Circulation最新文献

Background: No large registries of patients with acute eosinophilic myocarditis (EM) are available. However, EM is perceived as a cardiac disease with high mortality, affecting mainly young and middle-aged adults according to small series and case reports. Awareness of the clinical presentation, associated systemic conditions, treatments, and outcomes of this uncommon condition is an unmet need.

Methods: In this international, multicenter, retrospective cohort study, 53 centers screened 193 patients with histologically proven acute EM between 1992 and 2023. After the exclusion of patients with insufficient data (n=10), symptoms lasting >30 days (n=19), or histological diagnosis not confirmed after review (n=8), 156 patients were included.

Results: Median age at presentation was 48 years (quartile 1-3, 34-59 years) with male predominance (67.3%), and only 2 were pediatric cases (≤16 years of age; 1.3%). The main signs and symptoms at presentation were dyspnea (75.6%), fever (61.3%), and chest pain (53.2%). Unexpectedly, peripheral eosinophilia was reported in only 57.4% of cases, with a median cell count of 630 eosinophils/μL. The median left ventricular ejection fraction at presentation was 32% (quartile 1-3, 25%-48%). The disorders most frequently associated with EM were eosinophilic granulomatosis with polyangiitis (22.4% of cases) and hypersensitivity forms (14.1%). Idiopathic/undefined forms accounted for 44.9% of cases, and miscellaneous causes accounted for 18.6%. In-hospital death or need for heart transplantation (HTx) occurred in 23 patients (14.7%; 22 deaths and 1 HTx), despite 43.6% being treated with temporary mechanical circulatory support and 92.3% being treated with immunosuppressive agents. Estimated rates of death or HTx at 1 and 3 years were 19.0% and 23.8%. Increased age, decreased left ventricular ejection fraction on admission, and no immunosuppressive therapy during hospitalization were independent predictors of death or HTx. A nonsignificant higher occurrence of deaths or HTx was observed in the hypersensitivity form (46.1%) compared with the eosinophilic granulomatosis with polyangiitis-associated form (13.1%) at 3 years (P=0.15).

Conclusions: Acute EM can often present without peripheral eosinophilia, and rates of in-hospital and midterm mortality or HTx are high. Endomyocardial biopsy is required to reach the final diagnosis of EM because relying on peripheral eosinophilia can lead to missing diagnosis. In-hospital immunosuppression is associated with HTx-free survival, although tailored immunosuppressive therapies are needed to improve outcomes.

Registration: https://www.clinicaltrials.gov; Unique identifier: NCT06447935.

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.

Premenopausal women presenting with acute coronary syndrome (ACS) are a unique and often underrecognized patient population. Although they are traditionally considered at lower cardiovascular risk than other groups, we have begun to appreciate the potential risk for ACS in this younger subset of women. Whereas atherosclerotic disease (obstructive or nonobstructive) accounts for most presentations, a substantial number are attributable to nonatherosclerotic causes, including spontaneous coronary artery dissection, epicardial coronary artery spasm, and coronary embolism. A major challenge at present is the lack of specific data and evidence for the diagnosis and management of these women. Unfortunately, as a result of several factors, diagnostic delays, misclassification, and mistreatment appear to be more frequent than for other patient groups. Of great concern, younger women less often receive guideline-directed therapies after ACS, and younger women with ACS have been shown to have worse outcomes than young men with ACS. Management should be tailored to the unique pathophysiology in premenopausal women, emphasizing early diagnosis, a low threshold for invasive angiography if appropriate, and special consideration in the pregnant patient. Secondary prevention must address traditional cardiovascular and disease-specific risk factors, with consideration of current or future pregnancies and lactation. Participation in cardiac rehabilitation is associated with improved outcomes and must be strongly encouraged, whereas attention to potential post-ACS depression and anxiety is an important aspect of holistic care. Increased patient and health care professional awareness and improved representation in research are critical to closing the knowledge and outcome gaps in premenopausal women with ACS.