Circulation最新文献

Background: The COVID-19 pandemic, caused by SARS-CoV-2, has led to the first approval of mRNA vaccines in humans. By producing the full-length SARS-CoV-2 Spike protein, they induce protective antiviral immunity. Acute myopericarditis (AMP) development after vaccination has repeatedly been reported; however, the pathogenesis of this complication remains elusive.

Methods: In-depth phenotyping of peripheral blood T cells was undertaken in cohorts of patients who developed AMP after mRNA vaccination, patients hospitalized for severe COVID-19, and healthy subjects with no cardiac side effects after mRNA vaccine. Validation studies were carried out using an experimental model of cardiac inflammation, in which a shared epitope elicits functional responses in patients and mice and induces AMP.

Results: We show that T cells from patients with AMP recognize vaccine-encoded Spike epitopes homologous to those of cardiac self-proteins. One of these epitopes, mimicking an amino acid sequence from a cardiomyocyte-expressed K⁺ channel, induced AMP in mice. When functional responses to the Kv2 were analyzed, patients with AMP after mRNA vaccination, but not patients with COVID-19, displayed an expanded pattern of cytokine production similar to that observed in AMP mice and in autoimmune myocarditis. Crucially, T-cell autoimmunity segregates to cardiotropic cMet (c-mesenchymal epithelial transition factor)-expressing T cells and is prevented by cMet inhibition, suggesting that heart homing imprinting, permitted by the unique mRNA vaccine biodistribution, is required for AMP development.

Conclusions: AMP development after mRNA vaccines is mediated by distinct immune components, including molecular mimicry, T-cell receptor affinity, and, importantly, homing imprinting.

Background: The clinical use of risk scores to guide treatment decisions and improve clinical outcomes has rarely been prospectively evaluated. This study aimed to evaluate whether a biomarker-based ABC-AF risk score-guided multidimensional treatment strategy improves long-term outcomes in patients with AF.

Methods: The multicenter, registry-based, randomized, controlled, open-label study enrolled adults with AF. In the ABC-AF strategy arm, the investigator was informed of each individual's ABC-AF score risks for stroke and bleeding, which were used as decision support to tailor treatment recommendations, including preference for type of direct oral anticoagulant treatment. In the standard of care arm, patient management was at the discretion of the investigator. Primary outcome was a composite of stroke or death. Secondary outcomes included stroke, death, major bleeding events, and their composite outcome.

Results: The intention-to-treat population comprised 3933 patients with a median age of 73.7 years; 33.6% were women, 51.3% had paroxysmal AF, 11.2% had a previous stroke or transient ischemic attack, and 85.7% had oral anticoagulant treatment. After randomization, 97.8% in the ABC-AF strategy arm and 92.6% in the standard of care arm received OACs (P<0.0001). Enrollment was prematurely terminated owing to safety concerns with a trend toward higher mortality in patients with CHA₂DS₂-VASc scores of ≥3, and the study was therefore underpowered for its primary objective. Over a median follow-up of 2.6 years, 175 primary events (3.18/100 patient-years [100PY]) occurred in the ABC-AF strategy and 148 (2.67/100PY) in the standard of care arm (hazard ratio [HR], 1.19 [95% CI, 0.96-1.48]; P=0.12). Major bleeding events were 152 (2.82/100PY) versus 141 (2.61/100PY; HR, 1.08 [95% CI, 0.86-1.36]; P=0.50), stroke 48 (0.87/100PY) versus 41 (0.74/100PY; HR, 1.18 [95% CI, 0.78-1.79]; P=0.44), death 136 (2.44/100PY) versus 113 (2.02/100PY; HR, 1.21 [95% CI, 0.94-1.55]; P=0.13), and rates of composite stroke, death, or major bleeding 277 (5.21/100PY) versus 244 (4.55/100PY; HR, 1.14 [95% CI, 0.96-1.36]; P=0.13). Primary outcome results were similar across ABC-AF score subgroups (interaction P=0.98).

Conclusions: The individually tailored multidimensional treatment strategy, based on ABC-AF risk scores, did not improve clinical outcomes compared with usual guideline-based care in patients with AF. The results emphasize the need for prospective testing of the use of risk stratification and precision medicine tools in different clinical settings before implementation in routine care.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03753490.

Background: Cardiovascular disease caused by atherosclerosis is responsible for 18 million deaths annually, highlighting a significant need for new medical therapies, especially for patients who are not eligible for percutaneous interventions. Atherosclerosis is driven by the accumulation of low-density lipoprotein (LDL) and the formation of foam cells, accompanied by oxidative stress and the accumulation of oxidized LDL (OxLDL), a pro-inflammatory molecule. Lowering LDL 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 significant systemic side effects. Over the past decade, chimeric antigen receptor (CAR) T cells have been used to treat cancer, resolve cardiac fibrosis, and restore immune balance in autoimmune diseases. In some instances, T regulatory cells endowed with CAR (CAR Tregs) have been developed to treat autoimmunity through antigen-specific immunosuppression.

Methods: Using an inducible Treg 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 oxidized LDL and may offer a new therapeutic option for atherosclerosis.