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Background: Diabetic myocardial disorder (DbMD, evidenced by abnormal echocardiography or cardiac biomarkers) is a form of stage B heart failure (SBHF) at high risk for progression to overt HF. SBHF is defined by abnormal LV morphology and function and/or abnormal cardiac biomarker concentrations. Objective: To compare the evolution of four DbMD groups based on biomarkers alone, systolic and diastolic dysfunction alone, or their combination. Methods: The Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) trial was a Phase 3 randomised trial of an aldose reductase inhibitor in patients with well-controlled type 2 diabetes mellitus (T2DM). The 1858 potential participants (age 67 ± 7 years; 50% women) were screened for SBHF based on abnormal echocardiography or biomarkers (N-terminal pro-B-type natriuretic peptide ≥ 40 ng/L or high sensitivity cardiac troponin T ≥ 10 ng/L [women] and ≥ 16 ng/L [men]). Exercise capacity (peak VO2) was reduced in 669 with DbMD (age 68 ± 7, 50% women), and peak VO2 was reassessed at 15 months. Results: The 1463 (79%) participants with DbMD were allocated to four clusters; 907 (49%) showed isolated elevation of cardiac biomarkers, 301 (16%) with systolic dysfunction/hypertrophy, 162 (9%) with diastolic dysfunction and 93 (5%) comprised an overlap cluster (combined diastolic, systolic or LV geometric abnormalities). Reduced VO2 (< 75% predicted) was present in 669 (46%); 72% of those with both systolic and diastolic dysfunction, 56% of those with systolic dysfunction and LVH, 53% of those with diastolic dysfunction and 38% with biomarkers alone (p < 0.0001). In 669 patients followed over 15 months, there was a similar small decrement in VO2 in all groups. Conclusions: Among individuals with T2DM and SBHF, reduced functional capacity is most prevalent in those with multiple physiological disturbances. However, there was no difference between phenogroups in the evolution of exercise intolerance. Trial Registration: ARISE-HF, NCT04083339. [ABSTRACT FROM AUTHOR] more...

Aims: Reverse ventricular remodelling, defined as a decrease in left ventricular end‐systolic volume indexed to body surface area (LVESVI) or an increase in left ventricular ejection fraction (LVEF), is associated with improved clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, the underlying pathophysiological mechanisms remain unclear. Methods and results: We evaluated paired core‐lab assessed echocardiograms and measurements of 92 biomarkers at baseline and 8 months thereafter in 419 participants with HFrEF. Reverse ventricular remodelling was defined as a >5% LVEF increase or >15% LVESVI relative decrease between baseline and 8 months. We evaluated the association between baseline biomarkers and their changes with reverse ventricular remodelling in the prospectively randomized controlled VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) trial. Of 419 patients (median age 66 [interquartile range 57–74] years, 27.4% women), 206 (49.2%) had reverse ventricular remodelling (either a 5% LVEF increase or a 15% LVESVI decrease). There were no differences in baseline biomarker concentrations between patients with versus those without reverse ventricular remodelling on follow‐up. However, in patients with reverse ventricular remodelling there were significant decreases in biomarkers relating to inflammation and cardiac metabolism; particularly the tumour necrosis factor superfamily member 13B (ratio 0.82, 95% confidence interval [CI] 0.77–0.88), growth differentiation factor‐15 (ratio 0.74, 95% CI 0.66–0.84), and insulin‐like growth factor binding protein 7 (ratio 0.80, 95% CI 0.73–0.88). Conclusions: Reverse ventricular remodelling in patients with HFrEF is associated with a decrease of biomarkers related to inflammation and cardiac metabolism. [ABSTRACT FROM AUTHOR] more...

Aims: Many patients with heart failure (HF) have chronic kidney disease (CKD) and may not tolerate mineralocorticoid receptor antagonists. We investigated the efficacy and safety of the novel mineralocorticoid receptor modulator balcinrenone in combination with dapagliflozin in a phase 2b study. Methods and results: From January 2021 to October 2023, we randomized 133 adults with symptomatic HF, ejection fraction <60%, estimated glomerular filtration rate (eGFR) ≥30 to ≤60 ml/min/1.73 m2 and urinary albumin‐to‐creatinine ratio (UACR) ≥30 to <3000 mg/g, to receive balcinrenone 15, 50 or 150 mg/day plus dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day plus placebo, for 12 weeks. Enrolment was stopped early because of slow recruitment. Relative reductions in UACR from baseline to week 12 (primary endpoint) were not significantly different between the balcinrenone plus dapagliflozin groups versus dapagliflozin plus placebo. There was no clear balcinrenone dose–response relationship. There were possible dose‐dependent increases in serum potassium levels, reduced eGFR in the highest dose group, and non‐significant trends towards reduced N‐terminal pro‐B‐type natriuretic peptide levels. Hyperkalaemia adverse events led to discontinuation in two participants receiving balcinrenone plus dapagliflozin and none in those receiving dapagliflozin plus placebo. Conclusion: While the smaller than planned sample size limits interpretation, we did not see significant reduction in UACR in patients treated with balcinrenone plus dapagliflozin compared with dapagliflozin plus placebo. [ABSTRACT FROM AUTHOR] more...

Sodium–glucose cotransporter 2 (SGLT2) inhibitors were initially developed for their glucose-lowering effects and have shown a modest glycaemic benefit in people with type 2 diabetes mellitus (T2DM). In the past decade, a series of large, robust clinical trials of these therapies have demonstrated striking beneficial effects for various care goals, transforming the chronic disease therapeutic landscape. Cardiovascular safety studies in people with T2DM demonstrated that SGLT2 inhibitors reduce cardiovascular death and hospitalization for heart failure. Subsequent trials in participants with heart failure with reduced or preserved left ventricular ejection fraction demonstrated that SGLT2 inhibitors have beneficial effects on heart failure outcomes. In dedicated kidney outcome studies, SGLT2 inhibitors reduced the incidence of kidney failure among participants with or without diabetes. Post hoc analyses have suggested a range of other benefits of these drugs in conditions as diverse as metabolic dysfunction-associated steatotic liver disease, kidney stone prevention and anaemia. SGLT2 inhibitors have a generally favourable adverse effect profile, although patient selection and medication counselling remain important. Concerted efforts are needed to better integrate these agents into routine care and support long-term medication adherence to close the gap between clinical trial outcomes and those achieved in the real world. Here, the authors discuss the beneficial effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors for a range of clinical outcomes beyond glucose lowering, including kidney and cardiovascular protection. They also discuss the need for implementation and adherence initiatives to help translate the benefits of these agents into real-world clinical outcomes. Key points: Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of kidney disease progression in people with or without diabetes as well as the risk of acute kidney injury and hyperkalaemia. SGLT2 inhibitors reduce the risk of cardiovascular death and heart failure hospitalization among people with type 2 diabetes mellitus and have beneficial effects on key heart failure outcomes irrespective of diabetes status or left ventricular ejection fraction. SGLT2 inhibitors modestly lower systolic and diastolic blood pressure without a significant increase in risk of hypotensive episodes and have modest benefits for weight loss. Other benefits of SGLT2 inhibitors include improvements in liver outcomes in people with metabolic dysfunction-associated steatotic liver disease, reduced risk of symptomatic kidney stone events, improvements in anaemia outcomes and potential reductions in the risk of new-onset atrial fibrillation and new-onset diabetes. SGLT2 inhibitors have a generally favourable adverse effect profile but are associated with increased risk of genital mycotic infections and a small increased risk of diabetic ketoacidosis; they should be used with caution in people with unstable volume status owing to the risk of hypovolaemia. Prescription of SGLT2 by clinicians and patient adherence are suboptimal despite strong evidence for the efficacy and cost-effectiveness of these therapies. [ABSTRACT FROM AUTHOR] more...

Asia is the fastest-growing and most populous region of the world, accounting for 60% of the worldwide cardiovascular disease burden.1 It is also vastly heterogeneous. The representation of "Asia" in clinical trials varies widely, spanning from Japan to India, and comprises <10% of cardiometabolic clinical trials enrollment.1 The lack of granularity in Asian ancestry data within these trials raises concerns about the generalizability of trial findings to this diverse population. This concern is particularly salient in the context of heart failure, which is a global health problem affecting millions of individuals and placing a significant burden on health systems. Although significant strides have been made in understanding and managing heart failure clinically, data specific to Asian populations are now emerging. The exclusion of Asians in clinical studies extends beyond cardiovascular diseases, and acknowledging this exclusionary past will allow a future with a more nuanced understanding of potential disparities in the epidemiology, treatment, and management of heart failure. [ABSTRACT FROM AUTHOR] more...

Aims: Mitiperstat (formerly AZD4831) is a novel selective myeloperoxidase inhibitor. Currently, no effective therapies target comorbidity‐induced systemic inflammation, which may be a key mechanism underlying heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). Circulating neutrophils secrete myeloperoxidase, causing oxidative stress, microvascular endothelial dysfunction, interstitial fibrosis, cardiomyocyte remodelling and diastolic dysfunction. Mitiperstat may therefore improve function of the heart and other organs, and ameliorate heart failure symptoms and exercise intolerance. ENDEAVOR is a combined, seamless phase 2b–3 study of the efficacy and safety of mitiperstat in patients with HFpEF/HFmrEF. Methods: In phase 2b, approximately 660 patients with heart failure and ejection fraction >40% are being randomized 1:1:1 to mitiperstat 2.5 mg, 5 mg or placebo for 48 weeks. Eligible patients have baseline 6‐min walk distance (6MWD) of 30–400 m with a <50 m difference between screening and randomization and Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ‐TSS) ≤90 points at screening and randomization. The dual primary endpoints are change from baseline to week 16 in 6MWD and KCCQ‐TSS. The sample size provides 85% power to detect placebo‐adjusted improvements of 21 m in 6MWD and 6.0 points in KCCQ‐TSS at overall two‐sided alpha of 0.05. Safety is monitored throughout treatment, with a focus on maculopapular rash. In phase 3 of ENDEAVOR, approximately 820 patients will be randomized 1:1 to mitiperstat or placebo. Conclusion: ENDEAVOR is the first phase 2b–3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF. [ABSTRACT FROM AUTHOR] more...

A significant proportion of patients experience delays in the diagnosis of heart failure due to the non‐specific signs and symptoms of the syndrome. Diagnostic tools such as measurement of natriuretic peptide concentrations are fundamentally important when screening for heart failure, yet are frequently under‐utilized. This clinical consensus statement provides a diagnostic framework for general practitioners and non‐cardiology community‐based physicians to recognize, investigate and risk‐stratify patients presenting in the community with possible heart failure. [ABSTRACT FROM AUTHOR] more...

Aims: The aim of this study was to evaluate efficacy and safety of rapid up‐titration of guideline‐directed medical therapies (GDMT) in men and women hospitalized for acute heart failure (AHF). Methods and results: In STRONG‐HF, AHF patients were randomized just prior to discharge to either usual care (UC) or a high‐intensity care (HIC) strategy of GDMT up‐titration. In these analyses, we compared the implementation, efficacy, and safety of the HIC strategy between men and women. In the randomized AHF population, 416/1078 (39%) were women. By day 90, a higher proportion of both sexes in the HIC group had been up‐titrated to full doses of GDMT compared to UC. Overall, there were no differences in the primary endpoint between the sexes. The primary endpoint, 180‐day heart failure readmission or death, occurred in 15.8% HIC women versus 23.5% women in the UC group (adjusted hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.40–1.13) and in 14.9% HIC men versus 23.5% UC men (adjusted HR 0.57, 95% CI 0.38–0.88) (adjusted interaction p = 0.65). There was no significant treatment‐by‐sex interaction in quality‐of‐life improvement or in adverse events, including serious or fatal adverse events. Conclusion: The results of the current analyses suggest that a rapid up‐titration of GDMT immediately after an AHF hospitalization can and should be implemented similarly in men and women, as it results in reduction of 180‐day all‐cause death or heart failure readmission, quality‐of‐life improvement in both men and women with a similar safety profile. [ABSTRACT FROM AUTHOR] more...

Background: Despite advances in the treatment of heart failure (HF) with reduced ejection fraction, people with HF continue to have a high risk of mortality and hospitalisation. Patients also suffer from poor quality of life, with reduced societal and economic participation. The burden of HF on patients and healthcare systems is extraordinary, yet awareness remains low. This survey was conducted to identify gaps in general public and policymaker knowledge around HF. Methods: A closed-question web-based survey of the general public and policymakers was conducted between February and October 2020. Study outcomes assessed the participants' awareness and understanding of HF symptoms, risk factors and mortality, and views around hospital admissions in their country. Responses were collected using multiple-choice questions. Results: The survey was completed by 26,272 general public respondents in 13 countries and 281 government and public sector policymakers in nine countries. While 99% of general public respondents had heard of HF, their understanding of the condition and its symptoms was poor, and only 6% identified that shortness of breath, fatigue, and leg swelling were the main symptoms of HF. Of policymaker respondents, 14% identified HF as the leading cause of avoidable hospitalisations, and only 4% recognised that ~ 87% of government spending on HF is related to hospitalisations. Conclusions: Major gaps were identified in the understanding of HF and the burden it places on patients and their caregivers, healthcare systems and society. This study confirms an ongoing need for national policy strategies and investment to raise awareness of the importance of HF prevention, early diagnosis, and implementation of effective treatments to reduce hospitalisations and death. [ABSTRACT FROM AUTHOR] more...

This Viewpoint discusses the potential challenges to the operational conduct of clinical trials in the Asia-Pacific region, where there is a high rate of cardiovascular disease, and provides possible solutions. [ABSTRACT FROM AUTHOR] more...

Aims In patients with heart failure (HF), hospitalization rates are increasing, particularly for non-HF causes and over half may be avoidable. Self-monitoring of symptoms plays a key part in the early identification of deterioration. Our objective was to develop expert consensus for a core outcome set (COS) of symptoms to be monitored by patients, using validated single-item patient-reported outcome measures (PROMs), focused on the key priority of reducing admissions in HF. Methods and results A rigorous COS development process incorporating systematic review, modified e-Delphi and nominal group technique (NGT) methods. Participants included 24 HF patients, 4 carers, 29 HF nurses, and 9 doctors. In three Delphi and NGT rounds, participants rated potential outcomes on their importance before a HF or a non-HF admission using a 5-point Likert scale. Opinion change between rounds was assessed and a two-thirds threshold was used for outcome selection. Item generation using systematic review identified 100 validated single-item PROMs covering 34 symptoms or signs, relevant to admission for people with HF. De-duplication and formal consensus processes, resulted in a COS comprising eight symptoms and signs; shortness of breath, arm or leg swelling, abdomen bloating, palpitations, weight gain, chest pain, anxiety, and overall health. In the NGT, a numerical rating scale was selected as the optimal approach to symptom monitoring. Conclusion Recognition of a range of HF-specific and general symptoms, alongside comorbidities, is an important consideration for admission prevention. Further work is needed to validate and integrate the COS in routine care with the aim of facilitating faster identification of clinical deterioration. [ABSTRACT FROM AUTHOR] more...

Chronic kidney disease (CKD) as identified by a reduced estimated glomerular filtration rate (eGFR) is a common comorbidity in patients with heart failure with reduced ejection fraction (HFrEF). The presence of CKD is associated with more severe heart failure, and CKD itself is a strong independent risk factor of poor cardiovascular outcome. Furthermore, the presence of CKD often influences the decision to start, uptitrate, or discontinue possible life-saving HFrEF therapies. Because pivotal HFrEF randomized clinical trials have historically excluded patients with stage 4 and 5 CKD (eGFR <30 mL/min/1.73 m2), information on the efficacy and tolerability of HFrEF therapies in these patients is limited. However, more recent HFrEF trials with novel classes of drugs included patients with more severe CKD. In this review on medical therapy in patients with HFrEF and CKD, we show that for both all-cause mortality and the combined end point of cardiovascular death or heart failure hospitalization, most drug classes are safe and effective up to CKD stage 3B (eGFR minimum 30 mL/min/1.73 m2). For more severe CKD (stage 4), there is evidence of safety and efficacy of sodium glucose cotransporter 2 inhibitors, and to a lesser extent, angiotensin-converting enzyme inhibitors, vericiguat, digoxin and omecamtiv mecarbil, although this evidence is restricted to improvement of cardiovascular death/heart failure hospitalization. Data are lacking on the safety and efficacy for any HFrEF therapies in CKD stage 5 (eGFR < 15 mL/min/1.73 m2 or dialysis) for either end point. Last, although an initial decline in eGFR is observed on initiation of several HFrEF drug classes (angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/mineralocorticoid receptor antagonists/angiotensin receptor blocker neprilysin inhibitors/sodium glucose cotransporter 2 inhibitors), renal function often stabilizes over time, and the drugs maintain their clinical efficacy. A decline in eGFR in the context of a stable or improving clinical condition should therefore not be cause for concern and should not lead to discontinuation of life-saving HFrEF therapies. [ABSTRACT FROM AUTHOR] more...

Background: Both sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists reduce cardiovascular events among patients with type 2 diabetes. However, no cardiovascular outcome trial has evaluated the long-term effects of their combined use. The AMPLITUDE-O trial (Effect of Efpeglenatide on Cardiovascular Outcomes) reported that once-weekly injections of the glucagon-like peptide-1 receptor agonists efpeglenatide (versus placebo) reduced major adverse cardiovascular events (MACEs); MACEs, coronary revascularization, or unstable angina hospitalization (expanded MACEs); a renal composite outcome; and MACEs or death in people with type 2 diabetes and cardiovascular or renal disease. The trial uniquely stratified randomization by baseline or anticipated use of SGLT2 inhibitors and included the highest prevalence at baseline (N=618, 15.2%) of SGLT2 inhibitor use among glucagon-like peptide-1 receptor agonist cardiovascular outcome trials to date. Its results were analyzed to estimate the combined effect of SGLT2 inhibitors and efpeglenatide on clinical outcomes.Methods: Cardiovascular and renal outcomes were analyzed with Cox proportional hazards models adjusted for region, SGLT2 inhibitor randomization strata, and the SGLT2 inhibitor-by-treatment interaction. Continuous variables were analyzed with a mixed-effects models for repeated measures that also included an interaction term.Results: The effect (hazard ratio [95% CI]) of efpeglenatide versus placebo in the absence and presence of baseline SGLT2 inhibitors on MACEs (0.74 [0.58-0.94] and 0.70 [0.37-1.30], respectively), expanded MACEs (0.77 [0.62-0.96] and 0.87 [0.51-1.48]), renal composite (0.70 [0.59-0.83] and 0.52 [0.33-0.83]), and MACEs or death (0.74 [0.59-0.93] and 0.65 [0.36-1.19]) did not differ by baseline SGLT2 inhibitor use (P for all interactions >0.2). The reduction of blood pressure, body weight, low-density lipoprotein cholesterol, and urinary albumin-to-creatinine ratio by efpeglenatide also appeared to be independent of concurrent SGLT2 inhibitor use (all interaction P≥0.08). Last, adverse events did not differ by baseline SGLT2 inhibitor use.Conclusions: The efficacy and safety of efpeglenatide appear to be independent of concurrent SGLT2 inhibitor use. These data support combined SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist therapy in type 2 diabetes. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03496298. [ABSTRACT FROM AUTHOR] more...

Schematic showing a suggested approach to heart failure treatment across the ejection fraction spectrum, where some therapies are used in the presence of reduced LV contractility or eccentric LV remodeling, whereas others are used to address the congestive state regardless of ejection fraction. Keywords: heart failure EN heart failure 1193 1195 3 10/19/22 20221018 NES 221018 For decades, ejection fraction (EF) has been the principal metric we use to clinically characterize cardiac function, and yet its use to phenotype heart failure (HF) has hindered our understanding of the syndrome and its possible therapies. [Extracted from the article] more...

Since Singapore became an independent nation in 1965, the development of its health-care system has been underpinned by an emphasis on personal responsibility for health, and active government intervention to ensure access and affordability through targeted subsidies and to reduce unnecessary costs. Singapore is achieving good health outcomes, with a total health expenditure of 4·47% of gross domestic product in 2016. However, the health-care system is contending with increased stress, as reflected in so-called pain points that have led to public concern, including shortages in acute hospital beds and intermediate and long-term care (ILTC) services, and high out-of-pocket payments. The main drivers of these challenges are the rising prevalence of non-communicable diseases and rapid population ageing, limitations in the delivery and organisation of primary care and ILTC, and financial incentives that might inadvertently impede care integration. To address these challenges, Singapore's Ministry of Health implemented a comprehensive set of reforms in 2012 under its Healthcare 2020 Masterplan. These reforms substantially increased the capacity of public hospital beds and ILTC services in the community, expanded subsidies for primary care and long-term care, and introduced a series of financing health-care reforms to strengthen financial protection and coverage. However, it became clear that these measures alone would not address the underlying drivers of system stress in the long term. Instead, the system requires, and is making, much more fundamental changes to its approach. In 2016, the Ministry of Health encapsulated the required shifts in terms of the so-called Three Beyonds-namely, beyond health care to health, beyond hospital to community, and beyond quality to value. [ABSTRACT FROM AUTHOR] more...

The recent U.S. Food and Drug Administration expanded indication for sacubitril/valsartan introduces a new potential taxonomy for heart failure, with no reference to "preserved" ejection fraction but referring to "below normal" ejection fraction as those most likely to benefit. This review summarizes the evolution of nomenclature in heart failure and examines evidence showing that patients with ejection fraction in the "mid range" may benefit from neurohormonal blockade similar to those with more severely reduced (<40%) ejection fraction. Furthermore, prominent sex differences have been observed wherein the benefit of neurohormonal blockade appears to extend to a higher ejection fraction range in women compared to men. Based on emerging evidence, revised nomenclature is proposed defining heart failure with "reduced" (<40%), "mildly reduced," and "normal" (≥55% in men, ≥60% in women) ejection fraction. Such nomenclature signals consideration of potentially beneficial therapies in the largest group of patients with reduced or mildly reduced ejection fraction. [ABSTRACT FROM AUTHOR] more...

This study of real‐world data from the Maccabi database in Israel compared the risk of heart failure hospitalization (HHF) or death in patients with type 2 diabetes (T2D) initiating sodium‐glucose cotransporter‐2 (SGLT2) inhibitors versus other glucose‐lowering drugs (OGLDs) according to baseline left ventricular (LV) ejection fraction (EF). After propensity‐matching patients by baseline EF there were 10 614 episodes of treatment initiation; 57% had diabetes for >10 years, the mean glycated haemoglobin level was 66 mmol/mol (8.2%), ∼43% had cardiovascular disease, ∼7% had heart failure and ∼ 20% had chronic kidney disease. A total of 2876 patients (∼9%) had reduced EF (<50%). Over a mean follow‐up of 1.5 years there were 371 HHFs or deaths, 88 (23.7%) in patients with reduced EF. Initiation of SGLT2 inhibitors versus OGLDs was associated with lower risk of HHF or death overall (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.46‐0.70]; P < 0.001) and in patients with both reduced EF (HR 0.61, 95% CI 0.40‐0.93) and preserved EF (HR 0.55, 95% CI 0.43‐0.70), with no significant heterogeneity (Pinteraction = 0.72). Our findings from real‐world clinical practice show that the lower risk of HHF and death associated with use of SGLT2 inhibitors versus OGLDs is consistent in T2D patients with both reduced and preserved EF. [ABSTRACT FROM AUTHOR] more...

Aims: D‐dimer is a marker of fibrin degradation that reflects intravascular coagulation. Therefore, plasma concentrations of D‐dimer might predict thromboembolic risk and rivaroxaban treatment effect. The aims of this study were to investigate the association between D‐dimer levels and the risk of stroke and other thrombotic, bleeding and fatal events, and whether D‐dimer concentrations could predict rivaroxaban 2.5 mg twice daily (vs. placebo) effect in patients enrolled in the COMMANDER‐HF trial who were in sinus rhythm, had heart failure with reduced ejection fraction and coronary artery disease. Methods and results: Survival models with treatment‐by‐plasma D‐dimer interaction. Baseline measurement of D‐dimer was available in 4107 (82%) of 5022 patients enrolled. Median (percentile25–75) follow‐up was 21 (12.9–32.8) months. The median (percentile25–75) plasma concentration of D‐dimer was 360 (215–665) ng/mL. The D‐dimer tertiles were: (i) ≤255 ng/mL; (ii) 256–515 ng/mL; and (iii) >515 ng/mL. Patients within the tertile 3 were older, and had lower body mass index, blood pressure, haemoglobin, estimated glomerular filtration rate, and left ventricular ejection fraction. Higher plasma D‐dimer concentrations were independently associated with higher rates of death, stroke, and venous thromboembolism. For example, the all‐cause death adjusted hazard ratio (HR) (95%CI) of tertile 3 vs. tertile 1 was 1.77 [95% confidence interval (CI) 1.48–2.11; P < 0.001]. The effect of rivaroxaban was similar in each tertile of D‐dimer for all outcomes except stroke. Patients within the tertile 3 had the greatest absolute and relative stroke reduction (tertile 1: HR 1.16, 95% CI 0.49–2.74; tertile 2: HR 1.45, 95% CI 0.77–2.73; tertile 3: HR 0.36, 95% CI 0.18–0.70; P for interaction = 0.008). The number‐needed‐to‐treat to prevent one stroke in tertile 3 was 36. Conclusions: In COMMANDER‐HF, rivaroxaban reduced the risk of stroke but the benefit may be confined to patients with D‐dimer concentrations above 515 ng/mL. Prospective trials are warranted to confirm these findings. [ABSTRACT FROM AUTHOR] more...

Impaired left atrial (LA) function in heart failure with preserved ejection fraction (HFpEF) is associated with adverse outcomes. A subgroup of HFpEF may have LA myopathy out of proportion to left ventricular (LV) dysfunction; therefore, we sought to characterize HFpEF patients with disproportionate LA myopathy. In the prospective, multicenter, Prevalence of Microvascular Dysfunction in HFpEF study, we defined disproportionate LA myopathy based on degree of LA reservoir strain abnormality in relation to LV myopathy (LV global longitudinal strain [GLS]) by calculating the residuals from a linear regression of LA reservoir strain and LV GLS. We evaluated associations of disproportionate LA myopathy with hemodynamics and performed a plasma proteomic analysis to identify proteins associated with disproportionate LA myopathy; proteins were validated in an independent sample. Disproportionate LA myopathy correlated with better LV diastolic function but was associated with lower stroke volume reserve after passive leg raise independent of atrial fibrillation (AF). Additionally, disproportionate LA myopathy was associated with higher pulmonary artery systolic pressure, higher pulmonary vascular resistance, and lower coronary flow reserve. Of 248 proteins, we identified and validated 5 proteins (involved in cardiomyocyte stretch, extracellular matrix remodeling, and inflammation) that were associated with disproportionate LA myopathy independent of AF. In HFpEF, LA myopathy may exist out of proportion to LV myopathy. Disproportionate LA myopathy is a distinct HFpEF subtype associated with worse hemodynamics and a distinct proteomic signature, independent of AF. [ABSTRACT FROM AUTHOR] more...

Importance: Patients with heart failure and preserved ejection fraction (HFpEF) are at high risk of mortality, hospitalizations, and reduced functional capacity and quality of life.d>Objective: To assess the efficacy of the oral soluble guanylate cyclase stimulator vericiguat on the physical limitation score (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ).Design, Setting, and Participants: Phase 2b randomized, double-blind, placebo-controlled, multicenter trial of 789 patients with chronic HFpEF and left ventricular ejection fraction 45% or higher with New York Heart Association class II-III symptoms, within 6 months of a recent decompensation (HF hospitalization or intravenous diuretics for HF without hospitalization), and with elevated natriuretic peptides, enrolled at 167 sites in 21 countries from June 15, 2018, through March 27, 2019; follow-up was completed on November 4, 2019.Interventions: Patients were randomized to receive vericiguat, up-titrated to 15-mg (n = 264) or 10-mg (n = 263) daily oral dosages, compared with placebo (n = 262) and randomized 1:1:1.Main Outcomes and Measures: The primary outcome was change in the KCCQ PLS (range, 0-100; higher values indicate better functioning) after 24 weeks of treatment. The secondary outcome was 6-minute walking distance from baseline to 24 weeks.Results: Among 789 randomized patients, the mean age was 72.7 (SD, 9.4) years; 385 (49%) were female; mean EF was 56%; and median N-terminal pro-brain natriuretic peptide level was 1403 pg/mL; 761 (96.5%) completed the trial. The baseline and 24-week KCCQ PLS means for the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 60.0 and 68.3, 57.3 and 69.0, and 59.0 and 67.1, respectively, and the least-squares mean changes were 5.5, 6.4, and 6.9, respectively. The least-squares mean difference in scores between the 15-mg/d vericiguat and placebo groups was -1.5 (95% CI, -5.5 to 2.5; P = .47) and between the 10-mg/d vericiguat and placebo groups was -0.5 (95% CI, -4.6 to 3.5; P = .80). The baseline and 24-week 6-minute walking distance mean scores in the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 295.0 m and 311.8m , 292.1 m and 318.3 m, and 295.8 m and 311.4 m, and the least-squares mean changes were 5.0 m, 8.7 m, and 10.5 m, respectively. The least-squares mean difference between the 15-mg/d vericiguat and placebo groups was -5.5 m (95% CI, -19.7 m to 8.8 m; P = .45) and between the 10-mg/d vericiguat and placebo groups was -1.8 m (95% CI, -16.2 m to 12.6 m; P = .81), respectively. The proportions of patients who experienced symptomatic hypotension were 6.4% in the 15-mg/d vericiguat group, 4.2% in the 10-mg/d vericiguat group, and 3.4% in the placebo group; those with syncope were 1.5%, 0.8%, and 0.4%, respectively.Conclusions and Relevance: Among patients with HFpEF and recent decompensation, 24-week treatment with vericiguat at either 15-mg/d or 10-mg/d dosages compared with placebo did not improve the physical limitation score of the KCCQ.Trial Registration: ClinicalTrials.gov Identifier: NCT03547583. [ABSTRACT FROM AUTHOR] more...

Accumulating evidence points to the existence of an inflammatory‐metabolic phenotype of heart failure with a preserved ejection fraction (HFpEF), which is characterized by biomarkers of inflammation, an expanded epicardial adipose tissue mass, microvascular endothelial dysfunction, normal‐to‐mildly increased left ventricular volumes and systolic blood pressures, and possibly, altered activity of adipocyte‐associated inflammatory mediators. A broad range of adipogenic metabolic and systemic inflammatory disorders – e.g. obesity, diabetes and metabolic syndrome as well as rheumatoid arthritis and psoriasis – can cause this phenotype, independent of the presence of large vessel coronary artery disease. Interestingly, when compared with men, women are both at greater risk of and may suffer greater cardiac consequences from these systemic inflammatory and metabolic disorders. Women show disproportionate increases in left ventricular filling pressures following increases in central blood volume and have greater arterial stiffness than men. Additionally, they are particularly predisposed to epicardial and intramyocardial fat expansion and imbalances in adipocyte‐associated proinflammatory mediators. The hormonal interrelationships seen in inflammatory‐metabolic phenotype may explain why mineralocorticoid receptor antagonists and neprilysin inhibitors may be more effective in women than in men with HFpEF. Recognition of the inflammatory‐metabolic phenotype may improve an understanding of the pathogenesis of HFpEF and enhance the ability to design clinical trials of interventions in this heterogeneous syndrome. [ABSTRACT FROM AUTHOR] more...

How to Incorp... Sex differences in pharmacokinetics and pharmacodynamics are rarely considered in determination of trial dose selection. Female patients have a higher bleeding risk with anticoagulation and antiplatelet therapies than male patients, with significant mortality risk associated with these bleeding events. [Extracted from the article] more...

The article offers information on the U.S. Food and Drug Administration guidance recommended rigorous evaluations of cardiovascular safety for new glucose-lowering therapies. It mentions the cardiovascular outcome trials (CVOTs) have shown benefits with regard to the progression of chronic kidney disease; and also mentions clinicians are reminded that sodium-glucose cotransporter 2 inhibitors (SGLT2) have emerged as powerful cardiovascular therapies. more...

Abstract Cardiac troponin is a sensitive and specific biomarker for acute myocardial injury and has been used in the diagnosis of acute coronary syndromes, and has emerged as a tool for identifying high risk individuals for primary preventive therapy. Recent evidence has emerged indicating that high-sensitivity cardiac troponin assays, which allow robust detection of very low troponin concentrations, could detect subclinical injury in asymptomatic patients. On 24 March 2018, a group of cardiologists from the Asia Pacific region convened to review the data and discuss the potential utility of high-sensitivity troponin I (hsTnI) in the risk assessment of cardiovascular disease in the general population. The group recognized the immense burden of cardiovascular disease in the Asia-Pacific region, and the limitations of current risk stratification strategies. Data demonstrates that cardiac biomarkers like hsTnI could improve risk stratification, and thresholds for hsTnI in cardiovascular disease risk classification have been developed in Caucasian populations but not validated in Asian populations. There is an urgent need to improve cardiovascular risk assessment in the Asia Pacific general population, validate the Asian threshold of high risk and prove the utility of targeting these high-risk individuals for primary preventive strategies. Highlights • The global burden of cardiovascular disease is burgeoning in Asia Pacific • Current cardiovascular disease risk stratification strategies are inadequate • Cardiac biomarkers may improve cardiovascular risk assessment in the population • There is an urgent need to validate biomarker risk thresholds in Asian populations [ABSTRACT FROM AUTHOR] more...

This article discusses the potential differences in optimal doses of heart failure medications between women and men. It highlights the biological factors that may contribute to these differences, such as variations in body composition, drug absorption, metabolism, and elimination. The article presents findings from observational studies that suggest women may require lower doses than men to achieve significant clinical benefits, particularly for certain medications. However, it emphasizes the need for further research and the inclusion of sex-specific data on adverse effects to establish truly personalized and effective treatment guidelines for both women and men with heart failure. The article also addresses the existing disparities in the treatment of women with heart failure and calls for more representative inclusion of women in clinical trials. [Extracted from the article] more...

Background: Randomized trials demonstrated a lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high CV risk. Prior real-world data suggested similar SGLT-2i effects in T2D patients with a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe.Objectives: The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions.Methods: New users of SGLT-2i and oGLDs were identified via claims, medical records, and national registries in South Korea, Japan, Singapore, Israel, Australia, and Canada. Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching. Hazard ratios (HRs) for death, hospitalization for heart failure (HHF), death or HHF, MI, and stroke were assessed by country and pooled using weighted meta-analysis.Results: After propensity-matching, there were 235,064 episodes of treatment initiation in each group; ∼27% had established CV disease. Patient characteristics were well-balanced between groups. Dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin accounted for 75%, 9%, 8%, 4%, 3%, and 1% of exposure time in the SGLT-2i group, respectively. Use of SGLT-2i versus oGLDs was associated with a lower risk of death (HR: 0.51; 95% confidence interval [CI]: 0.37 to 0.70; p < 0.001), HHF (HR: 0.64; 95% CI: 0.50 to 0.82; p = 0.001), death or HHF (HR: 0.60; 95% CI: 0.47 to 0.76; p < 0.001), MI (HR: 0.81; 95% CI: 0.74 to 0.88; p < 0.001), and stroke (HR: 0.68; 95% CI: 0.55 to 0.84; p < 0.001). Results were directionally consistent across both countries and patient subgroups, including those with and without CV disease.Conclusions: In this large, international study of patients with T2D from the Asia Pacific, the Middle East, and North America, initiation of SGLT-2i was associated with a lower risk of CV events across a broad range of outcomes and patient characteristics. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614). [ABSTRACT FROM AUTHOR] more...

Aim: Steroidal mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, are strongly recommended in the treatment of patients with chronic heart failure (HF) with reduced left ventricular ejection fraction (LVEF), but the balance of efficacy and safety in those with higher LVEF has not been well established. Broad use of steroidal MRAs has further been limited in part due to safety concerns around risks of hyperkalaemia, gynecomastia, and kidney dysfunction. These risks may be mitigated by the unique pharmacological properties of the non‐steroidal MRA finerenone. The FINEARTS‐HF trial is designed to evaluate the long‐term efficacy and safety of the selective non‐steroidal MRA finerenone among patients with HF with mildly reduced or preserved ejection fraction. Methods: FINEARTS‐HF is a global, multicentre, event‐driven randomized trial evaluating oral finerenone versus matching placebo in symptomatic patients with HF with LVEF ≥40%. Adults (≥40 years) with HF with New York Heart Association class II–IV symptoms, LVEF ≥40%, evidence of structural heart disease, and diuretic use for at least the previous 30 days were eligible. All patients required elevated natriuretic peptide levels: for patients in sinus rhythm, N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) ≥300 pg/ml (or B‐type natriuretic peptide [BNP] ≥100 pg/ml) were required, measured within 30 days (in those without a recent worsening HF event) or within 90 days (in those with a recent worsening HF event). Qualifying levels of NT‐proBNP or BNP were tripled if a patient was in atrial fibrillation at screening. Estimated glomerular filtration rate <25 ml/min/1.73 m2 or serum potassium >5.0 mmol/L were key exclusion criteria. Patients were enrolled irrespective of clinical care setting (whether hospitalized, recently hospitalized, or ambulatory). The primary endpoint is the composite of cardiovascular death and total (first and recurrent) HF events. The trial started on 14 September 2020 and has validly randomized 6001 participants across 37 countries. Approximately 2375 total primary composite events are targeted. Conclusions: The FINEARTS‐HF trial will determine the efficacy and safety of the non‐steroidal MRA finerenone in a broad population of hospitalized and ambulatory patients with HF with mildly reduced or preserved ejection fraction. Clinical Trial Registration: ClinicalTrials.gov NCT04435626 and EudraCT 2020‐000306‐29. [ABSTRACT FROM AUTHOR] more...

Heart failure remains a leading cause of morbidity and mortality globally. Within the last 5 years, many new developments have been seen in the area of heart failure, including completely new therapies, mechanistic insights, as well as novel strategies to phenotype and segment the condition. Borlaug I et al i .[1] focus on the emerging problem of obesity and heart failure with preserved ejection fraction (HFpEF), which represents indeed one of the greatest unmet health problems in the field of cardiovascular medicine in the 21st century. [Extracted from the article] more...

Background: Right ventricular (RV) dysfunction is recognized as a major prognostic factor in left-sided heart failure (HF). However, the relative contribution of RV dysfunction in HF with preserved (HFpEF) vs. reduced ejection fraction (HFrEF) is unclear. Methodsand results: Right ventricular longitudinal strain (RVLS), tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) were determined by echocardiography in 657 age- and gender-matched groups of patients with HFpEF [left ventricular ejection fraction (LVEF) =50%; n=219] and HFrEF (LVEF <50%; n=219) and in controls without HF (n=219) from an Asian population-based cohort study. Across control to HFpEF and HFrEF groups, RV function deteriorated as measured by RVLS (-26.7±5%, -22.7±6.6% and -18.2±6.7%, respectively) and TAPSE (21.0±3.9, 17.5±5.1 and 14.7±4.7 mm, respectively), whereas PASP increased (26.8±7.1, 34.5±11.9 and 39.3±16.2 mmHg, respectively) (all P<0.001). Controlling for PASP in control, HFpEF and HFrEF subjects, the magnitude of RVLS/PASP (-1.06±0.32, -0.75±0.32 and -0.56±0.36, respectively) and TAPSE/PASP ratios (0.83±0.23, 0.54±0.24 and 0.55±0.29, respectively) similarly decreased across groups. Right ventricular dysfunction (by both TAPSE and RVLS) was independently associated with left ventricular systolic dysfunction and atrial fibrillation, but not with PASP. Among patients with HF, both TAPSE/PASP and RVLS/PASP ratios were related to the composite endpoint of all-cause death and HF hospitalization, even after multivariable adjustment [hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.14-0.74 and HR 3.09; 95% CI 1.52-6.26, respectively], with no difference between HFrEF and HFpEF. Conclusions: Right ventricular dysfunction is present in HFpEF and is even more pronounced in HFrEF for any given degree of pulmonary hypertension. It is independently predicted by left ventricular dysfunction but not by PASP. Right ventricular-arterial coupling is prognostically important in HF regardless of LVEF. [ABSTRACT FROM AUTHOR] more...

Background: Right ventricular (RV) dysfunction is recognized as a major prognostic factor in left-sided heart failure (HF). However, the relative contribution of RV dysfunction in HF with preserved (HFpEF) vs. reduced ejection fraction (HFrEF) is unclear.Methods and Results: Right ventricular longitudinal strain (RVLS), tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) were determined by echocardiography in 657 age- and gender-matched groups of patients with HFpEF [left ventricular ejection fraction (LVEF) ≥50%; n=219] and HFrEF (LVEF <50%; n=219) and in controls without HF (n=219) from an Asian population-based cohort study. Across control to HFpEF and HFrEF groups, RV function deteriorated as measured by RVLS (-26.7 ± 5%, -22.7±6.6% and -18.2 ± 6.7%, respectively) and TAPSE (21.0 ± 3.9, 17.5 ± 5.1 and 14.7 ± 4.7 mm, respectively), whereas PASP increased (26.8 ± 7.1, 34.5 ± 11.9 and 39.3 ± 16.2 mmHg, respectively) (all P<0.001). Controlling for PASP in control, HFpEF and HFrEF subjects, the magnitude of RVLS/PASP (-1.06 ± 0.32, -0.75 ± 0.32 and -0.56 ± 0.36, respectively) and TAPSE/PASP ratios (0.83 ± 0.23, 0.54 ± 0.24 and 0.55 ± 0.29, respectively) similarly decreased across groups. Right ventricular dysfunction (by both TAPSE and RVLS) was independently associated with left ventricular systolic dysfunction and atrial fibrillation, but not with PASP. Among patients with HF, both TAPSE/PASP and RVLS/PASP ratios were related to the composite endpoint of all-cause death and HF hospitalization, even after multivariable adjustment [hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.14-0.74 and HR 3.09; 95% CI 1.52-6.26, respectively], with no difference between HFrEF and HFpEF.Conclusions: Right ventricular dysfunction is present in HFpEF and is even more pronounced in HFrEF for any given degree of pulmonary hypertension. It is independently predicted by left ventricular dysfunction but not by PASP. Right ventricular-arterial coupling is prognostically important in HF regardless of LVEF. [ABSTRACT FROM AUTHOR] more...

Aims: During right heart catheterization, pulmonary artery wedge pressure (PAWP) is often assumed to reflect left ventricular filling pressure. We sought to determine the impact of atrial fibrillation (AF) on the relationship between PAWP and left ventricular filling pressure, as measured by left ventricular end-diastolic pressure (LVEDP).Methods and Results: We performed simultaneous left and right heart catheterization in 123 patients (mean age 69 years, 28% with AF) referred for suspicion of pulmonary hypertension (PH). The correlation between PAWP and LVEDP was moderate (R2 = 0.42). The relationship between PAWP and LVEDP was modified by heart rhythm (P for interaction <0.01). In sinus rhythm, PAWP underestimated LVEDP (Bland-Altman mean difference: -2.96 mmHg, limits of agreement 6.6 to -12.5; R2  = 0.54), whereas in AF, PAWP overestimated LVEDP (Bland-Altman mean difference: 4.76 mmHg; limits of agreement: 12.2 to -3.3; R2 = 0.58). These differences impacted the differentiation between pre- and post-capillary PH, dependent on the use of either PAWP or LVEDP. In AF, post-capillary PH based on PAWP would have been classified as pre-capillary PH in 35% of patients if based on LVEDP. The opposite is true for sinus rhythm where 31% of pre-capillary PH based on PAWP would have been classified as post-capillary PH if based on LVEDP.Conclusion: The relationship between PAWP and LVEDP varies by heart rhythm, with PAWP being higher than LVEDP among AF patients and lower than LVEDP among patients in sinus rhythm. Rhythm status and influences on the PAWP-LVEDP relationship should be considered when distinguishing between pre-capillary and post-capillary PH. [ABSTRACT FROM AUTHOR] more...

Aims During right heart catheterization, pulmonary artery wedge pressure (PAWP) is often assumed to reflect left ventricular filling pressure. We sought to determine the impact of atrial fibrillation (AF) on the relationship between PAWP and left ventricular filling pressure, as measured by left ventricular end-diastolic pressure (LVEDP). Methods and results We performed simultaneous left and right heart catheterization in 123 patients (mean age 69 years, 28% with AF) referred for suspicion of pulmonary hypertension (PH). The correlation between PAWP and LVEDP was moderate (R2 = 0.42). The relationship between PAWP and LVEDP was modified by heart rhythm (P for interaction <0.01). In sinus rhythm, PAWP underestimated LVEDP (Bland-Altman mean difference: -2.96 mmHg, limits of agreement 6.6 to -12.5; R2 =0.54), whereas in AF, PAWP overestimated LVEDP (Bland-Altman mean difference: 4.76 mmHg; limits of agreement: 12.2 to -3.3; R2 = 0.58). These differences impacted the differentiation between pre- and post-capillary PH, dependent on the use of either PAWP or LVEDP. In AF, post-capillary PH based on PAWP would have been classified as pre-capillary PH in 35% of patients if based on LVEDP. The opposite is true for sinus rhythm where 31% of pre-capillary PH based on PAWP would have been classified as post-capillary PH if based on LVEDP. Conclusion The relationship between PAWP and LVEDP varies by heart rhythm, with PAWP being higher than LVEDP among AF patients and lower than LVEDP among patients in sinus rhythm. Rhythm status and influences on the PAWP-LVEDP relationship should be considered when distinguishing between pre-capillary and post-capillary PH. [ABSTRACT FROM AUTHOR] more...

An introduction is presented in which the editor discusses articles in the issue on topics including research for obese heart failure, risk factors in diagnosis of heart failure with preserved ejection fraction (HFpEF) and medications in patients with cardiac arrest. more...

Atrial fibrillation (AF) and heart failure with a preserved ejection fraction (HFpEF) are closely intertwined disorders that afflict millions of people, many of whom are obese or have diabetes mellitus or other proinflammatory conditions. These relationships may reflect the fact that patients with both AF and HFpEF have a more advanced stage of the underlying myopathy than patients with only AF or only HFpEF. [Extracted from the article] more...

Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) are age-related conditions that are increasing in prevalence, commonly coexist, and share clinical features. This review provides a practical update on the epidemiology, pathophysiology, diagnosis, and management of patients with concomitant HFpEF and AF. Epidemiological studies highlight the close and complex links between HFpEF and AF, the shared risk factors, the high AF occurrence in the natural history of HFpEF, and the independent contribution of each condition to poor outcomes. Diagnosis of HFpEF in the setting of AF is challenging because the symptoms overlap. AF is associated with changes in echocardiographic parameters and circulating natriuretic peptides that confound HFpEF diagnosis. Symptomatic improvement with diuretic therapy supports the presence of HFpEF in patients with concomitant AF. Important knowledge gaps need to be addressed by a multidisciplinary and translational research approach to develop novel therapies that can improve prognosis. [ABSTRACT FROM AUTHOR] more...

In a Guest Editorial, Kazem Rahimi, Carolyn Lam, and Steven Steinhubl call for interdisciplinary research and personalized cardiovascular care to better manage patients with cardiovascular disease and multimorbidity. [ABSTRACT FROM AUTHOR] more...

The article discusses the authors' views on the increasing role of podcasting as a form of digital communication platform for the dissemination of evidence-based medicine and in sharing clinical knowledge. They explain the potential of social media for medical audiences in reviewing information when they want, where the want, and how they want. The authors have identified the factors affecting medical review of medical podcasts that affect listening quality. more...

Background: We examined the association of sex with clinical characteristics and outcomes in patients following myocardial infarction (MI) in the Valsartan in Acute Myocardial Infarction Trial (VALIANT). Methods and Results: A total of 4570 women and 10 133 men with heart failure (HF), left ventricular systolic dysfunction or both were enrolled 0.5-10 days after myocardial infarction (MI) and followed for a median of 24.7 months. Compared with men, women were older, had more comorbidities, and were more likely to present in Killip Class III/IV and experience post-infarction angina or HF. After adjusting for baseline differences, both short-term and longer-term mortality were similar in men and women. However, women were more likely than men to experience the composite outcome of cardiovascular death, MI, HF, stroke, and resuscitation from cardiac arrest [adjusted hazard ratio (HR) 1.15; 95% confidence interval (CI); 1.06-1.24, P=0.001], mainly owing to an increased risk of hospitalization for HF (adjusted HR 1.36; 95% CI 1.22-1.52; P<0.001). In a subset of patients who underwent echocardiographic study (n=603), women had smaller left ventricular volumes indexed by body size than men but similar ejection fractions and similar changes in ventricular volumes from baseline to 1 month and 20 months. Conclusions: In VALIANT, the risk of HF following MI was higher in women than men after adjusting for age and comorbidities, although the risk of other fatal and non-fatal outcomes were similar. The higher long-term risk of HF in women appears to be independent of the extent of left ventricular systolic dysfunction or remodelling compared with men. [ABSTRACT FROM AUTHOR] more...

Background We examined the association of sex with clinical characteristics and outcomes in patients following myocardial infarction ( MI) in the Valsartan in Acute Myocardial Infarction Trial ( VALIANT). Methods and Results A total of 4570 women and 10 133 men with heart failure ( HF), left ventricular systolic dysfunction or both were enrolled 0.5-10 days after myocardial infarction ( MI) and followed for a median of 24.7 months. Compared with men, women were older, had more comorbidities, and were more likely to present in Killip Class III/ IV and experience post-infarction angina or HF. After adjusting for baseline differences, both short-term and longer-term mortality were similar in men and women. However, women were more likely than men to experience the composite outcome of cardiovascular death, MI, HF, stroke, and resuscitation from cardiac arrest [adjusted hazard ratio ( HR) 1.15; 95% confidence interval ( CI); 1.06-1.24, P = 0.001], mainly owing to an increased risk of hospitalization for HF (adjusted HR 1.36; 95% CI 1.22-1.52; P < 0.001). In a subset of patients who underwent echocardiographic study ( n = 603), women had smaller left ventricular volumes indexed by body size than men but similar ejection fractions and similar changes in ventricular volumes from baseline to 1 month and 20 months. Conclusions In VALIANT, the risk of HF following MI was higher in women than men after adjusting for age and comorbidities, although the risk of other fatal and non-fatal outcomes were similar. The higher long-term risk of HF in women appears to be independent of the extent of left ventricular systolic dysfunction or remodelling compared with men. [ABSTRACT FROM AUTHOR] more...

Aims Women are more likely to develop heart failure with preserved ejection fraction ( HFpEF) than men. We studied the relationship between sex and cardiovascular structure and function in patients with HFpEF. Methods and results The study included 279 participants from the PARAMOUNT study (57% women) with analysable baseline echocardiograms (mean age 71 years, 94% hypertensive, 38% diabetic). We assessed sex-based differences in baseline clinical characteristics and measures of cardiovascular structure/function. Coronary artery disease was less common in women than in men. Women were more obese and symptomatic, and less likely to have albuminuria. Women had higher indexed left ventricular ( LV) wall thicknesses, worse diastolic function (lower E′, P = 0.002; higher E/E′, P < 0.001), while LV mass and LV volumes indexed for height2.7 were similar. Nonetheless, female sex was associated with a trend towards higher prevalence of abnormal LV geometry (defined as concentric hypertrophy, or eccentric hypertrophy, or concentric remodelling) at baseline (unadjusted P = 0.028, adjusted P = 0.056) and 12 weeks' follow up (unadjusted P = 0.001, adjusted P = 0.006), but not at 36 weeks' follow up (unadjusted P = 0.81, adjusted P = 0.99). Despite higher LV ejection fraction in women, global LV strain was similar between the sexes, while Tissue Doppler Imaging S′ mitral velocity was lower in women. Both LV diastolic and systolic stiffness were higher in women than men ( P < 0.001), even adjusting for LV concentricity and clinical covariates. We observed no sex differences in systolic arterial- LV coupling, as women also had higher absolute arterial elastance compared with men, although this difference was not significant after adjusting for height2.7. Conclusion More pronounced diastolic dysfunction may contribute to the greater predisposition for HFpEF in women compared with men. [ABSTRACT FROM AUTHOR] more...

The absence of an interaction means that the effects of the 2 drugs are independent of each other, and, therefore, the effect of efpeglenatide occurred on top of the effect of the SGLT2 inhibitors. Article Information Sources of Funding The AMPLITUDE-O trial (Effect of Efpeglenatide on Cardiovascular Outcomes) was funded by Sanofi. Groothof et al note that the Kaplan-Meier curves for the subgroup of individuals receiving sodium-glucose cotransporter-2 (SGLT2) inhibitors at baseline cross in Figure A and D.[1] This is because of the relatively small number of major adverse cardiovascular event outcomes (n=42; Table S2) that occurred in that subgroup during follow-up and is unrelated to the question of proportionality. [Extracted from the article] more...

Aims Our aim is to determine mortality and morbidity in Asian patients under clinical management for heart failure (HF). Specifically, we will define the incidence of, and risk factors for, sudden cardiac death, as well as the socio-cultural factors influencing therapeutic choices in these patients. Methods This is a prospective observational multinational Asian registry of 5000 patients with symptomatic HF (stage C) and LV systolic dysfunction (EF ≤ 40%) involving 44 centres across 11 Asian regions (China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Philippines, Singapore, Taiwan and Thailand). Data collection includes demographic variables, clinical symptoms, functional status, date of HF diagnosis and prior cardiovascular investigations, clinical risk factors, lifestyle factors, socio-economic status, and survey of cultural beliefs, health practices, and attitudes towards device therapy. Centre-level characteristics (case load, referral pattern, specialization, and infrastructure) are also obtained. Patients uniformly undergo standard 12-lead ECG and transthoracic echocardiography at baseline, and are followed over 3 years for outcomes of death or hospitalization. The mode of death and cause of hospitalization are adjudicated by a central event adjudication committee using pre-specified criteria. Perspective By providing prospective data regarding the demographics, risk factors, and outcomes of Asian patients under treatment for HF, the ASIAN-HF registry is expected to advance fundamental understanding of the burden and predictors of death and hospitalization among these patients. The knowledge gained will be important for guiding resource allocation and planning preventive strategies to address the unmet and growing clinical needs of patients with cardiovascular disease in Asia. Trial registration NCT01633398 [ABSTRACT FROM AUTHOR] more...

Understanding how patients with heart failure with preserved ejection fraction (HFPEF) die provides insight into the natural history and pathophysiology of this complex syndrome, thereby allowing better prediction of response to therapy in designing clinical trials. This review summarizes the current state of knowledge surrounding mortality rates, modes of death, and prognostic factors in HFPEF. Despite the lack of uniform reporting, the following conclusions may be drawn from previous studies. The mortality burden of HFPEF is substantial, ranging from 10% to 30% annually, and higher in epidemiological studies than in clinical trials. Mortality rates compared with heart failure with reduced ejection fraction (HFREF) appear to be strongly influenced by the type of study, but are clearly elevated compared with age- and co-morbidity-matched controls without heart failure. The majority of deaths in HFPEF are cardiovascular deaths, comprising 51–60% of deaths in epidemiological studies and ∼70% in clinical trials. Among cardiovascular deaths, sudden death and heart failure death are the leading cardiac modes of death in HFPEF clinical trials. Compared with HFREF, the proportions of cardiovascular deaths, sudden death, and heart failure deaths are lower in HFPEF. Conversely, non-cardiovascular deaths constitute a higher proportion of deaths in HFPEF than in HFREF, particularly in epidemiological studies, where this difference may be related to fewer coronary heart deaths in HFPEF. Key mortality risk factors, including age, gender, body mass index, burden of co-morbidities, and coronary artery disease, offer some explanation for the differences in mortality rates observed across studies. [ABSTRACT FROM AUTHOR] more...