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

Patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), a mitochondrial fatty acid oxidation (FAO) disorder, frequently present with cardiomyopathy and can suffer from life-threatening arrhythmias and heart failure. Although these remain the leading causes of death, the pathophysiology remains unknown. We used an LCHADD mouse model to examine the mechanisms of impaired cardiac function. We previously determined that LCHADD mice (Hadha c.1528G>C homozygotes) recapitulate human disease and develop cardiomyopathy. We performed electrophysiological tests on LCHADD and wild-type (WT) mice, followed by cardiac tissue and molecular expression analysis. LCHADD mice showed significantly increased frequency of atrial premature beats, premature ventricular contractions, atrial flutter, atrial fibrillation, and nonsustained ventricular tachycardia (NSVT) after β-agonist stimulation compared with WT mice. Long QRS and long QT intervals were also observed when compared with WT mice. LCHADD heart sections demonstrated increased cardiomyocyte cross-sectional area, increased lipid and collagen deposition, and decreased glycogen deposits. There was global sympathetic denervation in LCHADD hearts compared with WT. Differentially expressed gene analysis showed increased expression of glycolytic and glutathione synthesis enzymes, and decreased expression of tricarboxylic acid (TCA) cycle enzymes, Ca⁺⁺ signaling, and cardiac muscle contraction proteins. LCHADD cardiomyopathy has a hypertrophic phenotype with diffuse fibrosis, accumulation of lipids, and lower glycogen storage in the absence of obesity. LCHADD cardiomyocyte metabolism suggests a shift from FAO toward glycolysis with chronic oxidative stress. Energy deficiency and lipotoxicity likely influence Ca⁺⁺ signaling and cardiac contraction. Long QRS and QT intervals with global sympathetic denervation may predispose the heart to repolarization abnormalities susceptible to arrhythmias and increased risk of sudden cardiac arrest and death.NEW & NOTEWORTHY As major cardiac events and heart failure are the leading causes of death among individuals with LCHADD, we are committed to identify better treatment options. To undertake this, we characterized LCHADD cardiomyopathy using a mouse model. We identified a hypertrophic cardiomyopathy with diffuse fibrosis, extensive lipid accumulation, increased oxidative stress, and global sympathetic denervation with long QT intervals and arrhythmia susceptibility likely caused by cardiomyocyte energetic remodeling, altered homeostasis, and cardiac conduction dysregulation.

Adults with type 1 diabetes (T1D) often exhibit exaggerated increases in blood pressure during exercise, but the mechanisms driving this abnormal response remain unclear. We investigated whether heightened activation of the exercise pressor reflex and oxidative stress contribute to this phenomenon. Fifteen adults with uncomplicated T1D (7 women; 27 ± 10 yr; HbA1c 7.1 ± 1.5%) and 20 healthy adults (11 women; 26 ± 9 yr; HbA1c 5.1 ± 0.3%) performed graded intensities of isometric handgrip, followed by postexercise ischemia (PEI) to isolate the muscle metaboreflex and a cold pressor test (CPT). Beat-to-beat mean arterial pressure (MAP) and heart rate were recorded continuously, and serum oxidized LDL (oxLDL), a marker of oxidative stress, was measured. Patients with T1D exhibited a greater pressor response during handgrip exercise [e.g., 40% maximal voluntary contraction (MVC) ΔMAP in T1D = 41 ± 10 vs. healthy = 34 ± 9 mmHg, P = 0.047], and this augmented pressor response was evident as early as 30 s of isometric handgrip. In contrast, MAP responses during PEI (last 30 s of PEI at 40% MVC; T1D = 34 ± 11 vs. healthy = 32 ± 11 mmHg; P = 0.774) and CPT were not different between the groups. Serum oxLDL concentration was significantly elevated in patients with T1D and positively correlated with the magnitude of exercise pressor response (e.g., 40% MVC handgrip; r = 0.744, P = 0.006). Altogether, these findings suggest that patients with T1D have augmented increases in exercise pressor reflex, likely driven by heightened muscle mechanoreflex activity. Importantly, elevated oxidative stress is a potential underlying mechanism that at least, in part, contributes to the exaggerated exercise pressor response in patients with T1D.NEW & NOTEWORTHY Patients with type 1 diabetes (T1D) exhibit exaggerated pressor response during isometric handgrip, which was apparent at 30 s following the onset of contraction. When the muscle metaboreflex was isolated, pressor response was not different across the groups, indicating that augmented pressor response may be primarily driven by mechanosensitive afferents. Elevated oxLDL in T1D was positively correlated with exercise pressor response, suggesting that oxidative stress potentially contributes to the augmented exercise pressor response in T1D.

The physical attributes of continuous capillaries, the glycocalyx, and endothelial tight junctions, influence the distribution of forces that affect transcapillary solvent and solute transport. The traditional Starling hypothesis does not account for the effects of transcapillary solvent flux on the protein content of the pericapillary space, whereas the "Revised" Starling model (RSM) incorporates the impact of the glycocalyx and endothelial tight junctions on transcapillary solute flux, which results in an inhomogeneous distribution of oncotic pressures across the capillary wall. We compared the regulation of intravascular volume during dialysis using two, 2-compartment models: one based on the traditional Starling model (TSM) and the other based on the RSM. We evaluated the two models using data from two patients undergoing hemodialysis during which the ultrafiltration rate was varied to perturb the system and reveal the dynamics of transcapillary and lymphatic solvent and solute (protein) fluxes. Both models fit the observed changes in hematocrit and calculated changes in plasma and interstitial volumes well. However, the predicted mechanisms whereby intravascular volume and mass balance were maintained differed significantly: the RSM predicted that all interstitial fluid and protein were returned to the intravascular space by lymphatic flow, whereas the TSM predicted that interstitial fluid and protein were returned to the intravascular space from both lymphatic flow and fluxes of solvent and protein from the interstitial space into the venous end of the capillary. Thus, the RSM emphasizes the central role of lymphatic return on the rate of vascular refilling from the interstitial space when ultrafiltration reduces blood volume.NEW & NOTEWORTHY A novel computer model of vascular refilling, which incorporated the impact of glycocalyx and endothelial tight junctions, demonstrated that fluid and protein leave the vascular space through the capillary wall and return to the circulation exclusively through lymphatic mechanisms during ultrafiltration during dialysis. The vascular refill rate, capillary exit + ultrafiltration, and lymphatic return can be estimated during ultrafiltration to compare predicted vascular dynamics in either the traditional or revised Starling hypothesis.

Ventricular function is vital in patients with single ventricles but repeated surgeries and changes in ventricular volume load may change the relation between longitudinal and radial function. To expand the knowledge of cardiac mechanics in this population, the aim of this study was to assess longitudinal and radial contribution to stroke volume using cardiac magnetic resonance (CMR) imaging in patients before and after Fontan operation. We also aimed to assess if the atrioventricular coupling was intact in these patients despite multiple pericardiotomies. Twelve children underwent CMR before and after completion of Fontan circulation. Endocardial borders of the atria and the ventricle as well as the epicardial border of the heart were delineated. The percentage of the stroke volume attributed to longitudinal and radial function was calculated and pulmonary venous blood flow during the cardiac cycle was assessed. Longitudinal function correlated strongly with atrial filling (r²=0.90, ICC=0.92) and its contribution to stroke volume was 40 [38-49] % before and 39 [33-45] % after completion of Fontan circulation (p=0.092). All patients lacked the late systolic flow peak in the pulmonary veins corresponding to the lack of a normal right ventricle. In conclusion, patients with single ventricles exhibit preserved atrioventricular coupling but the ventricle has lower longitudinal and higher radial contribution to stroke volume as a consequence of the passive pulmonary blood flow relative to healthy hearts. Completion of Fontan circulation does not change this relationship.

Autonomic dysfunction is a common clinical feature of wild-type transthyretin amyloidosis (wtATTR) that may include disease-related changes in baroreflex function. We tested the hypothesis that central and peripheral hemodynamic responses to progressive lower-body negative pressure (LBNP; -10, -20, -30, -40 mmHg; 5 minutes per stage)-induced hypovolemia would be attenuated in patients with wtATTR (n=13, 74±6 yrs) compared with control subjects with HFpEF of non-amyloid etiology (n=13, 72±4 yrs). Changes in heart rate (HR) and stroke volume (SV) during LBNP assessed central cardiac responsiveness, and changes in forearm blood flow (FBF) and vascular conductance (FVC) evaluated peripheral vascular responsiveness. Lower levels of LBNP (-10 and -20 mmHg) were used to evaluate the cardiopulmonary baroreflex, while higher levels of LBNP (-30 and -40 mmHg) assessed integrated (cardiopulmonary + arterial) baroreflex function. There were no group differences in LBNP-induced changes in HR or SV at any stage of LBNP (P>0.05 for all comparisons). Vasoconstriction, as quantified by changes in FVC, was reduced during higher levels of LBNP in wtATTR (CON -0.20 ± 0.20 mL/min/mmHg; wtATTR, -0.04 ± 0.17 mL/min/mmHg; P = 0.011) and -40 mmHg (CON -0.26 ± 0.22 mL/min/mmHg; wtATTR, -0.02 ± 0.20 mL/min/mmHg; P < 0.01). MAP was unchanged across all levels of LBNP in controls, but decreased in the wtATTR group at the highest level of LBNP (P=0.039). These findings provide new evidence for derangements in integrative baroreflex function beyond what is present in HFpEF from non-amyloid etiology that may contribute to blood pressure dysregulation during orthostasis in wtATTR.

Background. Traditional echocardiographic metrics of right ventricular (RV) function including tricuspid annular plane systolic excursion (TAPSE) and 2-dimensional (2D) strain are limited to the description of longitudinal systolic function. These metrics however fails to account for the complex, 3-dimensional (3D) deformation of the RV. Methods. 3D echocardiograms (3DE) were obtained simultaneous during clinically indicated right heart catheterization (RHC). We determined the maximum principal surface strain (PS_Max) and angle (ϴ_Max) of RV surface deformation in PAH and control patients. Results. We compared 22 control patients to 37 patients with PAH, of whom 11 met hemodynamic criteria for right heart (RH) failure. Compared to 2D descriptors of RV function, PS_Max was significantly different between controls and PAH patients and between PAH patients with and without RH failure. ϴ_Max was oriented progressively longitudinally in PAH patients without RH failure compared PAH patients with RH failure [37.5(34.3 - 40.8)˚ vs. 34.3(32.1 - 36.2)˚, p=0.042] and in PAH patients with worse NYHA functional class. 30-day outcomes were significantly different with an optimal cutoff of PS_Max of -21.4%, with a hazard ratio of 6.8 (95% CI 1.3 to 35.2, p=0.022). Conclusion. PS_Max is a robust marker of RH failure and provides prognostic value in PAH beyond conventional 2D descriptors of RH function. Progressive longitudinal deformation of ϴ_Max is associated with worse RH function and functional class.

A genome-wide association study (GWAS) identified neuron navigator 3 (NAV3) as a potential genetic determinant of myocardial recovery in dilated cardiomyopathy (DCM). This study aimed to understand its functional role in cardiac pathophysiology by leveraging omics approaches. Single-cell RNA-seq transcriptomic data from previously published adult human hearts indicates that NAV3 expression is highest in cardiac fibroblasts, suggesting its functional role in these cells. In vitro, stimulation of primary human ventricular cardiac fibroblasts with TGF-β1, induced NAV3 expression in a dose and time-dependent manner. siRNA-mediated knockdown of NAV3 significantly attenuated TGF-β1-induced fibroblast activation, reducing the expression of α-SMA, collagens, and fibronectin. RNA sequencing of NAV3-silenced fibroblasts confirmed by Western blot revealed upregulation of cell cycle regulators and downregulation of profibrotic markers, suggesting that NAV3 facilitates TGF-β1-induced cell cycle arrest and fibroblast-to-myofibroblast transition. Notably, NAV3 silencing did not alter canonical SMAD2/3 phosphorylation, implying a role for NAV3 in modulating non-canonical fibrotic signaling through other pathways. Our findings provide functional and mechanistic insights into NAV3's novel role in cardiac fibrosis, showing that reduced NAV3 expression attenuates TGF-β1-mediated fibroblast activation by regulating cell cycle signaling. These results support further investigation of NAV3 as a potential modulator of cardiac fibrosis and myocardial recovery in DCM.

Placental insufficiency associated with impaired uteroplacental blood flow is the leading cause of human fetal growth restriction. While preclinical studies have examined the effects of global reductions in uterine blood flow, the downstream consequences of a focal disruption in flow remains unknown. We investigate how murine maternal canal occlusion(s) impacts placental development and fetal growth. Pregnant CD-1 mice at embryonic (E) day 15.5 underwent abdominal surgery to exteriorize the uterus. Under ultrasound guidance, zero, one or two of the, typically three, placental canals were microinjected with an embolizing agent. Survival at term (E18.5) was 81% for shams, 62% for single embolized, and 24% for the double embolized. Surviving double embolized fetuses weighed significantly less than both internal and external controls. The brain-to-liver volume ratio was significantly elevated in the singles and doubles versus controls (p = 0.00537, p = 0.00861) and shams (p = 0.01207, p = 0.017738). Placental histopathology, and 3D MRI confirmed, a reduction in junctional zone volume and significantly higher whole placenta-to-junctional zone volume ratio in the single embolized cohort (9.66, 95% CI [8.23-11.1]) compared to naïve controls and shams (6.21, 95% CI [4.79-7.63], p = 0.0298; (6.20, 95% CI [4.71-7.70], p = 0.00394, respectively). Canal occlusion resulted in impaired fetal growth and altered placental morphology yet did not cause focal placental infarction typical of impaired uteroplacental blood flow in humans. This placental model of fetal growth restriction may be amenable to testing new intervention strategies aimed at supporting fetal growth when placental function is impaired.

Traumatic brain injury (TBI) is a prevalent neurological condition with long-term consequences that extend beyond the brain. Individuals with a history of TBI are at increased risk for cardiovascular complications, but the mechanisms remain poorly understood. Here, we tested the hypothesis that mild-to-moderate chronic cerebral hypoperfusion, modelled via bilateral carotid artery stenosis (BCAS), exacerbates cardiac dysfunction following TBI. Male and female Swiss Webster mice (8-10 weeks old) were randomly assigned to Sham, BCAS, TBI, and BCAS+TBI groups. Cerebral blood flow (CBF) was evaluated at rest and after acetazolamide challenge to evaluate cerebrovascular reserve. Neuroinflammation was assessed in the insular cortex, using IBA-1 and GFAP immunostaining. Cardiac function was evaluated using transthoracic echocardiography, and myocardial morphology was detected by hematoxylin and eosin staining. TBI significantly reduced cardiac function in both sexes, whereas BCAS had no effect by itself. Similar structural changes in cardiomyocytes, such as decreased nuclear density and increased nuclear size, were observed in both TBI and BCAS+TBI mice. BCAS alone robustly elicited gliosis in the insular cortex in the absence of cardiac dysfunction. BCAS+TBI also decreased CBF and cerebrovascular reactivity, along with enhanced glial activation in the insula. These results indicate that TBI-elicited cardiac injury is accompanied by neuroinflammation in central autonomic centers, and preexisting cerebral hypoperfusion does not increase cardiac vulnerability. This study highlights the role of the brain-heart axis as a key driving force in post-TBI morbidity and raises the possibility that cerebrovascular health may serve as a mediator of cardiac outcomes following brain injury.