Trans and nonbinary adults assigned female at birth (TNBF) are at elevated cardiovascular risk, an effect proposed to occur secondary to testosterone use. However, gender minority (GM) stress may also contribute to cardiovascular risk. Therefore, we examined the relative association of GM stress and testosterone to blood pressure (BP) and its regulation in TNBF adults. In 24 TNBF adults (12 not using and 12 using testosterone), GM stress was derived from a standardized composite score of seven psychosocial scales, and total testosterone was measured via radioimmunoassay. BP was assessed at rest and during acute physical (cold pressor test; CPT) and psychological (stroop colour word test; SCWT) stress. Resting systolic (SBP; 115±7 vs 115±13mmHg; P=0.978) and diastolic BP (DBP; 68±6 vs 68±11mmHg; P=0.995) did not differ between testosterone non-users and users. Backward elimination linear regression indicated that GM stress was negatively associated (SBP: β: -0.589, P=0.002; DBP: β: -0.492, P=0.006) and total testosterone was positively associated (SBP: β: 0.301, P=0.079; DBP: β: 0.422, P=0.013) with BP responses to the SCWT (SBP: R2=0.430, P=0.003; DBP: R2=0.553, P=0.001), but not resting BP or BP responses to the CPT. Our findings suggest that greater GM stress exposure blunts BP responses to psychological, but not physical, stress, whereas higher total testosterone levels are associated with greater BP responses to psychological stress among TNBF adults. Given established links between BP, its regulation, and cardiovascular risk, these data highlight the importance of integrating both physiological and psychological factors when examining cardiovascular risk in TNBF adults.
Chelonians are commonly sedated with α₂-adrenoceptor agonists, such as medetomidine, and bradycardia is consistently reported following administration. This may reflect a baroreflex response to α₂-mediated peripheral vasoconstriction and increased systemic vascular resistance, but the vascular contribution to these cardiovascular effects has not been directly investigated. Here, we tested the hypothesis that α₂-adrenoceptors contribute predominantly to vascular contraction in chelonians, contrasting with the α₁-adrenoceptor-dominant regulation described in mammals. Mesenteric resistance arteries from three chelonian species spanning two chelonian families (Stigmochelys pardalis, Mauremys reevesii and Mauremys sinensis) were studied using wire myography. Concentration-response curves were generated for the nonselective α-adrenoceptor agonist noradrenaline, the selective α₁-adrenoceptor agonist methoxamine, and the α₂-adrenoceptor agonists medetomidine, detomidine, xylazine and romifidine. The effects of α₂-adrenoceptor antagonism with vatinoxan and α₁-adrenoceptor antagonism with prazosin were also assessed. Medetomidine and detomidine produced robust, concentration-dependent vasoconstriction, whereas xylazine and romifidine produced weak or inconsistent responses. Vatinoxan attenuated α₂-adrenoceptor agonist-induced responses, although the magnitude and nature of antagonism differed between species and experimental conditions. Noradrenaline-induced contraction was also attenuated by vatinoxan, whereas methoxamine produced little or no contraction and prazosin had minimal effects on noradrenaline responses. These findings support a predominant functional contribution of α₂-adrenoceptors to vascular contraction in the chelonian systemic arteries studied, with comparatively little detectable contribution from α₁-adrenoceptors. This adrenergic organization differs from the α₁-dominant vascular regulation typical of mammals and identifies chelonian arteries as a useful comparative model for α₂-adrenoceptor-mediated vascular control. The findings also provide a mechanistic basis for the peripheral vascular component of the cardiovascular response to α₂-adrenoceptor agonist sedation in chelonians.
Excessive hypercholesterolemia (eHC) in pregnancy is associated with complications such as preeclampsia, yet its impact on maternal cardiac adaptation and long-term cardiovascular health remains unclear. We hypothesized that eHC impairs maternal cardiac structure and function during pregnancy and that these effects persist postpartum. Sprague Dawley rats were fed either a control diet (CTL) or high cholesterol diet (eHC) from gestational day (GD) 6-20 (term=22 days). Echocardiography was performed before pregnancy, at GD20, and 3 months postpartum. Plasma and left ventricular tissue were collected at GD20 and postpartum for molecular analyses. CTL dams demonstrated normal pregnancy-associated cardiac adaptations, including increased diastolic left ventricular internal diameter, stroke volume, cardiac output, and diastolic left ventricular volume in late pregnancy, with normalization postpartum. These adaptations were attenuated in eHC dams. In late pregnancy, eHC dams exhibited reduced stroke volume and cardiac output compared with CTL, along with alterations in diastolic function, including reduced mitral valve A' velocity. Postpartum, eHC dams showed changes in diastolic indices, including reduced mitral valve A-wave velocity and E'/A' ratio. Measures of systolic performance (ejection fraction and fractional shortening) were unchanged between groups. Molecular analyses revealed increased cardiomyocyte size, altered collagen remodeling characterized by an increased COL1-to-COL3 ratio, and elevated CD31 expression in eHC dams during pregnancy. Postpartum, collagen remodeling was evident, but now with reduced COL1 and increased COL3 expression. Together, these findings demonstrate that eHC disrupts normal maternal cardiac adaptation during pregnancy and promotes adverse remodeling and cardiac dysfunction postpartum, with potential implications for long-term cardiovascular disease risk.
Preclinical porcine models of myocardial infarction (MI) are essential for cardiovascular research but often require lengthy surgeries with variable outcomes. We developed a minimally invasive mini-thoracotomy approach to maximize procedural success, minimize operative time, and ensure reproducible infarct induction. Eleven Lanyu Miniature Pigs (25-30 kg) were assigned to an MI group (n = 7) or sham control group (n = 4). MI was induced by permanent left anterior descending (LAD) coronary artery ligation via mini-thoracotomy. Six of seven MI pigs (85.7%) survived, with a mean skin-to-skin operative time of 35.83 ± 2.86 minutes, whereas all sham controls survived without complications. Infarction was confirmed by post-ligation ST-segment elevation and pathological Q waves. Serial echocardiography and speckle-tracking strain analysis at baseline, 1 week, and 3 months revealed consistent regional systolic dysfunction in the MI group, though inter-animal variability was observed in certain functional parameters. Cross-sectional area-based ejection fraction was significantly reduced at the papillary muscle and apical levels by 1 week, persisting through 3 months. Speckle-tracking showed corresponding reductions in radial strain, particularly apically. Progressive ventricular remodeling was evident from an increased left ventricular mass index, and Masson's trichrome staining confirmed extensive myocardial fibrosis distal to the ligation sites (mean fibrotic area 25.6 ± 4.3%). Sham controls retained preserved structure and function throughout. In conclusion, this minimally invasive porcine MI model provides a highly feasible, rapid, and reproducible translational platform, integrating surgical accessibility with robust functional and histological validation for investigating post-infarction remodeling and evaluating cardiovascular therapeutics.
Higher diastolic aortic pressure is associated with central arterial elastic recoil function and may help preserve peripheral perfusion. Japanese female pearl divers, called "Ama," exhibit lower arterial stiffness as an adaptation to lifelong repeated diving, but whether this translates into enhanced diastolic blood flow remains unclear. This study investigated aortic and carotid hemodynamic profiles to determine whether female pearl divers demonstrate enhanced diastolic blood flow in association with diastolic aortic pressure. A total of 61 middle-aged and elderly female pearl divers (<65-yr group: n = 23, 53 ± 9 yr; ≥65-yr group: n = 38, 72 ± 4 yr, representing middle-aged and older groups, respectively) and 94 female nondivers (<65-yr group: n = 48, 53 ± 9 yr; ≥65-yr group: n = 46, 73 ± 5 yr) were studied. Aortic pressure was estimated from applanation tonometry of carotid arterial pressure waveforms via a general transfer function. Carotid blood flow was calculated from blood velocity and diameter of the common carotid artery. Diastolic aortic pressure-time integral and carotid flow volume were calculated as areas under the waveforms from the dicrotic notch to end-diastole. Compared with nondivers, pearl divers exhibited a higher diastolic aortic pressure-time integral (main effect of group, P < 0.01). Moreover, diastolic carotid blood flow volume was also greater in pearl divers than in nondivers (main effect of group, P < 0.01). Therefore, compared with female nondivers, lifelong female pearl divers may have lower central arterial stiffness that enhances diastolic aortic pressure, thereby preserving greater carotid blood flow during diastole.NEW & NOTEWORTHY This study indicated that, compared with female nondivers, lifelong female pearl divers exhibited higher diastolic carotid blood flow alongside higher aortic pressure during diastole. Therefore, lifelong repeated diving exposure may lead to decreased arterial stiffness, which can facilitate higher diastolic aortic pressure and thereby enhance distal arterial blood flow during diastole.
Smoking disrupts cardiac autonomic regulation, vascular biology, and platelet function; however, the acute and longer-term cardiovascular effects of resurging and emerging tobacco and marijuana products remain incompletely characterized. We investigated the impact of exposure to smoke and aerosol from several tobacco and marijuana products on cardiac function, platelet activity, and myocardial susceptibility to ischemia-reperfusion myocardial infarction (MI). Male and female Sprague-Dawley rats underwent single or daily 5-min pulsatile exposure sessions to emissions from tobacco cigarettes, e-cigarettes (JUUL), heated tobacco products (IQOS), marijuana cigarettes, or cannabinoid-depleted ("placebo") marijuana cigarettes, with an air negative control. Cardiac function was assessed immediately after single exposure by echocardiography and intraventricular hemodynamics. Platelet aggregation was measured immediately after single exposure and 1 day after repeated (2-wk) exposure. Myocardial infarct size, normalized to area at risk, was assessed following MI after repeated (4-wk) exposure. Single exposure to tobacco smoke or JUUL aerosol reduced left ventricular ejection fraction relative to preexposure. Acute marijuana smoke exposure similarly impaired left ventricular function assessed by hemodynamics. Single exposure to tobacco, marijuana, and placebo marijuana smoke increased collagen-induced platelet aggregation, with more pronounced responses in females, whereas repeated (2-wk) exposure to smoke/aerosol from tobacco cigarettes, JUUL, IQOS, and placebo marijuana increased platelet aggregation across groups. Notably, repeated (4-wk) exposure to tobacco smoke/aerosol or marijuana smoke before MI reduced myocardial tissue preservation, resulting in greater infarct size post MI. These findings indicate that individual tobacco and marijuana smoking and vaping similarly impair cardiac function, enhance platelet reactivity, and reduce myocardial tolerance to ischemia-reperfusion injury.NEW & NOTEWORTHY Inhalable products marketed as reduced-harm alternatives to combustible cigarettes, including e-cigarettes, heated tobacco products, and marijuana, produce rapid and sustained adverse cardiovascular effects. Even brief exposure impairs cardiac function and enhances platelet aggregation, whereas prior exposure increases myocardial susceptibility to ischemia-reperfusion injury, resulting in larger infarcts following myocardial infarction. These findings challenge the perception that noncombustible or "reduced-harm" products are cardiovascularly benign.
The salt sensitivity of blood pressure (SSBP) is rarely assessed and represents a critical barrier in precision hypertension treatment. The current approaches to assess salt sensitivity are labor- and resource-intensive, limiting their clinical implementation. The salt sensitivity index (SSI), derived from 24-h ambulatory blood pressure monitoring (ABPM) data, has been proposed as a clinical diagnostic approach to classify individuals at low-, intermediate-, or high-risk for SSBP. This study utilized the Dietary Approaches to Stop Hypertension (DASH)-Sodium Trial control diet arm dataset (n = 170), in which SSBP was assessed by the gold-standard dietary approach, to address the hypothesis that identification of a high-risk SSI can predict the individual SSBP. In the high-risk SSI category, 72% of participants exhibited a salt-sensitive phenotype. For all participants with a high-risk SSI (male and female and normotensive and hypertensive), sensitivity (ability to correctly identify individuals with SSBP) was 85%, specificity (ability to correctly identify individuals without SSBP) was 41%, positive predictive value (probability that a person who tests positive has SSBP) was 72%, negative predictive value (probability that a person who tests negative does not have SSBP) was 60%, and accuracy was 69%. For hypertensive participants only with a high-risk SSI (males and females), sensitivity was 86%, specificity was 44%, the positive predictive value increased to 83%, the negative predictive value was 50%, and accuracy increased to 76%. This study validates the identification of a high-risk SSI, based on 24-h ABPM, as a generalizable, implementable approach for the clinical diagnosis of SSBP, with potentially greater clinical diagnostic value in hypertensive versus normotensive individuals.NEW & NOTEWORTHY This study, conducted in the DASH-Sodium dataset, validates the identification of a high-risk salt sensitivity index, based on 24-h ambulatory blood pressure monitoring, as a generalizable, easily implementable approach for the clinical diagnosis of the salt sensitivity of blood pressure. As this approach possesses greater sensitivity and comparable accuracy to the furosemide-based inpatient protocol, we believe that the assessment of the salt sensitivity index in hypertensive patients represents an advance in precision hypertension management.
Acute kidney injury (AKI) affects up to 50% of patients undergoing cardiopulmonary bypass, yet early diagnostic biomarkers and targeted therapies remain limited. Although AKI is attributed to bypass-induced renal ischemia, the underlying molecular mechanisms are poorly understood. This study characterizes renal inflammatory dynamics in cardiac surgery patients, beginning intraoperatively. One hundred adults undergoing cardiopulmonary bypass were enrolled at the Quebec Heart and Lung Institute in Canada (July 2021 - April 2024). Urine and plasma samples were collected before and up to 5 days post-bypass. Pro-inflammatory P2Y14 receptor ligands (UDP-sugars) were quantified by LC-ESI-MS/MS, and kidney injury marker-1 (KIM-1) and inflammatory mediators were measured by multiplex immunoassays. AKI was defined using modified KDIGO criteria: serum creatinine increase ≥ 0.3 mg/dL or urine output ≤ 0.5 mL/kg/h for 24 hours postoperatively. Urinary UDP-sugars increased significantly within 0-4 hours post-bypass in AKI patients, while plasma levels remained unchanged. Urinary UDP-sugars correlated with KIM-1 at 4 hours and preceded pro-inflammatory cytokines (CXCL1, CCL2, and IL-18), which peaked at 12 hours. Immunofluorescence localized P2Y14 to collecting duct apical membranes, and detected CD45+/myeloperoxidase (MPO)+ neutrophils in ischemic human kidneys. Patients with elevated UDP-sugars showed significantly higher inflammatory markers compared to those with low levels. In conclusion, UDP-sugars released by damaged renal tubules trigger inflammatory cytokine secretion in AKI patients. The UDP-sugar/P2Y14 axis represents a novel early predictor and therapeutic target for cardiac surgery-associated AKI. The robust expression of P2Y14 and the presence of proinflammatory immune cells in human ischemic kidneys further support the potential of this therapeutic strategy.
Understanding the causes of ventricular arrhythmias after myocardial infarction (MI) remains a major challenge to academic and clinical medicine. Key concepts in the pathophysiology underlying such events are based on studies in rodents, in whom altered sarcoplasmic reticulum (SR) calcium handling is key even in chronic stages after MI. Since cardiac electrophysiology in rodents has important differences from humans, an overview of insights directly from large animals and humans is needed. Our objective was to provide a summary of existing literature on the role of SR calcium handling in ventricular tachyarrhythmias after the acute phase of MI in large animals and humans. We conducted a systematic search of original articles on calcium handling after MI in large animals and humans, summarized key findings, and assessed risk of bias in the included articles. Twenty-five studies explicitly measuring cellular calcium handling after MI in large animals or human tissue were included. Overall, the studies were somewhat ambiguous regarding calcium transient amplitude and kinetics; but consistently showed increased frequency of calcium sparks, calcium waves, delayed afterdepolarizations and reduced t-tubule density; and some reported increased propensity for calcium alternans. Abundance and posttranslational modification of calcium handling proteins were less consistent. In conclusion, existing evidence from large animals and human material supports a role for altered calcium handling in ventricular arrhythmias after MI. However, the evidence is still limited. More studies in such models are needed to provide mechanistic explanations that can be used as a basis for development of new therapies.
Cardiac arrhythmias are suspected as a major cause of sudden cardiac death (SCD) in pulmonary arterial hypertension (PAH); however, the mechanisms underlying right ventricle (RV) electrical remodeling, arrhythmias, and SCD in PAH remain unclear. We investigated the mechanisms of increased susceptibility to SCD during progressive PAH in the Fischer CDF rat monocrotaline (MCT) model. Echocardiography, electrocardiogram, and cardiac catheterization were performed at 4 and 5 wk post MCT injection (MCT-4 and MCT-5 groups, respectively). Hearts were isolated and Langendorff-perfused, and changes in action potential (AP) duration (APD) were evaluated by voltage optical mapping. A progressive increase in RV systolic pressure was observed in MCT-4 and MCT-5 compared to control. In MCT-4, we observed RV hypertrophy with preserved cardiac function and chamber size, indicating adaptive RV remodeling. Conversely, maladaptive RV remodeling was seen in MCT-5, indicated by reduced cardiac function, along with increased RV internal diameter. Electrically, we observed delayed repolarization and prolongation of RV AP and QT interval in the MCT-5 compared to control and MCT-4. Electrical changes were consistent with decreased Kcnh2, Kcnk2, and Scn7a expression in the RV. Reduced RV vascular density together with upregulation of hypoxia-regulated genes were noted in MCT-5 compared to control, which along with the observed ST elevation suggests RV ischemia. In summary, Fischer CDF rats develop maladaptive RV functional and electrical remodeling at 5 wk post MCT that is associated with reduced RV potassium and sodium channel expression and elevated markers of RV ischemia. These changes may contribute to increased susceptibility to arrhythmias and SCD in PAH.NEW & NOTEWORTHY This study shows maladaptive right ventricle (RV) functional and electrical remodeling in pulmonary arterial hypertension (PAH) in Fischer CDF rats, a rat strain that is susceptible to sudden cardiac death in PAH. The electrical changes in the RV were associated with reduced expression of potassium and sodium channels in the RV, reduced RV vascular density, and elevated markers of RV ischemia. Combination of these changes may increase the risk of sudden cardiac death in PAH.
Patients with chronic inflammatory disorders, including inflammatory bowel disease (IBD), carry an increased risk of cardiovascular disease. The 2022 ORAL Surveillance study reported that the pan-selective Janus kinase inhibitor (JAKi) tofacitinib was associated with increased risk of major adverse cardiovascular events (MACE) among patients with rheumatoid arthritis compared with antitumor necrosis factor (anti-TNF) therapy. This prompted guideline changes regarding the use of all JAKis, including upadacitinib, a JAK1-selective drug approved for use in chronic inflammatory conditions, including IBD. However, the mechanism underlying JAKi-related MACE outcomes and the significance of JAK selectivity relative to TNF inhibition remain unclear. Microvascular dysfunction (MVD) is a predictor of MACE. Flow-mediated dilation (FMD) is a measure of MVD. Using an established ex vivo model of resistance arterioles isolated from adipose tissue, we performed the first mechanistic comparison of antitumor necrosis factor (anti-TNF; infliximab), pan-JAK inhibitor (tofacitinib), and JAK1-selective (upadacitinib) therapies on human microvascular endothelial function. Arterioles were obtained from low-cardiovascular-risk subjects of both sexes. Isolated microvessels were incubated with drugs of interest. Flow-mediated dilation (FMD), an assessment of MVD, was measured before and after nitric oxide (NO) synthase inhibition or hydrogen peroxide (H2O2) scavenging. No therapy statistically altered FMD magnitude, yet underlying mechanisms differed. Control and infliximab-treated vessels maintained physiologic NO-mediated dilation. Tofacitinib induced a shift toward pathologic H2O2-mediated dilation. Upadacitinib impaired NO-dependent dilation without evidence of compensatory H2O2 signaling. In summary, anti-TNF therapy and selective versus nonselective JAKi differentially modulate endothelial mechanisms of vasodilation, suggesting unique microvascular phenotypes with potential implications for cardiovascular risk.NEW & NOTEWORTHY This is the first ex vivo mechanistic comparison of antitumor necrosis factor therapy (infliximab) and selective (upadacitinib) versus nonselective (tofacitinib) Janus kinase inhibition in human microvessels. Flow-mediated dilation showed no statistical differences; however, the mechanisms driving endothelial dilation varied. We report a shift from nitric oxide- to hydrogen peroxide-mediated dilation with tofacitinib, a distinct phenotype with upadacitinib, and nitric oxide-dependent dilation with infliximab, suggesting differential effects of IBD therapies on microvascular endothelial physiology.
Reported prevalence of cardiovascular disease (CVD) risk factors and phenotypes varies widely. In multi-cohort analyses, such variation reflects population risk, care setting, and data capture. We harmonized baseline data from four analytic cohorts (N=54,188, aged ≥50 years) in five GLOB-cAGE member studies: pooled community (n=956), primary care (n=49,849), acute CVD registry (n=2,723), and chronic CVD cohort (n=660). Any risk-factor was hypertension, diabetes, or dyslipidemia. Any CVD phenotype was ischemic heart disease, heart failure, or atrial fibrillation/flutter. At age 60-74 years, any risk-factor prevalence ranged from 10.4% in primary care to 91.4% in the acute CVD registry (P<0.001); any CVD phenotype prevalence ranged from 4.4% to 47.0% (P<0.001). In the pooled community cohort, any risk-factor prevalence increased from 28.9% at age 50-59 to 85.0% at ≥75 (adjacent q<0.001), while age-sex-standardized any CVD phenotype prevalence remained comparatively low (10.6%). Any CVD phenotype prevalence increased with risk-factor-count, with the clearest gradients in the acute CVD registry (35.8% to 64.2%; P for trend<0.001) and pooled community cohort (6.4% to 19.6%; P for trend<0.001). Among participants with any CVD phenotype, female age distributions were older than male distributions in primary care and the acute CVD registry (female-minus-male median age difference, +3.7 and +5.0 years; both P<0.001). Across diverse care settings, harmonized summary constructs identified interpretable patterns in cardiovascular risk and CVD burden. These real-world data support cardiovascular prevention across ageing, highlight substantial CVD burden among women at older ages, and provide a framework for longitudinal analyses across real-world cohorts.
