Obesity and Cardiovascular Health.

Obesity has risen to epidemic levels worldwide over the past few decades and has become a huge global health burden owing to its direct contribution to the development of some of the most prevalent chronic diseases including diabetes, hypertension, hyperlipidemia, and other cardiovascular diseases. Obesity is a disease of positive energy balance resulting from complex interactions between abnormal neurohumoral responses and an individual's socioeconomic, environmental, behavioral, and genetic factors leading to a state of chronic inflammation. Understanding the complex nature of the disease is crucial in determining the best approach to combat its rising numbers. Despite recent advancements in pharmacological therapy for treatment of obesity, reversing weight gain and maintaining weight loss is challenging due to the relapsing nature of the disease. Prevention, therefore, remains the key which needs to start in-utero and continued throughout life. This review summarizes the role obesity plays in pathophysiology of various cardiovascular diseases both by directly affecting endothelial and myocyte function and indirectly by enhancing major cardiovascular risk factors like diabetes, hypertension, and hyperlipidemia. We highlight the importance of a holistic approach needed to prevent and treat this debilitating disease. Particularly, we analyze the effects of plant-based diet, regular exercise, and non-exercise activity thermogenesis (NEAT) on obesity and overall cardiorespiratory fitness (CRF). Moreover, we discuss the significance of individualizing obesity management with a multimodal approach including lifestyle modifications, pharmacotherapy, and bariatric surgery to tackle this chronic disease.

Standardized Definitions for Cardiogenic Shock Research and Mechanical Circulatory Support Devices: Scientific Expert Panel From the Shock Academic Research Consortium (SHARC).

The Shock Academic Research Consortium is a multi-stakeholder group, including representatives from the US Food and Drug Administration and other government agencies, industry, and payers, convened to develop pragmatic consensus definitions useful for the evaluation of clinical trials enrolling patients with cardiogenic shock, including trials evaluating mechanical circulatory support devices. Several in-person and virtual meetings were convened between 2020 and 2022 to discuss the need for developing the standardized definitions required for evaluation of mechanical circulatory support devices in clinical trials for cardiogenic shock patients. The expert panel identified key concepts and topics by performing literature reviews, including previous clinical trials, while recognizing current challenges and the need to advance evidence-based practice and statistical analysis to support future clinical trials. For each category, a lead (primary) author was assigned to perform a literature search and draft a proposed definition, which was presented to the subgroup. These definitions were further modified after feedback from the expert panel meetings until a consensus was reached. This manuscript summarizes the expert panel recommendations focused on outcome definitions, including efficacy and safety.

Importance of the 'area under the curve' from serial NT-proBNP measurements during treatment with sacubitril/valsartan.

AIMS: Serial assessment of natriuretic peptides is widely utilized in heart failure clinics. Uncertainty exists regarding the value of multiple natriuretic peptide measurements and how they might be best interpreted. METHODS AND RESULTS: Six hundred thirty-two patients with heart failure with reduced ejection fraction (<40%) and complete biomarker data were enrolled to receive sacubitril/valsartan. Patients underwent periodic study visits during 1-year follow-ups. Echocardiographic data and cardiac biomarkers, including N-terminal pro-B-type natriuretic peptide (NT-proBNP) were collected during study visits. Patients were categorized into three groups based on tertiles of baseline NT-proBNP levels. The area under the curve (AUC) of NT-proBNP measurements across study visits was calculated. Compared with patients with higher AUC (and thus higher concentrations over a longer period of time), those with lower AUC were younger, had a lower prevalence of chronic kidney disease, prior coronary artery bypass graft, atrial fibrillation, and higher body-mass index. A significant interaction existed between baseline NT-proBNP and subsequent AUC for predicting LVEF change across visits (P-value < 0.001): among those with lower baseline NT-proBNP, similar improvements in left ventricular (LV) volumes LV ejection fraction, and LV mass index were observed across subsequent AUC (P-value > 0.1). However, among those with higher baseline NT-proBNP, those with lower subsequent AUC had a greater improvement in cardiac remodelling indices (P-value < 0.05). CONCLUSIONS: Serial NT-proBNP monitoring (integrating the totality of measurements as an AUC) during treatment with sacubitril/valsartan informs unique information regarding the future changes in cardiac remodelling indices, especially among those with higher NT-proBNP levels at baseline.

Vascular Disease Burden, Outcomes and Benefits with Empagliflozin in Heart Failure: Insights From the EMPEROR-Reduced Trial.

BACKGROUND: The presence of ischemic heart disease impacts prognosis in patients affected by heart failure and reduced ejection fraction (HFrEF). It is not well known how the extent of vascular disease impacts prognoses and responses to therapy in this setting. METHODS: In this post hoc analysis of the EMPEROR-Reduced trial, outcomes and the effects of empagliflozin, were assessed in study participants according to the extent (none vs mono1 vs poly [≥ 2] vascular bed) of vascular disease. Vascular disease was defined as investigator-reported coronary artery disease (CAD), peripheral artery disease (PAD) and cerebrovascular disease at baseline. Cox proportional-hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Incidence rates are presented per 100 person-years (py) of follow-up. RESULTS: Of the 3730 study participants enrolled, 1324 (35.5%) had no vascular disease, 1879 (50.4%) had monovascular disease, and 527 (14.1%) had polyvascular disease. Participants with polyvascular disease tended to be older and male and to have had histories of hypertension, diabetes and smoking. In the placebo arm, a significantly higher risk for cardiovascular death existed in those with polyvascular disease (HR 1.57, 95% CI1.02, 2.44, compared to those with no vascular disease). In adjusted analysis, the benefit of empagliflozin in cardiovascular death or hospitalization due to HF, HF hospitalization, cardiovascular death, renal composite endpoint, estimated glomerular filtration slope changes, and health status scores were seen across the 3 groups (interaction P > 0.05 for all) but were attenuated in those with polyvascular disease. Adverse events were higher in those with polyvascular disease, but no major differences were noted between empagliflozin or placebo assignment in the 3 groups. CONCLUSION: In patients with HFrEF, the extent of vascular disease is associated with the risk for adverse cardiovascular outcomes. Empagliflozin offers cardiovascular and renal benefits in HFrEF across the extent of vascular disease, but this benefit is attenuated in those with polyvascular disease.

Age, Sex, and Outcomes in Heart Failure With Reduced EF: Insights From the VICTORIA Trial.

BACKGROUND: Age and sex influence treatment and outcomes in patients with heart failure (HF). OBJECTIVES: The authors examined the associations of age and sex with clinical characteristics, background therapies, outcomes, and response to vericiguat in this post hoc analysis of 5,050 VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) patients with HF and reduced ejection fraction; 1,568 (31%) were ≥75 years of age, of whom 445 (24%) were women. METHODS: Clinical characteristics were compared across age (<65, 65 to <75, and ≥75 years) and sex. The treatment effect of vericiguat was estimated by age and sex on the primary composite outcome (time to first HF hospitalization or cardiovascular death) using Cox proportional hazards regression. RESULTS: Compared with younger patients, those ≥75 years of age had more class III and IV symptoms, higher N-terminal pro-B-type natriuretic peptide levels, and worse kidney function but had the lowest use of triple therapy. No sex differences in triple therapy existed by age, but achieving target doses of triple therapy was less likely in older patients. Men ≥75 years of age were more than twice as likely to receive defibrillators and 65% more likely to undergo cardiac resynchronization than women. The primary composite outcome was nominally lower in women than men across all age groups. Vericiguat dosing did not differ between sexes in each age group, and its beneficial effect on the primary endpoint was not modified by age (continuous age, Pinteraction = 0.169; categorical age, Pinteraction = 0.189); and sex (3-way interaction; P = 0.847). CONCLUSIONS: Although elderly women received less intense background HF therapy than men, their prognosis was nominally better. The benefit of vericiguat was independent of age and sex. (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534).

Changes in mid-regional pro-adrenomedullin during treatment with sacubitril/valsartan.

AIMS: Adrenomedullin is a vasodilatory peptide with a role in microcirculatory and endothelial homeostasis. Adrenomedullin is a substrate for neprilysin and may therefore play a role in beneficial effects of sacubitril/valsartan (Sac/Val) treatment. METHODS AND RESULTS: Mid-regional pro-adrenomedullin (MR-proADM) was measured in 156 patients with heart failure with reduced ejection fraction (HFrEF) treated with Sac/Val and 264 patients with heart failure with preserved ejection fraction (HFpEF) randomized to treatment with Sac/Val or valsartan. Echocardiography and Kansas City Cardiomyopathy Questionnaire results were collected at baseline and after 6 and 12 months in the HFrEF cohort. Median (Q1-Q3) baseline MR-proADM concentrations were 0.80 (0.59-0.99) nmol/L in HFrEF and 0.88 (0.68-1.20) nmol/L in HFpEF. After 12 weeks of treatment with Sac/Val, MR-proADM increased by median 49% in HFrEF and 60% in HFpEF, while there were no significant changes in valsartan-treated patients (median 2%). Greater increases in MR-proADM were associated with higher Sac/Val doses. Changes in MR-proADM correlated weakly with changes in N-terminal pro-B-type natriuretic peptide, cardiac troponin T and urinary cyclic guanosine monophosphate. Increases in MR-proADM were associated with decreases in blood pressure, but not significantly associated with changes in echocardiographic parameters or health status. CONCLUSIONS: MR-proAD concentrations rise substantially following treatment with Sac/Val, in contrast to no change from valsartan. Change in MR-proADM from neprilysin inhibition did not correlate with improvements in cardiac structure and function or health status. More data are needed regarding the role of adrenomedullin and its related peptides in the treatment of heart failure. CLINICAL TRIAL REGISTRATION: PROVE-HF ClinicalTrials.gov Identifier: NCT02887183, PARAMOUNT ClinicalTrials.gov Identifier: NCT00887588.

Background Medical Therapy and Clinical Outcomes From the VICTORIA Trial.

BACKGROUND: We examined whether the primary composite outcome (cardiovascular death or heart failure hospitalization) was related to differences in background use and dosing of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction enrolled in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction), a randomized trial of vericiguat versus placebo. METHODS: We evaluated the adherence to guideline use of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, angiotensin receptor-neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. We assessed basic adherence; indication-corrected adherence accounting for guideline indications and contraindications; and dose-corrected adherence (indication-corrected adherence+≥50% of drug dose target). Associations between study treatment and the primary composite outcome according to the adherence to guidelines were assessed using multivariable adjustment; adjusted hazard ratios with 95% CIs and Pinteraction are reported. RESULTS: Of 5050 patients, 5040 (99.8%) had medication data at baseline. For angiotensin-converting enzyme inhibitor, angiotensin-receptor blockers, and angiotensin receptor-neprilysin inhibitors, basic adherence to guidelines was 87.4%, indication-corrected was 95.7%, and dose-corrected was 50.9%. For beta-blockers, basic adherence was 93.1%, indication-corrected was 96.2%, and dose-corrected was 45.4%. For mineralocorticoid receptor antagonists, basic adherence was 70.3%, indication-corrected was 87.1%, and dose-corrected was 82.2%. For triple therapy (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, or angiotensin receptor-neprilysin inhibitors+beta-blocker+mineralocorticoid receptor antagonist), basic adherence was 59.7%, indication-corrected was 83.3%, and dose-corrected was 25.5%. Using basic or dose-corrected adherence, the treatment effect of vericiguat was consistent across adherence to guidelines groups, with or without multivariable adjustment with no treatment heterogeneity. CONCLUSIONS: Patients in VICTORIA were well treated with heart failure with reduced ejection fraction medications. The efficacy of vericiguat was consistent across background therapy with very high adherence to guidelines accounting for patient-level indications, contraindications, and tolerance. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02861534.

Effect of SGLT2 Inhibitors on Cardiovascular Outcomes Across Various Patient Populations.

BACKGROUND: The effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on heart failure (HF) outcomes and cardiovascular (CV) death in patients with varying combinations of type 2 diabetes mellitus (T2DM), HF, and chronic kidney disease (CKD) are uncertain. OBJECTIVES: The authors conducted a meta-analysis assessing the effects of SGLT2 inhibitors on HF outcomes and CV death across different patient populations. METHODS: Online databases were queried up to November 2022 for primary and secondary analyses of trials of SGLT2 inhibitors in patients with HF, T2DM, or CKD. Outcomes of interest were composite of first heart failure hospitalization (HFH) or CV death (first HFH/CV death), first HFH, and CV death. Data were pooled by means of a random-effects model to derive HRs and 95% CIs. RESULTS: Thirteen trials (n = 90,413) were included. Compared with placebo, SGLT2 inhibitors reduced the risk of first HFH/CV death by 24% in HF (HR: 0.76; 95% CI: 0.72-0.81), 23% in T2DM (HR: 0.77; 95% CI: 0.73-0.81), and 23% in CKD (HR: 0.77; 95% CI: 0.72-0.82). The benefit was consistent in HF with reduced or preserved ejection fraction, HF with or without T2DM, and HF with or without CKD. The benefit was also consistent in T2DM with or without CKD, T2DM without HF, CKD without HF, and in patients with all 3 comorbidities. SGLT2 inhibitors significantly reduced CV death by 16% in HF, 15% in T2DM, and 12% in CKD. CONCLUSIONS: SGLT2 inhibitors reduce HF events and CV death in cohorts of HF, T2DM and CKD, and these effects appear consistent in patients with varying combinations of these diseases.

Iron Deficiency in Heart Failure: A Scientific Statement from the Heart Failure Society of America.

Iron deficiency is present in approximately 50% of patients with symptomatic heart failure and is independently associated with worse functional capacity, lower quality of, life and increased mortality. The purpose of this document is to summarize current knowledge of how iron deficiency is defined in heart failure and its epidemiology and pathophysiology, as well as pharmacological considerations for repletion strategies. This document also summarizes the rapidly expanding array of clinical trial evidence informing when, how, and in whom to consider iron repletion.

Safety and Efficacy of Empagliflozin and Diuretic Use in Patients with Heart Failure and Preserved Ejection Fraction: A Post Hoc Analysis of the EMPEROR-Preserved Trial.

Importance: The diuretic effect of sodium-glucose cotransporter 2 inhibitors may result in interaction with background diuretic therapy in patients with heart failure and preserved ejection fraction (HFpEF). Objective: To assess the safety and efficacy of empagliflozin in combination with background diuretic therapy and the association of empagliflozin with the need for conventional diuretics. Design, Setting, and Participants: This was a post hoc analysis of the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved). EMPEROR-Preserved was a phase 3, randomized, placebo-controlled, double-blind clinical trial conducted from March 2017 to April 2021. Patients with class II to IV heart failure and left ventricular ejection fraction greater than 40% were included. Of 5988 patients enrolled, 5815 (97.1%) had baseline data on diuretic use and were included in this analysis, which was conducted from November 2021 to August 2022. Interventions: Participants in EMPEROR-Preserved were randomized to empagliflozin or placebo. In this analysis, participants were divided into 4 subgroups: no diuretics and furosemide-equivalent diuretic dose of less than 40 mg, 40 mg, and greater than 40 mg at baseline. Main Outcomes and Measures: The main outcomes of interest were first hospitalization for heart failure (HHF) or cardiovascular death (CV death) and its components. Association of empagliflozin vs placebo with outcomes by baseline diuretic status (no diuretic vs any dose) and dose (no diuretic, <40 mg, 40 mg, and > 40mg) was assessed. Association of empagliflozin use with changes in diuretic therapy was also studied. Results: Among 5815 patients (mean [SD] age, 71.9 [9.4] years; 2594 [44.6%] female) with known baseline diuretic use, 1179 (20.3%) were not taking diuretics, 1725 (29.7%) were taking less than 40 mg, 1772 (30.5%) were taking 40 mg, and 1139 (19.6%) were taking greater than 40 mg. In the placebo arm, patients with higher diuretic doses had worse outcomes. Empagliflozin decreased the risk of HHF or CV death, regardless of background diuretic status (hazard ratio [HR], 0.81; 95% CI, 0.70-0.93] for the diuretic group vs HR, 0.72; 95% CI, 0.48-1.06 for the nondiuretic group; P for interaction = .58). Similarly, diuretic status was not associated with changes in improvements in first HHF, total HHF, rate of decline in estimated glomerular filtration rate, and Kansas City Cardiomyopathy Questionnaire 23 clinical summary score with empagliflozin. Findings were consistent when patients were categorized by diuretic dose. Empagliflozin was associated with a decreased likelihood of diuretic dose escalation (HR, 0.74; 95% CI, 0.65-0.84) and an increased likelihood of de-escalation (HR, 1.15; 95% CI, 1.02-1.30). Empagliflozin was associated with an increased risk of volume depletion in patients taking diuretics (HR, 1.34; 95% CI, 1.13-1.59). Conclusion: In this study, treatment with empagliflozin was similar regardless of diuretic use or dose. Empagliflozin use was associated with decreased conventional diuretic dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT03057951.

Health status across major subgroups of patients with heart failure and preserved ejection fraction.

AIMS: There are limited data on health status and changes in it over time across major subgroups of patients with heart failure and preserved ejection fraction (HFpEF), including ejection fraction spectrum, age, sex, region, body mass index (BMI), and comorbidities including diabetes, chronic kidney disease (CKD), anaemia, and atrial fibrillation/flutter. METHODS AND RESULTS: In the EMPEROR-Preserved trial, the Kansas City Cardiomyopathy Questionnaire (KCCQ) was assessed at baseline, 12, 32 and 52 weeks. Determinants of baseline KCCQ score and change over time, and the impact of empagliflozin on KCCQ scores were studied in specified subgroups. A Cox model was used to assess the association between 5- and 10-point increase and 5-point decrease in KCCQ score from baseline to week 12 and later outcomes. Among 2979 participants in the placebo arm, mean KCCQ clinical summary score (CSS) was 70.7 (20.8). Older age, female sex, BMI, anaemia, and a history of diabetes, and CKD were associated with worse scores. KCCQ-CSS score improved during follow-up; patients with atrial fibrillation/flutter at enrollment (p trend = 0.014) and CKD (p trend < 0.001) had less improvement. A 5-point increase in KCCQ-CSS at week 12 was associated with lower risk of cardiovascular death or heart failure hospitalization (5%), cardiovascular death (8%), and first heart failure hospitalization (4%) subsequently. A similar trend was seen with KCCQ total symptom score (TSS) and overall summary score (OSS). Empagliflozin improved KCCQ-CSS, -TSS and -OSS scores similarly across subgroups studied except for greater improvement in patients with the highest BMI (p trend = 0.153, 0.08 and 0.078, respectively). CONCLUSION: Health status in patients with HFpEF is impaired, especially in elderly, women, and those with obesity and comorbidities. Empagliflozin improved health status among all key subgroups studied with a greater effect in obese patients.

Circulating Angiokines Are Associated With Reverse Remodeling and Outcomes in Chronic Heart Failure.

BACKGROUND: We sought to determine whether circulating modifiers of endothelial function are associated with cardiac structure and clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). METHODS: We measured 25 proteins related to endothelial function in 99 patients from the GUIDE-IT study. Protein levels were evaluated for association with echocardiographic parameters and the incidence of all-cause death and hospitalization for heart failure (HHF). RESULTS: Higher concentrations of angiopoietin 2 (ANGPT2), vascular endothelial growth factor receptor 1 (VEGFR1) and hepatocyte growth factor (HGF) were significantly associated with worse function and larger ventricular volumes. Over time, decreases in ANGPT2 and, to a lesser extent, VEGFR1 and HGF, were associated with improvements in cardiac size and function. Individuals with higher concentrations of ANGPT2, VEGFR1 or HGF had increased risks for a composite of death and HHF in the following year (HR 2.76 (95% CI 1.73-4.40) per 2-fold change in ANGPT2; HR 1.76 (95% CI 1.11-2.79) for VEGFR1; and HR 4.04 (95% CI 2.19-7.44) for HGF). CONCLUSIONS: Proteins related to endothelial function associate with cardiac size, cardiac function and clinical outcomes in patients with HFrEF. These results support the concept that endothelial function may be an important contributor to the progression to and the recovery from HFrEF.

Prediction of Left Ventricular Ejection Fraction Change Following Treatment With Sacubitril/Valsartan.

BACKGROUND: Sacubitril/valsartan (Sac/Val) improves left ventricular ejection fraction (LVEF) in heart failure (HF) with reduced ejection fraction regardless of previous treatments. Improvements in LVEF may change eligibility for primary implantable cardioverter-defibrillator (ICD) placement. Awaiting LVEF improvement may expose patients to potential risks for arrhythmic complications. OBJECTIVES: The authors sought to develop a model predicting LVEF change after Sac/Val therapy. METHODS: A total of 416 persons with HF and LVEF of <35% were included in this analysis. Following initiation of Sac/Val, echocardiographic parameters were measured serially for 1 year. A machine learning algorithm was implemented to develop a risk model for predicting the persistence of LVEF of <35% after 1 year and was validated in a separate group of study participants. RESULTS: Baseline LVEF, left ventricular mass index, HF duration, age, N-terminal pro-B-type natriuretic peptide concentration at baseline and change by day 14, and body mass index were the most significant factors for identifying lack of LVEF improvement to ≥35% after 1 year. In the training and validation cohorts, the areas under the model curve for predicting lack of LVEF improvement were 0.92 and 0.86, respectively. Three categories of likelihood for LVEF of <35% after 1 year of Sac/Val treatment were developed based on the model predictions: 3.8%, 30.1%, and 83.7%. During follow-up, arrhythmia event rates were 0.9%, 2.9%, and 6.7% in these groups, respectively. CONCLUSIONS: Many persons with HF with reduced ejection fraction eligible for ICD insertion experience an increase in LVEF to ≥35% after treatment with Sac/Val. Early identification of those less likely to improve their LVEF might allow for more refined selection of primary ICD candidates. (Effects of Sacubitril/Valsartan Therapy on biomarkers, Myocardial Remodeling, and Outcomes [PROVE-HF]; NCT02887183).

Impact of Empagliflozin in Heart Failure With Reduced Ejection Fraction in Patients With Ischemic Versus Nonischemic Cause.

Background Outcomes and treatment effects of therapy may vary according to the cause of heart failure (HF). Methods and Results In this post hoc analysis of the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) trial, the effect of empagliflozin on cardiovascular and renal outcomes was assessed according to the cause of HF. The cause of HF was investigator reported and stratified as ischemic or nonischemic. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% CIs. Of the 3730 patients enrolled, 1929 (51.7%) had ischemic cause. In the placebo arm, patients with ischemic cause of HF did not have a significantly higher risk of cardiovascular mortality (HR, 1.21 [95% CI, 0.90-1.63]) and hospitalization for HF (HR, 0.90 [95% CI, 0.72-1.12]) compared with nonischemic cause. Empagliflozin compared with placebo significantly reduced the risk of cardiovascular death or hospitalization for HF in patients with ischemic and nonischemic cause (HR, 0.82 [95% CI, 0.68-0.99] for ischemic and HR, 0.67 [95% CI, 0.55-0.82] for nonischemic cause; P interaction=0.15). The benefit of empagliflozin on HF hospitalization, the renal composite end point, estimated glomerular filtration slope changes, and health status scores were also consistent in both groups without treatment by cause modification. Conclusions Empagliflozin offers cardiovascular and renal benefits in patients with heart failure with reduced ejection fraction regardless of the cause of HF. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.