Basal Blood Flow Research Articles

Early coronary artery atherosclerosis in humans is associated with attenuated coronary retention of klotho

Abstract Background Vascular aging is a key feature of cardiovascular disease. α-klotho (klotho) is a protein inversely associated with aging and may contribute to vascular repair. Lower levels of systemic klotho have been identified in humans with features of early and advanced coronary atherosclerosis. It remains unknown if circulating klotho is present within human coronary circulation and whether cardiovascular klotho retention correlates with atherosclerosis. Purpose The current study aimed to assess the presence of klotho within coronary circulation compared to systemic circulation and hypothesized that net coronary klotho retention is attenuated in patients with early age-related features of coronary artery disease (CAD). Methods A total of 42 patients that underwent clinically indicated coronary angiogram for chest pain that had no obstructive CAD underwent intravascular ultrasound (IVUS) assessment were retrospectively examined. Virtual histology assessed coronary plaque characteristics. Blood samples simultaneously collected from the proximal aorta and coronary sinus were used for klotho detection using enzyme-linked immunosorbent assay. The net gradient of klotho across cardiovascular circulation was calculated by multiplying the arteriovenous klotho gradient by basal coronary blood flow. A net positive gradient indicated less cardiovascular klotho retention; a net negative gradient indicated greater cardiovascular klotho retention. Results Overall, participants were age 54±10 years old and 76% were female. There were overall higher levels of klotho within the coronary sinus (median 0.49 ng/mL [0.15; 1.69]) compared to systemic circulation (median 0.30 ng/mL [0.16; 1.14]). Participant groups were determined by those with positive (n = 20) or negative (n = 22) cardiovascular retention of klotho. Both groups were similar in age (56 ±2 vs. 51 ±2 years old, p = 0.080), gender (72% vs. 80% female, p = 0.580), and had similar occurrences of traditional cardiovascular comorbidities. Those with less cardiovascular klotho retention in the coronary vascular bed had significantly greater degree of non-obstructive coronary artery plaque (Gensini score 3.5 vs. 0, p < 0.001) and had higher percent plaque burden (46% [35; 53] vs. 34% [28; 46], p = 0.044) than those with greater cardiovascular klotho retention. Conclusions Patients with early coronary atherosclerosis may be characterized by attenuated retention of klotho within coronary circulation. Moreover, humans appear to have higher circulating klotho in coronary circulation than in systemic circulation. The current study may support a role for mechanism or potential therapeutic target for klotho in coronary atherosclerosis in humans.

Oxidative stress initiates hemodynamic change in CKD-induced heart disease.

Chronic kidney disease (CKD) predisposes to cardiac remodeling and coronary microvascular dysfunction. Studies in swine identified changes in microvascular structure and function, as well as changes in mitochondrial structure and oxidative stress. However, CKD was combined with metabolic derangement, thereby obscuring the contribution of CKD alone. Therefore, we studied the impact of CKD on the heart and combined proteome studies with measurement of cardiac function and perfusion to identify processes involved in cardiac remodeling in CKD. CKD was induced in swine at 10-12weeks of age while sham-operated swine served as controls. 5-6months later, left ventricular (LV) function and coronary flow reserve were measured. LC-MS-MS-based proteomic analysis of LV tissue was performed. LV myocardium and kidneys were histologically examined for interstitial fibrosis and oxidative stress. Renal embolization resulted in mild chronic kidney injury (increased fibrosis and urinary NGAL). PV loops showed LV dilation and increased wall stress, while preload recruitable stroke work was impaired in CKD. Quantitative proteomic analysis of LV myocardium and STRING pre-ranked functional analysis showed enrichments in pathways related to contractile function, reactive oxygen species, and extracellular matrix (ECM) remodeling, which were confirmed histologically and associated with impaired total anti-oxidant capacity. H2O2 exposure of myocardial slices from CKD, but not normal swine, impaired contractile function. Furthermore, in CKD, mitochondrial proteins were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow. Thus, mild CKD induces alterations in mitochondrial proteins along with contractile proteins, oxidative stress and ECM remodeling, that were associated with changes in cardiac function and perfusion.

Repeated passive heat treatment increases muscle tissue capillarization, but does not affect postprandial muscle protein synthesis rates in healthy older adults.

Prolonged passive heat treatment (PHT) has been suggested to trigger skeletal muscle adaptations that may improve muscle maintenance in older individuals. To assess the effects of PHT on skeletal muscle tissue capillarization, perfusion capacity, protein synthesis rates, hypertrophy and leg strength, 14 older adults (9males, 5 females; 73 ± 6years) underwent 8weeks of PHT (infrared sauna: 3× per week, 45min at ∼60°C). Before and after PHT we collected muscle biopsies to assess skeletal muscle capillarization and fibre cross-sectional area (CSA). Basal and postprandial muscle tissue perfusion kinetics and protein synthesis rates were assessed using contrast-enhanced ultrasound and primed continuous l-[ring-13C6]phenylalanine infusions, respectively. One-repetition maximum (1RM) leg strength and vastus lateralis muscle CSA were assessed. Type I and type II muscle fibre capillarization strongly increased following PHT (capillary-to-fibre perimeter exchange index: +31 ± 18 and +33 ± 30%, respectively; P<0.001). No changes were observed in basal (0.24 ± 0.27 vs. 0.18 ± 0.11 AU; P=0.266) or postprandial (0.20 ± 0.12 vs. 0.18 ± 0.14 AU; P=0.717) microvascular blood flow following PHT. Basal (0.048 ± 0.014 vs. 0.051 ± 0.019%/h; P=0.630) and postprandial (0.041 ± 0.012 vs. 0.051 ± 0.024%/h; P=0.199) muscle protein synthesis rates did not change in response to prolonged PHT. Furthermore, no changes in vastus lateralis muscle CSA (15.3 ± 4.6 vs. 15.2 ± 4.6 cm2; P=0.768) or 1RM leg strength (46 ± 12 vs. 47 ± 12 kg; P=0.087) were observed over time. In conclusion, prolonged PHT increases muscle tissue capillarization but this does not improve muscle microvascular blood flow or increase muscle protein synthesis rates in healthy, older adults. Prolonged PHT does not induce skeletal muscle hypertrophy or increase leg strength in healthy, older adults. KEY POINTS: Repeated exposure to heat has been suggested to trigger skeletal muscle adaptive responses. We investigated the effect of 8weeks of whole-body passive heat treatment (PHT; infrared sauna: 3× per week for 45min at ∼60°C) on skeletal muscle tissue capillarization, perfusion capacity, basal, and postprandial muscle protein synthesis rates, muscle (fibre) hypertrophy, and leg strength in healthy, older adults. Prolonged PHT increases muscle tissue capillarization, but this does not improve muscle microvascular blood flow or increase muscle protein synthesis rates. Despite increases in muscle tissue capillarization, prolonged PHT does not suffice to induce skeletal muscle hypertrophy or increase leg strength in healthy, older adults.

Vascular Signaling Plasticity Reprograms Blood Delivery Mechanisms to Meet Fluctuating Neuronal Energy Needs

Neuronal computation is metabolically expensive and depends on precision delivery of energy substrates—oxygen and glucose—via tightly coordinated blood flow to ensure that energy demands are continually met. This is facilitated by neurovascular coupling (NVC)—a range of mechanisms matching neural activity to local blood flow. These NVC mechanisms are typically considered invariant, and whether they are reshaped according to ever-changing neuronal metabolic needs has not been examined. We present evidence that neural activity continually reprograms the blood flow control mechanisms embedded in the local vasculature, a process we refer to as ‘vascular signaling plasticity’ (VSP). Using an established enrichment paradigm, we find that animals housed in conditions that increase input to the barrel cortex for 7 days exhibit profound neuronal plasticity in this region. This resculpts local vascular reactivity to elevate blood delivery. Indeed, VSP results in increased basal capillary blood flow and augmented activity of vasodilatory agents in vivo manifesting as increased red blood cell (RBC) flux responses to capillary stimulation and upstream diameter changes measured using 2-photon laser scanning microscopy. Moreover, the sensitivity of capillaries to stimulation is also dramatically elevated in an ex vivo isolated capillary-arteriole preparation. Using K+-mediated capillary-to-arteriole electrical signaling as a springboard to study the molecular underpinnings of VSP, we find that this process induces a ~70% increase in the density of strong inward rectifier K+ (Kir2.1) currents in capillary endothelial cells, which profoundly augments the retrograde hyperpolarization generated by these channels to control upstream diameter at the level of the penetrating arteriole. Through whole-cell patch clamp electrophysiology, we characterize the mechanism of VSP induction and recapitulate this phenomenon in vitro. We validate our findings through Crispr/Cas9-mediated endothelial cell-specific knockout of the transcription factor responsible for VSP induction. Our data thus recast the vasculature as a plastic, brain-wide activity sensing network that is continually reshaped at the molecular level by local neuronal input, leading to precisely-tuned blood delivery to meet continually fluctuating neural energy needs. VSP represents a new dimension to brain plasticity that may underpin a range of vital physiological processes and is likely disrupted in numerous brain pathologies with a blood flow component. This work was supported by the American Heart Association (23POST1023086), and NIH grants 1DP2NS121347, 1R01AG066645, and 5R01NS115401. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Oxidative stress: A driving force in CKD induced heart failure

Background: Several clinical investigations have shown that individuals with renal impairment are more likely to experience heart failure. Cardiac remodeling happens relatively early in the course of kidney injury, yet research into identification of common markers of cardiorenal signaling remains insuffcient. This may be because studies conducted in small animal models do not accurately reflect the complexity of the disease. To bridge the translational gap, we developed a swine model for chronic kidney disease (CKD) Aim: We employed proteome studies to clarify the pathophysiological impact of chronic kidney disease (CKD) on the heart and correlate to cardiac function and perfusion in order to offer mechanistic insights. Methods: We used microspheres to embolise both kidneys of swine at 10-12 weeks of age while sham operated swine served as controls. Post 6 months, we performed pressure volume loops to assess cardiac function, while coronary flow reserve (CFR) was measured by intracoronary infusion of adenosine in control and CKD. (LC-MS-MS based proteomic analyses of left ventricular tissue was performed. Paraffn embedded myocardium and kidney tissues were histologically examined for interstitial fibrosis and oxidative stress. Results: Renal embolization resulted in mild chronic kidney injury as evidenced by increased fibrosis staining and urinary NGAL (24±4 vs 48±9 pg/ml). Hemodynamic parameters showed increased wall stress (20±3 vs 40±7 ml*mmHg/g) as well as increase of end diastolic volume (1.5±0.1 vs 1.9±0.1 ml/kg) indicating dilation of the left ventricle in CKD. Quantitative proteomic analysis detected significant differences in the left ventricle of the controls when compared to those with CKD and STRING pre-ranked functional analysis showed enrichments in pathways related to reactive oxygen species. Furthermore, we detected alterations of pathways associated with remodeling of the extracellular matrix (ECM), Oxidative stress and ECM remodeling were confirmed histologically. Interestingly, in CKD we found that mitochondrial proteins like cytochrome oxidase (MT-CO2) and ATP5 synthase subunit were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow (0.48±0.05 vs 0.87±0.11 ml/min/g). Conclusions: Our proteomic data in swine model provides strong evidence that mild CKD can induce early alterations in mitochondrial function along with oxidative stress and ECM remodeling. Thus, we aim to further our understanding by applying our proteomic findings in conjunction with functional hemodynamic data in this swine model of cardiorenal disease. German Center for Cardiovascular Research (DZHK81Z0600207 to D.M. and P.S.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Making the case for resistance training in improving vascular function and skeletal muscle capillarization.

Through decades of empirical data, it has become evident that resistance training (RT) can improve strength/power and skeletal muscle hypertrophy. Yet, until recently, vascular outcomes have historically been underemphasized in RT studies, which is underscored by several exercise-related reviews supporting the benefits of endurance training on vascular measures. Several lines of evidence suggest large artery diameter and blood flow velocity increase after a single bout of resistance exercise, and these events are mediated by vasoactive substances released from endothelial cells and myofibers (e.g., nitric oxide). Weeks to months of RT can also improve basal limb blood flow and arterial diameter while lowering blood pressure. Although several older investigations suggested RT reduces skeletal muscle capillary density, this is likely due to most of these studies being cross-sectional in nature. Critically, newer evidence from longitudinal studies contradicts these findings, and a growing body of mechanistic rodent and human data suggest skeletal muscle capillarity is related to mechanical overload-induced skeletal muscle hypertrophy. In this review, we will discuss methods used by our laboratories and others to assess large artery size/function and skeletal muscle capillary characteristics. Next, we will discuss data by our groups and others examining large artery and capillary responses to a single bout of resistance exercise and chronic RT paradigms. Finally, we will discuss RT-induced mechanisms associated with acute and chronic vascular outcomes.

The effect of transdermal combined product on the state of microcirculatory blood flow in patients with chronic venous insufficiency

Introduction. Treatment of patients with severe chronic venous insufficiency of the lower extremities is complex and along with compression therapy includes transdural use of drugs. Aim. To study the microcirculatory blood flow of the tissues of the distal segments of the lower limbs in patients with severe chronic venous insufficiency and the possibility of its correction with the use of a combined product for local application.Materials and мethods. The study included 40 patients suffering from varicose vein disease with chronic venous insufficiency of C3-C5 stages according to CEAP. In the main group of patients (n = 30) the transdermal combined product Detragel® was used; patients of the comparison group (n = 10) received only basic compression therapy of functional class II. The basis for the assessment of microcirculation of the lower limbs soft tissues was the analysis of the results of laser doppler flowmetry. Results. At local use of Detragel® in combination with elastic bandage in 91% of observations, there was a statically significant decrease of basal blood flow less than 4.0 pf. units (p &lt; 0.05). The mean basal blood flow was 2.7 ± 0.6 pf. units (1.6–3.9 pf. units, 95% CI), which was consistent with normal values. Statistically significant decrease in veno-arteriolar response to 51.5 ± 10.8% (36.0–68.8%, 95% CI) was recorded in 75% of cases after 14 days of topical treatment, although veno-arteriolar response decreased to normal in only 53% of cases. Conclusion. Correction of microcirculatory disorders in patients with varicose vein disease should include local use of medicine.

The microvascular bed of the skin of lower limbs in patients with intermittent lameness and coronary heart disease as a possible model of their myocardial microcirculation

Purpose: to assess possibility to extrapolate findings of skin microvascular bed examination in lower extremities with laser Doppler flowmetry in patients with obliterating atherosclerosis as a model of their myocardial microcirculation in coronary heart disease.Material and methods. Males with angiographically confirmed coronary heart disease (n = 70) and obliterating atherosclerosis in lower limbarteries (n = 74) were taken in the study. Microcirculation of the skin in the left forearm in the Zakharyin – Head zone in patients with coronaryheart disease and skin microcirculation in the foot of affected limb in patients with obliterating atherosclerosis of arteries of lower extremities were examined with laser Doppler flowmetry. The basal blood flow, amplitude-frequency spectrum of its oscillations, myogenic, neurogenic vascular tone and occlusion parameters were assessed as well. Comparison groups included 50 practically healthy males for the patients with coronary heart disease and 20 males – for the patients with obliterating atherosclerosis of arteries of lower extremities. Patients were examinedat the initial stage and in 2–3 weeks after endovascular restoration of blood flow in the myocardium and lower limbs.Results and discussion. At the initial research stage, the microcirculation picture in patients with coronary heart disease and obliterating ath-erosclerosis in lower extremities differed from that of healthy individuals by shifts covering all links of the microvascular bed and characterizedby constriction of the precapillary segment, a statistically significant decrease in median values of capillary blood flow by 17.5 and 43.1 %,microvascular blood flow reserve – by 11.2 and 31.0 %, as well as by the increase in arteriolovenular blood bypass – by 10.3 and 70.8 %,respectively. After the restoration of blood flow in lower extremities in patients with obliterating atherosclerosis, muscular pain disappeared,and the ankle-shoulder index got normalized. At the same time, one could observe a statistically significant increase in the capillary blood flow(+13.6 %), the increase of reserve potential in microvascular bed (+20.6 %) with the simultaneous decrease of vascular tone in the precapillarysegment (–15.1 %) and of the blood bypass index (–25.0 %). Better clinical picture after coronary angioplasty in patients with coronary heart disease was accompanied with a similar and unidirectional tendency to positive changes in the microvascular bed.Conclusion. As far as etiopathogenetic mechanisms and clinical manifestations of coronary heart disease and obliterating atherosclerosis in arteries of lower extremities have much in common and microcirculatory shifts in forearm and foot skin in these patients before and after angioplasty are unidirectional, all these allow to suggest that one can see similar changes in the myocardium microcirculatory system in patients with coronary heart disease. Thus, it opens possibilities to have a targeted medicamentous impact at the microvascular level.

Functional condition of microcirculation in the zone of intestinal anastomosis during postoperative period upon stimulation of its regeneration (experimental study)

Objectives: to conduct a comparative assessment of the functional condition of microcirculation of the digestive anastomosis zone in the early and delayed postoperative period upon local usage of autogenic growth factors (PRP). The experiment was performed on 30 mature laboratory rabbits. All animals underwent the imposition of two digestive "end-to-end" intestinal anastomosis: the control one at a distance of 15 cm from the ileocecal angle and the experimental one retreating 30 cm from the imposed anastomosis. The experimental anastomosis differed from the control one by using a method of local stimulation of its regeneration via injecting of platelet-riched-plasm (PRP). A comparative assessment of the functional state of the microcirculation of the intestinal anastomosis zone was carried out on the 3rd, 7th, 14th days in the postoperative period using the method of laser doppler flowmetry (LDF). The obtained data determined the ability of the PRP method to improve the conditions of the regenerative process in the intestinal anastomosis zone by increasing the rate of basal blood flow and tissue perfusion, the rates of which have maximum values in the early postoperative period (3 day).

АЛГОРИТМ ОКАЗАНИЯ МЕДИЦИНСКОЙ ПОМОЩИ ПАЦИЕНТАМ С ЗАБОЛЕВАНИЯМИ СЛИЗИСТОЙ ОБОЛОЧКИ РТА

The relevance of this work is due to the high prevalence of diseases of the oral mucosa, which have a chronic protracted nature. Underdiagnosis of patients at a dental appointment often leads to complications of various kinds. The aim of the work is to develop an algorithm for providing dental care to patients with diseases of the oral mucosa. 146 patients who applied for dental care took part in the examination. As a result of clinical examination and additional diagnostic methods, defects of the oral mucosa were detected in 19.8% of patients. The patients underwent a basic examination, the nature and intensity of pain on the Hossley-Bergman scale were determined, the area of erosive and ulcerative defects was calculated. Additional examination methods included electromyography and laser Doppler flowmetry. Electromyographic examination during the "bruxism" test made it possible to diagnose muscle hypertension, which is a predictor of the development of chronic injuries. Doppler flowmetry reflected the state and genesis of microcirculatory disorders of the oral mucosa. Thus, there is a decrease in the microcirculation parameter, the mean square deviation and the basal blood flow rate. Carrying out a full-fledged diagnostic complex allows both to identify the root causes of the development of pathologies, and to prescribe pathogenetic therapy taking into account the identified disorders. Timely diagnosis makes it possible to identify pathology at an early stage, which will prevent the development of a number of complications, such as the transition to a more severe form of the disease and malignancy of the decubital ulcer. Compliance by dentists with the algorithm of providing medical care to patients with diseases of the oral mucosa will allow timely identification and elimination of the etiological factor, timely restoration of the functions of the oral mucosa, normalize the functional state of the body.

Functional state of skin microvascular bed according to laser doppler flowmetry in patients with arterial hypertension combined with hypercholesterolemia

Introduction. The great importance of risk factors, such as arterial hypertension (AH) and low-density lipoprotein cholesterol (LDL-H), for development of cardiovascular diseases, makes highly relevant to obtain the data of the nature of microcirculation (MC) changes that are a key link of maintaining homeostasis under their concomitant influence. Aim – to evaluate functional state of skin microvascular bed using laser Doppler flowmetry in patients with arterial hypertension (AH) and combined with hypercholesterolemia. Materials and Methods. The study involved 37 practically healthy volunteers and 94 patients with 2–3 stage of AH, which were divided into 2 groups: Gr.1 with LDL-CH level ≤3.5 mmol/l (n = 35) and Gr.2 with LDL-H level &gt;3.5 mmol/l (n = 59). MC of the forearm skin was assessed by laser Doppler flowmetry. Parameters of basal blood flow, the amplitude-frequency spectrum of its fluctuations, nutritional MC, and parameters of occlusion test were evaluated. Results. Analyzing rhythm structure of blood flow fluctuations, statistically significant decrease in standardized parameters of their amplitude in endothelial and myogenic frequency ranges was revealed in patients with elevated LDL-CH levels compared to patients of Gr.1 by 19.7 % and 9.7 % (р = 0.045), respectively, which indicated weakening of endothelial function and constriction of precapillary segment of MC. These changes were accompanied by decrease in reserve of microvascular blood flow by 9.1 % in Gr.2 of patients (p = 0.044) with pronounced trend towards reduction of capillary perfusion and activation of blood flow through arteriolovenular shunts. Conclusion. More pronounced functional disorders of MC, characterized by endothelial dysfunction, constriction of precapillary segment, and decrease in reserve potential of tissue hemoperfusion were revealed in AH patients with atherogenic hyperlipidemia vs AH patients.

The role of microcirculation in the conducting structures of the nervous system in patients with vibration disease burdened by metabolic syndrome

Introduction. The study of microcirculation processes in peripheral nerve damage remains a necessary area of experimental and clinical research, because the microvascular bed is one of the most important systems in which the disease manifests itself in the early stages. The aim of the study is to identify the role of microcirculation disorders in the state of central and peripheral conductive structures in patients with vibration disease (VD) associated with combined exposure to general and local vibration, and burdened with metabolic syndrome (MS) and diabetes mellitus (DM). Materials and methods. Group 1 included patients with VD associated with combined exposure to general and local vibration, group 2 - persons diagnosed with VD, burdened with MS, group 3 - with a diagnosis of VD, burdened with DM. At the 1st stage of the study, basal blood flow was studied, at the 2 nd stage - load functional tests (respiratory and occlusive). The state of sensory and motor axons of the nervous system was determined. Results. In patients of the examined groups, there was proved a relationship between the indicators of the state of peripheral nerves and central structures with the indicators of microcirculation, the state of the myogenic level of regulation, with the index of specific oxygen consumption and the index of relative perfusion oxygen saturation in the microcirculation. In patients with VD, burdened with MS and DM, an association was found between changes in axons with an indicator of the intensity of functioning of the regulatory systems of the microvascular bed, indicators of the levels of active regulation of microcirculation (myogenic, neurogenic and endothelial) and indicators characterizing the dynamic state of the microcirculation system. Limitations. The disadvantage of the study is the fact that the parameters of the microcirculation system determined in the peripheral departments were extrapolated to the central structures, and were not determined in the capillary network of the brain. Conclusion. Changes in the microcirculatory bed were established to be a link in the pathogenesis of demyelination processes in VB associated with the combined effects of general and local vibration, and vibration disease burdened with MS and DM.

Modelling and experimental study of thermo-physiological responses of human exercising in cold environments

A numerical human thermo-physiological model is developed with the consideration of characteristics of exercising people in cold environments. The developed model is characterized by: 1) the concept of net exercise efficiency which is used to correct the calculation of metabolic heat production by excluding mechanical energy; 2) the effects of low temperature on basal metabolic rate and basal blood flow rate; 3) the integration with a multi-layer clothing model to calculate the heat and moisture transfer through the clothing system, which takes into account the air gaps between the clothing layers to reflect the ventilation and air penetration effect from the ambient wind. Human subject experiment is conducted in a climate chamber to validate the proposed model. The human subject experiment is also carried out in a cold environment (−5 °C) combined with different air velocity conditions (still air, 2 m/s), taking into account the activities of different intensities (standing statically, 2 km/h walking and 7 km/h running). Thermo-physiological parameters including the core temperature, 8-point local skin temperatures and the clothing layer temperatures, are measured during the experiment. Comparison between the predicted and experimental results gives the root mean squared error (RMSE) of core temperature and mean skin temperature of 0.06–0.10 °C and 0.17–0.27 °C, respectively. RMSE values for local skin and clothing layer temperatures are no higher than 1.5 °C and most within 0.8 °C. The model is also validated with published data under various ambient temperature and activity intensity conditions. The proposed model is shown to be capable of predict the thermo-physiological responses of people exposed and exercising in cold environments.

Ventilatory Muscle Training for Early Cardiac Rehabilitation Improved Functional Capacity and Modulated Vascular Function of Individuals Undergoing Coronary Artery Bypass Grafting: Pilot Randomized Clinical Trial.

Background: Cardiac rehabilitation with aerobic exercises is the first strategy for nonpharmacological treatment in the postoperative period of individuals undergoing coronary artery bypass grafting (CABG) to improve functional capacity and vascular health. However, other exercise modalities remain uncertain regarding the same benefits. Objectives: Evaluation of the effect of different modalities of exercise, such as early cardiac rehabilitation on subjects submitted to CABG in the six-minute walk test (6-MWT) and on the percentage of flow-mediated dilatation (FMD) of the brachial artery. Methods: A randomized clinical trial in which 15 patients (62.7 ± 6.7 years) who underwent CABG were randomly assigned to the following groups: isometric (IG, Handgrip Jamar®), ventilatory muscle training (VG, PowerBreathe®) and control (CG, conventional respiratory and motor physiotherapy). All patients were attended to physically twice a day (20 min/session) for a consecutive week after the CABG (hospital admission). Functional capacity was assessed by 6-MWT and endothelial function was assessed through the technique of FMD, before and after (~7 days) admission to CABG. The doppler ultrasound videos were analyzed by Cardiovascular Suite® software (Quipu, Pisa, Italy) to measure %FMD. Statistics: Generalized estimation equation, followed by Bonferroni post hoc (p < 0.05). Results: Systolic, diastolic and mean arterial pressure (SBP/DBP/MAP, respectively) were 133, 76 and 95 mmHg. The groups presented walking meters (m) distance before and after intervention of: IGbasal 357.80 ± 47.15 m vs. IGpost 306.20 ± 61.63 m, p = 0.401 (+51 m); VGbasal 261.50 ± 19.91 m vs. VGpost 300.75 ± 26.29 m, p = 0.052 (+39 m); CG basal 487.83 ± 83.23 m vs. CGpost 318.00 ± 31.08, p = 0.006 (−169 m). %FMD before and after intervention was IGbasal 10.4 ± 4.8% vs. IGpost 2.8 ± 2.5%, p = 0.152; VGbasal 9.8 ± 5.1% vs. VGpost 11.0 ± 6.1%, p = 0.825; CGbasal 9.2 ± 15.8% vs. CGpost 2.7 ± 2.6%, p = 0.710 and resting mean basal blood flow was IGbasal 162.0 ± 55.0 mL/min vs. IGpost 129.9 ± 63.7 mL/min, p = 0.662; VGbasal 83.74 ± 12.4 mL/min vs. VGpost 58.7 ± 17.1 mL/min, p = 0.041; CGbasal 375.6 ± 183.7 mL/min vs. CGpost 192.8 ± 115.0 mL/min, p = 0.459. Conclusions: Ventilatory muscle training for early cardiac rehabilitation improved acute functional capacity and modulated mean flow of individuals undergoing CABG.

Metabolic Stress Impairs Pericyte Response to Optogenetic Stimulation in Pancreatic Islets.

Pancreatic islets are highly vascularized micro-organs ensuring whole body glucose homeostasis. Islet vascular cells play an integral part in sustaining adequate insulin release by beta cells. In particular, recent studies have demonstrated that islet pericytes regulate local blood flow velocity and are required for maintenance of beta cell maturity and function. In addition, increased metabolic demand accompanying obesity alters islet pericyte morphology. Here, we sought to explore the effects of metabolic stress on islet pericyte functional response to stimulation in a mouse model of type 2 diabetes, directly in the pancreas in vivo . We found that high fat diet induced islet pericyte hypertrophy without alterations in basal local blood flow. However, optogenetic stimulation of pericyte activity revealed impaired islet vascular responses, despite increased expression of genes encoding proteins directly or indirectly involved in cell contraction. These findings suggest that metabolic stress impinges upon islet pericyte function, which may contribute to beta cell failure during T2D.

Impaired skin microvascular endothelial reactivity in critically ill COVID-19 patients

BackgroundSome clinical and histological studies have reported that SARS-CoV-2 infection may damage the endothelium. However, the impact of this virus on endothelial function in vivo remains poorly characterized. In this single-center pilot observational study, we performed iontophoresis of acetylcholine coupled with Laser doppler to investigate microvascular endothelial reactivity in COVID-19 patients compared to patients with non-COVID-19 bacterial pneumonia (NCBP) patients.ResultsDuring three consecutive months, 32 COVID-19 patients and 11 control NCBP patients with acute respiratory failure were included. The median age was 59 [50–68] and 69 [57–75] years in COVID-19 and NCBP groups, respectively (P = 0.11). There was no significant difference in comorbidities or medications between the two groups, except for body mass index, which was higher in COVID-19 patients. NCBP patients had a higher SAPS II score compared to COVID-19 patients (P < 0.0001), but SOFA score was not different between groups (P = 0.51). Global hemodynamic and peripheral tissue perfusion parameters were not different between groups. COVID-19 patients had significantly lower skin microvascular basal blood flow than NCBP patients (P = 0.02). In addition, endothelium-dependent microvascular reactivity was threefold lower in COVID-19 patients than NCBP patients (P = 0.008).ConclusionsBoth baseline skin microvascular blood flow and skin endothelial-dependent microvascular reactivity were impaired in critically ill COVID-19 patients compared to NCBP patients, despite a lower disease severity score supporting a specific pathogenic role of SARS-CoV-2 on the endothelium.

Effect of Arterial Stiffness and Cerebral Pulsatility on Hippocampal Tissue Integrity in Healthy Adults

Elevated large elastic artery (i.e. aorta and common carotid) stiffness has emerged as a risk factor of cognitive impairment in older adults. Stiffening of these arteries leads to increased pulsatile energy transmission into the brain, which may result in structural damage to neuronal tissue, and potentially precipitate cognitive decline. In this regard, changes to microstructural integrity of the hippocampus (HC), a brain structure essential for memory encoding, may reflect the impact of age‐related increases in arterial stiffness and pulsatile blood flow through the middle cerebral artery (MCA). Therefore, the purpose of this study was to determine whether large elastic artery stiffness and associated pulsatile hemodynamics are related with HC integrity in healthy adults across the lifespan. We included 25 participants (16M/9F, age: 44±16 y; age range: 22‐69 y; BMI: 27±5 kg/m2; BP: 115±11/71±10 mmHg) in this study. Aortic stiffness was assessed as carotid‐femoral pulse wave velocity (PWV) using applanation tonometry (AtCor Medical, Sydney, Australia). Common carotid artery (CCA) stiffness was measured using duplex ultrasound (Logiq e, GE Healthcare, Chicago, IL) and analyzed with an offline wall‐tracking software (Cardiovascular Suite, Pisa, Italy). CCA blood pressures were acquired from applanation tonometry. Transcranial Doppler ultrasound was used to measure basal mean blood flow velocity of the MCA (MCAv) from which Gosling’s pulsatility index (PI) was calculated as the difference between peak systolic MCAv and end‐diastolic MCAv over mean MCAv. HC tissue integrity was measured using magnetic resonance elastography (MRE), which was acquired using a Siemens 3T Prisma MRI scanner coupled with shear waves generated via a pneumatic actuator (Resoundant, Rochester, MN) at 50 Hz. Bilateral HC stiffness (µ) and HC damping ratio (ξ) were estimated from MRE displacement data using a nonlinear inversion algorithm. A correlation matrix was used to determine if arterial stiffness, vascular hemodynamics, and other lifestyle factors (e.g., age, sex, BMI) were related with HC integrity. BMI (r=‐0.40, p=0.048), CCA pulse pressure (PP) (r=‐0.61, p=0.001), and MCAv PI (r=‐0.48, p=0.01) were associated with HC µ while age (r=0.66, p=0.0004), BMI (r=0.45, p=0.02), SBP (r=0.52, p= 0.008), aortic PWV (r=0.65, p=0.0004), and CCA stiffness (r=0.60, p=0.002) were associated with HC ξ. Next, multiple linear regressions were performed to determine the independent associations among arterial stiffness, vascular hemodynamics of interest, and HC integrity while correcting for age and BMI. HC µ remained significantly associated with CCA PP (β=‐0.52, p=0.03) and was trending towards negative association with MCAv PI (β=‐0.37, p=0.06). There were no significant independent associations among the variables of interest and HC ξ, however, together these variables significantly explained variance in HC ξ (R2=0.37, p=0.03). Our results suggest increased pulsatile pressure through the carotid artery along with elevated cerebral pulsatility negatively impacts HC tissue integrity. Future studies should consider how our current findings affect functional outcomes like memory and age‐related neurological conditions.

AT1R‐mediated neurodegeneration is part of the etiology of hypertension‐associated cognitive impairment

Hypertension has now been closely associated to cognitive impairment, due to its contribution to cerebrovascular dysfunction. To investigate whether there is neuronal mechanism, hypertension was induced in C57BL/6j male mice (6 months) by DOCA‐salt treatment (1.5 mg/g, s.c., 28 days). Firstly, behavioral study, which contains object location behavioral task, novel object recognition, Barnes maze, and nesting score test, was performed to assess cognitive function, meanwhile, blood pressure (BP) was monitored by tail‐cuff device. In NT (non‐transgenic) mice, DOCA+1%NaCl increases BP significantly, before vs. after DOCA (systolic BP): 114.8 ±0.94 vs. 133.7 ±3.3 mmHg. In whole, compared to sham controls, the treated NT mice performed worse in all four behavioral tests, indicating cognition decline after DOCA‐salt treatment. Later, brain tissues were collected to evaluate possible degenerative alterations in neurons by transmission electron microscope (TEM) imaging, Golgi‐Cox staining, fluorescence‐activated cell sorting (FACS) and qRT‐PCR. It was shown via the TEM that DOCA‐salt hypertension induces mitochondrial damage and morphological changes in prefrontal cortical neurons, meanwhile, Golgi‐Cox staining revealed decreased numbers of dendritic spines, suggesting the onset of neurodegeneration in DOCA‐salt hypertension. In both prefrontal cortex and hippocampus, the mRNA levels of BDNF (brain‐derived neurotrophic factor) and PI4KIIIβ (phosphatidylinositol 4‐kinase IIIβ) were found to be significantly lower in hypertensive NT mice. Using FACS, neurons were sorted from those regions, then analyzed via qRT‐PCR, which identified that the downregulated expression of PI4KIIIβ takes place in neurons. Using laser speckle contrast imaging system, we detected only decreased functional hyperemia, but no impairment in basal cerebral blood flow of the hypertensive mice, suggesting that the neurodegeneration is not caused by cerebral ischemia. We previously demonstrated that neuronal angiotensin type 1 receptors (AT1R) plays a pivotal role in the maintenance of neurogenic hypertension, and here we hypothesized that activation of AT1R could also exacerbate hypertension‐induced reduction in neuronal function. Particularly, in the hippocampal CA1 of adult mice, treatment of angiotensin II (Ang‐II, 500 nM, bath application) induces a significant inhibition in the induction of long‐term potentiation (LTP), while pre‐treatment with losartan (5 μM, 15 min), the AT1R antagonist, can efficiently block this Ang‐II‐induced inhibition, supporting the involvement of neuronal AT1R. Indeed, in mice with selective deletion of neuronal AT1aR, DOCA‐salt‐induced neurodegeneration was attenuated, as evidenced by significantly higher mRNA levels of cortical BDNF and PI4KIIIβ, compared with the NT. In summary, our data suggest that neuron‐expressing AT1R participates in the development of hypertension‐associated cognitive impairment, independently of vascular AT1R.

Simvastatin Improves Microcirculatory Function in Nonalcoholic Fatty Liver Disease and Downregulates Oxidative and ALE-RAGE Stress.

Increased reactive oxidative stress, lipid peroxidation, inflammation, and fibrosis, which contribute to tissue damage and development and progression of nonalcoholic liver disease (NAFLD), play important roles in microcirculatory disorders. We investigated the effect of the modulatory properties of simvastatin (SV) on the liver and adipose tissue microcirculation as well as metabolic and oxidative stress parameters, including the advanced lipoxidation end product–receptors of advanced glycation end products (ALE-RAGE) pathway. SV was administered to an NAFLD model constructed using a high-fat–high-carbohydrate diet (HFHC). HFHC caused metabolic changes indicative of nonalcoholic steatohepatitis; treatment with SV protected the mice from developing NAFLD. SV prevented microcirculatory dysfunction in HFHC-fed mice, as evidenced by decreased leukocyte recruitment to hepatic and fat microcirculation, decreased hepatic stellate cell activation, and improved hepatic capillary network architecture and density. SV restored basal microvascular blood flow in the liver and adipose tissue and restored the endothelium-dependent vasodilatory response of adipose tissue to acetylcholine. SV treatment restored antioxidant enzyme activity and decreased lipid peroxidation, ALE-RAGE pathway activation, steatosis, fibrosis, and inflammatory parameters. Thus, SV may improve microcirculatory function in NAFLD by downregulating oxidative and ALE-RAGE stress and improving steatosis, fibrosis, and inflammatory parameters.

Neurovascular disease: 2022 update.

In this update we present a series of papers focused on topics that have emerged in vascular disease over the prior year. The first two papers focus on the pathogenesis of vascular malformations, the first on brain arteriovenous malformations, and the second on cerebral cavernous malformations. These disorders can lead to significant brain injuries from intracerebral hemorrhage (if they rupture) or other neurological complications, including seizures. The next set of papers reflects work that has advanced our understanding of how the brain and the immune system "communicate" after brain injury, including stroke (papers 3-6). The first of these shows that T cells are involved in white matter repair after ischemic injury, an effect dependent on microglia, demonstrating the important cross-talk between innate and adaptive immunity. The next two papers focus on B cells, which have been relatively understudied in the context of brain injury. The contribution of antigen-experienced B cells from the meninges and skull bone marrow, rather than blood-derived B cells in neuroinflammation opens up a very novel area of investigation. The possibility that antibody secreting B cells may contribute to vascular dementia will certainly be an active area for future investigations. Similarly, in paper 6, investigators found that CNS-infiltrating myeloid cells can originate from brain borders tissues. These cells have unique transcriptional signatures that are distinct from their blood-derived counterparts, and likely contribute to myeloid cell infiltration from bone-marrow niches in close proximity to the brain. The contribution of microglia, the primary innate immune cell of the brain, to amyloid deposition and propagation is then discussed, followed by work on how perivascular Aβ is potentially cleared along the cerebral vessels in patients with cerebral amyloid angiopathy. The final two papers focus on the contribution of senescent endothelial cells and pericytes. The first used a model of accelerated senescence (Hutchinson-Gilford progeria syndrome; HGPS) and shows the translational potential of an approach to reduce telomere shortening to slow aging. The final paper demonstrates how capillary pericytes contribute to basal blood flow resistance and slow modulation of blood flow throughout the brain. Interestingly, several of the papers identified therapeutic strategies that could be potentially translated into clinical populations.