Juhi K. Parekh

Background: The PREVENT-HF equations estimate 10-year risk of overall heart failure (HF), inclusive of both HF with preserved and reduced ejection fraction (HFpEF; HFrEF). Given differential risk factor profiles, pathophysiology, and therapeutic strategies for each HF subtype, we sought to examine the performance of PREVENT-HF for subtype-specific risk assessment. Methods: We included data from five pooled longitudinal cohort studies (baseline exam 1989 to 2013) and two longitudinal primary-care electronic health record-based samples (Beth Israel Deaconess Medical Center [BIDMC], baseline 2004 to 2014; Mass General Brigham [MGB], baseline 2001 to 2018). We assessed the performance of the PREVENT-HF equations in predicting 10-year incident HFrEF and HFpEF, including model discrimination (area under the receiver operating characteristic curve [AUROC]; average precision [AP]/event rate) and calibration (integrated calibration index [ICI]), in adults aged 30-79 years without prevalent cardiovascular disease or HF. Results: The pooled cohort studies included 23,652 (55% women, age 60 ± 13 years), of whom 1,232 developed HF (432 [35%] HFpEF, 522 [42%] HFrEF). The BIDMC sample included 29,815 (55% women, 50 ± 13 years), of whom 259 (1%) developed HF (133 [51%] HFpEF, 101 [39%] HFrEF). MGB included 138,999 (62% women, 52 ± 13 years), of whom 1050 developed HF (586 [56%] HFpEF, 381 [36%] HFrEF). PREVENT-HF demonstrated better discrimination for HFpEF than HFrEF across all samples: in the pooled cohorts, the AUROC for HFpEF was 0.824 (95% CI 0.807, 0.839) versus 0.789 (95% CI 0.770, 0.807) for HFrEF; in BIDMC, the AUROC for HFpEF was 0.897 (95% CI 0.874, 0.918) versus 0.833 (95% CI 0.791, 0.869) for HFrEF; in MGB, the AUROC for HFpEF was 0.864 (95% CI 0.848, 0.880) versus 0.797 (95% CI 0.771, 0.820) for HFrEF. Similar results were reflected in the AP/event rate ratios: 2.92 (95% CI 2.47, 3.54) for HFpEF compared to 2.66 (95% CI 2.33, 3.14) for HFrEF in the pooled cohorts; 8.08 (95% CI 6.12, 12.30) for HFpEF compared to 5.12 (95% CI 3.84, 8.17) for HFrEF in BIDMC; and 6.84 (95% CI 5.66, 8.28) for HFpEF compared to 4.12 (95% CI 3.37, 5.16) for HFrEF in MGB. Calibration was similar for HFpEF and HFrEF across samples. For example, in the pooled cohorts, the ICI for HFpEF was 0.041 (95% CI 0.039, 0.043) and for HFrEF was 0.038 (95% CI 0.036, 0.040). Conclusions: PREVENT-HF demonstrated excellent discrimination for both HF subtypes across community-based cohorts and real-world samples, with consistently better discrimination for HFpEF as compared to HFrEF. Given PREVENT-HF was developed to estimate overall HF risk rather than subtype-specific risk, future studies are needed to establish subtype-specific risk thresholds.

Background: Sex differences in clinical presentations of heart failure (HF) are pervasive, yet differences in invasive hemodynamic measures across HF subtypes remain incompletely characterized. Understanding these distinctions is critical, as sex‐specific physiology influences disease progression and prognostic assessment in HF. Methods: We conducted a retrospective cohort study of 1818 patients with HF who underwent clinically indicated right heart catheterization, stratified by preserved versus reduced ejection fraction. We examined the association of sex with invasive hemodynamic measures of right ventricular, pulmonary vascular, and left ventricular function using multivariable linear regression. Results: We studied n=709 individuals with heart failure with preserved ejection fraction (HFpEF) (44% women, mean age 68±10 years) and n=1109 with heart failure with reduced ejection fraction (HFrEF) (26% women, mean age 64±12 years). Women and men had similar measures of right ventricular function across HF subtypes (multivariable‐adjusted P >0.05 for all). However, women with both HFpEF and HFrEF exhibited worse pulmonary vascular function, with significantly higher pulmonary vascular resistance and lower pulmonary artery compliance (multivariable‐adjusted P P =0.01 for HFpEF; P <0.001 for HFrEF). Conclusions: Among a large hospital‐based sample of patients with HF, women and men exhibited similar indices of right ventricular function, despite women having worse pulmonary vascular function. Cardiac power index was similar between sexes in both HFpEF and HFrEF, whereas aortic pulsatility index was higher in women with HFrEF. Taken together, sex differences in hemodynamic measures were largely similar across individuals with HFpEF and HFrEF. Future studies are needed to delineate clinical implications of these sex differences.

BACKGROUND: The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines introduced elevated natriuretic peptide (NP) levels as a criterion for defining stage B heart failure (HF), or pre-HF, to identify individuals at greatest risk for future HF. Given the known NP deficiency in obesity, we aimed to assess whether a single NP cut point would disproportionately up-classify individuals with versus without obesity to stage B HF. METHODS: Participants free of HF from 5 community-based cohorts were included. We examined the reclassification of individuals to stage B HF using the 2022 versus 2013 guidelines, stratified by obesity class. Cox proportional hazards models were used to assess the association of NPs with incident HF across obesity classes. RESULTS: Among 32 735 participants, 35% had normal weight, 40% were overweight, 17% had obesity class 1, and 8% had obesity class 2/3. When applying the 2022 versus 2013 criteria, the proportion of individuals up-classified to stage B HF using the NP criterion was 62% among those with normal weight, 51% for those overweight, 47% for individuals with obesity class 1, and 42% for individuals with obesity class 2/3. Over a median follow-up of 13 years, 3077 HF events occurred. Both higher NP and body mass index were associated with greater HF risk, as expected ( P <0.0001 for both). Importantly, body mass index modified the association of NP with HF risk, such that higher NP concentration was associated with greater HF risk among individuals with lower body mass index. The optimal NT-proBNP (N-terminal pro-B-type natriuretic peptide) cut point to predict future HF risk was lower among individuals with obesity (80 pg/mL; 95% CI, 53–121) compared with normal-weight individuals (109 pg/mL; 95% CI, 80–157). CONCLUSIONS: The application of a single NP cut point resulted in fewer individuals with obesity being up-classified to stage B HF compared with normal-weight individuals. Adjusting NP cut points for individuals with obesity may improve the accuracy of HF risk stratification.

Background: Sex differences in obesity and fat distribution may in part explain differences in cardiovascular risk in men versus women. We sought to examine sex differences in the associations of obesity and adiposity measures with cardiovascular disease–related protein biomarkers. Methods and Results: In a cross‐sectional observational cohort study, we examined whether the association of obesity (body mass index [BMI] and waist circumference) and adiposity measures (visceral adipose tissue) with biomarkers demonstrates effect modification by sex using multiplicative interaction terms in multivariable linear regression models. Among 3143 participants (mean age, 50 years; 49% women), sex modified the association of BMI, waist circumference, and visceral adipose tissue with cardiovascular disease–related protein biomarkers (7 for BMI, 3 for waist circumference, and 23 for visceral adipose tissue, false discovery rate [FDR]‐q _int 1 ‐microglobulin levels in men but not in women (ß, −0.113; SE, 0.028; P P =0.78 in women). By contrast, higher BMI was associated with higher adipsin levels in men and women, but the association was more pronounced in women (ß, 0.287; SE, 0.023; P P <0.001 in men). The associations of higher visceral adipose tissue with biomarkers representing adiposity, inflammation, and fibrosis were more pronounced in women versus men. Conclusions: We found that sex modified the associations of obesity and adipose traits with cardiovascular risk ascertained by cardiovascular disease–related biomarkers including markers of adiposity, inflammation, and fibrosis. These findings highlight potential biological pathways that may underlie some of the observed differences in obesity‐related cardiovascular disease between women and men.

BACKGROUND: Although heart failure with preserved ejection fraction (HFpEF) has become the predominant heart failure subtype, it remains clinically under-recognized. HFpEF diagnosis is particularly challenging in the setting of obesity given the limitations of natriuretic peptides and resting echocardiography. We examined invasive and noninvasive HFpEF diagnostic criteria among individuals with obesity and dyspnea without known cardiovascular disease to determine the prevalence of hemodynamic HFpEF in the community. METHODS: Research volunteers with dyspnea and obesity underwent resting echocardiography; participants with possible pulmonary hypertension qualified for invasive cardiopulmonary exercise testing. HFpEF was defined using rest or exercise pulmonary capillary wedge pressure criteria (≥15 mm Hg or Δpulmonary capillary wedge pressure/Δcardiac output slope, >2.0 mm Hg·L ⁻¹ ·min ⁻ 1). RESULTS: Among n=78 participants (age, 53±13 years; 65% women; body mass index, 37.3±6.8 kg/m ² ), 40 (51%) met echocardiographic criteria to undergo invasive cardiopulmonary exercise testing. In total, 24 participants (60% among the cardiopulmonary exercise testing group, 31% among the total sample) were diagnosed with HFpEF by rest or exercise pulmonary capillary wedge pressure (n=12) or exercise criteria (n=12). There were no differences in NT-proBNP (N-terminal pro-B-type natriuretic peptide; 79 [62–104] versus 73 [57–121] pg/mL) or resting echocardiography (mitral E/e′ ratio, 9.1±3.1 versus 8.0±2.7) among those with versus without HFpEF ( P >0.05 for all). Distributions of HFpEF diagnostic scores were similar, with the majority classified as intermediate risk (100% versus 93.75% [H ₂ FPEF] and 87.5% versus 68.75% [HFA-PEFF (Heart Failure Association Pretest assessment, echocardiography and natriuretic peptide, functional testing, and final etiology)] in those with versus without HFpEF). CONCLUSIONS: Among adults with obesity and dyspnea without known cardiovascular disease, at least a third had clinically unrecognized HFpEF uncovered on invasive cardiopulmonary exercise testing. Clinical, biomarker, resting echocardiography, and diagnostic scores were similar among those with and without HFpEF. These results suggest clinical underdiagnosis of HFpEF among individuals with obesity and dyspnea and highlight limitations of noninvasive testing in the identification of HFpEF.

BACKGROUND: Right ventricular (RV) dysfunction is associated with increased mortality across a spectrum of cardiovascular diseases. The role of obesity in RV dysfunction and adverse outcomes is unclear. METHODS: We examined patients undergoing right heart catheterization between 2005 and 2016 in a hospital-based cohort. Linear regression was used to examine the association of obesity with hemodynamic indices of RV dysfunction (pulmonary artery pulsatility index, right atrial pressure:pulmonary capillary wedge pressure ratio, RV stroke work index). Cox models were used to examine the association of RV function measures with clinical outcomes. RESULTS: Among 8285 patients (mean age, 63 years; 40% women), higher body mass index was associated with worse indices of RV dysfunction, including lower pulmonary artery pulsatility index (β, −0.23; SE, 0.01; P P P P _interaction ≤0.005 for PAPi and RA:PCWP ratio), such that the effect of RV dysfunction was more pronounced at higher body mass index. CONCLUSIONS: Patients with obesity had worse hemodynamic measured indices of RV function across a broad hospital-based sample. While RV dysfunction was associated with worse clinical outcomes including mortality and heart failure hospitalization, this association was especially pronounced among individuals with higher body mass index.

BACKGROUND: Obesity and adiposity are associated with an increased risk of heart failure with preserved ejection fraction (HFpEF); yet, specific underlying mechanisms remain unclear. We sought to examine the association of obesity-related biomarkers including adipokines (leptin, resistin, adiponectin), inflammatory markers (CRP [C-reactive protein], IL-6 [interleukin-6]), and insulin resistance (HOMA-IR) with HFpEF status, exercise capacity, and cardiovascular outcomes. METHODS: We studied 509 consecutive patients with left ventricular ejection fraction ≥50% and chronic dyspnea, who underwent clinically indicated cardiopulmonary exercise test with invasive hemodynamic monitoring between 2006 and 2017. We defined HFpEF based on the presence of elevated left ventricular filling pressures at rest or during exercise. Fasting blood samples collected at the time of the cardiopulmonary exercise test were used to assay obesity-related biomarkers. We examined the association of log-transformed biomarkers with HFpEF status and exercise traits using multivariable-adjusted logistic regression models. RESULTS: We observed associations of obesity-related biomarkers with measures of impaired exercise capacity including peak VO ₂ ( P ≤0.002 for all biomarkers). The largest effect size was seen with leptin, where a 1-SD higher leptin was associated with a 2.35 mL/kg per min lower peak VO ₂ (β, −2.35±0.19; P P ≤0.002 for all), and chronotropic response (CRP, IL-6, homeostatic model assessment of insulin resistance, leptin, and resistin; P <0.05 for all). Our findings suggest that among the obesity-related biomarkers studied, higher levels of leptin and CRP are independently associated with increased odds of HFpEF, with odds ratios of 1.36 (95% CI, 1.09–1.70) and 1.25 (95% CI, 1.03–1.52), respectively. CONCLUSIONS: Specific obesity-related pathways including inflammation, adipokine signaling, and insulin resistance may underlie the association of obesity with HFpEF and exercise intolerance.

Background: Premature and early menopause are independently associated with greater risk of cardiovascular disease (CVD). However, mechanisms linking age of menopause with CVD remain poorly characterized. Methods and Results: We measured 71 circulating CVD protein biomarkers in 1565 postmenopausal women enrolled in the FHS (Framingham Heart Study). We examined the association of early menopause with biomarkers and tested whether early menopause modified the association of biomarkers with incident cardiovascular outcomes (heart failure, major CVD, and all‐cause death) using multivariable‐adjusted linear regression and Cox models, respectively. Among 1565 postmenopausal women included (mean age 62 years), 395 (25%) had a history of early menopause. Of 71 biomarkers examined, we identified 7 biomarkers that were significantly associated with early menopause, of which 5 were higher in women with early menopause including adrenomedullin and resistin, and 2 were higher in women without early menopause including insulin growth factor‐1 and CNTN1 (contactin‐1) (Benjamini‐Hochberg adjusted P P _int <0.05). Conclusions: Early menopause is associated with circulating levels of CVD protein biomarkers and appears to modify the association between select biomarkers with incident cardiovascular outcomes. Identified biomarkers reflect several distinct biological pathways, including inflammation, adiposity, and neurohormonal regulation. Further investigation of these pathways may provide mechanistic insights into the pathogenesis, prevention, and treatment of early menopause‐associated CVD.