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

Fetal growth restriction (FGR) secondary to placental insufficiency often leads to morbidity and mortality in the perinatal period. Fetal adaptations such as "brain sparing" blood flow redistribution offer some protection, but predicting whether a fetus in this state will survive is challenging. The goal of this research was to identify vascular responses predictive of stillbirth or hypoxia based on serial Doppler ultrasound measurement in a mouse model of FGR. We performed serial Doppler ultrasound observations of fetal blood flow redistribution in a murine model of FGR, where prolongation of pregnancy was induced pharmacologically with progesterone in 56 CD-1 mice. Observations were made at E18.5 (physiologic term), E19.5 (term +1), and E20.5 (term +2). Flow velocity waveforms were obtained from the middle cerebral artery (MCA), ductus arteriosus (DA), main pulmonary artery (MPA), ductus venosus (DV), umbilical artery (UA), and umbilical vein (UV). Following euthanasia, pimonidazole immunohistochemistry quantified tissue hypoxia. Among 56 pregnancies, the strongest predictor of stillbirth was low DA peak systolic velocity at E19.5 (<217 mm/s, P = 0.021, R² = 0.52). Among survivors, cerebral hypoxia was predicted by elevated MCA peak systolic (>26.6 mm/s, P = 0.022, R² = 0.59) and end-diastolic velocity (>10.1 mm/s, P = 0.043, R² = 0.53, whereas high MPA flow (>0.73 mL/min, P = 0.029, R² = 0.51) predicted hepatic hypoxia. Overall, fetuses with a weaker pulmonary blood flow redistribution response were found to have worse outcomes, despite cerebral vasodilation. This minimally invasive murine model offers valuable insights into this pathophysiology of FGR-related stillbirth and highlights the prognostic potential of assessing fetal brain flow and pulmonary perfusion in tandem during sonographic surveillance of high-risk pregnancies.NEW & NOTEWORTHY Fetal growth restriction, often caused by placental disease, is an important cause of fetal injury and stillbirth. Understanding how the fetus adapts under these conditions is key to predicting survival. Here we report physiological adaptations in a mouse of model of fetal growth restriction that predict the risk of stillbirth.

The global rise in obesity parallels the increasing rates of hypertension and cardiovascular disease (CVD). These trends, and recent clinical and experimental data, have revealed that obesity abolishes the protection from CVD typically conferred by female sex, predisposing young, premenopausal women to vascular dysfunction and hypertension. Findings from our group demonstrated that, in females, obesity induces hypertension via activation of the leptin-aldosterone-mineralocorticoid receptor (MR) axis. However, the origin of this sex-specific mechanism remains unknown. Based on the known effects of estrogen on blood pressure (BP) and vascular function, we tested the contribution of sex hormones. Sham and ovariectomy (OVX) surgeries were conducted in obese female agouti yellow mice to preserve or deplete female sex hormones, respectively. OVX did not significantly alter blood pressure (BP) nor autonomic control of BP or adrenal aldosterone synthase (CYP11B2) expression; however, it impaired endothelial relaxation with no further alterations to vascular function. Chronic leptin receptor blockade decreased BP in both sham and OVX mice and restored endothelium-dependent relaxation, suggesting a lack of contribution of female sex hormones to the mechanism of hypertension. Stimulation of HAC15 and human primary adrenocortical cells with female and male sex steroid hormones did not alter CYP11B2 expression. Furthermore, quantification of CYP11B2 expression in discarded human adrenal glands revealed increases with obesity in women in comparison to men and no alterations with menopause in obese hypertensive women. Collectively, these findings support that female sex hormones do not regulate aldosterone production nor do they drive the sex-specific mechanism underlying obesity-associated hypertension.NEW & NOTEWORTHY Obesity induces hypertension in females through the leptin-aldosterone-mineralocorticoid axis; however, the origin of this sex-specific mechanism remains unknown. Utilizing obese female mice, ovariectomy did not significantly impair blood pressure (BP), vascular function, or aldosterone synthase, whereas leptin receptor blockade lowered BP and restored vascular reactivity. In human cells and tissues, sex hormones did not alter aldosterone synthase expression. These data indicate that sex hormones do not drive the sex difference in the mechanism of obesity-associated hypertension.

Machine learning has become an important tool in precision medicine and aging research. We introduce the cardiovascular autonomic age (CAA) gap, a novel metric quantifying the deviation between machine learning-estimated biological age and chronological age based on autonomic cardiovascular function. High-resolution electrocardiograms and continuous blood pressure recordings at rest were collected from 1,060 healthy individuals. From these signals, 29 autonomic indices were derived, including time-, frequency-, and symbol-domain heart rate variability, cardiovascular coupling, pulse wave dynamics, and QT interval features. A Gaussian process regression model was trained on 879 participants to estimate biological age, yielding the CAA. The deviation between CAA and chronological age defined the CAA gap, which was evaluated in two test sets stratified by cardiovascular risk (CVR) using the Framingham risk score. At a 0.5% threshold, the high-CVR group showed a markedly increased CAA gap (+11 yr), whereas the low-CVR group demonstrated a slightly negative gap (-1 yr). In the high-risk group, the slope of predicted versus actual age suggested accelerated physiological aging. CAA correlated positively with the Framingham risk score (r = 0.42, P < 0.001), and the CAA gap correlated with deviation from normative risk (r = 0.31, P = 0.002). Across thresholds, elevated CAA in the high-CVR group was consistently observed, with moderate effect sizes ranging from 0.32 to 0.46. These findings suggest that the CAA gap may serve as a sensitive and interpretable indicator of cardiovascular risk and aging, with potential relevance for early detection and longitudinal assessment.NEW & NOTEWORTHY The cardiovascular autonomic age (CAA) gap is a new machine learning-based marker that reveals when the body ages faster than the clock. Using resting-state cardiovascular recordings from 1,000+ participants, we show that individuals with higher cardiovascular risk exhibit accelerated autonomic aging. The CAA gap could become a sensitive, interpretable tool for early detection and long-term monitoring.

Cardiotoxicity is a significant adverse effect of chemotherapy, particularly in breast cancer survivors, especially those undergoing aggressive treatment regimens or with pre-existing cardiovascular conditions. This presents a major challenge for cardio-oncologists, who must balance the effective treatment of cancer with minimizing the risk of cardiovascular damage. Addressing this challenge requires a comprehensive understanding of the mechanisms by which chemotherapy agents induce cardiotoxicity, and the development of reliable methods for early detection and the identification of effective cardioprotective strategies. Preclinical animal models have served as indispensable tools for elucidating underlying mechanisms and assessing the efficacy of potential cardioprotective strategies. This review aims to explore the key signaling pathways implicated in this process, focusing on mechanisms such as oxidative stress, reactive oxygen species generation, inflammatory pathways, cellular damage, and mitochondrial dysfunction. It also discusses advancements in detection techniques and cardioprotective strategies that have shown great promise in preserving cardiac function during cancer treatment without diminishing the effectiveness of chemotherapy. Ultimately, this review emphasizes the need to integrate cardiotoxicity management into breast cancer treatment protocols to enhance patient survival and quality of life.

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease characterized by myocardial inflammation and fibrosis, ventricular dysfunction, and arrhythmias, and is a leading cause of sudden cardiac death in young adults. Acute binge alcohol consumption is a common behavior of young adults and is known to cause transient cardiac stress; however, its impact on ACM remains unclear. Wild-type and homozygous desmoglein-2 mutant (Dsg2^mut/mut) mice, a robust mouse model of ACM, were gavaged with 5 g/kg of alcohol or equivalent volume/kg of saline (placebo), twice weekly from 8 to 24 wk of age to determine the effects of repeat binges on ACM disease progression. Survival, cardiac function, ectopic burden, myocardial fibrosis, and inflammatory signaling were evaluated using echocardiography, electrocardiography, histology, and molecular assays, respectively. Of note, alcohol-treated Dsg2^mut/mut mice exhibited increased mortality compared with placebo-treated counterparts, accompanied by increased ventricular ectopics in Dsg2^mut/mut mice that died prematurely. Increased biventricular fibrosis was noted in alcohol-treated Dsg2^mut/mut mice and demonstrated a strong, positive correlation with peak blood alcohol concentration. Although alcohol-treated mice displayed decreased phosphorylated NF-κB and JNK2 myocardial levels, elevated levels of cytoplasmic and extracellular localization of HMGB1 were noted. Our findings demonstrate that acute binge alcohol exacerbates disease progression in a desmosomal-linked ACM mouse, likely through enhanced fibrotic remodeling and altered inflammatory signaling. These outcomes highlight the potential danger of binge alcohol consumption in genetically susceptible subjects with ACM, further underscoring the role of environmental factors in ACM onset and progression.NEW & NOTEWORTHY We report that acute binge alcohol consumption in a robust mouse model of arrhythmogenic cardiomyopathy (ACM) significantly elevated ventricular arrhythmias, mortality, cardiomyocyte cell death via the loss of nuclear HMGB1, and extensive myocardial fibrosis. These findings demonstrate that binge drinking may serve as an environmental factor that contributes to disease progression in subjects with ACM, highlighting the need for clinical awareness regarding alcohol use in this vulnerable population.

Pannexins (PANX1, PANX2, PANX3) are a family of large-pore, ion and metabolite channels present throughout the blood and lymphatic vascular networks. PANX1 has near-ubiquitous expression in the cardiovascular system and is the most highly studied pannexin in both homeostatic and disease conditions. In smooth muscle, endothelium, and blood cells, PANX1 acts at the cell surface as an ATP efflux channel to drive many vascular processes such as vasoconstriction, blood pressure, endothelial barrier function, platelet aggregation, and acute hypoxic responses. Conversely, PANX2 and PANX3 are understudied and exhibit a more intracellular localization pattern, with endothelial PANX3 modulating blood pressure through channel-independent mechanisms. In this review, we discuss the cellular localization and function of pannexins throughout the cardiovascular system, including resistance arteries, veins, lymphatics, large vessels, erythrocytes, platelets, pericytes, hearts, and lungs, as well as how this cellular activity corresponds to vascular physiology at the organism level. We also discuss the contribution of pannexins to the development and progression of various cardiovascular diseases, such as hypertension, edema, sepsis, atherosclerosis, aortic aneurysms, myocardial infarction, ischemia reperfusion, and thrombosis. In most cardiovascular diseases, PANX1 exacerbates disease development and progression, as evidenced by PANX1 channel blockade or genetic deletion in murine models improving disease outcomes, whereas the beneficial action of PANX3 in healthy vessels seems to be lost in conditions such as hypertension. With the prevalence of cardiovascular diseases and the associated burden on patients and healthcare systems, pannexin-based therapeutics may represent a novel alternative or combinatorial strategy for the treatment of many vascular conditions.

Despite clear benefits in the long term, exercise transiently increases cardiovascular risk during and immediately after exertion. Cannabis use has similarly been associated with cardiovascular events, but its effects on cardiovascular function and potential interaction with exercise remain poorly understood. We examined cardiovascular responses during and after exercise following cannabis use, to elucidate their combined effects. In a within-subject design, participants either inhaled cannabis with a high Δ-9-tetrahydrocannabinol (THC) content via smoking (S-THC) or vaporizing (V-THC), or vaporized cannabis with a high cannabidiol (CBD) content (V-CBD). Cardiovascular effects of cannabis were assessed through measures of arterial stiffness, endothelial function, and cardiac function performed at rest and following 20 min of maximal exercise (n = 14). Exercising cardiac function was evaluated separately using stress echocardiography (n = 22). Blood pressure was assessed before, during, and after the 20-min maximal cycling test. Smoking THC-predominant cannabis elevated postexercise pulse pressure (pre vs. post; control: 42 ± 6 vs. 41 ± 7 mmHg, S-THC: 43 ± 4 vs. 50 ± 9 mmHg, V-THC: 44 ± 5 vs. 46 ± 8 mmHg, and V-CBD: 43 ± 4 vs. 43 ± 7 mmHg; P < 0.01). The effect of exercise on arterial stiffness and endothelial function was not modified by cannabis; however, septal isovolumic contraction time (baseline: 72 ± 19 ms, control: 76 ± 20 ms, S-THC: 60 ± 11 ms, V-THC: 66 ± 12 ms, and V-CBD: 69 ± 16 ms; P = 0.01) was reduced in S-THC compared with after control exercise (P = 0.048), indicating altered systolic function. Blood pressure during maximal cycling was similar regardless of exposure. Systolic function, diastolic function, and ventricular mechanics during exercise were unaffected by cannabis. THC-predominant cannabis increases pulse pressure and alters cardiac, but not vascular, function after exercise. Cannabis does not affect blood pressure or cardiac function during exercise. These findings demonstrate the nuanced effects of combining cannabis use and exercise on cardiovascular physiology.NEW & NOTEWORTHY Smoking THC-predominant cannabis increases postexercise pulse pressure following exertion. This effect was not observed with CBD-predominant cannabis. Cannabis alters postexercise cardiac function, with THC reducing isovolumic contraction time, suggesting cannabinoid-specific changes in ventricular systolic performance. Vascular responses to exercise remain unchanged by cannabis, as arterial stiffness and endothelial function were unaffected, indicating that exercise may attenuate the acute vascular effects of cannabis. Exercising blood pressure and cardiac function were not impacted by cannabis inhalation.

Clonal hematopoiesis of indeterminate potential (CHIP) refers to the age-related expansion of hematopoietic stem cells bearing somatic mutations in the absence of overt hematological malignancy. Emerging evidence suggests that CHIP is not merely a marker of aging, but an active driver of metainflammation, a chronic systemic inflammatory state arising from metabolic dysregulation. Indeed, several studies have linked CHIP with an increased risk of cardiovascular, renal, and hepatic diseases, which are known to be driven by inflammation. CHIP also appears to be associated with upstream metabolic precursors such as obesity and type 2 diabetes, suggesting its involvement across the cardiometabolic disease continuum. Importantly, this relationship may be bidirectional: systemic inflammation promotes CHIP expansion, whereas CHIP mutations further fuel inflammation. Thus, anti-inflammatory agents that mitigate CHIP-driven inflammation may have a future therapeutic role in cardiometabolic diseases. Furthermore, gene-based therapies offer exciting opportunities for precision approaches in CHIP. This review aims to synthesize emerging evidence that links CHIP with cardiovascular, renal, and hepatic diseases, emphasizing shared inflammatory pathways. Moreover, the review aims to highlight current knowledge gaps, including the need to establish causality between CHIP and cardiometabolic diseases. Furthermore, it emphasizes the need for future research in both human populations and preclinical models to elucidate the underlying mechanisms that could ultimately position CHIP at the forefront of cardiometabolic medicine.