AIMS:While elevated heart rate is an established marker of risk in HF, the prognostic relevance of heart rate is less certain in patients with comorbid atrial fibrillation/flutter (AFF). We investigated the associations between heart rate and outcomes according to AFF status in 5 HFmrEF/HFpEF clinical trials. METHODS:In a participant-level pooled analysis of the CHARM-Preserved, I-PRESERVE, TOPCAT-Americas, PARAGON-HF, and DELIVER trials, associations between baseline heart rate and outcomes according to AFF status on ECG at enrolment were assessed with multivariable Cox and Poisson regression models. The primary outcome was CV death or HF hospitalization. RESULTS:Among 19 975 participants, 5816 (29%) had AFF on baseline ECG. Patients with AFF were older, more frequently male, had a higher baseline heart rate (75 vs 68 bpm, P < .001), and had an increased risk for the primary outcome (adj HR 1.19 [1.10-1.27]). A significant interaction between heart rate, AFF status, and clinical outcomes was observed, such that patients in sinus rhythm had higher event rates with increasing heart rates, while the incident rates for participants in AFF were similar across the range of baseline heart rate (Pinteraction < .001 for the primary outcome). This relationship was not further modified by concomitant β-blocker use. CONCLUSIONS:In this analysis of five HFmrEF/HFpEF trials, baseline heart rate was associated with significantly higher rates of events only in patients in sinus rhythm but not in those with AFF. The optimal management of AFF in the context of HFmrEF/HFpEF requires a dedicated study.

Importance Right ventricular (RV) dysfunction is common among patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and portends worse prognosis. The effects of vutrisiran on RV function remain incompletely characterized. Objective To determine the prevalence and prognostic importance of RV dysfunction in ATTR-CM, and to evaluate the effect of vutrisiran on RV function. Design, Setting, and Participants This post hoc analysis of the HELIOS-B randomized clinical trial (December 2019 and August 2021) included participants with ATTR-CM who had adequate echocardiographic images. Median (IQR) follow-up was 36 (33-36) months. Data analysis was performed from September to December 2025. Interventions Vutrisiran, 25 mg, subcutaneously every 12 weeks vs placebo. Main Outcomes and Measures The primary outcome was a composite of all-cause mortality and recurrent cardiovascular events. RV function was assessed using tricuspid annular systolic myocardial velocity (RV S′), RV fractional area change (RV FAC), RV free wall strain (RVFWS), and RVFWS indexed to pulmonary artery systolic pressure (RVFWS/PASP). Associations with outcomes and treatment effects were evaluated. Results Among 655 participants with ATTR-CM who were randomized, 548 had adequate echocardiographic images. The mean (SD) age was 75 (7) years; 506 patients (92%) were men and 42 (8%) were women. RV dysfunction was more prevalent if defined by abnormal RVFWS (absolute RVFWS ≤20%, 85%) vs RV S′ (≤9.5cm/s, 56%) or RV FAC (≤35%, 31%). Patients in the worst RVFWS quartile (<10.8%, n = 137) had lower estimated glomerular filtration rate, lower left ventricular ejection fraction, and more advanced National Amyloidosis Centre (NAC) stage. Worse RVFWS and RVFWS/PASP were significantly associated with greater risk of all-cause mortality and recurrent cardiovascular events, independent of clinical characteristics, NAC stage, and LV global longitudinal strain. In contrast, associations of RV S′ and RV FAC with outcomes were attenuated after multivariable adjustment. At 30 months, vutrisiran stabilized RVFWS (between-group difference: 1.6%, 95% CI, 0.7 to 2.6%) and improved RVFWS/PASP compared with placebo (between-group difference: +0.08%/mm Hg; 95% CI, 0.03%/mm Hg to 0.13%/mm Hg), with no significant effect on RV FAC (−1.6%; 95% CI, −3.7% to 0.6%). Conclusions and Relevance RV dysfunction assessed by RVFWS is highly prevalent in ATTR-CM and independently predicts mortality and recurrent CV events, whereas conventional RV measures may underestimate RV dysfunction and lack independent prognostic value. This study found that, consistent with its beneficial effects on other measures of cardiac structure and function, vutrisiran stabilized RVFWS and improved RVFWS/PASP at 30 months. Trial Registration ClinicalTrials.gov Identifier: NCT04153149

Importance Left atrial (LA) dysfunction may play an important role in the pathophysiology of transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and is driven by LA remodeling and amyloid infiltration. Objectives To evaluate the prognostic significance of LA structure and function among patients with ATTR-CM and to assess the effects of vutrisiran on these parameters. Design, Setting, and Participants Post hoc analyses were conducted of the HELIOS-B phase 3 randomized clinical trial, which enrolled patients with ATTR-CM between December 2019 and August 2021 at 87 sites in 26 countries. Median (IQR) follow-up was 36 (33-36) months. Data were analyzed from July through November 2025. Interventions Vutrisiran (25 mg subcutaneously every 3 months) vs placebo. Main Outcomes and Measures The primary outcome was all-cause mortality (ACM) and recurrent cardiovascular events. LA structure (LA volume index [LAVi]) and function (LA reservoir [LASr], conduit [LAScd], and contractile strain [LASct]) were assessed, including the effect of vutrisiran on these measures at 30 months. Results A total of 655 patients were enrolled. Among 644 patients with measurable LA strain (median [IQR] age, 77 [72-80] years; 48 female patients [7.5%]; 569 (88.4%) with wild-type ATTR), mean (SD) LA strain measures were substantially below normal (LASr: 9.5% [6.0%]; LAScd: 6.9% [3.9%]; LASct: 4.2% [4.0%]). Patients with worse LASr had more advanced disease, more atrial fibrillation, and more left ventricular systolic and diastolic dysfunction. LASr and LASct were independently associated with ACM and recurrent cardiovascular events (LASr: hazard ratio [HR] per 5% worsening, 1.37; 95% CI, 1.13-1.68; P = .002; LASct: HR per 5% worsening, 1.53; 95% CI, 1.08-2.17; P = .02), recurrent heart failure hospitalizations (LASr: HR, 1.66; 95% CI, 1.22-2.25; P = .001; LASct: HR, 2.23; 95% CI. 1.46-3.71; P < .001), and incident atrial fibrillation (LASr: HR, 1.30; 95% CI, 1.03-1.63; P = .03; LASct: HR, 2.02; 95% CI, 1.38-2.96; P < .001). In contrast, LAVi was not associated with these outcomes. LA strain measures at baseline did not modify the treatment effect of vutrisiran on ACM and recurrent cardiovascular events (LASr: P value for interaction = .60; LAScd: P value for interaction = .58; LASct: P value for interaction = .47). Vutrisiran attenuated worsening in LA strain vs placebo at month 30 (LASr: +1.2%; 95% CI, +0.4% to +1.9%; LAScd: +0.8%; 95% CI, +0.3% to +1.4%; LASct: +0.8%; 95% CI, 0% to +1.6%). Conclusions and Relevance Per the results of this secondary analysis of the HELIOS-B randomized clinical trial, LA dysfunction is common among patients with ATTR-CM and portends a worse prognosis. Consistent with its beneficial effects on other measures of cardiac structure and function, vutrisiran attenuated worsening in LA strain at 30 months, supporting the importance of LA function in the pathophysiology of ATTR-CM and the ability of silencer therapy with vutrisiran to attenuate worsening atrial myopathy in amyloid heart disease. Trial Registration ClinicalTrials.gov Identifier: NCT04153149

BACKGROUND:American Heart Association and American College of Cardiology guidelines articulate 4 aortic stenosis (AS) stages to highlight its progressive nature, but limited data exist on cardiac alterations in sub-severe stages. METHODS:ARIC (Atherosclerosis Risk in Communities) study participants with protocol echocardiography at Visit 5 (V5; 2011-2013) and free of aortic valve (AV) replacement or cardiovascular disease were classified by ACC/AHA AS stages at V5 and Visit 7 (V7; 2018-2019). AS stage progression was defined as AV replacement or hospitalization, or a higher stage at V7. Associations of AS stage at V5 and AS stage progression from V5 to V7 with cardiac structure and function were assessed using multivariable linear regression. Associations of extra-AV cardiac abnormality categories with AS stage progression were assessed by multivariable logistic regression. RESULTS:Of 5206 V5 participants (age 75±5 years, 40% men), AS stages A and B at V5 were associated with greater left ventricular wall thickness, mass, and filling pressure measures at both V5 and V7 compared with Stage 0. Among 1562 participants with assessable AS stage at V7, AS stage progression occurred in 370 and was associated with greater worsening of these measures (all P<0.02). The presence of both left ventricular and left atrial extra-AV abnormalities was associated with greater likelihood of AS stage progression (odds ratio 1.7 [95% CI, 1.2-2.6], P=0.009). CONCLUSIONS:Early AS stages are associated with greater left ventricular mass and diastolic dysfunction, and AS stage progression is associated with worsening of these measures. The presence of both left ventricular and left atrial extra-AV abnormalities is associated with a greater likelihood of early AS stage progression.

BACKGROUND: Systolic blood pressure is a prognostic marker in acute heart failure, but the prognostic implications of in-hospital changes in systolic blood pressure are unclear. We assessed the association between in-hospital systolic blood pressure changes and outcomes in a real-world, multinational cohort of acute heart failure patients. METHODS: We analysed consecutive patients hospitalised for acute heart failure between 2005 and 2020 at two tertiary-care centres (CHUV, Switzerland; NCCIM, Kyrgyzstan) with available systolic blood pressure measurements at admission and discharge. Patients were classified into four systolic blood pressure trajectory categories: stable normal/low (systolic blood pressure consistently <140 mm Hg or minor increase, Δ<10), increasing (systolic blood pressure rose ≥10 mm Hg from <140 to ≥140 mm Hg), decreasing (systolic blood pressure dropped ≥10 mm Hg from ≥140 to <140 mm Hg), stable elevated (systolic blood pressure consistently ≥140 mm Hg or minor decrease, Δ<10). The primary outcome of the study was a composite of first heart failure hospitalisation or all-cause mortality, assessed over a 1-year follow-up period. The association between categories and the primary outcome was assessed with Cox models, adjusted for relevant covariates. RESULTS: Among 1490 patients (80% Swiss, 56% male, age 75 ± 13 years), 621 experienced the primary outcome at 1 year. Compared to those with stable normal/low systolic blood pressure, patients with decreasing systolic blood pressure had a significantly lower risk of the primary outcome (adjusted HR: 0.81; 95% CI: 0.66–0.99; p = 0.040), with no significant differences for the other systolic blood pressure trajectories. Results remained consistent regardless of sex, age and left ventricular ejection fraction (Pinteraction for all >0.05). CONCLUSION: In this real-world, multinational cohort of 1490 acute heart failure patients, in-hospital decline in systolic blood pressure was independently associated with improved outcomes in those with an elevated systolic blood pressure at admission.

Importance:Right ventricular (RV) dysfunction is common among patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and portends worse prognosis. The effects of vutrisiran on RV function remain incompletely characterized. Objective:To determine the prevalence and prognostic importance of RV dysfunction in ATTR-CM, and to evaluate the effect of vutrisiran on RV function. Design, Setting, and Participants:This post hoc analysis of the HELIOS-B randomized clinical trial (December 2019 and August 2021) included participants with ATTR-CM who had adequate echocardiographic images. Median (IQR) follow-up was 36 (33-36) months. Data analysis was performed from September to December 2025. Interventions:Vutrisiran, 25 mg, subcutaneously every 12 weeks vs placebo. Main Outcomes and Measures:The primary outcome was a composite of all-cause mortality and recurrent cardiovascular events. RV function was assessed using tricuspid annular systolic myocardial velocity (RV S'), RV fractional area change (RV FAC), RV free wall strain (RVFWS), and RVFWS indexed to pulmonary artery systolic pressure (RVFWS/PASP). Associations with outcomes and treatment effects were evaluated. Results:Among 655 participants with ATTR-CM who were randomized, 548 had adequate echocardiographic images. The mean (SD) age was 75 (7) years; 506 patients (92%) were men and 42 (8%) were women. RV dysfunction was more prevalent if defined by abnormal RVFWS (absolute RVFWS ≤20%, 85%) vs RV S' (≤9.5cm/s, 56%) or RV FAC (≤35%, 31%). Patients in the worst RVFWS quartile (<10.8%, n = 137) had lower estimated glomerular filtration rate, lower left ventricular ejection fraction, and more advanced National Amyloidosis Centre (NAC) stage. Worse RVFWS and RVFWS/PASP were significantly associated with greater risk of all-cause mortality and recurrent cardiovascular events, independent of clinical characteristics, NAC stage, and LV global longitudinal strain. In contrast, associations of RV S' and RV FAC with outcomes were attenuated after multivariable adjustment. At 30 months, vutrisiran stabilized RVFWS (between-group difference: 1.6%, 95% CI, 0.7 to 2.6%) and improved RVFWS/PASP compared with placebo (between-group difference: +0.08%/mm Hg; 95% CI, 0.03%/mm Hg to 0.13%/mm Hg), with no significant effect on RV FAC (-1.6%; 95% CI, -3.7% to 0.6%). Conclusions and Relevance:RV dysfunction assessed by RVFWS is highly prevalent in ATTR-CM and independently predicts mortality and recurrent CV events, whereas conventional RV measures may underestimate RV dysfunction and lack independent prognostic value. This study found that, consistent with its beneficial effects on other measures of cardiac structure and function, vutrisiran stabilized RVFWS and improved RVFWS/PASP at 30 months. Trial Registration:ClinicalTrials.gov Identifier: NCT04153149.

Importance:Left atrial (LA) dysfunction may play an important role in the pathophysiology of transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and is driven by LA remodeling and amyloid infiltration. Objectives:To evaluate the prognostic significance of LA structure and function among patients with ATTR-CM and to assess the effects of vutrisiran on these parameters. Design, Setting, and Participants:Post hoc analyses were conducted of the HELIOS-B phase 3 randomized clinical trial, which enrolled patients with ATTR-CM between December 2019 and August 2021 at 87 sites in 26 countries. Median (IQR) follow-up was 36 (33-36) months. Data were analyzed from July through November 2025. Interventions:Vutrisiran (25 mg subcutaneously every 3 months) vs placebo. Main Outcomes and Measures:The primary outcome was all-cause mortality (ACM) and recurrent cardiovascular events. LA structure (LA volume index [LAVi]) and function (LA reservoir [LASr], conduit [LAScd], and contractile strain [LASct]) were assessed, including the effect of vutrisiran on these measures at 30 months. Results:A total of 655 patients were enrolled. Among 644 patients with measurable LA strain (median [IQR] age, 77 [72-80] years; 48 female patients [7.5%]; 569 (88.4%) with wild-type ATTR), mean (SD) LA strain measures were substantially below normal (LASr: 9.5% [6.0%]; LAScd: 6.9% [3.9%]; LASct: 4.2% [4.0%]). Patients with worse LASr had more advanced disease, more atrial fibrillation, and more left ventricular systolic and diastolic dysfunction. LASr and LASct were independently associated with ACM and recurrent cardiovascular events (LASr: hazard ratio [HR] per 5% worsening, 1.37; 95% CI, 1.13-1.68; P = .002; LASct: HR per 5% worsening, 1.53; 95% CI, 1.08-2.17; P = .02), recurrent heart failure hospitalizations (LASr: HR, 1.66; 95% CI, 1.22-2.25; P = .001; LASct: HR, 2.23; 95% CI. 1.46-3.71; P < .001), and incident atrial fibrillation (LASr: HR, 1.30; 95% CI, 1.03-1.63; P = .03; LASct: HR, 2.02; 95% CI, 1.38-2.96; P < .001). In contrast, LAVi was not associated with these outcomes. LA strain measures at baseline did not modify the treatment effect of vutrisiran on ACM and recurrent cardiovascular events (LASr: P value for interaction = .60; LAScd: P value for interaction = .58; LASct: P value for interaction = .47). Vutrisiran attenuated worsening in LA strain vs placebo at month 30 (LASr: +1.2%; 95% CI, +0.4% to +1.9%; LAScd: +0.8%; 95% CI, +0.3% to +1.4%; LASct: +0.8%; 95% CI, 0% to +1.6%). Conclusions and Relevance:Per the results of this secondary analysis of the HELIOS-B randomized clinical trial, LA dysfunction is common among patients with ATTR-CM and portends a worse prognosis. Consistent with its beneficial effects on other measures of cardiac structure and function, vutrisiran attenuated worsening in LA strain at 30 months, supporting the importance of LA function in the pathophysiology of ATTR-CM and the ability of silencer therapy with vutrisiran to attenuate worsening atrial myopathy in amyloid heart disease. Trial Registration:ClinicalTrials.gov Identifier: NCT04153149.

Objective: Hyperglycemia (pre-diabetes and diabetes, DM) is associated with heart failure (HF). We aimed to identify distinct metabolites for subclinical cardiac dysfunction (CD), a precursor of HF, in hyperglycemic vs. euglycemic groups. Method: We used data from the ARIC study (Atherosclerosis Risk in Communities). In HF-free 2492 participants at baseline (2011-2013), 1297 were hyperglycemic (HbA1c>5.7%, fasting glucose>100 mg/dL, DM medication, or a DM diagnosis) and 1195 were euglycemic. We performed logistic regression for the association of 790 metabolites and CD, defined by echocardiographic abnormalities (LV hypertrophy, systolic or diastolic dysfunction) or elevated biomarkers (NTproBNP>125 pg/mL or HS troponin T>14 ng/L in women, >22 ng/L in men) at baseline in two glycemic groups separately. We used Cox regression to evaluate the association between CD-related metabolites (i.e., significant metabolites in the cross-sectional analyses) with HF risk. Analyses were adjusted for clinical risk factors and multiple comparisons (FDR< 5%) and replicated in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Results: 34 out of 790 and 16 out of 790 metabolites were associated with CD in the hyperglycemic (15% Black, 33% men) and euglycemic (22% Black, 47% men) groups, respectively. Metabolites previously identified as microvascular disease-related markers (e.g., pseudouridine, N6-carbamoylthreonyladenosine, N6-acetyllysine, N2, N5-diacetylornithine) were associated with CD in the hyperglycemic group (Fig1). Carbohydrate and cofactor-derived metabolites (e.g., gulonate, erythrocyte) were associated with CD in the euglycemic group (Fig1). 10 and 12 distinct CD-related metabolites in hyperglycemic and euglycemic groups, respectively, were also prospectively associated with HF risk (Hazard Ratios 1.2-1.9)(Fig2). 24 out of 34 and 11 out of 16 CD-related metabolites in the hyperglycemic and euglycemic groups, respectively, were available for validation in HCHS/SOL (n 1202, 34% men). The results were consistent with ARIC, where 10 and 12 distinct CD-related metabolites showed nominal significant association with incident HF in two glycemic groups, respectively. Conclusion: Metabolites known for microvascular complications (retinopathy, kidney disease) were associated with CD among hyperglycemic participants, supporting the premise that microvascular dysfunction contributes to HF pathogenesis in people with hyperglycemia.

Introduction: Right ventricular dysfunction is common among patients with transthyretin amyloid cardiomyopathy (ATTR-CM) and is associated with worse prognosis. In HELIOS-B, vutrisiran reduced rates of all-cause mortality (ACM) and recurrent cardiovascular (CV) events among patients with ATTR-CM compared with placebo and had beneficial effects on cardiac structure and function. Its effects on right ventricular free wall strain (RVFWS) are unknown. Hypotheses: RVFWS is associated with clinical outcomes among patients with ATTR-CM. Vutrisiran has favorable effects on RVFWS. Methods: HELIOS-B randomized 655 patients with ATTR-CM to vutrisiran (25mg subcutaneously every 12 weeks) or placebo. Echocardiograms were performed serially during follow-up. The association of baseline RVFWS with ACM and recurrent CV events was investigated using a modified Andersen-Gill model, adjusted for age, sex, ATTR disease type, National Amyloidosis Centre (NAC) stage, RV fractional area change (FAC), and tricuspid annular systolic myocardial velocity (RV S’), and stratified by baseline tafamidis use and treatment assignment. Changes in RVFWS from baseline to month 30 were evaluated using linear regression, adjusted for baseline RVFWS and clinical characteristics. Results: Among 548 (84%) patients with available baseline RVFWS (age 75 ± 7 years, 92% men, 88% wild-type ATTR), mean RVFWS was -14.5± 5.1%. RV dysfunction was prevalent in a greater proportion of patients using RVFWS (>-20%, 85%) as compared with RV S’ (<9.5cm/s, 54%) or RV FAC (<35%, 27%). Patients in the worst RVFWS quartile (>-10.9%, n=137) had more atrial fibrillation, lower eGFR, lower LVEF and worse NYHA class and NAC disease stage. Worse RVFWS at baseline was associated with a heightened risk of ACM and recurrent CV events (adjusted RR 1.38, 95% CI: 1.17 - 1.63), independent of demographic characteristics, ATTR disease type, NAC stage and non-deformation-based metrics of RV function. At 30 months, RVFWS remained stable in the vutrisiran group (0.1%, 95% CI: -0.6, 0.8%) and declined in the placebo group (2.0%, 95% CI:1.2, 2.7), between group difference (-1.6%, 95% CI: -2.6, -0.7%). Conclusions: RVFWS is markedly impaired among patients with ATTR-CM and is strongly and independently associated with higher risk of ACM and recurrent CV events. Consistent with its beneficial effects on other measures of cardiac structure and function, vutrisiran stabilized RVFWS at 30 months compared with worsening in the placebo group.

Introduction: Amyloid infiltration of the atria and cardiac remodeling in response to elevations in intracardiac filling pressures lead to atrial dysfunction in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). In the HELIOS-B trial, vutrisiran reduced rates of all-cause mortality and recurrent cardiovascular (CV) events among patients with ATTR-CM and had favorable effects on cardiac structure and ventricular function. The effects of vutrisiran on left atrial reservoir strain (LASr), a measure of left atrial function, have not been described. Hypotheses: LASr is prognostically important in patients with ATTR-CM. Vutrisiran has favorable effects on LASr. Methods: In the HELIOS-B trial, 655 patients with ATTR-CM were randomized to receive vutrisiran (25 mg subcutaneously every 12 weeks) versus placebo. Echocardiograms were performed serially throughout the trial. Associations of baseline LASr with all-cause mortality as well as all-cause mortality and recurrent CV events were evaluated using Poisson regression models adjusted for age, ATTR disease type, National Amyloidosis Centre (NAC) disease stage, atrial fibrillation/flutter, left atrial volume index, LVEF, baseline tafamidis use and treatment assignment. Changes in LASr from baseline to month 30 were assessed using linear regression, adjusted for baseline LASr and relevant clinical covariates. Results: Among the 644 (98%) patients with available baseline LASr (mean age 75 ± 7 years, 93% men, 88% wild-type ATTR), median LASr was 8.2% [IQR 5.4-12.1%]. Patients with worse LASr were more frequently men, had more atrial fibrillation and worse eGFR, LVEF, NAC disease stage and NYHA functional class. Worse LASr was independently associated with a greater risk of all-cause mortality as well as all-cause mortality and recurrent CV events (Panels A-B). At 30 months, LASr worsened less in the vutrisiran group (-0.9%, 95% CI: -1.5, -0.3%) compared with the placebo group (-2.3%, 95% CI: -3.0, -1.5%) with a between group difference of 1.2% (95% CI: 0.4-2.0%) (Panel C). Conclusions: Impairment in LASr is common among patients with ATTR-CM and is significantly and independently associated with all-cause mortality and recurrent CV events. Consistent with its beneficial effects on other measures of cardiac structure and function, vutrisiran attenuated worsening in LASr at 30 months compared with placebo. These findings support the central role of LA function in the pathophysiology of ATTR-CM.

In the HELIOS-B randomized clinical trial, the RNA interference therapeutic agent vutrisiran reduced the risk of all-cause mortality and recurrent cardiovascular events among patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). In this secondary analysis of HELIOS-B, we evaluated vutrisiran’s effects on echocardiographic measures of cardiac structure and function in patients with ATTR-CM receiving vutrisiran or placebo ( n = 654, 93% men). At 30 months after treatment, as compared to the placebo group, vutrisiran treatment attenuated increases in mean left ventricular (LV) wall thickness (least squares mean difference: −0.4 mm; 95% confidence interval (CI): −0.8, 0.0; P = 0.03) and LV mass index (−10.6 g m − 2 ; 95% CI: −18.0, −3.3; P < 0.01). Vutrisiran treatment also attenuated declines in LV ejection fraction (2.0%; 95% CI: 0.3, 3.7; P = 0.02), absolute global longitudinal strain (1.2%; 95% CI: 0.7, 1.7; P < 0.01) and LV stroke volume (4.1 ml; 95% CI: 1.7, 6.4; P < 0.01), and decreased both the average ratio of early diastolic transmitral flow velocity to early diastolic mitral annular tissue velocity (−2.0; 95% CI: −2.9, −1.2; P < 0.01) and the early to late diastolic transmitral flow velocities ratio (−0.3; 95% CI: −0.6, −0.0; P = 0.04), as compared to placebo. Consistent with its clinical benefits, these echocardiographic findings indicate favorable effects of vutrisiran on cardiac structure and function in patients with ATTR-CM. ClinicalTrials.gov registration: NCT04153149 .

Background Transthyretin amyloid cardiomyopathy (ATTR-CM), caused by deposition of transthyretin amyloid fibrils in the heart, is associated with high morbidity and mortality. In HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy), the RNA interference therapeutic agent vutrisiran reduced rates of the primary composite outcome of all-cause death and recurrent cardiovascular events among patients with ATTR-CM and had beneficial effects on cardiac structure and function over 30 months. Objectives The purpose of this study was to investigate associations of echocardiographic measures of cardiac structure and function with the primary outcome and to assess whether favorable changes in cardiac structure and function with vutrisiran were associated with improvements in outcomes. Methods HELIOS-B randomized 655 patients with ATTR-CM to vutrisiran (25 mg subcutaneously every 12 weeks) or placebo. Echocardiograms were performed at baseline and months 12, 18, 24, and 30. Associations of baseline echocardiographic parameters with the primary outcome were analyzed using modified Andersen-Gill models adjusted for age, sex, ATTR disease type, and National Amyloidosis Centre stage, and stratified by baseline tafamidis use and treatment assignment. Changes in cardiac function from baseline to month 18 were compared between treatment arms and related to outcomes in landmark analyses. Results Among the 654 participants with available echocardiographic data (median age 77 years, 93% male, 88% wild-type transthyretin), baseline left and right ventricular systolic and diastolic function were independently associated with the primary outcome (HR per unit increase, left ventricular ejection fraction, 0.90 per 5% increase, 95% CI: 0.86-0.95; absolute global longitudinal strain, 0.92 per 1% increase, 95% CI: 0.89-0.96; tricuspid annular systolic myocardial velocity, 0.94 per 1-cm/s increase, 95% CI: 0.90-0.98; average E/e’, 1.03 per 1-U increase, 95% CI: 1.01-1.04). At 18 months, vutrisiran attenuated declines in left ventricular and right ventricular systolic function (least squares mean difference: left ventricular ejection fraction, 1.6%, 95% CI: 0.1-3.2; absolute global longitudinal strain, 0.7%, 95% CI: 0.3-1.2; tricuspid annular systolic myocardial velocity, 0.5 cm/s, 95% CI: 0.1-0.9). Worsening in these parameters at 18 months was associated with a heightened risk of the primary outcome. Conclusions Echocardiographic measures of biventricular systolic and diastolic function provide important prognostic information beyond National Amyloidosis Centre stage in patients with ATTR-CM. Vutrisiran improved diastolic function and attenuated declines in left ventricular and right ventricular systolic function over 18 months. The benefits on cardiac function with vutrisiran may partly underlie its beneficial effects on clinical outcomes.

Background Tricuspid regurgitation (TR) is associated with older age and a heightened mortality rate. Limited data exist on TR prevalence and prognostic significance in community‐based older adults. Methods Among 3046 participants in the ARIC (Atherosclerosis Risk in Communities) study who underwent echocardiography at the seventh study visit, TR severity was assessed as none/trace, mild, moderate, or severe by a board‐certified cardiologist. Multivariable linear and logistic regression models assessed associations of TR severity with clinical characteristics, echocardiographic measures, and self‐reported dyspnea. Multivariable Cox proportional hazard models evaluated associations with incident adjudicated heart failure (HF) and death. Results Mean age was 81±4 years, 58% were women, and 25% reported Black race. TR prevalence was 29% mild, 7% moderate, and 1% severe. Greater TR severity was associated with older age, female sex, prevalent HF, and worse cardiac structure and function. Associations with dyspnea were not statistically different in fully adjusted models. Over a median follow‐up of 3.7 (interquartile range, 2.6–4.3) years, there were 154 incident HF events and 412 deaths. Higher TR severity was associated with heightened risk of incident HF after adjusting for demographics, comorbidities, and measures of left ventricular structure and function (hazard ratio, 1.28 [95% CI, 1.01–1.64] per increment in severity category; P=0.04). Greater TR severity was associated with all‐cause death after adjusting for demographics (P=0.003) but not after further adjustment (P=0.3). Conclusions TR is common in older adults and is associated with worse cardiac structure and function. Greater TR severity is independently associated with a greater risk of developing HF.

Introduction Transthyretin cardiomyopathy (ATTR-CM) is associated with high morbidity and mortality. Vutrisiran, an RNA interference therapeutic, rapidly knocks down circulating levels of TTR, thus suppressing the amyloid deposition that drives disease progression. In HELIOS-B, vutrisiran decreased risks of cardiovascular (CV) events and all-cause mortality (ACM) for patients with ATTR-CM. Vutrisiran also positively impacted echocardiographic measures of left ventricular (LV) structure and function compared to placebo. Effects on systolic and diastolic function were observed as early as month 12 of treatment. Objective To evaluate the impact of vutrisiran on echocardiographic measures of cardiac structure and function, and their prognostic value, in patients with ATTR-CM. Method HELIOS-B is a phase 3, randomized, double-blind, placebo-controlled, multicenter study. HELIOS-B randomized 655 patients with wild-type ATTR (wtATTR) or hereditary ATTR-CM to vutrisiran (25mg) or placebo Q3M. The primary endpoint was a composite of ACM and recurrent CV events (CV hospitalizations and urgent heart failure visits) assessed separately in the overall population and in the monotherapy population (defined as patients not on tafamidis at baseline). Patients underwent echocardiograms at baseline, months 12, 18, 24, and 30. The association of select echocardiographic parameters on outcomes, and the impact of vutrisiran on echocardiographic parameters was assessed. Results At baseline (median age 77 years, 93% male, 88% wtATTR) mean LV ejection fraction was 56±13%, absolute peak longitudinal strain 14±3%, and mean LV wall thickness 1.8±0.3cm. Prespecified analyses evaluating the prognostic significance of echocardiographic parameters and the impact of vutrisiran will be presented. Conclusion Improvements in cardiac structure and function support the benefits of vutrisiran in reducing the risk of CV events and ACM compared to placebo for patients with ATTR-CM.These results will likely demonstrate the prognostic significance of echocardiographic parameters of cardiac structure and function on later clinical outcomes of CV events and ACM, as well as the impact of vutrisiran treatment to improve cardiac structure and function.

Continuous-flow left ventricular assist devices (CF-LVADs) improve quality of life and survival in patients with advanced heart failure but are frequently complicated by gastrointestinal bleeding (GIB). Reduced pulsatile flow may induce mucosal hypoxia, upregulating factors such as hypoxia-inducible factor (HIF)-1α and triggering neo-angiogenesis, leading to the development of gastrointestinal angiodysplasias (GIADs), a common cause of GIB. Digoxin inhibits HIF-1α and may prevent GIAD development, although its impact on the incidence of GIB remains uncertain. This meta-analysis (PROSPERO ID: CRD42024626222) evaluated the association between digoxin use and GIB occurrence (primary outcome) in patients with CF-LVADs. Research articles including adults with CF-LVADs, comparing digoxin users versus nonusers were included. Overall, four studies were included (n = 14,917; age 55 ± 13 years, 21% female) with 2,742 patients in the digoxin group and 12,175 in the no-digoxin group. Continuous-flow left ventricular assist device was axial (HeartMate II) in 78% of cases and centrifugal (HeartMate 3/HeartWare) in 22%. Digoxin use was associated with a nonsignificant lower risk of GIB (hazard ratio [HR]: 0.70; 95% confidence interval [CI]: 0.49-1.01). However, regarding GIAD-related GIB, digoxin was associated with a significantly lower risk (HR: 0.33; 95% CI: 0.13-0.82). Among 14,917 patients with CF-LVADs, digoxin use was associated with a trend toward a lower risk of GIB and a lower risk of GIAD-related GIB.

BACKGROUND:Sleep apnea is common in patients with heart failure with preserved ejection fraction (HFpEF). However, the impact of sleep apnea on cardiac structure, function, and outcomes is not well understood. We assessed clinical outcomes and echocardiographic characteristics in participants of the PARAGON-HF echocardiographic substudy. METHODS:PARAGON-HF was a randomized clinical trial of sacubitril/valsartan vs valsartan in patients with heart failure (HF) and left ventricular ejection fraction (LVEF) ≥45%. Echocardiographic variables were adjusted for clinically relevant parameters at baseline. The risk of total HF hospitalization (HFH) and cardiovascular (CV) death by sleep apnea status was analyzed using the semiparametric method of Lin, Wei, Yang, and Ying (LWYY). RESULTS:Among 1097 patients in the PARAGON-HF echocardiographic substudy, 133 (12.1%) had a reported history of sleep apnea. Those with sleep apnea were younger (72 vs 74 years), more often men (64% vs 45%), and had a higher body mass index (33 vs 29 kg/m2). They also had a higher prevalence of diabetes (53% vs 39%) and lower diastolic blood pressure. At baseline, those with sleep apnea had greater adjusted left ventricular (LV) mass index (93 vs 87 g/m²), worse absolute LV global longitudinal strain (15% vs 16%), and worse absolute right ventricular (RV) free wall longitudinal strain (17% vs 19%). Patients with sleep apnea experienced a higher risk of HFH and CV death than those without (adjusted risk ratio = 1.57, 95% CI 1.05, 2.35, P = 0.029), independent of LVEF (P = 0.92). CONCLUSIONS:Patients with HFpEF and sleep apnea exhibited evidence of LV remodeling, subclinical biventricular myocardial dysfunction, and an increased risk of adverse CV events compared to those without sleep apnea, regardless of LVEF.