Arman Qamar

Effect of interleukin 1β inhibition in cardiovascular disease.

Purpose of review Atherosclerosis is greatly influenced by inflammatory mediators at all phases. Recent studies have suggested a causal role of one such mediator, interleukin 1&bgr; (IL-1&bgr;), in the development of atherosclerotic vascular disease. This review highlights recent investigation of the role of IL-1&bgr; in atherosclerosis and the potential of its inhibition as a promising therapeutic strategy for the treatment of atherosclerotic vascular disease. Recent findings Studies in animals have generally shown decreased atherosclerotic plaque burden in atherosclerosis-prone mice deficient in IL-1&bgr; and increased plaque in mice exposed to excess IL-1&bgr;. In humans, IL-1&bgr; was found in greater concentrations in atherosclerotic human coronary arteries compared with normal coronary arteries. Preclinical and clinical studies of IL-1&bgr; inhibition have shown efficacy in the treatment of several inflammatory disorders, suggesting that IL-1&bgr; may be a novel therapeutic target for anti-inflammatory therapy in atherosclerosis, such as coronary artery disease (CAD). Summary IL-1&bgr; inhibition offers an interesting and biology-based opportunity to test the potential beneficial effects of an anti-inflammatory therapeutic strategy in patients with CAD. A large clinical trial evaluating the impact of IL-1&bgr; inhibition in CAD is ongoing and will be an important test of the inflammation hypothesis in CAD.

Differential Association of Plasma Angiopoietin-Like Proteins 3 and 4 With Lipid and Metabolic Traits

Objective—Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) are secreted proteins that inhibit lipoprotein lipase in vitro. Genetic variants at the ANGPTL3 and ANGPTL4 gene loci are significantly associated with plasma lipid traits. The aim of this study was to evaluate the association of plasma ANGPTL3 and ANGPTL4 concentrations with lipid and metabolic traits in a large community-based sample. Approach and Results—Plasma ANGPTL3 and ANGPTL4 levels were measured in 1770 subjects using a validated ELISA assay. A Pearson unadjusted correlation analysis and a linear regression analysis adjusting for age, sex, and race were performed. ANGPTL3 levels were significantly positively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels (both P<2×10−5) but not triglycerides. In contrast, ANGPTL4 levels were significantly negatively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (both P<2×10−5) and positively associated with triglycerides (P=0.003). In addition, ANGPTL4, but not ANGPTL3, levels were significantly positively associated with fasting blood glucose and metabolic syndrome. Conclusions—Despite having similar biochemical effects in vitro, plasma ANGPTL3 and ANGPTL4 concentrations have nearly opposite relationships with plasma lipids. ANGPTL4 is strongly negatively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol and positively with multiple features of the metabolic syndrome including triglycerides, whereas ANGPTL3 is positively associated with low-density lipoprotein cholesterol and high-density lipoprotein cholesterol and not with metabolic syndrome traits including triglycerides. Although ANGPTL3 and ANGPTL4 both inhibit lipoprotein lipase in vitro and influence lipoprotein metabolism in vivo, the physiology of these related proteins and their effects on lipoproteins is clearly divergent and complex.

Plasma Apolipoprotein C-III Levels, Triglycerides, and Coronary Artery Calcification in Type 2 Diabetics

Objective—Triglyceride-rich lipoproteins have emerged as causal risk factors for developing coronary heart disease independent of low-density lipoprotein cholesterol levels. Apolipoprotein C-III (ApoC-III) modulates triglyceride-rich lipoprotein metabolism through inhibition of lipoprotein lipase and hepatic uptake of triglyceride-rich lipoproteins. Mutations causing loss-of-function of ApoC-III lower triglycerides and reduce coronary heart disease risk, suggestive of a causal role for ApoC-III. Little data exist about the relationship of ApoC-III, triglycerides, and atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Here, we examined the relationships between plasma ApoC-III, triglycerides, and coronary artery calcification in patients with T2DM. Approach and Results—Plasma ApoC-III levels were measured in a cross-sectional study of 1422 subjects with T2DM but without clinically manifest coronary heart disease. ApoC-III levels were positively associated with total cholesterol (Spearman r=0.36), triglycerides (r=0.59), low-density lipoprotein cholesterol (r=0.16), fasting glucose (r=0.16), and glycosylated hemoglobin (r=0.12; P<0.0001 for all). In age, sex, and race-adjusted analysis, ApoC-III levels were positively associated with coronary artery calcification (Tobit regression ratio, 1.78; 95% confidence interval, 1.27–2.50 per SD increase in ApoC-III; P<0.001). As expected for an intermediate mediator, these findings were attenuated when adjusted for both triglycerides (Tobit regression ratio, 1.43; 95% confidence interval, 0.94–2.18; P=0.086) and separately for very low–density lipoprotein cholesterol (Tobit regression ratio, 1.14; 95% confidence interval, 0.75–1.71; P=0.53). Conclusions—In persons with T2DM, increased plasma ApoC-III is associated with higher triglycerides, less favorable cardiometabolic phenotypes, and higher coronary artery calcification, a measure of subclinical atherosclerosis. Therapeutic inhibition of ApoC-III may thus be a novel strategy for reducing plasma triglyceride-rich lipoproteins and cardiovascular risk in T2DM.

Effects of Niacin, Statin, and Fenofibrate on Circulating Proprotein Convertase Subtilisin/Kexin Type 9 Levels in Patients With Dyslipidemia

Recent trials demonstrated substantial improvement in lipid parameters with inhibition of proprotein convertase subtilisin-like/kexin type 9 (PCSK9). Although statins and fibrates have been reported to increase plasma PCSK9 levels, the effect of niacin on PCSK9 is unknown. We investigated the impact of niacin, atorvastatin, and fenofibrate on PCSK9 levels in 3 distinct studies. A statin-only study randomized 74 hypercholesterolemic patients to placebo, atorvastatin 10 mg/day, or atorvastatin 80 mg/day for 16 weeks. A dose-related increase in PCSK9 was noted such that atorvastatin 80 mg increased PCSK9 by a mean +27% (95% confidence interval [CI] +12 to +42), confirming the effect of statin therapy on raising PCSK9. A second study randomized 70 patients with carotid atherosclerosis to simvastatin 20 mg/day, simvastatin 80 mg/day, or simvastatin 20 mg/extended-release (ER) niacin 2 g/day. PCSK9 levels were increased with statin therapy, but decreased with the simvastatin 20 mg/ER niacin combination (mean -13%, CI -3 to -23). A final study involved 19 dyslipidemic participants on atorvastatin 10 mg with serial addition of fenofibric acid 135 mg followed by ER niacin 2 g/day. Fenofibric acid led to a +23% (CI +10 to +36, p = 0.001) increase in PCSK9; the addition of niacin resulted in a subsequent -17% decrease (CI -19 to -5, p = 0.004). A positive association was noted between change in PCSK9 and low-density lipoprotein cholesterol levels (r = 0.62, p = 0.006) with the addition of niacin. In conclusion, niacin therapy offsets the increase in PCSK9 levels noted with statin and fibrate therapy. A portion of the low-density lipoprotein cholesterol reduction seen with niacin therapy may be due to reduction in PCSK9.

Stroke Prevention in Atrial Fibrillation in Patients With Chronic Kidney Disease

Case Presentation: A 68-year-old woman with hypertension, diabetes mellitus, and congestive heart failure presented to the emergency department with palpitations. On physical examination, her heart rate was 130 bpm and irregularly irregular, her blood pressure was 120/70 mm Hg, and she weighed 60 kg. The ECG demonstrated atrial fibrillation (AF) with a rapid ventricular rate. Laboratory evaluation was remarkable for a serum creatinine of 1.3 mg/dL. Her symptoms resolved with heart rate control. AF is the most common arrhythmia in patients with chronic kidney disease (CKD) and is associated with increased risk of stroke and thromboembolism. The risk of stroke increases as renal function declines. Conversely, patients with CKD, particularly those on hemodialysis, are at an increased risk of bleeding. Oral anticoagulation is the most effective form of thromboprophylaxis in patients with AF at increased risk of stroke. Concern for bleeding has resulted in the underuse of anticoagulation in these patients. Warfarin and novel oral anticoagulants (NOACs) have been shown to be effective in preventing stroke in the general population of patients with AF. However, most randomized trials of antithrombotic therapy have excluded patients with severe renal impairment (estimated creatinine clearance [eCrCl] <30 mL·min−1·1.73 m−2). Thus, whether antithrombotic therapy with warfarin and NOACs is safe and reduces stroke in patients with AF and CKD is unclear. The CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes mellitus, prior stroke or transient ischemic attack or thromboembolism [doubled], vascular disease, age 65–74 years, sex category), as recommended in the current guidelines, should be used to determine stroke risk and indication for anticoagulation in patients with AF, including those with CKD. Periodic re-evaluation is recommended to assess stroke and bleeding risk. Aspirin monotherapy is not effective in stroke prevention in AF, including in patients …

Current status of data on cangrelor

P2Y12 receptor inhibition in addition to aspirin is the cornerstone of treatment in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI). Despite advances in contemporary antithrombotic therapy, periprocedural thrombotic complications such as myocardial infarction and stent thrombosis remain a major concern in patients treated with PCI. Current practice guidelines recommend treatment with a P2Y12 receptor inhibitor as early as possible in patients with ACS. Existing oral P2Y12 receptors inhibitors (clopidogrel, prasugrel, or ticagrelor) have several limitations such as delayed onset and offset of action, interindividual variation, and only oral availability. Cangrelor, an intravenous, fast-onset, direct-acting P2Y12 receptor inhibitor offers potent platelet inhibition that is rapidly reversible. In large randomized trials, cangrelor has shown substantial reduction in ischemic events with no increase in severe bleeding compared with clopidogrel among patients undergoing PCI. Cangrelor is approved as an adjunct to PCI to reduce the risk of periprocedural MI, repeat coronary revascularization, and stent thrombosis in patients who have not been pretreated with a P2Y12 receptor inhibitor and are not receiving a glycoprotein IIb/IIIa inhibitor. This review aims at providing a comprehensive analysis of the current evidence pertaining to the role of cangrelor in contemporary practice.

Anticoagulation therapy: Balancing the risks of stroke and bleeding in CKD

Whether anticoagulation with warfarin is safe and reduces risk of stroke in patients with atrial fibrillation and chronic kidney disease is unclear. A recent observational study shows a net clinical benefit of warfarin—without increased risk of bleeding—in this population, including in patients on dialysis.

Extended-release Niacin Acutely Suppresses Postprandial Triglyceridemia

OBJECTIVE Postprandial triglyceridemia predicts cardiovascular events. Niacin might lower postprandial triglycerides by restricting free fatty acids. Immediate-release niacin reduced postprandial triglycerides, but extended-release niacin failed to do so when dosed the night before a fat challenge. The study aims were to determine whether extended-release niacin dosed before a fat challenge suppresses postprandial triglycerides and whether postprandial triglycerides are related to free fatty acid restriction. METHODS A double-blinded, placebo-controlled, random-order crossover experiment was performed, in which healthy volunteers took 2 g extended-release niacin or placebo 1 hour before heavy cream. We sampled blood over 12 hours and report triglycerides and free fatty acid as means ± standard deviation for incremental area under the curve (AUC) and nadir. RESULTS By combining 43 fat challenges from 22 subjects, postprandial triglycerides incremental AUC was +312 ± 200 mg/dL*h on placebo versus +199 ± 200 mg/dL*h on extended-release niacin (33% decrease, P=.02). The incremental nadir for free fatty acid was -0.07 ± 0.15 mmol/L on placebo versus -0.27 ± 0.13 mmol/L on extended-release niacin (P<.0001), and free fatty acid incremental AUC decreased from +2.9 ± 1.5 mmol/L*h to +1.5 ± 1.5 mmol/L*h on extended-release niacin (20% decrease, P=.0015). The incremental AUC for triglycerides was strongly related to the post-dose decrease in free fatty acid (r = +0.58, P=.0007). CONCLUSIONS Given right before a fat meal, even a single dose of extended-release niacin suppresses postprandial triglyceridemia. This establishes that postprandial triglycerides suppression is an acute pharmacodynamic effect of extended-release niacin, probably the result of marked free fatty acid restriction. Further study is warranted to determine whether mealtime dosing would augment the clinical efficacy of extended-release niacin therapy.

Targeting ApoC-III to Reduce Coronary Disease Risk

Triglyceride-rich lipoproteins (TRLs) are causal contributors to the risk of developing coronary artery disease (CAD). Apolipoprotein C-III (apoC-III) is a component of TRLs that elevates plasma triglycerides (TGs) through delaying the lipolysis of TGs and the catabolism of TRL remnants. Recent human genetics approaches have shown that heterozygous loss-of-function mutations in APOC3, the gene encoding apoC-III, lower plasma TGs and protect from CAD. This observation has spawned new interest in therapeutic efforts to target apoC-III. Here, we briefly review both currently available as well as developing therapies for reducing apoC-III levels and function to lower TGs and cardiovascular risk. These therapies include existing options including statins, fibrates, thiazolidinediones, omega-3-fatty acids, and niacin, as well as an antisense oligonucleotide targeting APOC3 currently in clinical development. We review the mechanisms of action by which these drugs reduce apoC-III and the current understanding of how reduction in apoC-III may impact CAD risk.

Cangrelor Use Since FDA Approval: A Single-Center, Real-World Experience at a Tertiary Care Hospital

Cangrelor, a rapidly acting, intravenous P2Y12 inhibitor, has been approved for use during percutaneous coronary intervention (PCI). The 3 phase 3 CHAMPION (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials collectively provided robust randomized data in