Circulation最新文献

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.

Background: Recent randomized trials have demonstrated that for patients with severe tricuspid regurgitation (TR), transcatheter tricuspid valve interventions (TTVI) improve patients' symptoms, function, and quality of life and that the amount of health status improvement correlates with the extent of TR reduction. Defining this relationship in greater detail can potentially provide insight into device selection and patient-specific treatment goals. We therefore sought to better understand the relationship between both baseline TR severity and change in TR after TTVI and the extent of improvement in health status after TTVI.

Methods: As part of the Tri-QOL (Kansas City Cardiomyopathy Questionnaire Validation in Tricuspid Valve Disease) study, data from 11 studies of TTVI devices were transferred to the US Food and Drug Administration to harmonize and anonymize before analysis by an independent center. This secondary, observational analysis used patient-level data from the 6 single-arm studies of patients who underwent TTVI to explore the association of change in KCCQ-OS with TR grade using multivariable models, adjusted for age, sex, chronic lung disease, and baseline KCCQ-OS. The primary model included TR grade at baseline, TR grade at 1 month, and the interaction between the two.

Results: Among 1056 patients with ≥severe TR who underwent TTVI, mean age was 79.1±7.1 years, 60.3% were female, and mean baseline Kansas City Cardiomyopathy Questionnaire-overall summary score [KCCQ-OS] was 49.5±22.3. Baseline TR grade was severe in 33.5%, massive in 35.9%, and torrential in 30.6%. One-month after TTVI, TR was none/trace in 21.7%, mild in 27.2%, moderate in 28.1%, and ≥evere in 23.1%, while the mean change in KCCQ-OS was 17.0±21.3 points. In a multivariable model that included TR grade at baseline, TR grade at 1 month, and their interaction, there was a strong association between reduction in TR and improvement in KCCQ-OS, with no consistent evidence of a threshold of TR grade below which there was no further improvement in KCCQ-OS. However, among patients with baseline torrential TR, the extent of health status improvement plateaued for patients achieving moderate or less TR at 1 month (ie, a 3-grade improvement from baseline).

Conclusions: Health status improvement after TTVI was most strongly associated with the degree of TR reduction, although there was minimal additional improvement for most patients beyond a 3-grade reduction in TR. These findings support the goal of achieving mild or less TR with TTVI, although patients with torrential TR at baseline may be well served if moderate TR can be achieved.