Circulation最新文献

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 inhibition 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.

Background: Previous transcatheter valve therapy registry analyses of transcatheter mitral valve in valve (MViV) replacement of degenerated bioprosthesis reported early experience in the United States. Given recent increases in transseptal MViV volumes and introduction of the SAPIEN 3 Ultra valve, it is important to determine contemporary outcomes for patients undergoing transseptal SAPIEN 3/SAPIEN 3 Ultra MViV replacement.

Methods: The Society of Thoracic Surgeons (STS)/American College of Cardiology Transcatheter Valve Therapy Registry was used to extract data for all patients undergoing transseptal SAPIEN 3/SAPIEN 3 Ultra MViV from 2015 to September 2022. Primary efficacy outcome was 1-year all-cause mortality. Secondary end points included 30-day mortality, functional class, quality of life, and mitral valve performance. Primary safety outcomes were device success and in-hospital complications.

Results: A total of 4243 patients with a mean±SD STS score of 9.2±7.7 underwent transseptal MViV at 455 sites. The rate of Mitral Valve Academic Research Consortium technical (96.6%) success was high, and procedural complications were low. All-cause in-hospital, 30-day, and 1-year mortality rates were 3.2%, 4.3%, and 13.4%, respectively. Significant improvements in New York Heart Association class (New York Heart Association I/II, 18% to 87%) and quality of life (Kansas City Cardiomyopathy Questionnaire score, 38 to 78) were noted at 1 year (P<0.0001 for both) after MViV. Upon stratifying by STS scores, it was observed that the low-risk group (STS<4) had a significantly lower in-hospital mortality rate of 0.4%, whereas the intermediate-risk group (STS, 4-8) had an in-hospital mortality rate of 1.9%. From 2015 to 2022, the number of transseptal MViV cases/year increased significantly, whereas procedure times, length of stay, and intensive care unit hours shortened significantly. At the same time, there was a significant trend toward reduced in-hospital (P=0.0005), 30-day (P=0.004), and 1-year mortality rates (P=0.01).

Conclusions: This multicenter, prospective study reports excellent procedural outcomes, acceptable 1-year mortality rates, and a significant improvement in quality of life for patients undergoing transseptal MViV in the contemporary era. Patients in the low-risk and intermediate-risk STS score categories had significantly better outcomes compared with those in the high-risk category. MViV is a reasonable therapy for the majority of patients with degenerated bioprosthetic mitral valves, who are anatomical candidates.

Background: Complete revascularization is the standard treatment for patients with ST-segment-elevation myocardial infarction and multivessel disease. The FIRE trial (Functional Assessment in Elderly Myocardial Infarction Patients With Multivessel Disease) confirmed the benefit of complete revascularization in a population of older patients, but the follow-up is limited to 1 year. Therefore, the long-term benefit (>1 year) of this strategy in older patients is debated. To address this, an individual patient data meta-analysis was conducted in patients with ST-segment-elevation myocardial infarction ≥75 years of age enrolled in randomized clinical trials investigating complete versus culprit-only revascularization strategies.

Methods: PubMed, Embase, and the Cochrane database were systematically searched to identify randomized clinical trials comparing complete versus culprit-only revascularization. Individual patient-level data were collected from the relevant trials. The primary end point was death, myocardial infarction, or ischemia-driven revascularization. The secondary end point was cardiovascular death or myocardial infarction.

Results: Data from 7 randomized clinical trials encompassing 1733 patients (917 randomized to culprit-only and 816 to complete revascularization) were analyzed. The median age was 79 [interquartile range, 77-83] years. Of the patients, 595 (34%) were female. Follow-up ranged from a minimum of 6 months to a maximum of 6.2 years (median, 2.5 [interquartile range, 1-3.8] years). Complete revascularization reduced the primary end point up to 4 years (hazard ratio, 0.78 [95% CI, 0.63-0.96]) but not at the longest available follow-up (hazard ratio, 0.83 [95% CI, 0.69-1.01]). Complete revascularization significantly reduced the occurrence of cardiovascular death or myocardial infarction at the longest available follow-up (hazard ratio, 0.76 [95% CI, 0.58-0.99]). This was observed even when censoring the follow-up at each year. Long-term rate of death did not differ between complete and culprit-only revascularization arms.

Conclusions: In this individual patient data meta-analysis of older patients with ST-segment-elevation myocardial infarction and multivessel disease, complete revascularization reduced the primary end point of death, myocardial infarction, or ischemia-driven revascularization up to 4 years. At the longest follow-up, complete revascularization reduced the composite of cardiovascular death or myocardial infarction but not the primary end point.

Registration: URL: https://www.crd.york.ac.uk/prospero/; Unique identifier: CRD42022367898.

Background: Pulmonary hypertension, characterized by vascular remodeling, currently lacks curative therapeutic options. The dysfunction of pulmonary artery endothelial cells plays a pivotal role in the initiation and progression of pulmonary hypertension (PH). ErbB3 (human epidermal growth factor receptor 3), also recognized as HER3, is a member of the ErbB family of receptor tyrosine kinases.

Methods: Microarray, immunofluorescence, and Western blotting analyses were conducted to investigate the pathological role of ErbB3. Blood samples were collected for biomarker examination from healthy donors or patients with hypoxic PH. The pathological functions of ErbB3 were further validated in rodents subjected to chronic hypoxia- and Sugen-induced PH, with or without adeno-associated virus-mediated ErbB3 overexpression, systemic deletion, or endothelial cell-specific ErbB3 knockdown. Primary human pulmonary artery endothelial cells and pulmonary artery smooth muscle cells were used to elucidate the underlying mechanisms.

Results: ErbB3 exhibited significant upregulation in the serum, lungs, distal pulmonary arteries, and pulmonary artery endothelial cells isolated from patients with PH compared with those from healthy donors. ErbB3 overexpression stimulated hypoxia-induced endothelial cell proliferation, exacerbated pulmonary artery remodeling, elevated systolic pressure in the right ventricle, and promoted right ventricular hypertrophy in murine models of PH. Conversely, systemic deletion or endothelial cell-specific knockout of ErbB3 yielded opposite effects. Coimmunoprecipitation and proteomic analysis identified YB-1 (Y-box binding protein 1) as a downstream target of ErbB3. ErbB3 induced nuclear translocation of YB-1 and subsequently promoted hypoxia-inducible factor 1/2α transcription. A positive loop involving ErbB3-periostin-hypoxia-inducible factor 1/2α was identified to mediate the progressive development of this disease. MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH.

Conclusions: Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH.