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Background: Although beta-blockers are not recommended for the treatment of heart failure with preserved ejection fraction (HFpEF) according to the latest European Society of Cardiology and American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines, these therapies remain commonly used for comorbidity management. There has been concern that beta-blockers may adversely influence clinical outcomes by limiting chronotropic response in HFpEF. Objectives: This study sought to examine the contemporary use and implications of beta-blockers in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HFpEF. Methods: In the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, a total of 6,263 patients with symptomatic heart failure (HF) with a left ventricular ejection fraction (LVEF) >40% were randomized to dapagliflozin or placebo across 20 countries. In this prespecified analysis, efficacy and safety outcomes were examined according to beta-blocker use at randomization. The primary outcome was cardiovascular death or worsening HF. Results: Overall, beta-blockers were used in 5,177 patients (83%), with wide variation by geographic region. Beta-blocker use was associated with a lower risk of the primary outcome in covariate-adjusted models (HR: 0.70; 95% CI: 0.60-0.83). Dapagliflozin consistently reduced the risk of the primary outcome in patients taking beta-blockers (HR: 0.82; 95% CI: 0.72-0.94) and in patients not taking beta-blockers (HR: 0.79; 95% CI: 0.61-1.03; Pinteraction = 0.85), with similar findings for key secondary endpoints. Adverse events were balanced between patients randomized to dapagliflozin and placebo, regardless of background beta-blocker use. Conclusions: In patients with HFmrEF or HFpEF who were enrolled in

Introduction:Meta-analyses show postive effects of telemedicine in heart failure (HF) management on hospitalisation, mortality and costs. However, these effects are heterogeneous due to variation in the included HF population, the telemedicine components and the quality of the comparator usual care. Still, telemedicine is gaining acceptance in HF management. The current nationwide study aims to identify (1) in which subgroup(s) of patients with HF telemedicine is (cost-)effective and (2) which components of telemedicine are most (cost-) effective. Methods and analysis:The RELEASE-HF ('REsponsible roLl-out of E-heAlth through Systematic Evaluation -Heart Failure') study is a multicentre, observational, registry-based cohort study that plans to enrol 6480 patients with HF using data from the HF registry facilitated by the Netherlands Heart Registration. Collected data include patient characteristics, treatment information and clinical outcomes, and are measured at HF diagnosis and at 6 and 12 months afterwards. The components of telemedicine are described at the hospital level based on closed-ended interviews with clinicians and at the patient level based on additional data extracted from electronic health records and telemedicine-generated data. The costs of telemedicine are calculated using registration data and interviews with clinicians and finance department staff. To overcome missing data, additional national databases will be linked to the HF registry if feasible. Heterogeneity of the effects of offering telemedicine compared with not offering on days alive without unplanned hospitalisations in 1 year is assessed across predefined patient characteristics using exploratory stratified analyses. The effects of telemedicine components are assessed by fitting separate models for component contrasts. Ethics and dissemination:The study has been approved by the Medical Ethics Committee 2021 of the University Me

Aims: Current heart failure (HF) guidelines recommend to prescribe four drug classes in patients with HF with reduced ejection fraction (HFrEF). A clear challenge exists to adequately implement guideline-directed medical therapy (GDMT) regarding the sequencing of drugs and timely reaching target dose. It is largely unknown how the paradigm shift from a serial and sequential approach for drug therapy to early parallel application of the four drug classes will be executed in daily clinical practice, as well as the reason clinicians may not adhere to new guidelines. We present the design and rationale for the real-world TITRATE-HF study, which aims to assess sequencing strategies for GDMT initiation, dose titration patterns (order and speed), intolerance for GDMT, barriers for implementation, and long-term outcomes in patients with de novo, chronic, and worsening HF. Methods and results: A total of 4000 patients with HFrEF, HF with mildly reduced ejection fraction, and HF with improved ejection fraction will be enrolled in >40 Dutch centres with a follow-up of at least 3 years. Data collection will include demographics, physical examination and vital parameters, electrocardiogram, laboratory measurements, echocardiogram, medication, and quality of life. Detailed information on titration steps will be collected for the four GDMT drug classes. Information will include date, primary reason for change, and potential intolerances. The primary clinical endpoints are HF-related hospitalizations, HF-related urgent visits with a need for intravenous diuretics, all-cause mortality, and cardiovascular mortality. Conclusions: TITRATE-HF is a real-world multicentre longitudinal registry that will provide unique information on contemporary GDMT implementation, sequencing strategies (order and speed), and prognosis in de novo, worsening, and chronic HF patients.

Background: Progressive cardiovascular diseases (eg, heart failure, atrial fibrillation, and coronary artery disease) are often diagnosed late in high-risk individuals with common comorbidities that might mimic or mask symptoms, such as chronic obstructive pulmonary disease (COPD) and type 2 diabetes. We aimed to assess whether a proactive diagnostic strategy consisting of a symptom and risk factor questionnaire and low-cost and accessible tests could increase diagnosis of progressive cardiovascular diseases in patients with COPD or type 2 diabetes in primary care. Methods:In this multicentre, pragmatic, cluster-randomised, controlled trial (RED-CVD), 25 primary care practices in the Netherlands were randomly assigned to usual care or a proactive diagnostic strategy conducted during routine consultations and consisting of a validated symptom questionnaire, followed by physical examination, N-terminal-pro-B-type natriuretic peptide measurement, and electrocardiography. We included adults (≥18 years) with type 2 diabetes, COPD, or both, who participated in a disease management programme. Patients with an established triple diagnosis of heart failure, atrial fibrillation, and coronary artery disease were excluded. In the case of abnormal findings, further work-up or treatment was done at the discretion of the general practitioner. The primary endpoint was the number of newly diagnosed cases of heart failure, atrial fibrillation, and coronary artery disease, adjudicated by an expert clinical outcome committee using international guidelines, at 1-year follow-up, in the intention-to-treat population. Findings: Between Jan 31, 2019, and Oct 7, 2021, we randomly assigned 25 primary care centres: 11 to usual care and 14 to the intervention. We included patients between June 21, 2019, and Jan 31, 2022. Following exclusion of ineligible patients and those who did not give informed consent, 1216 participants were includ

Aim: Inhibition of microRNA (miR)-132 effectively prevents and reverses adverse cardiac remodelling, making it an attractive heart failure (HF) target. CDR132L, a synthetic antisense oligonucleotide selectively blocking pathologically elevated miR-132, demonstrated beneficial effects on left ventricular (LV) structure and function in relevant preclinical models, and was safe and well tolerated in a Phase 1b study in stable chronic HF patients. Patients with acute myocardial infarction (MI) and subsequent LV dysfunction and remodelling have limited therapeutic options, and may profit from early CDR132L treatment. Methods: The HF-REVERT (Phase 2, multicenter, randomized, parallel, 3-arm, placebo-controlled Study to Assess Efficacy and Safety of CDR132L in Patients with Reduced Left Ventricular Ejection Fraction after Myocardial Infarction) evaluates the efficacy and safety of CDR132L in HF patients post-acute MI (n = 280), comparing the effect of 5 and 10 mg/kg CDR132L, administered as three single intravenous doses 28 days apart, in addition to standard of care. Key inclusion criteria are the diagnosis of acute MI, the development of systolic dysfunction (LV ejection fraction ≤45%) and elevated N-terminal pro-B-type natriuretic peptide. The study consists of a 6-month double-blinded treatment period with the primary endpoint LV end-systolic volume index and relevant secondary endpoints, followed by a 6-month open-label observation period. Conclusion: The HF-REVERT trial may underpin the concept of miR-132 inhibition to prevent or reverse cardiac remodelling in post-MI HF. The results will inform the design of subsequent outcome trials to test CDR132L in HF.

Background: Patients with heart failure (HF) with mildly reduced or preserved ejection fraction in Asia may have different clinical characteristics and outcomes compared with patients from other parts of the world.Objectives: The purpose of this study was to investigate the clinical characteristics, safety, and efficacy of dapagliflozin in patients in Asia vs outside Asia in the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial. Methods: In the DELIVER trial, patients with HF and left ventricular ejection fraction >40% were enrolled across 353 sites in 20 countries. The effects of dapagliflozin vs placebo on primary (composite of worsening HF or cardiovascular death) and secondary outcomes were compared in patients from Asia vs outside Asia. Results: Among 6,263 participants, 1,226 (19.6%) were enrolled in Asia. Participants from Asia were less likely to have diabetes, hypertension, history of myocardial infarction, or obesity. After adjusting for clinically relevant characteristics, those in Asia had similar risks of primary composite outcome compared with those from outside Asia (HR: 0.97; 95% CI: 0.82-1.15). Those in Asia had a lower risk of all-cause mortality compared with those enrolled outside Asia (HR: 0.54; 95% CI: 0.44-0.66). Enrollment from Asia did not modify the effect of dapagliflozin on the primary outcome (Pinteraction = 0.54). Serious adverse events and rates of drug discontinuation were also balanced in both treatment arms, irrespective of enrollment in Asia vs outside Asia. Conclusions: In the global DELIVER trial, dapagliflozin reduced the risk of CV death or worsening HF events and was well tolerated among participants enrolled in both Asia and other geographic regions.

Background: Sleep apnea is more common in patients with heart failure (HF) than in the general population, but little is known about its association with clinical outcomes in various HF phenotypes or how it might modify the effect of HF therapy. Objectives: To examine the prevalence of sleep apnea, its association with outcomes and the effects of dapagliflozin in patients with HF with and without sleep apnea in a pooled analysis of 2 trials comparing dapagliflozin to placebo in HFrEF (DAPA-HF trial) and HFmrEF/HFpEF (DELIVER trial). Methods: A history of sleep apnea was investigator-reported. The primary outcome was a composite of worsening HF or cardiovascular death. Results: The prevalence of sleep apnea was 5.7% and 7.8% in patients with HFrEF and HFmrEF/HFpEF, respectively. The primary outcome occurred at a rate of 16.0 in participants with sleep apnea compared to 10.6 per 100 person-years in those without (adjusted HR 1.29 [95%CI, 1.10–1.52]). Compared with placebo, dapagliflozin reduced the risk of the primary endpoint to the same extent in patients with (HR 0.78 [95% CI, 0.59–1.03]) and without sleep apnea (HR 0.79 [0.72–0.87]) [Pinteraction = 0.93]. The beneficial effects of dapagliflozin on other clinical outcomes and symptom burden, physical function, and quality of life were consistent in participants with and without sleep apnea. Conclusions: In DAPA-HF and DELIVER, the true prevalence of sleep apnea was likely underestimated. An investigator-reported history of sleep apnea was associated with higher rates of worsening HF events. The benefits of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. Clinical trial registration: Unique identifiers: NCT01920711 Condensed Abstract: In a pooled analysis of the DAPA-HF and DELIVER trials of more than 11,000 patients with heart failure (HF) across the range of ejection fractions, an investigator-reported history of sleep apnea was associated with higher rates

Aims: Heart failure (HF) is a chronic and progressive syndrome associated with a poor prognosis. While it may seem intuitive that the risk of adverse outcomes varies across the different stages of HF, an overview of these risks is lacking. This study aims to determine the risk of all-cause mortality and HF hospitalizations associated with new-onset HF, chronic HF (CHF), worsening HF (WHF), and advanced HF. Methods and results: We performed a systematic review of observational studies from 2012 to 2022 using five different databases. The primary outcomes were 30-day and 1-year all-cause mortality, as well as 1-year HF hospitalization. Studies were pooled using random effects meta-analysis, and mixed-effects meta-regression was used to compare the different HF groups. Among the 15 759 studies screened, 66 were included representing 862 046 HF patients. Pooled 30-day mortality rates did not reveal a significant distinction between hospital-admitted patients, with rates of 10.13% for new-onset HF and 8.11% for WHF (p = 0.10). However, the 1-year mortality risk differed and increased stepwise from CHF to advanced HF, with a rate of 8.47% (95% confidence interval [CI] 7.24–9.89) for CHF, 21.15% (95% CI 17.78–24.95) for new-onset HF, 26.84% (95% CI 23.74–30.19) for WHF, and 29.74% (95% CI 24.15–36.10) for advanced HF. Readmission rates for HF at 1 year followed a similar trend. Conclusions: Our meta-analysis of observational studies confirms the different risk for adverse outcomes across the distinct HF stages. Moreover, it emphasizes the negative prognostic value of WHF as the first progressive stage from CHF towards advanced HF.

Aims:Recently, a genetic variant-specific prediction model for phospholamban (PLN) p.(Arg14del)-positive individuals was developed to predict individual major ventricular arrhythmia (VA) risk to support decision-making for primary prevention implantable cardioverter defibrillator (ICD) implantation. This model predicts major VA risk from baseline data, but iterative evaluation of major VA risk may be warranted considering that the risk factors for major VA are progressive. Our aim is to evaluate the diagnostic performance of the PLN p.(Arg14del) risk model at 3-year follow-up. Methods:We performed a landmark analysis 3 years after presentation and selected only patients with no prior major VA. Data were and results collected of 268 PLN p.(Arg14del)-positive subjects, aged 43.5 ± 16.3 years, 38.9% male. After the 3 years landmark, subjects had a mean follow-up of 4.0 years (± 3.5 years) and 28 (10%) subjects experienced major VA with an annual event rate of 2.6% [95% confidence interval (CI) 1.6–3.6], defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death. The PLN p.(Arg14del) risk score yielded good discrimination in the 3 years landmark cohort with a C-statistic of 0.83 (95% CI 0.79–0.87) and calibration slope of 0.97. Conclusion:The PLN p.(Arg14del) risk model has sustained good model performance up to 3 years follow-up in PLN p.(Arg14del)positive subjects with no history of major VA. It may therefore be used to support decision-making for primary prevention ICD implantation not merely at presentation but also up to at least 3 years of follow-up.

Aims: Remote haemodynamic monitoring with an implantable pulmonary artery (PA) sensor has been shown to reduce heart failure (HF) hospitalizations and improve quality of life. Cost-effectiveness analyses studying the value of remote haemodynamic monitoring in a European healthcare system with a contemporary standard care group are lacking. Methods and results: A Markov model was developed to estimate the cost-effectiveness of PA-guided therapy compared to the standard of care based upon patient-level data of the MONITOR-HF trial performed in the Netherlands in patients with chronic HF (New York Heart Association class III and at least one previous HF hospitalization). Cost-effectiveness was measured as the incremental cost per quality-adjusted life year (QALY) gained from the Dutch societal perspective with a lifetime horizon which encompasses a wide variety of costs including costs of hospitalizations, monitoring time, telephone contacts, laboratory assessments, and drug changes in both treatment groups. In the base-case analysis, PA-guided therapy increased costs compared to standard of care by €12 121. The QALYs per patient for PA-guided therapy and standard of care was 4.07 and 3.481, respectively, reflecting a gain of 0.58 QALYs. The resulting incremental cost-effectiveness ratio was €20 753 per QALY, which is below the Dutch willingness-to-pay threshold of €50 000 per QALY gained for HF. Conclusions: The current cost-effectiveness study suggests that remote haemodynamic monitoring with PA-guided therapy on top of standard care is likely to be cost-effective for patients with symptomatic moderate-to-severe HF in the Netherlands.

Background. A single albuminuria measurement is reported to be an independent predictor of cancer risk. Whether change in albuminuria is also independently associated with cancer is not known. Methods. We included 64 303 subjects of the Stockholm CREAtinine Measurements( SCREAM) project without a history of cancer and with at least two urine albumin-creatinine ratio( ACR) tests up to 2 years apart. Albuminuria changes were quantified by the fold-change in ACR over 2 years, and stratified into the absence of clinically elevated albuminuria( i.e. never) , albuminuria that remained constant, and albuminuria that increased or decreased. The primary outcome was overall cancer incidence. Secondary outcomes were site-specific cancer incidences. Results. During a median follow-up of 3.7( interquartile range 3.6-3.7) years, 5126 subjects developed de novo cancer. After multivariable adjustment including baseline estimated glomerular filtration rate and baseline ACR, subjects with increasing ACR over 2 years had a 19%( hazard ratio 1.19; 95% confidence interval 1.08-1.31) higher risk of overall cancer compared with those who never had clinically elevated ACR. No association with cancer risk was seen in the groups with decreasing or constant ACR. Regarding site-specific cancer risks, subjects with increasing ACR or constant ACR had a higher risk of developing urinary tract and lung cancer. No other associations between 2-year ACR changes and site-specific cancers were found. Conclusions. Increases in albuminuria over a 2-year period are associated with a higher risk of developing overall, urinary tract and lung cancer, independent of baseline kidney function and albuminuria. These data add important weight to the link that exists between albuminuria and cancer incidence.

Background: Conventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being in a single outcome. Objectives: To overcome this limitation, we tested an integrated measure that includes days lost from death and hospitalization, and additional days of full health lost through diminished well-being. Methods: The effect of dapagliflozin on this integrated measure was assessed in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, which examined the efficacy of dapagliflozin, compared with placebo, in patients with NYHA functional class II to IV heart failure and a left ventricular ejection fraction ≤40%. Results: Over 360 days, patients in the dapagliflozin group (n = 2,127) lost 10.6 ± 1.0 (2.9%) of potential follow-up days through cardiovascular death and heart failure hospitalization, compared with 14.4 ± 1.0 days (4.0%) in the placebo group (n = 2,108), and this component of all measures of days lost accounted for the greatest between-treatment difference (−3.8 days [95% CI: −6.6 to −1.0 days]). Patients receiving dapagliflozin also had fewer days lost to death and hospitalization from all causes vs placebo (15.5 ± 1.1 days [4.3%] vs 20.3 ± 1.1 days [5.6%]). When additional days of full health lost (ie, adjusted for Kansas City Cardiomyopathy Questionnaire–overall summary score) were added, total days lost were 110.6 ± 1.6 days (30.7%) with dapagliflozin vs 116.9 ± 1.6 days (32.5%) with placebo. The difference in all measures between the 2 groups increased over time (ie, days lost by death and hospitalization −0.9 days [−0.7%] at 120 days, −2.3 days [−1.0%] at 240 days, and −4.8 days [−1.3%] at 360 days). Conclusions: Dapagliflozin reduced the total days of potential full health lost due to death, hospitalizations, and impaired well-being, and this benefit increased over time during the

Aims Management of comorbidities represents a critical step in optimal treatment of heart failure (HF) patients. However, minimal attention has been paid whether comorbidity burden and their prognostic value changes over time. Therefore, we examined the association between comorbidities and clinical outcomes in HF patients between 2002 and 2017. Methods and results The 2002-HF cohort consisted of patients from The Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) trial (n = 1,032). The 2017-HF cohort were outpatient HF patients enrolled after hospitalization for HF in a tertiary referral academic hospital (n = 382). Kaplan meier and cox regression analyses were used to assess the association of comorbidities with HF hospitalization and all-cause mortality. Patients from the 2017-cohort were more likely to be classified as HF with preserved ejection fraction (24 vs 15%, p < 0.001), compared to patients from the 2002-cohort. Comorbidity burden was comparable between both cohorts (mean of 3.9 comorbidities per patient) and substantially increased with age. Higher comorbidity burden was significantly associated with a comparable increased risk for HF hospitalization and all-cause mortality (HR 1.12 [1.02-1.22] and HR 1.18 [1.05-1.32]), in the 2002- and 2017-cohort respectively. When assessing individual comorbidities, obesity yielded a statistically higher prognostic effect on outcome in the 2017-cohort compared to the 2002-HF cohort (p for interaction 0.026). Conclusion Despite major advances in HF treatment over the past decades, comorbidity burden remains high in HF and influences outcome to a large extent. Obesity emerges as a prominent comorbidity, and efforts should be made for prevention and treatment. [GRAPHICS] ., Funding Agencies|Dutch Heart Foundation [2017-21, 2017-11, 2018-30, 2020B005, 2000Z003, 03-005-2021-T005]; leDucq Foundation (Cure PhosphoLambaN induced Cardiomyopathy (Cure-PLaN)); European Research Council (SECRETE-HF) [ERC CoG 818715]; Mandema-Stipendium of the Junior Scientific Masterclass of the University Medical Center Groningen [202010]

A Kinase Interacting Protein 1 (AKIP1) is a signalling adaptor that promotes mitochondrial respiration and attenuates mitochondrial oxidative stress in cultured cardiomyocytes. We sought to determine whether AKIP1 influences mitochondrial function and the mitochondrial adaptation in response to exercise in vivo. We assessed mitochondrial respiratory capacity, as well as electron microscopy and mitochondrial targeted-proteomics in hearts from mice with cardiomyocyte-specific overexpression of AKIP1 (AKIP1-TG) and their wild type (WT) littermates. These parameters were also assessed after four weeks of voluntary wheel running. In contrast to our previous in vitro study, respiratory capacity measured as state 3 respiration on palmitoyl carnitine was significantly lower in AKIP1-TG compared to WT mice, whereas state 3 respiration on pyruvate remained unaltered. Similar findings were observed for maximal respiration, after addition of FCCP. Mitochondrial DNA damage and oxidative stress markers were not elevated in AKIP1-TG mice and gross mitochondrial morphology was similar. Mitochondrial targeted-proteomics did reveal reductions in mitochondrial proteins involved in energy metabolism. Exercise performance was comparable between genotypes, whereas exercise-induced cardiac hypertrophy was significantly increased in AKIP1-TG mice. After exercise, mitochondrial state 3 respiration on pyruvate substrates was significantly lower in AKIP1-TG compared with WT mice, while respiration on palmitoyl carnitine was not further decreased. This was associated with increased mitochondrial fission on electron microscopy, and the activation of pathways associated with mitochondrial fission and mitophagy. This study suggests that AKIP1 regulates the mitochondrial proteome involved in energy metabolism and promotes mitochondrial turnover after exercise. Future studies are required to unravel the mechanistic underpinnings and whether the mitochondrial changes are required for the AKIP1-in

Aim: COVID-19 may affect clinical risk in patients with heart failure. DELIVER began before and was conducted during the COVID-19 pandemic. This study aimed to evaluate the association between COVID-19 and clinical outcomes among DELIVER participants. Methods and results: Participants with chronic heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) were randomized to dapagliflozin or placebo across 350 sites in 20 countries. COVID-19 was investigator-reported and the contribution of COVID-19 to death was centrally adjudicated. We assessed (i) the incidence of COVID-19, (ii) event rates before/during the pandemic, and (iii) risks of death after COVID-19 diagnosis compared to risks of death in participants without COVID-19. Further, we performed a sensitivity analysis assessing treatment effects of dapagliflozin vs. placebo censored at pandemic onset. Of 6263 participants, 589 (9.4%) developed COVID-19, of whom 307 (52%) required/prolonged hospitalization. A total of 155 deaths (15% of all deaths) were adjudicated as definitely/possibly COVID-19-related. COVID-19 cases and deaths did not differ by randomized assignment. Death rate in the 12 months following diagnosis was 56.1 (95% confidence interval [CI] 48.0–65.6) versus 6.4 (95% CI 6.0–6.8)/100 participant-years among trial participants with versus without COVID-19 (adjusted hazard ratio [aHR] 8.60, 95% CI 7.18–10.30). Risk was highest 0–3 months following diagnosis (153.5, 95% CI 130.3–180.8) and remained elevated at 3–6 months (12.6, 95% CI 6.6–24.3/100 participant-years). After excluding investigator-reported fatal COVID-19 events, all-cause death rates in the 12 months following diagnosis among COVID-19 survivors (n = 458) remained higher (aHR 2.46, 95% CI 1.83–3.33) than rates for all trial participants from randomization, with censoring of participants who developed COVID-19 at the time of diagnosis. Dapagliflozin reduced cardiovascular death/w

Obesity-related heart failure with preserved ejection fraction (HFpEF) has become a well-recognized HFpEF subphenotype. Targeting the unfavorable cardiometabolic profile may represent a rational treatment strategy. This study investigated semaglutide, a glucagon-like peptide-1 receptor agonist that induces significant weight loss in patients with obesity and/or type 2 diabetes mellitus and has been associated with improved cardiovascular outcomes. In a mouse model of HFpEF that was caused by advanced aging, female sex, obesity, and type 2 diabetes mellitus, semaglutide, compared with weight loss induced by pair feeding, improved the cardiometabolic profile, cardiac structure, and cardiac function. Mechanistically, transcriptomic, and proteomic analyses revealed that semaglutide improved left ventricular cytoskeleton function and endothelial function and restores protective immune responses in visceral adipose tissue. Strikingly, treatment with semaglutide induced a wide array of favorable cardiometabolic effects beyond the effect of weight loss by pair feeding. Glucagon-like peptide-1 receptor agonists may therefore represent an important novel therapeutic option for treatment of HFpEF, especially when obesity-related.

Aims Adjustment of treatment based on remote monitoring of pulmonary artery (PA) pressure may reduce the risk of hospital admission for heart failure (HF). We have conducted a meta-analysis of large randomized trials investigating this question. Methods A systematic literature search was performed for randomized clinical trials with PA pressure monitoring devices in patients and results with HF. The primary outcome of interest was the total number of HF hospitalizations. Other outcomes assessed were urgent visits leading to treatment with intravenous diuretics, all-cause mortality, and composites. Treatment effects are expressed as hazard ratios, and pooled effect estimates were obtained applying random effects meta-analyses. Three eligible randomized clinical trials were identified that included 1898 outpatients in New York Heart Association functional classes II–IV, either hospitalized for HF in the prior 12 months or with elevated plasma NT-proBNP concentrations. The mean followup was 14.7 months, 67.8% of the patients were men, and 65.8% had an ejection fraction ≤40%. Compared to patients in the control group, the hazard ratio (95% confidence interval) for total HF hospitalizations in those randomized to PA pressure monitoring was 0.70 (0.58–0.86) (P = .0005). The corresponding hazard ratio for the composite of total HF hospitalizations, urgent visits and all-cause mortality was 0.75 (0.61–0.91; P = .0037) and for all-cause mortality 0.92 (0.73–1.16). Subgroup analyses, including ejection fraction phenotype, revealed no evidence of heterogeneity in the treatment effect. Conclusion The use of remote PA pressure monitoring to guide treatment of patients with HF reduces episodes of worsening HF and subsequent hospitalizations.

Despite improvements in cancer survival, cancer therapy–related cardiovascular toxicity has risen to become a prominent clinical challenge. This has led to the growth of the burgeoning field of cardio-oncology, which aims to advance the cardiovascular health of cancer patients and survivors, through actionable and translatable science. In these Global Cardio-Oncology Symposium 2023 scientific symposium proceedings, we present a focused review on the mechanisms that contribute to common cardiovascular toxicities discussed at this meeting, the ongoing international collaborative efforts to improve patient outcomes, and the bidirectional challenges of translating basic research to clinical care. We acknowledge that there are many additional therapies that are of significance but were not topics of discussion at this symposium. We hope that through this symposium-based review we can highlight the knowledge gaps and clinical priorities to inform the design of future studies that aim to prevent and mitigate cardiovascular disease in cancer patients and survivors.

Background: Insulin-like growth factor–binding protein-7 (IGFBP-7) has been proposed as a potential prognostic biomarker in heart failure (HF), but the association between elevation in IGFBP-7 and HF outcomes in ambulant patients with heart failure with reduced ejection fraction (HFrEF) is unknown. Objectives: The authors addressed this question in a post hoc analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. Methods: The primary outcome was a composite of cardiovascular death or a worsening HF event. The risk of adverse outcome was compared across tertiles of IGFBP-7 concentration by means of Cox proportional hazard models adjusted for N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT). The efficacy of randomized treatment across IGFBP-7 tertiles was assessed. Change in IGFBP-7 at 12 months was compared with the use of geometric means. Results: A total of 3,158 patients had IGFBP-7 measured at baseline, and 2,493 had a repeated measure at 12 months. Patients in the highest tertile of IGFBP-7 had evidence of more advanced HFrEF. The adjusted HR for the primary endpoint in tertile 3, compared with tertile 1, was 1.48 (95% CI: 1.17-1.88). There was no modification of the benefit of dapagliflozin by baseline IGFBP-7 (P interaction = 0.34). Dapagliflozin did not change IGFBP-7 levels over 1 year (P = 0.34). Conclusions: Higher IGFBP-7 in patients with HFrEF was associated with worse clinical profile and an increased risk of adverse clinical outcomes. IGFBP-7 provided prognostic information incremental to clinical variables, NT-proBNP, and hsTnT. The benefit of dapagliflozin was not modulated by IGFBP-7 level. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124)

BACKGROUND: Hospitalization is recognized as a sentinel event in the disease trajectory of patients with heart failure (HF), but not all patients experiencing clinical decompensation are ultimately hospitalized. Outpatient intensification of diuretics is common in response to symptoms of worsening HF, yet its prognostic and clinical relevance, specifically for patients with HF with mildly reduced or preserved ejection fraction, is uncertain.METHODS: In this prespecified analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we assessed the association between various nonfatal worsening HF events (those requiring hospitalization, urgent outpatient visits requiring intravenous HF therapies, and outpatient oral diuretic intensification) and rates of subsequent mortality. We further examined the treatment effect of dapagliflozin on an expanded composite end point of cardiovascular death, HF hospitalization, urgent HF visit, or outpatient oral diuretic intensification.RESULTS: In DELIVER, 4532 (72%) patients experienced no worsening HF event, whereas 789 (13%) had outpatient oral diuretic intensification, 86 (1%) required an urgent HF visit, 585 (9%) had an HF hospitalization, and 271 (4%) died of cardiovascular causes as a first presentation. Patients with a first presentation manifesting as outpatient oral diuretic intensification experienced rates of subsequent mortality that were higher (10 [8-12] per 100 patient-years) than those without a worsening HF event (4 [3-4] per 100 patient-years) but similar to rates of subsequent death after an urgent HF visit (10 [6-18] per 100 patient-years). Patients with an HF hospitalization as a first presentation of worsening HF had the highest rates of subsequent death (35 [31-40] per 100 patient-years). The addition of outpatient diuretic intensification to the adjudicated DELIVER primary e

Phospholamban (PLN; p.Arg14del) cardiomyopathy is an inherited disease caused by the pathogenic p.Arg14del variant in the PLN gene. Clinically, it is characterized by malignant ventricular arrhythmias and progressive heart failure.1,2 Cardiac fibrotic tissue remodelling occurs early on in PLN p.Arg14del carriers.3,4 Eplerenone was deemed a treatment candidate because of its beneficial effects on ventricular remodelling and antifibrotic properties.5,6 We conducted the multicentre randomized trial ‘intervention in PHOspholamban RElated CArdiomyopathy STudy’ (i-PHORECAST) to assess whether treatment with eplerenone of asymptomatic PLN p.Arg14del carriers attenuates disease onset and progression.

Cardiomyopathies represent significant contributors to cardiovascular morbidity and mortality. Over the past decades, a progress has occurred in characterization of the genetic background and major pathophysiological mechanisms, which has been incorporated into a more nuanced diagnostic approach and risk stratification. Furthermore, medications targeting core disease processes and/or their downstream adverse effects have been introduced for several cardiomyopathies. Combined with standard care and prevention of sudden cardiac death, these novel and emerging targeted therapies offer a possibility of improving the outcomes in several cardiomyopathies. Therefore, the aim of this document is to summarize practical approaches to the treatment of cardiomyopathies, which includes the evidence-based novel therapeutic concepts and established principles of care, tailored to the individual patient aetiology and clinical presentation of the cardiomyopathy. The scope of the document encompasses contemporary treatment of dilated, hypertrophic, restrictive and arrhythmogenic cardiomyopathy. It was based on an expert consensus reached at the Heart Failure Association online Workshop, held on 18 March 2021.

Background: Elevated circulating carbohydrate antigen 125 (CA125) is a marker of congestion and a predictor of outcomes in acute heart failure (HF). Less is known about CA125 in chronic ambulatory HF with reduced ejection fraction. Objectives: This study examined the association between baseline CA125 (and changes in CA125) and outcomes in patients with HF with reduced ejection fraction in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; NCT03036124) trial and its relationship with the effect of dapagliflozin. Methods: The primary outcome was a composite of a first episode of worsening HF or cardiovascular death. CA125 was measured at baseline and 12 months following randomization. Results: Median baseline CA125 was 13.04 U/mL (IQR: 8.78-21.13 U/mL) in 3,123 of 4,774 patients with available data. Compared with CA125 ≤35 U/mL (upper limit of normal), patients with CA125 >35 U/mL were at a higher risk of the primary outcome (adjusted HR: 1.59; 95% CI: 1.29-1.96). The adjusted risks of the primary outcome relative to quartile 1 (Q1) (≤8.78 U/mL) were as follow: Q2, 8.79-13.04 U/mL (HR: 0.94; 95% CI: 0.71-1.24); Q3, 13.05-21.13 U/mL (HR: 1.22; 95% CI: 0.94-1.59); Q4, ≥21.14 U/mL (HR: 1.63; 95% CI: 1.28-2.09). The beneficial effect of dapagliflozin compared with placebo on the primary outcome was consistent whether CA125 was analyzed in quartiles (interaction P = 0.13) or as a continuous variable (interaction P = 0.75). The placebo-corrected relative change in CA125 at 12 months was −5.2% (95% CI: −10.6% to 0.5%; P = 0.07). Conclusions: In DAPA-HF, elevated CA125 levels were an independent predictor of the risk of worsening HF or cardiovascular death. Dapagliflozin reduced the risk of worsening HF or cardiovascular death regardless of baseline CA125.

Background: Cancer and heart failure (HF) are the leading causes of death in the Western world. Shared mechanisms such as fibrosis may underlie either disease entity, furthermore it is unknown whether this relationship is sex-specific. Objectives: We sought to investigate how fibrosis-related biomarker galectin-3 (gal-3) aids in identifying individuals at risk for new-onset cancer and HF, and how this differs between sexes. Methods: Gal-3 was measured at baseline and at 4-year follow-up in 5,786 patients of the PREVEND (Prevention of Renal and Vascular Endstage Disease) study. The total follow-up period was 11.5 years. An increase of ≥50% in gal-3 levels between measurements was considered relevant. We performed sex-stratified log-rank tests and Cox regression analyses overall and by sex to evaluate the association of gal-3 over time with both new-onset cancer and new-onset HF. Results: Of the 5,786 healthy participants (50% males), 399 (59% males) developed new-onset cancer, and 192 (65% males) developed new-onset HF. In males, an increase in gal-3 was significantly associated with new-onset cancer (both combined and certain cancer-specific subtypes), after adjusting for age, body mass index, hypertension, smoking status, estimated glomerular filtration rate, diabetes mellitus, triglycerides, coronary artery disease, and C-reactive protein (HR: 1.89; 95% CI: 1.32-2.71; P < 0.001). Similar analyses demonstrated an association with new-onset HF in males (HR: 1.77; 95% CI: 1.07-2.95; P = 0.028). In females, changes in gal-3 over time were neither associated with new-onset cancer nor new-onset HF. Conclusions: Gal-3, a marker of fibrosis, is associated with new-onset cancer and new-onset HF in males, but not in females.

Aims: Because an increased risk of amputation with canagliflozin was reported in the CANVAS trials, there has been a concern about the safety of sodium-glucose cotransporter 2 inhibitors in patients with peripheral artery disease (PAD) who are at higher risk of amputation. Methods and results: A patient-level pooled analysis of the DAPA-HF and DELIVER trials, which evaluated the efficacy and safety of dapagliflozin in patients with heart failure (HF) with reduced, mildly reduced/preserved ejection fraction, respectively, was conducted. In both trials, the primary outcome was the composite of worsening HF or cardiovascular death, and amputation was a prespecified safety outcome. Peripheral artery disease history was available for 11 005 of the total 11 007 patients. Peripheral artery disease was reported in 809 of the 11 005 patients (7.4%). Median follow-up was 22 months (interquartile range 17-30). The rate of the primary outcome (per 100 person-years) was higher in PAD patients than that in non-PAD patients: 15.1 [95% confidence interval (CI) 13.1-17.3) vs. 10.6 (10.2-11.1]; adjusted hazard ratio 1.23 (95% CI 1.06-1.43). The benefit of dapagliflozin on the primary outcome was consistent in patients with [hazard ratio 0.71 (95% CI 0.54-0.94)] and without PAD [0.80 (95% CI 0.73-0.88)] (Pinteraction = 0.39). Amputations, while more frequent in PAD patients, were not more common with dapagliflozin, compared with placebo, irrespective of PAD status (PAD, placebo 4.2% vs. dapagliflozin 3.7%; no PAD, placebo 0.4% vs. dapagliflozin 0.4%) (Pinteraction = 1.00). Infection rather than ischaemia was the main trigger for amputation, even in patients with PAD. Conclusion: The risk of worsening HF or cardiovascular death was higher in patients with PAD, as was the risk of amputation. The benefits of dapagliflozin were consistent in patients with and without PAD, and dapagliflozin did not increase the risk of amputation.

Importance: In the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, dapagliflozin reduced the risk of time to first worsening heart failure (HF) event or cardiovascular death in patients with HF with mildly reduced or preserved ejection fraction (EF). Objective: To evaluate the effect of dapagliflozin on total (ie, first and recurrent) HF events and cardiovascular death in this population. Design, Setting, and Participants: In this prespecified analysis of the DELIVER trial, the proportional rates approach of Lin, Wei, Yang, and Ying (LWYY) and a joint frailty model were used to examine the effect of dapagliflozin on total HF events and cardiovascular death. Several subgroups were examined to test for heterogeneity in the effect of dapagliflozin, including left ventricular EF. Participants were enrolled from August 2018 to December 2020, and data were analyzed from August to October 2022. Interventions: Dapagliflozin, 10 mg, once daily or matching placebo. Main Outcomes and Measures: The outcome was total episodes of worsening HF (hospitalization for HF or urgent HF visit requiring intravenous HF therapies) and cardiovascular death. Results: Of 6263 included patients, 2747 (43.9%) were women, and the mean (SD) age was 71.7 (9.6) years. There were 1057 HF events and cardiovascular deaths in the placebo group compared with 815 in the dapagliflozin group. Patients with more HF events had features of more severe HF, such as higher N-terminal pro-B-type natriuretic peptide level, worse kidney function, more prior HF hospitalizations, and longer duration of HF, although EF was similar to those with no HF events. In the LWYY model, the rate ratio for total HF events and cardiovascular death for dapagliflozin compared with placebo was 0.77 (95% CI, 0.67-0.89; P <.001) compared with a hazard ratio o

Importance: Dapagliflozin has been shown to improve overall health status based on aggregate summary scores of the Kansas City Cardiomyopathy Questionnaire (KCCQ) in patients with heart failure (HF) with mildly reduced or preserved ejection fraction enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. A comprehensive understanding of the responsiveness of individual KCCQ items would allow clinicians to better inform patients on expected changes in daily living with treatment. Objective: To examine the association of dapagliflozin treatment with changes in individual components of the KCCQ. Design, Setting, and Participants: This is a post hoc exploratory analysis of DELIVER, a randomized double-blind placebo-controlled trial conducted at 353 centers in 20 countries from August 2018 to March 2022. KCCQ was administered at randomization and 1, 4, and 8 months. Scores of individual KCCQ components were scaled from 0 to 100. Eligibility criteria included symptomatic HF with left ventricular ejection fraction greater than 40%, elevated natriuretic peptide levels, and evidence of structural heart disease. Data were analyzed from November 2022 to February 2023. Main Outcomes and Measures: Changes in the 23 individual KCCQ components at 8 months. Interventions: Dapagliflozin, 10 mg, once daily or placebo. Results: Baseline KCCQ data were available for 5795 of 6263 randomized patients (92.5%) (mean [SD] age, 71.5 [9.5] years; 3344 male [57.7%] and 2451 female [42.3%]). Dapagliflozin was associated with larger improvements in almost all KCCQ components at 8 months compared with placebo. The most significant improvements with dapagliflozin were observed in frequency of lower limb edema (difference, 3.2; 95% CI, 1.6-4.8; P <.001), sleep limitation by shortness of breath (difference, 3.0; 95% CI, 1.6-4.4; P <.001), and limitation in desired activities by shortness of breath (difference

Background: Elevated circulating carbohydrate antigen 125 (CA125) is a marker of congestion and a predictor of outcomes in acute heart failure (HF). Less is known about CA125 in chronic ambulatory HF with reduced ejection fraction. Objectives: This study examined the association between baseline CA125 (and changes in CA125) and outcomes in patients with HF with reduced ejection fraction in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; NCT03036124) trial and its relationship with the effect of dapagliflozin. Methods: The primary outcome was a composite of a first episode of worsening HF or cardiovascular death. CA125 was measured at baseline and 12 months following randomization. Results: Median baseline CA125 was 13.04 U/mL (IQR: 8.78-21.13 U/mL) in 3,123 of 4,774 patients with available data. Compared with CA125 ≤35 U/mL (upper limit of normal), patients with CA125 >35 U/mL were at a higher risk of the primary outcome (adjusted HR: 1.59; 95% CI: 1.29-1.96). The adjusted risks of the primary outcome relative to quartile 1 (Q1) (≤8.78 U/mL) were as follow: Q2, 8.79-13.04 U/mL (HR: 0.94; 95% CI: 0.71-1.24); Q3, 13.05-21.13 U/mL (HR: 1.22; 95% CI: 0.94-1.59); Q4, ≥21.14 U/mL (HR: 1.63; 95% CI: 1.28-2.09). The beneficial effect of dapagliflozin compared with placebo on the primary outcome was consistent whether CA125 was analyzed in quartiles (interaction P = 0.13) or as a continuous variable (interaction P = 0.75). The placebo-corrected relative change in CA125 at 12 months was −5.2% (95% CI: −10.6% to 0.5%; P = 0.07). Conclusions: In DAPA-HF, elevated CA125 levels were an independent predictor of the risk of worsening HF or cardiovascular death. Dapagliflozin reduced the risk of worsening HF or cardiovascular death regardless of baseline CA125.

Aims: The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial demonstrated the sodium–glucose cotransporter 2 inhibitor dapagliflozin to be beneficial in patients with symptomatic heart failure (HF) with improved ejection fraction (HFimpEF; those with prior left ventricular ejection fraction ≤40% that had improved to >40% by enrolment). Whether this benefit differs by background medical therapy is unclear. The current study aims to determine the efficacy and safety of dapagliflozin among patients with HFimpEF by background medical therapy. Methods and results: Treatment effects on the primary endpoint (worsening HF or cardiovascular death) were assessed by number of background HF medical therapies (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor–neprilysin inhibitor, evidence-based beta-blocker, and mineralocorticoid receptor antagonist). Among the 6263 patients randomized in DELIVER, 1151 (18%) had HFimpEF. Of those, 21% of patients were on 0–1 therapies, 44% were on two therapies, and 35% were on three therapies. During 2.3 years of median follow-up, the incidence rate of the primary outcome was 9.7, 8.8, and 8.4 per 100 person-years for patients on 0–1, 2 and 3 HF medications at baseline, respectively. Treatment effects with dapagliflozin on the primary outcome may be greater in patients with HFimpEF on 0–1 therapies at baseline (pinteraction = 0.09), driven mostly by a significant interaction for HF hospitalization (pinteraction = 0.023) with no evidence of effect modification for cardiovascular death (pinteraction = 0.65). Treatment effects of dapagliflozin on the primary outcome were, however, consistent when assessed across the modified Heart Failure Collaboratory Medical Therapy Score integrating both therapeutic use and dosing (pinteraction = 0.39). The use of dapa

Aim: Chronic obstructive pulmonary disease (COPD) is common in heart failure with a mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) and is associated with worse outcomes. In a pre-specified analysis of DELIVER, we investigated the relationship between COPD status and outcomes, and the efficacy and safety of dapagliflozin, compared with placebo, according to COPD status. Methods and results: Patients with severe pulmonary disease (including COPD) were excluded from the trial. The primary outcome was a composite of cardiovascular death or worsening heart failure. Of the 6261 patients with data on baseline COPD status, 694 (11.1%) had a known history of this condition. The risk of the primary endpoint was higher in patients with mild-to-moderate COPD compared with those without COPD (adjusted hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.08–1.51). The benefit of dapagliflozin on the primary outcome was consistent irrespective of COPD status (no COPD: HR 0.82 [95% CI 0.72–0.93]; COPD: HR 0.82 [95% CI 0.62–1.10]; pinteraction = 0.98). Consistent effects were observed for heart failure, cardiovascular, and all-cause hospitalization, and deaths, and composites of these. Dapagliflozin, as compared with placebo, improved the Kansas City Cardiomyopathy Questionnaire scores from baseline to 8 months to a similar extent in patients with and without mild-to-moderate COPD (pinteraction ≥ 0.63). Adverse events and treatment discontinuation were not more frequent with dapagliflozin than with placebo irrespective of COPD status. 'Conclusions: Mild-to-moderate COPD is common in patients with HFmrEF/HFpEF and is associated with worse outcomes. The beneficial effects of dapagliflozin compared with placebo on clinical events and symptoms were consistent, regardless of COPD status. Clinical Trial Registration: ClinicalTrials.gov NCT03619213.

Aims: To determine the cost-effectiveness of dapagliflozin, added to usual care, in patients with heart failure (HF) with mildly reduced or preserved ejection fraction for the UK, German and Spanish payers using detailed patient-level data from the Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial. Methods and results:A lifetime Markov state-transition cohort model was developed. Quartiles of the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) defined health states and monthly transition count data informed transition probabilities. Multivariable generalized estimating equations captured the incidence of HF hospitalizations and urgent HF visits, while cardiovascular deaths and all-cause mortality were estimated using adjusted parametric survival models. Health state costs were assigned to KCCQ-TSS quartiles (2021 British pound [GBP]/Euro) and patient-reported outcomes were sourced from DELIVER. Future values of costs and effects were discounted according to country-specific rates. In the UK, dapagliflozin treatment was predicted to increase quality-adjusted life years (QALYs) and life-years by 0.231 and 0.354, respectively, and extend the time spent in the best quartile of KCCQ-TSS by 4.2 months. Comparable outcomes were projected for Germany and Spain. The incremental cost-effectiveness ratios were £7761, €9540 and €5343/QALY in the UK, Germany and Spain, respectively. According to regional willingness-to-pay thresholds, 91%, 89% and 92% of simulations in the UK, Germany and Spain, respectively, were cost-effective following probabilistic sensitivity analyses. Conclusion: Dapagliflozin, added to usual care, is very likely cost-effective for HF with mildly reduced or preserved ejection fraction in several European countries.

AIMS: Telemonitoring modalities in heart failure (HF) have been proposed as being essential for future organization and transition of HF care, however, efficacy has not been proven. A comprehensive meta-analysis of studies on home telemonitoring systems (hTMS) in HF and the effect on clinical outcomes are provided. METHODS AND RESULTS: A systematic literature search was performed in four bibliographic databases, including randomized trials and observational studies that were published during January 1996-July 2022. A random-effects meta-analysis was carried out comparing hTMS with standard of care. All-cause mortality, first HF hospitalization, and total HF hospitalizations were evaluated as study endpoints. Sixty-five non-invasive hTMS studies and 27 invasive hTMS studies enrolled 36 549 HF patients, with a mean follow-up of 11.5 months. In patients using hTMS compared with standard of care, a significant 16% reduction in all-cause mortality was observed [pooled odds ratio (OR): 0.84, 95% confidence interval (CI): 0.77-0.93, I2: 24%], as well as a significant 19% reduction in first HF hospitalization (OR: 0.81, 95% CI 0.74-0.88, I2: 22%) and a 15% reduction in total HF hospitalizations (pooled incidence rate ratio: 0.85, 95% CI 0.76-0.96, I2: 70%). CONCLUSION: These results are an advocacy for the use of hTMS in HF patients to reduce all-cause mortality and HF-related hospitalizations. Still, the methods of hTMS remain diverse, so future research should strive to standardize modes of effective hTMS.

Background: Because clinical characteristics and prognosis vary by geographic region in patients with heart failure (HF), the response to treatment may also vary. A previous report suggested that the efficacy of sodium-glucose cotransporter-2 inhibitor efficacy in heart failure with reduced ejection fraction (HFrEF) may be modified by region. Objectives: The goal of this study was to examine the efficacy and safety of dapagliflozin in patients with HF according to geographic region. Methods: We conducted a patient-level pooled analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trials, which evaluated the effects of dapagliflozin in HFrEF and heart failure with mildly reduced ejection fraction (HFmrEF)/heart failure with preserved ejection fraction (HFpEF), respectively. The primary outcome was the composite of worsening HF or cardiovascular death. Results: Among 11,007 patients, 5,159 (46.9%) were enrolled in Europe, 1,528 (13.9%) in North America, 1,998 (18.2%) in South America, and 2,322 (21.1%) in Asia. The rate of the primary outcome (per 100 person-years) was higher in North America (13.9 [95% CI: 12.5-15.4]) than in other regions: Europe 10.8 (95% CI: 10.1-11.5), South America 10.0 (95% CI: 9.0-11.1), and Asia 10.5 (95% CI: 9.5-11.5). The benefit of dapagliflozin on the primary outcome was not modified by region: dapagliflozin vs placebo HR: Europe, 0.85 (95% CI: 0.75-0.96); North America, 0.75 (95% CI: 0.61-0.93); South America, 0.72 (95% CI: 0.58-0.89); and Asia, 0.74 (95% CI: 0.61-0.91) (P interaction = 0.40). This was the same when evaluated separately for HFrEF (P interaction = 0.39) and HFmrEF/HFpEF (P interaction = 0.84). Patients in North America discontinued randomized treatment more frequently than did those elsewhere (placebo disconti

AIMS: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection fraction. In this study, the safety and efficacy of dapagliflozin according to background diuretic therapy and the influence of dapagliflozin on longitudinal diuretic use were evaluated. METHODS AND RESULTS: In this pre-specified analysis of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, the effects of dapagliflozin vs. placebo were assessed in the following subgroups: no diuretic, non-loop diuretic, and loop diuretic furosemide equivalent doses of <40, 40, and >40 mg, respectively. Of the 6263 randomized patients, 683 (10.9%) were on no diuretic, 769 (12.3%) were on a non-loop diuretic, and 4811 (76.8%) were on a loop diuretic at baseline. Treatment benefits of dapagliflozin on the primary composite outcome were consistent by diuretic use categories (Pinteraction = 0.64) or loop diuretic dose (Pinteraction = 0.57). Serious adverse events were similar between dapagliflozin and placebo arms, irrespective of diuretic use or dosing. Dapagliflozin reduced new initiation of loop diuretics by 32% [hazard ratio (HR) 0.68; 95% confidence interval (CI): 0.55-0.84, P < 0.001] but did not influence discontinuations/disruptions (HR 0.98; 95% CI: 0.86-1.13, P = 0.83) in follow-up. First sustained loop diuretic dose increases were less frequent, and sustained dose decreases were more frequent in patients treated with dapagliflozin: net difference of -6.5% (95% CI: -9.4 to -3.6; P < 0.001). The mean dose of loop diuretic increased over time in the placebo arm, a longitudinal increase that was significantly attenuated with treatment with dapagliflozin (placebo-corrected treatment effect of -2.5 mg/year; 95% CI: -1.5, -3.7, P < 0.001). CONCLUSION: In patients with heart failure with mildly reduced or preserved ejectio

Multiple landmark trials have helped to advance the treatment of heart failure with reduced ejection fraction (HFrEF) significantly over the past decade. These trials have led to the introduction of four main drug classes into the 2021 ESC guideline, namely angiotensin-receptor neprilysin inhibitors/angiotensin-converting-enzyme inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors. The life-saving effect of these therapies has been shown to be additive and becomes apparent within weeks, which is why maximally tolerated or target doses of all drug classes should be strived for as quickly as possible. Recent evidence, such as the STRONG-HF trial, demonstrated that rapid drug implementation and up-titration is superior to the traditional and more gradual step-by-step approach where valuable time is lost to up-titration. Accordingly, multiple rapid drug implementation and sequencing strategies have been proposed to significantly reduce the time needed for the titration process. Such strategies are urgently needed since previous large-scale registries have shown that guideline-directed medical therapy (GDMT) implementation is a challenge. This challenge is reflected by generally low adherence rates, which can be attributed to factors considering the patient, health care system, and local hospital/health care provider. This review of the four medication classes used to treat HFrEF seeks to present a thorough overview of the data supporting current GDMT, discuss the obstacles to GDMT implementation and up-titration, and identify multiple sequencing strategies that could improve GDMT adherence. Graphical Abstract: Sequencing strategies for GDMT implementation. GDMT: guideline-directed medical therapy; ACEi: angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; ARNi: angiotensin receptor–neprilysin inhibitor; BB: beta-blocker; MRA: mineralocorticoid receptor antagonist; SGLT2i: sodium–glu

Background: Studies focusing on sex differences in circulating proteins in patients with heart failure with reduced ejection fraction (HFrEF) are scarce. Insight into sex-specific cardiovascular protein profiles and their associations with the risk of adverse outcomes may contribute to a better understanding of the pathophysiological processes involved in HFrEF. Moreover, it could provide a basis for the use of circulating protein measurements for prognostication in women and men, wherein the most relevant protein measurements are applied in each of the sexes. Methods: In 382 patients with HFrEF, we performed tri-monthly blood sampling (median follow-up: 25 [13–31] months). We selected all baseline samples and two samples closest to the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization) or censoring. We then applied an aptamer-based multiplex proteomic assay identifying 1105 proteins previously associated with cardiovascular disease. We used linear regression models and gene-enrichment analysis to study sex-based differences in baseline levels. We used time-dependent Cox models to study differences in the prognostic value of serially measured proteins. All models were adjusted for the MAGGIC HF mortality risk score and p-values for multiple testing. Results: In 104 women and 278 men (mean age 62 and 64 years, respectively) cumulative PEP incidence at 30 months was 25% and 35%, respectively. At baseline, 55 (5%) out of the 1105 proteins were significantly different between women and men. The female protein profile was most strongly associated with extracellular matrix organization, while the male profile was dominated by regulation of cell death. The association of endothelin-1 (Pinteraction < 0.001) and somatostatin (Pinteraction = 0.040) with the PEP was modified by sex, independent of clinical characteristics. Endothelin-1 was more strongl

Aims: Patients with heart failure experience a high burden of symptoms and physical limitations, and poor quality of life. Dapagliflozin reduces heart failure hospitalization and cardiovascular death in patients with reduced, mildly reduced, and preserved ejection fractions. We examined the effects of dapagliflozin on health status, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), across the full spectrum of left ventricular ejection fraction (LVEF). Methods and results: Participant-level data were pooled from the DAPA-HF and DELIVER trials. Both trials were randomized, global, double-blind, placebo-controlled trials of patients with symptomatic heart failure and elevated natriuretic peptides. DAPA-HF and DELIVER included patients with LVEF ≤40% and LVEF >40%, respectively. KCCQ was evaluated at randomization and at 4 and 8 months post-randomization; the effect of dapagliflozin versus placebo on KCCQ total symptom score (TSS) was a pre-specified secondary outcome in both trials. Interaction testing was performed to assess potential heterogeneity in the effects of dapagliflozin versus placebo on KCCQ-TSS, clinical summary score (CSS), overall summary score (OSS), and physical limitation score (PLS), by continuous LVEF using restricted cubic splines. Responder analyses examining the proportion of patients with meaningful deterioration (≥5 point decline) and meaningful improvements (≥5 point increase) in KCCQ-TSS was assessed across LVEF categories. Of 11 007 randomized participants, 10 238 (93%) had full data on KCCQ-TSS at randomization. Benefits of dapagliflozin versus placebo on KCCQ-TSS, -CSS, -OSS, -PLS, at 8 months were consistent across the full range of LVEF (pinteraction = 0.19, 0.10, 0.12, 0.10, respectively). In responder analyses, fewer dapagliflozin- versus placebo-treated patients had clinically meaningful deteriorations in KCCQ-TSS (overall: 21% vs. 23%; LVEF ≤40%: 21% vs. 29%; LVEF 41–60%: 21% vs. 26%; LVEF >60%: 22%

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

Aims: Dapagliflozin resulted in significant and sustained reductions in first and recurrent heart failure (HF) hospitalizations among patients with HF across the spectrum of ejection fraction. How treatment with dapagliflozin differentially impacts hospitalization for HF of varying complexity is not well studied. Methods and results: In the DELIVER and DAPA-HF trials, we examined the effects of dapagliflozin on adjudicated HF hospitalizations of varying complexity and hospital length of stay (LOS). HF hospitalizations requiring intensive care unit stay, intravenous vasoactive therapies, invasive/non-invasive ventilation, mechanical fluid removal or mechanical circulatory support were categorized as complicated. The balance was classified as uncomplicated. Of the total 1209 HF hospitalizations reported in DELIVER, 854 (71%) were uncomplicated and 355 (29%) were complicated. Of the total 799 HF hospitalizations reported in DAPA-HF, 453 (57%) were uncomplicated and 346 (43%) were complicated. Relative to patients experiencing a first uncomplicated HF hospitalization, those with complicated HF hospitalizations had a significantly higher in-hospital mortality both in DELIVER (16.7% vs. 2.3%, p < 0.001) and DAPA-HF (15.1% vs. 3.8%, p < 0.001). Dapagliflozin similarly reduced total ‘uncomplicated’ (DELIVER: rate ratio [RR] 0.67, 95% confidence interval [CI] 0.55–0.82 and DAPA-HF: RR 0.69, 95% CI 0.54–0.87) and ‘complicated’ HF hospitalizations (DELIVER: RR 0.82, 95% CI 0.63–1.06 and DAPA-HF: RR 0.75, 95% CI 0.58–0.97). Dapagliflozin consistently reduced hospitalizations irrespective of their LOS: <5 days (DELIVER: RR 0.76, 95% CI 0.58–0.99 and DAPA-HF: RR 0.58, 95% CI 0.42–0.80) or ≥5 days (DELIVER: RR 0.71, 95% CI 0.58–0.86 and DAPA-HF: RR 0.77, 95% CI 0.62–0.94). Conclusion: A substantial proportion of hospitalizations (∼30–40%) among patients with HF irrespective of ejection fraction required intensification of treatment beyond standard intravenous diuretics

Purpose of Review: Immune checkpoint inhibitors (ICIs) have improved the field of cancer, especially in patients with advanced malignancies. Nevertheless, cardiovascular immune-related adverse events (irAEs) with high mortality and morbidity have been observed, including myocarditis, pericarditis, and vasculitis. To date, only a few clinical risk factors have been described and are currently being investigated. Recent Findings: In this review, we address the four most prevailing risk factors for cardiovascular irAEs. ICI combination therapy is a predominant risk factor for developing ICI-mediated myocarditis. Additionally, ICI combined with other anti-cancer treatments (e.g., tyrosine kinase inhibitors, radiation, chemotherapy) seems to increase the risk of developing cardiovascular irAEs. Other risk factors include female sex, pre-existing cardiovascular disease, and specific tumors, on which we will further elaborate in this review. Summary: An a priori risk strategy to determine who is at risk to develop these cardiovascular irAEs is needed. Insights into the impact of risk factors are therefore warranted to help clinicians improve care and disease management in these patients.

Aims: Patients recently hospitalized for heart failure (HF) often have unstable haemodynamics and experience worsening renal failure, and are at elevated risk for recurrent HF events. In DELIVER, dapagliflozin reduced HF events or cardiovascular death including among patients who were hospitalized or recently hospitalized. Methods and results: We examined the effects of dapagliflozin versus placebo on estimated glomerular filtration rate (eGFR) slope (acute and chronic), 1-month change in systolic blood pressure, and the occurrence of serious hypovolaemic or renal adverse events in patients with and without HF hospitalization within 30 days of randomization. The 654 (90 randomized during hospitalization, 147 1–7 days post-discharge and 417 8–30 days post-discharge) recently hospitalized patients had lower baseline eGFR compared with those without recent HF hospitalization (median [interquartile range] 55 [43, 71] vs. 60 [47, 75] ml/min/1.73 m2). Dapagliflozin consistently reduced the risk of all-cause (pinteraction = 0.20), cardiac-related (pinteraction = 0.75), and HF-specific (pinteraction = 0.90) hospitalizations, irrespective of recent HF hospitalization. In those recently hospitalized, acute placebo-corrected eGFR reductions with dapagliflozin were modest and similar to patients without recent hospitalization (−2.0 [−4.1, +0.1] vs. −3.4 [−3.9, −2.9] ml/min/1.73 m2, pinteraction = 0.12). Dapagliflozin's effect to slow chronic eGFR decline was similar regardless of recent hospitalization (pinteraction = 0.57). Dapagliflozin had a minimal effect on 1-month systolic blood pressure and to a similar degree in patients with and without recent hospitalization (−1.3 vs.−1.8 mmHg, pinteraction = 0.64). There was no treatment-related excess in renal or hypovolaemic serious adverse events, irrespective of recent HF hospitalization. Conclusion: In patients recently hospitalized with H

Background: Cardio-renal-metabolic (CRM) conditions are individually common among patients with heart failure (HF), but the prevalence and influence of overlapping CRM conditions in this population have not been well-studied. Objectives: This study aims to evaluate the impact of overlapping CRM conditions on clinical outcomes and treatment effects of dapagliflozin in HF. Methods: In this post hoc analysis of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we evaluated the prevalence of comorbid CRM conditions (atherosclerotic cardiovascular disease, chronic kidney disease, and type 2 diabetes), their impact on the primary outcome (cardiovascular death or worsening HF), and treatment effects of dapagliflozin by CRM status. Results: Among 6,263 participants, 1,952 (31%), 2,245 (36%), and 1,236 (20%) had 1, 2, and 3 additional CRM conditions, respectively. HF alone was uncommon (13%). Greater CRM multimorbidity was associated with older age, higher body mass index, longer-duration HF, worse health status, and lower left ventricular ejection fraction. Risk of the primary outcome increased with higher CRM overlap, with 3 CRM conditions independently associated with highest risk of primary events (adjusted HR: 2.16 [95% CI: 1.72-2.72]; P < 0.001) compared with HF alone. Relative benefits of dapagliflozin on the primary outcome were consistent irrespective of the type of CRM overlap (P interaction = 0.773) and by the number of CRM conditions (P interaction = 0.734), with greatest absolute benefits among those with highest CRM multimorbidity. Estimated 2-year numbers needed to treat with dapagliflozin to prevent 1 primary event were approximately 52, 39, 33, and 24 for participants with 0, 1, 2, and 3 additional CRM conditions at baseline, respectively. Adverse events between treatment arms were similar across the CRM spectrum. Conclusions: CRM multimorbidity was common and assoc

Importance: Gout is common in patients with heart failure (HF), and sodium-glucose cotransporter 2 inhibitors, a foundational treatment for HF, reduce uric acid levels. Objective: To examine the reported prevalence of gout at baseline, the association between gout and clinical outcomes, and the effect of dapagliflozin in patients with and without gout and the introduction of new uric acid-lowering therapy and colchicine. Design, Setting, and Participants: This post hoc analysis used data from 2 phase 3 randomized clinical trials conducted in 26 countries, DAPA-HF (left ventricular ejection fraction [LVEF] ≤40%) and DELIVER (LVEF >40%). Patients with New York Heart Association functional class II through IV and elevated levels of N-terminal pro-B-type natriuretic peptide were eligible. Data were analyzed between September 2022 and December 2022. Intervention: Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. Main Outcomes and Measures: The primary outcome was the composite of worsening HF or cardiovascular death. Results: Among 11005 patients for whom gout history was available, 1117 patients (10.1%) had a history of gout. The prevalence of gout was 10.3% (488 of 4747 patients) and 10.1% (629 of 6258 patients) in those with an LVEF up to 40% and greater than 40%, respectively. Patients with gout were more often men (897 of 1117 [80.3%]) than those without (6252 of 9888 [63.2%]). The mean (SD) age was similar between groups, 69.6 (9.8) years for patients with gout and 69.3 (10.6) years for those without. Patients with a history of gout had a higher body mass index, more comorbidity, and lower estimated glomerular filtration rate and were more often treated with a loop diuretic. The primary outcome occurred at a rate of 14.7 per 100 person-years (95% CI, 13.0-16.5) in participants with gout compared with 10.5 per 100 person-years (95% CI, 10.1-11.0) in those without (adjusted hazard ratio [HR], 1.15; 95% CI, 1.01-1.31). A

Within the aging population, the frequency of cancer is increasing dramatically. In addition, multiple genetic and environmental factors lead to common multifactorial diseases, including cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, and metabolic-associated fatty liver disease. In recent years, there has been a growing awareness of the connection between cancer and multifactorial diseases, as well as how one can affect the other, resulting in a vicious cycle. Although the exact mechanistic explanations behind this remain to be fully explored, some progress has been made in uncovering the common pathologic mechanisms. In this review, we focus on the nature of the link between cancer and common multifactorial conditions, as well as specific shared mechanisms, some of which may represent either preventive or therapeutic targets. Rather than organ-specific interactions, we herein focus on the shared mechanisms among the multifactorial diseases, which may explain the increased cancer risk. More research on this subject will highlight the significance of developing new drugs that target multiple systems rather than just one disease.

Background: Relative fat mass (RFM) is a novel sex-specific anthropometric equation (based on height and waist measurements) to estimate whole-body fat percentage. Objective: To examine associations of RFM with incident type-2 diabetes (T2D), and to benchmark its performance against body-mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR). Methods: This prospective longitudinal study included data from three Dutch community-based cohorts free of baseline diabetes. First, we examined data from the PREVEND cohort (median age and follow-up duration: 48.0 and 12.5 years, respectively) using Cox regression models. Validation was performed in the Lifelines (median age and follow-up duration: 45.5 and 3.8 years, respectively) and Rotterdam (median age and follow-up duration: 68.0 and 13.9 years, respectively) cohorts. Results: Among 7961 PREVEND participants, 522 (6.6%) developed T2D. In a multivariable model, all adiposity indices were significantly associated with incident T2D (P all<0.001). While 1 SD increase in BMI, WC and WHR were associated with 68%, 77% and 61% increased risk of developing T2D [Hazard ratio (HR) BMI: 1.68 (95%CI: 1.57-1.80), HR WC: 1.77 (95% CI: 1.63-1.92) and HR WHR: 1.61 (95%CI: 1.48-1.75)], an equivalent increase in RFM was associated with 119% increased risk [HR: 2.19 (95%CI: 1.96-2.44)]. RFM was associated with incident T2D across all age groups, with the largest effect size in the youngest (<40 years) age category [HR: 2.90 (95%CI: 2.15-3.92)]. Results were broadly similar in Lifelines (n = 93,870) and Rotterdam (n = 5279) cohorts. Conclusions: RFM is strongly associated with new-onset T2D and displays the potential to be used in the general practice setting to estimate the risk of future diabetes.