Impaired Blood Flow Research Articles

Treatment of open extensive injuries and destruction of the hand

Department of Traumatology, Orthopedics and Surgery of Extreme Conditions, Russian State Medical University, MoscowThe work is based on the experience of treating 382 patients with extensive open injuries and 95 patients with destruction of the hand. The main importance is attached to the timely and high-quality primary surgical treatment of the wound and the correct choice of surgical treatment tactics (primary or delayed performance of restorative operations). The use of low-traumatic methods of osteosynthesis during the primary surgical treatment of the wound in case of hand injuries accompanied by impaired blood flow in the main type helps to reduce the frequency of necrotic complications. Long-term results of treatment are known in 357 patients. 40% of them are disabled of the III group, which is due to the severity of the injuries. Of 357 patients, 318 (89%) returned to work

Mental Stress and Cardiovascular Health-Part I.

Epidemiological studies have shown that a substantial proportion of acute coronary events occur in individuals who lack the traditional high-risk cardiovascular (CV) profile. Mental stress is an emerging risk and prognostic factor for coronary artery disease and stroke, independently of conventional risk factors. It is associated with an increased rate of CV events. Acute mental stress may develop as a result of anger, fear, or job strain, as well as consequence of earthquakes or hurricanes. Chronic stress may develop as a result of long-term or repetitive stress exposure, such as job-related stress, low socioeconomic status, financial problems, depression, and type A and type D personality. While the response to acute mental stress may result in acute coronary events, the relationship of chronic stress with increased risk of coronary artery disease (CAD) is mainly due to acceleration of atherosclerosis. Emotionally stressful stimuli are processed by a network of cortical and subcortical brain regions, including the prefrontal cortex, insula, amygdala, hypothalamus, and hippocampus. This system is involved in the interpretation of relevance of environmental stimuli, according to individual’s memory, past experience, and current context. The brain transduces the cognitive process of emotional stimuli into hemodynamic, neuroendocrine, and immune changes, called fight or flight response, through the autonomic nervous system and the hypothalamic–pituitary–adrenal axis. These changes may induce transient myocardial ischemia, defined as mental stress-induced myocardial ischemia (MSIMI) in patients with and without significant coronary obstruction. The clinical consequences may be angina, myocardial infarction, arrhythmias, and left ventricular dysfunction. Although MSIMI is associated with a substantial increase in CV mortality, it is usually underestimated because it arises without pain in most cases. MSIMI occurs at lower levels of cardiac work than exercise-induced ischemia, suggesting that the impairment of myocardial blood flow is mainly due to paradoxical coronary vasoconstriction and microvascular dysfunction.

Is vascular insulin resistance an early step in diet-induced whole-body insulin resistance?

There is increasing evidence that skeletal muscle microvascular (capillary) blood flow plays an important role in glucose metabolism by increasing the delivery of glucose and insulin to the myocytes. This process is impaired in insulin-resistant individuals. Studies suggest that in diet-induced insulin-resistant rodents, insulin-mediated skeletal muscle microvascular blood flow is impaired post-short-term high fat feeding, and this occurs before the development of myocyte or whole-body insulin resistance. These data suggest that impaired skeletal muscle microvascular blood flow is an early vascular step before the onset of insulin resistance. However, evidence of this is still lacking in humans. In this review, we summarise what is known about short-term high-calorie and/or high-fat feeding in humans. We also explore selected animal studies to identify potential mechanisms. We discuss future directions aimed at better understanding the ‘early’ vascular mechanisms that lead to insulin resistance as this will provide the opportunity for much earlier screening and timing of intervention to assist in preventing type 2 diabetes.

Regulation of DAPK1 by Natural Products: An Important Target in Treatment of Stroke.

Stroke is a sudden neurological disorder that occurs due to impaired blood flow to an area of the brain. Stroke can be caused by the blockage or rupture of a blood vessel in the brain, called ischemic stroke and hemorrhagic stroke, respectively. Stroke is more common in men than women. Atrial fibrillation, hypertension, kidney disease, high cholesterol and lipids, genetic predisposition, inactivity, poor nutrition, diabetes mellitus, family history and smoking are factors that increase the risk of stroke. Restoring blood flow by repositioning blocked arteries using thrombolytic agents or endovascular therapy are the most effective treatments for stroke. However, restoring circulation after thrombolysis can cause fatal edema or intracranial hemorrhage, and worsen brain damage in a process known as ischemia-reperfusion injury. Therefore, there is a pressing need to find and develop more effective treatments for stroke. In the past, the first choice of treatment was based on natural compounds. Natural compounds are able to reduce the symptoms and reduce various diseases including stroke that attract the attention of the pharmaceutical industry. Nowadays, as a result of the numerous studies carried out in the field of herbal medicine, many useful and valuable effects of plants have been identified. The death-associated protein kinase (DAPK) family is one of the vital families of serine/threonine kinases involved in the regulation of some biological functions in human cells. DAPK1 is the most studied kinase within the DAPKs family as it is involved in neuronal and recovery processes. Dysregulation of DAPK1 in the brain is involved in the developing neurological diseases such as stroke. Natural products can function in a variety of ways, including reducing cerebral edema, reducing brain endothelial cell death, and inhibiting TNFα and interleukin-1β (IL-1β) through regulating the DAPK1 signal against stroke. Due to the role of DAPK1 in neurological disorders, the aim of this article was to investigate the role of DAPK1 in stroke and its modulation by natural compounds.

Regulatory mechanisms of retinal ganglion cell death in normal tension glaucoma and potential therapies.

Normal tension glaucoma (NTG) is a multifactorial optic neuropathy characterized by normal intraocular pressure, progressive retinal ganglion cell (RGC) death, and glaucomatous visual field loss. Recent studies have described the mechanisms underlying the pathogenesis of NTG. In addition to controlling intraocular pressure, neuroprotection and reduction of RGC degeneration may be beneficial therapies for NTG. In this review, we summarized the main regulatory mechanisms of RGC death in NTG, including autophagy, glutamate neurotoxicity, oxidative stress, neuroinflammation, immunity, and vasoconstriction. Autophagy can be induced by retinal hypoxia and axonal damage. In this process, ischemia can cause mutations of optineurin and activate the nuclear factor-kappa B pathway. Glutamate neurotoxicity is induced by the over-stimulation of N-methyl-D-aspartate membrane receptors by glutamate, which occurs in RGCs and induces progressive glaucomatous optic neuropathy. Oxidative stress also participates in NTG-related glaucomatous optic neuropathy. It impairs the mitochondrial and DNA function of RGCs through the apoptosis signal-regulating kinase-JUN N-terminal kinase pathway. Moreover, it increases inflammation and the immune response of RGCs. Endothelin 1 causes endothelial dysfunction and impairment of ocular blood flow, promoting vasospasm and glaucomatous optic neuropathy, as a result of NTG. In conclusion, we discussed research progress on potential options for the protection of RGCs, including TANK binding kinase 1 inhibitors regulating autophagy, N-methyl-D-aspartate receptor antagonists inhibiting glutamate toxicity, ASK1 inhibitors regulating mitochondrial function, and antioxidants inhibiting oxidative stress. In NTG, RGC death is regulated by a network of mechanisms, while various potential targets protect RGCs. Collectively, these findings provide insight into the pathogenesis of NTG and potential therapeutic strategies.

SUMOylation in peripheral tissues under low perfusion-related pathological states.

SUMOylation is described as a posttranslational protein modification (PTM) that is involved in the pathophysiological processes underlying several conditions related to ischemia- and reperfusion-induced damage. Increasing evidence suggests that, under low oxygen levels, SUMOylation might be part of an endogenous mechanism, which is triggered by injury to protect cells within the central nervous system. However, the role of ischemia-induced SUMOylation in the periphery is still unclear. This article summarizes the results of recent studies regarding SUMOylation profiles in several diseases characterized by impaired blood flow to the cardiorenal, gastrointestinal, and respiratory systems. Our review shows that although ischemic injury per sedoes not always increase SUMOylation levels, as seen in strokes, it seems that in most cases the positive modulation of protein SUMOylation after peripheral ischemia might be a protective mechanism. This complex relationship warrants further investigation, as the role of SUMOylation during hypoxic conditions differs from organ to organ and is still not fully elucidated.

THE EFFECT OF RENAL DENERVATION ON CEREBRAL BLOOD FLOW IN DIABETIC PATIENTS WITH RESISTANT HYPERTENSION

Objective: Long-term and persistent increase in blood pressure (BP) leads to vascular remodeling, which deteriorates cerebral blood flow. The combination of hypertension (HTN) with diabetes mellitus (DM) accelerates the vascular damage and impairs the cerebral blood flow autoregulation, which may be accompanied by an uncompensated decrease in cerebral perfusion in response to a decrease in BP. Renal denervation (RDN) leads to a rapid and sustained decrease in BP, therefore the aim of this study was to assess of changes in cerebral blood flow in patients with resistant HTN (RHTN) and type 2 DM at 6 month after the intervention. Design and method: Evaluation of cerebral blood flow was performed in 21 patients with RHTN and type 2 DM, who were included in single-arm prospective interventional studies (protocol numbers NCT01499810 and NCT02667912 on ClinicalTrials.gov) (mean age 61.4 ± 7.6 years, mean office (systolic/diastolic) BP (SBP/DBP) 167.1 ± 19.4/85.6 ± 15.9 mmHg, HbA1c 7.1 ± 1.3%, 8 men (32%), 19 pts (91%) had atherosclerosis of internal carotid arteries (ICA) with mean values of stenosis 22.2 ± 9.7%). All patients were undergone to ambulatory 24-hour BP, Doppler high-resolution ultrasound of ICA and middle cerebral arteries (MCA) at baseline and 6 month follow-up. The patients were instructed not to change their medication regimen during the study. Results: There was a significant decrease in mean 24-hour BP (systolic/diastolic) (-12.6/-7.3 mmHg, p < 0.05). At the same time, there was no deterioration in blood flow of ICA and MCA at 6 months after RDN. Conclusions: Our data indicate that the significant decrease in BP after RDN does not lead to deterioration of cerebral blood flow and therefore indicates the safety of this procedure for the brain in patients with RHTN with type 2 DM.

225-LB: Impaired Microvascular Responses May Explain Health Disparities and Impaired Metabolic Flexibility in Hispanic Residents of the Rio Grande Valley

Purpose: Impaired skeletal muscle microvascular blood flow (MBF) is one of the earliest pathophysiologies of type 2 diabetes (T2D) . People with a family history of T2D (FH+ are at greater risk for developing T2D than those with no family history (FH-) . Further, we have shown that normoglycemic Caucasian FH+ individuals have impaired skeletal muscle microvascular responses and metabolic flexibility (MF - ability to switch substrate oxidation upon stimulation) to a mixed meal challenge (MMC) when compared with matched FH- (p<0.01) , suggesting early vascular insulin resistance. Mexican Hispanic individuals have the highest prevalence of T2D in the US and make up ∼95% of Hispanic residents of the Rio Grande Valley (HRGV) where T2D diagnosis rates are ∼3x the national average. Therefore, we sought to determine if impaired MBF responses are present in healthy HRGV. Methods: 15 FH- and 13 FH+ HRGV were recruited to assess MF and MBF responses to a MMC. MF was measured via indirect calorimetry and MBF via contrast-enhanced ultrasound while fasting and again 60-min post MMC. Results: No changes in skeletal MBF were noted in FH- (1.21 ± 0.53 SEM and 0.86 ± 0.23 SEM fasting and postprandial MBF respectively) or FH+ (2.17 ± 0.98 SEM and 1.49 ± 0.66 SEM fasting and postprandial MBF respectively) groups. Abdominal adipose MBF responses increased in FH+ (-2.3 ± 0.71 SEM, p=0.004) , but not in FH- (-0.49 ± 0.39 SEM p=0.39) . FH+ display impaired postprandial metabolic flexibility (MF) responses during 60-min of testing post-MMC. Neither blood glucose responses (99.3 ± 1.3 SEM and 102.27 ± 2.1 SEM fasting and post-prandial respectively, p=0.2) nor body composition differed between FH groups. Conclusions: HRGV display impaired skeletal muscle MBF responses, indicating early vascular insulin resistance. Further, the impairment in MF in FH+ may be partially explained by increased adipose MBF responses, as adipose is less metabolically active than skeletal muscle. Disclosure R. D. Russell: None. Y. Tai: None. S. Marupudi: None.

Automatic Classification of 15 Leads ECG Signal of Myocardial Infarction Using One Dimension Convolutional Neural Network

Impaired blood flow caused by coronary artery occlusion due to thrombus can cause damage to the heart muscle which is often called Myocardial Infarction (MI). To avoid the complexity of MI diseases such as heart failure or arrhythmias that can cause death, it is necessary to diagnose and detect them early. An electrocardiogram (ECG) signal is a diagnostic medium that can be used to detect acute MI. Diagnostics with the help of data science is very useful in detecting MI in ECG signals. The purpose of study is to propose an automatic classification framework for Myocardial Infarction (MI) with 15 lead ECG signals consisting of 12 standard leads and 3 Frank leads. This research contributes to the improvement of classification performance for 10 MI classes and normal classes. The PTB dataset trained with the proposed 1D-CNN architecture was able to produce average accuracy, sensitivity, specificity, precision and F1-score of 99.98%, 99.91%, 99.99%, 99.91, and 99.91%. From the evaluation results, it can be concluded that the proposed 1D-CNN architecture is able to provide excellent performance in detecting MI attacks.

Pathogenesis of sepsis-associated encephalopathy: more than blood-brain barrier dysfunction.

Sepsis-associated encephalopathy is a common neurological complication of sepsis and is responsible for higher mortality and poorer long-term outcomes in septic patients. Sepsis-associated encephalopathy symptoms can range from mild delirium to deep coma, which occurs in up to 70% of patients in intensive care units. The pathological changes in the brain associated with sepsis include cerebral ischaemia, cerebral haemorrhage, abscess and progressive multifocal necrotic leukoencephalopathy. Several mechanisms are involved in the pathogenesis of sepsis-associated encephalopathy, such as blood-brain barrier dysfunction, cerebral blood flow impairment, glial cell activation, leukocyte transmigration, and neurotransmitter disturbances. These events are interrelated and influence each other, thereforethey do not act as independent factors. This review is focused on new evidence showing the pathological process of sepsis-associated encephalopathy.

Towards Immunotherapy-Induced Normalization of the Tumor Microenvironment.

Immunotherapies modulate the function of immune cells to eradicate cancer cells through various mechanisms. These therapies are successful across a spectrum of cancers, but they are curative only in a subset of patients. Indeed, a major obstacle to the success of immunotherapies is the immunosuppressive nature of the tumor microenvironment (TME), comprising the stromal component and immune infiltrate of tumors. Importantly, the TME in most solid cancers is characterized by sparsely perfused blood vessels resulting from so-called pathological angiogenesis. In brief, dysregulated development of new vessels results in leaky tumor blood vessels that inefficiently deliver oxygen and other nutrients. Moreover, the occurrence of dysregulated fibrosis around the lesion, known as pathological desmoplasia, further compresses tumor blood vessels and impairs blood flow. TME normalization is a clinically tested treatment strategy to reverse these tumor blood vessel abnormalities resulting in stimulated antitumor immunity and enhanced immunotherapy efficacy. TME normalization includes vascular normalization to reduce vessel leakiness and reprogramming of cancer-associated fibroblast to decompress vessels. How immunotherapies themselves normalize the TME is poorly understood. In this review, we summarize current concepts and progress in TME normalization. Then, we review observations of immunotherapy-induced TME normalization and discuss the considerations for combining vascular normalizing and immunotherapies. If TME could be more completely normalized, immunotherapies could be more effective in more patients.

Effect of progressive muscle relaxation technique on self-esteem and self- efficacy among coronary artery diseases patients

Background: Coronary artery disease is a common heart condition that involves atherosclerotic plaque formation in the vessel lumen. This leads to impairment in blood flow and thus oxygen delivery to the myocardium. It is a cause of major morbidity and mortality rate. Low self-esteem and efficacy are major problems in coronary artery diseases patients. A progressive muscle relaxation technique is one of the complementary therapies which has positive impacts on self-efficacy and self-esteem, revocable personal resource that influences disease outcomes, rehabilitation adherence, and health-related quality of life. Aim: To evaluate the effect of progressive muscle relaxation technique on self-esteem and self-efficacy among coronary artery disease patients. Design: A quasi-experimental research design was used to achieve the aim of this study. Sample: 100 adult patients with coronary artery disease were selected on purpose as the sample. The study and control groups, each with 50 patients, were equally and randomly assigned to the participants. Setting: This study was conducted at the cardiology unit and outpatient clinics at Ain Shams University Hospital. Tools: the used tools were: Tool (1) a structured interviewing questionnaire, Tool (2) a cardiac self-efficacy scale, Tool (3) a cardiac exercise self-efficacy scale, and Tool (4) Coopersmith Self-Esteem Inventory.

Assessment of the fetoplacental complex and hemostasis system status in perinatal care of pregnant women with fetal congenital malformations

Research objective: to assess the morpho-functional status of the fetoplacental complex and hemostasis system in pregnant women with congenital malformations in the fetus to prevent antenatal fetal death and determine further tactics of management and delivery.Materials and methods. The state of fetoplacental circulation was studied in 120 pregnant women with fetal congenital malformations in the third trimester by Doppler assessment of blood flow in the umbilical artery (UA) and middle cerebral artery (MCA) in the fetus, with resistance index, pulse index and maximum systolic and terminal diastolic velocities ratio. The functional activity of the hemostasis system was assessed by low-frequency piezoelectric thromboelastography. Morphological examination of the placenta was performed. The control group included 25 pregnant women without fetal congenital malformations.Results. In case of Doppler flow disturbances in UA and combination of these disturbances with hypercoagulability, the probability of antenatal fetal death if there were congenital malformations ranged from 2–3 to 7–14 days (r = 0.51 and r = 0.55, respectively). A high risk of antenatal fetal death occurred with blood flow disorders in the UA and MCA (r = 0.70), as well as with blood flow disorders in the UA in combination with hypercoagulation and inhibition of fibrinolysis (r = 0.78). The highest risk of antenatal death occurred in case of impaired blood flow in the MCA with hypercoagulation and inhibition of fibrinolysis (r = +0.99).An urgent delivery within a day is indicated when there are blood flow disorders in the UA or MCA, combined with hypercoagulation and inhibition of fibrinolysis. The respiratory distress syndrome is treated by administering a surfactant at gestational ages up to 34 weeks. Delivery within 2–3 days is indicated in case of impaired blood flow in the UA and hypercoagulation, this allows preventing of respiratory distress syndrome with corticosteroids if the gestational age is less than 34 weeks. Conclusions. In pregnant women with fetal congenital malformations, significant disturbances in blood flow in the UA (increased resistance index and maximum systolic and final diastolic velocities ratio) and decreased pulse index in the MCA were revealed, which indicates intrauterine hypoxia and centralization of blood flow. The functional activity of the hemostasis system was characterized by an increase in the blood coagulation potential in the vascular-platelet, a coagulation unit, which was accompanied by morphological and functional changes in the placenta in response to hypoxia.Implementation of the proposed algorithm for perinatal support of pregnant women with fetal congenital malformations and placental dysfunction helps to optimize pregnancy management and delivery, reduce perinatal morbidity and mortality.

Increased contribution of KCa channels to muscle contraction induced vascular and blood flow responses in sedentary and exercise trained ZFDM rats

In resistance arteries, endothelium-dependent hyperpolarization (EDH)-mediated vasodilatation is depressed in diabetes. We hypothesized that downregulation of KCa channel derived EDH reduces exercise-induced vasodilatation and blood flow redistribution in diabetes. To test this hypothesis, we evaluated vascular function in response to hindlimb muscle contraction, and the contribution of KCa channels in anaesthetised ZFDM, metabolic disease rats with type 2 diabetes. We also tested whether exercise training ameliorated the vascular response. Using in vivo microangiography, the hindlimb vasculature was visualized before and after rhythmic muscle contraction (0.5s tetanus every 3s, 20 times) evoked by sciatic nerve stimulation (40Hz). Femoral blood flow of the contracting hindlimb was simultaneously measured by an ultrasonic flowmeter. The contribution of KCa channels was investigated in the presence and absence of apamin and charybdotoxin. We found that vascular and blood flow responses to muscle contraction were significantly impaired at the level of small artery segments in ZFDM fa/fa rats compared to its lean control fa/+ rats. The contribution of KCa channels was also smaller in fa/fa than in fa/+ rats. Low-intensity exercise training for 12weeks in fa/fa rats demonstrated minor changes in the vascular and blood flow response to muscle contraction. However, the KCa-derived component in the response to muscle contraction was much greater in exercise trained than in sedentary fa/fa rats. These data suggest that exercise training increases the contribution of KCa channels among endothelium-dependent vasodilatory mechanisms to maintain vascular and blood flow responses to muscle contraction in this metabolic disease rat model. KEY POINTS: Microvascular dysfunction in type 2 diabetes impairs blood flow redistribution during exercise and limits the performance of skeletal muscle and may cause early fatigability. Endothelium-dependent hyperpolarization (EDH), which mediates vasodilatation in resistance arteries, is known to be depressed in animals with diabetes. Here, we report that low-intensity exercise training in ZFDM rats increased the KCa channel-derived component in the vasodilator responses to muscle contraction compared to that in sedentary rats, partly as a result of the increase in KCNN3 expression. These results suggest that low-intensity exercise training improves blood flow redistribution in contracting skeletal muscle in metabolic disease with diabetes via upregulation of EDH.

White Matter Alterations in Depressive Disorder.

Depressive disorder is the most prevalent affective disorder today. Depressive disorder has been linked to changes in the white matter. White matter changes in depressive disorder could be a result of impaired cerebral blood flow (CBF) and CBF self-regulation, impaired blood-brain barrier function, inflammatory factors, genes and environmental factors. Additionally, white matter changes in patients with depression are associated with clinical variables such as differential diagnosis, severity, treatment effect, and efficacy assessment. This review discusses the characteristics, possible mechanisms, clinical relevance, and potential treatment of white matter alterations caused by depressive disorders.

Perfusion imaging techniques in lower extremity peripheral arterial disease.

Lower limb peripheral arterial disease (PAD) characterizes the impairment of blood flow to extremities caused by arterial stenoses or occlusions. Evaluation of PAD is based on clinical examination, calculation of ankle-brachial index and imaging studies such as ultrasound, CT, MRI and digital subtraction angiography. These modalities provide significant information about location, extension and severity of macrovasular lesions in lower extremity arterial system. However, they can be also used to evaluate limb perfusion, using appropriate techniques and protocols. This information may be valuable for assessment of the severity of ischemia and detection of hypoperfused areas. Moreover, they can be used for planning of revascularization strategy in patients with severe PAD and evaluation of therapeutic outcome. These techniques may also determine prognosis and amputation risk in patients with PAD. This review gives a basic overview of the perfusion techniques for lower limbs provided by imaging modalities such as ultrasound, CT, MRI, digital subtraction angiography and scintigraphy and their clinical applications for evaluation of PAD and revascularization outcome.

Prenatal alcohol exposure contributes to negative pregnancy outcomes by altering fetal vascular dynamics and the placental transcriptome

BackgroundPrenatal alcohol exposure (PAE) has been shown to alter fetal blood flow in utero and is also associated with placental insufficiency and intrauterine growth restriction (IUGR), suggesting an underlying connection between perturbed circulation and pregnancy outcomes.MethodsTimed‐pregnant C57/BL6NHsd mice, bred in‐house, were exposed by gavage on gestational day 10 (GD10) to ethanol (3 g/kg) or purified water, as a control. Pulse‐wave Doppler ultrasound measurements for umbilical arteries and ascending aorta were obtained post‐gavage (GD12, GD14, GD18) on 2 fetuses/litter. RNA from the non‐decidual (labyrinthine and junctional zone) portion of placentas was isolated and processed for RNA‐seq and subsequent bioinformatic analyses, and the association between transcriptomic changes and fetal phenotypes assessed.ResultsExposure to ethanol in pregnant mice on GD10 attenuates umbilical cord blood flow transiently during gestation, and is associated with indices of IUGR, specifically decreased fetal weight and morphometric indices of cranial growth. Moreover, RNA‐seq of the fetal portion of the placenta demonstrated that this single exposure has lasting transcriptomic changes, including upregulation of Tet3, which is associated with spontaneous abortion. Weighted gene co‐expression network analysis (WGCNA) identified erythrocyte differentiation and homeostasis as important pathways associated with improved umbilical cord blood flow as gestation progresses. WGCNA also identified sensory perception of chemical stimulus/odorant and receptor activity as important pathways associated with cranial growth.ConclusionOur data suggest that PAE perturbs the expression of placental genes relevant for placental hematopoiesis and environmental sensing, resulting in transient impairment of umbilical cord blood flow and, subsequently, IUGR.

Association between circulating CD34-positive cell count and height loss among older men

Height loss starting in middle age is reportedly significantly associated with death due to cardiovascular disease. Impaired blood flow is the main pathology in cardiovascular disease. Hematopoietic stem cells such as CD34-positive cells play an important role in maintaining the microcirculation and preventing impaired blood flow by activating endothelial repair and angiogenesis. Therefore, circulating CD34-positive cell count could be associated with height loss. To clarify the association between circulating CD34-positive cell count and height loss, we conducted a follow-up study of 363 Japanese men aged 60–69 years over 2 years. Height loss was defined as being in the highest quartile of height decrease per year. Independent of known cardiovascular risk factors, circulating CD34-positive cell count was significantly inversely associated with height loss. The fully adjusted odds ratio (OR) and 95% confidence interval (CI) of height loss for circulating CD34-positive cell count (logarithmic values) was 0.49 (0.32, 0.74). This study suggests that a lower capacity to maintain the microcirculation due to a fewer CD34-positive cells might affect height loss.

In Vivo Characterization of a Red Light-Activated Vasodilation: A Photobiomodulation Study.

Nitric oxide dependent vasodilation is an effective mechanism for restoring blood flow to ischemic tissues. Previously, we established an ex vivo murine model whereby red light (670 nm) facilitates vasodilation via an endothelium derived vasoactive species which contains a functional group that can be reduced to nitric oxide. In the present study we investigated this vasodilator in vivo by measuring blood flow with Laser Doppler Perfusion imaging in mice. The vasodilatory nitric oxide precursor was analyzed in plasma and muscle with triiodide-dependent chemiluminescence. First, a 5–10 min irradiation of a 3 cm2 area in the hind limb at 670 nm (50 mW/cm2) produced optimal vasodilation. The nitric oxide precursor in the irradiated quadriceps tissue decreased significantly from 123 ± 18 pmol/g tissue by both intensity and duration of light treatment to an average of 90 ± 17 pmol/g tissue, while stayed steady (137 ± 21 pmol/g tissue) in unexposed control hindlimb. Second, the blood flow remained elevated 30 min after termination of the light exposure. The nitric oxide precursor content significantly increased by 50% by irradiation then depleted in plasma, while remained stable in the hindlimb muscle. Third, to mimic human peripheral artery disease, an ameroid constrictor was inserted on the proximal femoral artery of mice and caused a significant reduction of flow. Repeated light treatment for 14 days achieved steady and significant increase of perfusion in the constricted limb. Our results strongly support 670 nm light can regulate dilation of conduit vessel by releasing a vasoactive nitric oxide precursor species and may offer a simple home-based therapy in the future to individuals with impaired blood flow in the leg.

Enhancement of Endothelial KCa Channel Activity as a Novel Strategy to Oppose Atherosclerosis

Atherosclerosis represents a major risk factor for cardiovascular disease and is associated with endothelial dysfunction (ED), which facilitates fatty plaque formation, impairs blood flow and increases arterial stiffness. A hallmark feature of ED is decreased bioavailability of nitric oxide (NO). We have previously reported that pharmacological activation of endothelial Ca2+‐activated K+ channels (KCa2.3 and KCa3.1) can oppose ED by enhancing endothelium‐dependent vasodilation.We hypothesized that improving endothelial function will mitigate the development and/or severity of atherosclerosis in Apoe knockout (Apoe‐/‐) mice. Administration of the KCa channel activator SKA‐31 was utilized to improve endothelial function in vivo.Experimentally, male, 8‐week old Apoe‐/‐ mice on a regular chow diet were administered one of three daily treatments for 16 weeks: SKA‐31 (10 mg/kg), the KCa3.1 channel blocker senicapoc (40 mg/kg), or drug vehicle alone. Pharmacological inhibition of KCa3.1 channels is reported to reduce atherosclerosis in Apoe‐/‐ mice and was utilized as a benchmark. Drugs were formulated in miglyol and condensed milk, which was readily ingested by the mice. Cardiac function and arterial pulse wave velocity (PWV) were assessed by echocardiography under isoflurane anesthesia. Atherosclerotic lesions in the aorta were visualized by Oil‐Red‐O staining and select tissue histology was carried out using H&E staining. Abdominal aortic contractility and relaxation were measured by wire myography in drug‐treated Apoe‐/‐ mice and age/sex‐matched wild‐type C57/BL6 mice.At the end of drug treatment, left ventricular (LV) ejection fraction, fractional shortening and LV posterior wall thickness were not different in Apoe‐/‐ mice treated with either SKA‐31 or senicapoc compared with vehicle. Measurements of aortic PWV showed no significant differences among the three groups, which indicated that neither drug treatment decreased aortic stiffness. Oil‐Red‐O staining of the thoracic aorta and aortic arch revealed fatty plaque formation in Apoe‐/‐ mice (i.e. 10‐12% of area) compared with WT controls (< 1%), however, neither SKA‐31 nor senicapoc treatments reduced plaque formation vs. vehicle. Phenylephrine (PE)‐evoked contraction of abdominal aortic rings appeared similar in WT and vehicle/drug treated Apoe‐/‐ mice, whereas endothelium‐dependent, acetylcholine‐induced relaxation of PE‐constricted aortic rings was enhanced in aortic rings from mice treated with SKA‐31 and senicapoc vs. vehicle. Although relaxation to the smooth muscle vasodilator sodium nitroprusside was augmented in Apoe‐/‐ mice compared with WT, this response was not altered by drug treatment.While both SKA‐31 and senicapoc improved aortic endothelial function, neither drug decreased plaque formation or aortic stiffness, perhaps due to the later onset of these events in the progression of atherosclerotic pathology. We will investigate this likelihood by feeding Apoe‐/‐ mice a high fat diet to accelerate the development of plaque formation and arterial stiffness to determine the effects of both drug treatments on these later stages of atherosclerosis.