Transthyretin amyloidosis prevalence and characteristics in Korean patients with heart failure with preserved or mildly reduced ejection fractions.

The diagnosis and awareness of transthyretin amyloidosis cardiomyopathy (ATTR-CM) in heart failure with left ventricular ejection fraction (LVEF) > 40% remains under-recognized. This study aimed to investigate the prevalence and characteristics of ATTR-CM in patients with heart failure with LVEF > 40%. Patients with LVEF > 40% and maximal left ventricular wall thickness (MWT) > 10 mm who underwent bone scintigraphy were retrospectively investigated. Patients with a definite cause of heart failure were excluded. ATTR-CM was diagnosed when grade 2 or 3 myocardial uptake was observed on scintigraphy. Among 97 patients (male, 62.5%; median age, 69 years), 13 (13.4%) were diagnosed with ATTR-CM (wild type, 69.2%; hereditary type, 30.8%). Age or biomarker levels did not differ significantly; however, all patients with ATTR-CM were male. The ATTR-CM group had a significantly higher prevalence of polyneuropathy or carpal tunnel syndrome than the non-ATTR-CM group, accompanied by a longer PR interval, thicker MWT, larger left atrial volume index, and higher E/e'. Accordingly, ATTR was present in a substantial number, particularly among men. Clinicians should suspect ATTR when a male patient exhibits neurologic symptoms, diastolic dysfunction, and a long PR interval.

Predictive value of the left atrioventricular coupling index for recurrence after radiofrequency ablation of paroxysmal atrial fibrillation.

BACKGROUND: Although patients with paroxysmal atrial fibrillation (PAF) are preferred to undergo catheter ablation (CA), the high possibility of recurrence following surgery is still concerning. We aimed to evaluate the ability of the left atrioventricular coupling index (LACI), which is the ratio of the left atrium end-diastolic volume to the left ventricle end-diastolic volume, to predict PAF recurrence after CA. METHODS: Patients with PAF undergoing CA for the first time between January 2018 and June 2021 were admitted and grouped by recurrence within a year. LACI was measured before CA using ultrasonography. Risk factors identified by multivariable logistic regression analysis, and the area under the receiver operating characteristic (ROC) curve was used to assess the ability of LACI to predict PAF recurrence after CAP. RESULTS: Among the 204 patients treated at our hospital, 164 patients were included in the research after eliminating those who were lost to follow-up. Among them, 56 individuals had recurrence following a 90-day blanking period. Recurrence is more likely in elderly patients with high blood pressure. Patients who suffered recurrence exhibited lower left atrial ejection fraction and increased LACI, left atrial volume minimum, and left atrium volume index maximum. LACI was an independent risk factor for postoperative recurrence (OR: 1.526, 95% CI: 1.325-1.757, P < 0.001), and ROC displayed remarkable predictive value [area under the curve (AUC) = 0.868]. CONCLUSIONS: High LACI is significantly associated with postoperative recurrence in PAF patients, and LACI has incremental prognostic value to predict recurrence.

Diagnostic and prognostic value of microRNA423-5p in patients with heart failure.

OBJECTIVES: MicroRNAs are considered as a class of potential biomarkers for HF. This study aimed to retrospectively evaluate the diagnostic and prognostic value of microRNA423-5p in patients with HF. METHODS: The observational group comprised 98 patients diagnosed with HF due to coronary atherosclerotic heart disease (n = 45), hypertension (n = 26), or cardiac valve insufficiency (n = 27). Conversely, the control group consisted of 30 healthy volunteers without any history of HF. These patients were further classified into heart function class II (n = 33), class III (n = 32), and class IV (n = 33) according to the NYHA classification. Of these patients, 33 were diagnosed with HF with mid-range ejection fraction (HFmrEF) and the remaining 65 with HF with reduced ejection fraction (HFrEF). The diagnostic and prognostic significance of microRNA423-5p in patients with HF was assessed through laboratory parameter assessments (microRNA423-5p and B-type natriuretic peptide test, BNP), cardiac ultrasound evaluations (left ventricular ejection fraction, LVEF), and subsequent follow-up assessments. RESULTS: In this study, we found that patients with HF exhibited notably elevated levels of microRNA423-5p and BNP, as well as significantly lower LVEF values. A significant positive correlation between microRNA423-5p and BNP indicators was validated. In addition, our study also revealed an elevation in the level of microRNA423-5p correlating with the progression of the HF. The combined evaluation of LEVF, BNP, and microRNA423-5p demonstrated superior diagnostic efficacy in comparison to the solitary use of BNP. CONCLUSIONS: Elevated levels of microRNA423-5p in the serum of patients with HF suggest its potential utility as a novel biomarker for both the diagnosis and prognosis of this condition.

Clinical features between paroxysmal and nonparoxysmal atrial fibrillation: a comparative analysis in eastern China.

BACKGROUND: Atrial fibrillation (AF) has emerged as a notable public health issue in China due to the aging population and rapid urbanization. This study aimed to describe the characteristics of patients with AF (paroxysmal and nonparoxysmal) and investigate the association between left ventricular ejection fraction (LVEF) levels and AF subtypes to facilitate early prevention in patients with AF. METHOD: Patients with AF who presented at the cardiology department of the First People's Hospital of Yancheng were recruited in this study. In univariate and multivariate logistic regression analyses, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the relationships between each dependent variable and nonparoxysmal AF. The restricted cubic splines (RCS) curve was employed to explore the linear relationship between LVEF and nonparoxysmal AF on a continuous scale. Subgroup analysis was applied to examine the stability of the results. RESULTS: The study included a total of 2054 patients who were diagnosed with AF. 652 (31.74%) patients had paroxysmal AF, and 1402 (68.26%) had nonparoxysmal AF. Multivariate logistic regression analyses indicated that compared to those with paroxysmal AF, patients with nonparoxysmal AF tended to have a higher prevalence of coronary artery disease, lower levels of LVEF, and an elevated heart rate. Additionally, RCS curves also showed that LVEF was negatively and linearly associated with the nonparoxysmal AF. Furthermore, the association between LVEF and nonparoxysmal AF was stronger among patients with hypertension and obesity (P for interaction < 0.05). CONCLUSIONS: Patients with nonparoxysmal AF have a more advanced AF burden and the transition from paroxysmal to nonparoxysmal AF should be recognized in time, especially to treat the corresponding comorbidities (including hypertension and obesity) more consistently.

Association between triglyceride glycemic index and ejection fraction preserved heart failure in hypertensive patients.

Background: The triglyceride-glucose (TyG) index is regarded as an independent predictor of cardiovascular disease consequences and a reliable surrogate measure of insulin resistance (IR). However, the correlation analysis between triglyceride glucose index and heart failure with preserved ejection fraction in patients with essential hypertension remains unknown. Methods: A single-center, retrospective study was conducted with patients diagnosed with essential hypertension at the First Affiliated Hospital of Xinjiang Medical University, from December 2018 to September 2020. Participants were selected based on specific inclusion and exclusion criteria, with their clinical data and laboratory tests collected. The study employed Spearman's correlation analysis, logistic regression models, restricted cubic spline plots, and receiver operating characteristic (ROC) curves to investigate the relationships between the TyG index and HFpEF. Results: Out of 1,602 enrolled hypertensive patients, 992 were included in the analysis after applying exclusion criteria. Patients were categorized into tertiles based on the TyG index, which showed that patients in the highest tertile had characteristics associated with a higher risk of HFpEF, including age, body mass index (BMI), systolic blood pressure (SBP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and left ventricular mass index (LVMI). A significant, independent association between the TyG index and HFpEF was confirmed, with an odds ratio (OR) of 5.127 (95% CI [3.894-6.856]). Furthermore, an S-shaped nonlinear relationship was observed between the TyG index and the incidence of HFpEF (nonlinear p < 0.001). TyG index (AUC: 0.824, 95% CI [0.795-0.854]), NT-proBNP (AUC: 0.840, 95% CI [0.816-0.864]), and LVMI (AUC: 0.847, 95% CI [0.820-0.875]) showed good predictive ability for HFpEF. In addition, the TyG+LVMI combination demonstrated the strongest predictive ability (AUC: 0.907, 95% CI [0.887-0.927]). Conclusion: The study underscores a significant association between IR, as indicated by the TyG index, and the development of HFpEF in hypertensive patients. It highlights the critical role of metabolic dysfunction in the pathophysiology of HFpEF, advocating for a broader perspective on cardiovascular risk management.

Increased preload and echocardiographic assessment of diastolic function.

AIMS: Echocardiographic diastolic parameters are used to diagnose and monitor increased left ventricular filling pressure (LVFP) and we hypothesized that increased loading conditions cause increased E/e'. Our aim was to assess the effect of preload augmentation on diastolic parameters among both healthy subjects and subjects with known cardiac disease. METHODS AND RESULTS: We included 129 subjects merged from two cohorts; one dialysis cohort (n = 47) and one infusion cohort (n = 82). Echocardiography was performed immediately before and after hemodialysis (HD) or saline infusion, under low and high loading conditions. Elevated LVFP was defined as septal E/e' ≥ 15 and/or lateral E/e' ≥ 13 at high-loading conditions. The population was divided according to elevated LVFP (n = 31) and normal LVFP (n = 98). The load difference for the population was 972 ± 460 mL, with no differences in load difference between elevated and normal LVFP (p NS). The subjects with elevated LVFP were older (63 ± 11 vs. 46 ± 16 years, p < .001), and had lower LV ejection fraction (50 ± 14 vs. 59 ± 8.1%, p < .01). After augmented preload, EDV increased in the normal LVFP group (p < .01) but remained unchanged in the elevated LVFP group (p NS). Both E and e' increased among the subjects with normal LVFP, whereas E/e' remained unchanged (∆E/e' +.1 [-.5-1.2]), p NS). Among the subjects with elevated, LVFP we observed increased E but not e', resulting in significantly increased E/e' (∆ average E/e' +2.4 [0-4.0], p < .01). CONCLUSION: Augmented preload does not seem to affect E/e' among subjects with normal LVFP, whereas E/e' seems to increase significantly among subjects with elevated LVFP.

Heart Failure With Reduced Ejection Fraction Polypill Implementation Strategy in India: A Convergent Parallel Mixed Methods Study.

Introduction: A polypill-based implementation strategy has been proposed to increase rates of guideline-directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction. This has the potential to improve mortality and morbidity in India and undertreated populations globally. Methods: We conducted a convergent parallel mixed methods study integrating quantitative data from stakeholder surveys using modified implementation science outcome measures and qualitative data from key informant in-depth interviews. Our objective was to explore physician, nurse, pharmacist, and patient perspectives on a HFrEF polypill implementation strategy in India from January 2021 to April 2021. Quantitative and qualitative data were integrated to develop an Implementation Research Logic Model. Results: Among 69 respondents to the stakeholder survey, there was moderate acceptability (mean [SD] 3.8 [1.0]), appropriateness (3.6 [1.0]), and feasibility (3.7 [1.0]) of HFrEF polypill implementation strategy. Participants in the key-informant in-depth interviews (n = 20) highlighted numerous relative advantages of the HFrEF polypill innovation including potential to simplify medication regimens and improve patient adherence. Key relative disadvantages elucidated, include concerns about side effects and interruption of multiple GDMT medications due to polypill discontinuation for side effects or hospitalizations. Based on this data, the proposed implementation strategies in the Implementation Research Logic Model include 1) HFrEF polypills, 2) HFrEF polypill initiation, titration, and maintenance protocols, and 3) HFrEF polypill laboratory monitoring protocols for safety which we postulate will lead to desired clinical and implementation outcomes through multiple mechanisms including increased medication adherence to a single pill. Conclusion: This study demonstrates that a HFrEF polypill-based implementation strategy is considered acceptable, feasible, and appropriate among healthcare providers in India. We identified contextually relevant determinants, strategies, mechanism, and outcomes outlined in an Implementation Research Logic Model to inform future research to improve heart failure care in South Asia.

Novel combined echocardiographic score comprising prognostically validated measures of left ventricular size and function to predict long-term survival following myocardial infarction: A proposal to improve risk stratification.

BACKGROUND: While left ventricular ejection fraction (LVEF) is the primary variable utilized for prognosis following myocardial infarction (MI), it is relatively indiscriminate for survival in patients with mildly reduced (> 40%) or preserved LVEF (> 50%). Improving risk stratification in patients with mildly reduced or preserved LVEF remains an unmet need, and could be achieved by using a combination approach using prognostically validated measures of left-ventricular (LV) size, geometry, and function. AIMS: The aim of this study was to compare the prognostic utility of a Combined Echo-Score for predicting all-cause (ACM) and cardiac mortality (CM) following MI to LVEF alone, including the sub-groups with LVEF > 40% and LVEF > 50%. METHODS: Retrospective data on 3094 consecutive patients with MI from 2013 to 2021 who had inpatient echocardiography were included, including both patients with ST-elevation MI (n = 869 [28.1%]) and non-ST-elevation MI (n = 2225 [71.9%]). Echo-Score consisted of LVEF < 40% (2 points) or LVEF < 50% (1 point), and 1 point each for left atrial volume index > 34 mL/m2, septal E/e' > 15, abnormal LV mass-index, tricuspid regurgitation velocity > 2.8 m/s, and abnormal LV end-systolic volume-index. Simple addition was used to derive a score out of 7. RESULTS: At a median follow-up of 4.5 years there were 445 deaths (130 cardiac deaths). On Cox proportional-hazards multivariable analysis incorporating significant clinical and echocardiographic predictors, Echo-Score was an independent predictor of both ACM (HR 1.34, p < .001) and CM (HR 1.59, p < .001). Inter-model comparisons of model 𝛘2, Harrel's C and Somer's D, and Receiver operating curves confirmed the superior prognostic value of Echo-Score for both endpoints compared to LVEF. In the subgroups with LVEF > 40% and LVEF > 50%, Echo-Score was similarly superior to LVEF for predicting ACM and CM. CONCLUSIONS: An Echo-Score composed of prognostically validated LV parameters is superior to LVEF alone for predicting survival in patients with MI, including the subgroups with mildly reduced and preserved LVEF. This could lead to improved patient risk stratification, better-targeted therapies, and potentially more efficient use of device therapies. Further studies should be considered to define the benefit of further investigation and treatment in high-risk subgroups.

The effects of SGLT-2 inhibitors on echocardiographic indices and antioxidative properties in patients with heart failure with reduced ejection fraction and diabetes mellitus.

OBJECTIVE: Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) are a new class of drugs that lower blood glucose and reduce mortality in heart failure patients with reduced ejection fraction (HFrEF). They also have antioxidant effects. The exact mechanism of SGLT-2i is unknown. This study investigated the effects of SGLT-2i on asprosin, matrix metalloproteinase (MMP), and tissue inhibitor of MMP (TIMP-1) concentrations and echocardiographic measurements of strain in the left heart chamber. PATIENTS AND METHODS: This prospective follow-up study included 56 patients with HFrEF and diabetes mellitus (DM) who did not initially receive SGLT-2 inhibitors. The control group consisted of 30 healthy individuals. Patients with HFrEF were administered either empagliflozin (n=28) or dapagliflozin (n=28) in addition to their treatment. The patient group was evaluated for left ventricular global longitudinal strain (LVGLS), left atrial (LA) strain, and LA volumes at the beginning and third month of the study. The control group had blood collected once, while the patient group had it twice: at the start of the trial, on the same day as the echocardiographic evaluation, and at the end of the third month after starting an SGLT-2i. Serum levels of asprosin, MMP-1 and TIMP-1 were assessed. RESULTS: LVGLS increased significantly in HFrEF patients at the third-month assessment compared to baseline (-8.6±2.3% vs. -9±2.5%, respectively; p<0.001), but there was no significant difference in LVEF (p=0.593). A substantial increase was observed in the left atrial ejection fraction (LAEF) compared to baseline values (36.3±9.4% vs. 42.1±8.7%, respectively; p<0.001), driven by a reduction in minimal LA volume [32.5 (19-96) ml vs. 32 (20-86) ml, respectively; p=0.018]. Compared to baseline evaluation, LA reservoir [13 (6-25) vs. 16.5 (2-26), respectively; p<0.001] and contraction strain (7.7±4.3 vs. 9.4±5.6, respectively; p=0.014) values were also enhanced at the third month. Between the baseline and the 3rd month, the patient group's LA conduit strain (p=0.122) and LA maximum volume (p=0.716) remained unchanged. Serum asprosin significantly increased (11.7±5.1 ng/mL vs. 14±9.4 ng/mL, respectively; p=0.032); however, no statistically significant alteration was detected in MMP (p=0.278) and TIMP-1 levels (p=0.401). CONCLUSIONS: SGLT-2i are associated with elevated levels of LVGLS, LAEF, LA contraction strain, and LA reservoir strain. SGLT-2i medications may improve plasma asprosin levels to boost energy metabolism, reduce oxidative stress and reactive oxygen radicals.

The effect of excessive trabeculation on cardiac rotation-A multimodal imaging study.

BACKGROUND: Cardiac rotational parameters in primary symptomatic left ventricular noncompaction (LVNC) with preserved left ventricular ejection fraction (LVEF) are not well understood. We aimed to analyze cardiac rotation measured with cardiac magnetic resonance feature-tracking (CMR-FT) and speckle-tracking echocardiography (Echo-ST) in LVNC morphology subjects with preserved LVEF and different genotypes and healthy controls. METHODS: Our retrospective study included 54 LVNC subjects with preserved LVEF and 54 control individuals. We evaluated functional and rotational parameters with CMR in the total study population and with echocardiography in 39 LVNC and 40 C individuals. All LVNC subjects were genotyped with a 174-gene next-generation sequencing panel and grouped into the subgroups: benign (B), variant of uncertain significance (VUS), and pathogenic (P). RESULTS: In comparison with controls, LVNC subjects had reduced apical rotational degree (p = 0.004) and one-third had negative apical rotation. While the degree of apical rotation was comparable between the three genetic subgroups, they differed significantly in the direction of apical rotation (p<0.001). In contrast to control and B groups, all four studied cardiac rotational patterns were identified in the P and VUS subgroups, namely normal rotation, positive and negative rigid body rotation, and reverse rotation. When the CMR-FT and Echo-ST methods were compared, the direction and pattern of cardiac rotation had moderate to good association (p<0.001) whereas the rotational degrees showed no reasonable correlation or agreement. CONCLUSION: While measuring cardiac rotation using both CMR-FT and Echo-ST methods, subclinical mechanical differences were identified in subjects with LVNC phenotype and preserved LVEF, especially in cases with genetic involvement.

The role of body composition in left ventricular remodeling, reverse remodeling, and clinical outcomes for heart failure with mildly reduced ejection fraction: more knowledge to the "obesity paradox".

BACKGROUND: Although the "obesity paradox" is comprehensively elucidated in heart failure (HF) with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), the role of body composition in left ventricular (LV) remodeling, LV reverse remodeling (LVRR), and clinical outcomes is still unclear for HF with mildly reduced ejection fraction (HFmrEF). METHODS: Our study is a single-centre, prospective, and echocardiography-based study. Consecutive HFmrEF patients, defined as HF patients with a left ventricular ejection fraction (LVEF) between 40 and 49%, between January 2016 to December 2021 were included. Echocardiography was re-examined at 3-, 6-, and 12-month follow-up to assess the LVRR dynamically. Body mass index (BMI), fat mass, fat-free mass, percent body fat (PBF), CUN-BAE index, and lean mass index (LMI) were adopted as anthropometric parameters in our study to assess body composition. The primary outcome was LVRR, defined as: (1) a reduction higher than 10% in LV end-diastolic diameter index (LVEDDI), or a LVEDDI < 33 mm/m2, (2) an absolute increase of LVEF higher than 10 points compared with baseline echocardiogram, or a follow-up LVEF ≥50%. The secondary outcome was a composite of re-hospitalization for HF or cardiovascular death. RESULTS: A total of 240 HFmrEF patients were enrolled in our formal analysis. After 1-year follow-up based on echocardiography, 113 (47.1%) patients developed LVRR. Patients with LVRR had higher fat mass (21.7 kg vs. 19.3 kg, P = 0.034) and PBF (28.7% vs. 26.6%, P = 0.047) compared with those without. The negative correlation between anthropometric parameters and baseline LVEDDI was significant (all P < 0.05). HFmrEF patients with higher BMI, fat mass, PBF, CUN-BAE index, and LMI had more pronounced and persistent increase of LVEF and decline in LV mass index (LVMI). Univariable Cox regression analysis revealed that higher BMI (HR 1.042, 95% CI 1.002-1.083, P = 0.037) and fat mass (HR 1.019, 95% CI 1.002-1.036, P = 0.026) were each significantly associated with higher cumulative incidence of LVRR for HFmrEF patients, while this relationship vanished in the adjusted model. Mediation analysis indicated that the association between BMI and fat mass with LVRR was fully mediated by baseline LV dilation. Furthermore, higher fat mass (aHR 0.957, 95% CI 0.917-0.999, P = 0.049) and PBF (aHR 0.963, 95% CI 0.924-0.976, P = 0.043) was independently associated with lower risk of adverse clinical events. CONCLUSIONS: Body composition played an important role in the LVRR and clinical outcomes for HFmrEF. For HFmrEF patients, BMI and fat mass was positively associated with the cumulative incidence of LVRR, while higher fat mass and PBF predicted lower risk of adverse clinical events but not LMI.

[Study on direct ventricular assist loading mode based on a finite element method].

To investigate the biomechanical effects of direct ventricular assistance and explore the optimal loading mode, this study established a left ventricular model of heart failure patients based on the finite element method. It proposed a loading mode that maintains peak pressure compression, and compared it with the traditional sinusoidal loading mode from both hemodynamic and biomechanical perspectives. The results showed that both modes significantly improved hemodynamic parameters, with ejection fraction increased from a baseline of 29.33% to 37.32% and 37.77%, respectively, while peak pressure, stroke volume, and stroke work parameters also increased. Additionally, both modes showed improvements in stress concentration and excessive fiber strain. Moreover, considering the phase error of the assist device's working cycle, the proposed assist mode in this study was less affected. Therefore, this research may provide theoretical support for the design and optimization of direct ventricular assist devices.

Metabolomic profiling identifies novel metabolites associated with cardiac dysfunction.

Metabolic comorbidities, such as obesity and diabetes, are associated with subclinical alterations in both cardiac structure/function and natriuretic peptides prior to the onset of heart failure (HF). Despite this, the exact metabolic pathways of cardiac dysfunction which precede HF are not well-defined. Among older individuals without HF in the Multi-Ethnic Study of Atherosclerosis (MESA), we evaluated the associations of 47 circulating metabolites measured by 1H-NMR with echocardiographic measures of cardiac structure and function. We then evaluated associations of significant metabolites with circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP). In a separate cohort, we evaluated differences between top metabolites in patients with HF with preserved ejection fraction (HFpEF) and comorbidity-matched controls. Genetic variants associated with top metabolites (mQTLs) were then related to echocardiographic measures and NT-proBNP. Among 3440 individuals with metabolic and echocardiographic data in MESA (62 ± 10 years, 52% female, 38% White), 10 metabolites broadly reflective of glucose and amino acid metabolism were associated with at least 1 measure of cardiac structure or function. Of these 10 metabolites, 4 (myo-inositol, glucose, dimethylsulfone, carnitine) were associated with higher NT-proBNP and 2 (d-mannose, acetone) were associated with lower NT-proBNP. In a separate cohort, patients with HFpEF had higher circulating myo-inositol levels compared with comorbidity-matched controls. Genetic analyses revealed that 1 of 6 known myo-inositol mQTLs conferred risk of higher NT-proBNP. In conclusion, metabolomic profiling identifies several novel metabolites associated with cardiac dysfunction in a cohort at high risk for HF, revealing pathways potentially relevant to future HF risk.

Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials.

BACKGROUND: Heart failure with mildly reduced or preserved ejection fraction (hereafter referred to as HFpEF) is the most common type of heart failure and is associated with a high risk of hospitalisation and death, especially in patients with overweight, obesity, or type 2 diabetes. In the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide improved heart failure-related symptoms and physical limitations in participants with HFpEF. Whether semaglutide also reduces clinical heart failure events in this group remains to be established. METHODS: We conducted a post-hoc pooled, participant-level analysis of four randomised, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) to examine the effects of once-weekly subcutaneous semaglutide (2·4 mg in SELECT, STEP-HFpEF, and STEP-HFpEF DM; 1·0 mg in FLOW) on heart failure events. The STEP-HFpEF and STEP-HFpF DM trials enrolled participants with obesity-related HFpEF, the SELECT trial enrolled participants with atherosclerotic cardiovascular disease and overweight or obesity, and the FLOW trial enrolled participants with type 2 diabetes and chronic kidney disease. Hence, for this analysis, we include all participants from the STEP-HFpEF trials and those with an investigator-reported history of HFpEF from SELECT and FLOW. The main outcomes for this analysis were the composite endpoint of time to cardiovascular death or first worsening heart failure event (defined as hospitalisation or urgent visit due to heart failure), time to first worsening heart failure event, and time to cardiovascular death. Efficacy and safety endpoints were analysed with the full analysis set (ie, all participants randomly assigned to treatment, according to the intention-to-treat principle). The SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials are registered at ClinicalTrials.gov, NCT03574597, NCT03819153, NCT04788511, and NCT04916470, respectively, and all are complete. FINDINGS: Across the four trials, 3743 (16·8%) of 22 282 participants had a history of HFpEF (1914 assigned to semaglutide and 1829 assigned to placebo). In this group of participants with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or heart failure events (103 [5·4%] of 1914 in the semaglutide group had events vs 138 [7·5%] of 1829 in the placebo group; hazard ratio [HR] 0·69 [95% CI 0·53-0·89]; p=0·0045). Semaglutide also reduced the risk of worsening heart failure events (54 [2·8%] vs 86 [4·7%]; HR 0·59 [0·41-0·82]; p=0·0019). No significant effect on cardiovascular death alone was seen (59 [3·1%] vs 67 [3·7%]; HR 0·82 [0·57-1·16]; p=0·25). A lower proportion of patients treated with semaglutide had serious adverse events than did those who were treated with placebo (572 [29·9%] vs 708 [38·7%]). INTERPRETATION: In patients with HFpEF, semaglutide reduced the risk of the combined endpoint of cardiovascular death or worsening heart failure events, and worsening heart failure events alone, whereas its effect on cardiovascular death alone was not significant. These data support the use of semaglutide as an efficacious therapy to reduce the risk of clinical heart failure events in patients with HFpEF, for whom few treatment options are currently available. FUNDING: Novo Nordisk.

Effects of Sotagliflozin on Health Status in Patients With Worsening Heart Failure: Results From SOLOIST-WHF.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve health status in heart failure (HF) across the left ejection fraction ejection spectrum. However, the effects of SGLT1 and SGLT2 inhibition on health status are unknown. OBJECTIVES: These prespecified analyses of the SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trial examined the effects of sotagliflozin vs placebo on HF-related health status. METHODS: SOLOIST-WHF randomized patients hospitalized or recently discharged after a worsening HF episode to receive sotagliflozin or placebo. The primary endpoint was total number of HF hospitalizations, urgent HF visits, and cardiovascular death. Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) score was a prespecified secondary endpoint. This analysis evaluated change in the KCCQ-12 score from baseline to month 4. RESULTS: Of 1,222 patients randomized, 1,113 (91%) had complete KCCQ-12 data at baseline and 4 months. The baseline KCCQ-12 score was low overall (median: 41.7; Q1-Q3: 27.1-58.3) and improved by 4 months in both groups. Sotagliflozin vs placebo reduced the risk of the primary endpoint consistently across KCCQ-12 tertiles (Ptrend = 0.54). Sotagliflozin-treated patients vs those receiving placebo experienced modest improvement in KCCQ-12 at 4 months (adjusted mean change: 4.1 points; 95% CI: 1.3-7.0 points; P = 0.005). KCCQ-12 improvements were consistent across prespecified subgroups, including left ventricular ejection fraction <50% or ≥50%. More patients receiving sotagliflozin vs those receiving placebo had at least small (≥5 points) improvements in KCCQ-12 at 4 months (OR: 1.38; 95% CI: 1.06-1.80; P = 0.017). CONCLUSIONS: Sotagliflozin improved symptoms, physical limitations, and quality of life within 4 months after worsening HF, with consistent benefits across baseline demographic and clinical characteristics. (Effect of Sotagliflozin on Cardiovascular Events in Participants With Type 2 Diabetes Post Worsening Heart Failure [SOLOIST-WHF]; NCT03521934).