Circulation最新文献

Background: Exercise-induced physiological cardiac growth regulators may protect the heart from ischemia/reperfusion (I/R) injury. Homeobox-containing 1 (Hmbox1), a homeobox family member, has been identified as a putative transcriptional repressor and is downregulated in the exercised heart. However, its roles in exercise-induced physiological cardiac growth and its potential protective effects against cardiac I/R injury remain largely unexplored.

Methods: We studied the function of Hmbox1 in exercise-induced physiological cardiac growth in mice after 4 weeks of swimming exercise. Hmbox1 expression was then evaluated in human heart samples from deceased patients with myocardial infarction and in the animal cardiac I/R injury model. Its role in cardiac I/R injury was examined in mice with adeno-associated virus 9 (AAV9) vector-mediated Hmbox1 knockdown and in those with cardiac myocyte-specific Hmbox1 ablation. We performed RNA sequencing, promoter prediction, and binding assays and identified glucokinase (Gck) as a downstream effector of Hmbox1. The effects of Hmbox1 together with Gck were examined in cardiomyocytes to evaluate their cell size, proliferation, apoptosis, mitochondrial respiration, and glycolysis. The function of upstream regulator of Hmbox1, ETS1, was investigated through ETS1 overexpression in cardiac I/R mice in vivo.

Results: We demonstrated that Hmbox1 downregulation was required for exercise-induced physiological cardiac growth. Inhibition of Hmbox1 increased cardiomyocyte size in isolated neonatal rat cardiomyocytes and human embryonic stem cell-derived cardiomyocytes but did not affect cardiomyocyte proliferation. Under pathological conditions, Hmbox1 was upregulated in both human and animal postinfarct cardiac tissues. Furthermore, both cardiac myocyte-specific Hmbox1 knockout and AAV9-mediated Hmbox1 knockdown protected against cardiac I/R injury and heart failure. Therapeutic effects were observed when sh-Hmbox1 AAV9 was administered after I/R injury. Inhibition of Hmbox1 activated the Akt/mTOR/P70S6K pathway and transcriptionally upregulated Gck, leading to reduced apoptosis and improved mitochondrial respiration and glycolysis in cardiomyocytes. ETS1 functioned as an upstream negative regulator of Hmbox1 transcription, and its overexpression was protective against cardiac I/R injury.

Conclusions: Our studies unravel a new role for the transcriptional repressor Hmbox1 in exercise-induced physiological cardiac growth. They also highlight the therapeutic potential of targeting Hmbox1 to improve myocardial survival and glucose metabolism after I/R injury.

Aortopathy encompasses a spectrum of conditions predisposing to dilation, aneurysm, dissection, or rupture of the aorta and other blood vessels. Aortopathy is diagnosed commonly in children, from infancy through adolescence, primarily affecting the thoracic aorta, with variable involvement of the peripheral vasculature. Pathogeneses include connective tissue disorders, smooth muscle contraction disorders, and congenital heart disease, including bicuspid aortic valve, among others. The American Heart Association has published guidelines for diagnosis and management of thoracic aortic disease. However, these guidelines are predominantly focused on adults and cannot be applied adeptly to growing children with emerging features, growth and developmental changes, including puberty, and different risk profiles compared with adults. Management to reduce risk of progressive aortic dilation and dissection or rupture in children is complex and involves genetic testing, cardiovascular imaging, medical therapy, lifestyle modifications, and surgical guidance that differ in many ways from adult management. Pediatric practice varies widely, likely because aortopathy is pathogenically heterogeneous, including genetic and nongenetic conditions, and there is limited published evidence to guide care in children. To optimize care and reduce variation in management, experts in pediatric aortopathy convened to generate this scientific statement regarding the cardiovascular care of children with aortopathy. Available evidence and expert consensus were combined to create this scientific statement. The most common causes of pediatric aortopathy are reviewed. This document provides a general framework for cardiovascular management of aortopathy in children, while allowing for modification based on the personal and familial characteristics of each child and family.

Background: Pulmonary hypertension (PH) is a major complication linked to adverse outcomes in heart failure with preserved ejection fraction (HFpEF), yet no specific therapies exist for PH associated with HFpEF (PH-HFpEF). We have recently reported on the role of skeletal muscle SIRT3 (sirtuin-3) in modulation of PH-HFpEF, suggesting a novel endocrine signaling pathway for skeletal muscle modulation of pulmonary vascular remodeling.

Methods: Using skeletal muscle-specific Sirt3 knockout mice (Sirt3^skm-/-) and mass spectrometry-based comparative secretome analysis, we attempted to define the processes by which skeletal muscle SIRT3 defects affect pulmonary vascular health in PH-HFpEF.

Results: Sirt3^skm-/- mice exhibited reduced pulmonary vascular density accompanied by pulmonary vascular proliferative remodeling and elevated pulmonary pressures. Comparative analysis of secretome by mass spectrometry revealed elevated secretion levels of LOXL2 (lysyl oxidase homolog 2) in SIRT3-deficient skeletal muscle cells. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of Sirt3^skm-/- mice, a rat model of PH-HFpEF, and humans with PH-HFpEF. In addition, expression levels of CNPY2 (canopy fibroblast growth factor signaling regulator 2), a known proliferative and angiogenic factor, were increased in pulmonary artery endothelial cells and pulmonary artery smooth muscle cells of Sirt3^skm-/- mice and animal models of PH-HFpEF. CNPY2 levels were also higher in pulmonary artery smooth muscle cells of subjects with obesity compared with nonobese subjects. Moreover, treatment with recombinant LOXL2 protein promoted pulmonary artery endothelial cell migration/proliferation and pulmonary artery smooth muscle cell proliferation through regulation of CNPY2-p53 signaling. Last, skeletal muscle-specific Loxl2 deletion decreased pulmonary artery endothelial cell and pulmonary artery smooth muscle cell expression of CNPY2 and improved pulmonary pressures in mice with high-fat diet-induced PH-HFpEF.

Conclusions: This study demonstrates a systemic pathogenic impact of skeletal muscle SIRT3 deficiency in remote pulmonary vascular remodeling and PH-HFpEF. This study suggests a new endocrine signaling axis that links skeletal muscle health and SIRT3 deficiency to remote CNPY2 regulation in the pulmonary vasculature through myokine LOXL2. Our data also identify skeletal muscle SIRT3, myokine LOXL2, and CNPY2 as potential targets for the treatment of PH-HFpEF.

Background: Studies of the neurovascular contribution to dementia have largely focused on cerebral small vessel disease (CSVD), but the role of intracranial atherosclerotic disease (ICAD) remains unknown in the general population. The objective of this study was to determine the risk of incident dementia from ICAD after adjusting for CSVD and cardiovascular risk factors in a US community-based cohort.

Methods: We acquired brain magnetic resonance imaging examinations from 2011 through 2013 in 1980 Black and White participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective cohort conducted in 4 US communities. Magnetic resonance imaging examinations included high-resolution vessel wall magnetic resonance imaging and magnetic resonance angiography to identify ICAD. Of these participants, 1590 without dementia, without missing covariates, and with adequate magnetic resonance image quality were followed through 2019 for incident dementia. Associations between ICAD and incident dementia were assessed using Cox proportional hazard ratios adjusted for CSVD (characterized by white matter hyperintensities, lacunar infarctions, and microhemorrhages), APOE4 genotype (apolipoprotein E gene ε4), and cardiovascular risk factors.

Results: The mean age (SD) of study participants was 77.4 (5.2) years. ICAD was detected in 34.6% of participants. After a median follow-up of 5.6 years, 286 participants developed dementia. Compared with participants without ICAD, the fully adjusted hazard ratios (95% CIs) for incident dementia in participants with any ICAD, with ICAD only causing stenosis ≤50%, and with ICAD causing stenosis >50% in ≥1 vessel were 1.57 (1.17-2.11), 1.41 (1.02-1.95), and 1.94 (1.32-2.84), respectively. ICAD was associated with dementia even among participants with low white matter hyperintensities burden, a marker of CSVD.

Conclusions: ICAD was associated with an increased risk of incident dementia, independent of CSVD, APOE4 genotype, and cardiovascular risk factors. The increased risk of dementia was evident even among participants with low CSVD burden, a group less likely to be affected by vascular dementia, and in participants with ICAD causing only low-grade stenosis. Our results suggest that ICAD may partially mediate the effect that cardiovascular risk factors have on the brain leading to dementia. Both ICAD and CSVD must be considered to understand the vascular contributions to cognitive decline.