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Metabolic dysfunction associated steatotic liver disease (MASLD) has been linked to heart failure with preserved ejection fraction (HFpEF). We sought to understand association between individuals with amounts of liver adiposity greater than would be predicted by their body mass index (BMI) in order to understand whether this disproportionate liver fat (DLF) represents a proxy of metabolic risk shared between liver and heart disease. We studied 2,932 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) who received computed tomography (CT) measurements of hepatic attenuation. Quartiles of DLF were compared and multivariable linear regression was performed to evaluate the association of DLF with clinical, echocardiographic, and quality of life metrics. Compared to the lowest quartile of DLF, individuals in the highest quartile of DLF were more likely to be male (52.0% vs 47.1%, P <.001), less likely to be Black or African American (14.8 % vs 38.1% P <.001), have higher rates of dysglycemia (31.9% vs 16.6%, P <.001) and triglycerides (140 [98.0, 199.0] vs 99.0 [72.0, 144.0] mg/dL, P >.001). These individuals had lower global longitudinal strain (−0.13 [−0.25, −0.02], P =.02), stroke volumes (−1.05 [−1.76, −0.33], P <.01), lateral e' velocity (−0.10 [−0.18, −0.02], P =.02), and 6-minute walk distances (−4.25 [−7.62 to −0.88], P =.01). DLF is associated with abnormal metabolic profiles and ventricular functional changes known to be associated with HFpEF and may serve as an early metric to assess for those that may progress to clinical HFpEF. [Display omitted] [ABSTRACT FROM AUTHOR]

Splanchnic vasoconstriction augments transfer of blood volume from the abdomen into the thorax, which may increase filling pressures and hemodynamic congestion in patients with noncompliant hearts. Therapeutic interruption of splanchnic nerve activity holds promise to reduce hemodynamic congestion in patients with heart failure with preserved ejection fraction (HFpEF). Here we describe (1) the rationale and design of the first sham-controlled, randomized clinical trial of splanchnic nerve ablation for HFpEF and (2) the 12-month results of the lead-in (open-label) trial's participants. REBALANCE-HF is a prospective, multicenter, randomized, double-blinded, sham-controlled clinical trial of endovascular, transcatheter, right-sided greater splanchnic nerve ablation for volume management (SAVM) in patients with HFpEF. The primary objectives are to evaluate the safety and efficacy of SAVM and identify responder characteristics to inform future studies. The trial consists of an open-label lead-in phase followed by the randomized, sham-controlled phase. The primary efficacy endpoint is the reduction in pulmonary capillary wedge pressure (PCWP) at 1-month follow-up compared to baseline during passive leg raise and 20W exercise. Secondary and exploratory endpoints include health status (Kansas City Cardiomyopathy Questionnaire), 6-minute walk test distance, New York Heart Association class, and NTproBNP levels at 3, 6 and 12 months. The primary safety endpoint is device- or procedure-related serious adverse events at the 1-month follow-up. The lead-in phase of the study, which enrolled 26 patients with HFpEF who underwent SAVM, demonstrated favorable safety outcomes and reduction in exercise PCWP at 1 month post-procedure and improvements in all secondary endpoints at 6 and 12 months of follow-up. The randomized phase of the trial (n = 44 SAVM; n = 46 sham) has completed enrollment, and follow-up is ongoing. REBALANCE-HF is the first sham-controlled randomized clinical trial of greater splanchnic nerve ablation in HFpEF. Initial 12-month open-label results are promising, and the results of the randomized portion of the trial will inform the design of a future pivotal clinical trial. SAVM may offer a promising therapeutic option for patients with HFpEF. NCT04592445 [ABSTRACT FROM AUTHOR]

• A machine learning algorithm was adapted into a tool to estimate risk of ATTRwt-CM in hypothetical patient scenarios. • The adapted model performed well in classifying patients with ATTRwt-CM and patients with HF. • This novel framework could serve as a simple and easily implementable tool to aid the clinical assessment of patient risk for ATTRwt-CM. Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM), an increasingly recognized cause of heart failure (HF), often remains undiagnosed until later stages of the disease. A previously developed machine learning algorithm was simplified to create a random forest model based on 11 selected phenotypes predictive of ATTRwt-CM to estimate ATTRwt-CM risk in hypothetical patient scenarios. Using U.S. medical claims datasets (IQVIA), International Classification of Diseases codes were extracted to identify a training cohort of patients with ATTRwt-CM (cases) or nonamyloid HF (controls). After assessment in a 20% test sample of the training cohort, model performance was validated in cohorts of patients with International Classification of Diseases codes for ATTRwt-CM or cardiac amyloidosis vs nonamyloid HF derived from medical claims (IQVIA) or electronic health records (Optum). The simplified model performed well in identifying patients with ATTRwt-CM vs nonamyloid HF in the test sample, with an accuracy of 74%, sensitivity of 77%, specificity of 72%, and area under the curve of 0.82; robust performance was also observed in the validation cohorts. This simplified machine learning model accurately estimated the empirical probability of ATTRwt-CM in administrative datasets, suggesting it may serve as an easily implementable tool for clinical assessment of patient risk for ATTRwt-CM in the clinical setting. Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM for short) is a frequently overlooked cause of heart failure. Finding ATTRwt-CM early is important because the disease can worsen rapidly without treatment. Researchers developed a computer program that predicts the risk of ATTRwt-CM in patients with heart failure. In this study, the program was used to check for 11 medical conditions linked to ATTRwt-CM in the medical claims records of patients with heart failure. The program was 74% accurate in identifying ATTRwt-CM in patients with heart failure and was then used to develop an educational online tool for doctors (the wtATTR-CM estimATTR). The proportions of patients with ATTRwt-CM and odds ratios associated with ATTRwt-CM:nonamyloid HF for the 11 phenotypes included in the simplified random forest model. ATTRwt, wild-type transthyretin amyloidosis; ATTRwt-CM, wild-type transthyretin amyloid cardiomyopathy; HFpEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction. [Display omitted] [ABSTRACT FROM AUTHOR]

A hallmark of heart failure (HF), whether it presents itself during rest or periods of physical exertion, is the excessive elevation of intracardiac filling pressures at rest or with exercise. Many mechanisms contribute to the elevated intracardiac filling pressures, and notably, the concept of volume redistribution has gained attention as a cause of the elevated intracardiac filling pressures in patients with HF, particularly HF with preserved ejection fraction, who often present without symptoms at rest, with shortness of breath and fatigue appearing only during exertion. This phenomenon suggests cardiopulmonary system non-compliance and inappropriate volume distribution between the stressed and unstressed blood volume components. A substantial proportion of the intravascular blood volume is in the splanchnic vascular compartment in the abdomen. Preclinical and clinical investigations support the critical role of the sympathetic nervous system in modulating the capacitance and compliance of the splanchnic vascular bed via modulation of the greater splanchnic nerve (GSN). The GSN activation by stressors such as exercise causes excessive splanchnic vasoconstriction, which may contribute to the decompensation of chronic HF via volume redistribution from the splanchnic vascular bed to the central compartment. Accordingly, for example, GSN ablation for volume management has been proposed as a potential therapeutic intervention to increase unstressed blood volume. Here we provide a comprehensive review of the role of splanchnic circulation in the pathogenesis of HF and potential novel treatment options for redistributing blood volume to improve symptoms and prognosis in patients with HF. Volume Redistribution Concept: Splanchnic Circulation. [Display omitted] • The body's total blood volume is the sum of stressed and unstressed blood volume. • Splanchnic circulation constitutes the body's largest blood volume reservoir. • Volume redistribution may play a critical role in the congestion in heart failure. • Sympathetic nervous system controls splanchnic circulation via greater splanchnic nerve. • Splanchnic nerve modulation may serve a potential therapeutic use in heart failure. [ABSTRACT FROM AUTHOR]

• Whether dapagliflozin is beneficial in patients with sleep apnea and heart failure, across the range of ejection fractions, is unknown. • In a pooled individual-level meta-analysis of DAPA-HF and DELIVER, investigator-reported sleep apnea was associated with a greater risk of worsening heart failure events. • Dapagliflozin, compared with placebo, reduced the risk of clinical outcomes and improved health-related quality of life in patients with and without sleep apnea. Sleep apnea is more common in patients with heart failure (HF) than in the general population, but little is known about its association with clinical outcomes in various HF phenotypes or how it might modify the effect of HF therapy. To examine the prevalence of sleep apnea, its association with outcomes and the effects of dapagliflozin in patients with HF with and without sleep apnea in a pooled analysis of 2 trials comparing dapagliflozin to placebo in HFrEF (DAPA-HF trial) and HFmrEF/HFpEF (DELIVER trial). A history of sleep apnea was investigator-reported. The primary outcome was a composite of worsening HF or cardiovascular death. The prevalence of sleep apnea was 5.7% and 7.8% in patients with HFrEF and HFmrEF/HFpEF, respectively. The primary outcome occurred at a rate of 16.0 in participants with sleep apnea compared to 10.6 per 100 person-years in those without (adjusted HR 1.29 [95%CI, 1.10–1.52]). Compared with placebo, dapagliflozin reduced the risk of the primary endpoint to the same extent in patients with (HR 0.78 [95% CI, 0.59–1.03]) and without sleep apnea (HR 0.79 [0.72–0.87]) [P interaction = 0.93]. The beneficial effects of dapagliflozin on other clinical outcomes and symptom burden, physical function, and quality of life were consistent in participants with and without sleep apnea. In DAPA-HF and DELIVER, the true prevalence of sleep apnea was likely underestimated. An investigator-reported history of sleep apnea was associated with higher rates of worsening HF events. The benefits of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. Unique identifiers: NCT01920711 In a pooled analysis of the DAPA-HF and DELIVER trials of more than 11,000 patients with heart failure (HF) across the range of ejection fractions, an investigator-reported history of sleep apnea was associated with higher rates of worsening HF events but not mortality. The beneficial effects of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. These findings provide further evidence for dapagliflozin as a new treatment option for patients with heart failure across the range of ejection fractions. [ABSTRACT FROM AUTHOR]

Obesity and insulin resistance are prevalent in heart failure with preserved ejection fraction (HFpEF) and are associated with adverse cardiovascular outcomes. Measuring insulin resistance is difficult outside of research settings, and its correlation to parameters of myocardial dysfunction and functional status is unknown. A total of 92 HFpEF patients with New York Heart Association class II to IV symptoms underwent clinical assessment, 2D echocardiography, and 6-min walk (6 MW) test. Insulin resistance was defined by estimated glucose disposal rate (eGDR) using the formula: eGDR = 19.02 − [0.22 × body mass index (BMI), kg/m2] − (3.26 × hypertension, presence) − (0.61 × glycated hemoglobin, %). Lower eGDR indicates increased insulin resistance (unfavorable). Myocardial structure and function were assessed by left ventricular (LV) mass, average E/e' ratio, right ventricular systolic pressure, left atrial volume, LV ejection fraction, LV longitudinal strain (LVLS), and tricuspid annular plane systolic excursion. Associations between eGDR and adverse myocardial function were evaluated in unadjusted and multivariable-adjusted analyses using analysis of variance testing and multivariable linear regression. Mean age (SD) was 65 (11) years, 64 % were women, and 95 % had hypertension. Mean (SD) BMI was 39 (9.6) kg/m2, glycated hemoglobin 6.7 (1.6) %, and eGDR 3.3 (2.6) mg × kg−1 min−1. Increased insulin resistance was associated with worse LVLS in a graded fashion [mean (SD) −13.8 % (4.9 %), −14.4 % (5.8 %), −17.5 % (4.4 %) for first, second, and third eGDR tertiles, respectively, p = 0.047]. This association persisted after multivariable adjustment, p = 0.040. There was also a significant association between worse insulin resistance and decreased 6 MW distance on univariate analysis, but not on multivariable adjusted analysis. Our findings may inform treatment strategies focused on the use of tools to estimate insulin resistance and selection of insulin sensitizing drugs which may improve cardiac function and exercise capacity. Insulin resistance is associated with subclinical myocardial dysfunction and reduced functional capacity in heart failure with preserved ejection fraction. Created with BioRender.com. [Display omitted] • Insulin resistance can be estimated by the eGDR calculation using clinical metrics. • Increasing insulin resistance is associated with worsened LV strain in HFpEF. • Increasing insulin resistance is also associated with decreased 6-min walk time. • Use of insulin sensitizers (metformin, SGLT2 inhibitors) may improve these metrics. [ABSTRACT FROM AUTHOR]

Aortic valve calcification (AVC) is a principal mechanism underlying aortic stenosis (AS). This study sought to determine the prevalence of AVC and its association with the long-term risk for severe AS. Noncontrast cardiac computed tomography was performed among 6,814 participants free of known cardiovascular disease at MESA (Multi-Ethnic Study of Atherosclerosis) visit 1. AVC was quantified using the Agatston method, and normative age-, sex-, and race/ethnicity-specific AVC percentiles were derived. The adjudication of severe AS was performed via chart review of all hospital visits and supplemented with visit 6 echocardiographic data. The association between AVC and long-term incident severe AS was evaluated using multivariable Cox HRs. AVC was present in 913 participants (13.4%). The probability of AVC >0 and AVC scores increased with age and were generally highest among men and White participants. In general, the probability of AVC >0 among women was equivalent to men of the same race/ethnicity who were approximately 10 years younger. Incident adjudicated severe AS occurred in 84 participants over a median follow-up of 16.7 years. Higher AVC scores were exponentially associated with the absolute risk and relative risk of severe AS with adjusted HRs of 12.9 (95% CI: 5.6-29.7), 76.4 (95% CI: 34.3-170.2), and 380.9 (95% CI: 169.7-855.0) for AVC groups 1 to 99, 100 to 299, and ≥300 compared with AVC = 0. The probability of AVC >0 varied significantly by age, sex, and race/ethnicity. The risk of severe AS was exponentially higher with higher AVC scores, whereas AVC = 0 was associated with an extremely low long-term risk of severe AS. The measurement of AVC provides clinically relevant information to assess an individual's long-term risk for severe AS. [Display omitted] [ABSTRACT FROM AUTHOR]

In the STEP-HFpEF trial, 2.4 mg semaglutide produced marked improvements in heart failure-related symptoms, physical limitations, and exercise function, and reduced inflammation and body weight in individuals with obesity HFpEF phenotype. These data usher in a new paradigm of targeting obesity as a therapeutic strategy in HFpEF. [ABSTRACT FROM AUTHOR]

Catastrophic disruptions in care delivery threaten the operational efficiency and potentially the validity of clinical research efforts, in particular randomized clinical trials. Most recently, the COVID-19 pandemic affected essentially all aspects of care delivery and clinical research conduct. While consensus statements and clinical guidance documents have detailed potential mitigation measures, few real-world experiences detailing clinical trial adaptations to the COVID-19 pandemic exist, particularly among, large, global registrational cardiovascular trials. We outline the operational impact of COVID-19 and resultant mitigation measures in the Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial, one of the largest and most globally diverse experiences with COVID-19 of any cardiovascular clinical trial to date. Specifically, we address the needed coordination between academic investigators, trial leadership, clinical sites, and the supporting sponsor to ensure the safety of participants and trial staff, to maintain the fidelity of trial operations, and to prospectively adapt statistical analyses plans to evaluate the impact of COVID-19 and the pandemic at large on trial participants. These discussions included key operational issues such as ensuring delivery of study medications, adaptations to study visits, enhanced COVID-19 related endpoint adjudication, and protocol and analytical plan revisions. Our findings may have important implications for establishing consensus on prospective contingency planning in future clinical trials. Clinicaltrial.gov: NCT03619213. NCT03619213. [ABSTRACT FROM AUTHOR]

• There is a high prevalence of "poor sleep" across sleep health domains in HFpEF (16–78%). • Poorer sleep health was associated with greater BMI and intermuscular thigh fat in HFpEF patients. • Research is needed to determine whether sleep is a potential candidate for individual or adjunctive interventions to address obesity in HFpEF. There are bi-directional relationships between sleep disturbances and obesity, both of which are prevalent in patients with heart failure with preserved ejection fraction (HFpEF). However, little is known about the sleep-obesity association in HFpEF. To determine associations of multidimensional sleep health, night movement, sleep fragmentation, and sleep-disordered breathing (SDB) risk with overall and regional adiposity in HFpEF patients. Men and women with HFpEF (n = 49) were assessed via 14-day actigraphy, Pittsburgh Sleep Quality Index, and Epworth Sleepiness Scale to derive multidimensional sleep health. SDB risk was assessed via Berlin Questionnaire. Body composition was measured using anthropometry; MRI quantification of epicardial, abdominal, liver, and thigh adipose tissue was performed in a subsample (n = 22). Spearman correlation (rs) and linear regression analyses (β coefficient) were used to estimate bivariate and age-adjusted associations. Multidimensional sleep health was inversely associated with BMI (rs = -0.50, p <.001; unadjusted: β = -4.00, 95%CI: -5.87, -2.13; age-adjusted: β = -2.48, 95%CI: -4.65, -0.30), thigh subcutaneous adipose tissue (rs = -0.50, p =.018; unadjusted: β = -36.95, 95%CI: -67.31, -6.59), and thigh intermuscular fat (age-adjusted: β = -0.24, 95%CI: -0.48, -0.01). Night movement and sleep fragmentation were associated with greater intermuscular thigh and lower liver fat. High SDB risk was associated with a higher visceral-to-subcutaneous ratio of abdominal adiposity and lower thigh adiposity. Adverse multidimensional sleep health is associated with higher adiposity measures in HFpEF patients. Further studies are needed to determine whether intervening on sleep could ameliorate excess adiposity or whether weight loss could improve sleep quality in HFpEF. [ABSTRACT FROM AUTHOR]

Postoperative atrial fibrillation (POAF) is a common complication after coronary artery bypass grafting (CABG). Currently, there is no reliable way to determine preoperatively which patients will develop POAF following CABG. The aim of this study was to determine whether preoperative left atrial (LA) strain analysis might identify patients destined to develop POAF following CABG. From 2016 to 2018, 211 patients who had a preoperative left ventricular ejection fraction >50% and adequate preoperative, predischarge, and follow-up echo images for interpretation underwent isolated CABG surgery. Postoperatively, patients had continuous rhythm monitoring until hospital discharge. Retrospective speckle-tracking analysis of preoperative echocardiograms was performed to calculate preoperative left ventricular global longitudinal strain and LA compliance and contraction strains in 92 matched patients. Multivariate logistic regression and Cox proportional hazards models were used to determine the predictors of POAF after CABG. POAF occurred in 50 patients (24%). They were older, had longer intensive care unit and hospital stays, and a slightly greater 30-day mortality (P =.07). Preoperative LA volume index was larger in the patients with POAF but still "normal" as defined by current guidelines. However, preoperative LA compliance and contraction strains were significantly lower in patients who developed POAF after CABG. Decreased preoperative LA strain measurements, especially LA-fractional area change, LA-emptying fraction, and LA-reservoir strain, taken jointly, are more specific and sensitive than other preoperative parameters in identifying patients who will develop POAF following CABG. The ability to identify patients preoperatively who are destined to develop POAF following CABG provides a basis for limiting POAF prophylactic therapy to only those patients undergoing CABG who are most likely to benefit from it rather than to all patients undergoing CABG. A total of 211 patients undergoing isolated coronary artery bypass grafting (CABG) who had a retrospective analysis of their preoperative standard echo parameters and strain analysis of their LA, left ventricle, and right ventricle using 2-dimensional (2D) speckle-tracking echocardiogram analysis. The patients were divided into 2 groups for comparison based on whether or not they developed postoperative atrial fibrillation (POAF). The 50 patients who had abnormal preoperative LA strain measurements developed POAF. The 161 patients who had normal preoperative LA strain measurements did not develop POAF. [Display omitted] [ABSTRACT FROM AUTHOR]

The stoichiometric, direct and functional interaction of amyloid precursor protein (APP)- and Notch-derived gamma secretase substrates with nicastrin is discussed. Extracellular DAP domain of nicastrin is important only for gamma-secretase-substrate recognition and not for catalysis.

STEP-HFpEF, a 52 week trial conducted in patients with obesity phenotype of heart failure with preserved ejection fraction (HFpEF) and no type 2 diabetes, examined the effects of once-weekly semaglutide 2.4 mg versus placebo on HF-related symptoms, physical limitations, and exercise function, as well as inflammation and body weight (BW). Except for sodium-glucose co-transporter 2 inhibitors, previous HF therapies have shown differential effects across the spectrum of left ventricular ejection fraction (LVEF). In this pre-specified analysis, we investigated the effects of semaglutide on the primary and key secondary endpoints across the range of LVEF in the STEP-HFpEF Trial. STEP-HFpEF randomized 529 participants with symptomatic HF, LVEF ≥45% and body mass index of ≥30 kg/m2 to receive once weekly semaglutide 2.4 mg or placebo. Key exclusion criteria were prior or planned bariatric surgery, self-reported change in BW >11 pounds (5 kilograms) within 90 days prior to randomization, and a HbA1c level ≥6.5% or prior medical history of diabetes. Dual primary endpoints were change from baseline in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and BW. Confirmatory secondary endpoints included change in 6-minute walk distance (6MWD), hierarchical composite endpoint (death, HF events and change in KCCQ-CSS and 6MWD) and change in C-reactive protein (CRP). For this analysis, patients were stratified based on baseline LVEF of 45-49%, 50-59%, and ≥60%. The effects of semaglutide versus placebo on the dual primary and confirmatory secondary endpoints were examined across these LVEF categories. Overall, the median LVEF in STEP-HFpEF was 57%; 16.1, 40.6, and 43.3% of participants had LVEF of 45-49%, 50-59%, and ≥60%, respectively. Baseline characteristics of patients in the three LVEF based sub-groups are shown in the Table. The effects of semaglutide compared with placebo on the dual primary and confirmatory secondary outcomes across these LVEF categories will be presented. STEP-HFpEF is the first clinical trial of pharmacotherapy to specifically target the obesity phenotype of HFpEF. In this pre-specified analysis, we will examine whether the effects of semaglutide on symptoms, physical limitations, exercise function, as well as inflammation and BW in this patient population are consistent across the range of LVEF. [ABSTRACT FROM AUTHOR]

Background: South Asian Americans experience disproportionately high burden of cardiovascular diseases. Estimating predicted heart failure (HF) risk distribution may facilitate targeted prevention. We estimated the distribution of 10-year predicted risk of incident HF in South Asian Americans and evaluated the associations with social determinants of health and clinical risk factors.Methods and Results: In the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study, we calculated 10-year predicted HF risk using the Pooled Cohort Equations to Prevent Heart Failure multivariable model. Distributions of low (<1%), intermediate (1%-5%), and high (≥5%) HF risk, identified overall and by demographic and clinical characteristics, were compared. We evaluated age- and sex-adjusted associations of demographic characteristics and coronary artery calcium with predicted HF risk category using ordinal logistic regression. In 1159 participants (48% women), with a mean age of 57 ± 9 years, 40% had a low, 37% had an intermediate, and 24% had a high HF risk. Significant differences in HF risk distribution existed across demographic (income, education, birthplace) and clinical (diabetes, hypertension, body mass index, coronary artery calcium) groups (P < .01). Significant associations with high predicted HF risk were observed for a family of income 75,000/year or more (adjusted odds ratio 0.5 [95% confidence interval (CI) 0.4-0.7]), college education (0.6 [95% CI 0.4-0.9]), birthplace in another South Asian country (1.9 [95% CI 1.2-3.2], vs. born in India), and prevalent coronary artery calcium (2.6 [95% CI 1.9-3.6]).Conclusions: Almost two-thirds of South Asian Americans in the MASALA cohort are at intermediate or high predicted 10-year HF risk, with varying risk across demographic and clinical characteristics. [ABSTRACT FROM AUTHOR]

Exercise intolerance (EI) is the primary manifestation of chronic heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure among older individuals. The recent recognition that HFpEF is likely a systemic, multiorgan disorder that shares characteristics with other common, difficult-to-treat, aging-related disorders suggests that novel insights may be gained from combining knowledge and concepts from aging and cardiovascular disease disciplines. This state-of-the-art review is based on the outcomes of a National Institute of Aging-sponsored working group meeting on aging and EI in HFpEF. We discuss aging-related and extracardiac contributors to EI in HFpEF and provide the rationale for a transdisciplinary, "gero-centric" approach to advance our understanding of EI in HFpEF and identify promising new therapeutic targets. We also provide a framework for prioritizing future research, including developing a uniform, comprehensive approach to phenotypic characterization of HFpEF, elucidating key geroscience targets for treatment, and conducting proof-of-concept trials to modify these targets. [ABSTRACT FROM AUTHOR]

Background: Diagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging. We aimed to evaluate the generalizability of the HFA-PEFF (Heart Failure Association Pre-test assessment, Echocardiography & natriuretic peptide, Functional testing, Final etiology) and weighted H2FPEF (Heavy, 2 or more Hypertensive drugs, atrial Fibrillation, Pulmonary hypertension, Elder age > 60, elevated Filling pressures) diagnostic algorithms and associations with HF severity, coronary microvascular dysfunction and proteomic biomarkers.Methods and Results: Diagnostic likelihood of HFpEF was calculated in the prospective, multinational PROMIS-HFpEF (Prevalence of microvascular dysfunction in HFpEF) cohort using current European Society of Cardiology recommendations, HFA-PEFF and H2FPEF algorithms. Associations between the 2 algorithms and left atrial function, Doppler-based coronary flow reserve, 6-minute walk test, quality of life, and proteomic biomarkers were investigated. Of 181 patients with an EF of ≥50%, 129 (71%) and 94 (52%) fulfilled criteria for high likelihood HFpEF as per HFA-PEFF and H2FPEF, and 28% and 46% were classified as intermediate likelihood, requiring additional hemodynamic testing. High likelihood HFpEF patients were older with higher prevalence of atrial fibrillation and lower global longitudinal strain and left atrial reservoir strain (P < .001 for all variables). left atrial reservoir strain and global longitudinal strain were inversely associated with both HFA-PEFF and H2FPEF scores (TauB = -0.35 and -0.46 and -0.21 and -0.31; P < .001 for all). There were no associations between scoring and 6-minute walk test, quality of life, and coronary flow reserve. Both scores were associated with biomarkers related to inflammation, oxidative stress, and fibrosis.Conclusions: Although the HFA-PEFF and H2FPEF scores were associated with measures of HF severity and biomarkers related to HFpEF, they demonstrated a modest and differential ability to identify HFpEF noninvasively, necessitating additional functional testing to confirm the diagnosis. [ABSTRACT FROM AUTHOR]

Background: Independent associations between cardiovascular risk factor exposures during midlife and later life development of heart failure (HF) with preserved ejection fraction (HFpEF) versus reduced EF (HFrEF) have not been previously studied.Methods: We pooled data from 4 US cohort studies (Atherosclerosis Risk in Communities, Cardiovascular Health, Health , Aging and Body Composition, and Multi-Ethnic Study of Atherosclerosis) and imputed annual risk factor trajectories for body mass index, systolic and diastolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, and glucose starting from age 40 years. Time-weighted average exposures to each risk factor during midlife and later life were calculated and analyzed for associations with the development of HFpEF or HFrEF.Results: A total of 23,861 participants were included (mean age at first in-person visit, 61.8 ±1 0.2 years; 56.6% female). During a median follow-up of 12 years, there were 3666 incident HF events, of which 51% had EF measured, including 934 with HFpEF and 739 with HFrEF. A high midlife systolic blood pressure and low midlife high-density lipoprotein cholesterol were associated with HFrEF, and a high midlife body mass index, systolic blood pressure, pulse pressure, and glucose were associated with HFpEF. After adjusting for later life exposures, only midlife pulse pressure remained independently associated with HFpEF.Conclusions: Midlife exposure to cardiovascular risk factors are differentially associated with HFrEF and HFpEF later in life. Having a higher pulse pressure during midlife is associated with a greater risk for HFpEF but not HFrEF, independent of later life exposures. [ABSTRACT FROM AUTHOR]

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by left ventricular hypertrophy and decreased exercise capacity. Fibroblast growth factor 23 (FGF23), a hormone involved in phosphate, vitamin D, and iron homeostasis, is linked to left ventricular hypertrophy and HF. We measured c-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels and examined their associations with exercise capacity in patients with HFpEF.Methods and Results: Using multivariable linear regression and linear mixed models, we studied the associations of cFGF23 and iFGF23 with baseline and mean weekly change over 24 weeks in peak oxygen consumption and 6-minute walk distance in individuals enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF trial. Our study population included 172 individuals with available plasma for cFGF23 and iFGF23 measurements. Median (25th-75th percentile) baseline cFGF23 and iFGF23 levels were 208.7 RU/mL (132.1-379.5 RU/mL) and 90.3 pg/mL (68.6-128.5 pg/mL), respectively. After adjustment for cardiovascular disease and hematologic and kidney parameters, higher cFGF23 was independently associated with a lower peak oxygen consumption at baseline. Higher iFGF23 was independently associated with shorter 6-minute walk distance at baseline. No significant associations were appreciated with the longitudinal outcomes.Conclusions: In patients with HFpEF, higher FGF23 levels are independently associated with decreased exercise capacity at baseline. [ABSTRACT FROM AUTHOR]

Background: Coronary microvascular dysfunction (CMD) is common in heart failure with preserved ejection fraction (HFpEF). We assessed the association of CMD with hospitalization and mortality in HFpEF.Methods and Results: We assessed the 1-year outcomes in patients from the PROMIS-HFpEF study, a prospective observational study of patients with chronic stable HFpEF undergoing coronary flow reserve measurements. Outcomes were (1) time to cardiovascular (CV) death/first HF hospitalization, (2) CV death/recurrent HF hospitalizations, (3) all-cause death/first HF hospitalization, and (4) first and (5) recurrent all-cause hospitalizations. CMD was defined as coronary flow reserve of <2.5. Time to CV death/first hospitalization was compared by log-rank test and recurrent HF and all-cause hospitalizations by Poisson test. Of 263 patients enrolled, 257 were evaluable at 1 year. Where the coronary flow reserve was interpretable (n = 201), CMD was present in 150 (75%). The median follow-up was 388 days (Q1, Q3 365, 418). The outcome of CV death/first HF hospitalization occurred in 15 patients (4 CV deaths). The incidence rate was in CMD 96 per 1000 person-years, 95% confidence interval 54-159, vs non-CMD 0 per1000 person-years, 95% confidence interval 0-68, P = .023, and remained significant after accounting for selected clinical variables. In patients with CMD, the incidence rates were significantly higher also for CV death/recurrent HF hospitalizations, all-cause death/first HF, and recurrent but not first all-cause hospitalization.Conclusions: In this exploratory assessment of the prognostic role of CMD in HFpEF, CMD was independently associated with primarily CV- and HF-specific events. The high prevalence of CMD and its CV and HF specific prognostic role suggest CMD may be a potential treatment target in HFpEF. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. Some patients develop elevated filling pressures exclusively during exercise and never require hospitalization, whereas others periodically develop congestion that requires inpatient treatment. The features differentiating these cohorts are unclear.Methods: We performed a secondary analysis of 7 National Institutes of Health-sponsored multicenter trials of HFpEF (EF ≥ 50%, N = 727). Patients were stratified by history of hospitalization because of HF, comparing patients never hospitalized (HFpEFNH) to those with a prior hospitalization (HFpEFPH). Currently hospitalized (HFpEFCH) patients were included to fill the spectrum. Clinical characteristics, cardiac structure, biomarkers, quality of life, functional capacity, activity levels, and outcomes were compared.Results: As expected, HFpEFCH (n = 338) displayed the greatest severity of congestion, as assessed by N-terminal pro B-type natriuretic peptide levels, edema and orthopnea. As compared to HFpEFNH (n = 109), HFpEFPH (n = 280) displayed greater comorbidity burden, with more lung disease, renal dysfunction and anemia, along with lower activity levels (accelerometry), poorer exercise capacity (6-minute walk distance and peak exercise capacity), and more orthopnea. Patients with current or prior hospitalization displayed higher rates of future HF hospitalization, but quality of life was similarly impaired in all patients with HFpEF, regardless of hospitalization history.Conclusions: A greater burden of noncardiac organ dysfunction, sedentariness, functional impairment, and higher event rates distinguish patients with HFpEF and prior HF hospitalization from those never hospitalized. Despite lower event rates, quality of life is severely and similarly limited in patients with no history of hospitalization. These data suggest that the 2 clinical profiles of HFpEF may require different treatment strategies. [ABSTRACT FROM AUTHOR]

Background: A randomized, sham-controlled trial in patients with heart failure (HF) and left ventricular ejection fraction (LVEF) ≥40% demonstrated reductions in pulmonary capillary wedge pressure (PCWP) with a novel transcatheter InterAtrial Shunt Device (IASD). Whether this hemodynamic effect will translate to an improvement in cardiovascular outcomes and symptoms requires additional study.Study Design and Objectives: REDUCE Elevated Left Atrial Pressure in Patients with Heart Failure II (REDUCE LAP HF-II) is a multicenter, prospective, randomized, sham-controlled, blinded trial designed to evaluate the clinical efficacy of the IASD in symptomatic HF and elevated left atrial pressures. Up to 608 HF patients age ≥ 40 years with LVEF ≥40%, PCWP ≥25 mm Hg during supine ergometer exercise, and PCWP ≥5 mm Hg higher than right atrial pressure will be randomized 1:1 to the IASD versus sham control. Key exclusion criteria include hemodynamically significant valvular disease, evidence of pulmonary arterial hypertension, and right heart dysfunction. The primary endpoint is a hierarchical composite, analyzed by the Finkelstein-Schoenfeld methodology, that includes (1) cardiovascular mortality or first nonfatal ischemic stroke through 12 months; (2) total (first plus recurrent) HF hospitalizations or healthcare facility visits for intravenous diuretics up to 24 months, analyzed when the last randomized patient completes 12 months of follow-up; and (3) change in Kansas City Cardiomyopathy Questionnaire overall summary score from baseline to 12 months. Follow-up echocardiography will be performed at 6, 12, and 24 months to evaluate shunt flow and cardiac chamber size/function. Patients will be followed for a total of 5 years after the index procedure.Conclusions: REDUCE LAP-HF II is designed to evaluate the clinical efficacy of the IASD device in patients with symptomatic HF with elevated left atrial pressure and LVEF ≥40%. [ABSTRACT FROM AUTHOR]

Background: Diastolic dysfunction (DD) is common and occurs at an earlier age among human immunodeficiency virus-infected (HIV+) individuals, but the mechanisms and consequences of DD among HIV+ individuals are unclear.Methods and Results: The Characterization of Heart Function on Antiretroviral Therapy (CHART) study was a multicenter cross-sectional case-control study of treated and virally suppressed HIV+ individuals with (DD+) and without DD (DD-). All patients had normal ejection fraction (>50%), no significant valvular disease, and no history of coronary revascularization or persistent atrial fibrillation. Overall, 94 DD+ and 101 DD- patients were included. DD+ patients were older with higher body mass index (BMI) and more likely to have hypertension, renal dysfunction, and dyslipidemia. Groups were similar with respect to sex, race, CD4 count, and HIV RNA copies. N-terminal pro-B-type natriuretic peptide levels (median 36 [23, 85] vs 26 [12, 49] pg/mL, P < .01) and high-sensitivity troponin I (3.6 [2.6, 5.1] vs 2.5 [1.8, 3.5] pg/mL, P < .01) were higher among DD+ patients. The latter had similar left atrial size, but increased stiffness (conduit strain: 23.5 [17.5, 36.9] vs 30.0 [22.9, 37.0], P < .01) and impaired relaxation (reservoir strain: 39.7 [32.0, 58.0] vs 45.9 [37.0, 60.6], P = .04). On cardiac magnetic resonance, the prevalence of focal fibrosis was higher among DD+ patients (19.0% vs 5.3%, P < .01). DD+ patients demonstrated higher levels of carboxyl-terminal telopeptide of collagen type I (P = .04), and trends toward higher interleukin-6 and oxidized low-density lipoprotein levels (P ≤ .08). Kansas City Cardiomyopathy Questionnaire physical limitation (87.1±21.4 vs 93.1±18.1, P = .01) and symptom frequency scores were lower among DD+ patients (86.0±21.5 vs 92.5±16.8, P = .01).Conclusions: In this contemporary HIV+ population receiving antiretroviral therapy, DD was associated with multiple alterations in cardiac structure and function, including myocardial fibrosis and left atrial abnormalities, and worse quality of life. Further studies are needed to assess longitudinal changes in these parameters and their potential as therapeutic targets to prevent progressive cardiac remodeling and dysfunction in HIV. [ABSTRACT FROM AUTHOR]

Background: Heart failure with preserved ejection fraction (HFpEF) is a significant cause of morbidity and mortality worldwide. Exercise intolerance is the main symptom of HFpEF and is associated with a poor quality of life and increased mortality. Currently, there are no approved medications for the treatment of HFpEF. Praliciguat (IW-1973), a novel soluble guanylate cyclase stimulator that may help restore deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine 3',5'-monophosphate signaling, is being investigated for the treatment of patients with HFpEF.Methods: CAPACITY HFpEF is a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial designed to evaluate the safety and efficacy of praliciguat over 12 weeks in approximately 184 patients with HFpEF. Eligible patients must have evidence supporting clinical HFpEF and at least 2 of the following 4 conditions associated with NO deficiency: diabetes/prediabetes, hypertension, obesity, and age >70 years. The primary efficacy end point is the change from baseline in peak VO2 by cardiopulmonary exercise test (CPET). Secondary end points include the change from baseline in 6-minute walk test distance and the change in ventilatory efficiency on CPET, as well as number of CPET responders. Other exploratory end points include changes in echocardiographic parameters, New York Heart Association functional classification, cardiac events, blood and urine biomarkers pathophysiologically relevant to heart failure, and patient-reported outcomes including Kansas City Cardiomyopathy Questionnaire.Conclusions: The CAPACITY HFpEF trial will provide data on short-term safety and efficacy of praliciguat on peak exercise capacity, as well as multiple secondary end points of submaximal functional capacity, patient-reported outcomes, and biomarkers. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure with preserved ejection fraction (HFpEF) and chronic kidney disease (CKD) represent a high-risk phenotype. The Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial enrolled a high proportion of CKD participants, allowing investigation into differences in HFpEF by CKD status.Methods and Results: Among 212 participants, we investigated the associations of CKD with biomarkers, cardiac structure, and exercise capacity, and identified predictors of change in estimated glomerular filtration rate (eGFR) over trial follow-up. CKD participants (eGFR ≤60 mL/min/1.73m2) were older, had more comorbidities, and had worse diastolic function. Lower eGFR was associated with higher levels of endothelin-1, N-terminal pro-B-type natriuretic peptide, aldosterone, uric acid, and biomarkers of fibrosis (P < .05 for all). Whereas lower eGFR was associated with worse peak oxygen consumption (VO2) after adjustment for demographics, clinical comorbidities, exercise modality, ejection fraction, and chronotropic index (β coefficient per 1 SD decrease in eGFR: -0.61, 95% CI: -1.01, -0.22, P = .002), this association was attenuated after further adjustment for hemoglobin (β coefficient: -0.26, 95% CI: -0.68, 0.16, P = .22). Hemoglobin mediated 35% of the association between eGFR and peak VO2. Sildenafil therapy was independently associated with worsening eGFR over the trial (β coefficient: -2.79, 95% CI: -5.34, -0.24, P = .03).Conclusion: Renal dysfunction in HFpEF is characterized by echocardiographic and biomarker profiles indicative of more advanced disease, and reduced hemoglobin is a strong mediator of the association between renal dysfunction and low exercise capacity. Sildenafil therapy was associated with worsening of renal function in RELAX. [ABSTRACT FROM AUTHOR]

Background: Although left atrial (LA) mechanical dysfunction in heart failure with preserved ejection fraction (HFpEF) is associated with poor clinical outcomes, the influence of LA myopathy on temporal changes in cardiovascular biomarkers is unclear.Methods and Results: We evaluated biomarker correlates of LA myopathy, as defined by reduced LA strain, and the associations of LA strain with longitudinal changes in biomarkers among participants in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial. LA speckle-tracking was performed on baseline echocardiograms of RELAX participants to measure LA reservoir and LA contractile strain. Of the 216 RELAX participants, 169 (78%) had measurable LA strain and biomarker data. Participants with LA reservoir strain below median (13.5%, interquartile range: 10%-22.5%) were older, more likely to have atrial fibrillation, and had higher jugular venous pressure (P < .05 for all). At baseline, higher levels of endothelin-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin I were independently associated with lower LA reservoir and contractile strain (Padjusted < .05 for all comparisons). Higher LA reservoir strain (β coefficient per 1-unit increase: -21.2, 95% CI: -38.8, -3.7; P = .02) was independently associated with reduction in NT-proBNP at 24 weeks.Conclusion: In HFpEF, LA myopathy is characterized by elevation in biomarkers of neurohormonal activation and myocardial necrosis. Lower LA function is associated with continued elevation in NT-proBNP over time, suggesting that LA myopathy is associated with persistent congestion in HFpEF. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity display a number of pathophysiologic features that may render them more or less vulnerable to negative effects of decongestion on renal function, including greater right ventricular remodeling, plasma volume expansion and pericardial restraint. We aimed to contrast the renal response to decongestion in obese compared to nonobese patients with HFpEF METHODS AND RESULTS: National Institutes of Health heart failure network studies that enrolled patients with acute decompensated HFpEF (EF ≥ 50%) were included (DOSE, CARRESS, ROSE, and ATHENA). Obese HFpEF was defined as a body mass index ≥ 30 kg/m2. Compared to nonobese HFpEF (n = 118), patients with obese HFpEF (n = 214) were an average of 9 years younger (71 vs 80 years,< 0.001), were more likely to have diabetes (64% vs 31%, P< 0.001) but had less atrial fibrillation (56% vs 75%, P< 0.001). Renal dysfunction (glomerular filtration rate < 60 mL/min/1.73m2) was present in 82% of patients, and there was no difference at baseline between obese and nonobese patients. Despite similar weight loss through decongestive therapies, obese patients with HFpEF demonstrated greater rise in creatinine (Cr) and decline in glomerular filtration rate, with a 2-fold higher incidence of mild worsening renal function (rise in Cr ≥ 0.3 mg/dL) (28 vs 14%, P = 0.008) and a substantially greater increase in severe worsening of renal function (rise in Cr > 0.5 mg/dL) (9 vs 0%, P = 0.002).Conclusions: Despite being nearly a decade younger, obese patients with HFpEF experience greater deterioration in renal function during decongestion than do nonobese patients with HFpEF. Further study to elucidate the complex relationships between volume distribution, cardiorenal hemodynamics and adiposity in HFpEF is needed. [ABSTRACT FROM AUTHOR]

Several atrial shunt devices and procedures are in development for patients with heart failure (HF), including those with HF and preserved ejection fraction (HFpEF), with the goal of decreasing left atrial (LA) pressure at rest and during exertion in these patients. A number of phase 3 trials of atrial shunts in HF are ongoing; however, to date, only 1 large, randomized, sham-controlled pivotal trial (REDUCE LAP-HF II, which studied the Corvia Atrial Shunt Device [8-mm diameter]) has been completed. The overall REDUCE LAP-HF II trial was neutral, but responder analyses indicated that approximately 50% of patients enrolled in the trial (who had peak exercise PVR <1.74 WU and no pacemaker/ICD) benefited from atrial shunting, with lower HF events and improvement in health status compared to placebo. A confirmatory randomized trial (RESPONDER-HF) is underway to validate these results. Nevertheless, there is debate about the long-term effects of left-to-right shunting on cardiac structure/function (especially the right ventricle [RV]), and whether an 8-mm shunt size is too large, thereby resulting in progressive RV enlargement and/or dysfunction. We sought to determine the long-term effects (up to 24 months) of the Corvia Atrial Shunt Device on cardiac structure/function compared to a sham procedure. REDUCE LAP-HF II (n=626) was a multi-center, randomized, sham-controlled, blinded trial in patients with HF, LVEF ≥40%, and peak exercise PCWP ≥25 mmHg. Comprehensive echo was performed at baseline and at 1-, 6-, 12-, and 24-month follow-up intervals, and interpreted by a central echo core lab blinded to treatment status. Changes from baseline to follow-up in echo indices were analyzed within each treatment group (using paired-tests) and between treatment groups (using linear regression, controlling for the baseline value). Mixed models for repeated measures (MMRM) analyses were used to evaluate between-group differences in echo indices over time. Cardiac chamber volumes, LV systolic and diastolic function, RV function, LV and RV tissue velocities, hemodynamics, Qp:Qs, LA function, and mitral and tricuspid regurgitation severity were analyzed at each time point. Exploratory analyses were performed to evaluate whether changes in cardiac structure/function over time differed by responder vs. non-responder status. The REDUCE LAP-HF II echo completion rate was high (88%, 86%, 85%, and 76% at 1-, 6-, 12-, and 24-mo., respectively). All echo measurements at each time point have been completed, and the results of the comprehensive REDUCE LAP-HF II echo analyses will be available in time for the HFSA Scientific Sessions. Detailed and comprehensive long-term echo data from REDUCE LAP-HF II provide important insights into the effects of atrial shunt treatment (vs. sham control) on cardiac structure/function over time. These results have implications for the entire field of shunt devices and procedures, which remain an intensive area of investigation in patients with HF. [ABSTRACT FROM AUTHOR]

A phase 2, randomized, double-blind, placebo-controlled, 28-day trial evaluating the oral transthyretin (TTR) stabilizer acoramidis enrolled 49 individuals with symptomatic TTR amyloid cardiomyopathy (ATTR-CM). Here we report an update on long-term data in the open-label extension (OLE) study. Participants who completed the phase 2 study and enrolled in the OLE (n=47) received oral acoramidis HCl 800 mg twice daily. Clinical and laboratory assessments were performed on days 1, 14, and 45, and at 3-month intervals thereafter. Two established assays assessed TTR stabilization: fluorescent probe exclusion (FPE; measures binding site occupancy), and Western blot (WB; quantifies tetrameric TTR persistence under conditions of accelerated dissociation). As of January 6, 2023, 25/47 participants remained in the study. The median (25th-75th percentile) time since phase 2 enrollment was 55 (18.56-55.29) months. Acoramidis was generally well tolerated; adverse events were consistent with disease severity, concurrent illness, and/or age. Median (25th-75th percentile) change from baseline to Month 45 in NT-pro BNP was −144 (−643 to 242) pg/mL (Figure). Serum TTR change from baseline at Month 45 is also shown (Figure). Updated data on maintenance of near-complete stabilization at Month 45 by ex vivo assays of TTR stabilization will be provided. In patients with symptomatic ATTR-CM, long-term treatment with acoramidis remains generally well tolerated and is associated with both stable median NT-proBNP levels and sustained increases in serum TTR. In this ongoing open-label study, at least 53% of patients with ATTR-CM and NYHA Class II or III at entry to the phase 2 trial have survived for a median follow-up of 4.6 years. Further evaluation of acoramidis in a phase 3 randomized clinical trial is ongoing. [ABSTRACT FROM AUTHOR]

Phosphodiesterases (PDE) degrade cyclic guanosine monophosphate (cGMP), the second messenger which mediates the cardioprotective effects of natriuretic peptides (NP). High NP to cGMP ratio may reflect PDE activity. Few data exist on correlates of NP/cGMP in patients with heart failure with preserved ejection (HFpEF). Among patients with HFpEF in the RELAX trial, we examined 1) cross-sectional correlates of circulating NT-proBNP to cGMP ratio 2) whether selective PDE-5 inhibition by sildenafil changed the ratio, and 3) whether the effect of sildenafil on 24-week outcomes varied according to baseline ratio. In 212 subjects NT-proBNP to cGMP ratio was calculated at randomization and 24-weeks. Correlates of the ratio and its change were examined in multivariable proportional odds models. Whether baseline ratio modified the effect of sildenafil on outcomes was examined in models including interaction terms. Higher NT-proBNP to cGMP ratio associated with greater LV mass and troponin, the presence of atrial fibrillation, and lower eGFR and peak VO 2. Compared with placebo, sildenafil did not alter the ratio from baseline to 24 weeks (p = 0.17). The effect of sildenafil on 24-week change in peak VO 2 , LV mass, or clinical composite outcome was not modified by baseline NT-proBNP to cGMP ratio (p-interaction > 0.30 for all). Among patients with HFpEF, higher NT-proBNP to cGMP ratio associated with an adverse cardio-renal phenotype which was not improved by selective PDE-5 inhibition. PDEs other than PDE-5 may contribute to the adverse phenotype associated with a high NP to cGMP ratio in HFpEF. Trial Registration ClinicalTrials.gov Identifier: NCT007 [ABSTRACT FROM AUTHOR]

The HELP Trial demonstrated that once a week intravenous (IV) levosimendan infusions improve hemodynamics and exercise capacity in patients with pulmonary hypertension with heart failure and preserved ejection fraction (PH-HFpEF). However, a daily oral formulation would offer an advantage of stable dosing and eliminate the risk of line infections and thrombosis. Patients with PH-HFpEF who are receiving chronic IV levosimendan can be transitioned to oral levosimendan safely without sacrificing efficacy. Patients with PH-HFpEF who were in the open label extension study of the HELP Trial for more than 18 months volunteered to enroll in this transition protocol. Patients were initiated with 1 mg/day of oral levosimendan 5-7 days after the last IV levosimendan infusion. The oral dose was increased every 2 weeks by 1 mg/day to a maximum of 4 mg/day over an 8 week period. The highest daily dose was determined by the investigator based on clinical assessments of symptoms and side effects. The primary safety endpoints were change in resting heart rate and blood pressure from baseline to final visit of the transition protocol and all other adverse events. Secondary efficacy endpoints included change in six-minute walk distance (6MWD), serum brain natriuretic peptide (BNP) or NT-proBNP levels, and quality of life as assessed by Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CS) and overall summary score (KCCQ-OS) from baseline to final visit of the transition protocol. All comparisons were the baseline and at week 6-8 measurements at the highest daily dose of levosimendan. Eighteen patients (70 ± 10 yrs, 72% women) participated in the transition study. The final dose of oral levosimendan in fifteen patients was 3 mg/day at 6 weeks, and in three patients was 4 mg/day at 8 weeks. One patient experienced a serious adverse event (SAE) unrelated to study drug and was discontinued. There were no SAEs related to oral levosimendan. The mean change in resting heart rate was 4.9 (SD ± 7.5) beats/min and mean systolic arterial blood pressure was 4.1 (SD ± 12.6) mm Hg. The mean change in 6MWD (n=17) was 13.1 (SD ± 39.5) meters, BNP (n=8) was -133.3 (SD ± 136.6) pg/dl, and NT-proBNP (n=7) was -239.4 (SD ± 548.1) pg/dl. The mean KCCQ-TS, KCCQ-CS and KCCQ-OS score (n=16) improved by 4.7, 2.5 points and 3.7 points, respectively. The transition to oral levosimendan was well tolerated without safety concerns over a 6-8-week period in patients with PH-HFpEF who had been receiving IV levosimendan for more than 18 months. Oral levosimendan was also associated with further improvements in 6MWD, BNP/NT-ProBNP, and KCCQ scores. Oral levosimendan at 3-4 mg/day appears to be a superior formulation for chronic use in PH-HFpEF. [ABSTRACT FROM AUTHOR]

Due to the occurrence of natural plague outbreaks and its historical usage as a biological weapon, Yersinia pestis is considered one of the high-priority biological threat agents. It can remain viable in certain environments including water for >100 days. Because of its slow-growth characteristic, it usually takes three or more days to detect and confirm the identity of viable Y. pestis cells by PCR, serological, or biochemical assays when using the traditional microbiological plate-culture-based analysis, and that too, assuming faster growing microbes present in a water sample do not mask the Y. pestis colonies and interfere with analysis. Therefore, a rapid-viability Polymerase Chain Reaction (RV-PCR) method was developed for detection of Y. pestis. The RV-PCR method combines 24 h-incubation broth culture in a 48-well plate, and pre- and post-incubation differential PCR analyses, thereby allowing for rapid and high-throughput sample analysis compared with the current plate culture method. One chromosomal and two plasmid gene target-based real-time PCR assays were down-selected, showing ca. 10 genome equivalent detection; the chromosomal assay was then used for RV-PCR method development. A 101-cell level (10–99 cells) sensitivity of detection was demonstrated even with complex sample backgrounds including known PCR inhibitors (ferrous sulfate and humic acid), as well as metal oxides and microbes present in Arizona Test Dust (ATD). The method sensitivity was maintained in the presence of dead Y. pestis cells up to 104 cells per sample. While affording high-throughput and rapid sample analysis, the 48-well plate format used in this method for sample enrichment significantly reduced labor requirements and generation of BioSafety Level-3 (BSL-3) laboratory waste as compared to the usual microbiological plate-culture-based methods. This method may serve as a model for other vegetative bacterial pathogens. • Rapid detection of viable Y. pestis is critical during a high-consequence plague bioterrorism incident. • Pre- and post-enrichment differential PCR analysis-based method provides more timely results than the culture-based method. • High-throughput 48-well plate format, small foot-print, economical, and generates less biohazardous waste. • Effectively detects viable pathogen cells with typical inhibitors found in water samples. [ABSTRACT FROM AUTHOR]

There is a growing number of individuals living with heart failure (HF) with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). Long-term prognosis remains poor in both cases, especially in HFpEF, which is rising in incidence and lacks effective therapeutics. In both HFrEF and HFpEF, there is evidence that elevated inflammatory biomarkers, implicating innate immune cells such as macrophages, are associated with worsened clinical outcomes. Macrophage subsets are active in both inflammatory and reparative processes, yet our understanding of the causative roles for these cells in HF development and progression is incomplete. Here, we discuss recent findings interrogating the role of macrophages in inflammation and its resolution in the context of HF, with a specific focus on HFrEF versus HFpEF. Highlights The increasing prevalence of HF and HFpEF, which lacks beneficial therapeutics, necessitates a better understanding of the mechanisms of disease pathogenesis. Inflammation is correlated with adverse clinical outcomes in HF patients. Although results from clinical trials with broad immunosuppression have failed to show any effect, specific targeting of proinflammatory cytokines has conferred clinical benefits. Phagocytes, including macrophages, regulate inflammatory and reparative processes. Distinct subsets with inflammatory function were recently identified in the human heart and may be linked to HF development and progression. [ABSTRACT FROM AUTHOR]

Background: Patients with heart failure (HF) often show signs of right ventricular (RV) dysfunction. The RV function of coupled with the pulmonary circulation (tricuspid annular plane systolic excursion [TAPSE]/pulmonary arterial systolic pressure [PASP]) has been shown to divide HF patients into distinct prognostic strata, but less is known about which factors influence this prognostic marker, and whether those factors can be modified. We sought to obtain normative values and discern the individual effects of age, sex, and fluid overload on RV function.Methods and Results: Sixty healthy subjects aged 20-80 years were enrolled in this prospective study. Right heart catheterization with hemodynamic measurements were performed at rest after a rapid saline solution infusion (10 mL/kg, 150 mL/min). Linear regression and Spearman correlation models were used to estimate associations between TAPSE/PASP and relevant variables. In healthy persons of all ages, the median (5th-95th percentiles) normative TASPE-PASP ratio was 1.25 (0.81-1.78) mm/mm Hg. The correlation between progressive age and declining TAPSE/PASP was significant (r = -0.35; P = .006). Sex did not influence TAPSE/PASP (P = .30). Rapid fluid expansion increased central venous pressure from 5 ± 2 mm Hg to 11 ± 4 mm Hg after fluid infusion (P < .0001). This resulted in a 32% decrease in the TAPSE-PASP ratio after fluid infusion, compared to baseline (P < .0001).Conclusions: The TAPSE-PASP ratio was affected by age, but not sex. TAPSE/PASP is not only a reflection of intrinsic RV function and pulmonary vascular coupling, but fluid status also dynamically affects this index of RV function. Normative values with invasive measurements were obtained for future assessment of HF patients. [ABSTRACT FROM AUTHOR]