American journal of physiology. Heart and circulatory physiology最新文献

Although two-dimensional (2-D) speckle-tracking echocardiography (STE) is important for the clinical quantification of myocardial function, it remains unknown whether increased frame rates during exercise STE augment tracking success and absolute deformation values. Overall, 19 participants (15 males and 4 females; aged 26.7 ± 4.8) underwent stepwise exercise testing on a recumbent bicycle. Exercise started at 50 W, increasing by 30 W every 3 min until a target heart rate (HR) of 130-140 beats/min was reached. During the last 90 s of each exercise stage, echocardiographic sequences for offline quantification of longitudinal strain (LS), peak twist, untwisting velocity, basal rotation, and apical rotation were acquired with high [high frames per second (HFPS)], medium [medium frames per second (MFPS)], and low-frames per second (LFPS)]. Differences in tracking success were determined by using Chi-square test, and the impact of different frame rates on absolute deformation values was compared by using mixed-model analysis. Utilization of HFPS significantly improved tracking success for parasternal short-axis images. LS acquired at HFPS was the highest at baseline and across all the exercise stages. Similar trends were observed for twist, peak untwisting velocity, and apical rotation, whereas basal rotation showed no differences. Mixed-model analysis revealed a significant impact of frame rate setting on LS (P < 0.05) and untwisting velocity (P < 0.05). In contrast to recommendations by leading organizations advocating for frame rates between 40 and 80 frames per second (fps) during resting conditions, with a proportional increase as heart rate rises, our findings suggest that consistently maintaining the frame rate at the highest feasible level is preferable for achieving optimal-tracking success and accuracy in STE.NEW & NOTEWORTHY This study demonstrates the benefits of high frame per second (HFPS) rate settings in speckle-tracking echocardiography, achieving superior-tracking success and higher deformation values, including longitudinal strain and untwisting velocity, compared with lower frame rates. These advantages, particularly evident at elevated heart rates, highlight the importance of high temporal resolution for accurate cardiac imaging under stress conditions. The findings support prioritizing HFPS in clinical and research settings to improve tracking reliability and data accuracy.

In spite of the ongoing efforts to probe the metabolic signatures of stable (SA) from unstable (UA) angina, it is concerning that to date there are no clinically validated circulatory biochemical signatures against the intrinsic anatomical changes that are screened by invasive coronary angiography. Hence, the aim of this study is to generate precise biochemical fingerprints using filtered serum-based metabolomics and high-throughput nuclear magnetic resonance (NMR) spectroscopy to accurately distinguish the metabolic signatures of patients suffering with SA or UA angina. The study includes 118 filtered serum samples from patients suffering from UA (n = 50) and SA (n = 68). High-resolution NMR spectroscopy was used to assess the metabolic remodeling in these cohorts. Subsequently, principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA), and artificial neural network (ANN) analysis were adapted to engender a precise prediction model. Analysis of the receiver operating characteristic (ROC) curve was conducted to determine the clinical usefulness of metabolic markers. The outcome revealed that the metabolic profile for the underlying disease is characterized by altered metabolite levels in UA relative to SA. Creatinine, 3-OH butyrate, and aspartate level could differentiate 100% of UA from SA with 100% sensitivity and specificity. To monitor and determine UA from patients with SA, ¹H NMR-based filtered serum metabolic profiling seems to be a promising, less invasive, and faster investigative approach.NEW & NOTEWORTHY There are no metabolic signatures present to identify unstable from stable angina. Coronary angiography identifies anatomical changes after the event of unstable angina, but NMR-based metabolomics identifies unstable from stable angina within 4 h. Creatinine, 3-OH butyrate, and aspartate were able to segregate unstable from stable angina.

Nearly 70 years after studies first showed that the offspring of vitamin A (retinol, ROL)-deficient rats exhibit structural cardiac defects and over 20 years since the role of vitamin A's potent bioactive metabolite hormone, all-trans retinoic acid (ATRA), was elucidated in embryonic cardiac development, the role of the vitamin A metabolites, or retinoids, in adult heart physiology and heart and vascular disease, remains poorly understood. Studies have shown that low serum levels of retinoic acid correlate with higher all-cause and cardiovascular mortality, though the relationship between circulating retinol and ATRA levels, cardiac tissue ATRA levels, and intracellular cardiac ATRA signaling in the context of heart and vascular disease has only begun to be addressed. We have recently shown that patients with idiopathic dilated cardiomyopathy show a nearly 40% decline of in situ cardiac ATRA levels, despite adequate local stores of retinol. Moreover, we and others have shown that the administration of ATRA forestalls the development of heart failure (HF) in rodent models. In this review, we summarize key facets of retinoid metabolism and signaling and discuss mechanisms by which impaired ATRA signaling contributes to several HF hallmarks including hypertrophy, contractile dysfunction, poor calcium handling, redox imbalance, and fibrosis. We highlight unresolved issues in cardiac ATRA metabolism whose pursuit will help refine therapeutic strategies aimed at restoring ATRA homeostasis.

The incidence of heart failure with preserved ejection fraction (HFpEF) in women significantly increases following menopause. This trend cannot solely be attributed to chronological aging, as evidenced by the more gradual increase in prevalence among men, suggesting that menopause is a provocative event for HFpEF. However, the underlying mechanisms remain elusive and challenging to investigate in human subjects; moreover, an attempt to create HFpEF in ovariectomized (OVX) mice was unsuccessful. In this study, we created an animal model that resembles HFpEF in women undergoing natural menopause. We used 4-vinylcyclohexene dioxide (VCD) to induce "ovary-intact" menopause, combined with the 2hit regimen (HFpEF inducing regimen) to model postmenopausal HFpEF. The female-VCD-2hit mice demonstrate diastolic dysfunction. At the left ventricle (LV) levels, the increased stiffness coefficient of end-diastolic pressure-volume relation (EDPVR), elevated LV end-diastolic pressure, and increased relaxation time constant indicate a heightened LV stiffness, delayed relaxation, and elevated LV filling pressure. At the cardiomyocyte level, the female-VCD-2hit mice exhibit increased cellular diastolic stiffness and delayed relaxation, suggesting that the observed LV dysfunction is derived from the cardiomyocytes. In addition, plasma N-terminal pro-β-type natriuretic peptide (NT-pro-BNP) levels were elevated, whereas Xbp1s transcript levels were reduced, further supporting the existence of HFpEF. Plasma-free testosterone was increased in VCD mice compared with premenopausal and OVX models. Further studies are required to determine whether the relative increase in testosterone is the factor driving HFpEF susceptibility in VCD mice. Ovary-intact postmenopausal status makes female mice vulnerable to HFpEF development. The VCD-2hit model develops a robust HFpEF-like phenotype and is suitable for studying female HFpEF.NEW & NOTEWORTHY Although ovariectomized mice were observed to be resistant to developing HFpEF, ovary-intact postmenopausal mice exhibited an HFpEF-like phenotype under metabolic stress conditions. The increased susceptibility of ovary-intact postmenopausal mice may be due to relative androgen excess conditions, as postmenopausal ovaries retain the ability to secrete androgens. Menopause should be viewed as the imbalance of estrogen and androgens rather than merely an estrogen deficiency, and the role of female androgens in postmenopausal HFpEF warrants further investigation.

Altered hemodynamics is a key factor for atherosclerosis. For decades, endothelial cell (EC) responses to fluid-generated wall shear stress have been the central focus for atherogenesis. However, circulating blood is not a cell-free fluid, it contains mechanosensitive red blood cells (RBCs) that are also subjected to altered hemodynamics and release a large amount of ATP, but their impact on atherosclerosis has been overlooked. The focus of this study is the role of shear stress (SS)-induced RBC-released ATP in atherosclerosis. Hypercholesterolemic mouse models with and without RBC-Pannexin 1 deletion were used for the study. Results showed that SS-induced release of ATP from RBCs was at µM concentrations, three-orders of magnitude higher than that from other cell types. Suppression of RBC-released ATP via deletion of Pannexin 1, a mechanosensitive ATP-permeable channel, reduced high-fat diet-induced aortic plaque burden by 40%-60%. Importantly, the location and the extent of aortic atherosclerotic lesions spatially matched with the ATP deposition profile at aortic wall predicted by a computational fluid dynamic (CFD) model. Furthermore, hypercholesterolemia increases EC susceptibility to ATP with potentiated increase in [Ca²⁺]_i, an initial signaling for aortic EC barrier dysfunction, and an essential cause for lipid accumulation and inflammatory cell infiltration. The computational prediction also provides a physics-based explanation for RBC-released ATP-induced sex disparities in atherosclerosis. Our study reveals an important role of RBC-released ATP in the initiation and progression of atherosclerosis. These novel findings provide a more comprehensive view of how altered hemodynamics and systemic risk factors synergistically contribute to atherosclerosis.NEW & NOTEWORTHY This study reveals that, in addition to fluid-derived wall shear stress, the disturbed blood flow-induced release of ATP from mechanosensitive red blood cells (RBCs), the major cellular components of blood, along with hypercholesterolemia-induced increases in endothelial cell susceptibility to ATP contribute significantly to the initiation and progression of atherosclerosis. These novel findings advance our current understanding of how altered hemodynamics and hypercholesterolemia synergistically contribute to atherosclerosis for the first time with the inclusion of RBCs.

The most fatal side effect associated with revolutionary immune checkpoint inhibitor (ICI) cancer therapies is myocarditis, a rare and devastating complication with a mortality rate approaching 40%. This review comprehensively examines the limited knowledge surrounding this recently recognized condition, emphasizing the absence of evidence-based therapeutic strategies, diagnostic modalities, and reliable biomarkers that hinder effective management. It explores advancements in preclinical models that are uncovering disease mechanisms and enabling the identification of therapeutic targets. These efforts have informed the design of early clinical trials aimed at reducing mortality. With the growing prevalence of ICI therapies in oncology, addressing critical gaps, such as long-term outcomes and risk stratification, has become increasingly urgent. By synthesizing current evidence, this work seeks to enhance understanding and guide the development of strategies to improve patient outcomes and ensure the continued safe use of ICIs in cancer care.

Middle-aged and older individuals with hypertension are often considered to be at increased risk during environmental heat waves due to blunted increases in skin blood flow and subsequently elevated core temperatures. Additionally, common antihypertensive medications (i.e., ACE inhibitors, diuretics, and beta blockers) can independently impair heat loss mechanisms, reportedly heightening heat related risk. If these groups are at increased risk, differences should be observed in the environmental conditions in which thermal balance can occur. Identifying critical environmental limits is an integrative method to determine the conditions that separate safe from unsafe heat exposure. Seventy-two participants (F=43) (63±11 yrs; range: 40-92 yrs) were exposed to progressive heat stress at a low metabolic rate. Thirty-seven of the participants were hypertensive (defined by current AHA guidelines for stage 1 hypertension) and 15 participants were taking antihypertensive medications. Experiments were conducted in both hot-dry (HD; up to 53°C, ≤25% rh) and warm-humid (WH; ~35°C, ≥50% rh) environments. One way ANOVA was used to compare normotensives with hypertensive individuals with and without the use of antihypertensive medications in the WH environment. Unpaired t-tests were used to compare differences between hypertensives and normotensives in the HD environment. No differences in critical environmental limits were observed in either environment among all groups (all p>0.05). These data challenge the hypotheses that hypertension increases heat-related risk. Despite potential alterations in heat loss mechanisms due to hypertension and antihypertensive medications, there were not differences in the compensable environmental conditions in individuals with stage 1 hypertension.

Pulmonary regurgitation is a common consequence following the repair of tetralogy of Fallot and can lead to heart failure. Early detection of right ventricular dysfunction remains challenging, and current clinical markers have limited predictive value to identify which patients are at risk for heart failure and require interventions. This study aimed to investigate the potential of ventriculo-arterial coupling as a marker of early right ventricular dysfunction in a porcine model of chronic pulmonary regurgitation following transannular patch repair of neonatal pulmonary stenosis. Neonatal swine were subjected to pulmonary artery banding for 1 month to induce RV pressure overload, followed by transannular patch repair (rTAP, n=10) to create chronic pulmonary regurgitation, and were compared to Sham animals (n=6). Longitudinal hemodynamic assessments, including pressure-volume analysis and cardiac magnetic resonance imaging, were performed. VAC was defined as the ratio of end-systolic elastance to effective arterial elastance. Over the follow-up period of 4 months, VAC was preserved in the rTAP group. Effective arterial elastance was significantly lower in rTAP animals (P=0.001), while end-systolic elastance remained unchanged. Lower end-diastolic pulmonary artery pressures and increased early systolic ejection were observed in rTAP, correlating with higher VAC. Ventriculo-arterial coupling remains preserved in chronic pulmonary regurgitation due to decreased afterload, making it unsuitable as an early marker for right ventricular dysfunction. Low afterload, a consequence of diastolic emptying of the pulmonary artery into the right ventricle, may pseudo-normalize systolic function. Alternative markers e.g. focusing on diastolic function and atrio-ventricular interactions should be investigated.

Females exhibit longer QT intervals and a higher risk of Long QT Syndrome (LQTS) associated arrhythmogenesis compared to males. While several studies suggest these sex disparities result from the effect of sex hormones on cardiac ion channels, the underlying mechanisms remain incompletely understood. This research investigates the arrhythmogenic effects, sex-specific risk, and mechanisms associated with LQTS linked to either to loss-of-function of the rapidly activating delayed rectifier K⁺ current (I_Kr), or gain-of-function of the L-type Ca²⁺ current (I_CaL). We primarily utilized the Tomek-Rodriguez (ToR-ORd) model of human ventricular cardiomyocytes and incorporated sex-specific parameterizations based on previous studies. The O'Hara-Rudy and Grandi-Bers models were used to demonstrate model-independence of the findings. We employed a populations-of-models approach to assess early afterdepolarization (EAD) susceptibility in control and LQTS male and female groups. All female models had consistently longer action potentials and were more prone to EADs than male models. In the ToR-ORd model, I_Kr loss-of-function led to EADs in 65.8% of females vs. 22.8% of males. I_CaL gain-of-function led to EADs in 66.2% of females but only 3.6% of males. Using logistic regression analysis, we identified key ionic predictors of EAD susceptibility, with G_CaL and Na⁺/Ca²⁺ exchanger (G_NCX) consistently emerging as positively and G_Kr as negatively associated to EADs across both sexes and LQTS types. Notably, higher G_NCX but lower G_Kr in female vs. male cardiomyocytes could explain heightened female EAD risk. Our studies explore the ionic traits that favor (or confer resilience against) EADs with potential implications for personalized treatments.