Circulation最新文献

Background: Blood pressure (BP)-lowering effects of structured exercise are well-established. Effects of 24-hour movement behaviors captured in free-living settings have received less attention. This cross-sectional study investigated associations between a 24-hour behavior composition comprising 6 parts (sleeping, sedentary behavior, standing, slow walking, fast walking, and combined exercise-like activity [eg, running and cycling]) and systolic BP (SBP) and diastolic BP (DBP).

Methods: Data from thigh-worn accelerometers and BP measurements were collected from 6 cohorts in the Prospective Physical Activity, Sitting and Sleep consortium (ProPASS) (n=14 761; mean±SD, 54.2±9.6 years). Individual participant analysis using compositional data analysis was conducted with adjustments for relevant harmonized covariates. Based on the average sample composition, reallocation plots examined estimated BP reductions through behavioral replacement; the theoretical benefits of optimal (ie, clinically meaningful improvement in SBP [2 mm Hg] or DBP [1 mm Hg]) and minimal (ie, 5-minute reallocation) behavioral replacements were identified.

Results: The average 24-hour composition consisted of sleeping (7.13±1.19 hours), sedentary behavior (10.7±1.9 hours), standing (3.2±1.1 hours), slow walking (1.6±0.6 hours), fast walking (1.1±0.5 hours), and exercise-like activity (16.0±16.3 minutes). More time spent exercising or sleeping, relative to other behaviors, was associated with lower BP. An additional 5 minutes of exercise-like activity was associated with estimated reductions of -0.68 mm Hg (95% CI, -0.15, -1.21) SBP and -0.54 mm Hg (95% CI, -0.19, 0.89) DBP. Clinically meaningful improvements in SBP and DBP were estimated after 20 to 27 minutes and 10 to 15 minutes of reallocation of time in other behaviors into additional exercise. Although more time spent being sedentary was adversely associated with SBP and DBP, there was minimal impact of standing or walking.

Conclusions: Study findings reiterate the importance of exercise for BP control, suggesting that small additional amounts of exercise are associated with lower BP in a free-living setting.

Background: The United Network of Organ Sharing made changes to the priority for allocation of hearts for transplantation (HT) in 2016 for pediatric patients and 2018 for adult patients. Although recent work has evaluated the impact of the revised allocation systems on mechanical circulatory support practices and waitlist outcomes, there are limited data that focus more specifically on the impact of the allocation changes on patients with congenital heart disease (CHD) or cardiomyopathy and how these relationships might differ in pediatric and adult patients.

Methods: The United Network of Organ Sharing database was queried for pediatric (<18 years of age) and adult (18-50 years of age) patients with a CHD or cardiomyopathy diagnosis listed for HT. Cohorts were grouped into preallocation and postallocation change eras: pediatric patients from January 1, 2011, to March 21, 2016, and January 1, 2017, to December 31, 2021; and adult patients from January 1, 2015, to October 17, 2018, and January 1, 2019, to December 31, 2021. Differences in era for survival or waitlist removal because of clinical deterioration from the time of HT listing were compared using competing risk models.

Results: We identified 11 637 patients listed for HT during the study period, including 2882 pediatric patients with CHD, 594 adults with CHD, 2348 pediatric patients with cardiomyopathy, and 5813 adults with cardiomyopathy. In a competing risk model adjusting for demographic and clinical factors, allocation changes were significantly associated with lower death or waitlist removal within 1 year of HT listing in infants with CHD (HR, 0.75 [0.57-0.99]; P=0.04), children with CHD (HR, 0.61 [0.43-0.86]; P=0.005), and adults with cardiomyopathy (HR, 0.60 [0.44-0.81]; P=0.001), but not in infants with cardiomyopathy, children with cardiomyopathy, or adults with CHD.

Conclusions: The recent allocation changes of the Organ Procurement and Transplantation Network associations with waitlist duration and outcome were not uniform across pediatric and adult cohorts with CHD or those with cardiomyopathy. Children with cardiomyopathy and adults with CHD did not experience the mortality benefits experienced by adults with cardiomyopathy and children with CHD. Future iterations of the allocation systems should consider differential access to mechanical circulatory support options for children and adults, patient sensitization status, and whether having separate systems for adults and children is the most appropriate method to allocate organs.

Background: Limited large-scale, real-world data exist on the prevalence and clinical impact of discordance between fractional flow reserve (FFR) and nonhyperemic pressure ratios (NHPRs).

Methods: The J-PRIDE registry (Clinical Outcomes of Japanese Patients With Coronary Artery Disease Assessed by Resting Indices and Fractional Flow Reserve: A Prospective Multicenter Registry) prospectively enrolled 4304 lesions in 3200 patients from 20 Japanese centers. The lesions were classified into FFR+/NHPR-, FFR-/NHPR+, FFR+/NHPR+, or FFR-/NHPR groups according to cutoff values of 0.89 for NHPRs and 0.80 for FFR. The primary study end point was the cumulative 1-year incidence of target vessel failure (a composite of cardiac death, target vessel-related myocardial infarction, and clinically driven target vessel revascularization) on a lesion basis.

Results: An NHPR cutoff value of 0.89, determined using online software, predicted an FFR of 0.80 across various NHPR types. Discordance between FFR and NHPRs was observed in 20% of lesions (FFR+/NHPR-, 11.2%; FFR-/NHPRs+, 8.8%). Revascularization was deferred in 42.9% and 88.4% of the FFR+/NHPR- and FFR-/NHPR+ groups, respectively. In deferred vessels, the FFR+/NHPR- and FFR-/NHPR+ groups showed a higher 1-year incidence of target vessel failure compared with the FFR-/NHPR- group (7.9% versus 5.5% versus 1.7%; for FFR+/NHPR-, adjusted hazard ratio [aHR], 4.89 [95% CI, 2.68-8.91]; P<0.001; for FFR-/NHPR+, aHR, 2.64 [95% CI, 1.49-4.69]; P<0.001). In revascularized vessels, the 1-year target vessel failure rate was numerically higher in the FFR-/NHPR+ group than in the FFR+/NHPR+ group (9.6% versus 3.4%; aHR, 2.27 [95% CI, 0.70-7.34]; P=0.17), although with similar outcomes between the FFR+/NHPR- and FFR+/NHPR+ groups (2.3% versus 3.4%; aHR, 0.96 [95% CI, 0.37-2.38]; P=0.93). The FFR+/NHPR- group benefited from revascularization compared with medical treatment (aHR, 0.26 [95% CI, 0.08-0.86]; P=0.027); the FFR-/NHPR+ group did not (aHR, 2.39 [95% CI, 0.62-9.21]; P=0.20).

Conclusions: Discordance between FFR and NHPRs was noted in 20% of lesions, and discordant deferred lesions resulted in worse outcomes than concordant negative lesions. Although the outcomes after deferring revascularization were comparable between the FFR+/NHPR- and FFR-/NHPR+ lesions, only FFR+/NHPR- lesions showed a benefit from revascularization compared with medical treatment, suggesting that an FFR-guided strategy is superior to an NHPR-guided strategy in discordant lesions.

Registration: URL: https://www.umin.ac.jp; Unique identifier: UMIN000038403.

Smokeless oral nicotine products are addictive, and their use has potential adverse effects on some but not all biomarkers of cardiovascular risk. The use of some types of these products, for instance, is associated with an increased mortality risk in those with ischemic heart or cerebrovascular disease. Similarly, smokeless tobacco has the potential to increase the risk of oral cancer, but the risks depend on the chemical composition of the product. The market of smokeless oral nicotine products has transformed since the last American Heart Association smokeless tobacco policy statement. Several varieties of tobacco-free oral nicotine products-including oral nicotine pouches; nontherapeutic nicotine gums, lozenges, and tablets; and nicotine gummies-have rapidly proliferated. The sales of oral nicotine pouches, in particular, have increased substantially; however, no data are available on their cardiovascular or health risks. In addition, synthetic (compared with tobacco-derived) nicotine has been used in some brands of oral nicotine products, but its cardiovascular and health effects have been inadequately studied. Robust public policy levers are identified to support ending addiction to all commercial tobacco products. Critical components and policy initiatives include clinicians emphasizing the prevention of tobacco product initiation and supporting cessation with established pharmacological and behavioral tobacco dependence treatment therapies as primary goals for achieving an end to commercial tobacco and nicotine addiction.

Background: Brugada syndrome (BrS) is a cardiac arrhythmia disorder that causes sudden death in young adults. Rare genetic variants in the SCN5A gene encoding the Na_v1.5 sodium channel and common noncoding variants at this locus are robustly associated with the condition. BrS is particularly prevalent in Southeast Asia but the underlying ancestry-specific factors remain largely unknown.

Methods: Genome sequencing of BrS probands and population-matched controls from Thailand was performed to identify rare noncoding variants at the SCN5A-SCN10A locus that were enriched in patients with BrS. A likely causal variant was prioritized by computational methods and introduced into human induced pluripotent stem cell (hiPSC) lines using CRISPR-Cas9. The effect of the variant on SCN5A expression and Na_v1.5 sodium channel current was then assessed in hiPSC-derived cardiomyocytes (hiPSC-CMs).

Results: A rare noncoding variant in an SCN5A intronic enhancer region was highly enriched in patients with BrS (detected in 3.9% of cases with a case-control odds ratio of 45.2). The variant affects a nucleotide conserved across all mammalian species and predicted to disrupt a Mef2 transcription factor binding site. Heterozygous introduction of the enhancer variant in hiPSC-CMs caused significantly reduced SCN5A expression from the variant-containing allele and a 30% reduction in Na_v1.5-mediated sodium current density compared with isogenic controls, confirming its pathogenicity. Patients with the variant had severe phenotypes, with 89% experiencing cardiac arrest.

Conclusions: This is the first example of a functionally validated rare noncoding variant at the SCN5A locus and highlights how genome sequencing in understudied populations can identify novel disease mechanisms. The variant partly explains the increased prevalence of BrS in this region and enables the identification of at-risk variant carriers to reduce the burden of sudden cardiac death in Thailand.

Background: Many specialized cells in adult organs acquire a state of cell cycle arrest and quiescence through unknown mechanisms. Our limited understanding of mammalian cell cycle arrest is derived primarily from cell culture models. Adult mammalian cardiomyocytes, a classic example of cell cycle arrested cells, exit the cell cycle postnatally and remain in an arrested state for the life of the organism. Cardiomyocytes can be induced to re-enter the cell cycle by YAP5SA, an active form of the Hippo signaling pathway effector YAP.

Methods: We performed clonal analyses to determine the cell cycle kinetics of YAP5SA cardiomyocytes. We also performed single-cell RNA sequencing, marker gene analysis, and functional studies to examine how YAP5SA cardiomyocytes progress through the cell cycle.

Results: We discovered that YAP5SA-expressing cardiomyocytes divided efficiently, with >20% of YAP5SA cardiomyocyte clones containing ≥2 cardiomyocytes. YAP5SA cardiomyocytes re-entered cell cycle at the G1/S transition and had an S phase lasting ≈48 hours. Sarcomere disassembly is required for cardiomyocyte progression from S to G2 phase and the induction of mitotic rounding. Although oscillatory Cdk expression was induced in YAP5SA cardiomyocytes, these cells inefficiently progressed through G2 phase. This is improved by inhibiting P21 function, implicating checkpoint activity as an additional barrier to YAP5SA-induced cardiomyocyte division.

Conclusions: Our data reveal that YAP5SA overcomes the mechanically constrained myocardial microenvironment to induce mitotic rounding with cardiomyocyte division, thus providing new insights into the in vivo mechanisms that maintain cell cycle quiescence in adult mammals.

Background: The Hippo pathway effector YAP (Yes-associated protein) plays an essential role in cardiomyocyte proliferation and heart regeneration. In response to physiological changes, YAP moves in and out of the nucleus. The pathophysiological mechanisms regulating YAP subcellular localization after myocardial infarction remain poorly defined.

Methods: We identified YAP acetylation at site K265 by in vitro acetylation followed by mass spectrometry analysis. We used adeno-associated virus to express YAP-containing mutations that either abolished acetylation (YAP-K265R) or mimicked acetylation (YAP-K265Q) and studied how acetylation regulates YAP subcellular localization in mouse hearts. We generated a cell line with YAP-K265R mutation and investigated the protein-protein interactors by YAP immunoprecipitation followed by mass spectrometry, then validated the YAP interaction in neonatal rat ventricular myocytes. We examined colocalization of YAP and TUBA4A (tubulin α 4A) by superresolution imaging. Furthermore, we developed YAP-K265R and αMHC-MerCreMer (MCM); Yap-loxP/K265R mutant mice to examine the pathophysiological role of YAP acetylation in cardiomyocytes during cardiac regeneration.

Results: We found that YAP is acetylated at K265 by CBP (CREB-binding protein)/P300 (E1A-binding protein P300) and is deacetylated by nicotinamide phosphoribosyltransferase/nicotinamide adenine dinucleotide/sirtuins axis in cardiomyocytes. After myocardial infarction, YAP acetylation is increased, which promotes YAP cytoplasmic localization. Compared with controls, mice that were genetically engineered to express a K265R mutation that prevents YAP K265 acetylation showed improved cardiac regenerative ability and increased YAP nuclear localization. Mechanistically, YAP acetylation facilitates its interaction with TUBA4A, a component of the microtubule network that sequesters acetylated YAP in the cytoplasm. After myocardial infarction, the microtubule network increased in cardiomyocytes, resulting in the accumulation of YAP in the cytoplasm.

Conclusions: After myocardial infarction, decreased sirtuin activity enriches YAP acetylation at K265. The growing TUBA4A network sequesters acetylated YAP within the cytoplasm, which is detrimental to cardiac regeneration.