Evaluation of antiamnesic activity of Salvia multicaulis essential oil on scopolamine-induced amnesia in rats: in vivo and in silico approaches.

Plants of genus Salvia have been used in folk medicine for wound healing, in the alleviation of stomach, liver, and rheumatism pains, as antioxidant, cognitive-enhancer, sedative and antiseptic, stimulant and tonic agents. The present study aimed to evaluate whether Salvia multicaulis essential oil (1% and 3%) administered for 21 days attenuates cognitive deficits and exhibits anxiolytic and antidepressant-profile in the scopolamine-induced amnesia in rats. Rats were randomly divided into six groups (n = 6): (1) control, (2) scopolamine (Sco, 0.7 mg/kg) (3, 4) S. multicaulis essential oil treatment groups (SEO, 1% and 3%), (5) diazepam (DIAZ, 1.5 mg/kg) and (6) tramadol (TRM, 10 mg/kg). To establish an animal model of amnesia, Sco (0.7 mg/kg), a muscarinic acetylcholine receptor antagonist, was injected into male Wistar rats. Y-maze (memory), radial arm-maze (memory), elevated plus-maze (anxiety), and forced swimming (depression) tests were employed. Molecular interactions of chemical compounds from the essential oil with the GABAA receptor was explored via molecular docking experiments. Using behavioral tests, we demonstrated that inhalation of S. multicaulis essential oil exerts significant antiamnesic activity as well as anxiolytic-antidepressant-like effects in the Sco-treated rats. Our data revealed that S. multicaulis oil could act as a promising phytopharmaceutical agent for improving dementia-related abnormalities.

Computer Simulations Reveal a Novel Blocking Mode of the hERG Ion Channel by the Antiarrhythmic Agent Clofilium.

The binding modes of many hERG ion channel blockers are well understood, but a notable exception is clofilium, a potent antiarrhythmic agent whose action relies on blocking the current mediated by hERG. From the previously hypothesized binding modes of clofilium to hERG, only two can explain most of the experimental results. In this study, computer simulations are performed in order to analyze the hypothesized binding modes and to identify the consensus one. This is accomplished by employing molecular dynamics (MD) simulations and interaction energy calculations. The results show an unexpected binding mode, in which the quaternary nitrogen is placed in the upper part of the inner cavity, interacting strongly with Ser624, while the chlorophenyl group is located in the lower part, in better agreement with previous experimental results. This novel binding position also explains the higher affinity of clofilium for the related hEag1 channel and was correlated with the possibility that potent hERG blockers interact in specific ways with the residues near the intracellular activation gate, offering a new explanation that could help predict the potency of other hERG-blocking compounds.

An antiarrhythmic agent as a promising lead compound for targeting the hEAG1 ion channel in cancer therapy: insights from molecular dynamics simulations.

Experimental evidence suggests that hERG and hEAG potassium channels may serve as important cancer therapy targets because either of the channel blockade or inactivation by different methods leads to inhibition of cancer cells growth and proliferation. However, there is no known hEAG specific blocker, and hERG blockade leads to adverse cardiac side effects, although it is currently used in treating certain types of arrhythmias. There have been some attempts to explain the channels blockade by clofilium, an antiarrhythmic agent, and the results lead to different possible binding modes. This study investigates for the first time the potential of using clofilium as a lead compound for finding a novel cancer therapy agent which may target ion channels. The implied findings from a comparative assessment of literature studies were verified using molecular dynamics simulations. The results indicate a particular structural difference between the two channels that could provide a novel and realistic way of using clofilium analogs which may target the hEAG1 ion channel in cancer therapy.

Optical coherence tomography findings after chronic total occlusion interventions: Insights from the "AngiographiC evaluation of the everolimus-eluting stent in chronic Total occlusions" (ACE-CTO) study (NCT01012869).

BACKGROUND: There is limited information on optical coherence tomography (OCT) findings after percutaneous coronary intervention (PCI) of chronic total occlusions (CTOs). OCT allows high resolution imaging that can enhance understanding of the vascular response after stenting of chronically occluded vessels. METHODS: The Angiographic Evaluation of the Everolimus-Eluting Stent in Chronic Total Occlusions (ACE-CTO) study collected angiographic and clinical outcomes from 100 patients undergoing CTO PCI with the everolimus-eluting stent (EES). OCT was performed 8-months post stenting in 62 patients. Every third frame was analyzed throughout the course of the stented arterial segment. Lumen contours were semi-automatically traced and stent struts were manually delineated, with automatic measurement of the strut to lumen distance. Struts on the luminal side of the lumen contour were classified as malapposed if the distance to the lumen contour exceeded 0.108mm. RESULTS: A total of 44,450 struts in 6047 frames were analyzed, of which 4113 9.3%, 95% confidence intervals [CI] 9.0% to 9.5%) were malapposed and 1230 (2.8%, 95% CI 2.6% to 2.9%) were uncovered. Fifty-five of 62 patients (88.7%, 95% CI 78.5% to 98.4%) had at least one malapposed stent strut and 50 patients (80.7%, 95% CI 69.2% to 88.6%) had at least one uncovered stent strut. Mean strut-intimal thickness of the apposed and malapposed struts was 0.126±0.140mm and -0.491±0.440mm, respectively. CONCLUSION: High rates of stent strut malapposition and incomplete stent strut coverage were observed after CTO PCI using EES, highlighting unique challenges associated with stent implantation in CTOs.

The AngiographiC Evaluation of the Everolimus-Eluting Stent in Chronic Total Occlusion (ACE-CTO) Study.

BACKGROUND: There are limited data on outcomes after implantation of second-generation drug-eluting stents in coronary chronic total occlusions (CTOs). We aimed to evaluate the frequency of angiographic restenosis and clinical outcomes after implantation of the everolimus-eluting stent (EES) in coronary CTOs. METHODS: One hundred patients undergoing successful CTO percutaneous coronary intervention using EES at our institution between 2009 and 2012 were enrolled. The primary study endpoint was binary in-segment restenosis at 8-month follow-up quantitative coronary angiography. Secondary endpoints included death, myocardial infarction, target-lesion and target-vessel revascularization, and symptom improvement. RESULTS: Mean age was 64 ± 7 years and 99% of the patients were men. The successful crossing technique was antegrade wiring in 51 patients, antegrade dissection/reentry in 24 patients, and retrograde in 25 patients. Binary angiographic restenosis occurred in 46% of the patients (95% confidence interval [CI], 35%-57%). The pattern of restenosis was focal, proliferative, and total occlusion in 19 lesions (46%), 14 lesions (34%), and 8 lesions (20%), respectively. At 12 months, the incidences of death, myocardial infarction, target-lesion revascularization, and target-vessel revascularization were 2%, 2%, 37%, and 39%, respectively. At 12 months, symptoms were improved, unchanged, or worse compared with baseline in 89 patients, 8 patients, and 1 patient, respectively (2 patients died before the 12-month follow-up). On multivariable analysis, smaller stent diameter was associated with higher risk for binary angiographic restenosis. CONCLUSION: High rates of angiographic restenosis and repeat revascularization were observed among patients receiving EES in coronary CTOs, but most had significant symptom improvement.

Titin isoforms, extracellular matrix, and global chamber remodeling in experimental dilated cardiomyopathy: functional implications and mechanistic insight.

BACKGROUND: Altered titin isoforms may modify cardiac function in heart failure (HF), but the nature of isoform switches and associated functional implications are not well defined. Limited studies have reported an increased compliant isoform (N2BA) expression in human systolic HF. Titin may also modulate stretch-regulated responses such as myocardial natriuretic peptide production. METHODS AND RESULTS: We characterized titin isoform expression and extracellular matrix in all 4 cardiac chambers and the left ventricular (LV) epicardium and endocardium in normal dogs (n=6) and those with HF (n=6) due to tachypacing and characterized functional implications at the LV myofiber and chamber level. Recognizing the potential for uncoupling of the extracellular matrix and cardiomyocyte in tachypacing, myocardial natriuretic peptide production, a molecular marker of stretch-regulated responses, was also assessed. All chambers were dilated in HF, but the extracellular matrix was not increased. HF dogs had markedly lower N2BA in the atria and right ventricle. In failing LVs, N2BA was decreased only in the epicardium, where myofiber passive stiffness was increased. However, LV chamber mechanics were driven by the marked LV dilatation, with no increase in LV diastolic stiffness. Natriuretic peptide concentrations increased markedly in the endocardium in relation to increases in LV wall stress. CONCLUSIONS: Tachypacing HF is characterized by decreases in compliant titin isoform expression in the atria, right ventricle, and LV epicardium. However, LV chamber mechanics are principally determined by geometric and extracellular matrix changes rather than titin-based myofiber stiffness in this model. Stretch-regulated myocardial responses (natriuretic peptide production) appeared intact, suggesting that the mechanotransduction role of titin was not impaired in HF.

Management of non-ST-Segment Elevation Myocardial Infarction.

Non-ST-segment elevation myocardial infarction (NSTEMI) is a major cause of cardiovascular morbidity and mortality in the United States. It represents the highest risk category of non-ST-segment elevation acute coronary syndromes (NSTEACS), for which timely diagnosis and appropriate therapy are paramount to improve outcomes. Evidence-based treatment, with combination of antiplatelet and anticoagulant therapy, and with serious consideration of early coronary angiography and revascularization along with anti-ischemic medical therapy, is the mainstay of management for NSTEMI. Aggressive risk-factor control after the acute event is imperative for secondary prevention of cardiovascular events. Applying in practice the American College of Cardiology/American Heart Association (ACC/AHA) guideline recommendations results in improved outcomes.

Acute and chronic reduction of functional mitral regurgitation in experimental heart failure by percutaneous mitral annuloplasty.

OBJECTIVES: We sought to determine acute and chronic efficacy of a percutaneous mitral annuloplasty (PMA) device in experimental heart failure (HF). Further, we evaluated the potential for adverse effects on left ventricular (LV) function and coronary perfusion. BACKGROUND: Reduction of mitral annular dimension with a PMA device in the coronary sinus may reduce functional mitral regurgitation (MR) in advanced HF. METHODS: Study 1: a PMA device was placed acutely in anesthetized open-chest dogs with rapid pacing-induced HF (n = 6) instrumented for pressure volume analysis. Study 2: in 12 anesthetized dogs with HF, fluoroscopic-guided PMA was performed, and dogs were followed for four weeks with continuing rapid pacing. RESULTS: Study 1: percutaneous mitral annuloplasty reduced annular dimension and severity of MR at baseline and with phenylephrine infusion to increase afterload (MR jet/left atrial [LA] area 26 +/- 1% to 7 +/- 2%, p < 0.05). Pressure volume analysis demonstrated no acute impairment of LV function. Study 2: no device was placed in two dogs because of prototype size limitations. Attempted PMA impaired coronary flow in three dogs. Percutaneous mitral annuloplasty (n = 7) acutely reduced MR (MR jet/LA area 43 +/- 4% to 8 +/- 5%, p < 0.0001), regurgitant volume (14.7 +/- 2.1 ml to 3.1 +/- 0.5 ml, p < 0.05), effective regurgitant orifice area (0.130 +/- 0.010 cm(2) to 0.040 +/- 0.003 cm(2), p < 0.05), and angiographic MR grade (2.8 +/- 0.3 device to 1.0 +/- 0.3 device, p < 0.001). In the conscious state, MR was reduced at four weeks after PMA (MR jet/LA area 33 +/- 3% HF baseline vs. 11 +/- 4% four weeks after device, p < 0.05) CONCLUSIONS: Percutaneous mitral annuloplasty results in acute and chronic reduction of functional MR in experimental HF.

Tachycardia during the valsalva maneuver: a sign of normal diastolic filling pressures.

Alteration of the loading conditions during the Valsalva maneuver is a helpful ancillary method in the noninvasive assessment of diastolic filling of the heart by Doppler echocardiography. When tachycardia is induced by the maneuver, mitral inflow velocity curves may become uninterpretable because of E velocity (the initial early diastolic velocity on the transmitral flow velocity curve) and A velocity (the velocity at atrial contraction on the transmitral flow velocity curve) wave fusion. To determine the clinical significance of the E velocity and A velocity wave fusion, our study assessed the relation between the heart rate response induced by the Valsalva maneuver and the left ventricular filling pressures measured during cardiac catheterization. In all, 77 patients performed the maneuver during continuous hemodynamic and electrocardiographic monitoring. The ratio between the baseline R-R interval and the shortest R-R interval during the maneuver was calculated. A ratio value higher than 1.1 was predictive of a pre-A pressure of less than 18 mm Hg (94% positive predictive value). Reflex tachycardia during the Valsalva maneuver and subsequent fusion of the E velocity and A velocity waves on the mitral velocity curves is a sign of normal left ventricular filling pressures.

Hemodynamic and humoral effects of vasopeptidase inhibition in canine hypertension.

Vasopeptidase inhibitors are potent new antihypertensive agents. The dual inhibition of ACE and neutral endopeptidase may result in synergistic humoral effects with unique hemodynamic actions. We investigated the hemodynamic and neurohumoral effects of vasopeptidase inhibition in conscious dogs made hypertensive by bilateral renal wrapping and subsequently instrumented for long-term assessment of left ventricular pressure and volume (n=8). Intravenous vasopeptidase inhibition (omapatrilat, 30 micromol/kg over 10 minutes) reduced peak left ventricular pressure (171+/-6 versus 130+/-6 mm Hg immediately after infusion, P<0.01) through arterial vasodilation (arterial elastance, 9.8+/-0.8 to 5.8+/-1.6 mm Hg/mL, P<0.01) and preload reduction (left ventricular end-diastolic volume, 51.1+/-6.8 to 46.0+/-6.9 mL, P<0.01). At 60 minutes, preload decreased further (40.5+/-5.9 mL, P<0.01 versus baseline). Vasopeptidase inhibition increased plasma levels of adrenomedullin (41.2+/-9.6 versus 72.3+/-15 pg/mL, P<0.01), whereas levels of the natriuretic peptides and cGMP were unchanged. Similar hemodynamic and humoral effects were observed with long-term therapy. Neither an equimolar dose of an ACE inhibitor (fosinopril) nor exogenous adrenomedullin had as potent of a hypotensive effect, and neither reduced preload. In summary, the potent short-term and long-term hypotensive effects of vasopeptidase inhibition were prominently mediated by preload reduction, an effect not reproduced by ACE inhibition nor adrenomedullin augmentation and not associated with enhanced natriuretic peptide levels. Combined arterial vasodilation and preload reduction may confer additional potency as well as unique cardioprotective effects. Synergistic effects on humoral and probably endothelial vasodilatory factors appear to be important in mediating the unique hemodynamic profile of vasopeptidase inhibition in this form of experimental hypertension.