Sanjiv J. Shah

Aims Obesity is causally related to the development of heart failure with preserved ejection fraction (HFpEF) but complicates the diagnosis and treatment of this disorder. We aimed to determine the relationship between severity of obesity and clinical, echocardiographic and haemodynamic parameters in a large cohort of patients with documented HFpEF. Methods and results The REDUCE LAP‐HF II trial randomized 626 patients with ejection fraction ≥40% and exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg to atrial shunt or sham procedure. We tested for associations between body mass index (BMI), clinical characteristics, cardiac structural and functional abnormalities, physical limitations, quality of life and outcomes with atrial shunt therapy. Overall, 60.9% of patients had BMI ≥30 kg/m2. As the severity of obesity increased, symptoms (Kansas City Cardiomyopathy Questionnaire score …

ImportanceAn initial decline in estimated glomerular filtration rate (eGFR) is expected after initiating a sodium-glucose cotransporter-2 inhibitor (SGLT2i) and has been observed across patients with diabetes, chronic kidney disease, and heart failure.ObjectiveTo examine the implications of initial changes in eGFR among patients with heart failure with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial.Design, Setting, and ParticipantsThis was a prespecified analysis of the results of the DELIVER randomized clinical trial, which was an international multicenter study of patients with EF greater than 40% and eGFR greater than or equal to 25. The DELIVER trial took place from August 2018 to March 2022. Data for the current prespecified study were …

BackgroundInflammation is a key driver of heart failure with preserved left ventricular ejection fraction. AZD4831 inhibits extracellular myeloperoxidase, decreases inflammation, and improves microvascular function in preclinical disease models.Methods and ResultsIn this double-blind phase 2a study (Safety and Tolerability Study of AZD4831 in Patients With Heart Failure [SATELLITE]; NCT03756285), patients with symptomatic heart failure, left ventricular ejection fraction of ≥40%, and elevated B-type natriuretic peptides were randomized 2:1 to once-daily oral AZD4831 5 mg or placebo for 90 days. We aimed to assess target engagement (primary end point: myeloperoxidase specific activity) and safety of AZD4831. Owing to coronavirus disease 2019, the study was terminated early after randomizing 41 patients (median age 74.0 years, 53.7% male). Myeloperoxidase activity was decreased by more than 50 …

Aims Left ventricular (LV) subclinical impairment has been described in heart failure with preserved ejection fraction (HFpEF). We assessed the relationship between LV myocardial deformation by strain imaging and recurrent hospitalization for heart failure (HF) or cardiovascular death in a large international HFpEF population. Methods and results We assessed two‐dimensional speckle‐tracking based global longitudinal strain (GLS) in 790 patients (mean age 74 ± 8 years, 54% female) with adequate image quality enrolled in the PARAGON‐HF echocardiography study. We examined the relationship of GLS with total HF hospitalizations and cardiovascular death (the primary composite outcome) after accounting for clinical confounders. Approximately 47% of the population had evidence of LV subclinical dysfunction, defined as absolute GLS <16%. Impaired GLS was significantly associated with higher values …

IntroductionA 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).HypothesisHere we report an update on long-term data in the open-label extension (OLE) study.MethodsParticipants 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).ResultsAs of January 6, 2023, 25/47 participants remained in the study. The median (25th-75th percentile) time since phase …

ObjectiveSplanchnic 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.MethodsREBALANCE-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 …

Background Current prevalence estimates of heart failure (HF) are primarily based on self-report or HF hospitalizations. There is an unmet need to define the prevalence and pathogenesis of early symptomatic HF, which may be undiagnosed and precedes HF hospitalization. Methods The MESA (Multi-Ethnic Study of Atherosclerosis) Early HF study was conducted during MESA exam 6 to determine the prevalence of early HF and investigate the transition from risk factors to early HF in a diverse population-based cohort of older adults. Between 2016 and 2018, 3285 MESA participants from 6 field centers underwent comprehensive speckle-tracking echocardiography with passive leg raise maneuver, Kansas City Cardiomyopathy Questionnaire, 6-minute walk test, arterial stiffness assessment, and proteomics (including NT-proBNP [N-terminal pro-B-type natriuretic peptide]). Results Median age was 73 (25th–75th …

Background Normalization of echocardiographic chamber measurements for body surface area may result in misclassification of individuals with obesity or sarcopenia. Normalization for alternative measures of body size may be preferable, but there remains a dearth of information on their normative values and association with cardiovascular function metrics. Methods and Results A total of 3032 individuals underwent comprehensive 2‐dimensional echocardiography at Exam 6 in MESA (Multi‐Ethnic Study of Atherosclerosis). In the subgroup of 608 individuals free of cardiopulmonary disease (69.5±7.0 years, 46% male, 48% White, 17% Chinese, 15% Black, 21% Hispanic), normative values were derived for left and right cardiac chamber measurements across a variety of ratiometric (body surface area, body mass index, height) and allometric (height1.6, height2.7) scaling parameters. Normative upper and lower …

Background Although beta-blockers are not recommended for the treatment of heart failure with preserved ejection fraction (HFpEF) according to the latest European Society of Cardiology and American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines, these therapies remain commonly used for comorbidity management. There has been concern that beta-blockers may adversely influence clinical outcomes by limiting chronotropic response in HFpEF. Objectives This study sought to examine the contemporary use and implications of beta-blockers in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HFpEF. Methods In the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, a total of 6,263 patients with symptomatic heart failure (HF) with a left ventricular ejection fraction …

BackgroundThe impact of mitral regurgitation (MR) and aortic regurgitation (AR) on left atrial (LA) remodeling is poorly understood and may affect clinical outcomes such as 6-minute walk distance (6MWD) and NT-proBNP.Methods2694 participants who attended MESA Exam 6 were included. Clinical characteristics, demographics, and echo measures were compared between participants with none, mild, or moderate MR and AR. Multivariable-adjusted linear regression models were used to measure the association between AR/MR and each LA strain measurement (adjusted for age, sex, body surface area, systolic blood pressure, and presence of atrial fibrillation).ResultsParticipants with moderate vs mild MR had reduced LA booster strain (p= 0.0001), a more dilated LA (p= 0.0001) and impaired LA booster (p= 0.001), conduit (p= 0.0104) and reservoir strain (p= 0.001) with passive leg raise. Those with moderate …

BackgroundAlthough sodium glucose co-transporter 2 inhibitors (SGLT2is) improve heart failure (HF)-related symptoms and outcomes in HF with preserved ejection fraction (HFpEF), underlying mechanisms remain unclear. In HF with reduced EF, dapagliflozin altered ketone and fatty acid metabolites vs placebo; however, metabolite signatures of SGLT2is have not been well elucidated in HFpEF.ObjectivesThe goal of this study was to assess whether SGLT2i treatment altered systemic metabolic pathways and their relationship to outcomes in HFpEF.MethodsTargeted profiling of 64 metabolites was performed from 293 participants in PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction Heart Failure), a 12-week, placebo-controlled trial of dapagliflozin. Linear regression assessed changes in metabolite factors defined by principal components analysis (PCA) with dapagliflozin vs placebo. The …

BackgroundObesity 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.MethodsA 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 …

ImportanceTafamidis has been shown to improve survival in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) compared with placebo. However, its effect on cardiac function has not been fully characterized.ObjectiveTo examine the effect of tafamidis on cardiac function in patients with ATTR-CM.Design, Setting, and ParticipantsThis was an exploratory, post hoc analysis of the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), a multicenter, international, double-blind, placebo-controlled phase 3 randomized clinical trial conducted from December 2013 to February 2018. The ATTR-ACT included 48 sites in 13 counties and enrolled patients aged 18 to 90 years with ATTR-CM. Data were analyzed from July 2018 to September 2023.InterventionPatients were randomized to tafamidis meglumine, 80 mg or 20 mg, or placebo for 30 months.Main Outcomes and MeasuresPatients were …

BackgroundSTEP-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.MethodsSTEP-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 …

Context The relationship between thyroid dysfunction and measures of myocardial disease in older individuals remains to be defined. Objective To evaluate the impact of thyroid dysfunction on structure and function of the left-heart chambers and blood markers of cardiac disease. Design Cross-sectional analysis. Setting The Cardiovascular Health Study, a community-based cohort of older individuals recruited from four urban areas in the United States. Patients Of 3163 participants studied, 2477 were euthyroid, 465 had subclinical hypothyroidism (SCH), 47 overt hypothyroidism (OH), 45 endogenous (endo) subclinical hyperthyroidism (endo-SCT), and 129 had exogenous (exo) SCT due to thyroid hormone supplementation. Interventions Clinical evaluation, blood sampling and biomarker …

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 …

BackgroundSleep 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.ObjectivesTo 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).MethodsA history of sleep apnea was investigator-reported. The primary outcome was a composite of worsening HF or cardiovascular death.ResultsThe 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 …

BackgroundWe sought to evaluate the performance of deep learning algorithms for measurement of echo estimators of invasively measured PCWP in a large multicenter clinical trial.MethodsREDUCE LAP-HF II, an RCT of the Corvia Atrial Shunt Device, involved 89 sites and 626 patients with HF and LVEF≥ 40%. At baseline, all patients underwent invasive measurement of PCWP (read centrally by a hemodynamic core lab [CCS Foundation]) and comprehensive echo (read centrally by core labs at U. Pennsylvania [2D/Doppler/tissue Doppler] and Northwestern [strain]). We used intraclass correlation coefficients, Bland-Altman analyses, and area under the receiver operating characteristic (AUROC) analyses to determine test characteristics of core lab vs. deep learning-based measurements (Us2. ai) for 5 echo estimators of PCWP: E/e’ratio (lateral, septal, and average); LA reservoir strain, and LV global …

BackgroundA common genetic variant of ICAM1 among African-American individuals (rs5491; p.K56M) is associated with heart failure (HF) hospitalization, but whether this risk is specific to heart failure with preserved ejection fraction (HFpEF) remains unclear. Older women are at high risk for HFpEF, and the relationship between rs5491 and HFpEF across the age spectrum is unknown.ObjectivesThis study assessed risk of HF and its subtypes conferred by ICAM1 p.K56M (rs5491).MethodsAssociations of rs5491 with risk of HF and its subtypes were estimated among African American individuals in WHI (Women’s Health Initiative). The study evaluated whether the association between rs5491 and HF hospitalizations was modified by baseline age. Subsequently, African-American women in WHI and MESA (Multi-Ethnic Study of Atherosclerosis) were pooled and analyses were repeated.ResultsAmong 8,401 women …

BackgroundMechanisms of benefit with SGLT2i in HF remain unclear. Dapagliflozin alters ketone and fatty acid oxidation in HFrEF, but similar effects were not observed in HFpEF. Here we examine whether metabolic effects of SGLT2i vary across the LVEF spectrum.MethodsMass spectrometry-based profiling of 61 metabolites was performed using plasma samples from 527 participants pooled from DEFINE-HF and PRESERVED-HF-12-week, placebo-controlled trials of dapagliflozin in HFrEF and HFpEF, respectively. Linear regression assessed changes in principal components analysis (PCA)-defined metabolite factors with treatment. Models adjusted for clinical covariates and FDR< 0.10 controlled for multiple comparisons.ResultsMean age was 66±11 years, 43% were female, and 33% were Black race. Of 12 PCA-derived metabolite factors, two (comprised of ketone and short/medium-chain acylcarnitines …