Circulation最新文献

Background: End-stage heart failure (HF) remains a major global health challenge, and left ventricular assist devices (LVADs) represent an important therapeutic option. LVAD-mediated mechanical unloading improves cardiac function and promotes myocardial recovery in many patients with HF. How cardiac unloading by LVADs leads to myocardial recovery and whether impairment of these processes underlies the limited myocardial recovery benefit in obese patients remain poorly understood.

Methods: Patients with HF with LVADs were recruited for an investigation of the correlation between patients' body mass index and their response to LVAD-mediated myocardial recovery. Moreover, a mouse model of heterotopic cervical heart transplantation was used to simulate LVAD unloading. Single-nucleus RNA sequencing and stable-isotope tracing metabolomics were performed to explore the changes of signaling pathways and metabolic processes in unloaded hearts. In vitro cyclic stretch assays were used to evaluate how reduced mechanical load regulates cardiomyocyte metabolic pathways. Unloaded hearts from HF mice were used to determine whether the identified metabolic process contributed to unloading-induced myocardial recovery. Furthermore, the unloaded hearts from obese HF mice were used to evaluate whether the identified metabolic process was attenuated by obesity.

Results: HF patients with a higher body mass index (≥28.0) and greater insulin resistance tended to have poorer LVAD-mediated myocardial recovery. Single-nucleus RNA sequencing demonstrated that mechanical unloading activated myocardial insulin signaling and increased glucose uptake. Stable-isotope tracing metabolomics revealed that glucose taken up by unloaded hearts was preferentially diverted into the pentose phosphate pathway. Mechanistically, reduced mechanical stress attenuated Hippo pathway activation in cardiomyocytes, facilitating insulin signaling and enhancing pentose phosphate pathway flux. The unloaded hearts from HF mice revealed that an increase in pentose phosphate pathway flux could reduce oxidative stress and exert cardioprotective effects. However, these benefits were blunted by insulin resistance in obese mice, whereas treatment with insulin sensitizers alleviated insulin resistance and restored unloading-mediated cardioprotection.

Conclusions: In failing hearts, unloading leads to activation of insulin signaling, resulting in increased glucose uptake and an enhanced pentose phosphate pathway to protect cardiomyocytes against oxidative stress. However, this cardioprotective effect is attenuated by obesity-induced insulin resistance. Administration of insulin sensitizers has the potential to improve LVAD-mediated myocardial recovery in obese patients with HF.

Background: Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV.

Methods: A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals).

Results: Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes (WNT4, LEF1, STRN, and KANK2) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90-2.25; P=5.43×10^-62) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank.

Conclusions: This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.

Background: The disruption of the blood-brain barrier (BBB) is a central pathogenic event in many central nervous system disorders. However, the mechanisms regulating BBB function remain incompletely understood, and effective treatments are lacking. Brain mural cells differ significantly from their peripheral counterparts, a distinction likely critical for maintaining BBB integrity.

Methods: We combined proteomic profiling of human brain vs peripheral mural cells with multiple ischemic stroke models (global apolipoprotein D [ApoD] knockout, mural cell-specific ApoD knockout, and adeno-associated virus-mediated ApoD overexpression) to evaluate the role of ApoD in BBB integrity. Mechanistic studies (co-immunoprecipitation, binding assays, including surface plasmon resonance, bio-layer interferometry, cross-linking mass spectrometry, and CD36 loss-of-function approaches, both in vitro and in vivo) were performed to determine how ApoD interacts with CD36 and inhibits its signaling. Finally, we assessed the effect of ApoD glycosylation on CD36 binding and tested therapeutic delivery of hypoglycosylated ApoD in stroke.

Results: Our study has shown an increased expression of ApoD in mural cells after ischemic stroke. We found that mural cell-derived ApoD functions as an inhibitory ligand of endothelial CD36, suppressing pathological endothelial proliferation, preserving BBB integrity, and promoting neurological recovery. Additionally, overexpression of ApoD in mural cells improved BBB integrity and enhanced functional recovery in ApoD-null mice. Mechanistically, ApoD competes with long-chain fatty acids for CD36 binding and directly attenuates downstream CD36 signaling. Furthermore, we reveal that peripheral hyperglycosylated ApoD (hyperglyco-ApoD) showed minimal effect on BBB integrity maintenance, whereas hypoglycosylation of ApoD enhances its binding affinity to CD36, amplifying its therapeutic efficacy. Exogenous administration of hypoglyco-ApoD via vein injection profoundly inhibited BBB disruption and improved neural function, especially in aging stroke.

Conclusions: Our work identifies a previously unrecognized paracrine mechanism in which mural cell-derived ApoD directly engages endothelial CD36 to restrain pathological endothelial proliferation, thereby preserving BBB integrity and promoting neurological recovery after stroke. These findings further suggest that hypoglycosylated ApoD, with its higher CD36-binding affinity, merits investigation as a potential strategy to enhance BBB repair in central nervous system disorders.

Metabolic and genetic abnormalities have long been noted in cardiovascular diseases, but the contribution of mitochondrial genetic (mitochondrial DNA [mtDNA]) variation is understudied. Mitochondrial genetics is complex in that each mitochondrion contains multiple mtDNA copies that may carry different variants, which is called heteroplasmy. Heteroplasmic variation is dynamic, increases with advancing age, and may contribute to aging-related cardiovascular diseases. Pathogenic variants in mitochondrial genes of the mtDNA or nuclear genome cause mitochondrial diseases, often with cardiac involvement, particularly in patients with adult-onset disease. Population-level studies have identified mtDNA variants associated with cardiovascular risk factors and disease, but evaluation of mtDNA genetic variation is often limited to only a handful of variants and small sample sizes. Studies in animal models have linked several mtDNA variants to cardiac remodeling and dysfunction and suggest a role for mitochondrial-nuclear genetic interactions in disease penetrance. The objective of this scientific statement is to outline the current state of understanding of the role of mitochondrial genetics in cardiovascular pathobiology and highlight important gaps in knowledge. The intended audience of this scientific statement is meant to be broad, spanning clinical, translational, and basic researchers and health care professionals. Despite remaining limitations and barriers, recent advances in genomic sequencing, mtDNA gene editing modalities, and the directed differentiation of stem cells to cardiovascular cell types are creating new opportunities to advance understanding of mitochondrial genetics in cardiovascular pathophysiology.

Background: Cardiovascular disease caused by atherosclerosis is responsible for 18 million deaths annually, highlighting a need for new medical therapies, especially for patients who are not eligible for percutaneous intervention. Atherosclerosis is driven by the accumulation of low-density lipoprotein and the formation of foam cells, accompanied by oxidative stress and the accumulation of oxidized low-density lipoprotein (OxLDL), a proinflammatory molecule. Lowering low-density lipoprotein levels is the mainstay of current treatment, along with blood pressure control and lifestyle changes, but to date, it has not been feasible to specifically target inflammatory pathways contributing to plaque development without considerable systemic side effects. Over the past decade, chimeric antigen receptor T cells have been used to treat cancer, resolve cardiac fibrosis, and restore immune balance in autoimmune diseases. In some instances, regulatory T cells endowed with chimeric antigen receptor (CAR Tregs) have been developed to treat autoimmunity through antigen-specific immunosuppression.

Methods: Using an inducible regulatory T cell platform, we created an anti-OxLDL-specific CAR Treg therapy and evaluated cell- and cytokine-mediated immunosuppression to reduce macrophage foam cell formation in vitro. We then tested murine anti-OxLDL CAR Tregs in immunocompetent mouse models of hyperlipidemia and atherosclerosis.

Results: Anti-OxLDL CAR Tregs reduced macrophage foam cell formation in vitro and significantly inhibited atherosclerotic plaque formation in vivo in immunocompetent mouse models.

Conclusions: Anti-OxLDL CAR Tregs mitigate inflammation and plaque deposition associated with OxLDL and may offer a new therapeutic option for atherosclerosis.