Circulation: Heart Failure最新文献

Background: Less than 1 in 3 patients in the United States with heart failure (HF) with reduced ejection fraction are receiving guideline-recommended medical therapy. Remote titration programs outside of structured episodes of care may address this issue and improve the implementation of guideline-recommended care.

Methods: AIM-POWER was a multicenter, open-label, clinical trial of participants with HF with reduced ejection fraction who were not optimized on medical therapy designed to evaluate the safety and efficacy of a digital intervention to guide optimal initiation and titration of pharmacological therapy. Participants were randomized 1:1 to a BiovitalsHF intervention or usual care and followed for 90 days. Participants receiving the intervention assessed their weight daily, and blood pressure and heart rate twice daily. These data were collected remotely and used to create outpatient medication titration recommendations from the BiovitalsHF platform to site clinicians every 2 weeks. The primary outcome was the between-group difference in the change in an HF optimal therapy score.

Results: We randomized 122 participants at 21 sites in the United States. The mean (±SD) age of the participants was 61.6±12.4 years, and 69% were male. The mean left ventricular ejection fraction was 29±6.7%, and the mean baseline HF optimal therapy score was 3.8±1.8 (range, 0-8). At 90 days after randomization, the change in the score was significantly greater in the intervention group than usual care group (1.72 ±1.75 intervention versus 0.44 ±1.18 usual care; P<0.001).

Conclusions: In participants with HF with reduced ejection fraction who were not yet optimized on medical therapy, a digital intervention that focused on the optimization of HF pharmacological therapy resulted in a significantly greater change in an HF optimal therapy score at 90 days than usual care.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04191330.

Background: Patients with cardiovascular conditions like heart failure (HF) often exhibit significant heterogeneity of the risk of clinical events. In clinical trials, large risk heterogeneity can result in an underestimation of treatment effects derived from Cox proportional hazards models. This occurs due to selection bias when estimating the hazard ratio, stemming from a disproportionate reduction of event-free patients in the control group compared with an effective active group over time, ultimately reducing the statistical power. Therefore, it is important to explore alternative analysis methods for outcome trials that are robust with respect to risk heterogeneity.

Methods: We used clinical data from 2 dapagliflozin HF trials-DAPA-HF (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction) and DELIVER (Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction) to characterize the extent of risk heterogeneity and nonproportionality of hazards in HF. We then evaluated a candidate method for estimating treatment effects in HF outcome trials, namely the survival proportional odds model, and compared this to traditional Cox regression in a simulation study.

Results: In the dapagliflozin trials, nonproportional hazards were a larger issue in the HFpEF population of the DELIVER trial compared with the more homogeneous heart failure with reduced ejection fraction population of the DAPA-HF trial. In simulations of populations with varying degrees of heterogeneity, the survival proportional odds model was more robust to heterogeneity and demonstrated higher power compared with traditional Cox regression in high heterogeneity populations, while performing similarly or slightly worse in more or less heterogeneous populations. Reanalyses of the dapagliflozin trials confirmed these findings, with the survival proportional odds model providing consistently higher power in the DELIVER trial and similar power in the DAPA-HF trial.

Conclusions: In HF trials, the survival proportional odds model is a viable and more robust alternative for analyzing time to event outcomes, also providing an intuitive interpretation of the treatment effect directly linked to survival probability: improved odds of being event-free in the active group compared with the control group.

Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03036124 and NCT03619213.

Background: Although chronic obstructive pulmonary disease (COPD) and heart failure with preserved ejection fraction often coexist with overlapping clinical features, they are usually studied separately. The SPIROMICS HF (Subpopulations and Intermediate Outcome Measures in COPD and Heart Failure Study) is testing hypotheses that new computed tomography emphysema subtypes are associated with specific cardiovascular phenotypes (eg, cor pulmonale, cor pulmonale parvus), common airway branch variants are associated with right heart dysfunction, and symptomatic tobacco-exposed persons with preserved spirometry have signs of increased left ventricular afterload.

Methods: SPIROMICS is a multicenter observational study of COPD with extensive pulmonary phenotyping of participants with ≥20 pack-years smoking and nonsmoking controls. COPD and COPD severity were defined by standard spirometric criteria and symptomatic tobacco-exposed persons with preserved spirometry by ≥20 pack-years, normal spirometry, and COPD Assessment Test score >10. SPIROMICS HF selected all participants in SPIROMICS visit 5 at major sites. Its comprehensive speckle-tracking echocardiography, which included physiological perturbations of leg raise and low-intensity exercise, was harmonized prospectively with the Multi-Ethnic Study of Atherosclerosis Early Heart Failure and HeartSHARE (Combining Omics, Deep Phenotyping, and Electronic Health Records for Heart Failure Subtypes and Treatment Targets) studies. The cardiopulmonary magnetic resonance imaging protocol with gadolinium administration included myocardial fibrosis sequences, pulmonary angiography, time-resolved 3-dimensional cine magnetic resonance imaging (4-dimensional flow) of venous return, and metronome-paced tachypnea to induce dynamic hyperinflation. Coronary artery calcium was assessed on computed tomography scans. The Kansas City Cardiomyopathy Questionnaire was administered.

Results: Of the final sample of 753 participants, 57% had COPD (15% mild, 27% moderate, and 15% severe), 18% had symptomatic tobacco-exposed persons with preserved spirometry, 16% were smoking controls, and 8% were nonsmoking controls. Reproducibility of the main measures from speckle-tracking echocardiography (intraclass correlation coefficient, 0.83-0.99), exercise echocardiography (intraclass correlation coefficient, 0.71-0.99) and magnetic resonance imaging (intraclass correlation coefficient, 0.57-0.99) were good-to-excellent, including in severe COPD.

Conclusions: SPIROMICS HF aims to characterize and understand cardiopulmonary interactions in COPD and COPD-related phenotypes to inform targeted treatments for combined cardiopulmonary failure.

Background: Hypertrophic cardiomyopathy (HCM) has traditionally been regarded as a disease of the sarcomere; however, it is in the midst of a paradigm shift with growing recognition of contributions beyond the sarcomere to the heterogeneity of HCM phenotypes. Innovative approaches are essential to uncover novel determinants and mechanisms underlying this heterogeneity. Top-down proteomics has emerged as a powerful method for analysis of proteoforms-the myriad protein products arising from genetic variants, posttranslational modifications, and splicing isoforms from a single gene-offering a more precise lens to understand the disease heterogeneity in HCM. Yet, how proteoforms are altered on a global scale in HCM has not been investigated.

Methods: Global top-down proteomics was performed on myocardial samples from patients with advanced obstructive HCM and nonfailing controls. Specifically, serial protein extraction enabled by the photocleavable surfactant, 4-hexylphenylazosulfonate (Azo), was utilized to solubilize diverse categories of proteins from minimal tissue, including membrane proteins. Subsequently, high-sensitivity top-down mass spectrometry was used to detect and quantify proteoforms across various cellular compartments.

Results: Using this global top-down proteomics approach, we have detected ≈2000 proteoforms across disparate cellular compartments, including the sarcoplasmic reticulum, cytoskeleton, mitochondria, and nucleus, in advanced obstructive HCM tissues. Quantitative analysis uncovered significant alterations not only in sarcomeric but also cytoskeletal, mitochondrial, nucleosome, and sarcoplasmic reticulum proteoforms in HCM as compared with nonfailing controls. Notably, we have discovered a significant proteoform crosstalk among the sarcomere, sarcoplasmic reticulum, and cytoskeleton. Moreover, we have identified a previously unrecognized decrease in succinylated mitochondrial proteoforms as a critical feature of the advanced obstructive HCM proteoform landscape, alongside a marked reduction in acetylation of nucleosome proteins.

Conclusions: This study represents the most comprehensive analysis of the proteoform landscape in HCM to date, uncovering pathways beyond the sarcomere that may contribute to HCM pathophysiology and identifying potential targets for development of therapeutic interventions.

Background: Patients with heart failure tend to experience higher rates of hospital readmissions compared with other ambulatory care-sensitive conditions. In Sweden, the nationwide Care Coordination Act (CCA) was introduced in January 2018 with the goal of improving care coordination, resulting in a reduction of readmissions and length of stay. There is insufficient knowledge regarding the effect of this reform on patients with heart failure.

Methods: We studied the association of implementing CCA on all-cause 30-day readmissions and length of stay for patients over 65 years of age with International Classification of Diseases code I50 (Heart Failure). The data set included all admissions with a primary diagnosis of heart failure among elderly, multimorbid patients between 2015 and 2019. An interrupted time series analysis using hierarchical mixed models with random effects clustered at the hospital ward level was conducted.

Results: A total of 111 414 admissions were included. The average readmission rate for patients with heart failure was 26.8% before and 26.7% after the CCA. The average length of stay was 8.4 days before the CCA and 8.1 days after. Mortality within 30 days was 7.3% before the CCA and 7.5% after. There were no significant differences between the periods before and after. In an analysis assessing the overall linear time trend 2 of 21 regions showed a reduction in readmissions and 10 in length of stay.

Conclusions: After introducing the CCA, no detectable impact was found on readmissions or mortality for patients with heart failure, which is in line with previous studies, such as those studying the US Hospital Readmission Reduction Program. Although no overall association with length of stay could be identified, it was reduced in several Swedish regions. The heterogeneity between regions could be used to understand the specific components needed to achieve the reduction of readmissions in future studies.

Background: Although the effects of various combinations of treatments on mortality and morbidity outcomes in heart failure with reduced ejection fraction (HFrEF) have been evaluated, the impact on quality of life is unknown. This study evaluated and compared the composite impact of pharmacological therapies on quality of life in HFrEF using a frequentist network meta-analysis and systematic review methodology.

Methods: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for randomized controlled trials published between January 1, 2021 and August 10, 2024. We included all contemporary and efficacious HFrEF therapies used in adults. The primary outcome was change in quality of life measured through the Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure Questionnaire, expressed as mean difference (MD).

Results: We identified 41 randomized controlled trials representing 41 145 patients (76.5% male). The trials had a median of 276 participants (105-464), a mean left ventricular ejection fraction of 28%, and a median follow-up time of 5 months (3-8). A combination of angiotensin receptor blocker/neprilysin inhibitors (ARNi)+β-blockers (BB)+sodium-glucose cotransporter 2 inhibitors (SGLT2i; MD, +5.3 [+0.4, +10.3]) was the most effective at improving quality of life followed by ARNi+BB+mineralocorticoid receptor antagonists (MRA)+SGLT2i (MD, +7.1 [-1.0 to +15.2]), ACE inhibitor+BB+MRA+SGLT2i (MD, +5.3 [-2.6, to +13.3]), and ACE inhibitor+BB+MRA+ivabradine (MD, +5.2 [-3.1 to +13.6]), which were not statistically significant. Individually, the most effective treatments for improving quality of life were SGLT2i (MD, +3.4 [+1.4 to +5.30]), ivabradine (MD, +3.3 [+0.1 to +6.4]), ARNi (MD, +2.6 [-3.2 to +8.5]), and MRA (MD, +1.8 [-4.8 to +8.4]).

Conclusions: A composite of ARNi+BB+SGLT2i or ARNi+BB+MRA+SGLT2i was the most effective at improving quality of life in patients with HFrEF.

Background: Some, but not all, patients with heart failure (HF) develop pulmonary vascular disease (PVD), which contributes to poor prognosis. Mechanisms leading to PVD in HF are poorly understood. We aimed to analyze transpulmonary gradients of proteins consumed or elaborated across the lungs to identify mediators of PVD by unbiased proteomics.

Methods: Overall, 21 controls and 160 patients with HF with reduced ejection fraction underwent pulmonary artery catheterization with blood sampling from postcapillary (wedged balloon) and precapillary (unwedged) position to obtain transpulmonary gradients. The samples from controls and HF from the highest (Q4, n=40) and lowest quartile (Q1, n=40) of pulmonary vascular resistance (PVR) were analyzed using the proteomic proximity extension assay (Olink) of 275 proteins. Venous blood concentrations or transpulmonary gradients were analyzed to identify biomarkers or potential mediators of PVD.

Results: Comparison of Q1 and Q4 of PVR identified PSP-D (pulmonary surfactant-associated protein D) as a marker of PVD. Examination of gradients across the lungs in high PVR HF revealed significant uptake of 18 proteins, mostly associated with inflammation (chemokines, oncostatin-M, MMP9 [matrix metalloproteinase 9]) or with TGF (transforming growth factor)/activin pathway (GDF2 [growth differentiation factor 2]/BMP9 [bone morphogenic protein 9]), and release of 5 proteins, notably IL (interleukin) 6 and IL33. In contrast, these protein gradients were negligible in controls and low PVR patients with HF. Active pulmonary release of IL6 contributed to systemic elevation of IL6 and correlated with right ventricular function.

Conclusions: The lungs of patients with HF with high PVR display abnormal uptake and release of proinflammatory cytokines from IL6/gp130 family (IL6, IL33, oncostatin-M), along with increased transpulmonary uptake of GDF2/BMP9. The study shows that proteins orchestrating inflammation or pulmonary vessel remodeling in group 1 pulmonary hypertension, are also operating in patients with PVD due to HF.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06331208.

Background: Fontan conversion (FC) is associated with a lower risk of atrial arrhythmias and thromboembolism, but it is unknown whether FC improves long-term survival. The purpose of this study was to assess the impact of FC on transplant-free survival.

Method: Adults with Fontan palliation were divided into 3 groups: (1) atriopulmonary Fontan connection; (2) atriopulmonary Fontan and subsequent FC to total cavopulmonary connection (TCPC); (3) TCPC at initial Fontan operation. The risk of death/transplant was compared between the 3 groups using Cox regression analysis.

Results: We studied 534 patients (age 27±9 years; males [N=298; 56%]). Patients were divided into atriopulmonary Fontan group (N=199, 37%); FC-TCPC (N=138, 26%); and TCPC (N=197, 37%). The FC-TCPC and TCPC groups have similar 15-year incidence of death/transplant (42% versus 47%; P=0.8), even after excluding the 8% operative mortality in the FC-TCPC group (38% versus 47%; P=0.3). On multivariable analyses, neither FC nor the type of Fontan connection was associated with death/transplant. Rather, the risk factors for death/transplant were older age, hepatorenal dysfunction, heart failure, and higher Fontan pressures. The prevalence and severity of these comorbidities increased with age, suggesting that these factors reflect the duration of Fontan physiology, rather than the type of Fontan connection.

Conclusions: These findings, in addition to the high operative mortality associated with FC, suggest that this may not be the optimal treatment option for most adults with atriopulmonary Fontan presenting with Fontan failure. Duration of Fontan physiology rather than the type of Fontan connection may be the main determinant of outcomes.