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

Chronic psychological stress is a recognized, yet understudied risk factor for heart disease, with potential sex-specific effects. We investigated whether chronic stress triggers sex-dependent cardiac dysfunction in isolated Wistar rat hearts subjected to ischemia-reperfusion injury. The experimental cohort underwent 1 h of daily restraint stress for 4 wk versus matched controls, followed by euthanasia (sodium pentobarbital) and heart excision for ex vivo perfusion. Blood analysis revealed sex-specific alterations in stress hormones and inflammatory markers. When compared with controls, chronic restraint stress (CRS) males displayed decreased plasma brain-derived neurotrophic factor (BDNF) levels (P < 0.05), whereas CRS females exhibited elevated plasma adrenocorticotropic hormone (ACTH) (P < 0.01) and reduced corticosterone (P < 0.001) alongside lower serum estradiol (P < 0.001) and estradiol/progesterone ratio (P < 0.01). Of note, CRS females showed increased serum cardiac troponin T (P < 0.05) and tumor necrosis factor-α (TNF-α) (P < 0.01) with suppressed interleukin (IL)-1α, IL-1β, IL-6, and IL-10 levels (P < 0.05) when compared with controls. Ex vivo Langendorff perfusions revealed that CRS female hearts displayed impaired postischemic functional recovery for baseline stroke volume (SV, P < 0.01), work performance (P < 0.05), aortic output (AO, P < 0.05), coronary flow (CF, P < 0.01), and overall cardiac output (CO, P < 0.01) when compared with matched controls and CRS males (P < 0.05). Our findings reveal intriguing sex-specific responses at both the systemic and functional levels in stressed hearts. Here, the dysregulation of stress hormones, proinflammatory state, and potential underlying cardiomyopathy in females following the stress protocol renders them more prone to damage following myocardial ischemia. This study emphasizes the importance of incorporating sex as a biological variable in cardiac research focusing on stress-related cardiomyopathy.NEW & NOTEWORTHY Although chronic psychological stress is a risk factor for cardiovascular diseases, the underlying mechanisms remain poorly understood. This study revealed that chronic restraint stress resulted in systemic changes (dysregulated stress hormones, proinflammatory state) and potential cardiomyopathy in females versus controls and their male counterparts. The stressed female hearts also displayed reduced functional recovery following ex vivo ischemia-reperfusion. This highlights the importance of incorporating sex as a biological variable in cardiac research.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Excessive stimulation of the inositol (1,4,5)-trisphosphate (IP₃) signaling pathway has been linked to AF through abnormal calcium handling. However, little is known about the mechanisms involved in this process. We expressed the fluorescence resonance energy transfer (FRET)-based cytosolic cyclic adenosine monophosphate (cAMP) sensor EPAC-S^H187 in neonatal rat atrial myocytes (NRAMs) and neonatal rat ventricular myocytes (NRVMs). In NRAMs, the addition of the α₁-agonist, phenylephrine (PE, 3 µM), resulted in a FRET change of 21.20 ± 7.43%, and the addition of membrane-permeant IP₃ derivative 2,3,6-tri-O-butyryl-myo-IP₃(1,4,5)-hexakis(acetoxymethyl)ester (IP₃-AM, 20 μM) resulted in a peak of 20.31 ± 6.74%. These FRET changes imply an increase in cAMP. Prior application of IP₃ receptor (IP₃R) inhibitors 2-aminoethyl diphenylborinate (2-APB, 2.5 μM) or Xestospongin-C (0.3 μM) significantly inhibited the change in FRET in NRAMs in response to PE. Xestospongin-C (0.3 μM) significantly inhibited the change in FRET in NRAMs in response to IP₃-AM. The FRET change in response to PE in NRVMs was not inhibited by 2-APB or Xestospongin-C. Finally, the localization of cAMP signals was tested by expressing the FRET-based cAMP sensor, AKAP79-CUTie, which targets the intracellular surface of the plasmalemma. We found in NRAMs that PE led to FRET change corresponding to an increase in cAMP that was inhibited by 2-APB and Xestospongin-C. These data support further investigation of the proarrhythmic nature and components of IP₃-induced cAMP signaling to identify potential pharmacological targets.NEW & NOTEWORTHY This study shows that indirect activation of the IP₃ pathway in atrial myocytes using phenylephrine and direct activation using IP₃-AM leads to an increase in cAMP and is in part localized to the cell membrane. These changes can be pharmacologically inhibited using IP₃R inhibitors. However, the cAMP rise in ventricular myocytes is independent of IP₃R calcium release. Our data support further investigation into the proarrhythmic nature of IP₃-induced cAMP signaling.

Hypertension is associated with decreased endothelial function through reduced contributions of nitric oxide (NO). We previously discovered that flow-induced NO production in resistance arteries of mice and humans critically depends on endothelial inwardly rectifying K⁺ (Kir2.1) channels. The goal of this study was to establish whether these channels contribute to the impairment of endothelial function, measured by flow-induced vasodilation (FIV) in peripheral resistance arteries of humans with hypertension. We measured FIV in vessels isolated from subcutaneous fat biopsies from 32 subjects: normotensive [n = 19; 30.6 ± 9.8 yr old; systolic blood pressure (SBP): 115.2 ± 7 mmHg; diastolic blood pressure (DBP): 75.3 ± 5.7 mmHg] and hypertensive (n = 13; 45.3 ± 15.3 yr old; SBP: 146.1 ± 15.2 mmHg; DBP: 94.4 ± 6.9 mmHg). Consistent with previous studies, we find that FIV is impaired in hypertensive adults as demonstrated by a significant reduction in FIV when compared with the normotensive adults. Furthermore, our data suggest that the impairment of FIV in hypertensive adults is partially attributed to a reduction in Kir2.1-dependent vasodilation. Specifically, we show that blocking Kir2.1 with ML133 or functionally downregulating Kir2.1 with endothelial-specific adenoviral vector containing dominant-negative Kir2.1 (dnKir2.1) result in a significant reduction in FIV in normotensive subjects but with a smaller effect in hypertensive adults. The Kir2.1-dependent vasodilation was negatively correlated to both SBP and DBP, indicating that the Kir2.1 contribution to FIV decreases as blood pressure increases. In addition, we show that exposing vessels from normotensive adults to acute high-pressure results in loss of Kir2.1 contribution, as high pressure impairs vasodilation. No effect is seen when these vessels were incubated with dnKir2.1. Overexpressing wtKir2.1 in the endothelium resulted in some improvement in vasodilation in arteries from all participants, with a greater recovery in hypertensive adults. Our data suggest that hypertension-induced suppression of Kir2.1 is an important mechanism underlying endothelial dysfunction in hypertension.NEW & NOTEWORTHY Impairment of endothelial function under high blood pressure is linked to the loss of inwardly rectifying K⁺ (Kir2.1) channels activity in human resistance arteries, leading to a reduction in flow-induced vasodilation and possibly leading to a vicious cycle between elevation of blood pressure, and further impairment of Kir2.1 function and flow-induced vasodilation.

Fractional flow reserve (FFR) measurements are recommended for assessing hemodynamic coronary stenosis severity. Intracoronary ECG (icECG) is easily obtainable and highly sensitive in detecting myocardial ischemia due to its close vicinity to the myocardium. We hypothesized that the remission time of myocardial ischemia on icECG after a controlled coronary occlusion accurately detects hemodynamically relevant coronary stenosis. This retrospective, observational study included patients with chronic coronary syndrome undergoing hemodynamic coronary stenosis assessment immediately following a strictly 1-min proximal coronary artery balloon occlusion with simultaneous icECG recording. icECG was used for a beat-to-beat analysis of the ST-segment shift during reactive hyperemia immediately following balloon deflation. The time from coronary balloon deflation until the ST-segment shift reached 37% of its maximum level, i.e., icECG ST-segment shift remission time (τ-icECG in seconds), was obtained by an automatic algorithm. τ-icECG was tested against the simultaneously obtained reactive hyperemia FFR at a threshold of 0.80 as a reference parameter. From 120 patients, 139 icECGs (age, 68 ± 10 yr old) were analyzed. Receiver operating characteristic (ROC) analysis of τ-icECG for the detection of hemodynamically relevant coronary stenosis at an FFR of ≤0.80 was performed. The area under the ROC curve was equal to 0.621 (P = 0.0363) at an optimal τ-icECG threshold of 8 s (sensitivity, 61%; specificity, 67%). τ-icECG correlated inversely and linearly with FFR (P = 0.0327). This first proof-of-concept study demonstrates that τ-icECG, a measure of icECG ST segment-shift remission after a 1-min coronary artery balloon occlusion accurately detects hemodynamically relevant coronary artery stenosis according to FFR at a threshold of ≥8 s.NEW & NOTEWORTHY Invasive hemodynamic measurements are recommended by the current cardiology guidelines to guide percutaneous coronary interventions in the setting of chronic coronary syndrome. However, those pressure-derived indices demonstrate several theoretical and practical limitations. Thus, this study demonstrates the accuracy of a novel, pathophysiology-driven approach using intracoronary ECG for the identification of hemodynamically relevant coronary lesions by quantitatively assessing myocardial ischemia remission.

Coronary vasomotor dysfunction, an important underlying cause of angina and nonobstructive coronary arteries (ANOCA), encompassing coronary vasospasm, coronary endothelial dysfunction, and/or coronary microvascular dysfunction, is clinically assessed by invasive coronary function testing (ICFT). As ICFT imposes a high burden on patients and carries risks, developing noninvasive alternatives is important. We evaluated whether coronary vasomotor dysfunction is a component of systemic microvascular endothelial and smooth muscle dysfunction and can be detected using laser speckle contrast analysis (LASCA). Forty-three consecutive patients with ANOCA underwent ICFT, with intracoronary acetylcholine, adenosine, and flow measurements, to assess coronary vasomotor dysfunction. Cutaneous microvascular function was assessed using LASCA in the forearm, combined with vasodilators acetylcholine, sodium nitroprusside, and insulin and using EndoPAT, by measuring the reactive hyperemia index (RHI). Of the 43 included patients with ANOCA (79% women, 59 ± 9 yr old), 38 patients had coronary vasomotor dysfunction, including 28 with coronary vasospasm, 26 with coronary endothelial dysfunction, and 18 with coronary microvascular dysfunction, with overlapping endotypes. Patients with and without coronary vasomotor dysfunction had similar peripheral flow responses to acetylcholine, insulin, and RHI. In contrast, coronary vasomotor dysfunction was associated with lower peripheral flow responses to sodium nitroprusside (P < 0.001). An absolute flow response to sodium nitroprusside of 83.95 APU resulted in 86.1% sensitivity and 80.0% specificity for coronary vasomotor dysfunction (area under the ROC curve, 0.883; P = 0.006). In conclusion, this study provides evidence of systemic vascular smooth muscle dysfunction in patients with ANOCA with coronary vasomotor dysfunction and the diagnostic value of peripheral microvascular function testing as a noninvasive tool for detecting coronary vasomotor dysfunction.NEW & NOTEWORTHY This study provides proof of concept that assessment of the peripheral vasculature, particularly vascular smooth muscle cells measured using the LASCA technology holds potential as a noninvasive tool for detecting coronary vasomotor dysfunction. This finding highlights the potential of the LASCA technology in, for example, medication studies for coronary vasomotor dysfunction, especially when investigating whether medication improves vascular function, as repeated peripheral measurements are less invasive than invasive coronary function testing, the current gold standard.

Influenza A virus (IAV) infection while primarily affecting the lungs, is often associated with cardiovascular complications. However, the mechanisms underlying this association are not fully understood. Here, we investigated the potential role of FBXL19, a member of the Skp1-Cullin-1-F-box family of E3 ubiquitin ligase, in IAV-induced cardiac inflammation. We demonstrated that FBXL19 overexpression in endothelial cells (ECs) reduced viral titers and IAV matrix protein 1 (M1) levels while increasing antiviral gene expression, including interferon (IFN)-α, -β, and -γ and RANTES (regulated on activation normal T cell expressed and secreted) in the cardiac tissue of IAV-infected mice. Moreover, EC-specific overexpression of FBXL19 attenuated the IAV infection-reduced interferon regulatory factor 3 (IRF3) level without altering its mRNA level and suppressed cardiac inflammation. Furthermore, IAV infection triggered cellular senescence programs in the heart as indicated by the upregulation of p16 and p21 mRNA levels and the downregulation of lamin-B1 levels, which were partially reversed by FBXL19 overexpression in ECs. Our findings indicate that EC-specific overexpression of FBXL19 protects against IAV-induced cardiac damage by enhancing interferon-mediated antiviral signaling, reducing cardiac inflammation, and suppressing cellular senescence programs.NEW & NOTEWORTHY Our study reveals a novel facet of IAV infection, demonstrating that it can trigger cellular senescence within the heart. Intriguingly, upregulation of endothelial FBXL19 promotes host innate immunity, reduces cardiac senescence, and diminishes inflammation. These findings highlight the therapeutic potential of targeting FBXL19 to mitigate IAV-induced cardiovascular complications.

Despite exercise intolerance being predictive of outcomes in pulmonary arterial hypertension (PAH), its underlying cardiac mechanisms are not well described. The aim of the study was to explore the biventricular response to exercise and its associations with cardiorespiratory fitness in children with PAH. Participants underwent incremental cardiopulmonary exercise testing and simultaneous exercise echocardiography on a recumbent cycle ergometer. Linear mixed models were used to assess cardiac function variance and associations between cardiac and metabolic parameters during exercise. Eleven participants were included with a mean age of 13.4 ± 2.9 yr old. Right ventricle (RV) systolic pressure (RVsp) increased from a mean of 59 ± 25 mmHg at rest to 130 ± 40 mmHg at peak exercise (P < 0.001), whereas RV fractional area change (RV-FAC) and RV-free wall longitudinal strain (RVFW-S_l) worsened (35.2 vs. 27%, P = 0.09 and -16.6 vs. -14.6%, P = 0.1, respectively). At low- and moderate-intensity exercise, RVsp was positively associated with stroke volume and O₂ pulse (P < 0.1). At high-intensity exercise, RV-FAC, RVFW-S_l, and left ventricular longitudinal strain were positively associated with oxygen uptake and O₂ pulse (P < 0.1), whereas stroke volume decreased toward peak (P = 0.04). In children with PAH, the increase of pulmonary pressure alone does not limit peak exercise, but rather the concomitant reduced RV functional reserve, resulting in RV to pulmonary artery (RV-PA) uncoupling, worsening of interventricular interaction and LV dysfunction. A better mechanistic understanding of PAH exercise physiopathology can inform stress testing and cardiac rehabilitation in this population.NEW & NOTEWORTHY In children with pulmonary arterial hypertension, there is a marked increase in pulmonary artery pressure during physical activity, but this is not the underlying mechanism that limits exercise. Instead, right ventricle-to-pulmonary artery uncoupling occurs at the transition from moderate to high-intensity exercise and correlates with lower peak oxygen uptake. This highlights the more complex underlying pathological responses and the need for multiparametric assessment of cardiac function reserve in these patients when feasible.

Traditional cardiovascular risk factors, including hypertension, only explain part of major adverse cardiac events (MACEs). Understanding what other risk factors contribute to MACE is essential for prevention. Constipation shares common risk factors with hypertension and is associated with an increased risk of several cardiovascular diseases. We hypothesized that constipation is an underappreciated risk factor for MACE. We used the population healthcare and genomic data in the UK Biobank (n = 408,354) to study the contribution of constipation (ICD10 K59.0) to the risk of MACE, defined by any episode of acute coronary syndrome (ACS), ischemic stroke, and heart failure (HF). Analyses were controlled for traditional cardiovascular risk factors. We also assessed genetic correlations (r_g) between constipation and MACE. Constipation cases (n = 23,814) exhibited a significantly higher risk of MACE compared with those with normal bowel habits [odds ratio (OR) = 2.15, P < 1.00 × 10^-300]. Constipation was also significantly associated with individual MACE subgroups, in order: HF (OR = 2.72, P < 1.00 × 10^-300), ischemic stroke (OR = 2.36, P = 2.02 × 10^-230), and ACS (OR = 1.62, P = 5.82 × 10^-113). In comparison with patients with constipation-free hypertension, patients with hypertension with constipation showed significantly higher odds of MACE (OR = 1.68, P = 1.05 × 10^-136) and a 34% increased risk of MACE occurrence (P = 2.3 × 10^-50) after adjustment for medications that affect gut motility and other traditional cardiovascular risk factors. Finally, we detected positive genetic correlations between constipation and MACE subgroups ACS (r_g = 0.27, P = 2.12 × 10^-6), ischemic stroke (r_g = 0.23, P = 0.011), and HF (r_g = 0.21, P = 0.0062). We identified constipation as a potential risk factor independently associated with higher MACE prevalence. These findings warrant further studies on their causal relationship and identification of pathophysiological mechanisms.NEW & NOTEWORTHY Analyzing 408,354 participants of the UK Biobank, we show that constipation cases exhibited a significantly higher risk of major adverse cardiac events (MACEs) than those with regular bowel habits. In comparison with patients with constipation-free hypertension, patients with hypertension with constipation showed significantly higher odds of MACE and a 34% increased risk of subsequent MACE occurrence. Finally, we detected positive genetic correlations between constipation and MACE. This association holds potential for therapeutic exploitation and prevention based on individuals' risk assessment.

Excess sodium consumption contributes to arterial dysfunction in humans. The C57BL/6 strain of mice has been used to identify mechanisms by which arterial dysfunction occurs after excess sodium consumption. However, there are concerns that C57BL/6 mice have strain-specific resistance to high-sodium (HS) diet-induced hypertension. To address this concern, we performed a meta-analysis to determine if excess sodium consumption in C57BL/6 mice induces arterial dysfunction. Databases were searched for HS versus standard diet studies that measured arterial function [i.e., systolic blood pressure (BP), endothelium-dependent dilation (EDD), and central arterial stiffness] in C57BL/6 mice. A total of 39 studies were included, demonstrating that the HS condition resulted in higher systolic BP than control mice with a mean difference of 9.8 mmHg (95% confidence interval [CI] = [5.6, 14], P < 0.001). Subgroup analysis indicated that the systolic BP was higher in HS compared with the control condition when measured during night compared with daytime with telemetry (P < 0.001). We also identified that the difference in systolic BP between HS and control was ∼2.5-fold higher when administered through drinking water than through food (P < 0.001). A total of 12 studies were included, demonstrating that the HS condition resulted in lower EDD than control with a weighted mean difference of -12.0% (95% CI = [-20.0, -4.1], P = 0.003). It should be noted that there was considerable variability across studies with more than half of the studies showing no effect of the HS condition on systolic BP or EDD. In summary, excess sodium consumption elevates systolic BP and impairs EDD in C57BL/6 mice.NEW & NOTEWORTHY C57BL/6 mice are perceived as resistant to high-sodium diet-induced arterial dysfunction. This meta-analysis demonstrates that excess sodium consumption elevates blood pressure and impairs endothelium-dependent dilation in C57BL/6 mice. Nighttime measurements show more pronounced blood pressure elevation. In addition, sodium administration via drinking water, compared with food, induces a greater blood pressure elevation. These findings may be influenced by outlier studies, as the majority of studies showed no adverse effect of excess sodium consumption on arterial function.

Type II diabetes mellitus (T2D) is a chronic metabolic disease and a risk factor for cardiovascular disease and cerebrovascular dysfunction including vascular dementia. Sex differences in the prevalence of T2D, dementia, and global genomic changes in the brain have been observed; however, most studies have been performed in males. Therefore, our aim was to evaluate the consequence of T2D on cognitive function and decipher the underlying molecular transcriptomic mechanisms of endothelial cells in an important brain memory center, the hippocampus, using a female murine diabetes model. We assessed cognitive function, metabolic parameters, and then performed hippocampal single-nuclei RNA sequencing (snRNA seq) in adult female db/db and control wild-type (WT) mice. db/db mice exhibited characteristic T2D metabolism with hyperglycemia, hyperinsulinemia, and hyperlipidemia when compared with WT mice. Female db/db mice presented cognitive decline compared with wild-type mice, as determined by open field and Morris water maze tests. snRNAseq showed that T2D induced significant changes in the global transcriptomic profile of hippocampal endothelial cells by modulating the expression of not only protein-coding genes but also long noncoding RNAs. These genes regulate cell-cell junctions, cell chemotaxis, actin cytoskeleton organization, and cell adhesion, suggesting that diabetes increases endothelial cell permeability. Observed genomic changes also correlated with the genetics of persons with clinical Alzheimer's disease and vascular dementia. In conclusion, T2D, by transcriptional and posttranscriptional regulation, regulates endothelial cell dysfunction predictive of increased vascular permeability, and negatively impacts cognitive function. Our work has implications for sex-specific molecular therapeutic targets for dementia in females.NEW & NOTEWORTHY Female db/db mice presented cognitive decline as determined by open field and Morris water maze tests. snRNAseq showed that T2D induced changes in the global transcriptomic profile of hippocampal endothelial cells by modulating the expression of not only protein-coding genes but also long noncoding RNAs. These genes regulate cell-cell junctions, cell chemotaxis, or cell adhesion, suggesting increased endothelial permeability. Genomic changes correlated with the genetics of persons with clinical Alzheimer's disease and vascular dementia.