Ischemic Dysfunction Research Articles

Novel Class of Central Renin Angiotensin Aldosterone System Inhibitor: Firibastat

Abstract Hypertension is one of the most important risk factors for the development of ischemic heart diseases, stroke, disability, vascular dementia, heart failure, renal dysfunction, retinopathy, and premature death. Despite the use of two or more blood pressure lowering medications, a considerable proportion of patients show poor control. Current antihypertensive medications show the limitation of use and effect in obese population, certain races like black population and also in renal impairment. Thus, there is an impending need to develop novel classes of antihypertensive agents acting on new targets with diversified mechanisms of action to more effectively manage raised blood pressure. With the introduction of the recent concept of overactive brain renin angiotensin system in cardiovascular disorders, attempts have been made to identify a molecule with the potential of inhibiting aminopeptidases involved in the formation of Angiotensin III. A novel aminopeptidase A inhibitor, also a prodrug Firibastat is currently undergoing development in Phase III clinical trials for hypertension as well as chronic heart failure. We hereby, provide an updated summary of evidence generated so far with Firibastat and also a glimpse into the therapeutic potential of this novel candidate extending beyond the spectrum of essential hypertension

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism rather than homocysteine increase the risk of ischemic stroke-associated executive dysfunction

Background: An executive dysfunction is a form of cognitive impairment commonly found in ischemic stroke patients with a significant impact on the patients' quality of life. The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and homocysteine ​​are considered important risk factors for stroke and various forms of cognitive dysfunction. This study aimed to investigate the association between the MTHFR C677T polymorphism and serum homocysteine levels and the risk of ischemic stroke-associated executive dysfunction. Method: 87 ischemic stroke patients within the first three months of stroke onset in West Nusa Tenggara General Hospital, Siti Hajar Hospital, and Mataram General Hospital were recruited. Serum homocysteine levels were assessed using ELISA. The MTHFR C677T polymorphism was analyzed using the PCR-RFLP procedure. The executive function of the patients was evaluated using Trail Making Test Part-B, verbal fluency, and backward digit span tests. Results: The mean age of the subjects was 54.1 years. CT scan data revealed that 78.2% of subjects had a small infarct size. The MTHFR C677T polymorphism frequency was 25.3%, consisting of 2.3% homozygous and 23.0% heterozygous mutants. Multivariate logistic regression analysis showed that patients with MTHFR C677T polymorphism were more likely to have executive dysfunction than those with the wild-type genotype of the MTHFR gene (OR 4.53, 95% CI 1.06–19.27, p = 0.041). However, patients with hyperhomocysteinemia (≥13 μmol/l) were not associated with an increased risk of executive dysfunction. Conclusion: The MTHFR C677T polymorphism was the risk factor for ischemic stroke executive dysfunction.

The Influence of Treadmill Training on the Bioelectrical Activity of the Lower Limb Muscles in Patients with Intermittent Claudication.

Aim: Intermittent claudication is the most common symptomatic manifestation of peripheral arterial disease (PAD), presenting as ischemic leg muscle pain and gait dysfunction. The aim of this study was to evaluate the changes in bioelectrical activity of the lower limb muscles activity in claudicating patients over a 12-week period of supervised treadmill training and to verify the hypothesis as to which muscles of lower limbs are activated by training treatment—the proximal, as compensatory mechanism, or the distal, which are the most ischemic. Methods: The study comprised 45 patients aged 60–70 years (height 168.8 ± 6.8 cm, weight 78.9 ± 9.2 kg) with PAD and unilateral intermittent claudication (Fontaine stage IIa/IIb), who participated in a 12-week supervised treadmill training program. Surface electromyography (sEMG) of the gastrocnemius lateralis (GaL), gastrocnemius medialis (GaM), tibialis anterior (TA), biceps femoris (BF), rectus femoris (RF) and gluteus medius (GM) muscles in the claudicated leg were continuously measured during the treadmill test. The average mean amplitude and mean amplitude range of the sEMG signal were analyzed. Results: During the treadmill test, after 12 weeks of training, the average mean amplitude of the GM (105 ± 43 vs. 74 ± 38%, p = 0.000008, ES = 0.76), BF (41 ± 22 vs. 33 ± 12%, p = 0.006, ES = 0.45) and GaM (134 ± 50 vs. 114 ± 30%, p = 0.007, ES = 0.48) muscles was significantly lower compared with baseline. The mean amplitude range was significantly decreased after 12 weeks of training in the GM (229 ± 64 vs. 181 ± 62%, p = 0.008, ES = 0.77) and BF (110 ± 69 vs. 84 ± 31%, p = 0.0002, ES = 0.48) muscles. After 12 weeks of training, the mean amplitude range of the TA muscle was significantly higher compared with baseline (104 ± 46 vs. 131 ± 53%, p = 0.001, ES = 0.54), but without significant changes in the average mean amplitude value. The most favorable changes, suggesting the lowest muscle fatigue and the highest walking capacity, were found in patients with the longest walking time. Conclusions: The obtained results may suggest that after 12 weeks of treadmill training, beneficial changes occurred in both the proximal and distal muscles. Therefore, greater foot plantar flexion and stronger push-off as well as greater hip extension may be considered the main mechanisms of observed gait pattern improvement. It may also be suggested that the therapy of gait alterations in patients with PAD should be focused not only on calf muscle pump improvement, but also on proximal hip extensor strengthening.

Strain-based characterization of electromechanical tissue properties using patient-specific simulation of dyssynchronous hearts: a pilot study

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation (ERA-CVD JTC2018 grant 2018T094; Dr. Dekker Program grant 2015T082 to J.L.) and the Netherlands Organisation for Scientific Research (NWO- ZonMw, VIDI grant 016.176.340 to J.L.) Background/Introduction Interpretation of regional strain patterns in patients with failing hearts is often challenging due to presence of different underlying tissue abnormalities, including electrical conduction delay and myocardial infarction (MI). Purpose To test whether an automatic strain-based computer simulation algorithm can differentiate between electrical and ischemic contractile dysfunction in patients with mechanical dyssynchrony. Methods Three heart failure patients with reduced left ventricular ejection fraction (33 ± 3%) and wide QRS (160 ± 7ms, LBBB morphology) were retrospectively included, two with and one without MI. Longitudinal strain patterns obtained in 18 myocardial segments using speckle tracking echocardiography (STE) and left ventricular (LV) volume measurements were used as an input to the patient-specific simulation algorithm, which automatically optimizes a set of global and regional myocardial tissue parameters such that the regional strain patterns and global volumes simulated by the CircAdapt model of the human heart and circulation were similar to the strains and volumes measured in the patients. As output, the patient-specific simulations revealed onset time of mechanical activation (relative to first activated segment) and relative severity of contractile dysfunction in all 18 segments. We compared predicted mechanical activation delays and segmental contractile dysfunction values with independent measurements of QRS width and transmurality of late gadolinium enhancement (LGE), respectively. Results The model was able to reproduce the dyssynchronous regional strain patterns as measured in the patients (Figure 1: representative example). In all patients, significant septal—to-lateral wall mechanical activation delays (33-55ms) were predicted (Figure 2: blue bullseye plot of same patient used for figure 1), matching the presence of electrical activation delays on the patient’s ECGs (i.e. wide QRS and LBBB morphology). Furthermore, all simulations predicted a global loss of contractile dysfunction, matching the low ejection fractions reported in those patients. The simulations of the two patients with MI predicted more severe contractile dysfunction (>60%) in the regions with transmural LGE (Figure 2: red bullseye plot versus gold standard LGE-MRI image of same patient used for figure 1). Conclusion This pilot study demonstrated the ability of an automatic patient-specific simulation algorithm to differentiate between electrical and ischemic myocardial disease substrates in heart failure patients with electrical conduction abnormalities with and without MI. Future studies will investigate whether this computer algorithm can improve diagnosis of patients with mechanical dyssynchrony. Abstract Figure 1 Abstract Figure 2

COVID-19 Geçiren Pulmoner Sekeli Olmayan Hastalarda Kalıcı Dispne Nedeni Kardiyak Tutulumdur: Retrospektif Çalışma

Objective: Several forms of cardiovascular involvement have been described in acute coronavirus disease-2019 (COVID-19) infection and also it has been shown that acute infection is responsible for cardiac symptoms. However, the data on cardiac involvement and associated symptoms in chronic phase remains unclear. Recent evidence have shown that the reason for persistent dyspnea can be persistent cardiac dysfunction in post COVID-19 infection. The aim of our study was to investigate the relationship between persistent dyspnea and cardiac involvement in post COVID19 patients without pulmonary sequelae. Material and Methods: In our study, we recruited 30 post COVID-19 patients with dyspnea between January 2021 and July 2021. In all patients, the absence of pulmonary sequelae was detected with PFT and chest- CT. 2D-TTE, 2DSTE and MPS were performed for each case. Results: Left ventricular dysfunction was detected in 63.3% of patients and also 93.3% of patients had extensive abnormal GLS at 3 month follow-up. Of the patients, 33.3% had myocardial perfusion defect (MPD) and all MPDs were observed to be reversible defects. MPD was obviously seen in anterior wall (60%) and mid (20%) to apical (70%) segments. As compared with patients without MPD, patients with MPD had higher CK-MB (p: 0.016) and troponin I (p: 0.011), lesser PW thickness (p:0.020) and lower peak systolic strain rate at A2C view (p:0.031). Patients with NYHA III had more impaired GLS than patients with NYHA II (p:0.035). Conclusion: Our study suggests ischemic or nonischemic cardiac dysfunction may be associated with persistent dyspnea in post- COVID- 19 patients without lung sequelae.

Sigma Receptors Ligands: New insights into the Cardioprotective Potential

Cardiovascular diseases (CVDs) are primary reason of mortality and morbidity worldwide. Angina pectoris (AP), myocardial infarction (MI), silent myocardial ischemia and sudden cardiac death occur due to blockage in the coronary artery by atherosclerotic clot. Atherosclerotic clot is a systemic inflammatory process characterised by the accumulation and subsequent thickening of the wall by blood borne materials like low-density lipoproteins and macrophages/lymphocytes within the intima of arteries. These initial fatty streak lesions may also evolve into vulnerable plaques susceptible to rupture or erosion. Plaque rupture initiates both platelet adhesion and aggregation as well as the activation of the clotting cascade leading to so-called athero-thrombotic process and leads to coronary artery blockade. Coronary artery blockage interrupts the coronary blood supply leading to damage of myocardium. Multiple factors such as intra cellular (Ca2+, pH) and inter cellular (adhesion molecules) factors, inflammation, environmental toxins as well as metals and oxygen free radicals are involved in the pathogenesis of coronary artery diseases. Furthermore, certain sigma receptor ligands have been reported to show protective action against coronary artery diseases. Sigma receptor, a transmembrane protein, is expressed in many tissues including cardiovascular, liver and central nervous system. Sigma ligands significantly prevented the deviated biochemical parameters such as cardiac marker enzymes, lipid profile and antioxidant parameters to near normal status. Therefore, sigma receptor stimulation represents a new therapeutic strategy to prevent heart from ischemic and hypertrophic dysfunction in case of cardiovascular disorders. This review summarises the sigma receptors and cardioprotective potential of sigma receptor ligands. The article also provides a comprehensive account of structure, types and medical efficacy of cardioprotective sigma agonists.

Hyperkalemia as a cause of undertreatment with mineralcorticoid receptor antagonists for patients with newly onset of heart failure with reduced ejection fraction

Abstract Background Despite beneficial effects on mortality and morbidity the use of mineralocorticoid receptor antagonists (MRA) in patients with reduced ejection fraction (<40%) (HFrEF) remains poor. Hyperkalemia is assumed as an important cause, but the reported incidence is low and varies hugely. Thus, available data of magnitude of hyperkalemia in real life settings are insufficient to explain why under-utilization of MRA occurred. Aim To determine the incidence and magnitude of documented hyperkalemia and potential risk of hyperkalemia in patients with HFrEF in a real-world HF population. Methods Patients aged 18–85 years at the time of the baseline, hospitalized for newly onset of HFrEF between 2016–01–01 and 2019–12–31, were identified retrospectively and consecutively from hospital discharge records, by use of international classification of disease (ICD)-10 codes I50.0-I50.9 as principal diagnosis. Potential higher risk of hyperkalemia was based on an overall assessment of current potassium level, presence of diabetes mellitus and eGFR <30 ml/min at patient level. Results In total, 3456 patients with HF were identified, 642 (18.6%) were eligible, hospitalized for newly onset of HFrEF (66.8±12.7 years, 68.4% men and EF 29.4% ±6.8%). After six months 336 (52.3%) did not have MRA of which 279 (83%) never received MRAs and 57 (17%) had MRAs discontinued. Among patients on MRA treatment, 306 (14.4%) needed dose reduction. Occurrence of hypertension, ischemic heart disease, diabetes mellitus and renal dysfunction at baseline did not differ between groups with or without MRA. The incidence and magnitude of documented and potentially higher risk of hyperkalemia were assessed both at baseline and as highest potassium within six months after established diagnosis. Among patients without MRA after six months, at baseline only 3 (0.9%) patients had documented S/P-K ≥6 mmol/L, 7 (2.1%) patients had S/P-K 5.5–5.9 mmol/L and 26 (7.7%) patients had S/P-K 4.8–5.4 mmol/L. Moreover, 12.4% had potentially high risk of hyperkalemia at baseline. During the six-month follow up after initiation of HF therapy, 15 (4.5%) patients had documented hyperkalemia with S/P-K ≥6 mmol/L, 23 (6.8%) patients had S/P-K 5.4–5.9 mmol/L, and 123 (36.6%) patients had S/P-K 4.8–5.4 mmol/L during at least one occasion. Besides, 13.4% had potentially high risk of hyperkalemia. Hyperkalemia occurred frequently (40.4% vs 36.4%) in patients with discontinuation and dose reduction of MRA. Figure 1 presents the distribution of patients with risk of or documented hyperkalemia in the group without MRA. Conclusions Hyperkalemia was the most common cause for both discontinuation and dose reduction of MRA. Hyperkalemia was also increased significantly from baseline and during subsequent up-titration, with 4.6-fold increased risk for borderline hyperkalemia (S/P-K 4.8–5.4). This might explain why physicians refrain from prescribing MRAs to patients with HFrEF. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Vifor Pharma

Lactobacillus plantarum probiotic induces Nrf2-mediated antioxidant signaling and eNOS expression resulting in improvement of myocardial diastolic function.

Yorkshire swine were fed standard diet (n = 7) or standard diet containing applesauce rich in caffeic acid with Lactobacillus plantarum (n = 7) for 3 wk. An ameroid constrictor was next placed around the left coronary circumflex artery, and the dietary regimens were continued. At 14 wk, cardiac function, myocardial perfusion, vascular density, and molecular signaling in ischemic myocardium were evaluated. The L. plantarum-applesauce augmented NF-E2-related factor 2 (Nrf2) in the ischemic myocardium and induced Nrf2-regulated antioxidant enzymes heme oxygenase-1 (HO-1), NADPH dehydrogenase quinone 1 (NQO-1), and thioredoxin reductase (TRXR-1). Improved left ventricular diastolic function and decreased myocardial collagen expression were seen in animals receiving the L. plantarum-applesauce supplements. The expression of endothelial nitric oxide synthase (eNOS) was increased in ischemic myocardial tissue of the treatment group, whereas levels of asymmetric dimethyl arginine (ADMA), hypoxia inducible factor 1α (HIF-1α), and phosphorylated MAPK (pMAPK) were decreased. Collateral-dependent myocardial perfusion was unaffected, whereas arteriolar and capillary densities were reduced as determined by α-smooth muscle cell actin and CD31 immunofluorescence in ischemic myocardial tissue. Dietary supplementation with L. plantarum-applesauce is a safe and effective method of enhancing Nrf2-mediated antioxidant signaling cascade in ischemic myocardium. Although this experimental diet was associated with a reduction in hypoxic stimuli, decreased vascular density, and without any change in collateral-dependent perfusion, the net effect of an increase in antioxidant activity and eNOS expression resulted in improvement in diastolic function.NEW & NOTEWORTHY Colonization of the gut microbiome with certain strains of L. Plantarum has been shown to convert caffeic acid readily available in applesauce to 4-vinyl-catechol, a potent activator of the Nrf2 antioxidant defense pathway. In this exciting study, we show that simple dietary supplementation with L. Plantarum-applesauce-mediated Nrf2 activation supports vascular function, ameliorates myocardial ischemic diastolic dysfunction, and upregulates expression of eNOS.

Emerging roles of growth differentiation factor‑15 in brain disorders (Review)

Brain disorders, such as Alzheimer's and Parkinson's disease and cerebral stroke, are an important contributor to mortality and disability worldwide, where their pathogenesis is currently a topic of intense research. The mechanisms underlying the development of brain disorders are complex and vary widely, including aberrant protein aggregation, ischemic cell necrosis and neuronal dysfunction. Previous studies have found that the expression and function of growth differentiation factor-15 (GDF15) is closely associated with the incidence of brain disorders. GDF15 is a member of the TGFβ superfamily, which is a dimer-structured stress-response protein. The expression of GDF15 is regulated by a number of proteins upstream, including p53, early growth response-1, non-coding RNAs and hormones. In particular, GDF15 has been reported to serve an important role in regulating angiogenesis, apoptosis, lipid metabolism and inflammation. For example, GDF15 can promote angiogenesis by promoting the proliferation of human umbilical vein endothelial cells, apoptosis of prostate cancer cells and fat metabolism in fasted mice, and GDF15 can decrease the inflammatory response of lipopolysaccharide-treated mice. The present article reviews the structure and biosynthesis of GDF15, in addition to the possible roles of GDF15 in Alzheimer's disease, cerebral stroke and Parkinson's disease. The purpose of the present review is to summarize the mechanism underlying the role of GDF15 in various brain disorders, which hopes to provide evidence and guide the prevention and treatment of these debilitating conditions.

Discussion

Presenter: Dr Satoshi Kainuma Dr Robert E. Michler (New York, NY). Dr Kainuma, the American Association for Thoracic Surgery selection committee made an excellent decision in selecting your abstract for oral presentation. The topic is provocative in answering the question of whether multiple percutaneous coronary intervention (PCI) negatively influences clinical outcomes for ischemic mitral regurgitation, and your work could change clinical practice. Now, with the opportunity to carefully review your manuscript, it appears that an answer is close, but not yet definitive. The unifying aspect of the 2 comparison populations that you studied is that they both underwent restrictive annuloplasty for ischemic mitral regurgitation. Apart from this fact, the 2 groups were in fact very different. An operation such as coronary artery bypass grafting (CABG) is a major predictor of survival as is left ventricular ejection fraction. CABG was performed in significantly different numbers in each comparison group, 85% of 211 in the group with one or fewer PCIs, versus 47% of the 98 patients in the group with multiple PCIs. This fact alone may have led to differences in the outcomes measured and served as the primary driver of why the multiple PCI group did less well, in comparison to the single or no PCI group. Moreover, each additional operation performed would likely have influenced the outcomes measured. Because the multiple PCI group included 50% fewer total patients, the influence of these additional procedures may have negatively influenced the results for the group. And, another cofounding variable such as surgical ventricular reconstruction, which is a highly technical and demanding operation, with its own morbidity and mortality, was performed in 61 of the 211 patients with no or 1 PCI and 35 of the 98 patients with multiple PCIs. Was CABG required less frequently in the multiple PCI group because PCI was so successful in reperfusion of the at-risk territory or because the coronary anatomy was inherently bad? Or worse yet, perhaps the PCI—the prior PCI—had inflamed, sclerosed, and narrowed the distal vessel, making it ungraftable in the eyes of the surgeon? Dr Satoshi Kainuma (Suita, Osaka, Japan). Thank you, Professor Michler, for your great comments and important question. I think both are the reasons why patients with multiple PCI groups were not amenable to CABG. I mean that they were more likely to have more severe disease of the vessel, so bypass surgery was difficult. In addition to that, the result of the PCI was excellent for some patients, whereas not in others. So, I guess both factors were the reasons to explain the infrequent rates of concomitant bypass surgery for patients with multiple PCIs. Dr Michler. Was ischemic mitral regurgitation present at the time of the original PCI? And if it was, was the decision to perform a restrictive annuloplasty made because the desire was to avoid bypass surgery or was the belief that it might in and of itself reduce the grade of ischemic mitral regurgitation? Dr Kainuma. Thank you for your great question. Unfortunately, every patient was not evaluated in terms of ischemic mitral regurgitation at the time of the PCI. This is a problem. And secondly, interventionists in Japan are quite aggressive and prefer to do PCI whenever they see the ischemic mitral regurgitation. Probably because they do not consider that CABG is the best coronary revascularization therapy for patients with ischemic mitral regurgitation and myocardial dysfunction. So, Japanese cardiologists and interventionists are well trained in terms of the procedural aspect, but not with patient selection or indication for the PCI, especially for patients with stable coronary artery disease.

Exercise as a multi-modal disease-modifying medicine in systemic sclerosis: An introduction by The Global Fellowship on Rehabilitation and Exercise in Systemic Sclerosis (G-FoRSS).

Systemic sclerosis (SSc) is a heterogeneous multisystem autoimmune disease whereby its main pathological drivers of disability and damage are vascular injury, inflammatory cell infiltration, and fibrosis. These mechanisms result in diffuse and diverse impairments arising from ischemic circulatory dysfunction leading to painful skin ulceration and calcinosis, neurovascular aberrations hindering gastrointestinal (GI) motility, progressive painful, incapacitating or immobilizing effects of inflammatory and fibrotic effects on the lungs, skin, articular and periarticular structures, and muscle. SSc-related impairments impede routine activities of daily living (ADLs) and disrupt three critical life areas: work, family, social/leisure, and also impact on psychological well-being. Physical activity and exercise are globally recommended; however, for connective tissue diseases, this guidance carries greater impact on inflammatory disease manifestations, recovery, and cardiovascular health. Exercise, through myogenic and vascular phenomena, naturally targets key pathogenic drivers by downregulating multiple inflammatory and fibrotic pathways in serum and tissue, while increasing circulation and vascular repair. G-FoRSS, The Global Fellowship on Rehabilitation and Exercise in Systemic Sclerosis recognizes the scientific basis of and advocates for education and research of exercise as a systemic and targeted SSc disease-modifying treatment. An overview of biophysiological mechanisms of physical activity and exercise are herein imparted for patients, clinicians, and researchers, and applied to SSc disease mechanisms, manifestations, and impairment. A preliminary guidance on exercise in SSc, a research agenda, and the current state of research and outcome measures are set forth.

Evaluation of risk factors for postoperative ICU admission in a tertiary care hospital – A case control study

Background & objective: Appropriate decisions regarding admission of potential patients to intensive care unit (ICU) postoperatively are considered very important for the patient care. We evaluated the reasons and the risk factors for postoperative ICU admissions in our hospital. Methodology: This is a case-control study, that was done at Security Forces Hospital, Riyadh, during the period from July 2019 to December 2019. We included all patients who needed ICU admission postoperatively in the study as cases. The controls were the patients who had any surgical procedure during the same study period. Patients’ demographics, ASA status, medical co-morbidities and operation details were recorded. We then did univariate and multivariate logistic regression to analyze the data. A p-value of less than 0.05 was considered as significant. Results: We enrolled a total of 140 patients in the study, with 46 cases and 94 controls. In univariate analysis, age, ASA status, presence of hypertension, diabetes, ischemic heart disease, respiratory disease, renal dysfunction and neurological abnormalities were found to be statistically significant predictors for postoperative ICU admission. In multivariate analysis, ASA status and perioperative neurological abnormalities were the most significant risk factors for ICU admission. Conclusion: ASA status and presence of neurological abnormalities are the most significant risk factors associated with ICU admission in the postoperative period. Key words: Risk factors; ICU; ICU admission; Postoperative period; ASA status Citation: Huda AU, Rabbani U, Yasir M. Evaluation of risk factors for postoperative ICU admission in a tertiary care hospital – A case control study. Anesth. pain intensive care 2021;25(4):501–504. DOI: 10.35975/apic.v25i4.1581 Received: December 23, 2020, Reviewed: January 25, 2021, Accepted: July 7, 2021

MiR-1224 contributes to ischemic stroke-mediated natural killer cell dysfunction by targeting Sp1 signaling

BackgroundBrain ischemia compromises natural killer (NK) cell-mediated immune defenses by acting on neurogenic and intracellular pathways. Less is known about the posttranscriptional mechanisms that regulate NK cell activation and cytotoxicity after ischemic stroke.MethodsUsing a NanoString nCounter® miRNA array panel, we explored the microRNA (miRNA) profile of splenic NK cells in mice subjected to middle cerebral artery occlusion. Differential gene expression and function/pathway analysis were applied to investigate the main functions of predicted miRNA target genes. miR-1224 inhibitor/mimics transfection and passive transfer of NK cells were performed to confirm the impact of miR-1224 in NK cells after brain ischemia.ResultsWe observed striking dysregulation of several miRNAs in response to ischemia. Among those miRNAs, miR-1224 markedly increased 3 days after ischemic stroke. Transfection of miR-1224 mimics into NK cells resulted in suppression of NK cell activity, while an miR-1224 inhibitor enhanced NK cell activity and cytotoxicity, especially in the periphery. Passive transfer of NK cells treated with an miR-1224 inhibitor prevented the accumulation of a bacterial burden in the lungs after ischemic stroke, suggesting an enhanced immune defense of NK cells. The transcription factor Sp1, which controls cytokine/chemokine release by NK cells at the transcriptional level, is a predicted target of miR-1224. The inhibitory effect of miR-1224 on NK cell activity was blocked in Sp1 knockout mice.ConclusionsThese findings indicate that miR-1224 may serve as a negative regulator of NK cell activation in an Sp1-dependent manner; this mechanism may be a novel target to prevent poststroke infection specifically in the periphery and preserve immune defense in the brain.

A Novel High-Resolution Surface Electrocardiographic Method to Identify and Characterize Myocardial Scar: A Proof-of-Concept Study

BackgroundThe placement of the left ventricular (LV) lead in an area free of myocardial scar is an important determinant of cardiac resynchronization therapy response. We sought to develop and validate a simple, practical, and novel electrocardiographic (ECG)-based approach to intraoperatively identify the presence of LV scar. We hypothesized that there would be a reduction in the measured amplitude of the LV pacing stimulus on the skin surface using a high-resolution (HR) ECG when pacing from LV regions with scar compared with regions without scar. We term this the ECG Amplitude Signal Evaluation (EASE) method. MethodsConsecutive patients with ischemic LV systolic dysfunction and standard criteria for de novo cardiac resynchronization therapy implantation were prospectively enrolled. All underwent a preimplant contrast-enhanced cardiac magnetic resonance study to assess for scar. The average amplitude of the LV pacing impulse was sampled on HR surface ECG intraprocedurally and then compared with the cardiac magnetic resonance results. ResultsA total of 38 LV pacing sites were assessed among 13 recipients. The median voltage measured on the surface HR ECG in regions with scar was reduced by 41% (interquartile range, 17% to 63%), whereas there was no measurable change in voltage (interquartile range, 0 to 0%) in regions without scar compared with the maximal amplitude (Wilcoxon P < 0.0001). ConclusionThe EASE method appears to be of potential value as a novel intraoperative tool to guide LV lead placement to regions free of scar. Future work is required to validate the utility of this method in a larger patient cohort.

Cardioprotective effects of empagliflozin after ischemia and reperfusion in rats

The Sodium Glucose Co-Transporter-2 inhibitor, empagliflozin (EMPA), reduces mortality and hospitalisation for heart failure following myocardial infarction irrespective of diabetes status. While the findings suggest an inherent cardioprotective capacity, the mechanism remains unknown. We studied infarct size (IS) ex-vivo in isolated hearts exposed to global IR injury and in-vivo in rats subjected to regional myocardial ischemia reperfusion (IR) injury, in whom we followed left ventricular dysfunction for 28 days. We compared rats that were given EMPA orally for 7 days before, EMPA 1.5 h before IR injury and at onset of reperfusion and continued orally during the follow-up period. We used echocardiography, high resolution respirometry, microdialysis and plasma levels of β-hydroxybutyrate to assess myocardial performance, mitochondrial respiration and intermediary metabolism, respectively. Pretreatment with EMPA for 7 days reduced IS in-vivo (65 ± 7% vs. 46 ± 8%, p < 0.0001 while administration 1.5 h before IR, at onset of reperfusion or ex-vivo did not. EMPA alleviated LV dysfunction irrespective of the reduction in IS. EMPA improved mitochondrial respiration and modulated myocardial interstitial metabolism while the concentration of β-hydroxybutyric acid was only transiently increased without any association with IS reduction. EMPA reduces infarct size and yields cardioprotection in non-diabetic rats with ischemic LV dysfunction by an indirect, delayed intrinsic mechanism that also improves systolic function beyond infarct size reduction. The mechanism involves enhanced mitochondrial respiratory capacity and modulated myocardial metabolism but not hyperketonemia.

Post-Translational Modification Networks of Contractile and Cellular Stress Response Proteins in Bladder Ischemia.

Molecular mechanisms underlying bladder dysfunction in ischemia, particularly at the protein and protein modification levels and downstream pathways, remain largely unknown. Here we describe a comparison of protein sequence variations in the ischemic and normal bladder tissues by measuring the mass differences of the coding amino acids and actual residues crossing the proteome. A large number of nonzero delta masses (11,056) were detected, spanning over 1295 protein residues. Clustering analysis identified 12 delta mass clusters that were significantly dysregulated, involving 30 upregulated (R2 > 0.5, ratio > 2, p < 0.05) and 33 downregulated (R2 > 0.5, ratio < −2, p < 0.05) proteins in bladder ischemia. These protein residues had different mass weights from those of the standard coding amino acids, suggesting the formation of non-coded amino acid (ncAA) residues in bladder ischemia. Pathway, gene ontology, and protein–protein interaction network analyses of these ischemia-associated delta-mass containing proteins indicated that ischemia provoked several amino acid variations, potentially post-translational modifications, in the contractile proteins and stress response molecules in the bladder. Accumulation of ncAAs may be a novel biomarker of smooth muscle dysfunction, with diagnostic potential for bladder dysfunction. Our data suggest that systematic assessment of global protein modifications may be crucial to the characterization of ischemic conditions in general and the pathomechanism of bladder dysfunction in ischemia.

Lepidium meyenii (maca) and soy isoflavones reduce cardiac stunning of ischemia-reperfusion in rats by mitochondrial mechanisms

Background and aimPhytoestrogens are traditionally used for cardiovascular risks but direct effects on the ischemic heart remain unclear. Plants with phytoestrogens are used for reducing menopausic symptoms and they could also be cardioprotectives. Here we investigated whether maca (Lepidium meyenii) contains isoflavones and prevents cardiac stunning, in comparison to soy isoflavones. Experimental procedureBoth products were orally and daily administered to rats during 1 week before exposing isolated hearts to ischemia/reperfusion (I/R). Young male (YM), female (YF) and aged female (AgF) rats treated with maca (MACA, 1 g/kg/day) or soy isoflavones (ISOF, 100 mg/kg/day) were compared to acute daidzein (DAZ, 5 mg/kg i.p.) and non-treated rat groups. Isolated ventricles were perfused inside a calorimeter to simultaneously measure contractile and calorimetrical signals before and during I/R. Results and conclusionsMaca has genistein and daidzein. MACA and ISOF improved the post-ischemic contractile recovery (PICR) and muscle economy (P/Ht) in YM and YF hearts, but not in AgF hearts. DAZ improved PICR and P/Ht more in YM than in YF. The mKATP channels blockade reduced both PICR and P/Ht in DAZ-treated YM hearts, without affecting them in ISOF or MACA-treated YM hearts. In MACA treated YF hearts, the simultaneous blockade of NOS and mKATP channels, or the mNCX blockade reduced cardioprotection. Results show that subacute oral treatment with maca or with soy isoflavones was strongly preventive of cardiac ischemic dysfunction, more than the acute administration of a pure isoflavone (daidzein, genistein). Maca induced synergistic and complex mechanisms which prevented mitochondrial calcium overload.

THE RELATIONSHIP AMONG BRACHIAL SYSTOLIC BLOOD PRESSURE, MICROALBUMINURIA, AND 24-H URINARY EXCRETION ON CENTRAL SYSTOLIC PRESSURE IN RESISTANT HYPERTENSIVE PATIENTS

Objective: Resistant hypertensive patients have a high prevalence of target organ damage. Increased central systolic blood pressure (cSBP) is more relevant than the peripheral one in these patients, because heart, brain and kidneys are directly exposed to high cSBP levels. Moreover, it is directly related to left ventricular hypertrophy, left atrial size, ischemic heart disease, brain injury, and kidney dysfunction. Currently, assessing cSBP and Augmentation Index (Aix) can be helpful to stratify cardiovascular risk and there is evidence that an improvement on cSBP leads to reduction of cardiovascular events and guides the antihypertensive treatment with drugs that more effective on cSBP reduction.An open prospective study was conducted, to identify markers associated with high cSBP values in resistant hypertensive patients on antihypertensive treatment. Design and method: Seventy-two hypertensive patients were recruited in the Hypertension Outpatient Clinic of FAMERP (44 women/ 28 men). Clinical characteristics and biochemical data collected are shown in the Table 1. The central systolic arterial pressure (cSBP) and the augmentation index (AIx) were measured using Tonometry HEM 9000-A validated OMRON equipment (JAPAN). Results: Multiple regression (cSBP) showed positive correlation between cSBP and brachial SBP (p = 0,0243) and microalbuminuria (p = 0,0325) and negative correlation with 24-h urinary sodium (p = 0,0277). Table2 and Figures. Conclusions: In Resistant hypertensive patientes the microalbuminuria can be useful as a marker to Increased central systolic blood pressure (cSBP)

Increased Renal Dysfunction, Apoptosis, and Fibrogenesis Through Sympathetic Hyperactivity After Focal Cerebral Infarction.

Sympathetic nervous system plays an important role in secondary injury of diseases. Accumulating evidence has observed association between ischemic stroke and renal dysfunction, but the mechanisms are incompletely clear. In this study, we investigated whether sympathetic hyperactivity can cause the development of renal dysfunction, apoptosis, and fibrogenesis after focal cerebral infarction. To determine the renal consequences of focal cerebral ischemia, we subjected a mice model of transient middle cerebral artery occlusion (tMCAO) and examined systolic blood pressure, heart rate, renal structure and function, serum catecholamine, and cortisol levels, and the expression of active caspase-3 bcl-2, bax, and phosphorylated p38 MAPK after 8 weeks. We also analyzed the relationship between insular cortex infarction and acute kidney injury (AKI) in 172 acute anterior circulation ischemic stroke (ACIS) patients. Transient right middle cerebral artery occlusion induced sympathetic hyperactivity, renal dysfunction, upregulation of apoptosis, and fibrogenesis in kidneys of mice. Metoprolol treatment relieves the development of renal injury. Study in stroke patients demonstrated that insular cortex infarction, especially the right insular cortex infarction, is an independent risk factor of AKI. Focal cerebral ischemia in mice leads to the development of renal injury driven by sympathetic hyperactivity. Right insular cortex infarction is an independent risk factor of AKI in older patients. Understanding the brain-kidney interaction after stroke would have clinical implications for the treatment and overall patient outcome.

Depression: The Hidden Problem in Fabry Disease. A Review

Abstract Fabry disease (FD) is an X-linked disorder of glycosphingolipids caused by mutations of the GLA gene. The classical form presents with neuropathic pain and gastrointestinal complaints since childhood or adolescence and progressing into adulthood with ischemic stroke, cardiac dysfunction, and chronic kidney disease. Depression seems to be a frequent complication of FD but its frequently underdiagnosed and undertreated. Comorbid depression in different chronic diseases has been associated with an overall increase in disease burden and medical costs, impairment in activities of daily living, and impact on self-care and treatment adherence. In addition, a clear association between pain and depression has been observed in FD patients and appears to have an unequivocal neurobiological matrix. The aim of this review is to provide an overview of the literature on depression in patients with FD and to highlight some of the emerging issues on this topic. Further research to improve detection and to develop effective treatments for depression in this population is promptly needed.