Manmeet Singh

The role of insulin resistance in the pathogenesis of atherosclerotic cardiovascular disease: an updated review.

Insulin resistance is the main pathologic mechanism that links the constellation of clinical, metabolic and anthropometric traits with increased risk for cardiovascular disease and type II diabetes mellitus. These traits include hyperinsulinemia, impaired glucose intolerance, endothelial dysfunction, dyslipidemia, hypertension, and generalized and upper body fat redistribution. This cluster is often referred to as insulin resistance syndrome. The progression of insulin resistance to diabetes mellitus parallels the progression of endothelial dysfunction to atherosclerosis leading to cardiovascular disease and its complications. In fact, insulin resistance assessed by homeostasis model assessment (HOMA) has shown to be independently predictive of cardiovascular disease in several studies and one unit increase in insulin resistance is associated with a 5.4% increase in cardiovascular disease risk. This review article addresses the role of insulin resistance as a main causal factor in the development of metabolic syndrome and endothelial dysfunction, and its relationship with cardiovascular disease. In addition to this, we review the type of lifestyle modification and pharmacotherapy that could possibly ameliorate the effect of insulin resistance and reverse the disturbances in insulin, glucose and lipid metabolism.

Pathophysiology of coronary artery disease leading to acute coronary syndromes

Acute myocardial infarction (AMI) and sudden cardiac death (SCD) are among the most serious and catastrophic of acute cardiac disorders, accounting for hundreds of thousands of deaths each year worldwide. Although the incidence of AMI has been decreasing in the US according to the American Heart Association, heart disease is still the leading cause of mortality in adults. In most cases of AMI and in a majority of cases of SCD, the underlying pathology is acute intraluminal coronary thrombus formation within an epicardial coronary artery leading to total or near-total acute coronary occlusion. This article summarizes our current understanding of the pathophysiology of these acute coronary syndromes and briefly discusses new approaches currently being researched in an attempt to define and ultimately reduce their incidence.

The role of lipoprotein-associated phospholipase A2 on cardiovascular disease risk assessment and plaque rupture: a clinical review

During the last several last decades, reduction in lipids has been the main focus to decrease the risk of coronary heart disease (CHD). Several lines of evidence, however, have indicated that lipids account only for the <50% of variability in cardiovascular risk in the United States. Therefore, for better identification of people at high cardiovascular risk, a more effective and complete approach is required. Our understanding of atherosclerosis has shifted from a focal disease resulting in symptoms caused by severe stenosis to a systemic disease distinguished by plaque inflammation with a potential to rupture and thrombosis, turning a substenotic atherosclerotic lesion into a complete occlusive lesion. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a novel inflammatory biomarker that can provide much needed information about plaque inflammation and plaque stability. Lp-PLA(2) is among the multiple biomarkers that have been associated with increased CHD risk. In this present work, we review the evidence from previous studies addressing the effect of different therapies on decreasing Lp-PLA(2) and the role of direct Lp-PLA(2) inhibitors. This work also briefly reviews the evidence of Lp-PLA(2) clinical utility as a potential marker of vascular inflammation and formation of rupture prone plaques. Additionally, we also discuss the implication of available evidence in context of current cardiovascular inflammatory biomarkers recommendations and the evidence from epidemiologic studies addressing the relationship of Lp-PLA(2) and risk of cardiovascular disease.

Femoral Micropuncture or Routine Introducer Study (FEMORIS)

Objectives: The Micropuncture® 21-gauge needle may reduce complications related to vessel trauma from inadvertent venous or posterior arterial wall puncture. Methods: This was a single-center, multiple-user trial. Four hundred and two patients undergoing possible or definite percutaneous coronary intervention (PCI) were randomized 1:1 to an 18-gauge versus a 21-gauge needle. Patients and personnel pulling the sheaths and performing the follow-up were blinded. The primary end point was a composite of access bleeding. Events were tabulated following sheath removal, ≤24 h after the procedure and at the follow-up (at 1-2 weeks). End points were blindly adjudicated. Results: The event rate overall was 12.4% and did not differ significantly between groups, although the 21-gauge needle was found to reduce events by more than one third. An exploratory subgroup analysis of prespecified variables indicated that: patients who did not undergo PCI or elective procedures, female patients and those with a final sheath size of ≤6 Fr all had a significant or near-significant reduction of complications with Micropuncture. Conclusions: Although no significant differences between the use of the 18- and 21-gauge needles were observed, there was a 50-75% reduction with Micropuncture in several subgroups. The study was terminated prematurely. Access site complications may be reduced by the use of the 21-gauge needle, particularly when the risk of bleeding is not high. Further multicenter data will be required to confirm these hypothesis-generating observations.

Efficacy of Combination Drug Pulse Therapy in Maintaining Lipid Levels in Patients Intolerant of Daily Statin Use

The objective of this study was to evaluate the efficacy of combination drug pulse therapy in maintaining lipid levels in patients intolerant of a daily dose of statins. Twenty‐three patients, previously receiving aggressive statin therapy, were treated twice weekly with rosuvastatin or atorvastatin in different dosages along with ezetimibe as well as daily doses of bile acid sequestrant for a mean period of 4.5 months. The recommended National Cholesterol Education Program Adult Treatment Panel III goals had already been achieved in 78% of patients (n=18) before starting combination pulse therapy. This combination therapy significantly increased high‐density lipoprotein cholesterol values by 5.82% (t=2.138, P=.044), while the increases in total cholesterol, low‐density lipoprotein cholesterol, triglyceride, and apolipoprotein B levels compared with baseline were not statistically significant. Overall, 3 of 23 patients (13%) discontinued the combination therapy because of muscle‐related symptoms over a mean course of 4.5 months of treatment.

Resistant Hypertension and Associated Comorbidities in a Veterans Affairs Population

Resistant hypertension (RH) is understudied and its reported prevalence varies with study populations. The authors sought to determine its prevalence and association with certain comorbid conditions in a Veterans Affairs population. This cross‐sectional study utilized demographic and clinical data from 17,466 patients. Chi‐square or t test was used for comparing groups with and without RH. Multivariate logistic regression analysis was used to determine independent associations. Overall, the prevalence of RH was 9%, and 13% of all hypertensive patients met criteria for RH. After adjusting for confounding variables, RH was significantly associated with older age (odds ratio [OR], 1.007), higher body mass index (OR, 1.04), Framingham score (OR, 1.14), and coexisting coronary artery disease, cerebrovascular accident/transient ischemic attack, peripheral vascular disease, congestive heart failure, chronic kidney disease, diabetes mellitus, erectile dysfunction, and metabolic syndrome (OR, 1.3, 1.32, 1.29, 2.88, 2.13, 1.2, 1.12, and 1.2, respectively; all P<.05). Our results indicate a complex interplay of certain comorbid conditions among patients with RH and suggest the need for multifaceted interventions in this high‐risk population to prevent cardiovascular events.

Coronary Stents and Noncardiac Surgery: Current Clinical Challenges and Conundrums

This article discusses how perioperative physicians are currently faced with unique challenges when providing care for surgical patients who have undergone recent percutaneous transluminal coronary angioplasty with drug-eluting stent (DES) placement. Despite adhering to the currently recommended antiplatelet regimens, these patients may still be at risk for sustaining a myocardial infarction secondary to stent thrombosis during the perioperative period. Given the high morbidity and mortality rates associated with perioperative myocardial infarction, it is important that the perioperative care of surgical patients with previous DES placement should be discussed, evaluated, and clarified by all practitioners who may be involved in their care.

Lipoprotein-associated phospholipase A2 mass is significantly reduced in dyslipidemic patients treated with lifestyle modification and combination lipid-modifying drug therapy.

Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) mass is a novel inflammatory biomarker. In human blood, Lp-PLA(2) is predominately associated with low-density lipoprotein (LDL). This study examines the ability of lifestyle modification (diet and exercise) and combination lipid therapy to reduce Lp-PLA(2) levels while also determining the relationship between changes in LDL cholesterol and Lp-PLA(2). Thirty dyslipidemic patients who received lifestyle intervention and combination lipid therapy for an average of 6 months were included in these analyses (mean age, 60.9 years); 40% had stable angiographically established coronary artery disease, 40% had the metabolic syndrome, and 70% were men. Drug therapy included omega-3 fish oil, extended-release niacin, colesevelam hydrochloride, and a fixed combination of 10-mg ezetimibe and 40-mg simvastatin. The study revealed a 33% reduction in mean Lp-PLA(2) values (baseline 224.9+/-47.5 vs posttreatment 149.5+/-35.5 ng/mL; P<.001). Significant changes in mean LDL cholesterol from baseline (127.9+/-49.3 vs posttreatment 65.2+/-32.1 mg/dL; P<.001) were also observed. However, regression analysis revealed only a weak positive relationship between changes in LDL cholesterol and Lp-PLA(2) mass (R(2)=0.29; P<.01). Thus, Lp-PLA(2) mass is significantly reduced with lifestyle and combination lipid therapy. Changes in Lp-PLA(2) were only partially explained by the changes observed for LDL cholesterol.

Effects of lifestyle counseling and combination lipid-modifying therapy on lipoprotein-associated phospholipase A2 mass concentration.

BACKGROUND Lipoprotein-associated phospholipase A2 (Lp-PLA(2)) is a novel inflammatory biomarker that is associated with increased cardiovascular disease risk independent of and additive to traditional risk factors. Lp-PLA(2) activity is correlated with the degree of inflammation in the atherosclerotic plaque. In human blood, approximately 80% of Lp-PLA(2) is associated with low-density lipoproteins (LDL). Thus, it is hypothesized that changes in Lp-PLA(2) should imitate the changes in the LDL cholesterol. OBJECTIVE In this present study, we examined the efficacy of lifestyle intervention and combination lipid-lowering therapy on reducing the Lp-PLA(2) levels and determined the relationship between changes in LDL-C and Lp-PLA(2). METHODS This retrospective chart review study includes two hundred forty eight patients (58% men and 42% women) who completed the life style intervention in combination with pharmacologic therapy for an average period of 10.5 months. Life style modification included diet and exercise counseling. Combination therapy included omega 3 fish oil (2000mg/d), extended-release niacin (500-1000mg/d), ezetimibe (10mg/d), fenofibrate 160mg/d and colesevelam HCI (1850mg/d), as well as statins. The statins used were either simvastatin (20-40mg/d) or rosuvastatin (5-20mg/d). Sixty five percent (n=161) received low to medium doses of simvastatin, whereas 35% (n=87) received low to medium doses of rosuvastatin. RESULTS The study revealed a 32.5% reduction in mean Lp-PLA(2) values (baseline 181.1±41.5 vs 122.1±28.1 ng/mL after treatment; P<.001). The change observed in LDL-C was 41%, (baseline 126.2±43 vs 73.9±37.7mg/dL after treatment), which also was significant (P < .001). However, a Pearson correlation test analysis revealed only a weak positive association between changes in Lp-PLA(2) and LDL-C (r(2)=0.052, P < .001). CONCLUSION Lp-PLA(2) is reduced with the use of life style counseling and combination lipid lowering therapy. Results also revealed that changes in Lp-PLA(2) may be partially explained by the changes in LDL-C.

A Case of in-stent thrombosis in a patient with drug eluting stents during perioperative management with glycoprotein IIb/IIIa inhibitors

The management of patients with drug eluting stents (DES) who require early surgical intervention prior to the completion of antiplatelet therapy is challenging. Available literature suggests that bridging these high risk patients with glycoprotein IIb/IIIa (g2b3a) inhibitors could be efficacious in preventing stent thrombosis (Ben Morrison et al., Catheter Cardiovasc Interv 2012;79;575–582). However, this still remains to be proven in larger prospective studies. We report a case of stent thrombosis in a patient with DES planned for neurosurgery while on bridging g2b3a inhibitors therapy in the perioperative period.