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

Coronary artery disease (CAD) has traditionally been diagnosed and managed based on anatomical assessments of the epicardial coronary arteries. However, a growing body of evidence highlights the limitations of coronary angiography in evaluating the ischemic burden of atherosclerotic plaques. The coronary microcirculation is increasingly recognized for its pivotal role in myocardial ischemia. Coronary microvascular dysfunction (CMD) contributes significantly to both acute and chronic coronary syndromes, even in the absence of obstructive epicardial disease. Despite its clinical significance, CMD remains underdiagnosed due to the lack of routine assessment in contemporary cardiac catheterization practices. Emerging invasive and noninvasive techniques now enable comprehensive evaluation of coronary microvascular dysfunction (CMD) by assessing microvascular resistance, coronary flow reserve, and tissue-level perfusion. Advances in thermodilution-based indices, intracoronary Doppler, and functional coronary angiography continue to provide quantitative insights into microvascular physiology, whereas noninvasive modalities-including cardiac magnetic resonance (MRI), positron-emitted tomography (PET), transthoracic Doppler echocardiography, and computed tomography-based perfusion imaging-offer powerful tools for diagnosing CMD without the need for catheter-based assessment. Integrating these complementary approaches into clinical practice enhances risk stratification and supports personalized management strategies, particularly in patients with ischemia and nonobstructive coronary arteries (INOCA). This review explores in-depth the diagnostic tools and the quantitative metrics used or the invasive assessment of CMD, emphasizing their clinical utility and impact on patient management.

Electronic cigarettes (e-cigs) have rapidly gained popularity in the past 20 years. However, the health impacts of their use remain unclear. E-cigs generate aerosols by heating e-liquids containing solvent vehicles, nicotine, additives, and flavorant chemicals. This process not only aerosolizes the liquid ingredients but also generates a complex mixture of by-products, many of which are harmful. Recent studies have demonstrated that inhaling e-cig aerosols can disrupt cardiac electrophysiology and rhythm as well as autonomic regulation of the heart. Furthermore, recent and historical observations indicate that many individual e-cig constituents, such as nicotine, aldehydes, flavorants, polycyclic aromatic hydrocarbons, metals, and carbon monoxide, can impair cardiac electrophysiology and rhythmicity. Although it remains largely unclear which constituents pose the greatest harm, a growing body of in vivo animal experiments, in vitro studies, and clinical studies collectively indicate that e-cigs adversely alter electrophysiology and thus may increase risk for severe and fatal arrhythmias. Nonetheless, more studies are needed to determine how these effects translate to e-cig users and relate to specific constituent compounds. Here, we summarize the existing science detailing how e-cig aerosols and their individual constituents disturb cardiac electrophysiology and promote arrhythmia. Although direct evidence that e-cigs cause arrhythmias in humans remains elusive, research continues to advance the biological plausibility of a causal relationship between e-cig use and life-threatening disruptions in cardiac electrophysiology.

Human saphenous veins (SVs) are widely used as grafts in coronary artery bypass (CABG) surgery but often fail due to neointima formation. Little is known, however, regarding the cellular, transcriptomic, and proteomic dynamics of neointima formation in human veins. Here, we performed transcriptomics and proteomics analysis in an ex vivo tissue culture model of neointima formation in human SVs procured for CABG surgery. Histological examination demonstrated significant elastin degradation and neointima formation (indicated by increased neointima area and neointima-to-media ratio) in SVs subjected to tissue culture. Analysis of data from 72 patients suggests that the progression of SV remodeling and neointima formation differs according to sex and body mass index, which is negatively associated with neointima formation in males only. RNA sequencing demonstrated upregulation of proinflammatory and proliferation-related genes during neointima formation and identified novel processes, including increased cellular stress and DNA damage responses, reflecting tissue trauma associated with vein harvesting. Proteomic analysis identified upregulated extracellular matrix-related and coagulation/thrombosis proteins and downregulated metabolic proteins. Spatial transcriptomics, used to infer regionally enriched gene expression, suggested dynamic alterations in fibroblast and vascular smooth muscle cell (VSMC) states during neointima formation. Specifically, we identified the emergence of HES1⁺ and matrix metalloproteinase 2- and 14-positive (MMP2⁺/MMP14⁺) expression in VSMCs and fibroblasts, respectively, during neointima formation. Furthermore, our data suggest that MIR647, identified through screening, maintains VSMC contractile gene expression. Our findings suggest dynamic transcriptomic and proteomic changes during neointima formation in human veins and provide useful mechanistic information for the pathogenesis of SV graft disease.NEW & NOTEWORTHY Using multiomics and spatial transcriptomics, we uncover dynamic molecular and cellular changes driving neointima proliferation in human saphenous veins, the most common conduit for bypass surgery. Our study highlights sex- and body mass index-associated differences, novel fibroblast and smooth muscle cell states, and a role for microRNA-647 in preserving vascular contractile phenotype. These findings provide new insight into the mechanisms of vein graft failure and may guide future strategies to improve coronary bypass outcomes.

Patients with thoracic aortic disease (TAD; aneurysm and dissection) with well-controlled blood pressure are recommended to perform regular aerobic exercise of light-to-moderate intensity; however, the biomechanical impact on the aortic wall remains unknown. The aim of this study was to quantify aortic wall stress (AWS) and aortic mechanical efficiency [AME; AWS normalized to cardiac output (Qc)] during aerobic exercise in individuals with TAD. Fourteen participants with stable TAD (3 females, age 69 ± 9 yr; 8 with unrepaired aneurysms) and 11 age-matched controls (CON, 4 females, age 68 ± 7 yr) underwent comprehensive cardiac and aortic evaluation using magnetic resonance imaging. Assessments included Qc and aortic structural parameters (diameter and wall thickness), measured both at rest and during light-to-moderate intensity stepping exercise. Ascending AWS increased in response to light-to-moderate intensity exercise across both groups (P < 0.01), with no significant group-by-exercise interaction effect (P = 0.793). A similar pattern was observed in the descending aorta. Importantly, all AWS values measured during exercise remained below the established threshold for aneurysmal rupture (850-1,200 kPa), with the maximum recorded value being 323 kPa. Patients with TAD tended to exhibit lower AME (higher AWS/Qc slopes) in the ascending aorta (16.8 ± 12.8 vs. 9.2 ± 4.0 kPa/L/min; P = 0.062) but not in the descending aorta (P = 0.119). Our study provides new evidence to support the physical activity guidelines for people with aortic disease participating in moderate-intensity aerobic exercise. By integrating individual risk profiles with biomechanical data, we can continue to advance clinical understanding of safe and effective exercise in this population.NEW & NOTEWORTHY Patients with thoracic aortic disease (n = 14) did not show elevated aortic wall stress compared with age-matched controls (n = 11) during exercise. Aortic mechanical efficiency (increase in aortic wall stress relative to increase in cardiac output during exercise) may be impaired in patients with thoracic aortic disease. All exercise-induced aortic wall stress values remained well below the aneurysmal rupture threshold (800-1,200 kPa).

Women with a history of preeclampsia (hxPE) have an elevated risk of cardiovascular disease, likely in part from reduced endothelial function. Preeclampsia is also associated with increased risk of depression. Although evidence indicates that antidepressant pharmacotherapy may have vasculoprotective effects, it is unclear whether it preserves endothelial function in women with hxPE. We hypothesized that antidepressant-treated women with hxPE would have preserved endothelial function compared with unmedicated women with hxPE. Ten women with hxPE currently treated with an antidepressant (hxPE + AD), 10 not treated (hxPE - AD), and 10 unmedicated women with a history of uncomplicated pregnancy (HC) participated. Macrovascular endothelial function was measured via brachial artery flow-mediated dilation (FMD). Microvascular endothelial function and the nitric oxide (NO) component were assessed via cutaneous vascular conductance (CVC; %max) responses to graded infusions of acetylcholine (10^-10-10^-1 M) alone or with 15 mM N^G-nitro-l-arginine methyl ester (L-NAME; NO-synthase-inhibitor), respectively. Relative and absolute FMD in hxPE - AD were lower compared with HC (5.7 ± 0.3% vs. 7.5 ± 0.3%, P = 0.02; 0.18 ± 0.01 mm vs. 0.23 ± 0.01 mm, P = 0.02) and hxPE + AD (vs. 7.2 ± 0.6% and 0.23 ± 0.02 mm, both P ≤ 0.047). hxPE - AD had reduced microvascular endothelium-dependent vasodilation responses to acetylcholine compared with HC (P = 0.017). Peak CVC in hxPE - AD was lower than in HC (82.0 ± 2.9%max vs. 96.2 ± 2.0%max, P < 0.01) and hxPE + AD (vs. 92.3 ± 3.4%max, P = 0.04). L-NAME reduced microvascular dilation in all groups (P < 0.001). NO-dependent dilation did not differ among groups (P = 0.07). Collectively, macrovascular and microvascular endothelial function in hxPE + AD was greater than hxPE - AD and did not differ from HC, suggesting that antidepressant pharmacotherapy may preserve endothelial function in women with hxPE.NEW & NOTEWORTHY To our knowledge, this is the first study to demonstrate that chronic antidepressant use is associated with preserved endothelial function in women with a history of preeclampsia (hxPE). Compared with healthy controls, untreated women with hxPE had reduced macrovascular (brachial artery) and microvascular (cutaneous) endothelial function, whereas those treated with antidepressants exhibited preserved endothelial function. These findings suggest that antidepressants may modulate persistent endothelial dysfunction in these women following preeclampsia.

Mitochondrial respiration sustains the high energy demands of endurance exercise, yet the extent to which atrial, ventricular, and skeletal muscle mitochondria adapt remains uncertain. At the same time, endurance athletes face an increased risk of atrial fibrillation (AF), but the role of cardiac metabolism in arrhythmia susceptibility is poorly understood. Here, we compared mitochondrial respiration in skeletal muscle and across all four cardiac chambers between trained and untrained racehorses (n = 34) to investigate adaptations associated with long-term endurance exercise. We further examined whether cardiac metabolism was linked to AF propensity. All horses underwent treadmill performance testing, and mitochondrial respiration was assessed in permeabilized skeletal and cardiac muscle fibers. Cardiac RNA-sequencing and in vivo AF inducibility testing were performed in a subset of horses. Mitochondrial function varied by region: the left ventricle showed the greatest oxidative capacity, and the ventricles exceeded the atria in mitochondrial content. Trained horses showed improved skeletal complex I- and II-linked respiration, and skeletal muscle respiration correlated with aerobic performance. In contrast, cardiac mitochondrial content and mass-specific respiration were unchanged by endurance exercise, despite enrichment of mitochondrial complex I pathways on transcriptomic analysis. A greater cardiac capacity for fatty acid oxidation, but not mitochondrial respiration, was associated with protection against AF induction. These findings reveal tissue-specific mitochondrial adaptations to endurance exercise and implicate cardiac substrate preference, rather than respiratory capacity, as a potential determinant of AF vulnerability. This raises new questions about how different tissues adapt metabolically to exercise and the potential role of cardiac energetics in arrhythmogenesis.NEW & NOTEWORTHY This study reveals how endurance training shapes mitochondrial function in the heart and skeletal muscle. Using racehorses as a natural large-animal model, we compared mitochondrial respiration across all four cardiac chambers and skeletal muscle. Skeletal muscle mitochondria from trained horses showed greater respiratory capacity, whereas cardiac mitochondria did not. These findings uncover tissue-specific metabolic adaptations to exercise and highlight how cardiac energetics may influence susceptibility to atrial fibrillation in endurance athletes.

Sex differences in cardiovascular disease are well documented, with females often considered hormonally protected. However, some differences persist even after menopause, indicating nonhormonal influences. Endothelial dysfunction is an early contributor to cardiovascular disease, with endothelial cell senescence playing a key role. Senescence, an irreversible cell cycle arrest, can be replicative or stress-induced. This study investigates whether sex differences in endothelial senescence exist independent of hormonal influence and vary by stimulus. Senescence was induced by replication or irradiation in female and male human umbilical vein endothelial cells (HUVECs) (up to n = 7 each) cultured under hormone-free conditions. Senescence-associated β-galactosidase (SA-β-Gal) staining; telomere length; quantitative real-time PCR (RT-qPCR) of p21, p14, p16; and crystal violet assays were used to assess senescence. Replicative senescence was analyzed across passages 1-20 and stress-induced senescence 5 days after irradiation. Female HUVECs had a significantly longer replicative lifespan than male cells (P = 0.0012) despite similar proliferation. Telomere attrition occurred faster in male cells (P = 0.0034), with earlier expression of senescence markers. In contrast, after irradiation, female cells exhibited stronger senescence responses, including increased SA-β-Gal staining and elevated p21, p14, and p16 levels. This study identifies sex differences in endothelial cell senescence under hormone-free conditions, pointing to intrinsic cellular factors. Although male cells exhibited earlier senescence under replicative stress, female cells were more vulnerable to stress-induced senescence. Together, these results highlight the importance of sex- and stimulus-specific mechanisms in vascular aging.NEW & NOTEWORTHY This study reveals intrinsic, hormone-independent sex differences in endothelial cell senescence. Female HUVECs exhibit delayed replicative but enhanced stress-induced senescence compared with male cells. These opposing responses highlight that sex-specific mechanisms in vascular aging depend on the type of senescence stimulus. By using hormone-free conditions, the study underscores the importance of intrinsic cellular factors in endothelial biology and suggests that sex should be considered when investigating and targeting vascular aging and disease.

Aerobic exercise interventions improve peripheral endothelial function in healthy older males. This effect is inconsistently observed in healthy postmenopausal females, and possible mechanisms underlying this sex-related difference remain unknown. We tested the hypothesis that endothelial sensitivity to exercise-induced shear rate is reduced in healthy postmenopausal females and that it can be improved by acute folic acid consumption. Using a double-blind randomized crossover study design, 17 postmenopausal females (66 ± 8 yr) and 14 males (66 ± 6 yr) performed handgrip exercise at 20%, 40%, 60%, and 80% of maximal voluntary contraction after consuming a placebo or 5 mg of folic acid. Brachial artery diameter and blood velocity were measured continuously using high-resolution ultrasound and analyzed using edge-detection software. Endothelial sensitivity to shear rate was quantified as the slope of the linear regression between brachial artery dilation (% change from baseline) and shear rate. During the placebo visit, endothelial sensitivity to exercise-induced shear rate did not differ between females (0.102 ± 0.055%·s^-1) and males (0.091 ± 0.061%·s^-1, P = 0.603). Acute folic acid consumption did not improve endothelial sensitivity to exercise-induced shear rate in females (placebo: 0.102 ± 0.055%·s^-1, folic acid: 0.099 ± 0.062%·s^-1, P = 0.887) or males (placebo: 0.091 ± 0.061%·s^-1, folic acid: 0.102 ± 0.083%·s^-1, P = 0.697). Endothelial sensitivity to exercise-induced shear rate does not differ between healthy postmenopausal females and age-matched males. Acute folic acid consumption does not improve endothelial sensitivity to exercise-induced shear rate in healthy older females or males.NEW & NOTEWORTHY We hypothesized that endothelial sensitivity to exercise-induced shear rate is reduced in healthy postmenopausal females. In contrast to this hypothesis, endothelial sensitivity to increases in shear rate caused by handgrip exercise did not differ between healthy postmenopausal females and males of similar age. These results suggest that a reduced endothelial sensitivity to exercise-induced shear rate may not contribute to the inconsistent effect of aerobic exercise interventions on brachial artery flow-mediated dilation in healthy postmenopausal females.

Preeclampsia induces adverse cardiovascular outcomes for both mother and offspring. We established a novel leptin-induced mouse model of preeclampsia that induces hypertension, endothelial dysfunction, and fetal growth restriction, which are collectively ablated by endothelial cell mineralocorticoid receptor (MR) deletion. However, literature lacks preclinical evidence to use MR antagonism for preeclamptic patients. We hypothesize that eplerenone improves blood pressure, vascular function, and fetal outcomes in leptin-infused pregnant mice. We infused timed-pregnant Balb/c mice with saline (sham) or leptin via subcutaneous osmotic minipump and administered vehicle or eplerenone from gestation day (GD) 11-18 and GD15-18. We measured mean arterial blood pressure (BP) via radiotelemetry, vascular function in second-order mesenteric arteries by wire myography, and pup/placental weights on GD18. Eplerenone from GD11-18 ablated leptin-induced increases in BP but independently decreased fetal weight and placental efficiency. Eplerenone increased vascular contractility to phenylephrine and increased mRNA expression of NADPH oxidase (NOX) 1 and 2 in the placentas of pregnant mice in the GD11-18 cohort. We observed in our GD15-18 cohort that eplerenone no longer decreased fetal weight or placental efficiency and there was no increase in contractility to phenylephrine. In conclusion, our data suggest that although eplerenone improves leptin-induced hypertension in pregnant mice, eplerenone reduces fetal weight when administered at mid-, but not late-, gestation in pregnant mice.NEW & NOTEWORTHY There are limited advances in the treatment for preeclampsia. Leptin induces preeclampsia dependent on mineralocorticoid receptor (MR) activation; however, there is little preclinical data on the use of MR antagonists in hypertensive pregnancy. When administered at midgestation in hypertensive mouse pregnancy, eplerenone lowers blood pressure, but increases vasoconstriction in mesenteric arteries and reduces fetal growth. When administered later in pregnancy, eplerenone no longer restricts fetal growth or increases vasoconstriction.