Sandeep Singla

Regulation of autophagy and apoptosis in response to ox-LDL in vascular smooth muscle cells, and the modulatory effects of the microRNA hsa-let-7g

OBJECTIVES Regulation of autophagy and apoptosis during treatment of vascular smooth muscle cells (VSMCs) with pro-atherogenic stimuli, such as oxidized low density lipoprotein (ox-LDL), remains unclear. METHODS AND RESULTS We examined the expression of autophagy and apoptosis upon treatment of VSMCs with ox-LDL. Exposure to ox-LDL in modest amounts (10-40 μg/ml) enhanced autophagy (expression of beclin-1, LC3-II/LC3-1 ratio and Atg5) and apoptosis (expression of caspase-3, Bax, Bcl-2 and Bcl-xL); however, exposure to higher concentrations (≥ 60 μg/ml) induced high levels of apoptosis but autophagy declined. Pretreatment of VSMCs with the miRNA hsa-let-7 g inhibited autophagy, as LOX-1 expression and apoptosis declined. Hsa-let-7 g treatment also resulted in a decrease in intracellular ROS generation. Treatment with LOX-1 antibody had similar effects as hsa-let-7 g. Next, we studied autophagy and apoptosis in aortic segments from wild-type and LOX-1 knockout mice fed a high cholesterol diet, and observed increased autophagy as well as apoptosis in lipid-rich sections of aortas from wild-type mice and LOX-1 knockout mice (vs. corresponding controls); however, both autophagy and apoptosis in lipid-rich areas in aortic sections of LOX-1 knockout mice were less than in WT mice. These in vivo data are in keeping with in vitro data showing enhanced autophagy and apoptosis of VSMCs exposed to modest amount of ox-LDL. CONCLUSION This study provides first set of data on the regulation of autophagy and apoptosis in ox-LDL-treated VSMCs. Our observations also suggest that hsa-let-7 g acts as a critical regulator of autophagy and apoptosis by modulating LOX-1.

Current Concepts of the Role of Oxidized LDL Receptors in Atherosclerosis.

Atherosclerosis is characterized by accumulation of lipids and inflammatory cells in the arterial wall. Oxidized low-density lipoprotein (ox-LDL) plays important role in the genesis and progression of atheromatous plaque. Various scavenger receptors have been recognized in the past two decades that mediate uptake of ox-LDL leading to formation of foam cells. Inhibition of scavenger receptor A and CD36 has been shown to affect progression of atherosclerosis by decreasing foam cell formation. Lectin-type oxidized LDL receptor 1 (LOX-1) participates at various steps involved in the pathogenesis of atherosclerosis, and in experimental studies its blockade has been shown to affect the progression of atherosclerosis at multiple levels. In this review, we summarize the role of ox-LDL and scavenger receptors in the formation of atheroma with emphasis on effects of LOX-1 blockade.

Percutaneous intervention on the saphenous vein bypass grafts--long-term outcomes.

Background/Objective: In this era of drug eluting stents (DES), the long‐term outcome of percutaneous intervention (PCI) on saphenous venous grafts (SVG) is unknown. The objective of the study was to compare the long‐term outcomes of DES versus bare metal stent (BMS) in this population and to determine the predictors of outcomes. Methods: We reviewed the medical records of all patients who had PCI performed during January 2003 to February 2005 to obtain data cardiac risk factors, medications at discharge, angiographic details and outcomes. Results: One hundred and nine patient had PCI to SVG; of these, 37 patients received DES and the remaining had BMS. Over a mean follow‐up of 33 months, the PCI using DES was associated with 30% restenosis, 35% target vessel revascularization (TVR) and major adverse cardiac event (MACE) rate of 46% versus 35% restenosis, 38% TVR and 50% MACE rate with BMS. There was no significant difference in long‐term outcome with DES as compared to BMS. Conclusion: There was no difference in the long‐term outcomes of PCI on SVG irrespective of the type of stent used.

Cannabinoids and atherosclerotic coronary heart disease.

Marijuana is the most abused recreational drug in the United States. Cannabinoids, the active ingredients of marijuana, affect multiple organ systems in the human body. The pharmacologic effects of marijuana, based on stimulation of cannabinoid receptors CB1 and CB2, which are widely distributed in the cardiovascular system, have been well described. Activation of these receptors modulates the function of various cellular elements of the vessel wall, and may contribute to the pathogenesis of atherosclerosis. Clinically, there are reports linking marijuana smoking to the precipitation of angina and acute coronary syndromes. Recently, large published clinical trials with CB1 antagonist rimonabant did not show any significant benefit of this agent in preventing progression of atherosclerosis. In light of these findings and emerging data on multiple pathways linking cannabinoids to atherosclerosis, we discuss the literature on the role of cannabinoids in the pathophysiology of atherosclerosis. We also propose a marijuana paradox, which implies that inhalation of marijuana may be linked to precipitation of acute coronary syndromes, but modulation of the endocannabinoid system by a noninhalation route may have a salutary effect on the development of atherosclerosis.

The Risk of Adverse Cardiac and Bleeding Events Following Noncardiac Surgery Relative to Antiplatelet Therapy in Patients With Prior Percutaneous Coronary Intervention

Noncardiac surgery (NCS) may be required within the first year after percutaneous coronary intervention (PCI) in approximately 4% of patients and is the second most common reason for premature discontinuation of antiplatelet therapy (APT),which may, in turn, increase the risk of perioperative ischemic events, particularly stent thrombosis. Its continuation may increase the risk of perioperative bleeding. We review current information on the incidence of these events, particularly related to APT, describe potentially useful strategies to minimize the risks of adverse outcomes, and provide recommendations on APT use.

Review of Contemporary Antiarrhythmic Drug Therapy for Maintenance of Sinus Rhythm in Atrial Fibrillation

Atrial fibrillation (AF) is the most common rhythm disturbance seen in clinical practice, and its prevalence and incidence are rising rapidly as the population ages with its attendant complications. Management of AF involves anticoagulation, and fortunately new drugs for long-term anticoagulation are now available. Maintenance of sinus rhythm, though intuitively better than rate control strategy, has not been shown to offer mortality benefit. Still, maintenance of sinus rhythm is considered an appropriate therapeutic strategy when symptoms are not adequately controlled with rate control. Though significant advances have been made in ablation techniques for AF, pharmacological therapy is still the first line of treatment for rate control and maintenance of sinus rhythm, given ease of use, noninvasive nature, and limited experience with catheter-based ablation techniques. Class IC and III agents (Vaughan Williams classification) form the backbone for pharmacological maintenance of sinus rhythm. Dronedarone, a recently approved class III agent, provides a significant advance because of its relatively safe side effect profile. Currently drugs with selective atrial channels blocking properties, like Vernakalant, are being tested in trials and may provide an opportunity to maintain sinus rhythm with limited toxicity. Large trials are also being conducted to better define the efficacy of catheter-based ablation strategy as first-line treatment. Here, we review the current status of commonly used antiarrhythmic medications for the maintenance of sinus rhythm in AF.

Decorin in atherosclerosis

Atherosclerotic cardiovascular disease is a major cause of morbidity and mortality in the Western world. Despite tremendous strides in understandings its pathogenesis, it still remains a challenge because of gaps in our understanding of its initiation, progression and complications leading to the clinical syndromes of angina, acute coronary syndrome, cerebrovascular disease and peripheral vascular disease. Recent studies have provided impetus on the shift from models of atherosclerosis based on cellular interactions to models where the important role of extracellular matrix is recognized. Proteoglycans, especially those belonging to the small leucine-rich proteoglycan family of which decorin is a representative example, have come under close scrutiny for their role in atherogenesis. There is evidence from in vitro and in vivo animal models as well as humans to suggest an important role of decorin in attenuating progression of atherosclerosis. Decorin distribution in different blood vessels has been shown to inversely correlate with the tendency to develop atherosclerosis. Decorin seems to interact closely with different cellular components of the plaque milieu, thereby suggesting its role in influencing atherogenesis at different steps. Here we review the current understanding of the role of decorin in the pathogenesis of atherosclerosis.

Amiodarone-related hyponatremia: rare but potentially lethal.

Amiodarone is a one of the most commonly used antiarrhythmic drug with efficacy in both supraventricular and ventricular tachycardia. Hepatic, pulmonary, and thyroid adverse effect profiles of this drug are well described and mandate a close follow-up. We report a case of amiodarone-related hyponatremia, which is one of the rarest side effects associated with this medication and our case was unlike other previous case reports because severity of symptoms required hemodialysis for correction of hyponatremia despite trying dose reduction strategy.

Retrograde fractional flow reserve and recanalization of a chronic total occlusion of a saphenous venous graft

Chronic total occlusion (CTO) of the coronary artery represents a difficult group of lesions for percutaneous interventions. Conventionally, antegrade approach has been used to open these lesions, but recent literature provides evidence for the utility of retrograde approach in cases where initial antegrade approach is either not feasible or fails to recanalize the target vessel. This report illustrates retrograde CTO recanalization of saphenous vein graft (SVG) with fractional flow reserve utilization to determine ischemia in the territory of occluded SVG.

A patient with mexiletine-related psychosis

Mexiletine is a commonly used Class IB (Vaughan William classification) antiarrhythmic drug. We report a case of mexiletine-induced psychosis that was successfully managed by decreasing the dose and using alternative medications for management of ventricular tachycardia.