ResearchPad - cardiovascular-conditions-disorders-and-treatments https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Comprehensive assessment of coronary pulse wave velocity in anesthetized pigs]]> https://www.researchpad.co/article/elastic_article_8025 Four methods for measuring coronary pulse wave velocity (CoPWV) were compared in animal (n = 10) using two regular pressure guidewires. During decompression phase a trend exists for higher CoPWV and repeatability is better than during compression phase. When coronary blood flow is reduced, known methods assessing CoPWV are not applicable and only the template matching and a new “backward wave” method yields reliable results.

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<![CDATA[Carvedilol and metoprolol are both able to preserve myocardial function in type 2 diabetes]]> https://www.researchpad.co/article/Nc22c2d6a-231f-4c0c-bb28-d9eb3abccb66

Abstract

Purpose

Increasing cohorts of patients present with diabetic cardiomyopathy, and with no targeted options, treatment often rely on generic pharmaceuticals such as β‐blockers. β‐blocker efficacy is heterogenous, with second generation β‐blocker metoprolol selectively inhibiting β1‐AR, while third generation β‐blocker carvedilol has α1‐AR inhibition, antioxidant, and anti‐apoptotic actions alongside nonselective β‐AR inhibition. These additional properties have led to the hypothesis that carvedilol may improve cardiac contractility in the diabetic heart to a greater extent than metoprolol. The present study aimed to compare the efficacy of metoprolol and carvedilol on myocardial function in animal models and cardiac tissue from patients with type 2 diabetes and preserved ejection fraction.

Methods

Echocardiographic examination of cardiac function and assessment of myocardial function in isolated trabeculae was carried out in patients with and without diabetes undergoing coronary artery bypass grafting (CABG) who were prescribed metoprolol or carvedilol. Equivalent measures were undertaken in Zucker Diabetic Fatty (ZDF) rats following 4 weeks treatment with metoprolol or carvedilol.

Results

Patients receiving carvedilol compared to metoprolol had no difference in cardiac function, and no difference was apparent in myocardial function between β‐blockers. Both β‐blockers similarly improved myocardial function in diabetic ZDF rats treated for 4 weeks, without significantly affecting in vivo cardiac function.

Conclusions

Metoprolol and carvedilol were found to have no effect on cardiac function in type 2 diabetes with preserved ejection fraction, and were similarly effective in preventing myocardial dysfunction in ZDF rats.

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<![CDATA[Glucose‐induced oxidative stress and accelerated aging in endothelial cells are mediated by the depletion of mitochondrial SIRTs]]> https://www.researchpad.co/article/Na22d6eab-5378-421e-9004-747778d2064f

Abstract

Diabetic complications cause significant morbidity and mortality. Dysfunction of vascular endothelial cells (ECs), caused by oxidative stress, is a main mechanism of cellular damage. Oxidative stress accelerates EC senescence and DNA damage. In this study, we examined the role of mitochondrial sirtuins (SIRTs) in glucose‐induced oxidative stress, EC senescence, and their regulation by miRNAs. Human retinal microvascular endothelial cells (HRECs) were exposed to 5 mmol/L (normoglycemia; NG) or 25 mmol/L glucose (hyperglycemia; HG) with or without transfection of miRNA antagomirs (miRNA‐1, miRNA‐19b, and miRNA‐320; specific SIRT‐targeting miRNAs). Expressions of SIRT3, 4 and 5 and their targeting miRNAs were examined using qRT‐PCR and ELISAs were used to study SIRT proteins. Cellular senescence was investigated using senescence‐associated β‐gal stain; while, oxidative stress and mitochondrial alterations were examined using 8‐OHdG staining and cytochrome B expressions, respectively. A streptozotocin‐induced diabetic mouse model was also used and animal retinas and hearts were collected at 2 months of diabetes. In HRECs, HG downregulated the mRNAs of SIRTs, while SIRT‐targeting miRNAs were upregulated. ELISA analyses confirmed such downregulation of SIRTs at the protein level. HG additionally caused early senescence, endothelial‐to‐mesenchymal transition and oxidative DNA damage in ECs. These changes were prevented by the transfection of specific miRNA antagomirs and by resveratrol. Retinal and cardiac tissues from diabetic mice also showed similar reductions of mitochondrial SIRTs. Collectively, these findings demonstrate a novel mechanism in which mitochondrial SIRTs regulate glucose‐induced cellular aging through oxidative stress and how these SIRTs are regulated by specific miRNAs. Identifying such mechanisms may lead to the discovery of novel treatments for diabetic complications.

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<![CDATA[Hypovolemia and reduced hemoglobin mass in patients with heart failure and preserved ejection fraction]]> https://www.researchpad.co/article/N1b60bae1-f630-4f15-b84c-91bbf61c2926

Abstract

A fundamental tenet of heart failure (HF) pathophysiology hinges on a propensity for fluid retention leading to blood volume (BV) expansion and hemodilution. Whether this can be applied to heart failure patients with preserved ejection fraction (HFpEF) remains uncertain. The present study sought to determine BV status and key hormones regulating fluid homeostasis and erythropoiesis in HFpEF patients. BV and hemoglobin mass (Hbmass) were determined with high‐precision, automated carbon monoxide (CO) rebreathing in 20 stable HFpEF patients (71.5 ± 7.3 years, left ventricular ejection fraction = 55.7 ± 4.0%) and 15 healthy age‐ and sex‐matched control individuals. Additional measurements comprised key circulating BV‐regulating hormones such as pro‐atrial natriuretic peptide (proANP), copeptin, aldosterone and erythropoietin (EPO), as well as central hemodynamics and arterial stiffness via carotid–femoral pulse wave velocity (PWV). Carotid–femoral PWV was increased (+20%) in HFpEF patients versus control individuals. With respect to hematological variables, plasma volume (PV) did not differ between groups, whereas BV was decreased (−14%) in HFpEF patients. In consonance with the hypovolemic status, Hbmass was reduced (−27%) in HFpEF patients, despite they presented more than a twofold elevation of circulating EPO (+119%). Plasma concentrations of BV‐regulating hormones, including proANP (+106%), copeptin (+99%), and aldosterone (+62%), were substantially augmented in HFpEF patients. HFpEF patients may present with hypovolemia and markedly reduced Hbmass, underpinned by a generalized overactivation of endocrine systems regulating fluid homeostasis and erythropoiesis. These findings provide a novel perspective on the pathophysiological basis of the HFpEF condition.

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<![CDATA[Alpha‐calcitonin gene‐related peptide prevents pressure‐overload induced heart failure: role of apoptosis and oxidative stress]]> https://www.researchpad.co/article/N8e53f17a-5f83-4fa9-a359-249913deef0c

Abstract

Alpha‐calcitonin gene‐related peptide (α‐CGRP) is a 37‐amino acid neuropeptide that plays an important protective role in modulating cardiovascular diseases. Deletion of the α‐CGRP gene increases the vulnerability of the heart to pressure‐induced heart failure and the administration of a modified α‐CGRP agonist decreases this vulnerability. Systemic administration of α‐CGRP decreases blood pressure in normotensive and hypertensive animals and humans. Here we examined the protective effect of long‐term administration of native α‐CGRP against pressure‐overload heart failure and the likely mechanism(s) of its action. Transverse aortic constriction (TAC) was performed to induce pressure‐overload heart failure in mice. We found that TAC significantly decreased left ventricular (LV) fractional shortening, ejection fraction, and α‐CGRP content, and increased hypertrophy, dilation, and fibrosis compared to sham mice. Administration of α‐CGRP‐filled mini‐osmotic pumps (4 mg/kg bwt/day) in TAC mice preserved cardiac function and LV α‐CGRP levels, and reduced LV hypertrophy, dilation, and fibrosis to levels comparable to sham mice. Additionally, TAC pressure‐overload significantly increased LV apoptosis and oxidative stress compared to the sham mice but these increases were prevented by α‐CGRP administration. α‐CGRP administration in TAC animals decreased LV AMPK phosphorylation levels and the expression of sirt1, both of which are regulatory markers of oxidative stress and energy metabolism. These results demonstrate that native α‐CGRP is protective against pressure‐overload induced heart failure. The mechanism of this cardio‐protection is likely through the prevention of apoptosis and oxidative stress, possibly mediated by sirt1 and AMPK. Thus, α‐CGRP is a potential therapeutic agent in preventing the progression to heart failure, and the cardio‐protective action of α‐CGRP is likely the result of a direct cellular effect; however, a partial vasodilatory blood pressure‐dependent mechanism of α‐CGRP cannot be excluded.

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<![CDATA[ AKT and ERK1/2 activation via remote ischemic preconditioning prevents Kcne2‐dependent sudden cardiac death]]> https://www.researchpad.co/article/5c8011cfd5eed0c484a99ac0

Abstract

Sudden cardiac death (SCD) is the leading global cause of mortality. SCD often arises from cardiac ischemia reperfusion (IR) injury, pathologic sequence variants within ion channel genes, or a combination of the two. Alternative approaches are needed to prevent or ameliorate ventricular arrhythmias linked to SCD. Here, we investigated the efficacy of remote ischemic preconditioning (RIPC) of the limb versus the liver in reducing ventricular arrhythmias in a mouse model of SCD. Mice lacking the Kcne2 gene, which encodes a potassium channel β subunit associated with acquired Long QT syndrome were exposed to IR injury via coronary ligation. This resulted in ventricular arrhythmias in all mice (15/15) and SCD in 5/15 mice during reperfusion. Strikingly, prior RIPC (limb or liver) greatly reduced the incidence and severity of all ventricular arrhythmias and completely prevented SCD. Biochemical and pharmacological analysis demonstrated that RIPC cardioprotection required ERK1/2 and/or AKT phosphorylation. A lack of alteration in GSK‐3β phosphorylation suggested against conventional reperfusion injury salvage kinase (RISK) signaling pathway protection. If replicated in human studies, limb RIPC could represent a noninvasive, nonpharmacological approach to limit dangerous ventricular arrhythmias associated with ischemia and/or channelopathy‐linked SCD.

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<![CDATA[Mouse ECG findings in aging, with conduction system affecting drugs and in cardiac pathologies: Development and validation of ECG analysis algorithm in mice]]> https://www.researchpad.co/article/5af8eeb8463d7e0fe7c597c7

Abstract

Mouse models are extremely important in studying cardiac pathologies and related electrophysiology, but very few mouse ECG analysis programs are readily available. Therefore, a mouse ECG analysis algorithm was developed and validated. Surface ECG (lead II) was acquired during transthoracic echocardiography from C57Bl/6J mice under isoflurane anesthesia. The effect of aging was studied in young (2–3 months), middle‐aged (14 months) and old (20–24 months) mice. The ECG changes associated with pharmacological interventions and common cardiac pathologies, that is, acute myocardial infarction (AMI) and progressive left ventricular hypertrophy (LVH), were studied. The ECG raw data were analyzed with an in‐house ECG analysis program, modified specially for mouse ECG. Aging led to increases in P‐wave duration, atrioventricular conduction time (PQ interval), and intraventricular conduction time (QRS complex width), while the R‐wave amplitude decreased. In addition, the prevalence of arrhythmias increased during aging. Anticholinergic atropine shortened PQ time, and beta blocker metoprolol and calcium‐channel blocker verapamil increased PQ interval and decreased heart rate. The ECG changes after AMI included early JT elevation, development of Q waves, decreased R‐wave amplitude, and later changes in JT/T segment. In progressive LVH model, QRS complex width was increased at 2 and especially 4 weeks timepoint, and also repolarization abnormalities were seen. Aging, drugs, AMI, and LVH led to similar ECG changes in mice as seen in humans, which could be reliably detected with this new algorithm. The developed method will be very useful for studies on cardiovascular diseases in mice.

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<![CDATA[Hepatic vein pressure predicts GFR in cirrhotic patients with hemodynamic kidney dysfunction]]> https://www.researchpad.co/article/5b3dec95463d7e3effc384f7

Abstract

The role of “nephrocongestion” in hemodynamic renal disease is understudied. Intra‐abdominal hypertension accompanies liver disease and renal disease. Our hypothesis states that in those patients with liver disease, hepatic vein pressure measured during a transjugular intrahepatic portosystemic shunt (TIPS) procedure reflects intra‐abdominal pressure and predicts estimated glomerular filtration rate (eGFR). We gathered data from our clinical database and chart review on a cohort of cirrhotic patients who received TIPS at Montefiore as part of their clinical care between 2004 and 2014. We evaluated association of demographic and measured variables with eGFR in those subjects without end‐stage renal disease (ESRD). Using multivariate regression, we examined the relationship between eGFR and hepatic vein pressure while adjusting for age, proteinuria, and ultrasound evidence for parenchymal kidney disease. The mean age of the subjects was 57 years old. Two thirds of the patients were male, 23% were White, and 20% were Black. A higher percentage of patients with chronic kidney disease (CKD), as determined by lower than 60 mL/min/1.73 m2, had proteinuria and ultrasound evidence for parenchymal kidney disease. A multivariate linear regression showed a significant and negative association between hepatic vein pressure and eGFR when adjusting for age, race, and proteinuria. Hepatic vein pressure is negatively and significantly associated with eGFR in those patients with liver failure. This finding has major implications for the way we evaluate hemodynamic renal disease.

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<![CDATA[ ST/HR variables in firefighter exercise ECG – relation to ischemic heart disease]]> https://www.researchpad.co/article/5c61b98dd5eed0c48493ca07

Abstract

Exercise electrocardiography (ExECG) is regularly performed by Swedish firefighters by law. Heart rate‐corrected analysis of ST segment variables (ST/HR) has shown improved prediction of ischemic heart disease (IHD) compared to ST depression alone. This has not previously been extensively studied in asymptomatic persons with a low probability of IHD. We therefore evaluated the predictive performance of ST/HR analysis in firefighter ExECG. ExECG was studied in 521 male firefighters. During 8.4 ± 2.1 years, 2.3% (= 12) were verified with IHD by catheterization or myocardial scintigraphy (age 51.5 ± 5.5 years) and were compared with firefighters without imaging proof of IHD (44.2 ± 10.1 years). The predictive value of ST depression, ST/HR index, ST/HR slope, and area and rotation of the ST/HR loop was calculated as age‐adjusted odds ratios (OR), in 10 ECG leads. Predictive accuracy was analyzed with receiver operating characteristics (ROC) analysis. ST/HR index ≤−1.6 μV/bpm and ST/HR slope ≤−2.4 μV/bpm were associated with increased IHD risk in three individual leads (all OR > 1.0, < 0.05). ST/HR loop area lower than the fifth percentile of non‐IHD subjects indicated IHD risk in V4, V5, aVF, II, and –aVR (P < 0.05). ST depression ≤−0.1 mV was associated with IHD only in V4 (OR, 9.6, CI, 2.3‐40.0). ROC analysis of each of these variables yielded areas under the curve of 0.72 or lower for all variables and leads. Clockwise‐rotated ST/HR loops was associated with increased risk in most leads compared to counterclockwise rotation. The limited clinical value of ExECG in low‐risk populations was emphasized, but if performed, ST/HR analysis should probably be given more importance.

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<![CDATA[All‐optical control of cardiac excitation: combined high‐resolution optogenetic actuation and optical mapping]]> https://www.researchpad.co/article/5bd10c6e40307c3c97c2980e

Abstract

Cardiac tissue is an excitable system that can support complex spatiotemporal dynamics, including instabilities (arrhythmias) with lethal consequences. While over the last two decades optical mapping of excitation (voltage and calcium dynamics) has facilitated the detailed characterization of such arrhythmia events, until recently, no precise tools existed to actively interrogate cardiac dynamics in space and time. In this work, we discuss the combined use of new methods for space‐ and time‐resolved optogenetic actuation and simultaneous fast, high resolution optical imaging of cardiac excitation waves. First, the mechanisms, limitations and unique features of optically induced responses in cardiomyocytes are outlined. These include the ability to bidirectionally control the membrane potential using depolarizing and hyperpolarizing opsins; the ability to induce prolonged sustained voltage changes; and the ability to control refractoriness and the shape of the cardiac action potential. At the syncytial tissue level, we discuss optogenetically enabled experimentation on cell–cell coupling, alteration of conduction properties and termination of propagating waves by light. Specific attention is given to space‐ and time‐resolved application of optical stimulation using dynamic light patterns to perturb ongoing activation and to probe electrophysiological properties at desired tissue locations. The combined use of optical methods to perturb and to observe the system can offer new tools for precise feedback control of cardiac electrical activity, not available previously with pharmacological and electrical stimulation. These new experimental tools for all‐optical electrophysiology allow for a level of precise manipulation and quantification of cardiac dynamics comparable in robustness to the computational setting, and can provide new insights into pacemaking, arrhythmogenesis and suppression or cardioversion.

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