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• Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and cardiovascular events partly due to measurement methods that cannot distinguish between mature (uncleaved) and furin-cleaved forms of PCSK9. • Risk of the cardiovascular events in patients with the highest quartile of mature PCSK9 levels was similar to that in the lowest quartile. • PCSK9 levels could not predict future cardiovascular events, even when mature PCSK9 levels were measured in statin-treated patients with stable coronary artery disease. Previous studies have not found a consistent association between circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and the risk of cardiovascular events partly due to measurement methods that cannot distinguish between uncleaved and furin-cleaved forms of PCSK9. This is a prespecified sub-study of the REAL-CAD study which is a prospective, multicenter, randomized trial to compare high- versus low-dose statin in patients with stable coronary artery disease (CAD). The primary endpoint was major adverse cerebrovascular and cardiovascular events (MACCE) defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. In this case-cohort study, serum mature (uncleaved) and furin-cleaved PCSK9 levels obtained at 6 months after randomization were measured among 426 participants who developed MACCE (cases) and 1,478 randomly selected participants (sub-cohort). From 1,478 patients in the sub-cohort, the Cox proportional hazards models with a pseudolikelihood method for case-cohort design revealed that the risk of the primary endpoint in patients with the highest quartile of mature PCSK9 levels was similar to that in the lowest quartile (hazard ratio [HR] 0.809; 95% confidence intervals [CI], 0.541-1.209). Similarly, the HR for the highest to lowest quartiles of furin-cleaved PCSK9 was 0.948 (95% CI, 0.645-1.392) (P = 0.784). Compared to the lowest quartile, neither serum mature nor furin-cleaved PCSK9 levels predicted MACCE. In a large-scale secondary prevention cohort, serum mature and furin-cleaved PCSK9 levels did not provide useful information for predicting future cardiovascular events in statin-treated patients with stable CAD. [ABSTRACT FROM AUTHOR]

Background: Electrical storm (ES) is a life-threatening emergency in patients at high risk of ventricular tachycardia/ventricular fibrillation (VF), but the pathophysiology and molecular basis are poorly understood.Objective: The purpose of this study was to explore the electrophysiological substrate for experimental ES.Methods: A model was created by inducing chronic complete atrioventricular block in defibrillator-implanted rabbits, which recapitulates QT prolongation, torsades des pointes (TdP), and VF episodes.Results: Optical mapping revealed island-like regions with action potential duration (APD) prolongation in the left ventricle, leading to increased spatial APD dispersion, in rabbits with ES (defined as ≥3 VF episodes/24 h). The maximum APD and its dispersion correlated with the total number of VF episodes in vivo. TdP was initiated by an ectopic beat that failed to enter the island and formed a reentrant wave and perpetuated by rotors whose centers swirled in the periphery of the island. Epinephrine exacerbated the island by prolonging APD and enhancing APD dispersion, which was less evident after late Na+ current blockade with 10 μM ranolazine. Nonsustained ventricular tachycardia in a non-ES rabbit heart with homogeneous APD prolongation resulted from multiple foci with an electrocardiographic morphology different from TdP driven by drifting rotors in ES rabbit hearts. The neuronal Na+-channel subunit NaV1.8 was upregulated in ES rabbit left ventricular tissues and expressed within the myocardium corresponding to the island location in optically mapped ES rabbit hearts. The NaV1.8 blocker A-803467 (10 mg/kg, intravenously) attenuated QT prolongation and suppressed epinephrine-evoked TdP.Conclusion: A tissue island with enhanced refractoriness contributes to the generation of drifting rotors that underlies ES in this model. NaV1.8-mediated late Na+ current merits further investigation as a contributor to the substrate for ES. [ABSTRACT FROM AUTHOR]

Background: It has not yet been established whether higher-dose statins have beneficial effects on cardiovascular events in patients with stable coronary artery disease (CAD) and renal dysfunction.Methods: The REAL-CAD study is a prospective, multicenter, open-label trial. As a substudy, we categorized patients by an estimated glomerular filtration rate (eGFR) as follows: eGFR ≥60 (n = 7,768); eGFR ≥45 and <60 (n = 3,176); and eGFR <45 mL/Min/1.73 m2 (n = 1,164), who were randomized to pitavastatin 4mg or 1mg therapy. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina, and was assessed by the log-rank test and Cox proportional hazards model.Results: The baseline characteristics and medications were largely well-balanced between two groups. The magnitude of low-density lipoprotein cholesterol (LDL-C) reduction at 6 months in high- and low-dose pitavastatin groups was comparable among all eGFR categories. During a median follow-up of 3.9 years, high- compared with low-dose pitavastatin significantly reduced cardiovascular events in patients with eGFR ≥60 (hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58-0.91; P = .006), and reduced but not significant for patients with eGFR ≥45 and <60 (HR 0.85; 95% CI, 0.63-1.14; P = .27) or eGFR <45 mL/Min/1.73 m2 (HR 0.90; 95% CI 0.62-1.33; P = .61). An interaction test of treatment by eGFR category was not significant (P value for interaction = .30).Conclusion: Higher-dose pitavastatin therapy reduced LDL levels and cardiovascular events in stable CAD patients irrespective of eGFR level, although the effect on events appeared to be numerically lower in patients with lower eGFR. [ABSTRACT FROM AUTHOR]

Accurate vessel segmentation in ultrasound images is difficult to realize given the poor image quality of such images. In this study, a local-phase-based snake is proposed to improve the accuracy of vessel segmentation in ultrasound images. In the proposed snake framework, image energy is generated using the local phase of the ultrasound image. By using the intensity-invariant local phase, we can obtain identical image energies on all edges regardless of the strengths of their intensity contrasts. In addition, by minimizing the identical local-phase-based image energy, the snake can be pulled uniformly toward the strong and weak edges, and accurate vessel segmentation in ultrasound images can be achieved. The performance of the proposed segmentation method is evaluated using three types of vessels. We then compare it with the performances of the gradient-based standard snake and snake that uses the balloon model. The evaluation results show that the proposed local-phase-based snake accurately segments vessels from ultrasound images and performs better than the known methods. [ABSTRACT FROM AUTHOR]

Purpose We evaluated the safety and feasibility of a new anastomotic device that simplifies coronary distal anastomosis during minimally invasive and robotically assisted coronary artery bypass graft surgery (CABG). Description Fourteen miniature pigs underwent off-pump CABG using bilateral internal thoracic arteries (ITA), namely, left ITA to left anterior descending artery and right ITA to right coronary artery. The device was used for distal anastomosis in a device group (n = 11), and conventional 7-0 polypropylene suture in a control group (n = 3). Graft flow was measured intraoperatively. One-month, 3-month, and 6-month postoperative angiography evaluations were done. Histopathologic examination of the anastomosis was also done. Evaluation Baseline and intraoperative characteristics were similar in the two groups. There was no difference of anastomotic time between groups ( p = 0.59). Graft flows were also similar ( p = 0.55), with good diastolic pattern in both groups. Angiography demonstrated FitzGibbon A patency in all anastomoses of both groups at each evaluation period. Histopathologic examination showed nonspecific inflammatory changes in the device group. Conclusions The safety and feasibility of this anastomotic device for distal coronary anastomosis were shown in the swine model. [ABSTRACT FROM AUTHOR]

We present a coarse-to-fine dot array marker detection algorithm which can extract dot features with high accuracy and low uncertainty. The contribution of this paper is twofold: one is a configurable dot array marker detection framework which enables real-time multi-marker tracking with compact marker size (coarse detection); the other is a closed-form sub-pixel edge localization method including the formulation and the implementation (fine localization). The marker pattern together with the dot contours is detected in a fast but coarse way for efficiency consideration, using simple thresholding and hierarchical contour analysis. If the marker pattern matches with one of predefined marker descriptors, sub-pixel edge point localization of the dot contour is performed within the detected marker region by searching the zero-crossing in the convolution of the marker image with a Laplacian-of-Gaussian (LoG) kernel. A closed-form solution is proposed to localize the “true” edge point in a 3 × 3 neighborhood of a candidate pixel by solving a quartic equation. The dot center is finally extracted by ellipse fitting and re-ordered according to an orientation indicator. The algorithm was evaluated against both synthetic and real image data, and also in real applications where stereo visual trackers were implemented using the proposed marker detection algorithm. Experimental results show that (1) the marker detection algorithm yielded a feature detection error of less than 0.1 pixel with real-time performance; (2) the uncertainties in both localizing static 2-D dot features and 3-D pose tracking were obviously reduced by performing the sub-pixel localization; and (3) the feasibility of the marker tracking under stereo laparoscopic views was confirmed in an in vivo animal experiment. [ABSTRACT FROM AUTHOR]

Abstract: Hypercholesterolemia and dyslipidemia are independent risk factors for cardiovascular disease and death. Statins are the drugs of choice to decrease plasma cholesterol and have other beneficial actions beyond lipid-lowering leading to substantial improvements in cardiovascular morbidity and mortality. However, evaluation of the effects of statins to reduce overall morbidity and mortality must integrate metabolic consequences of statin therapy with its lipid-lowering effect. Indeed, reduction in LDL-cholesterol to target level achieved by statins does not completely eliminate risk of cardiovascular disease and may elevate metabolic risk factors that contribute to dysregulation of metabolic homeostasis. This may lead to increased incidence of diabetes and its cardiovascular complications that are explained, in part, by reciprocal relationships between insulin resistance and endothelial dysfunction. Genetic factors may determine 40–60% of total cholesterol levels and 70% of the efficacy of statin treatments. Metabolic and cardiovascular phenotypes that are either genetically determined or environmentally acquired are also important determinants of responses to specific statins. Moreover, differences between biological outcomes of specific statins or increasing dosages of statins result in differential metabolic actions due to off-target or unknown mechanism that have important implications for the use of statins to reduce overall morbidity and mortality. In this review, we discuss differential cardiovascular and metabolic pleiotropic actions of specific statins that interact in a context-dependent manner with patient phenotypes and genotypes. These important considerations may influence progression of atherosclerosis, risk of diabetes, and modulation of insulin resistance that help determine overall morbidity and mortality in patients undergoing statin therapy. [Copyright &y& Elsevier]

Background: Moderate global cooling of myocardial tissue was shown to destabilize 2-dimensional (2-D) reentry and facilitate its termination. Objective: This study sought to test the hypothesis that regional cooling destabilizes rotors and facilitates termination of spontaneous and DC shock-induced subepicardial reentry in isolated, endocardially ablated rabbit hearts. Methods: Fluorescent action potential signals were recorded from 2-D subepicardial ventricular myocardium of Langendorff-perfused rabbit hearts. Regional cooling (by 5.9°C ± 1.3°C) was applied to the left ventricular anterior wall using a transparent cooling device (10 mm in diameter). Results: Regional cooling during constant stimulation (2.5 Hz) prolonged the action potential duration (by 36% ± 9%) and slightly reduced conduction velocity (by 4% ± 4%) in the cooled region. Ventricular tachycardias (VTs) induced during regional cooling terminated earlier than those without cooling (control): VTs lasting >30 seconds were reduced from 17 of 39 to 1 of 61. When regional cooling was applied during sustained VTs (>120 seconds), 16 of 33 (48%) sustained VTs self-terminated in 12.5 ± 5.1 seconds. VT termination was the result of rotor destabilization, which was characterized by unpinning, drift toward the periphery of the cooled region, and subsequent collision with boundaries. The DC shock intensity required for cardioversion of the sustained VTs decreased significantly by regional cooling (22.8 ± 4.1 V, n = 16, vs 40.5 ± 17.6 V, n = 21). The major mode of reentry termination by DC shocks was phase resetting in the absence of cooling, whereas it was unpinning in the presence of cooling. Conclusion: Regional cooling facilitates termination of 2-D reentry through unpinning of rotors. [ABSTRACT FROM AUTHOR]

Abstract: Reciprocal relationships between endothelial dysfunction and insulin resistance suggest that therapies improving endothelial dysfunction will simultaneously improve insulin sensitivity and other metabolic parameters. However, previous studies with some statins either did not alter insulin sensitivity or promoted insulin resistance despite significant improvements in endothelial dysfunction and decreases in circulating pro-inflammatory markers. This may be due to pleiotropic or off-target effects of some statins to cause insulin resistance by diverse mechanisms unrelated to endothelial dysfunction. Indeed, there is evidence of other differential metabolic actions of distinct statins including effects on hydroxymethylglutaryl-CoA reductase inhibition, isoprotenoid synthesis, calcium release, glucose transport, insulin secretion, and/or insulin resistance. Pravastatin increases expression of adiponectin mRNA, enhances adiponectin secretion, increases plasma levels of adiponectin, and enhances insulin sensitivity in mice and humans. Clinical studies including large scale randomized controlled trials demonstrate potential differences between individual statins, with pravastatin promoting risk reduction for new onset of diabetes. Conversely, other statins including atorvastatin, rosuvastatin, and simvastatin all promote significant increase in this risk. Given the frequent concordance of metabolic diseases including diabetes, obesity, and metabolic syndrome with cardiovascular diseases associated with hyperlipidemia, it is important to understand the potential metabolic risks and benefits of therapies with distinct statins. In this review, we discuss these differential effects of statins on metabolic homeostasis and insulin sensitivity. [Copyright &y& Elsevier]

Summary: Objectives: Recent studies have demonstrated that not only plasma low-density lipoprotein (LDL) levels, but also the number of small dense LDL particles are involved in the development of arteriosclerosis. Anion exchange resins can reduce plasma LDL levels and affect LDL particle size via increasing triglycerides. In the present study, the effects of short-term colestimide administration on LDL particle size were investigated. Methods: Obese patients with primary hyperlipidemia (n =21) were administered 3000mg/day of colestimide for 1 month and fasting blood was obtained before and after the treatment. LDL particle size and number were measured by nuclear magnetic resonance (NMR) lipoprofile using magnetic resonance spectroscopy. Results: Levels of plasma LDL cholesterol decreased from 155.5mg/dl to 128.1mg/dl (p <0.001) and levels of apolipoprotein B decreased from 139.2mg/dl to 120.6mg/dl (p <0.001) by colestimide administration. Levels of high-density lipoprotein (HDL) cholesterol and triglyceride were unaltered. LDL particle size did not change, whereas LDL particle numbers decreased from 1920.3nmol/l to 1568.8nmol/l (p <0.01). Conclusions: Short-term administration of colestimide to patients with hyperlipidemia reduced LDL particle numbers. LDL particle size was not changed. [Copyright &y& Elsevier]

Abstract: Adiponectin is a protein secreted by adipose cells that may couple regulation of insulin sensitivity with energy metabolism and serve to link obesity with insulin resistance. Obesity-related disorders characterized by insulin resistance including the metabolic syndrome, diabetes, atherosclerosis, hypertension, and coronary artery disease are associated with both decreased adiponectin levels and endothelial dysfunction. Recent studies demonstrate that adiponectin has insulin-sensitizing effects as well as antiatherogenic properties. Lifestyle modifications and some drug therapies to treat atherosclerosis, hypertension, diabetes, and coronary heart disease have important effects in increasing adiponectin levels, decreasing insulin resistance, and improving endothelial dysfunction. In this review, we discuss insights into the relationships between adiponectin levels, insulin resistance, and endothelial dysfunction that are derived from various therapeutic interventions. The effects of lifestyle modifications and cardiovascular drugs on adiponectin levels and insulin resistance suggest plausible mechanisms that may be important for understanding and treating atherosclerosis and coronary heart disease. [Copyright &y& Elsevier]

Background: Modification of spiral wave (SW) reentry by antiarrhythmic drugs is a central issue to be challenged for better understanding of their benefits and risks. Objective: We investigated the effects of pilsicainide and/or verapamil, which block sodium and L-type calcium currents (INa and ICa,L), respectively, on SW reentry. Methods: A two-dimensional epicardial ventricular muscle layer was created in rabbit hearts by cryoablation (n = 32), and action potential signals were analyzed by high-resolution optical mapping. Results: During constant stimulation, pilsicainide (3–5 μM) caused a frequency-dependent decrease of conduction velocity (CV; by 20%–54% at 5 Hz) without affecting action potential duration (APD). Verapamil (3 μM) caused APD shortening (by 16% at 5 Hz) without affecting CV. Ventricular tachycardias (VTs) that were induced were more sustained in the presence of either pilsicainide or verapamil. The incidence of sustained VTs (>30 s)/all VTs per heart was 58% ± 9% for 5 μM pilsicainide vs. 22% ± 9% for controls and 62% ± 10% for 3 μM verapamil vs. 22% ± 8% for controls. The SWs with pilsicainide were characterized by slower rotation around longer functional block lines (FBLs), whereas those with verapamil were characterized by faster rotation around shorter FBLs. Combined application of 3 μM pilsicainide and 3 μM verapamil resulted in early termination of VTs (sustained VTs/all VTs per heart: 2% ± 2% vs. 29% ± 9% for controls); SWs showed extensive drift and decremental conduction, leading to their spontaneous annihilation. Conclusion: Blockade of either INa or ICa,L stabilizes SWs in a two-dimensional epicardial layer of rabbit ventricular myocardium to help their persistence, whereas blockade of both currents destabilizes SWs to facilitate their termination. [Copyright &y& Elsevier]

Abstract: Differential effects of sodium channel blockers, an I Kr blocker (nifekalant) and amiodarone on the spiral-type reentry, were investigated in rabbit hearts by using a high-resolution optical mapping system. Two-dimensional subepicardial layer of left ventricular myocardium with uniform anisotropy was prepared by endocardial cryoablation. During ventricular tachycardia (VT) elicited by cross-field stimulation, spiral-type excitations rotating around functional block lines (FBLs) were visualized. All the sodium channel blockers stabilized rotors; VT duration was prolonged in association with increases of FBLs and VT cycle length. The rotors in the presence of nifekalant were characterized by large meandering, long FBLs, and frequent front-tail interactions generating wave breaks. Amiodarone (acute application) increased FBLs and VT cycle length, but shortened the VT duration with minimal front-tail interaction. These results suggest that multifaceted drug action on both depolarization and repolarization may be required for the early termination of spiral-type reentry without causing breakup of rotors. [Copyright &y& Elsevier]

Background Effects of omega-3 fatty acids (n − 3 FA) combined with fenofibrate are not yet investigated, compared with fenofibrate. Methods This was a randomized, single-blind, placebo-controlled, parallel study. Age, sex, and body mass index were matched among groups. All patients were recommended to maintain a low fat diet. Fifty patients with hypertriglyceridemia in each group were given placebo, n − 3 FA 2 g + fenofibrate 160 mg (combination), or fenofibrate 160 mg, respectively daily for 2 months. Results Placebo, combination, and fenofibrate significantly decreased triglycerides by 7%, 41% and 30%, respectively and triglycerides/HDL cholesterol ratio by 11%, 45% and 32%, respectively relative to baseline measurements (all P < 0.05 by paired t -test). When compared with placebo and fenofibrate, these with combination were significant ( P < 0.001 by ANOVA). When compared with placebo, both combination and fenofibrate significantly decreased apolipoprotein B and non-HDL cholesterol and improved flow-mediated dilation and reduced CRP and fibrinogen (all P < 0.05 by ANOVA), however, there were no significant differences between combination and fenofibrate. When compared with placebo, both combination and fenofibrate significantly reduced insulin and glucose (both P < 0.05 by ANOVA), and improved insulin sensitivity ( P = 0.005 by ANOVA). However, there were no significant differences between combination and fenofibrate. Conclusions When compared with fenofibrate, combination significantly decreased triglycerides and triglycerides/HDL cholesterol ratio. Otherwise, combination and fenofibrate significantly reduced apolipoprotein B and non-HDL cholesterol and improved flow-mediated dilation and reduced CRP and fibrinogen to a similar extent. Also, combination and fenofibrate significantly improved insulin sensitivity to a similar extent by reducing insulin and glucose in patients with hypertriglyceridemia. [ABSTRACT FROM AUTHOR]