Kitzman, Dalane W.

BACKGROUND: Patients with heart failure (HF) have a high burden of symptoms and physical limitations, regardless of ejection fraction (EF). Whether the benefits of SGLT2 (sodium-glucose cotransporter-2) inhibitors on these outcomes vary across the full range of EF remains unclear. METHODS: Patient-level data were pooled from the DEFINE-HF trial (Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction) of 263 participants with reduced EF (≤40%), and PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure) of 324 participants with preserved EF (≥45%). Both were randomized, double-blind 12-week trials of dapagliflozin versus placebo, recruiting participants with New York Heart Association class II or higher and elevated natriuretic peptides. The effect of dapagliflozin on the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at 12 weeks was tested with ANCOVA adjusted for sex, baseline KCCQ, EF, atrial fibrillation, estimated glomerular filtration rate, and type 2 diabetes. Interaction of dapagliflozin effects on KCCQ-CSS by EF was assessed using EF both categorically and continuously with restricted cubic spline. Responder analyses, examining proportions of patients with deterioration, and clinically meaningful improvements in KCCQ-CSS were conducted using logistic regression. RESULTS: Of 587 patients randomized (293 dapagliflozin, 294 placebo), EF was ≤40, >40-≤60, and >60% in 262 (45%), 199 (34%), and 126 (21%), respectively. Dapagliflozin improved KCCQ-CSS at 12 weeks (placebo-adjusted difference 5.0 points [95% CI, 2.6–7.5]; P <0.001). This was consistent in participants with EF≤40 (4.6 points [95% CI, 1.0–8.1]; P =0.01), >40 to ≤60 (4.9 points [95% CI, 0.8–9.0]; P =0.02) and >60% (6.8 points [95% CI, 1.5–12.1]; P =0.01; P interaction =0.79). Benefits of dapagliflozin on KCCQ-CSS were also consistent when analyzing EF continuously ( P interaction =0.94). In responder analyses, fewer dapagliflozin-treated patients had deterioration and more had small, moderate, and large KCCQ-CSS improvements versus placebo; these results were also consistent regardless of EF (all P interaction values nonsignificant). CONCLUSIONS: In patients with HF, dapagliflozin significantly improves symptoms and physical limitations after 12 weeks of treatment, with consistent and clinically meaningful benefits across the full range of EF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT02653482 and NCT03030235.

Abstract Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous entity with complex pathophysiology and manifestations. Phenomapping is the process of applying statistical learning techniques to patient data to identify distinct subgroups based on patterns in the data. Phenomapping has emerged as a technique with potential to improve the understanding of different HFpEF phenotypes. Phenomapping efforts have been increasing in HFpEF over the past several years using a variety of data sources, clinical variables, and statistical techniques. This review summarizes methodologies and key takeaways from these studies, including consistent discriminating factors and conserved HFpEF phenotypes. We argue that phenomapping results to date have had limited implications for clinical care and clinical trials, given that the phenotypes, as currently described, are not reliably identified in each study population and may have significant overlap. We review the inherent limitations of aggregating and utilizing phenomapping results. Lastly, we discuss potential future directions, including using phenomapping to optimize the likelihood of clinical trial success or to drive discovery in mechanisms of the disease process of HFpEF.

Abstract Obesity and heart failure with preserved ejection fraction (HFpEF) represent two intermingling epidemics driving perhaps the greatest unmet health problem in cardiovascular medicine in the 21st century. Many patients with HFpEF are either overweight or obese, and recent data have shown that increased body fat and its attendant metabolic sequelae have widespread, protean effects systemically and on the cardiovascular system leading to symptomatic HFpEF. The paucity of effective therapies in HFpEF underscores the importance of understanding the distinct pathophysiological mechanisms of obese HFpEF to develop novel therapies. In this review, we summarize the current understanding of the cardiovascular and non-cardiovascular features of the obese phenotype of HFpEF, how increased adiposity might pathophysiologically contribute to the phenotype, and how these processes might be targeted therapeutically.

Abstract Aims A hallmark of heart failure with preserved ejection fraction (HFpEF) is impaired exercise capacity of varying severity. The main determinant of exercise capacity is cardiac output (CO), however little information is available about the relation between the constituents of CO – heart rate and stroke volume – and exercise capacity in HFpEF. We sought to determine if a heterogeneity in heart rate and stroke volume response to exercise exists in patients with HFpEF and describe possible clinical phenotypes associated with differences in these responses. Methods and results Data from two prospective trials of HFpEF ( n = 108) and a study of healthy participants ( n = 42) with invasive haemodynamic measurements during exercise were utilized. Differences in central haemodynamic responses were analysed with regression models. Chronotropic incompetence was present in 39–56% of patients with HFpEF and 3–56% of healthy participants depending on the definition used, but some ( n = 47, 44%) had an increase in heart rate similar to that of healthy controls. Patients with HFpEF had a smaller increase in their stroke volume index (SVI) (HFpEF: +4 ± 10 mL/m 2 , healthy participants: +24 ± 12 mL/m 2 , P < 0.0001), indeed, SVI fell in 28% of patients at peak exercise. Higher body mass index and lower SVI at rest were associated with smaller increases in heart rate during exercise, whereas higher resting heart rate, and angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker use were associated with a greater increase in SVI in patients with HFpEF. Conclusion The haemodynamic response to exercise was very heterogeneous among patients with HFpEF, with chronotropic incompetence observed in up to 56%, and 28% had impaired increase in SVI. This suggests that haemodynamic exercise testing may be useful to identify which HFpEF patients may benefit from interventions targeting stroke volume and chronotropic response.

Heart failure with preserved ejection fraction (HFpEF), a major public health problem that is rising in prevalence, is associated with high morbidity and mortality and is considered to be the greatest unmet need in cardiovascular medicine today because of a general lack of effective treatments. To address this challenging syndrome, the National Heart, Lung, and Blood Institute convened a working group made up of experts in HFpEF and novel research methodologies to discuss research gaps and to prioritize research directions over the next decade. Here, we summarize the discussion of the working group, followed by key recommendations for future research priorities. There was uniform recognition that HFpEF is a highly integrated, multiorgan, systemic disorder requiring a multipronged investigative approach in both humans and animal models to improve understanding of mechanisms and treatment of HFpEF. It was recognized that advances in the understanding of basic mechanisms and the roles of inflammation, macrovascular and microvascular dysfunction, fibrosis, and tissue remodeling are needed and ideally would be obtained from (1) improved animal models, including large animal models, which incorporate the effects of aging and associated comorbid conditions; (2) repositories of deeply phenotyped physiological data and human tissue, made accessible to researchers to enhance collaboration and research advances; and (3) novel research methods that take advantage of computational advances and multiscale modeling for the analysis of complex, high-density data across multiple domains. The working group emphasized the need for interactions among basic, translational, clinical, and epidemiological scientists and across organ systems and cell types, leveraging different areas or research focus, and between research centers. A network of collaborative centers to accelerate basic, translational, and clinical research of pathobiological mechanisms and treatment strategies in HFpEF was discussed as an example of a strategy to advance research progress. This resource would facilitate comprehensive, deep phenotyping of a multicenter HFpEF patient cohort with standardized protocols and a robust biorepository. The research priorities outlined in this document are meant to stimulate scientific advances in HFpEF by providing a road map for future collaborative investigations among a diverse group of scientists across multiple domains.

In observational studies, left ventricular mass (LVM) and structure are strong predictors of mortality and cardiovascular events. However, the effect of hypertension treatment on LVM reduction and its relation to subsequent outcomes is unclear, particularly at lower blood pressure (BP) targets. In an ancillary study of SPRINT (Systolic Blood Pressure Intervention Trial), where participants were randomly assigned to intensive BP control (target systolic BP target <120 mm Hg) versus standard BP control (<140 mm Hg), cardiac magnetic resonance imaging was performed at baseline and 18-month follow-up to measure: LVM, volumes, ejection fraction, and native T1 mapping for myocardial fibrosis. At baseline, 337 participants were examined (age: 64±9 years, 45% women); 300 completed the 18-month exam (153 intensive control and 147 standard control). In the intensive versus standard BP control group at 18 months, there was no difference in change in LVM (mean±SE =−2.7±0.5 g versus −2.3±0.7 g; P =0.368), ejection fraction, or native T1 ( P =0.79), but there was a larger decrease in LVM/end-diastolic volume ratio (−0.04±0.01 versus −0.01±0.01; P =0.002) a measure of concentric LV remodeling. There were fewer cardiovascular events in the intensive control group, but no significant association between the reduced events and change in LVM or any other cardiac magnetic resonance imaging measure. In SPRINT-HEART, contrary to our hypothesis, there were no significant between-group differences in LVM, function, or myocardial T1 at 18-month follow-up. These results suggests that mediators other than these LV measures contribute to the improved cardiovascular outcomes with intensive BP control.

The American Geriatrics Society convened a conference in Bethesda, Maryland, to explore models and studies of aging. This was the second of three conferences, supported by a U13 grant from the National Institute on Aging, to aid recipients of Grants for Early Medical/Surgical Specialists Transition to Aging Research (GEMSSTAR) in integrating geriatrics into their specialties. Recognizing that aging is the largest risk factor for multiple chronic diseases and age‐related loss of resilience, the conference organizers focused scientific sessions on how targeting age‐related mechanisms can delay, prevent, or reverse geriatric syndromes, age‐related chronic diseases, and loss of resilience. The rationale for studying models of aging as well as study designs, strategies, and challenges of studying human aging were reviewed. This article provides a summary of the full conference report, Models and Studies of Aging: Report from the U13 Conference Series, and summarizes key take‐home messages that were designed to support GEMSSTAR awardees in developing their research careers focused on aging research (see supplementary text for the full report). J Am Geriatr Soc 67:428–433, 2019.

Background: In individuals with a low diastolic blood pressure (DBP), the potential benefits or risks of intensive systolic blood pressure (SBP) lowering are unclear. Methods: SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized controlled trial that compared the effects of intensive (target <120 mm Hg) and standard (target <140 mm Hg) SBP control in 9361 older adults with high blood pressure at increased risk of cardiovascular disease. The primary outcome was a composite of cardiovascular disease events. All-cause death and incident chronic kidney disease were secondary outcomes. This post hoc analysis examined whether the effects of the SBP intervention differed by baseline DBP. Results: Mean baseline SBP and DBP were 139.7±15.6 and 78.1±11.9 mm Hg, respectively. Regardless of the randomized treatment, baseline DBP had a U-shaped association with the hazard of the primary cardiovascular disease outcome. However, the effects of the intensive SBP intervention on the primary outcome were not influenced by baseline DBP level ( P for interaction=0.83). The primary outcome hazard ratio for intensive versus standard treatment was 0.78 (95% confidence interval, 0.57–1.07) in the lowest DBP quintile (mean baseline DBP, 61±5 mm Hg) and 0.74 (95% confidence interval, 0.61–0.90) in the upper 4 DBP quintiles (mean baseline DBP, 82±9 mm Hg), with an interaction P value of 0.78. Results were similar for all-cause death and kidney events. Conclusions: Low baseline DBP was associated with increased risk of cardiovascular disease events, but there was no evidence that the benefit of the intensive SBP lowering differed by baseline DBP. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01206062.

Abstract Aims Patients with heart failure and preserved ejection fraction (HFpEF) are characterized by functional impairment and an abnormal haemodynamic response to exercise. The six-minute walk test (6MWT) serves as a standardized test for functional capacity quantification in heart failure patients, and is associated with cardiovascular outcomes. However, as the association between 6MWT and haemodynamic parameters during rest and exercise in HFpEF patients is unknown, we sought to elucidate this relationship. Methods and results Overall, 64 patients enrolled in the REDUCE LAP-HF trial completed a 6MWT at baseline. Univariate and multivariable linear regression models were used to assess the associations between 6MWT and measured or derived haemodynamic variables at baseline, during light/moderate exercise (20 W), and at peak supine exercise. The average 6MWT distance was 318 ± 106 m. At rest, in a multivariable model, only pulmonary capillary wedge pressure (PCWP) was significantly associated with 6MWT [coefficient: –5.4, 95% confidence interval (CI) –10.4, –0.5, P = 0.033]. During light/moderate exercise, mean pulmonary artery pressure was associated with 6MWT in a multivariable model (coefficient: –3.5, 95% CI –6.8, –0.3, P = 0.033). During peak exercise, central venous pressure, cardiac index (CI), and PCWP/CI correlated with 6MWT; however, workload corrected PCWP was the only variable independently associated with 6MWT (coefficient: –0.8, 95% CI –1.3, –0.4, P &lt; 0.001). The variance in 6MWT was modestly explained by measured or derived haemodynamic variables at rest or at any stage of exercise (r2 = 7–17%). Conclusion Workload corrected PCWP correlated best with 6MWT performance in HFpEF patients. Baseline haemodynamic variables were modestly correlated with 6MWT, suggesting that 6MWT performance in HFpEF patients may be significantly influenced by extra-cardiac factors.

The incidence and prevalence of most cardiovascular disorders increase with age, and cardiovascular disease ( CVD ) is the leading cause of death and major disability in adults aged 75 and older. Despite the effect of CVD on quality of life, morbidity, and mortality in older adults, individuals aged 75 and older have been markedly underrepresented in most major cardiovascular trials, and virtually all trials have excluded older adults with complex comorbidities, significant physical or cognitive disabilities, frailty, or residence in nursing homes and assisted living facilities. As a result, current guidelines are unable to provide evidence‐based recommendations for diagnosis and treatment of older adults typical of those encountered in routine clinical practice. The objectives of this scientific statement are to summarize current guideline recommendations as they apply to older adults, identify critical gaps in knowledge that preclude informed evidence‐based decision‐making, and recommend future research to close existing knowledge gaps. To achieve these objectives, a detailed review was conducted of current American College of Cardiology/American Heart Association ( ACC / AHA ) and American Stroke Association ( ASA ) guidelines to identify content and recommendations that explicitly targeted older adults. A pervasive lack of evidence to guide clinical decision‐making in older adults with CVD was found, as well as a paucity of data on the effect of diagnostic and therapeutic interventions on outcomes that are particularly important to older adults, such as quality of life, physical function, and maintenance of independence. Accordingly, there is a critical need for a multitude of large population‐based studies and clinical trials that include a broad spectrum of older adults representative of those seen in clinical practice and that incorporate relevant outcomes important to older adults in the study design. The results of these studies will provide the foundation for future evidence‐based guidelines applicable to older adults and enhance person‐centered care of older individuals with CVD in the United States and around the world.