Aging, and Body Composition) participants without prevalent HF who had arterial stiffness measured as carotid-femoral pulse wave velocity (cf-PWV) at baseline (n=2290). Adjusted Cox-proportional hazards models were constructed to determine the association between continuous and data-derived categorical measures (tertiles) of cf-PWV and incidence of HF and its subtypes (HFpEF [ejection fraction >45%] and HFrEF [ejection fraction ≤45%]). We observed 390 HF events (162 HFpEF and 145 HFrEF events) over 11.4 years of follow-up. In adjusted analysis, higher cf-PWV was associated with greater risk of HF after adjustment for age, sex, ethnicity, mean arterial pressure, and heart rate (hazard ratio [95% confidence interval] for cf-PWV tertile 3 versus tertile 1 [ref] =1.35 [1.05-1.73]). However, this association was not significant after additional adjustment for other cardiovascular risk factors (hazard ratio [95% confidence interval], 1.14 [0.88-1.47]). cf-PWV velocity was also not associated with risk of HFpEF and HFrEF after adjustment for potential confounders (most adjusted hazard ratio [95% confidence interval] for cf-PWV tertile 3 versus tertile 1 [ref]: HFpEF, 1.06 [0.72-1.56]; HFrEF, 1.28 [0.83-1.97]). In conclusion, arterial stiffness, as measured by cf-PWV, is not independently associated with risk of HF or its subtypes after adjustment for traditional cardiovascular risk factors.

Risk of Heart Failure With Preserved Ejection Fraction in Older Women After Contemporary Radiotherapy for Breast Cancer.

Cardiomyocytes are resistant to radiation. However, cardiac radiation exposure causes coronary microvascular endothelial inflammation, a perturbation implicated in the pathogenesis of heart failure (HF) and particularly HF with preserved ejection fraction (HFpEF). Radiotherapy for breast cancer results in variable cardiac radiation exposure and may increase the risk of HF. We conducted a population-based case-control study of incident HF in 170 female residents of Olmsted County, Minnesota (59 cases and 111 controls), who underwent contemporary (1998-2013) radiotherapy for breast cancer with computed tomography-assisted radiotherapy planning. Controls were matched to cases for age, tumor side, chemotherapy use, diabetes mellitus, and hypertension. Mean cardiac radiation dose (MCRD) in each patient was calculated from the patient's computed tomography images and radiotherapy plan. Mean age at radiotherapy was 69±9 years. Of HF cases, 38 (64%) had EF≥50% (HFpEF), 18 (31%) had EF<50% (HF with reduced EF), and 3 (5%) did not have EF measured. The EF was ≥40% in 50 of the 56 HF cases (89%) with an EF measurement. The mean interval from radiotherapy to HF was 5.8±3.4 years. The odds of HF was higher in patients with a history of ischemic heart disease or atrial fibrillation. The MCRD was 2.5 Gy (range, 0.2-13.1 Gy) and higher in cases (3.3±2.7 Gy) than controls (2.1±2.0 Gy; P=0.004). The odds ratio (95% confidence interval) for HF per log MCRD was 9.1 (3.4-24.4) for any HF, 16.9 (3.9-73.7) for HFpEF, and 3.17 (0.8-13.0) for HF with reduced EF. The increased odds of any HF or HFpEF with increasing MCRD remained significant after adjustment for HF risk factors and in sensitivity analyses matching by cancer stage rather than tumor side. Only 18.6% of patients experienced new or recurrent ischemic events between radiotherapy and the onset of HF. The relative risk of HFpEF increases with increasing cardiac radiation exposure during contemporary conformal breast cancer radiotherapy. These data emphasize the importance of radiotherapy techniques that limit MCRD during breast cancer treatment. Moreover, these data provide further support for the importance of coronary microvascular compromise in the pathophysiology of HFpEF.

Association of serum calcium and heart failure with preserved ejection fraction in patients with type 2 diabetes.

BackgroundType 2 diabetes mellitus (T2DM) is a recognized trigger factor for heart failure with preserved ejection fraction (HFpEF). Recent studies show that higher serum calcium level is associated with greater risk of both T2DM and heart failure. We speculate that increased serum calcium is related to HFpEF prevalence in patients with T2DM.MethodsIn this cross-sectional echocardiographic study, 807 normocalcemia and normophosphatemia patients with T2DM participated, of whom 106 had HFpEF. Multinomial logistic regression was carried out to determine the variables associated with HFpEF. The associations between serum calcium and metabolic parameters, as well as the rate of HFpEF were examined using bivariate linear correlation and binary logistic regression, respectively. The predictive performance of serum calcium for HFpEF was evaluated using the area under the receiver operating characteristic curve (AUC).ResultsPatients with HFpEF have significantly higher serum calcium than those without HFpEF. Serum calcium was positively associated with total cholesterol, triglycerides, low-density lipoprotein cholesterol, serum uric acid, HOMA-IR and fasting plasma glucose. Compared with patients in the lowest serum calcium quartile, the odds ratio (OR) for HFpEF in patients in the highest quartile was 2.331 (95 % CI 1.088–4.994, p = 0.029). When calcium was analyzed as a continuous variable, per 1 mg/dL increase, the OR (95 % CI) for HFpEF was [2.712 (1.471–5.002), p = 0.001]. Serum calcium can predict HFpEF [AUC = 0.673, 95 % CI (0.620–0.726), p < 0.001].ConclusionsAn increase in serum calcium level is associated with an increased risk of HFpEF in patients with T2DM.

Abstract 19850: Elevated Exercise Blood Pressure in Middle Aged Women Identifies Features of Stage A Heart Failure With Preserved Ejection Fraction (HFpEF)

Introduction: Elevated systolic blood pressure (SBP) during exercise is associated with abnormal vascular function and left ventricular (LV) hypertrophy. While women have lower exercise BP compared to men, few studies have explored the underlying sex differences associated with exercise BP response. We hypothesized women who generated higher exercise SBP would be more likely than men to have abnormal measures of cardiac and vascular stiffness as well as lower aerobic fitness, features associated with stage A HFpEF. Methods: We studied 85 (45% male) healthy normotensive middle aged subjects (53 ± 5 yrs). VO2 (Douglas bags) and BP (ECG gated electrosphygmomanometry) were measured at rest and maximal exercise. Resting cardiac function was assessed using echo (2D, 3D) and invasive measurement (right heart catheterization) of LV filling pressure under varying preloads. LV stiffness was calculated by curve fit of the diastolic portion of the pressure-volume curve. Aortic pulse wave velocity (PWV) and central aortic pressure were measured by arterial tonometry. Two factor ANCOVA was used to determine interaction between men and women using SBP as the independent variable. Results: In men, low fitness (peak VO2) was the best predictor of elevated exercise SBP. (R2 0.24) Similarly for women, fitness was predictive of exercise SBP in addition to vascular stiffness (PWV). (R2 0.55) When compared to men, women with elevated exercise SBP were distinctly more likely to have higher LV and vascular stiffness, impaired LV relaxation (IVRT; isovolumic relaxation time) as well as higher body fat percentage. (Table) Conclusions: In otherwise healthy middle aged women, elevated exercise BP was associated with increased LV and vascular stiffness, impaired LV relaxation and higher body fat, pre-clinical features consistent with stage A HFpEF. These relationships were not seen in men. Elevated exercise SBP in middle aged women may help identify a vulnerable population at risk for future HFpEF.

Low Fitness in Midlife: A Novel Therapeutic Target for Heart Failure with Preserved Ejection Fraction Prevention

Heart failure (HF) with preserved ejection fraction (HFpEF) is common and recalcitrant to any medical therapy, highlighting the need for novel strategies focused on its prevention. Recent studies have shown that low cardiorespiratory fitness (CRF) in middle age identifies a subgroup of individuals at particularly high risk for HF, particularly HFpEF. These findings suggest that low CRF in middle age represents an upstream marker for late-life HFpEF. Furthermore, evidence from recent epidemiological studies suggests that low CRF associated risk for HFpEF appears to be modifiable with improvement in CRF. The primary objective of this review is to provide an overview of the potential mechanisms through which exercise training and improvement in CRF may protect against the transition from a low fit stage to clinical HFpEF among at-risk sedentary, middle-age adults.

Lung Function Abnormalities are Highly Frequent in Patients with Heart Failure and Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFPEF) is the most prevalent form of heart failure in outpatients. Yet, the pathophysiology of this syndrome is unclear and pharmacological treatment does not improve prognosis. Because breathlessness during activities of daily living is the most frequent complaint of patients with HFPEF, we hypothesised that lung function may be often abnormal in these patients due to either a direct effect of HFPEF and/or shared risk factors. In this study we explore the frequency, type and severity of lung function abnormalities in HFPEF. We measured forced spirometry, static lung volumes, pulmonary diffusing capacity (DL(CO)) and arterial blood gases in 69 outpatients with newly diagnosed symptomatic HFPEF. We found that 94% of the patients showed abnormalities in at least one of the lung function measurements obtained: spirometry was abnormal in 59%, DL(CO) in 83% and arterial hypoxaemia was present in 62%. Their severity varied between patients, they were more prevalent in patients with NYHA functional class III/IV, and most often they were undiagnosed and untreated. Lung function abnormalities are very frequent in HFPEF patients. A greater awareness among clinicians may contribute to improve their management and health status.

Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND

Differences in clinical characteristics and outcome of patients with established heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) are well established. Data on epidemiology and prediction of new onset HFpEF, compared with HFrEF, have not been described. In 8592 subjects of the Prevention of Renal and Vascular End-stage Disease (PREVEND), a community-based, middle-aged cohort study, we performed cause-specific hazard analyses to study the predictive value of risk factors and established cardiovascular biomarkers on new onset HFrEF vs. HFpEF (left ventricular ejection fraction ≤ 40 and ≥ 50%, respectively). A P-value for competing risk (Pcr) <0.10 between HFrEF and HFpEF was considered statistically significant. All potential new onset heart failure cases were reviewed and adjudicated to HFrEF or HFpEF by an independent committee. During a median follow-up of 11.5 years, 374 (4.4%) subjects were diagnosed with heart failure, of which 125 (34%) with HFpEF and 241 (66%) with HFrEF. The average time to diagnosis of new onset HFrEF was 6.6 ± 3.6 years; it was 8.3 ± 3.3 years for HFpEF (P < 0.001). Male gender was associated with new onset HFrEF, whereas female gender with new onset HFpEF (Pcr < 0.001). Higher age and increased N-terminal pro-B-type natriuretic peptide (NT-proBNP) increased the risk for both HFpEF and HFrEF, although for age this was stronger for HFpEF (Pcr = 0.018), whereas NT-proBNP was stronger associated with risk for HFrEF (Pcr = 0.083). Current smokers, increased highly sensitive troponin T, and previous myocardial infarction conferred a significantly increased risk for HFrEF, but not for HFpEF (Pcr = 0.093, 0.091, and 0.061, respectively). Conversely, a history of atrial fibrillation, increased urinary albumin excretion (UAE), and cystatin C were significantly more associated with the risk for HFpEF, but not for HFrEF (Pcr < 0.001, 0.061, and 0.033, respectively). The presence of obesity at baseline was associated with comparable prognostic information for both HFpEF and HFrEF. Higher age, UAE, cystatin C, and history of atrial fibrillation are strong risk factors for new onset HFpEF. This underscores differential pathophysiological mechanisms for both subtypes of heart failure.

Arterial vasodilatory and ventricular diastolic reserves determine the stroke volume response to exercise in elderly female hypertensive patients

Elderly female hypertensives with arterial stiffening constitute a majority of patients with heart failure with preserved ejection fraction (HFpEF), a condition characterized by inability to increase cardiac stroke volume (SV) with physical exercise. As SV is determined by the interaction between the left ventricle (LV) and its load, we wished to study the role of arterial hemodynamics for exertional SV reserve in patients at high risk of HFpEF. Twenty-one elderly (67 ± 9 yr) female hypertensive patients were studied at rest and during supine bicycle stress using echocardiography including pulsed-wave Doppler to record flow in the LV outflow tract and arterial tonometry for central arterial pressure waveforms. Arterial compliance was estimated based on an exponential relationship between pressure and volume. The ratio of aortic pressure-to-flow in early systole was used to derive characteristic impedance, which was subsequently subtracted from total resistance (mean arterial pressure/cardiac output) to yield systemic vascular resistance (SVR). It was found that patients with depressed SV reserve (NoRes; reserve <15%; n = 10) showed decreased arterial compliance during exercise, while patients with SV reserve ≥15% (Res; n = 11) showed increased compliance. Exercise produced parallel increases in LV end-diastolic volume and arterial volume in Res patients while NoRes patients exhibited a lesser decrease in SVR and a drop in effective arterial volume. Poor SV reserve in elderly female hypertensives is due to simultaneous failure of LV preload and arterial vasodilatory reserves. Abnormal arterial function contributes to a high risk of HFpEF in these patients.

The diagnosis of heart failure in the community comparative validation of four sets of criteria in unselected older adults: The ICARe Dicomano study

Heart failure with preserved ejection fraction (HFpEF) is a growing epidemic owing to an increasingly obese and aging patient population. Making the diagnosis of HFpEF is often challenging because patients frequently have multiple comorbidities and alternative reasons for dyspnea and exercise intolerance, symptoms that are hallmark to the disease. Additionally, a universal diagnostic algorithm and definition of HFpEF is lacking. The treatment of HFpEF has been equally challenging, as there remain exceedingly few therapies show to improve survival in HFpEF and thus management to date has focused on intensive optimization of HFpEF risk factors. In this review, we highlight a stepwise approach to the diagnosis and treatment of HFpEF including (1) how to establish a clinical diagnosis of HFpEF, (2) when to refer for invasive diagnostic testing, (3) current treatment approaches to HFpEF including pharmacologic, nonpharmacologic, and risk factor modification interventions, and (4) when to refer to a dedicated HFpEF center or advanced heart failure specialist. With this systematic stepwise approach to HFpEF diagnosis and management, we aim to improve accurate diagnosis of the disease as well as raise awareness of available therapeutic options for this challenging patient population.