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

About 26 million people worldwide live with heart failure (HF), and hypertension is the primary cause in 25% of these cases. Autonomic dysfunction and sympathetic hyperactivity accompany cardiovascular diseases, including HF. However, changes in cardiac sympathetic innervation in HF are not well understood. We hypothesized that cardiac sympathetic innervation is disrupted in hypertension-induced HF. Male and female C57BL6/J mice were infused with Angiotensin II (AngII) for 4 weeks to generate hypertension leading to HF; controls were infused with saline. AngII-treated mice displayed HF phenotype including reduced cardiac function, hypertrophy, and fibrosis. AngII-treated mice also had significantly reduced sympathetic nerve density in the left ventricle, intraventricular septum, and right ventricle. In the left ventricle, the subepicardium remained normally innervated, while the subendocardium was almost devoid of sympathetic nerves. Loss of sympathetic fibers led to loss of norepinephrine content in the left ventricle. Several potential triggers for axon degeneration were tested and ruled out. AngII-treated mice had increased premature ventricular contractions after isoproterenol and caffeine injection. Although HF can induce a cholinergic phenotype and neuronal hypertrophy in stellate ganglia, AngII treatment did not induce a cholinergic phenotype or activation of trophic factors in this study. Cardiac neurons in the left stellate ganglion were significantly smaller in AngII-treated mice, while neurons in the right stellate were unchanged. Our findings show that AngII-induced HF disrupts sympathetic innervation, particularly in the left ventricle. Further investigations are imperative to unveil the mechanisms of denervation in HF and to develop neuromodulatory therapies for patients with autonomic imbalance.

Vascular dysfunction, marked by lower endothelial function and increased aortic stiffness, is a nontraditional risk factor that precedes the development of cardiovascular disease (CVD). However, the age at which these changes in vascular function occur in women and the degree to which reproductive hormones mediate these changes has not been characterized. Women free from major disease were enrolled across the adult life span (aged 18-70 yr, n = 140). Endothelial function was assessed as flow-mediated dilation (FMD) of the brachial artery during reactive hyperemia using duplex ultrasound and expressed as percent dilation. Aortic stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). Blood samples were obtained to quantify reproductive hormone concentration. Regression models determined age-related breakpoints and mediating factors between age and vascular outcomes. FMD declined with age with a breakpoint and steeper decline occurring at 47 yr of age. Thereafter, age was independently associated with lower FMD (B = -0.13, P < 0.001). cfPWV was relatively stable until a breakpoint at age 48, and age was independently associated with higher cfPWV thereafter (B = 0.10, P < 0.001). Path analysis revealed that the association between age and FMD was partially mediated by follicle-stimulating hormone (ab_ind = 0.051, P = 0.01) and progesterone (ab_ind = 0.513, P < 0.001) but not estradiol (ab_ind = -0.004, P = 0.08). No mediation was present for cfPWV. Age was associated with endothelial dysfunction and aortic stiffness in women beginning at 47 and 48 yr old, respectively, 3 to 4 yr before the average age of menopause. The association between age and endothelial dysfunction was explained in part by elevations in follicle-stimulating hormone and progesterone, but not declining estradiol.NEW & NOTEWORTHY We demonstrate that the age at which endothelial function declines and aortic stiffness increases in healthy women is 47 and 48, respectively. The inflection point in flow-mediated dilation (FMD) is 6 yr earlier than previously reported, and the association between age and FMD was mediated by follicle-stimulating hormone (FSH) and progesterone (P₄) but not estradiol (E₂).

Thyroid hormone dysfunction is frequently observed in patients with chronic illnesses including heart failure, which increases the risk of adverse events. This study examined the effects of thyroid hormones (THs) on cardiac transverse-tubule (TT) integrity, Ca²⁺ sparks, and nanoscale organization of ion channels in excitation-contraction (EC) coupling, including L-type calcium channel (Ca_V1.2), ryanodine receptor type 2 (RyR2), and junctophilin-2 (Jph2). TH deficiency was established in adult female rats by propyl-thiouracil (PTU) ingestion for 8 wk; followed by randomization to continued PTU without or with oral triiodo-l-thyronine (T3; 10 µg/kg/day) for an additional 2 wk (PTU + T3). Confocal microscopy of isolated cardiomyocytes (CMs) showed significant misalignment of TTs and increased Ca²⁺ sparks in thyroid-deficient CMs. Density-based spatial clustering of applications with noise (DBSCAN) analysis of stochastic optical reconstruction microscopy (STORM) images showed decreased (P < 0.0001) RyR2 cluster number per cell area in PTU CMs compared with euthyroid (EU) control myocytes, and this was normalized by T3 treatment. Ca_V1.2 channels and Jph2 localized within a 210 nm radius of the RyR2 clusters were significantly reduced in PTU myocytes, and these values were increased with T3 treatment. A significant percentage of the RyR2 clusters in the PTU myocytes had neither Ca_V1.2 nor Jph2, suggesting fewer functional clusters in EC coupling. Nearest neighbor distances between RyR2 clusters were greater (P < 0.001) in PTU cells compared with EU- and T3-treated CMs that correspond to disarray of TTs at the sarcomere z-discs. These results support a regulatory role of T3 in the nanoscale organization of RyR2 clusters and colocalization of Ca_V1.2 and Jph2 in optimizing EC coupling.NEW & NOTEWORTHY Thyroid hormone (TH) dysfunction exacerbates preexisting heart conditions leading to an increased risk of premature morbidity/mortality. Triiodo-l-thyronine (T3) optimizes cardiac excitation-contraction (EC) coupling by maintaining myocardial T-tubule (TT) structures and organization of calcium ion channels. Single-molecule localization microscopy shows T3 effects on the clustering of ryanodine receptors (RyR2) with colocalization of L-type calcium channels (Ca_V1.2) and junctophilin-2 (Jph2) at TT-SR structures. Heart disease with subclinical hypothyroidism/low T3 syndrome may benefit from TH treatment.

Nearly 1% of babies are born with congenital heart disease (CHD) - many of whom will require heart surgery within the first few years of life. A detailed understanding of cardiac maturation can help to expand our knowledge on cardiac diseases that develop during gestation, identify age-appropriate drug therapies, and inform clinical care decisions related to surgical repair and postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is limited. In this study, we collected right atrial tissue samples from pediatric patients (n=117) undergoing heart surgery. Patients were stratified into five age groups. We measured age-dependent adaptations in cardiac gene expression, and used computational modeling to simulate action potential and calcium transients. Enrichment of differentially expressed genes (DEGs) revealed age-dependent changes in several key biological processes (e.g., cell cycle, structural organization), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited age-dependent trends, with changes in calcium handling (I_NCX) and repolarization (I_K1) most strongly associated with an age-dependent decrease in the action potential plateau potential and increase in triangulation, respectively. We observed a shift in repolarization reserve, with lower I_Kr expression in younger patients, a finding potentially tied to an increased amplitude of I_Ks that could be triggered by elevated sympathetic activation in pediatric patients. Collectively, this study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology, shedding light on molecular mechanisms underlying cardiac maturation and function throughout development.

Sex differences in the development and progression of cardiovascular disease manifest across multiple life stages. These differences are associated with variations in cardiovascular morphology and function between the sexes. Although estrogens and sex hormones are associated with sex differences in cardiovascular diseases in reproductive adults, the molecular mechanisms of cardiovascular sex differences during development are largely unknown. Thus, we investigated sex differences in cardiovascular development. We employed a newly-developed coronary arteriogram system to visualize the morphology of the coronary arteries in murine anterior surface ventricles at embryonic day 17.5 by injecting nano-particle ink at a constant pressure. No sex difference was found in the length of ventricle. Based on the boundary value of the distribution of that length, the hearts were divided into "long" and "short" groups, and the diameters of the left coronary arteries were analyzed. The mean diameter of the coronary arteries was significantly smaller in females than in males only in the group with the longer length of ventricle. This ventricular size-specific sex difference was observed in the presence of vasodilators such as NOC7. When NOC7 was perfused into the left coronary arteries of embryonic day 17.5 mice, females with longer ventricles showed larger left coronary arteries than males. These sex differences in vasodilation capacity suggest that factors related to drug reactivity such as signaling pathways are present at a late embryonic stage. These results indicate that sex differences in the functional morphology of the left coronary arteries exist at a late embryonic stage in mice.

What is the purpose of sympathetic neuronal action potential (AP) discharge and recruitment patterns for human vascular regulation? This study tested the hypothesis that sympathetic neuronal discharge and recruitment patterns regulate neuropeptide Y (NPY) bioavailability. We used microneurography to record muscle sympathetic nerve activity (MSNA) and a continuous wavelet transform to detect sympathetic APs during a baseline condition and intravenous dexmedetomidine infusion (α₂-adrenergic agonist, 10 min loading infusion of 0.225 µg kg^-1; maintenance infusion of 0.1-0.5 µg kg h^-1) in six healthy individuals (5 females, 27 ± 6 years). Arterial blood samples provided NPY (enzyme-linked immunosorbent assay) and norepinephrine (Liquid Chromatography Tandem Mass Spectrometry) levels during baseline and the dexmedetomidine maintenance infusion. Linear mixed model regressions assessed the relationships between AP discharge, recruitment, and neurotransmitter levels. Across baseline and the dexmedetomidine condition, NPY levels were positively related to mean arterial pressure (β = 1.63 [0.34], P = 0.002), total AP clusters (β = 0.90 [0.22], P = 0.005), and AP frequency (β = 0.11 [0.03], P = 0.003). Norepinephrine levels were not related to mean arterial pressure (β = 0.03 [0.02], P = 0.133) but were positively related to total AP clusters (β = 19.50 [7.07], P = 0.030) and AP frequency (β = 2.66 [0.81], P = 0.014). These data suggest that sympathetic neuronal discharge and recruitment patterns regulate NPY and norepinephrine bioavailability in healthy adults. As such, sympathetic neuronal firing strategies are important for human vascular regulation.

Fetal echocardiography in twin to twin transfusion pregnancies treated with photocoagulation noted impaired cardiac function. Systematic information about cardiac structure or function and arterial distensibility after birth is not available. This study evaluated cardiovascular function and arterial dynamic properties in survivors of twin to twin transfusion syndrome. Eleven pairs of donor-recipient twins were compared with each other, and with 20 singletons of comparable gestational age. The twin cohort was born at 31.5±2 weeks gestational age; birthweights of donors-recipients were comparable (donors: 1358±421g vs recipients: 1617±460g, P=0.2). Significant inter-twin differences were noted for cardiac function parameters. Recipients had greater septal thickness (donors: 2.3±0.15 vs recipients: 2.7±0.36mm, P=0.01) and globularity (lower sphericity index [donors: 1.76±0.1 vs recipients: 1.62±0.12, P=0.009]). They also had lower cardiac function (tricuspid annular plane systolic excursion [donors: 4.6±0.5 vs recipients: 4.1±0.4mm, P=0.02) and right ventricular fractional area change [donors: 30±1 vs recipients: 27.7±1.3%, P=0.0001]). Comparing with singletons, differences were statistically more significant for recipients. Arterial distensibility however, was more affected in donors (higher arterial wall stiffness index [donors: 2.5±0.2 vs recipients: 2.2±0.2, P=0.008] and lower pulsatile diameter [donors: 51±5 vs recipients: 63±10 µm, P<0.0001). Comparing with singletons, the differences were statistically more significant for donors. Evaluation in the neonatal period noted that cardiac function and arterial distensibility is affected in TTTS twins. These cohorts will benefit from close postnatal follow up for resolution of cardiac and arterial impairments.

The second-generation myosin activator danicamtiv (DN) has shown improved function compared to the first generation myosin activator omecamtiv mecarbil (OM) in non-failing myocardium by enhancing cardiac force generation but attenuating slowed relaxation. However, whether the functional improvement with DN compared to OM persists in remodeled failing myocardium remain unknown. Therefore, this study aimed to investigate the differential contractile response to myosin activators in non-failing and failing myocardium. Mechanical measurements were performed in detergent-skinned myocardium isolated from donor and failing human hearts. Steady-state force, stretch activation responses, and loaded shortening velocity were analyzed at submaximal [Ca²⁺] in the absence or presence of 0.5 µmol/L OM or 2 µmol/L DN. The effects of DN and OM on Ca²⁺-sensitivity of force generation were determined by incubating myocardial preparations at various [Ca²⁺]. The inherent impairment in force generation and cross-bridge behavior sensitized failing myocardium to the effects of myosin activators. Specifically, increased Ca²⁺-sensitivity of force generation, slowed rates of cross-bridge recruitment and detachment following acute stretch, slowed loaded shortening velocity, and diminished power output were more prominent following treatment with OM or DN in failing myocardium compared to donor myocardium. Although these effects were less pronounced with DN compared to OM in failing myocardium, DN impaired contractile properties in failing myocardium that were not affected in donor myocardium. Our results indicate that similar to first-generation myosin activators, the DN-induced slowing of cross-bridge kinetics may result in a prolongation of systolic ejection and delayed diastolic relaxation in the heart failure setting.