Regenerative Effect of Umbilical Cord-Derived Mesenchymal Stromal Cells in a Rat Model of Established Limb Ischemia.

BACKGROUND: Although regenerative cell therapy is expected to be an alternative treatment for peripheral artery disease (PAD), many regenerative cell therapies have failed to show sufficient efficacy in clinical trials. Most preclinical studies have used acute ischemia models, despite PAD being a chronic disease. In addition, aging and atherosclerosis decrease the quality of a patient's stem cells. Therefore, using a non-acute ischemic preclinical model and stem cells with high regenerative potency are important for the development of effective regenerative therapy. In this study, we assessed the tissue regenerative potential of umbilical cord-derived mesenchymal stromal cells (UCMSCs), which could potentially be an ideal cell source, in a rat model of established ischemia.Methods and Results: The regenerative capacity of UCMSCs was analyzed in terms of angiogenesis and muscle regeneration. In vitro analysis showed that UCMSCs secrete high amounts of cytokines associated with angiogenesis and muscle regeneration. In vivo experiments in a rat non-acute ischemia model showed significant improvement in blood perfusion after intravenous injection of UCMSCs compared with injection of culture medium or saline. Histological analysis revealed UCMSCs injection enhanced angiogenesis, with an increased number of von Willebrand factor-positive microcapillaries, and improved muscle regeneration. CONCLUSIONS: These results suggest that intravenous administration of UCMSCs may be useful for treating patients with PAD.

EARLY DIAGNOSIS OF ASYMPTOMIC CHRONIC ISCHEMIA OF THE LOWER EXTREMITIES.

OBJECTIVE: The aim: To assess the possibility of using a questionnaire and determining the Ankle Brachial Index(ABI) for early diagnosis of asymptomatic ischemia of the lower extremities in patients with various somatic diseases. PATIENTS AND METHODS: Materials and methods: The study involved 294 patients who were receiving inpatient treatment at Communal Non-Profit Enterprise «Uzhgorod Central City Clinical Hospital¼,Communal Non-Profit Enterprise «Transcarpathian Regional Clinical Hospital¼ and Communal Non-Profit Enterprise «Uzhgorod District Clinical Hospital¼. The study was conducted in 36 patients of pulmonological, 52 - neurological, 22 - endocrinological, 28 - rheumatological, 67 - general therapeutic and 89 - surgical patients. In order to detect hidden ischemia, the patients were surveyed according to the Edinburg questionnaire, regional systolic pressure was measured on the tibial arteries of the lower extremities and calculation of the Bone-humerus index (ABI)at rest and after physical exertion (walking), also non-contact skin temperature was measured on the lower leg and thigh. RESULTS: Results: During the study, (ABI) less than 0.9 was found in 108 (36.7%) patients, while in 47 (43.5%) cases, (ABI) decreased only after exercise.In the majority of cases, 98 (90.7%) a decrease in (ABI) was observed on one lower limb. A decrease in the skin temperature of the lower extremities was observed in 141 (48%) patients, 134 (95.1%) of which were diagnosed with diabetes.Symptoms of hidden ischemia, according to the questionnaire, were found in 99 (33.7%) patients.Smoking was observed in 61 (56.5%) patients with symptoms of hidden ischemia. CONCLUSION: Conclusions: As a result of our study, it was found that the specificity of the Edinburg questionnaire in detecting the preclinical stage of ischemia of the lower extremities reaches 88.2%, and the sensitivity - 91.6%. The obtained results indicate the expediency of using the questionnaire in the complex of diagnostics of vascular pathology in patients of various profiles. False-negative results of(ABI)in people with diabetes are associated with mediacalcinosis. In such cases, it is necessary to assess the state of blood flow by measuring the pressure on the back of the foot after physical exertion.

Impaired microcirculatory function, mitochondrial respiration, and oxygen utilization in skeletal muscle of claudicating patients with peripheral artery disease.

Peripheral artery disease (PAD) is an atherosclerotic disease that impairs blood flow and muscle function in the lower limbs. A skeletal muscle myopathy characterized by mitochondrial dysfunction and oxidative damage is present in PAD; however, the underlying mechanisms are not well established. We investigated the impact of chronic ischemia on skeletal muscle microcirculatory function and its association with leg skeletal muscle mitochondrial function and oxygen delivery and utilization capacity in PAD. Gastrocnemius samples and arterioles were harvested from patients with PAD (n = 10) and age-matched controls (Con, n = 11). Endothelium-dependent and independent vasodilation was assessed in response to flow (30 µL·min-1), acetylcholine, and sodium nitroprusside (SNP). Skeletal muscle mitochondrial respiration was quantified by high-resolution respirometry, microvascular oxygen delivery, and utilization capacity (tissue oxygenation index, TOI) were assessed by near-infrared spectroscopy. Vasodilation was attenuated in PAD (P < 0.05) in response to acetylcholine (Con: 71.1 ± 11.1%, PAD: 45.7 ± 18.1%) and flow (Con: 46.6 ± 20.1%, PAD: 29.3 ± 10.5%) but not SNP (P = 0.30). Complex I + II state 3 respiration (P < 0.01) and TOI recovery rate were impaired in PAD (P < 0.05). Both flow and acetylcholine-mediated vasodilation were positively associated with complex I + II state 3 respiration (r = 0.5 and r = 0.5, respectively, P < 0.05). Flow-mediated vasodilation and complex I + II state 3 respiration were positively associated with TOI recovery rate (r = 0.8 and r = 0.7, respectively, P < 0.05). These findings suggest that chronic ischemia attenuates skeletal muscle arteriole endothelial function, which may be a key mediator for mitochondrial and microcirculatory dysfunction in the PAD leg skeletal muscle. Targeting microvascular dysfunction may be an effective strategy to prevent and/or reverse disease progression in PAD.NEW & NOTEWORTHY Ex vivo skeletal muscle arteriole endothelial function is impaired in claudicating patients with PAD, and this is associated with attenuated skeletal muscle mitochondrial respiration. In vivo skeletal muscle oxygen delivery and utilization capacity is compromised in PAD, and this may be due to microcirculatory and mitochondrial dysfunction. These results suggest that targeting skeletal muscle arteriole function may lead to improvements in skeletal muscle mitochondrial respiration and oxygen delivery and utilization capacity in claudicating patients with PAD.

SURGICAL TREATMENT IMMEDIATE RESULTS OF LOWER LIMBS CHRONIC CRITICAL ISCHEMIA IN IMMULTANEOUS DIRECT AND INDIRECT REVASCULARIZATION.

OBJECTIVE: The aim: To assess the immediate results of autovenous femoral-tibial shunting in combination with rotary osteotrepanation of the tibia by studying changes in the transcutaneous ptO2 tension in the tibia and foot tissues depending on the revascularization of the tibial arteries. PATIENTS AND METHODS: Materials and methods: We analyzed the treatment of 69 patients with obliterating atherosclerosis of the vessels of the lower extremities. According to the degree of ischemia of the lower extremities, the patients were distributed as follows: III A degree of ischemia - 20 (29%), III B - 28 (40.6%), IV - 21 (30.4%) patients. All patients had atherosclerotic lesions of the popliteal-tibial segment of the great arteries with preserved central blood flow in the aorto-iliac segment. RESULTS: Results: Occlusion of the anterior tibial artery was recorded significantly more often than the peroneal artery (72% and 42%, respectively, p = 0.05), but with the same frequency compared to the posterior tibial artery (68%, p = 0.61). The lesion of two or three arteries of the lower leg was recorded more often than occlusion of one (n = 51; 73.9% and n = 18; 26.1%). Occlusive-stenotic lesion of the popliteal artery was observed in 54 (78.2%) patients. The highest incidence of lesions of the tibial arteries was observed in the basin of the anterior tibial artery in 28 (40.6%) patients. Combined lesions of the anterior tibial artery and posterior tibial artery were diagnosed in 19 (27.5%) patients. Limited lesions of the posterior tibial artery were found in 15 (21.7%) patients. The combination of lesions of the posterior tibial artery and peroneal artery was diagnosed in 7 (10.2%) patients. CONCLUSION: Conclusions: 1. The patency of the femoral-tibial autovenous shunt during the year was 71%. High limb amputation was performed in 29% of patients. 2. According to CT data, the localization of trophic changes on the foot during critical ischemia of the lower extremities corresponds to the affected segment of the arterial angiosome, which supplies the corresponding area with blood. 3. After femoral-tibial autovenous bypass grafting, the highest levels of transcutaneous oxygen tension were observed in the basin of the posterior tibial artery and peroneal artery, and the lowest indicators of transcutaneous oxygen tension were observed in the basin of the anterior tibial artery. 4. During femoral-tibial autovenous shunting operations in combination with rotary osteotrepanation, the transcutaneous oxygen tension indices increased threefold in the angiosomal basin of the posterior tibial artery and peroneal artery, and twofold in the angiosomes of the dorsum of the foot and sole.

Coronary Sinus Reducer for the Treatment of Chronic Refractory Angina: Will This Challenge the Treatment of Coronary Chronic Total Occlusions?

PURPOSE OF REVIEW: The prevalence of angina despite optimal medical therapy is high among patients with coronary chronic total occlusions. Despite advancements in techniques and operator's experience, percutaneous revascularization of coronary chronic total occlusions is still associated with a not negligible risk of failures and complications. The Coronary Sinus Reducer, a new device developed to improve angina, has shown promising results in terms of efficacy and safety in patients with refractory symptoms. The aim of this review is to summarize the evidence so far available and to guide clinicians in the selection of patients with chronic total occlusions that could benefit more from Coronary Sinus Reducer implantation. RECENT FINDINGS: A recently published study suggests a clear value of this device in patients with chronic total occlusions. This is likely to be related to the presence of a well-developed collateral circulation. A careful evaluation of risks and benefits of both myocardial revascularization and Coronary Sinus Reducer implantation should be done in all the cases in order to better define the optimal strategy for the patient. The Coronary Sinus Reducer implantation has a rationale in patients with chronic total occlusion as an alternative or additional therapy to myocardial revascularization.

[Basic principles and approaches to medical rehabilitation of patients with atherosclerosis obliterans of lower limb arteries]. / Osnovnye printsipy i podkhody k meditsinskoi reabilitatsii bol'nykh s obliteriruyushchim aterosklerozom arterii nizhnikh konechnostei.

The review presents current data on the management of patients with atherosclerosis obliterans of the lower extremities. The main approaches to medical rehabilitation of patients with diseases of the arteries of the lower extremities are considered, tools for determining the rehabilitation potential depending on the stage of lower limb ischemia are proposed. The programs of physical and psychological rehabilitation, as well as the methods of physical and balneotherapy in accordance with the stages of medical rehabilitation, are determined. Modern rehabilitation methods are presented.

Phosphodiesterase type 5 inhibitor attenuates chronic ischemia-induced prostatic hyperplasia in a rat model.

BACKGROUND: Many elderly men suffer from benign prostatic hyperplasia (BPH). Recently, chronic ischemia in the prostate has been suggested to be related to BPH. Thus, the impact of chronic ischemia on the development of prostatic hyperplasia and the efficacy of phosphodiesterase type 5 (PDE5) inhibitor for hyperplasia were evaluated in a rat model with chronic ischemia induced by local atherosclerosis. METHODS: Eighteen male Sprague-Dawley rats were divided into three groups: sham operation, regular diet, placebo (SRP); arterial endothelial injury, high cholesterol diet, placebo (AHP); or arterial endothelial injury, high cholesterol diet, and tadalafil as a PDE5 inhibitor (AHT). The endothelial injury in the common iliac arteries was performed using a 2-Fr Fogarty arterial embolectomy catheter through an incision in the femoral artery into the common iliac artery. Diet and oral drugs were administrated for 8 weeks after surgery. At 8 weeks, blood flow to the ventral prostate (VP) was measured using laser speckle blood flow analysis, and the VP was histologically evaluated. RESULTS: In the AHP group, prostatic blood flow was reduced, and mean VP weight and the interstitial area were significantly enlarged compared with the SRP group. In the AHT group, tadalafil administration obviously ameliorated the reduction of prostatic blood flow relative to the AHP group. Importantly, mean VP weight and the morphological changes in the AHT group were significantly smaller than those in the AHP group. CONCLUSIONS: Enlargement of the VP resulted from chronic ischemia induced by local arteriosclerosis. Also, administration of tadalafil attenuated VP enlargement. Chronic ischemia in the prostate might thus contribute to the development of BPH, and PDE5 inhibitors might provide an innovative approach to preventing BPH.

Localized atrophy of the pontine base as a sequela of prolonged ischemia: Report of an autopsy case.

An 80-year-old man with a history of diabetes mellitus and hypertension died of a progressive neurological disorder characterized by truncal ataxia, extraocular movement disturbance, and muscular rigidity. Neuroradiological examination showed progressive atrophy restricted to the pontine base. Autopsy revealed localized atrophy of the pontine base, in which both neurons and nerve fibers were lost, especially in the central region. Medium-sized and small arteries in the parenchyma of the pontine base showed marked fibro-hyalinous thickening of the walls with luminal stenosis, but no distinct tissue defect as seen in lacunar infarct was observed. Perivascular lymphocytic infiltration was mostly absent, and reactive astrocytic proliferation was weak. The pontine tegmentum, midbrain, and medulla oblongata were well preserved. Localized atrophy of the pontine base is a rare pathological condition, and its pathogenesis in the present case can be best explained by a prolonged ischemic state (hypoperfusion) due to marked sclerotic changes of perforating arteries. It is unique that the lesions were restricted to the pontine base and the formation of lacunas was not observed. Localized metabolic derangement resembling that seen in central pontine myelinolysis might have also contributed to the pathogenesis of this peculiar localized atrophy.

Assessment of endothelial function in patients with initial manifestations of chronic cerebral ischemia

Introduction: Over the last decade, the number of patients with cerebrovascular diseases in Ukraine has grown by 1.5 times. This negative trend is based on the significant increase of vascular risk factors - arterial hypertension, dyslipidemia, sedentary lifestyle, excessive weight/obesity, diabetes mellitus, tobacco smoking, etc. - prevalence among the population of the country, their early development and combination of several vascular risk factors, which makes prevention of cerebrovascular diseases at their early stages a priority. The aim: Study of endothelial vasomotor function in patients with initial symptoms of chronic cerebral ischemia. Material and methods: The study included 260 patients of the main group (mean age 50.6±70.9) with initial manifestations of CCI and 30 persons of similar age of the control group. All the patients underwent a clinical neurological examination, MRI of the brain, ultrasonography with the establishment of flow-mediated endotelium-dependent dilatation (FMD) index based on the results of brachial artery compression test, as well as laboratory tests of endothelin-1 and nitrite levels. The patients were subdivided into 3 groups based on their MRI of the brain data: without structural changes of the brain (group 1), with initial vascular structural changes (group 2), with initial structural changes and mild cerebral atrophy (group 3). Results: Reliable differences of FMD index were established in the groups with different degrees of structural brain damage, and in comparison with the control group (р<0.001). Considerable downward trend of FMD index with increase of the number of existing vascular risk factors (VRF) was identified (p<0.05). An associative link with the presence of arterial hypertension (AH), its degree and FMD index (p<0.05) was established. It was shown that a thickened intima-media complex (ІМC) of common carotid arteries >0.9 mm had a significantly lower predetermination to FMD (р=0,001). Statistically significant lower FMD indices were registered in persons with endothelial vasomotor function disorder according to the biochemical markers: with endothelin level increase and nitrite level decrease (р<0.001). Conclusions: An associative link with the presence of endothelial dysfunction according to FMD index were established with different degrees of structural brain damage, with the presence of AH, with ІМC of common carotid arteries >0.9 mm, with endothelial vasomotor function disorder according to the biochemical markers: with endothelin level increase and nitrite level decrease.

[Treatment of necrotizing infection in patients with chronic arterial insufficiency of the lower extremities]. / Rezul'taty lecheniia nekrotiziruiushchei infektsii u patsientov s khronicheskoi arterial'noi nedostatochnost'iu nizhnikh konechnostei.

OBJECTIVE: To analyze the effectiveness of complex therapy of necrotizing infection using the original method of stimulation of angiogenesis in patients with chronic arterial insufficiency of the lower extremities. MATERIAL AND METHODS: In 53 patients, operations were performed using the proposed technologies for stimulation of angiogenesis. A control group consisting of 56 patients was formed to compare the results of treatment. They had standard vascular therapy for the correction of ischemia. Morphological studies of the muscles of the lower extremities included assessment of capillary bed density and spatial orientation of the capillaries before and after treatment. Computed angiography of the lower extremities followed by calculation of perfusion index was performed to assess changes in the microvasculature. Clinical evaluation of the results was carried out using R. Rutherford scale. RESULTS: Revascularization resulted significant augmentation of capillary bed density and the number of functioning capillaries in muscular tissue. This was accompanied by increased perfusion index and TcPO2 values. The effect of treatment is observed in 12-14 days after surgery and persists for a long time. The best outcomes are found in patients with ischemia grade IIb-III. Incidence of lower limb amputations was more than 2 times lower in the main group compared with the control group. CONCLUSION: Combined stimulation of angiogenesis including mechanical tunneling of the muscles of the affected limb and administration of platelet rich plasma is effective procedure. This method does not require complex equipment and may be used in the treatment of patients with complications of chronic lower limb ischemia and contraindicated direct arterial reconstruction.

[Endovascular surgery for critical ischemia of lower extremities with suppurative-necrotic lesion of the feet]. / Rentgenoéndovaskuliarnaia khirurgiia pri kriticheskoi ishemii nizhnikh konechnostei s gnoino-nekroticheskim porazheniem stop.

AIM: To improve treatment of patients with grade IV chronic ischemia of lower extremities via endovascular angioplasty combined with surgical methods for suppurative-necrotic lesions of the feet. MATERIAL AND METHODS: 51 patients with grade IV chronic ischemia of lower extremities underwent endovascular interventions (balloon angioplasty, stenting). A total of 23 stents were deployed in 16 patients including 12 stents in superficial and common femoral arteries, 5 in popliteal artery, 6 in iliac artery. There were no stents in crural arteries. The most perspective artery for wound healing was preferred in case of revascularization below popliteal segment. Necrectomy was performed along with angioplasty in patients with suppurative-necrotic lesion of the feet followed by delayed reconstructive operations if it was necessary. RESULTS: Endovascular surgery for grade IV chronic ischemia of lower extremities was associated with good immediate results in most cases due to revascularization and organ-sparing interventions for suppurative lesions of the feet. Current endovascular methods allow to perform successful re-operations to restore blood flow in previously repaired arteries and implanted stents with restenosis or thrombosis.

Reduced mitochondrial respiration in the ischemic as well as in the remote nonischemic region in postmyocardial infarction remodeling.

Scarring and remodeling of the left ventricle (LV) after myocardial infarction (MI) results in ischemic cardiomyopathy with reduced contractile function. Regional differences related to persisting ischemia may exist. We investigated the hypothesis that mitochondrial function and structure is altered in the myocardium adjacent to MI with reduced perfusion (MIadjacent) and less so in the remote, nonischemic myocardium (MIremote). We used a pig model of chronic coronary stenosis and MI (n = 13). Functional and perfusion MR imaging 6 wk after intervention showed reduced ejection fraction and increased global wall stress compared with sham-operated animals (Sham; n = 14). Regional strain in MIadjacent was reduced with reduced contractile reserve; in MIremote strain was also reduced but responsive to dobutamine and perfusion was normal compared with Sham. Capillary density was unchanged. Cardiac myocytes isolated from both regions had reduced basal and maximal oxygen consumption rate, as well as through complex I and II, but complex IV activity was unchanged. Reduced respiration was not associated with detectable reduction of mitochondrial density. There was no significant change in AMPK or glucose transporter expression levels, but glycogen content was significantly increased in both MIadjacent and MIremote Glycogen accumulation was predominantly perinuclear; mitochondria in this area were smaller but only in MIadjacent where also subsarcolemmal mitochondria were smaller. In conclusion, after MI reduction of mitochondrial respiration and glycogen accumulation occur in all LV regions suggesting that reduced perfusion does not lead to additional specific changes and that increased hemodynamic load is the major driver for changes in mitochondrial function.

Stress-induced ST elevation with or without concomitant ST depression is predictive of presence, location and amount of myocardial ischemia assessed by myocardial perfusion SPECT, whereas isolated stress-induced ST depression is not.

BACKGROUND: Evaluation of stress-induced ST deviations constitutes a central part when interpreting the findings from an exercise test. The aim of this analysis was to assess the pathophysiologic correlate of stress-induced ST elevation and ST depression with regard to presence, amount and location of myocardial ischemia as assessed by myocardial perfusion SPECT (MPS) in patients with suspected coronary artery disease. METHODS AND RESULTS: 226 patients who had undergone bicycle stress test in conjunction with MPS were included. Of these, 198 were consecutive patients while 28 patients were included on the basis of having stress-induced ST elevation mentioned in their clinical report. The amount and location of ST changes were related to MPS findings. Summed stress scores (SSS) from MPS images were used to measure the amount of stress-induced ischemia. The positive predictive values for detecting stress-induced ischemia were 28% for the consecutive patients with ST depression and 75% for patients with ST elevation. The maximum and sum of stress-induced ST elevations correlated with SSS (r(2)=0.58, p<0.001 and r(2)=0.73, p<0.001), whereas the maximum and sum of significant ST depressions did not (r(2)=0.022, p=0.08 and r(2)=0.024, p=0.10). The location of ST elevation corresponded to the location of ischemia by MPS (kappa=1.0), whereas the location of ST depression did not (kappa=0.20). CONCLUSIONS: Stress-induced ST elevation, with or without concomitant ST depression, is predictive of the presence, amount and location of myocardial ischemia assessed by MPS, whereas stress-induced ST depression without concomitant ST elevation is not.

Reversibility of White Matter Hyperintensity by Revascularization Surgery in Moyamoya Disease.

BACKGROUND: White matter lesions (WMLs) indicate progressive cerebral small vessel disease and are frequently observed in aging people and stroke patients. The purpose of this study was to evaluate WMLs and the influence of revascularization surgery for WMLs in patients with moyamoya disease. METHODS: A total of 42 hemispheres in 21 patients with moyamoya disease were included in this analysis. WMLs were detected on fluid-attenuated inversion recovery (FLAIR) imaging in 24 hemispheres. The distribution pattern of WMLs was categorized. WMLs were measured by manually creating a region of interest, and the total WML volume in the hemisphere was estimated and compared with the control group. Clinical features of patients with WMLs and postoperative changes were analyzed. RESULTS: The total WML volume in moyamoya disease was significantly higher than that of controls (P = .014). WMLs were observed in the internal watershed zone, especially in the watershed zone between the anterior cerebral artery and the middle cerebral artery. Patients with WMLs had significantly higher magnetic resonance angiography scores compared with controls (P = .015). A given patient's total WML volume per hemisphere was significantly decreased after surgery (P = .001). CONCLUSIONS: WMLs on FLAIR imaging increase in patients with moyamoya disease and are reversible by revascularization surgery. Improvement of cerebral blood flow is partly related to the decrease in WMLs. The present results provide insight into the potential role of revascularization surgery.

Stress cardiac magnetic resonance imaging provides effective cardiac risk reclassification in patients with known or suspected stable coronary artery disease.

BACKGROUND: A recent large-scale clinical trial found that an initial invasive strategy does not improve cardiac outcomes beyond optimized medical therapy in patients with stable coronary artery disease. Novel methods to stratify at-risk patients may refine therapeutic decisions to improve outcomes. METHODS AND RESULTS: In a cohort of 815 consecutive patients referred for evaluation of myocardial ischemia, we determined the net reclassification improvement of the risk of cardiac death or nonfatal myocardial infarction (major adverse cardiac events) incremental to clinical risk models, using guideline-based low (<1%), moderate (1% to 3%), and high (>3%) annual risk categories. In the whole cohort, inducible ischemia demonstrated a strong association with major adverse cardiac events (hazard ratio=14.66; P<0.0001) with low negative event rates of major adverse cardiac events and cardiac death (0.6% and 0.4%, respectively). This prognostic robustness was maintained in patients with previous coronary artery disease (hazard ratio=8.17; P<0.0001; 1.3% and 0.6%, respectively). Adding inducible ischemia to the multivariable clinical risk model (adjusted for age and previous coronary artery disease) improved discrimination of major adverse cardiac events (C statistic, 0.81-0.86; P=0.04; adjusted hazard ratio=7.37; P<0.0001) and reclassified 91.5% of patients at moderate pretest risk (65.7% to low risk; 25.8% to high risk) with corresponding changes in the observed event rates (0.3%/y and 4.9%/y for low and high risk posttest, respectively). Categorical net reclassification index was 0.229 (95% confidence interval, 0.063-0.391). Continuous net reclassification improvement was 1.11 (95% confidence interval, 0.81-1.39). CONCLUSIONS: Stress cardiac magnetic resonance imaging effectively reclassifies patient risk beyond standard clinical variables, specifically in patients at moderate to high pretest clinical risk and in patients with previous coronary artery disease. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01821924.

Establishment of a novel mouse model of renal artery coiling-based chronic hypoperfusion-related kidney injury.

Renal artery stenosis-induced chronic renal ischemia is an important cause of renal dysfunction, especially in older adults, and its incidence is currently increasing. To elucidate the mechanisms underlying chronic renal hypoperfusion-induced kidney damage, we developed a novel mouse model of renal artery coiling-based chronic hypoperfusion-related kidney injury. This model exhibits decreased renal blood flow and function, atrophy, and parenchymal injury in the coiled kidney, along with compensatory hypertrophy in the non-coiled kidney, without chronic hypertension. The availability of this mouse model, which can develop renal ischemia without genetic modification, will enhance kidney disease research by serving as a new tool to investigate the effects of acquired factors (e.g., obesity and aging) and genetic factors on renal artery stenosis-related renal parenchymal damage.

Managing chronic coronary syndrome: how do we achieve optimal patient outcomes?

INTRODUCTION: Chronic coronary syndrome (CCS) remains the leading cause of death worldwide with high admission/re-admission rates. Medical databases were searched on CCS & its management. AREAS COVERED: This review discusses phenotypes per stress-echocardiography, noninvasive/invasive testing (coronary computed-tomography angiography-CCTA; coronary artery calcium - CAC score; echocardiography assessing wall-motion, LV function, valvular disease; biomarkers), multidisciplinary management (risk factors/anti-inflammatory/anti-ischemic/antithrombotic therapies and revascularization), newer treatments (colchicine/ivabradine/ranolazine/melatonin), cardiac rehabilitation/exercise improving physical activity and quality-of-life, use of the implantable-defibrillator, and treatment with extracorporeal shockwave-revascularization for refractory symptoms. EXPERT OPINION: CCS is age-dependent, leading cause of death worldwide with high hospitalization rates. Stress-echocardiography defines phenotypes and guides prophylaxis and management. CAC is a surrogate for atherosclerosis burden, best for patients of intermediate/borderline risk. Higher CAC-scores indicate more severe coronary abnormalities. CCTA is preferred for noninvasive detection of CAC and atherosclerosis burden, determining stenosis' functional significance, and guiding management. Combining CAC score with CCTA improves diagnostic yield and assists prognosis. Echocardiography assesses LV wall-motion and function and valvular disease. Biomarkers guide diagnosis/prognosis. CCS management is multidisciplinary: risk-factor management, anti-inflammatory/anti-ischemic/antithrombotic therapies, and revascularization. Newer therapies comprise colchicine, ivabradine, ranolazine, melatonin, glucagon-like peptide-1-receptor antagonists. Cardiac rehabilitation/exercise improves physical activity and quality-of-life. An ICD protects from sudden death. Extracorporeal shockwave-revascularization treats refractory symptoms.

Nutritional habits in patients with peripheral arterial disease: Adherence to the mediterranean diet. / Hábitos nutricionales en los pacientes con enfermedad arterial periférica: adherencia a la dieta mediterránea.

INTRODUCTION: Adherence to the Mediterranean diet (Dietmed) exerts protective effects on cardiovascular disease (CVD). In the Lower Extremity Peripheral Arterial Disease (PAD) there are fewer studies that analyze these data. OBJECTIVE: To determine adherence to Dietmed and dietary habits in patients with PAD, according to a history of CVD (coronary and/or cerebral ischaemic pathology) and according to the ankle-brachial index (ABI ≥ or <0,5). MATERIAL AND METHODS: Cross-sectional analytical study carried out in a tertiary hospital. The sample was collected consecutively. Sociodemographic and clinical history, ankle-brachial index (ABI) and a 14-point Dietmed adherence dietary questionnaire were included. The analysis of categorical variables was carried out using the Pearson's Chi-Square test, the T-Student's statistic test for independent samples was used for parametric variables and the U. Mann-Whitney test for non-parametric variables. RESULTS: Of the 97 patients, 87,6% had low adherence to Dietmed, with no differences according to the severity of PAD. However, when we analysed the data according to whether or not they had a history of CVD, we observed a high adherence to some items included in Dietmed, specifically, in the CVD group, the consumption of lean meat (95,5% vs 64%; P=.004). In addition, we observed a significant difference in the consumption in the group without a history of CVD (32% vs 9,1%; P=.033). CONCLUSION: In our population, patients with PAD, regardless of the stage of the disease and whether they had associated coronary or cerebral ischaemic pathology, had low adherence to Dietmed. Therefore, it is important to implement nutritional education programmes in patients with PAD in all stages, as well as in those patients who have already suffered a vascular event, so that they maintain adherence to healthy dietary habits in the long term.

Dalfampridine improves sensorimotor function in rats with chronic deficits after middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: Stroke survivors often have permanent deficits that are only partially addressed by physical therapy. This study evaluated the effects of dalfampridine, a potassium channel blocker, on persistent sensorimotor deficits in rats with treatment initiated 4 or 8 weeks after stroke. METHODS: Rats underwent permanent middle cerebral artery occlusion. Sensorimotor function was measured using limb-placing and body-swing symmetry tests, which normally show a partial recovery from initial deficits that plateaus ≈4 weeks after permanent middle cerebral artery occlusion. Dalfampridine was administered starting at 4 or 8 weeks after permanent middle cerebral artery occlusion in 2 blinded, vehicle-controlled studies. Plasma samples were collected and brain tissue was processed for histologic assessment. RESULTS: Dalfampridine treatment (0.5-2.0 mg/kg) improved forelimb- and hindlimb-placing responses and body-swing symmetry in a reversible and dose-dependent manner. Plasma dalfampridine concentrations correlated with dose. Brain infarct volumes showed no differences between treatment groups. CONCLUSIONS: Dalfampridine improves sensorimotor function in the rat permanent middle cerebral artery occlusion model. Dalfampridine extended-release tablets (prolonged release fampridine outside the United States) are used to improve walking in patients with multiple sclerosis, and these preclinical data provide a strong rationale for examining the potential of dalfampridine to treat chronic stable deficits in stroke patients. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01605825.

Optogenetic Stimulation of mPFC Alleviates White Matter Injury-Related Cognitive Decline after Chronic Ischemia through Adaptive Myelination.

White matter injury (WMI), which reflects myelin loss, contributes to cognitive decline or dementia caused by cerebral vascular diseases. However, because pharmacological agents specifically for WMI are lacking, novel therapeutic strategies need to be explored. It is recently found that adaptive myelination is required for homeostatic control of brain functions. In this study, adaptive myelination-related strategies are applied to explore the treatment for ischemic WMI-related cognitive dysfunction. Here, bilateral carotid artery stenosis (BCAS) is used to model ischemic WMI-related cognitive impairment and uncover that optogenetic and chemogenetic activation of glutamatergic neurons in the medial prefrontal cortex (mPFC) promote the differentiation of oligodendrocyte precursor cells (OPCs) in the corpus callosum, leading to improvements in myelin repair and working memory. Mechanistically, these neuromodulatory techniques exert a therapeutic effect by inducing the secretion of Wnt2 from activated neuronal axons, which acts on oligodendrocyte precursor cells and drives oligodendrogenesis and myelination. Thus, this study suggests that neuromodulation is a promising strategy for directing myelin repair and cognitive recovery through adaptive myelination in the context of ischemic WMI.