Circulation最新文献

Clonal hematopoiesis (CH), the benign clonal expansion of hematopoietic stem cells, is often caused by somatic sequence variations in genes associated with hematologic malignancies. Over the past decade, CH has emerged as a risk factor for a wide range of cardiovascular diseases (CVDs), including atherosclerosis, heart failure, atrial fibrillation, and thrombosis. The cardiovascular risk associated with CH is heterogeneous; it varies on the basis of specific genes and variants, clone size, and various extrinsic features. Mechanistic studies suggest that CH contributes to CVDs through both gene-specific pathways and broader inflammatory processes. These include aberrant cytokine production, inflammasome activation, and other proinflammatory mechanisms, which can accelerate atherosclerosis, promote thrombogenesis, and impair vascular or myocardial function. These findings underscore the importance of addressing CH as a potential contributor to CVDs. CH is predominantly considered an age-related phenomenon, but lifelong influences on the fitness of genetic variants, including germline predispositions, obesity, chronic inflammation, and exposure to environmental toxins (eg, tobacco, certain cancer treatments), influence CH. A greater understanding of CH risk factors is therefore important for both individual and population-level risk assessments. Incorporating CH-associated risk into existing CVD risk prediction models may inform new personalized preventive or therapeutic approaches. No CH-specific therapies have proven efficacy in CVD treatment or prevention, but multiple molecular-based therapeutic hypotheses are beginning to be tested.

Background: Venous thromboembolism (VTE) is a leading cardiovascular disease, yet its etiology is incompletely understood. This study used large-scale, high-throughput aptamer-based proteomics to identify new circulating protein biomarkers and biological pathways for incident VTE.

Methods: We included 4 longitudinal cohorts (the ARIC study [Atherosclerosis Risk in Communities], CHS [Cardiovascular Health Study], MESA [Multi-Ethnic Study of Atherosclerosis], and the HUNT study [Trøndelag Health]) that identified 1371 incident noncancer VTEs among 20 737 participants followed for a maximum of 10 to 29 years. We used the SomaScan to measure baseline plasma levels of ≈5000 to 7000 proteins and examined the prospective relationships between the protein biomarkers and noncancer VTE. We then conducted an external replication of top VTE proteins in 783 incident noncancer VTEs among 39 097 participants in the UKB study (UK Biobank) based on the Olink proteomics platform. We used Cox proportional hazards regression to estimate the association between each protein biomarker and VTE risk. Mendelian randomization (MR) analysis was used to assess the possible causal associations between identified proteins and VTE risk.

Results: There were 23 proteins that exceeded a false discovery rate-adjusted P<0.05 (unadjusted P<6.5×10^-4) in the discovery meta-analysis of ARIC, CHS, and MESA and were replicated in HUNT at (unadjusted) P<0.05. Of these, 15 are new to VTE, and 3 of the 15 (transgelin, sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1, and TIMP4 [metalloproteinase inhibitor 4]) exceeded the Bonferroni corrected significance threshold in HUNT. Sixteen of the 23 top VTE proteins were available on the UKB Olink panel, of which 11 were replicated in the UKB study after Bonferroni correction. MR analysis of the 15 new proteins provided significant evidence for a possible causal role of TIMD4 (T-cell immunoglobulin and mucin domain-containing protein 4) (Bonferroni-corrected P<0.05) and suggestive evidence for TIMP4 and CST3 (cystatin-c) (unadjusted P<0.05) in VTE risk. The direction of association from the MR analyses was opposite of that from the VTE proteomics analysis for TIMP4 and TIMD4 but was consistent for CST3.

Conclusions: We identified several novel plasma proteins for VTE that reflect biological processes outside established VTE pathophysiology, including extracellular matrix regulation, immunity, immune-vascular endothelium interactions, and vascular senescence. Results may provide new modifiable targets to improve VTE risk stratification, prevention, or treatment.

Risk prediction has been used in the primary prevention of cardiovascular disease for >3 decades. Contemporary cardiovascular risk assessment relies on multivariable models, which integrate established cardiovascular risk factors and have evolved over time from the Framingham Risk Model to the pooled cohort equations to the PREVENT (Predicting Risk of CVD Events) equations. Recent scientific (ie, genomics, proteomics, metabolomics) and methodologic (ie, artificial intelligence) advances have led to a proliferation of novel models, biomarkers, and tools for potential use in risk prediction. In parallel, the growing armamentarium of preventive therapies, some with considerable cost, underscores the need for more accurate and precise risk assessment to prioritize those at highest risk who will derive the greatest absolute benefit. Accompanying the considerable enthusiasm for the potential of newer approaches to improve risk prediction is the need for rigorous evaluation and assessment of their performance (ie, accuracy, precision, incremental performance when added to contemporary multivariable risk models or established risk factors) and clinical utility (ie, actionability, scalability, generalizability) before adoption in clinical practice. Additional considerations in risk tool evaluation include reproducibility, cost-value considerations (including impact on downstream health care costs), and implications for health equity. This scientific statement defines a standardized framework for general considerations in risk prediction, statistical assessment of predictive utility, and critical appraisal of clinical utility and readiness. This scientific statement is intended to support clinicians, researchers, and policymakers in how best to evaluate current and emerging risk prediction tools and ultimately improve the prevention of cardiovascular disease in diverse populations.

Background: The high-dose inactivated influenza vaccine (HD-IIV) has demonstrated superior protection against a range of hospitalization end points versus standard-dose inactivated influenza vaccine (SD-IIV), but its effectiveness against specific cardiovascular outcomes and in those with pre-existing cardiovascular disease (CVD) is not well elucidated.

Methods: In a prespecified secondary analysis of the FLUNITY-HD (Pooled Analysis of Methodologically Harmonized Pragmatic Randomized Trials of High-Dose vs. Standard-Dose Influenza Vaccine Against Severe Clinical Outcomes) individual-level pooled data set integrating 2 methodologically harmonized pragmatic, individually randomized trials conducted in Denmark and Spain, we investigated the relative vaccine effectiveness of HD-IIV versus SD-IIV against severe cardiovascular outcomes and according to pre-existing CVD among adults ≥65 years of age. Data were primarily obtained from routine health care databases, with follow-up from 14 days after vaccination to May 31 the following year.

Results: The pooled data set encompassed 466 320 individually randomized participants, of whom 107 700 (23.1%) had a history of CVD. HD-IIV reduced the incidence of hospitalization for influenza or pneumonia, cardiorespiratory disease, laboratory-confirmed influenza, and any cause compared with SD-IIV, irrespective of the presence or absence of pre-existing CVD (P_interaction>0.66 for all outcomes). Compared with the SD-IIV group, the HD-IIV group had a significantly lower incidence of hospitalization for any CVD (HD-IIV, 1.15%, versus SD-IIV, 1.24%; relative vaccine effectiveness, 6.6% [95% CI, 1.6-11.4]; P=0.010), hospitalization for any respiratory disease (HD-IIV, 0.92%, versus SD-IIV, 0.98%; relative vaccine effectiveness, 6.5% [95% CI, 0.7-11.9]; P=0.027), and hospitalization for heart failure (HD-IIV, 0.11%, versus SD-IIV, 0.15%; relative vaccine effectiveness, 21.3% [95% CI, 7.6-33.0]; P=0.003).

Conclusions: In a prespecified pooled analysis of 466 320 individually randomized older adults, HD-IIV reduced the incidence of a wide range of severe cardiovascular and respiratory outcomes compared with SD-IIV, with consistent findings regardless of previous history of CVD. Among cardiovascular outcomes, the protective effect of HD-IIV versus SD-IIV was particularly pronounced against hospitalization for heart failure.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06506812.