Mitral Annular Tissue Velocity Predicts Survival in Patients With Primary Mitral Regurgitation.

BACKGROUND AND OBJECTIVES: Early diastolic mitral annular tissue (e') velocity is a commonly used marker of left ventricular (LV) diastolic function. This study aimed to investigate the prognostic implications of e' velocity in patients with mitral regurgitation (MR). METHODS: This retrospective cohort study included 1,536 consecutive patients aged <65 years with moderate or severe chronic primary MR diagnosed between 2009 and 2018. The primary and secondary outcomes were all-cause and cardiovascular mortality, respectively. According to the current guidelines, the cut-off value of e' velocity was defined as 7 cm/s. RESULTS: A total of 404 individuals were enrolled (median age, 51.0 years; 64.1% male; 47.8% severe MR). During a median 6.0-year follow-up, there were 40 all-cause mortality and 16 cardiovascular deaths. Multivariate analysis revealed a significant association between e' velocity and all-cause death (adjusted hazard ratio [aHR], 0.770; 95% confidence interval [CI], 0.634-0.935; p=0.008) and cardiovascular death (aHR, 0.690; 95% CI, 0.477-0.998; p=0.049). Abnormal e' velocity (≤7 cm/s) independently predicted all-cause death (aHR, 2.467; 95% CI, 1.170-5.200; p=0.018) and cardiovascular death (aHR, 5.021; 95% CI, 1.189-21.211; p=0.028), regardless of symptoms, LV dimension and ejection fraction. Subgroup analysis according to sex, MR severity, mitral valve replacement/repair, and symptoms, showed no significant interactions. Including e' velocity in the 10-year risk score improved reclassification for mortality (net reclassification improvement [NRI], 0.154; 95% CI, 0.308-0.910; p<0.001) and cardiovascular death (NRI, 1.018; 95% CI, 0.680-1.356; p<0.001). CONCLUSIONS: In patients aged <65 years with primary MR, e' velocity served as an independent predictor of all-cause and cardiovascular deaths.

Can CT measured LA diameter predict the presence and the degree of LV Diastolic Dysfunction?

Objective: This study was conducted to determine whether the presence and the degree of left ventricular diastolic dysfunction (LVDD) can be predicted by the simple LA diameter measured on computed tomography (CTLAD). Methods: Among adult patients who underwent both chest CT and echocardiography in the emergency department from January 2020 to December 2021, a retrospective cross-sectional study was conducted on patients in whom the time interval between the two tests was less than 24 hours. Receiver operating characteristic curve analysis was used to evaluate the diagnostic power of CTLAD for echocardiographic LVDD. Results: In a study involving 373 patients, 192 (51.5%) had LVDD. Among them, 122 (63.5%) had grade 1, 61 (31.8%) had grade 2, and 9 (4.7%) had ≥grade 3 LVDD. Median CTLAD values were 4.1cm for grade 1, 4.5cm for grade 2, and 4.9cm for ≥grade 3 LVDD. The AUC value of CTLAD in distinguishing LVDD of ≥grade 1, ≥grade 2 (optimal cutoff ≥4.4cm), and ≥grade 3 (optimal cutoff ≥4.5cm) were 0.588, 0.657 (with sensitivity 61.4%, specificity 66.0%, positive predictive value [PPV] 29.5%, negative predictive value [NPV] 88.1%, odds ratio [OR] 3.1), and 0.834 (with sensitivity 88.9%, specificity 70.1%, PPV 6.8%, NPV 99.6%, OR 18.7), respectively. Conclusion: CTLAD ≥4.4cm can be used as a rough reference value to distinguish LVDD of ≥grade 2, and CTLAD ≥4.5cm can be very reliably distinguish LVDD of ≥grade 3. CTLAD might be very useful parameter in predicting LVDD in environments where echocardiography is not available.

Effects of trimetazidine on heart failure with reduced ejection fraction and associated clinical outcomes: a systematic review and meta-analysis.

BACKGROUND: Despite maximal treatment, heart failure (HF) remains a major clinical challenge. Besides neurohormonal overactivation, myocardial energy homoeostasis is also impaired in HF. Trimetazidine has the potential to restore myocardial energy status by inhibiting fatty acid oxidation, concomitantly enhancing glucose oxidation. Trimetazidine is an interesting adjunct treatment, for it is safe, easy to use and comes at a low cost. OBJECTIVE: We conducted a systematic review to evaluate all available clinical evidence on trimetazidine in HF. We searched Medline/PubMed, Embase, Cochrane CENTRAL and ClinicalTrials.gov to identify relevant studies. METHODS: Out of 213 records, we included 28 studies in the meta-analysis (containing 2552 unique patients), which almost exclusively randomised patients with HF with reduced ejection fraction (HFrEF). The studies were relatively small (median study size: N=58) and of short duration (mean follow-up: 6 months), with the majority (68%) being open label. RESULTS: Trimetazidine in HFrEF was found to significantly reduce cardiovascular mortality (OR 0.33, 95% CI 0.21 to 0.53) and HF hospitalisations (OR 0.42, 95% CI 0.29 to 0.60). In addition, trimetazidine improved (New York Heart Association) functional class (mean difference: -0.44 (95% CI -0.49 to -0.39), 6 min walk distance (mean difference: +109 m (95% CI 105 to 114 m) and quality of life (standardised mean difference: +0.52 (95% CI 0.32 to 0.71). A similar pattern of effects was observed for both ischaemic and non-ischaemic cardiomyopathy. CONCLUSIONS: Current evidence supports the potential role of trimetazidine in HFrEF, but this is based on multiple smaller trials of varying quality in study design. We recommend a large pragmatic randomised clinical trial to establish the definitive role of trimetazidine in the management of HFrEF.

Early postoperative beta-blockers are associated with improved cardiac output after late complete repair of tetralogy of Fallot: a retrospective cohort study.

Tetralogy of Fallot is the most common cyanotic congenital heart disease. For decades, our institution has cared for humanitarian patients with late presentation of tetralogy of Fallot. They are characterized by severe right ventricular hypertrophy with consecutive diastolic dysfunction, increasing the risk of postoperative low cardiac output syndrome (LCOS). By right ventricular restrictive physiology, we hypothesized that patients receiving early postoperative beta-blockers (within 48 h after cardiopulmonary bypass) may have better diastolic function and cardiac output. This is a retrospective cohort study in a single-center tertiary pediatric intensive care unit. We included > 1-year-old humanitarian patients with a confirmed diagnosis of tetralogy of Fallot undergoing a complete surgical repair between 2005 and 2019. We measured demographic data, preoperative echocardiographic and cardiac catheterization measures, postoperative mean heart rate, vasoactive-inotropic scores, LCOS scores, length of stay, and mechanical ventilation duration. One hundred sixty-five patients met the inclusion criteria. Fifty-nine patients (36%) received early postoperative beta-blockers, associated with a lower mean heart rate, higher vasoactive-inotropic scores, and lower LCOS scores during the first 48 h following cardiopulmonary bypass. There was no significant difference in lengths of stay and ventilation. Conclusion: Early postoperative beta-blockers lower the prevalence of postoperative LCOS at the expense of a higher need for vasoactive drugs without any consequence on length of stay and ventilation duration. This approach may benefit the specific population of children undergoing a late complete repair of tetralogy of Fallot. What is Known: • Prevalence of low cardiac output syndrome is high following a late complete surgical repair of tetralogy of Fallot. What is New: • Early postoperative beta-blockade is associated with lower heart rate, prolonged relaxation time, and lower prevalence of low cardiac output syndrome. • Negative chronotropic agents like beta-blockers may benefit selected patients undergoing a late complete repair of tetralogy of Fallot, who are numerous in low-income countries.

Characterisation of the octogenarians presenting to the diagnostic heart failure clinic: SHEAF registry.

INTRODUCTION: Heart failure (HF) incidence is increasing in older adults with high hospitalisation and mortality rates. Treatment is complicated by side effects and comorbidities. We investigated the clinical characteristics of octogenarians presenting to the HF clinic. METHODS: Data were collected on octogenarians (80-89 years) referred to the HF clinic in two periods. The data included demographics, HF phenotype, comorbidities, symptoms and treatment. We investigate the temporal changes in clinical characteristics using χ2 test. We aimed to determine the clinical characteristics which were associated with optimisation of HF pharmacological intervention in the clinic, conducting multivariate regression analysis. Statistical significance is determined at p<0.05. RESULTS: Data were collected in April 2012 to January 2014 and in June 2021 to December 2022. In this cross-sectional study of temporal data, 571 octogenarians were referred to the clinic in the latter period, in whom the prevalence of HF was 68.48% (391 patients). HF with preserved ejection fraction (HFpEF) was the most common phenotype and increased significantly compared with the first period (46.3% and 29.2%, p<0.001). Frailty, chronic kidney disease and ischaemic heart disease increased significantly versus the first period (p<0.001). During the second period, and following the consultation, of the patients with HF with reduced ejection fraction (HFrEF), 86.4% and 82.7% were on a beta blocker and on an ACE inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, respectively. Clinical characteristics associated with further optimisations of HF pharmacological therapy in the HF clinic were: New York Heart Association (NYHA) functional class III and the presence of HFrEF phenotype CONCLUSIONS: With a prevalence of HF at 68% among the octogenarians referred to the HF clinic, HFpEF incidence is rising. The decision to optimise HF pharmacological treatment in octogenarians is driven by NYHA functional class III and the presence of HFrEF phenotype.

Epidemiology of heart failure in diabetes: a disease in disguise.

Left ventricular diastolic dysfunction (LVDD) without symptoms, and heart failure (HF) with preserved ejection fraction (HFpEF) represent the most common phenotypes of HF in individuals with type 2 diabetes mellitus, and are more common than HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF) and left ventricular systolic dysfunction (LVSD) in these individuals. However, diagnostic criteria for HF have changed over the years, resulting in heterogeneity in the prevalence/incidence rates reported in different studies. We aimed to give an overview of the diagnosis and epidemiology of HF in type 2 diabetes, using both a narrative and systematic review approach; we focus narratively on diagnosing (using the 2021 European Society of Cardiology [ESC] guidelines) and screening for HF in type 2 diabetes. We performed an updated (2016-October 2022) systematic review and meta-analysis of studies reporting the prevalence and incidence of HF subtypes in adults ≥18 years with type 2 diabetes, using echocardiographic data. Embase and MEDLINE databases were searched and data were assessed using random-effects meta-analyses, with findings presented as forest plots. From the 5015 studies found, 209 were screened using the full-text article. In total, 57 studies were included, together with 29 studies that were identified in a prior meta-analysis; these studies reported on the prevalence of LVSD (n=25 studies, 24,460 individuals), LVDD (n=65 studies, 25,729 individuals), HFrEF (n=4 studies, 4090 individuals), HFmrEF (n=2 studies, 2442 individuals) and/or HFpEF (n=8 studies, 5292 individuals), and on HF incidence (n=7 studies, 17,935 individuals). Using Hoy et al's risk-of-bias tool, we found that the studies included generally had a high risk of bias. They showed a prevalence of 43% (95% CI 37%, 50%) for LVDD, 17% (95% CI 7%, 35%) for HFpEF, 6% (95% CI 3%, 10%) for LVSD, 7% (95% CI 3%, 15%) for HFrEF, and 12% (95% CI 7%, 22%) for HFmrEF. For LVDD, grade I was found to be most prevalent. Additionally, we reported a higher incidence rate of HFpEF (7% [95% CI 4%, 11%]) than HFrEF 4% [95% CI 3%, 7%]). The evidence is limited by the heterogeneity of the diagnostic criteria over the years. The systematic section of this review provides new insights on the prevalence/incidence of HF in type 2 diabetes, unveiling a large pre-clinical target group with LVDD/HFpEF in which disease progression could be halted by early recognition and treatment.Registration PROSPERO ID CRD42022368035.

Echocardiographic artificial intelligence for pulmonary hypertension classification.

OBJECTIVE: The classification of pulmonary hypertension (PH) is crucial for determining the appropriate therapeutic strategy. We investigated whether machine learning (ML) algorithms may assist in echocardiographic PH prediction, where current guidelines recommend integrating several different parameters. METHODS: We obtained physical and echocardiographic data from 885 patients who underwent right heart catheterisation (RHC). Patients were classified into three groups: non-PH, precapillary PH and postcapillary PH, based on values obtained from RHC. Using 24 parameters, we created predictive models employing four different classifiers and selected the one with the highest area under the curve. We then calculated the macro-average classification accuracy for PH on the derivation cohort (n=720) and prospective validation data set (n=165), comparing the results with guideline-based echocardiographic assessment obtained from each cohort. RESULTS: Logistic regression with elastic net regularisation had the highest classification accuracy, with areas under the curves of 0.789, 0.766 and 0.742 for normal, precapillary PH and postcapillary PH, respectively. The ML model demonstrated significantly better predictive accuracy than the guideline-based echocardiographic assessment in the derivation cohort (59.4% vs 51.6%, p<0.01). In the independent validation data set, the ML model's accuracy was comparable to the guideline-based PH classification (59.4% vs 57.8%, p=0.638). CONCLUSIONS: This preliminary study suggests promising potential for our ML model in predicting echocardiographic PH. Further research and validation are needed to fully assess its clinical utility in PH diagnosis and treatment decision-making.

Association of HFA-PEFF score with clinical outcomes after catheter ablation for atrial fibrillation.

BACKGROUND: The Heart Failure Association Pretest assessment, echocardiography and natriuretic peptide, functional testing and final aetiology (HFA-PEFF) score has been developed for diagnosing heart failure with preserved ejection fraction (HFpEF), which is frequently associated with atrial fibrillation (AF). We aimed to investigate whether preprocedural HFA-PEFF score could be used to predict clinical outcomes in patients with AF who underwent catheter ablation (CA). METHODS: Overall, 1679 patients with AF who underwent primary CA (71±10 years, 1218 males (72.5%), median follow-up duration 3.3 years) from July 2011 to December 2019 were included in this retrospective study. HFpEF was defined as an HFA-PEFF score ≥5. The primary study outcome was 5-year major adverse cardiovascular and cerebrovascular events (MACCE), which is a composite of all-cause death, hospitalisation for heart failure (HF) and hospitalisation for stroke. RESULTS: The prevalence of HFpEF was 32.3%, but only 7.7% were diagnosed with HF at the time of CHADS2 scoring. Five-year MACCE occurred in 77 patients (4.6%). The cumulative 5-year incidence of MACCE was significantly higher in the HFpEF group than in the non-HFpEF group (11.2% vs 4.8% at 5 years, p<0.001). In the multivariable analysis, HFpEF by the HFA-PEFF score was associated with MACCE (adjusted HR 1.65, 95% CI 1.02 to 2.65, p=0.041). CONCLUSIONS: Early detection of HFpEF using the HFA-PEFF score may have clinical applications in guiding therapeutic decision-making and improving prognosis by preventing HF and stroke in patients with AF undergoing CA.

Indole-3-Propionic Acid Protects Against Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a common but poorly understood form of heart failure, characterized by impaired diastolic function. It is highly heterogeneous with multiple comorbidities, including obesity and diabetes, making human studies difficult. METHODS: Metabolomic analyses in a mouse model of HFpEF showed that levels of indole-3-propionic acid (IPA), a metabolite produced by gut bacteria from tryptophan, were reduced in the plasma and heart tissue of HFpEF mice as compared with controls. We then examined the role of IPA in mouse models of HFpEF as well as 2 human HFpEF cohorts. RESULTS: The protective role and therapeutic effects of IPA were confirmed in mouse models of HFpEF using IPA dietary supplementation. IPA attenuated diastolic dysfunction, metabolic remodeling, oxidative stress, inflammation, gut microbiota dysbiosis, and intestinal epithelial barrier damage. In the heart, IPA suppressed the expression of NNMT (nicotinamide N-methyl transferase), restored nicotinamide, NAD+/NADH, and SIRT3 (sirtuin 3) levels. IPA mediates the protective effects on diastolic dysfunction, at least in part, by promoting the expression of SIRT3. SIRT3 regulation was mediated by IPA binding to the aryl hydrocarbon receptor, as Sirt3 knockdown diminished the effects of IPA on diastolic dysfunction in vivo. The role of the nicotinamide adenine dinucleotide circuit in HFpEF was further confirmed by nicotinamide supplementation, Nnmt knockdown, and Nnmt overexpression in vivo. IPA levels were significantly reduced in patients with HFpEF in 2 independent human cohorts, consistent with a protective function in humans, as well as mice. CONCLUSIONS: Our findings reveal that IPA protects against diastolic dysfunction in HFpEF by enhancing the nicotinamide adenine dinucleotide salvage pathway, suggesting the possibility of therapeutic management by either altering the gut microbiome composition or supplementing the diet with IPA.

Effects of Semaglutide on Symptoms, Function, and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Obesity: A Prespecified Analysis of the STEP-HFpEF Trial.

BACKGROUND: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity experience a high burden of symptoms and functional impairment, and a poor quality of life. In the STEP-HFpEF trial (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity), once-weekly semaglutide 2.4 mg improved symptoms, physical limitations, and exercise function, and reduced inflammation and body weight. This prespecified analysis investigated the effects of semaglutide on the primary and confirmatory secondary end points across the range of the Kansas City Cardiomyopathy Questionnaire (KCCQ) scores at baseline and on all key summary and individual KCCQ domains. METHODS: STEP-HFpEF randomly assigned 529 participants with symptomatic HF, an ejection fraction of ≥45%, and a body mass index of ≥30 kg/m2 to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Dual primary end points change in KCCQ-Clinical Summary Score (CSS) and body weight. Confirmatory secondary end points included change in 6-minute walk distance, a hierarchical composite end point (death, HF events, and change in KCCQ-CSS and 6-minute walk distance) and change in C-reactive protein. Patients were stratified by KCCQ-CSS tertiles at baseline. Semaglutide effects on the primary, confirmatory secondary, and select exploratory end points (N-terminal pro-brain natriuretic peptide) were examined across these subgroups. Semaglutide effects on additional KCCQ domains (Total Symptom Score [including symptom burden and frequency], Physical Limitations Score, Social Limitations Score, Quality of Life Score, and Overall Summary Score) were also evaluated. RESULTS: Baseline median KCCQ-CSS across tertiles was 37, 59, and 77 points, respectively. Semaglutide consistently improved primary end points across KCCQ tertiles 1 to 3 (estimated treatment differences [95% CI]: for KCCQ-CSS, 10.7 [5.4 to 16.1], 8.1 [2.7 to 13.4], and 4.6 [-0.6 to 9.9] points; for body weight, -11 [-13.2 to -8.8], -9.4 [-11.5 to -7.2], and -11.8 [-14.0 to -9.6], respectively; Pinteraction=0.28 and 0.29, respectively); the same was observed for confirmatory secondary and exploratory end points (Pinteraction>0.1 for all). Semaglutide-treated patients experienced improvements in all key KCCQ domains (estimated treatment differences, 6.7-9.6 points across domains; P≤0.001 for all). Greater proportion of semaglutide-treated versus placebo-treated patients experienced at least 5-, 10-, 15-, and 20-point improvements in all KCCQ domains (odds ratios, 1.6-2.9 across domains; P<0.05 for all). CONCLUSIONS: In patients with HFpEF and obesity, semaglutide produced large improvements in HF-related symptoms, physical limitations, exercise function, inflammation, body weight, and N-terminal pro-brain natriuretic peptide, regardless of baseline health status. The benefits of semaglutide extended to all key KCCQ domains. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04788511.

Pathophysiological insights into machine learning-based subphenotypes of acute heart failure with preserved ejection fraction.

OBJECTIVE: The heterogeneous pathophysiology of the diverse heart failure with preserved ejection fraction (HFpEF) phenotypes needs to be examined. We aim to assess differences in the biomarkers among the phenotypes of HFpEF and investigate its multifactorial pathophysiology. METHODS: This study is a retrospective analysis of the PURSUIT-HFpEF Study (N=1231), an ongoing, prospective, multicentre observational study of acute decompensated HFpEF. In this registry, there is a predefined subcohort in which we perform multibiomarker tests (N=212). We applied the previously established machine learning-based clustering model to the subcohort with biomarker measurements to classify them into four phenotypes: phenotype 1 (n=69), phenotype 2 (n=49), phenotype 3 (n=41) and phenotype 4 (n=53). Biomarker characteristics in each phenotype were evaluated. RESULTS: Phenotype 1 presented the lowest value of N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitive C reactive protein, tumour necrosis factor-α, growth differentiation factor (GDF)-15, troponin T and cystatin C, whereas phenotype 2, which is characterised by hypertension and cardiac hypertrophy, showed the highest value of these markers. Phenotype 3 showed the second highest value of GDF-15 and cystatin C. Phenotype 4 presented a low NT-proBNP value and a relatively high GDF-15. CONCLUSIONS: Distinctive characteristics of biomarkers in HFpEF phenotypes would indicate differential underlying mechanisms to be elucidated. The contribution of inflammation to the pathogenesis varied considerably among different HFpEF phenotypes. Systemic inflammation substantially contributes to the pathophysiology of the classic HFpEF phenotype with cardiac hypertrophy. TRIAL REGISTRATION NUMBER: UMIN-CTR ID: UMIN000021831.

Resource utilisation and outcomes of people with heart failure in England: a descriptive analysis of linked primary and secondary care data - the PULSE study.

BACKGROUND: Heart failure (HF) is associated with high levels of resource use and mortality, but prior UK studies have not compared outcomes by HF subtype (HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF)) in large patient populations. This study investigated healthcare resource utilisation and mortality in patients with HF in England, overall and by HF subtype. METHODS: This non-interventional cohort study linked data from the Clinical Practice Research Datalink database to Hospital Episode Statistics inpatient and UK Office for National Statistics mortality data. Patients with a recorded HF diagnosis (new (incident) or existing (prevalent)) based on clinical codes or measures of ejection fraction between 2015 and 2019 were included. RESULTS: Of 383 896 patients identified with HF, 100 224 patients (26%) had a recorded subtype: 68 780 patients with HFrEF (69%) and 31 444 patients (31%) with HFpEF. In total, 918 553 person-years (PY) were included (median follow-up: 2.1 years): 625 619 PY (68%) for unknown HF subtype, 204 862 PY (22%) for HFrEF and 88 017 PY (10%) for HFpEF. Overall, 11% of patients experienced ≥1 HF hospitalisation. After age and sex adjustment, hospitalisations for HF (HHF; including recurrent hospitalisations) and HF-related general practitioner consultations occurred at rates of approximately 80/1000 and 124/1000 PY, respectively, and were highest for patients with HFrEF and unknown subtype. Overall, all-cause and cardiovascular mortality rates were 132/1000 and 49/1000 PY, respectively. Patients with unknown subtype had the highest 1-year and 5-year mortality (20% and 48%), followed by HFrEF (8% and 35%) and HFpEF (6% and 25%). CONCLUSIONS: HF is associated with high levels of healthcare resource use, mortality, HHF and comorbidities. Ensuring that patients receive early and appropriate guideline-directed therapies to manage HF and associated comorbidities is likely to improve patient care and reduce the burden of HF on the English healthcare system.

Single-Cell RNA Sequencing Reveals Metabolic Stress-Dependent Activation of Cardiac Macrophages in a Model of Dyslipidemia-Induced Diastolic Dysfunction.

BACKGROUND: Metabolic distress is often associated with heart failure with preserved ejection fraction (HFpEF) and represents a therapeutic challenge. Metabolism-induced systemic inflammation links comorbidities with HFpEF. How metabolic changes affect myocardial inflammation in the context of HFpEF is not known. METHODS: We found that ApoE knockout mice fed a Western diet recapitulate many features of HFpEF. Single-cell RNA sequencing was used for expression analysis of CD45+ cardiac cells to evaluate the involvement of inflammation in diastolic dysfunction. We focused bioinformatics analysis on macrophages, obtaining high-resolution identification of subsets of these cells in the heart, enabling us to study the outcomes of metabolic distress on the cardiac macrophage infiltrate and to identify a macrophage-to-cardiomyocyte regulatory axis. To test whether a clinically relevant sodium glucose cotransporter-2 inhibitor could ameliorate the cardiac immune infiltrate profile in our model, mice were randomized to receive the sodium glucose cotransporter-2 inhibitor dapagliflozin or vehicle for 8 weeks. RESULTS: ApoE knockout mice fed a Western diet presented with reduced diastolic function, reduced exercise tolerance, and increased pulmonary congestion associated with cardiac lipid overload and reduced polyunsaturated fatty acids. The main immune cell types infiltrating the heart included 4 subpopulations of resident and monocyte-derived macrophages, determining a proinflammatory profile exclusively in ApoE knockout- Western diet mice. Lipid overload had a direct effect on inflammatory gene activation in macrophages, mediated through endoplasmic reticulum stress pathways. Investigation of the macrophage-to-cardiomyocyte regulatory axis revealed the potential effects on cardiomyocytes of multiple inflammatory cytokines secreted by macrophages, affecting pathways such as hypertrophy, fibrosis, and autophagy. Finally, we describe an anti-inflammatory effect of sodium glucose cotransporter-2 inhibitor in this model. CONCLUSIONS: Using single-cell RNA sequencing , in a model of diastolic dysfunction driven by hyperlipidemia, we have determined the effects of metabolic distress on cardiac inflammatory cells, in particular on macrophages, and suggest sodium glucose cotransporter-2 inhibitors as potential therapeutic agents for the targeting of a specific phenotype of HFpEF.

Use of loop diuretics in patients with chronic heart failure: an observational overview.

INTRODUCTION: This study aimed to evaluate the use and dose of loop diuretics (LDs) across the entire ejection fraction (EF) spectrum in a large, 'real-world' cohort of chronic heart failure (HF) patients. METHODS: A total of 10 366 patients with chronic HF from 34 Dutch outpatient HF clinics were analysed regarding diuretic use and diuretic dose. Data regarding daily diuretic dose were stratified by furosemide dose equivalent (FDE)>80 mg or ≤80 mg. Multivariable logistic regression models were used to assess the association between diuretic dose and clinical features. RESULTS: In this cohort, 8512 (82.1%) patients used diuretics, of which 8179 (96.1%) used LDs. LD use was highest among HF with reduced EF (HFrEF) patients (81.1%) followed by HF with mild-reduced EF (76.1%) and HF with preserved ejection fraction EF (73.8%, p<0.001). Among all LDs users, the median FDE was 40 mg (IQR: 40-80). The results of the multivariable analysis showed that New York Heart Association classes III and IV and diabetes mellitus were one of the strongest determinants of an FDE >80 mg, across all HF categories. Renal impairment was associated with a higher FDE across the entire EF spectrum. CONCLUSION: In this large registry of real-world HF patients, LD use was highest among HFrEF patients. Advanced symptoms, diabetes mellitus and worse renal function were significantly associated with a higher diuretic dose regardless of left ventricular ejection fraction.

Outpatient Worsening Among Patients With Mildly Reduced and Preserved Ejection Fraction Heart Failure in the DELIVER Trial.

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 end point (cardiovascular death, HF hospitalization, or urgent HF visit) increased the overall number of patients experiencing an event from 1122 to 1731 (a 54% increase). Dapagliflozin reduced the need for outpatient diuretic intensification alone (hazard ratio, 0.72 [95% CI, 0.64-0.82]) and when analyzed as a part of an expanded composite end point of worsening HF or cardiovascular death (hazard ratio, 0.76 [95% CI, 0.69-0.84]). CONCLUSIONS: In patients with HF with mildly reduced or preserved ejection fraction, worsening HF requiring oral diuretic intensification in ambulatory care was frequent, adversely prognostic, and significantly reduced by dapagliflozin. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03619213.

Colchicine in patients with heart failure and preserved left ventricular ejection fraction: rationale and design of a prospective, randomised, open-label, crossover clinical trial.

INTRODUCTION: Systemic low-grade inflammation is a fundamental pathophysiological mechanism of heart failure with preserved left ventricular ejection fraction (HFpEF). The efficacy of anti-inflammatory therapy in HFpEF is largely understudied. The aim of the study is to assess the anti-inflammatory effect of colchicine in HFpEF by looking at inflammatory biomarkers: high-sensitivity C reactive protein (hsCRP) and soluble suppression of tumorigenicity 2 (sST2). METHODS AND ANALYSIS: This is a single-centre, prospective, randomised controlled, open-label, blinded-endpoint crossover clinical trial of stable but symptomatic patients with HFpEF. Patients will be randomised to either colchicine treatment 0.5 mg two times per day or usual care for 12 weeks followed by a 2-week washout period and crossover to 12 weeks of treatment with the alternate therapy. The primary objective is to investigate if administration of colchicine compared with usual care reduces inflammation in patients with HFpEF measured by primary endpoint sST2 and co-primary endpoint hsCRP at baseline and 12-week follow-up. Secondary objective is to determine if treatment with colchicine influences N-terminal pro-B-type natriuretic peptide levels, left ventricular diastolic function and remodelling, right ventricular systolic function and left atrial volumetric characteristics. We are aiming to enrol a total of 40 participants. This trial will answer the question if colchicine treatment reduces systemic low-grade inflammation and influences left ventricular diastolic function and remodelling with patients with HFpEF. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Ethics Committee of Sechenov University (reference: 03-22). TRIAL REGISTRATION NUMBER: NCT05637398.

A narrative review of heart failure with preserved ejection fraction in breast cancer survivors.

Advances in breast cancer (BC) treatment have contributed to improved survival, but BC survivors experience significant short-term and long-term cardiovascular mortality and morbidity, including an elevated risk of heart failure with preserved ejection fraction (HFpEF). Most research has focused on HF with reduced ejection fraction (HFrEF) after BC; however, recent studies suggest HFpEF is the more prevalent subtype after BC and is associated with substantial health burden. The increased HFpEF risk observed in BC survivors may be explained by treatment-related toxicity and by shared risk factors that heighten risk for both BC and HFpEF. Beyond risk factors with physiological impacts that drive HFpEF risk, such as hypertension and obesity, social determinants of health (SDOH) likely contribute to HFpEF risk after BC, impacting diagnosis, management and prognosis.Increasing clinical awareness of HFpEF after BC and screening for cardiovascular (CV) risk factors, in particular hypertension, may be beneficial in this high-risk population. When BC survivors develop HFpEF, treatment focuses on initiating guideline-directed medical therapy and addressing underlying comorbidities with pharmacotherapy or behavioural intervention. HFpEF in BC survivors is understudied. Future directions should focus on improving HFpEF prevention and treatment by building a deeper understanding of HFpEF aetiology and elucidating contributing risk factors and their pathogenesis in HFpEF in BC survivors, in particular the association with different BC treatment modalities, including radiation therapy, chemotherapy, biological therapy and endocrine therapy, for example, aromatase inhibitors. In addition, characterising how SDOH intersect with these therapies is of paramount importance to develop future prevention and management strategies.