Sony Tuteja

High-Density Lipoproteins in the Prevention of Cardiovascular Disease: Changing the Paradigm

High‐density‐lipoprotein cholesterol (HDL‐C) has been identified in population studies as an independent inverse predictor of cardiovascular events. Although the causal nature of this association has been questioned, HDL and its major protein, apolipoprotein (apo)A1, have been shown to prevent and reverse atherosclerosis in animal models. In addition, HDL and apoA1 have several putatively atheroprotective functions, such as the ability to promote efflux of cholesterol from macrophages in the artery wall, inhibit vascular inflammation, and enhance endothelial function. Therefore, HDL‐C and apoA1 have been investigated as therapeutic targets for coronary heart disease. However, recent clinical trials with drugs that raise HDL‐C, such as niacin and inhibitors of cholesteryl ester transfer protein, have been disappointing. Here, we review the current state of the science regarding HDL as a therapeutic target.

Pharmacokinetic Interactions of the Microsomal Triglyceride Transfer Protein Inhibitor, Lomitapide, with Drugs Commonly Used in the Management of Hypercholesterolemia

To characterize the effects of two doses (10 and 60 mg) of lomitapide—a microsomal triglyceride transfer protein inhibitor approved as adjunct treatment to lower low‐density lipoprotein cholesterol levels in patients with homozygous familial hypercholesterolemia—on the pharmacokinetics of several lipid‐lowering therapies: atorvastatin, simvastatin, rosuvastatin, fenofibrate, ezetimibe, and niacin.

Dyslipidaemia: Cardiovascular prevention—end of the road for niacin?

The recently published HPS2–THRIVE study has shown that the addition of extended release niacin to statin therapy in patients with well-controlled levels of LDL cholesterol does not reduce the risk of cardiovascular events and might even increase harm. Consequently, the use of niacin to increase levels of HDL cholesterol is not recommended.

Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype‐Guided Antiplatelet Therapy

CYP2C19 genotype‐guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions.

Expression of Calgranulin Genes S100A8, S100A9 and S100A12 Is Modulated by n-3 PUFA during Inflammation in Adipose Tissue and Mononuclear Cells.

Calgranulin genes (S100A8, S100A9 and S100A12) play key immune response roles in inflammatory disorders, including cardiovascular disease. Long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) may have systemic and adipose tissue-specific anti-inflammatory and cardio-protective action. Interactions between calgranulins and the unsaturated fatty acid arachidonic acid (AA) have been reported, yet little is known about the relationship between calgranulins and the LC n-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We explored tissue-specific action of calgranulins in the setting of evoked endotoxemia and n-3 PUFA supplementation. Expression of calgranulins in adipose tissue in vivo was assessed by RNA sequencing (RNASeq) before and after n-3 PUFA supplementation and evoked endotoxemia in the fenofibrate and omega-3 fatty acid modulation of endotoxemia (FFAME) Study. Subjects received n-3 PUFA (n = 8; 3600mg/day EPA/DHA) or matched placebo (n = 6) for 6–8 weeks, before completing an endotoxin challenge (LPS 0.6 ng/kg). Calgranulin genes were up-regulated post-LPS, with greater increase in n-3 PUFA (S100A8 15-fold, p = 0.003; S100A9 7-fold, p = 0.003; S100A12 28-fold, p = 0.01) compared to placebo (S100A8 2-fold, p = 0.01; S100A9 1.4-fold, p = 0.4; S100A12 5-fold, p = 0.06). In an independent evoked endotoxemia study, calgranulin gene expression correlated with the systemic inflammatory response. Through in vivo and in vitro interrogation we highlight differential responses in adipocytes and mononuclear cells during inflammation, with n-3 PUFA leading to increased calgranulin expression in adipose, but decreased expression in circulating cells. In conclusion, we present a novel relationship between n-3 PUFA anti-inflammatory action in vivo and cell-specific modulation of calgranulin expression during innate immune activation.

Genetic coding variants in the niacin receptor, hydroxyl-carboxylic acid receptor 2, and response to niacin therapy

Objective Niacin has been used for seven decades to modulate plasma lipids, but its mechanism of action is still unclear. We sought to determine whether variants in the niacin receptor gene, hydroxyl–carboxylic receptor 2 (HCAR2), are associated with lipid response to treatment. Participants and methods Coding variants, rs7314976 (p.R311C) and rs2454727 (p.M317I), were genotyped in 2067 participants from the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial. AIM-HIGH was a randomized, placebo-controlled trial that was conducted to assess the effect of extended-release niacin in patients with cardiovascular disease aggressively treated with low-density lipoprotein cholesterol-lowering therapy. Results There was no association of p.R311C or p.M317I with changes in low-density lipoprotein cholesterol, triglycerides, or high-density lipoprotein cholesterol at 1 year in groups receiving placebo or extended-release niacin. In White patients, the reduction in lipoprotein (a) [Lp(a)] in response to niacin was greater in homozygous carriers of the major 317M allele (−22.7%; P=0.005) compared with minor allele carriers (−15.3%). This was directionally consistent in the Black participants. Upon combining both groups, the reduction in Lp(a) in response to niacin was significantly greater in the homozygous major allele carriers (−23.0%; P=0.003) compared with minor allele carriers (−15.2%). Conclusion Understanding the genetic contribution toward variation in response to niacin therapy, including Lp(a) reduction, could uncover mechanisms by which niacin decreases Lp(a), an important independent risk factor for cardiovascular disease.

Pharmacogenetics in Cardiovascular Medicine

Purpose of ReviewPharmacogenetics is an important component of precision medicine. Even within the genomic era, several challenges lie ahead in the road towards clinical implementation of pharmacogenetics in the clinic. This review will summarize the current state of knowledge regarding pharmacogenetics of cardiovascular drugs, focusing on those with the most evidence supporting clinical implementation—clopidogrel, warfarin, and simvastatin.Recent FindingsThere is limited translation of pharmacogenetics into clinical practice primarily due to the absence of outcomes data from prospective, randomized, genotype-directed clinical trials. There are several ongoing randomized controlled trials that will provide some answers as to the clinical utility of genotype-directed strategies. Several academic medical centers have pushed towards clinical implementation, where the clinical validity data are strong. Their experiences will inform operational requirements of a clinical pharmacogenetics testing, including the timing of testing, incorporation of test results into the electronic health record, reimbursement, and ethical issues.SummaryPharmacogenetics of clopidogrel, warfarin, and simvastatin are three examples, where pharmacogenetics testing may provide added clinical value. Continued accumulation of evidence surrounding clinical utility of pharmacogenetics markers is imperative as this will inform reimbursement policy and drive adoption of pharamcogenetics into routine care.

Genomic medicine in the prevention and treatment of atherosclerotic cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of death in the world. Over the past decade considerable progress has been made in understanding the genomic basis of polygenic disorders including CVD. The future application of genomic medicine to the prevention and treatment of CVDs will ultimately lessen the burden of CVD. Given the complex nature of CVD, information derived from newer evolving fields, such as transcriptomics, proteomics and metabolomics, will allow us to fully interrogate features of the human genome to better understand disease pathogenesis and to identify new drug targets. In this article, we will review how genomics will allow enhanced risk prediction of cardiovascular events, provide personalized treatment options and hasten the drug development process, with a particular focus on atherosclerotic CVD.

Novel Anti-platelet Agents in Acute Coronary Syndrome: Mechanisms of Action and Opportunities to Tailor Therapy

Dual anti-platelet therapy, most commonly aspirin and clopidogrel, has been the standard of care for over a decade in patients who have experienced acute coronary syndrome, particularly when treated with coronary stenting. However, residual risk in patients receiving dual anti-platelet therapy post-acute coronary syndrome raises an unmet need for alternative therapy to clopidogrel. Consequently, novel anti-platelets agents including the P2Y12 receptor antagonists, such as prasugrel and ticagrelor, have emerged. Furthermore, using new methods to assess genetic polymorphisms and functional phenotypic assessments of platelet reactivity may become important in the development of personalized medicine and in developing tailored approaches to individual treatment. While robust large-scale evidence for genotypic- and phenotypic-guided therapy in improving outcomes is currently lacking, tremendous interest from various stakeholders including researchers, funding agencies, and industry continues to spur research endeavors in this arena. Further investigation is required in this emerging field to potentially offer improved platelet inhibition that may optimize cardioprotection and minimize bleeding risk in patients with acute coronary syndrome.

Branched-Chain Amino Acids: The Metabolic Link Between Type 2 Diabetes Mellitus and Cardiovascular Disease?

See Article by Tobias et al Cardiovascular disease (CVD) is the leading cause of death worldwide. Type 2 diabetes mellitus (T2D) is an independent risk factor for CVD, including stroke and heart disease.1,2 Both CVD and T2D share many risk factors, such as obesity, insulin resistance, dyslipidemia, inflammation, and hypertension, which led to the hypothesis that both conditions have common genetic and environmental origins,3 but the biological underpinnings establishing the link have not been fully elucidated. Despite the number of traditional risk factors used in current prediction models, a large proportion of CVD events occur in individuals with low predicted risk.4 Therefore, novel biomarkers are needed to improve risk stratification and enhance the opportunity for early intervention. Emerging technologies, such as high-throughput metabolomics and proteomics, can now provide unique insights into mechanisms underlying T2D and CVD by quantifying hundreds of metabolites or proteins across multiple pathways in a single measurement. Recently, these platforms have garnered much attention in the area of CVD biomarker discovery. Comprehensive metabolomic profiling led to the identification of a branched-chain amino acid (BCAA) signature (isoleucine, leucine, valine) with insulin resistance.5 The association of BCAAs with T2D has been confirmed in multiple epidemiological studies.6,7 In addition, BCAAs have been associated with CVD.8,9 However, it is unknown whether …