Canonical transient receptor potential channel 1 aggravates myocardial ischemia-and-reperfusion injury by upregulating reactive oxygen species.

The canonical transient receptor potential channel (TRPC) proteins form Ca2+-permeable cation channels that are involved in various heart diseases. However, the roles of specific TRPC proteins in myocardial ischemia/reperfusion (I/R) injury remain poorly understood. We observed that TRPC1 and TRPC6 were highly expressed in the area at risk (AAR) in a coronary artery ligation induced I/R model. Trpc1-/- mice exhibited improved cardiac function, lower serum Troponin T and serum creatine kinase level, smaller infarct volume, less fibrotic scars, and fewer apoptotic cells after myocardial-I/R than wild-type or Trpc6-/- mice. Cardiomyocyte-specific knockdown of Trpc1 using adeno-associated virus 9 mitigated myocardial I/R injury. Furthermore, Trpc1 deficiency protected adult mouse ventricular myocytes (AMVMs) and HL-1 cells from death during hypoxia/reoxygenation (H/R) injury. RNA-sequencing-based transcriptome analysis revealed differential expression of genes related to reactive oxygen species (ROS) generation in Trpc1-/- cardiomyocytes. Among these genes, oxoglutarate dehydrogenase-like (Ogdhl) was markedly downregulated. Moreover, Trpc1 deficiency impaired the calcineurin (CaN)/nuclear factor-kappa B (NF-κB) signaling pathway in AMVMs. Suppression of this pathway inhibited Ogdhl upregulation and ROS generation in HL-1 cells under H/R conditions. Chromatin immunoprecipitation assays confirmed NF-κB binding to the Ogdhl promoter. The cardioprotective effect of Trpc1 deficiency was canceled out by overexpression of NF-κB and Ogdhl in cardiomyocytes. In conclusion, our findings reveal that TRPC1 is upregulated in the AAR following myocardial I/R, leading to increased Ca2+ influx into associated cardiomyocytes. Subsequently, this upregulates Ogdhl expression through the CaN/NF-κB signaling pathway, ultimately exacerbating ROS production and aggravating myocardial I/R injury.

Time-restricted feeding alleviates cardiac dysfunction induced by simulated microgravity via restoring cardiac FGF21 signaling.

Dietary restriction has been well-described to improve health metrics, but whether it could benefit pathophysiological adaptation to extreme environment, for example, microgravity, remains unknown. Here, we investigated the effects of a daily rhythm of fasting and feeding without reducing caloric intake on cardiac function and metabolism against simulated microgravity. Male rats under ad libitum feeding or time-restricted feeding (TRF; food access limited to 8 hours every day) were subjected to hindlimb unloading (HU) to simulate microgravity. HU for 6 weeks led to left ventricular dyssynchrony and declined cardiac function. HU also lowered pyruvate dehydrogenase (PDH) activity and impaired glucose utilization in the heart. All these were largely preserved by TRF. TRF showed no effects on HU-induced loss of cardiac mass, but significantly improved contractile function of cardiomyocytes. Interestingly, TRF raised liver-derived fibroblast growth factor 21 (FGF21) level and enhanced cardiac FGF21 signaling as manifested by upregulation of FGF receptor-1 (FGFR1) expression and its downstream markers in HU rats. In isolated cardiomyocytes, FGF21 treatment improved PDH activity and glucose utilization, consequently enhancing cell contractile function. Finally, both liver-specific knockdown (KD) of FGF21 and cardiac-specific FGFR1 KD abrogated the cardioprotective effects of TRF in HU rats. These data demonstrate that TRF improves cardiac glucose utilization and ameliorates cardiac dysfunction induced by simulated microgravity, at least partially, through restoring cardiac FGF21 signaling, suggesting TRF as a potential countermeasure for cardioprotection in long-term spaceflight.

Steady-state cerebral autoregulation in older adults with amnestic mild cognitive impairment: linear mixed model analysis.

We examined whether the efficacy of steady-state cerebral autoregulation (CA) is reduced in older adults with amnestic mild cognitive impairment (aMCI), a prodromal stage of clinical Alzheimer disease (AD). Forty-two patients with aMCI and 24 cognitively normal older adults (NC) of similar age, sex, and education underwent stepwise decreases and increases in mean arterial pressure (MAP) induced by intravenous infusion of sodium nitroprusside and phenylephrine, respectively. Changes in cerebral blood flow (CBF) were measured repeatedly in the internal carotid and vertebral artery. Linear mixed modeling, including random effects of both individual intercept and regression slope, was used to quantify the MAP-CBF relationship accounting for nonindependent, repeated CBF measures. Changes in end-tidal CO2 (EtCO2) associated with changes in MAP were also included in the model to account for their effects on CBF. Marginal mean values of MAP were reduced by 13-14 mmHg during sodium nitroprusside and increased by 20-24 mmHg during phenylephrine infusion in both groups with similar doses of drug infusion. A steeper slope of changes in CBF in response to changes in MAP was observed in aMCI relative to NC, indicating reduced efficacy of CA (MAP × Group, P = 0.040). These findings suggest that cerebrovascular dysfunction may occur early in the development of AD.NEW & NOTEWORTHY Cerebral autoregulation is a fundamental regulatory mechanism to protect brain perfusion against changes in blood pressure that, if impaired, may contribute to the development of Alzheimer's disease. Using a linear mixed model, we demonstrated that the efficacy of cerebral autoregulation, assessed during stepwise changes in arterial pressure, was reduced in individuals with amnestic mild cognitive impairment, a prodromal stage of Alzheimer's disease. These findings support the hypothesis that cerebrovascular dysfunction may be an important underlying pathophysiological mechanism for the development of clinical Alzheimer's disease.

Cerebral Blood Flow, Oxygen Delivery, and Pulsatility Responses to Oxygen Inhalation at High Altitude: Highlanders vs. Lowlanders.

Objective: To determine whether the acute cerebral hemodynamic responses to oxygen inhalation are impacted by race or acclimation to high altitude. Methods: Three groups of young healthy males, who were Tibetans (highlanders, n = 15) with lifelong exposure to high altitude, and Han Chinese (lowlanders) with five-year (Han-5 yr, n = 15) and three-day (Han-3 d, n = 16) exposures, participated in the study at an altitude of 3658 m. Cerebral blood flow velocity (CBFV) was recorded for three minutes prior to and during pure oxygen inhalation (2 L/min), respectively, using a transcranial color-coded duplex (TCCD) sonography at the middle cerebral artery (MCA). The blood draw and simultaneous monitoring of blood pressure (BP), heart rate (HR), and finger arterial oxygen saturation (SaO2) were also performed. Results: Values are Mean ± SEM. The three groups had similar demographic characteristics and HR responses, with the group differences (P < 0.05) found in hemoglobin concentration (16.9 ± 0.9, 18.4 ± 1.3, and 15.5 ± 1.0 gm/dL), baseline BPs and HR as expected. Both the Tibetans and Han-5yr groups presented blunted BP responses to O2-inhalation when compared to the Han-3d group; more interestingly, the Tibetans showed significantly reduced responses compared with Han-5yr and Han-3d in CBFV, cerebral oxygen delivery (COD), and pulsatility index (PI) as assessed by Δ%CBFV/ΔSaO2 (-1.50 ± 0.25 vs. -2.24 ± 0.25 and -2.23 ± 0.27, P = 0.049 and 0.048), Δ%COD/ΔSaO2 (-0.52 ± 0.27 vs. -1.33 ± 0.26 and -1.38 ± 0.28, P = 0.044 and 0.031), and Δ%PI (7 ± 2 vs. 16 ± 3 and 16 ± 3 %, P = 0.036 and 0.023), respectively. Conclusion: These findings provide evidence on the Tibetans trait of a distinct cerebral hemodynamic regulatory pattern to keep more stable cerebral blood flow (CBF), oxygen delivery, and pulsatility in response to oxygen inhalation as compared with Han Chinese, which is likely due to a genetic adaptation to altitude.

Arterial Pressure, Heart Rate, and Cerebral Hemodynamics Across the Adult Life Span.

Age-related alterations in systemic and cerebral hemodynamics are not well understood. The purpose of this study is to characterize age-related alterations in beat-to-beat oscillations in arterial blood pressure (BP), heart rate (HR), cerebral blood flow (CBF), cardiac baroreflex sensitivity, and dynamic cerebral autoregulation across the adult life span. We studied 136 healthy adults aged 21 to 80 years (60% women). Beat-to-beat BP, HR, and CBF velocity were measured at rest and during sit-stand maneuvers to mimic effects of postural changes on BP and CBF. Transfer function analysis was used to assess baroreflex sensitivity and dynamic cerebral autoregulation. Carotid-femoral pulse wave velocity was measured to assess central arterial stiffness. Advanced aging was associated with elevated carotid-femoral pulse wave velocity, systolic and pulse BP, cerebrovascular resistance, and CBF pulsatility, but reduced mean CBF velocity. Compared with the young and middle-aged, older adults had lower beat-to-beat BP, HR, and CBF variability in the low-frequency ranges at rest, but higher BP and CBF variability during sit-stand maneuvers. Baroreflex sensitivity was reduced, whereas dynamic cerebral autoregulation gain was elevated at rest in older adults. Multiple linear regression analysis indicated that systolic BP variability is correlated positively with carotid-femoral pulse wave velocity independent of HR variability. In conclusion, advanced aging is associated with elevated pulsatility in BP and CBF; reduced beat-to-beat low-frequency oscillations in BP, HR, and CBF; and impaired baroreflex sensitivity and dynamic cerebral autoregulation at rest. The augmented BP and CBF variability in older adults during sit-stand maneuvers indicate diminished cardiovascular regulatory capability and increased hemodynamic stress on the cerebral circulation with aging.

Distribution of cardiac output to the brain across the adult lifespan.

A widely accepted dogma is that about 15-20% of cardiac output is received by the brain in healthy adults under resting conditions. However, it is unclear if the distribution of cardiac output directed to the brain alters across the adult lifespan and is modulated by sex or other hemodynamic variables. We measured cerebral blood flow/cardiac output ratio index in 139 subjects (88 women, age 21-80 years) using phase-contrast magnetic resonance imaging and echocardiography. Body mass index, cardiac systolic function (eject fraction), central arterial stiffness (carotid-femoral pulse wave velocity), arterial pressure, heart rate, physical fitness (VO2 max), and total brain volume were measured to assess their effects on the cardiac output-cerebral blood flow relationship. Cerebral blood flow/cardiac output ratio index decreased by 1.3% per decade associated with decreases in cerebral blood flow ( P < 0.001), while cardiac output remained unchanged. Women had higher cerebral blood flow, lower cardiac output, and thus higher cerebral blood flow/cardiac output ratio index than men across the adult lifespan. Age, body mass index, carotid-femoral pulse wave velocity, and arterial pressure all had negative correlations with cerebral blood flow and cerebral blood flow/cardiac output ratio index ( P < 0.05). Multivariable analysis adjusted for sex, age showed that only body mass index was negatively associated with cerebral blood flow/cardiac output ratio index (ß = -0.33, P < 0.001). These findings demonstrated that cardiac output distributed to the brain has sex differences and decreases across the adult lifespan and is inversely associated with body mass index.

Ultrasound-guided imaging of junctional adhesion molecule-A-targeted microbubbles identifies vulnerable plaque in rabbits.

Identification of vulnerable atherosclerotic plaques by imaging the molecular characteristics is intensively studied recently, in which verification of specific markers is the critical step. JAM-A, a junctional membrane protein, is involved in the plaque formation, while it is unknown whether it can serve as a marker for vulnerable plaques. Vulnerable and stable plaques were created in rabbits with high cholesterol diet with or without partial ligation of carotid artery respectively. Significant higher JAM-A expression was found in vulnerable plaques than that in stable plaques. Furthermore, JAM-A was not only expressed in the endothelium, but also abundantly expressed in CD68-positive area. Next, JAM-A antibody conjugated microbubbles (MBJAM-A) or control IgG-conjugated microbubbles (MBC) were developed by conjugating the biotinylated antibodies to the streptavidin modified microbubbles, and visualization by contrast-enhance ultrasound (CEUS). Signal intensity of MBJAM-A was substantially enhanced and prolonged in the vulnerable plaque and some of the MBJAM-A was found colocalized with CD68 positive macrophages. In addition, cell model revealed that MBJAM-A were able to be phagocytized by activated macrophages. Taken together, we have found that increase of JAM-A serves as a marker for vulnerable plaques and targeted CEUS would be possibly a novel non-invasive molecular imaging method for plaque vulnerability.

N-Acetyl Cysteine improves the diabetic cardiac function: possible role of fibrosis inhibition.

BACKGROUND: Diabetic cardiomyopathy is one of the leading causes of death in diabetes mellitus (DM) patients. This study aimed to explore the therapeutic implication of N-acetyl-L-cysteine (NAC, an antioxidant and glutathione precursor) and the possible underlying mechanism. METHODS: Thirty five 12-week-old male C57BL/6 mice were included. Twenty-five diabetic mice were induced by intraperitoneal injection of streptozocin (STZ, 150 mg/kg, Sigma-Aldrich) dissolved in a mix of citrate buffer after overnight fast. Mice with a blood glucose level above 13.5 mmol/L were considered diabetic. As a non-DM (diabetic) control, mice were injected with equal volume of citrate buffer. The 25 diabetic mice were divided into 5 groups with 5 animals in each group: including DM (diabetes without NAC treatment), and 4 different NAC treatment groups, namely NAC1, NAC3, NAC5 and NAC7, with the number defining the start time point of NAC treatment. In the 10 non-DM mice, mice were either untreated (Ctrl) or treated with NAC for 5 weeks (NAC only). Echocardiography was performed 12 weeks after STZ injection. Heart tissue were collected after echocardiography for Hematoxylin Eosin (HE) and Trichrome staining and ROS staining. Cardiac fibroblast cells were isolated, cultured and treated with high glucose plus NAC or the vehicle. qPCR analysis and CCK-8 assay were performed to observe fibrotic gene expression and cell proliferation. RESULTS: We found that both cardiac systolic function and diastolic function were impaired, coupled with excessive reactive oxygen stress and cardiac fibrosis 12 weeks after STZ induction. NAC significantly reduced ROS generation and fibrosis, together with improved cardiac systolic function and diastolic function. Strikingly, NAC1 treatment, which had the earlier and longer treatment, produced significant improvement of cardiac function and less fibrosis. In the cardiac fibroblasts, NAC blocked cardiac fibroblast proliferation and collagen synthesis induced by hyperglycemia. CONCLUSIONS: Our study indicates that NAC treatment in diabetes effectively protects from diabetic cardiomyopathy, possibly through inhibiting the ROS production and fibrosis, which warrants further clarification.

New method for noninvasive quantification of central venous pressure by ultrasound.

BACKGROUND: The central venous pressure (CVP) is essential for assessing the cardiac preload and circulating blood volume in clinic. The invasive CVP measurement by central venous catheter has been reported with various complications. The aim of this study was to develop a new noninvasive method for quantification of CVP by ultrasound. METHODS AND RESULTS: Seventy-six patients who had their CVP monitored for intraoperative or postoperative management were recruited. By accurate location of the collapse point of the internal jugular vein and the center of the right atrium using ultrasound imaging, the height of the fluid column between those 2 points was measured as the noninvasive CVP (CVPn). A total of 118 measurements were performed and compared with the invasive CVP (CVPi). Linear correlation analysis revealed a significant correlation between CVPi and CVPn (preoperative measurements, r=0.90; P<0.01 and postoperative measurements, r=0.93; P<0.01). Bland-Altman plots showed a good agreement between CVPi and CVPn with the mean difference of 0.22 mm Hg (preoperative measurements) and -0.09 mm Hg (postoperative measurements), respectively. CONCLUSIONS: The new noninvasive CVP quantification method based on the location of both the collapse point of internal jugular vein and the center of right atrium by ultrasound could be used as a reliable approach for monitoring the hemodynamic status in clinic.

Carotid Arterial Stiffness in Patients with Congenital Heart Disease-Related Pulmonary Hypertension Assessed with Radio Frequency Data Technique.

BACKGROUND: It has been well known that pulmonary hypertension (PH) caused by congenital heart disease (CHD) leads to reduced flexibility of the small pulmonary arteries, due to hemodynamic changes in the pulmonary circulation and alterations of the vasoactive profile. However, whether CHD-related PH affects the elasticity of the systemic arteries, such as the common carotid artery (CCA), has not been fully investigated. The purpose of this study was to explore the CCA stiffness in patients with CHD-related PH using the radio frequency data technique. METHODS: Forty patients with CHD were included. They were divided into PH and non-PH (NPH) groups by the right heart catheter-determined or regurgitation velocity-determined mean pulmonary arterial pressure (mPAP). MyLabTwice (Esaote, Genoa, Italy) ultrasound machine equipped with automatic quality intima-media thickness (QIMT) and quality arterial stiffness (QAS) capabilities was used to measure the left common carotid arterial (CCA) intima-media thickness and arterial stiffness parameters. RESULTS: The results have shown that the left CCA internal diameter, pulse wave velocity, arterial wall tension, and local diastolic pressure were increased in the CHD-related PH group compared with the CHD-related NPH group (all P < 0.05). The left CCA internal diameter negatively and significantly correlated with the mean PAP. CONCLUSIONS: Common carotid artery diameter and stiffness increase in patients with CHD-related pulmonary hypertension. QIMT and QAS ultrasound techniques may provide a comprehensive assessment of the CCA remodeling.

Mechanism study of pulsus paradoxus using mechanical models.

Pulsus paradoxus is an exaggeration of the normal inspiratory decrease in systolic blood pressure. Despite a century of attempts to explain this sign consensus is still lacking. To solve the controversy and reveal the exact mechanism, we reexamined the characteristic anatomic arrangement of the circulation system in the chest and designed these mechanical models based on related hydromechanic principles. Model 1 was designed to observe the primary influence of respiratory intrathoracic pressure change (RIPC) on systemic and pulmonary venous return systems (SVR and PVR) respectively. Model 2, as an equivalent mechanical model of septal swing, was to study the secondary influence of RIPC on the motion of the interventriclar septum (IVS), which might be the direct cause for pulsus paradoxus. Model 1 demonstrated that the simulated RIPC had different influence on the simulated SVR and PVR. It increased the volume of the simulated right ventricle (SRV) when the internal pressure was kept constant (8.16 cmH2O), while it had the opposite effect on PVR. Model 2 revealed the three major factors determining the respiratory displacement of IVS in normal and different pathophysiological conditions: the magnitude of RIPC, the pressure difference between the two ventricles and the intrapericardial pressure. Our models demonstrate that the different anatomical arrangement of the two venous return systems leads to a different effect of RIPC on right and left ventricles, and thus a pressure gradient across IVS that tends to shift IVS left- and rightwards. When the leftward displacement of IVS reaches a considerable amplitude in some pathologic condition such as cardiac tamponade, the pulsus paradoxus occurs.

Simultaneous beat-by-beat investigation of the effects of the Valsalva maneuver on left and right ventricular filling and the possible mechanism.

Although the influence of the Valsalva maneuver on the heart and circulatory system has been investigated, the mechanism of intrathoracic pressure influencing cardiovascular function is unclear. To test our hypothesis that the interaction between the anatomy-determined partially-intrathoracic system and the fully-intrathoracic system might explain those issues and help to disclose the mechanism, we used the Hitachi dual pulse wave Doppler echocardiographic apparatus to investigate simultaneously the beat-by-beat influence of 40-mmHg Valsalva maneuver on left and right cardiac ventricular filling in 30 male adult volunteers. The mitral and tricuspid blood inflow velocity spectra during the Valsalva maneuver were recorded simultaneously. The peak velocity (PV), velocity-time integral (VTI) and inflow volume (IV) of each cycle were measured or calculated. The PV, VTI and IV of the left heart remained unchanged at the first beat after the Valsalva maneuver onset (compared with those at rest, p>0.1) and then decreased gradually to the lowest at the 11±1.2th beat (range, 9th to 12th beat). Simultaneously, the PV, VTI and IV of the right heart decreased significantly (p<0.05) at the first cycle, decreased rapidly to the lowest at the 6±0.8th beat (range, 4th to 7th beat) and then increased gradually to the 9±1.3th beat (range, 8th to 10th beat). These results suggest that the left heart and right heart have different physiological responses to the Valsalva maneuver. These could be explained by our hypothesis, the interaction between the partially-intrathoracic system and the fully-intrathoracic system, which might help to disclose the mechanism of how intrathoracic pressure influences the heart and circulatory system.