Modeling effects of voltage dependent properties of the cardiac muscarinic receptor on human sinus node function

The cardiac muscarinic receptor (M2R) regulates heart rate, in part, by modulating the ace-tylcholine (ACh) activated K⁺ current I$_{K,ACh}$ through dissociation of G-proteins, that in turn activate K$_{ ACh}$ channels. Recently, M2Rs were noted to exhibit intrinsic voltage sensitivity, i.e. their affinity for ligands varies in a voltage dependent manner. The voltage sensitivity of M2R implies that the affinity for Ach (and thus the Ach effect) varies throughout the time course of a cardiac electrical cycle. The aim of this study was to investigate the contribution of M2R voltage sensitivity to the rate and shape of the human sinus node action potentials in physiological and pathophysiological conditions. We developed a Markovian model of the I$_{K,ACh}$ modulation by voltage and integrated it into a computational model of human sinus node. We performed simulations with the integrated model varying Ach concentration and voltage sensitivity. Low Ach exerted a larger effect on I$_{K,ACh}$ at hyperpolarized versus depolarized membrane voltages. This led to a slowing of the pacemaker rate due to an attenuated slope of phase 4 depolarization with only marginal effect on action potential duration and amplitude. We also simulated the theoretical effects of genetic variants that alter the voltage sensitivity of M2R. Modest negative shifts in voltage sensitivity, predicted to increase the affinity of the receptor for ACh, slowed the rate of phase 4 depolarization and slowed heart rate, while modest positive shifts increased heart rate. These simulations support our hypothesis that altered M2R voltage sensitivity contributes to disease and provide a novel mechanistic foundation to study clinical disorders such as atrial fibrillation and inappropriate sinus tachycardia

Histidine substitution in the most flexible fragments of firefly luciferase modifies its thermal stability.

Molecular dynamics (MD) at two temperatures of 300 and 340 K identified two histidine residues, His461 and His489, in the most flexible regions of firefly luciferase, a light emitting enzyme. We therefore designed four protein mutants H461D, H489K, H489D and H489M to investigate their enzyme kinetic and thermodynamic stability changes. Substitution of His461 by aspartate (H461D) decreased ATP binding affinity, reduced the melting temperature of protein by around 25 degrees C and shifted its optimum temperature of activity to 10 degrees C. In line with the common feature of psychrophilic enzymes, the MD data showed that the overall flexibility of H461D was relatively high at low temperature, probably due to a decrease in the number of salt bridges around the mutation site. On the other hand, substitution of His489 by aspartate (H489D) introduced a new salt bridge between the C-terminal and N-terminal domains and increased protein rigidity but only slightly improved its thermal stability. Similar changes were observed for H489K and, to a lesser degree, H489M mutations. Based on our results we conclude that the MD simulation-based rational substitution of histidines by salt-bridge forming residues can modulate conformational dynamics in luciferase and shift its optimal temperature activity

In-hospital and six-month outcomes of elderly patients undergoing primary percutaneous coronary intervention for acute st-elevation myocardial infarction

BACKGROUND: Elderly patients constitute a rapidly growing proportion of the population, and hence the increasing rises in the number of patients with ST-segment-elevation myocardial infarction (STEMI). Primary percutaneous coronary intervention (PCI), which is now established as the preferred reperfusion strategy in STEMI patients, has been inadequately investigated in this high-risk group. The aim of the present study was to investigate the in- hospital and 6-month outcomes of primary PCI in elderly patients (� 75 years) with STEMI. METHODS: A total of 100 elderly patients with STEMI including those with cardiogenic shock were included. Primary PCI procedures were performed in a tertiary referral center between 2009 and 2014. In-hospital and 6-month outcomes of patients were recorded and analyzed. RESULTS: The average age of the patients was 79.6 ± 3.8 years (range = 75-90 years) and 27.0 were women. Cardiovascular risk factors and prior events were common. Nearly, half of the patients had three-vessel disease and the left anterior descending artery (LAD) was the most common infarct-related artery. The presence of cardiogenic shock but not the other variables was associated with less anatomic and procedural success (P < 0.001). It was also the major independent predictors of 6-month mortality in the patients aged � 75 years, hazard ratio (HR) = 8.02; 95% confidence interval (CI): 1.75-25.97, P < 0.001. In-hospital mortality was 2.4% in the patients without and 83.0% in those with cardiogenic shock. CONCLUSION: Primary PCI in aged patients could be associated with low complication rates and improved survival if performed in high-volume centers with experienced operators. Considering the very high rate of mortality in patients with cardiogenic shock, there should be measures to treat these patients before the onset of hemodynamic instability. © 2016, Isfahan University of Medical Sciences(IUMS). All rights reserved

Comparison of prevalence of metabolic syndrome between idiopathic and secondary deep vein thrombosis

Background- The association of the metabolic syndrome with idiopathic or secondary deep vein thrombosis (DVT) remains uncertain. In addition, the relevance of the different features of the metabolic syndrome as an independent or pivotal risk factor for DVT is controversial. We aimed to evaluate the prevalence of the metabolic syndrome in patients with idiopathic or secondary DVT and also compare the prevalence of the different components of this syndrome in the two clinical etiological conditions of DVT. Methods- In a cross-sectional study, 115 consecutive patients with a recent objective diagnosis of DVT (idiopathic in 87 patients and secondary to a known risk factor in 28 patients) who were referred to Rajaei Heart Center between April 2009 and January 2010 were enrolled in the study. In all the patients, DVT was diagnosed by means of compression Doppler ultrasonography. The metabolic syndrome was defined according to the ATP III recommendations. Results- Overall prevalence of the metabolic syndrome in the study participants was 9.6, and the prevalence of the metabolic syndrome in patients with idiopathic or secondary DVT was 9.2 and 10.7, respectively, which was not different between them. Relative to the presence of the different numbers of the metabolic syndrome features, no difference was found between the groups with idiopathic or secondary DVT. The presence of no feature was found in 6.9 and 7.1, the presence of one feature was seen in 51.7 and 42.9, and the presence of two features was found in 32.2 and 39.3, respectively. Conclusion- Regardless of the etiology of DVT, the overall prevalence of the metabolic syndrome in our DVT subjects ranged from 9.2 to 10.7, and this prevalence was independent of the etiology (idiopathic or secondary) of DVT

The predictors of no-reflow phenomenon after primary angioplasty for acute myocardial infarction

Background: No-reflow phenomenon is a serious complication of primary Percutaneous Coronary Intervention (PCI), which may increase the risk of progressive myocardial damage, profound left ventricular dysfunction, and death. Objectives: This study aimed to investigate the incidence of no-reflow phenomenon and its clinical, para-clinical, and angiographic determinants in patients who underwent primary PCI for ST Elevation Myocardial Infarction (STEMI). Patients and Methods: This non-randomized prospective cohort study was conducted on 397 patients in a cardiovascular tertiary care center in Tehran, Iran from April 2012 to April 2014. The inclusion criteria of the study were presenting with acute STEMI of � 12 h duration or having admitted between 12 and 24 hours after onset with symptoms and signs of ongoing ischemia. The participants underwent standard coronary angiography. No-reflow phenomenon was defined as a Thrombolysis In Myocardial Infarction (TIMI) flow � 2 and no presence of spasm, distal embolization, or dissection after completion of the procedure. The association between no-reflow and its determinants was assessed by chi-square, student�s t-test, or Mann�Whitney U test. Logistic regression models were also used for multivariate analysis. P values < 0.05 were considered to be statistically significant. Results: The participants� mean (SD) age was of 59 (12.2) years and female/male ratio was 83/314. The incidence of no-reflow phenomenon was 63 (15.9). Besides, the results of multivariate analysis showed that only thrombus burden, lesion length, time to reperfusion, and type of occlusion had an adjusted association with this phenomenon. Conclusions: The study results suggested that no-reflow phenomenon after primary PCI would be predictable. Thus, preventive measures, such as using distal protective devices or administration of platelet glycoprotein IIb/IIIa antagonists, are advised to be used in high-risk patients. © 2016, Iranian Cardiovascular Research Journal. All rights reserved

Outcomes of chronic total occlusion percutaneous coronary intervention from the RAIAN (RAjaie - Iran) registry

Objective: While most of the evidence in CTO interventions emerge from Western and Japanese studies, few data have been published up today from the Middle East. Objective of this study was to evaluate technical success rates and clinical outcomes of an Iranian population undergoing CTO PCI in a tertiary referral hospital. Moreover, we sought to evaluate the efficacy of our CTO teaching program. Methods: This is a retrospective single-center cohort study including 790 patients who underwent CTO PCI performed by operators with different volumes of CTOs PCI performed per year. According to PCI result, all patients have been divided into successful (n&nbsp;=&nbsp;555, 70.3&nbsp;%) and unsuccessful (n&nbsp;=&nbsp;235, 29.7&nbsp;%) groups. Study endpoints were Major Adverse Cardiovascular Events and Health Status Improvement evaluated using the Seattle Angina Questionnaire at one year. Results: A global success rate of 70&nbsp;% for antegrade and 80&nbsp;% for retrograde approach was shown despite the lack of some CTO-dedicated devices. During the enrollment period, the success rate increased significantly among operators with a lower number of CTO procedures per year. One-year MACE rate was similar in both successful and unsuccessful groups (13.5&nbsp;% in successful and 10.6&nbsp;% in unsuccessful group, p&nbsp;=&nbsp;0.173). One year patients' health status improved significantly only in successful group. Conclusions: No significant differences of in-hospital and one-year MACE were found between the successful and unsuccessful groups. Angina symptoms and quality of life significantly improved after successful CTO PCI. The RAIAN registry confirmed the importance of operator expertise for CTO PCI success

Novel methodology for predicting the critical salt concentration of bubble coalescence inhibition

Bubble coalescence in some salt solutions can be inhibited if the salt concentration reaches a critical concentration Ccr. There are three models available for Ccr in the literature, but they fail to predict Ccr correctly. The first two models employ the van der Waals attraction power laws to establish Ccr from the discriminant of quadratic or cubic polynomials. To improve the two models, the third model uses the same momentum balance equation of the previous models but different intermolecular force generated by water hydration with exponential decaying. The third prediction for Ccr requires the experimental input for film rupture thickness and is incomplete. We show further in this paper that the third model is incorrect. We propose a novel methodology for determining C cr which resolves the mathematical uncertainties in modeling C cr and can explicitly predict it from any relevant intermolecular forces. The methodology is based on the discovery that Ccr occurs at the local maximum of the balance equation for the capillary pressure, disjoining pressure, and pressure of the Gibbs-Marangoni stress. The novel generic approach is successfully validated using nonlinear equations for complicated disjoining pressure

Molecular dynamics simulation of the early stages of the synthesis of periodic mesoporous silica

We present results of detailed atomistic modeling of the early stages of the synthesis of periodic mesoporous silica using molecular dynamics. Our simulations lead to the proposal of a mechanism that validates several previous experimental and modeling studies and answers many controversial issues regarding the synthesis of mesoporous silicas. In particular, we show that anionic silicates interact very strongly with cationic surfactants and, significantly adsorb on the surface of micelles, displacing a fraction of previously bound bromide counterions. This induces an increase in micelle size and also enhances silica condensation at the micelle surface. The presence of larger silica aggregates in solution further promotes the growth of micelles and, by binding to surfactant molecules in different micelles, their aggregation. This work demonstrates the crucial role played by silica in influencing, by way of a cooperative templating mechanism, the structure of the eventual liquid-crystal phase, which in turn determines the structure of the porous material

Percutaneous transluminal mitral commissurotomy in pregnant women with severe mitral stenosis

Background: Mitral stenosis tends to worsen during pregnancy because of the increase in the cardiac output and the heart rate. In nonresponders to medical therapy, percutaneous transluminal mitral commissurotomy (PTMC) may be performed when there is a suitable valvular anatomy. In this study, we aimed to investigate the clinical and fetal outcomes of pregnant women with mitral stenosis who underwent PTMC. Methods: Thirty-one patients undergoing PTMC during pregnancy were enrolled in this study. The mitral valve area (MVA), the transmitral valve mean gradient (MVMG), and the severity of mitral regurgitation were assessed pre- and postprocedurally by transthoracic and transesophageal echocardiography. The radiation time was measured during the procedure. The patients were followed up during pregnancy, and the neonates were monitored for weight, height, the head circumference, the birth Apgar score, and the adverse effects of radiation for at least 12 months. Results: PTMC was successfully performed on 29 (93.5) patients. No maternal death or pulmonary edema was reported. The mean MVA significantly increased (from 0.73±0.17 cm2to 1.28±0.24 cm2; P&lt;0.001), and the mean MVMG significantly decreased (from 19.62±5.91 mmHg to 8.90±4.73 mmHg; P&lt;0.001) after the procedure. A significant decrease in the systolic pulmonary artery pressure was also detected. Mitral regurgitation did not increase in severity in 16 (51.6) patients. There was no significant relationship between the Apgar score, weight, height, and the head circumference at birth and at the radiation time. Conclusion: In our series, PTMC during pregnancy was a safe and effective procedure. Lowering the radiation time with low frame-count techniques confers a significant decrease in radiation-related complications. © 2019, Tehran Heart Center. All Rights Reserved