Ajoe John Kattoor

Oxidative Stress in Atherosclerosis

Purpose of ReviewAtherosclerosis is now considered a chronic inflammatory disease. Oxidative stress induced by generation of excess reactive oxygen species has emerged as a critical, final common mechanism in atherosclerosis. Reactive oxygen species (ROS) are a group of small reactive molecules that play critical roles in the regulation of various cell functions and biological processes. Although essential for vascular homeostasis, uncontrolled production of ROS is implicated in vascular injury. Endogenous anti-oxidants function as checkpoints to avoid these untoward consequences of ROS, and an imbalance in the oxidant/anti-oxidant mechanisms leads to a state of oxidative stress. In this review, we discuss the role of ROS and anti-oxidant mechanisms in the development and progression of atherosclerosis, the role of oxidized low-density lipoprotein cholesterol, and highlight potential anti-oxidant therapeutic strategies relevant to atherosclerosis.Recent FindingsThere is growing evidence on how traditional risk factors translate into oxidative stress and contribute to atherosclerosis. Clinical trials evaluating anti-oxidant supplements had failed to improve atherosclerosis. Current studies focus on newer ROS scavengers that specifically target mitochondrial ROS, newer nanotechnology-based drug delivery systems, gene therapies, and anti-miRNAs. Synthetic LOX-1 modulators that inhibit the effects of Ox-LDL are currently in development.SummaryResearch over the past few decades has led to identification of multiple ROS generating systems that could potentially be modulated in atherosclerosis. Therapeutic approaches currently being used for atheroslcerotic vascular disease such as aspirin, statins, and renin-angiotensin system inhibitors exert a pleiotropic antioxidative effects. There is ongoing research to identify novel therapeutic modalities to selectively target oxidative stress in atherosclerosis.

Balancing Primary Prevention and Statin-Induced Diabetes Mellitus Prevention.

Diabetes mellitus (DM), a modern-day epidemic, is a significant risk factor for cardiovascular disease. It is believed that statins elevate the risk of incident DM. Multiple trials were suggestive of the hyperglycemic effect of long-term statin use. This has prompted the Food and Drug Administration to include the risk of DM in the product label of statins. New-onset DM with statin use is biologically plausible and can be explained based on the multiple pathways in glucose metabolism affected by statins. Most pivotal clinical trials on statins were not powered to adequately assess the risk of incident DM with statin use, and the results from multiple meta-analyses are mixed. Currently, the US Preventive Services Task Force recommend the use of statins for primary prevention in patients with at least 1 cardiovascular risk factor and a 10-year risk of >7.5%. With the new American College of Cardiology/American Heart Association guidelines, the number of patients eligible for statin therapy has increased exponentially, which also calls for caution and increased vigilance in prescribing physicians regarding the controversies surrounding statin use. This article aims to highlight the existing data on statin use for primary prevention in diabetics and nondiabetics and the association of statins use with new-onset DM and its postulated mechanisms.

Role of Ox-LDL and LOX-1 in Atherogenesis

Oxidized LDL (ox-LDL) plays a central role in atherosclerosis by acting on multiple cells such as endothelial cells, macrophages, platelets, fibroblasts and smooth muscle cells through LOX-1. LOX-1 is a 50 kDa transmembrane glycoprotein that serves as receptor for ox-LDL, modified lipoproteins, activated platelets and advance glycation end-products. Ox- LDL through LOX-1, in endothelial cells, causes increase in leukocyte adhesion molecules, activates pathways of apoptosis, increases reactive oxygen species and cause endothelial dysfunction. In vascular smooth muscle cells and fibroblasts, they stimulate proliferation, migration and collagen synthesis. LOX-1 expressed on macrophages inhibit macrophage migration and stimulate foam cell formation. They also stimulate generation of metalloproteinases and contribute to plaque instability and thrombosis. Drugs that modulate LOX-1 are desirable targets against atherosclerosis. Many naturally occurring compounds have been shown to modulate LOX-1 expression and atherosclerosis. Currently, novel drug design techniques are used to identify molecules that can bind to LOX-1 and inhibit its activation by ox-LDL. In addition, techniques using RNA interference and monoclonal antibody against LOX-1 are currently being investigated for clinical use.

Atherosclerosis and Gender-Related Differences

Coronary artery disease (CAD) remains the leading cause of mortality and morbidity world wide. Despite significant advances in our understanding of the atherogenesis, gender related differences in CAD remain unclear. It is generally assumed that the estrogens play a protective role in women in the premenopausal age group; however, hormone replacement therapy in postmenopausal women has not led to a significant decrease in cardiovascular events. Nonetheless, subtle differences at cellular level and in the plaque morphology have been identified in women as compared with men. Recent studies have shown a different pattern of atherosclerotic changes in the distribution of vessels, morphology of lesions and microvasculature between men and women. New markers of atherosclerosis such as G protein coupled estrogen receptors, Toll-like receptors and lipoprotein(a) also exhibit different patterns in men and women. Other studies have shown that women as compared to men have poorer prognosis after STEMI and CABG. An improved understanding the gender related pathophysiology will help in improved management of CAD in women.

The Current Focus of Heart Failure Clinical Trials

BACKGROUND Heart failure (HF) is a major global health problem. Clinical trials test efficacy, effectiveness, and safety of novel and emerging therapies in HF. We sought to determine the salient features of ongoing interventional clinical trials in HF. METHODS AND RESULTS We accessed the ClinicalTrials.gov registry of the National Institutes of Health (NIH) and the International Clinical Trials Registry Platform of the World Health Organization on January 1, 2017, and extracted pertinent information on current HF clinical trials for systematic review. Of 794 HF trials that met our inclusion criteria, almost one-half (49.1%) evaluated clinical end points and one-third (32.8%) examined imaging end points as primary outcomes. One-fourth (24.8%) were industry sponsored and one-third (35.6%) were university sponsored. The NIH and other United States federal agencies funded only 14 trials (1.8% of all trials; 10.7% of trials in the US). Among 536 HF trials with specified left ventricular ejection fraction status, 434 (81.0%) focused on HF with reduced ejection fraction (HFrEF) and only 102 (19.0%) trials targeted HF with preserved ejection fraction (HFpEF). CONCLUSIONS Ongoing HF trials are predominantly sponsored by nongovernmental funding agencies. Although HFpEF occurs as commonly as HFrEF in the community, the number of clinical trials targeting HFpEF is substantially lower compared with HFrEF.

Vitamin E and its anticancer effects

Abstract Vitamin E is a lipid soluble vitamin comprising of eight natural isoforms, namely, α, β, δ, γ isoforms of tocopherol and α, β, δ, γ isoforms of tocotrienol. Many studies have been performed to elucidate its role in cancer. Until last decade, major focus was on alpha tocopherol and its anticancer effects. However, major clinical trials using alpha-tocopherol like SELECT trial and ATBC trial did not yield meaningful results. Hence there was a shift of focus to gamma-tocopherol, delta-tocopherol and tocotrienol. Unlike alpha-tocopherol, gamma-tocopherol and delta-tocopherol can scavenge reactive nitrogen species in addition to reactive oxygen species. Antiangiogenic effect, inhibition of HMG CoA reductase enzyme and inhibition of NF-κB pathway make the anti-cancer effects of tocotrienols unique compared to other vitamin E isoforms. Preclinical research on non-alpha tocopherol isoforms of vitamin E showed promising data on their anticancer effects. In this review, we deal with the current understanding on the potential mechanisms involved in the anticancer effects of vitamin E and the controversies in this field over last three decades. We also highlight the need to conduct further research on the anticancer effects of non-alpha-tocopherol isoforms in larger population and clinical setting.

Thiamine Therapy for Heart Failure: a Promise or Fiction?

Thiamine (vitamin B1) is an essential water-soluble vitamin required for cellular energy production. Thiamine pyrophosphate (TPP) is a coenzyme in the pentose phosphate pathway for transketolation of glucose-6-phosphate to ribose-5-phosphate. In the Kreb’s cycle, TPP is needed for the functioning of the pyruvate dehydrogenase complex (which converts pyruvate to acetyl CoA) and alpha-ketoglutarate dehydrogenase (which converts alpha-ketoglutarate to succinate). These reactions are needed for aerobic metabolism and production of ATP. Thiamine also helps in the conduction of nerve impulses, independent of its coenzyme functions. It is important for maintenance of nerve membrane stability and modulates membrane ion channels for efficient nerve conduction [1]. Humans neither synthesize thiamine nor store it in large quantities [2]. Thus, oral intake is the primary determinant of thiamine stores in the body. As per the 1980 Committee on Dietary Allowance, Food, and Nutrition Board, the recommended daily allowance of thiamine for adults is about 1.2 mg daily for men and 1 mg daily for women [3]. Thiamine levels can be estimated in different ways. Direct measurement of serum thiamine is not a reliable indicator of total body thiamine stores as most of it is present inside the cells. The erythrocyte transketolase activity (ETKA) is an indirect measure of thiamine levels in the body and has high sensitivity as erythrocytes are the first cell line to be affected by low thiamine levels [4]. Another useful method is high-performance liquid chromatography (HPLC) to directly measure TPP concentration in erythrocytes. Deficiency of thiamine is far more common in underdeveloped and developing countries due to high incidence of poor nutritional status. In developed countries, thiamine deficiency is seen in patients with chronic alcohol use, patients on total parenteral nutrition, and in patients who have undergone weight loss surgery. Clinical signs of marginal thiamine deficiency are non-specific, like anorexia, weight loss, fatigue, sleep disorders, and depression [5]. Severe thiamine deficiency in diet causes beriberi. Dry beriberi presents as a symmetric peripheral sensorimotor neuropathy. On the other hand, the major manifestations of wet beriberi are tachycardia, cardiomegaly, high-output heart failure, and pedal edema, in addition to neuropathy. Direct impairment of myocardial energy production has been proposed as a possible basis for the development of heart failure state seen in beriberi (because of loss of thiamine’s beneficial role in metabolic reactions) [6]. Decreased activity of pyruvate dehydrogenase due to thiamine deficiency results in build-up of pyruvate, which is then shunted towards anaerobic conversion into lactate [7]. This accumulation of lactate causes a decrease in peripheral resistance, thereby increasing venous return to the heart (preload). This increase in preload coupled with myocardial dysfunction has been proposed to be a basis of congestive heart failure in thiamine deficiency [8]. Heart failure is a major cause of mortality and morbidity in the West. Around 6.5 million Americans have heart failure and nearly a million new cases are being identified annually [9]. Though thiamine supplementation is recommended in highoutput heart failure state seen in severe thiamine deficiency, its utility in the heart failure patients at large is unclear. Heart failure being a prominent feature of thiamine deficiency, several investigators have evaluated the potential of thiamine therapy in heart failure patients. In this review, we aim to discuss the utility of thiamine therapy in patients with heart failure.

Mitral valve vegetation diagnosed with oesophageal ultrasound with bronchoscope (EUS-B)

Oesophageal ultrasound with bronchoscope (EUS-B) is designed to evaluate mediastinal structures. We describe a case of a 78-year-old woman who presented with altered mental status for 2 weeks. CT head revealed a subacute infarct in the right middle cerebral artery distribution. She was also found to have a lung mass on chest imaging. EUS-B-guided fine needle aspiration demonstrated the presence of adenocarcinoma in station 7 lymph node and in the mass. Immunohistochemistry confirmed it to be a lung primary as the Thyroid Transcription Factor-1 (TTF-1) was strongly positive. During the procedure, the cardiac valves were evaluated, and a mitral valve vegetation was noted. Formal echocardiography confirmed the presence of the vegetation. During hospital stay, the patient developed fever. Her blood cultures grew oxacillin-resistant Staphylococcus aureus. She was subsequently treated for infective endocarditis. We suggest that the use of EUS-B to routinely scan adjacent structures during a procedure may help obtain additional clinical information that may be critical to patient management.

Alternate day versus daily atorvastatin in low-density lipoprotein cholesterol reduction: A meta-analysis

Statins are the mainstay treatment for hyperlipidemia. They are hydroxymethylglutaryl- CoA inhibitors and cause reduction in low-density lipoprotein cholesterol (LDL-c) levels. Atorvastatin is one of the most commonly used statins. These drugs are usually prescribed in a daily dose regimen. Due to the long duration of action and prolonged effect on hepatocytes, alternate day atorvastatin therapy is theoretically as effective as daily dose atorvastatin. Several studies have compared the efficacy of alternate day and daily atorvastatin in LDL-c reduction. The authors performed a metaanalysis on these studies to find evidence for alternate day atorvastatin use in LDL-c reduction. The studies comparing alternate day and daily atorvastatin regimens were selected after a literature search. LDL-c reduction in both the alternate and daily groups were calculated from the data provided in the individual studies. The mean difference in LDL-c reduction was compared between the alternate day and daily atorvastatin groups. Metaanalysis performed on the studies revealed that the mean difference in LDL-c reduction among the alternate day and daily groups was only 8.36 mg/dL (95% CI −0.49 to 17.20). This difference was statistically not significant but trends toward a daily regimen. Further subgroup analysis suggested that the difference in LDL-c reduction is smaller in an atorvastatin-naive patient population (mean difference 0.92 mg/dL [95% CI −13.55 to 15.39 mg/dL]) and also in populations with fewer risk factors for cardiovascular disease (mean difference 3.79 mg/dL (95% CI −6.40 to 13.98 mg/dL]). In conclusion, the use of alternate day atorvastatin can reduce the cost by one-half and possibly offset many of its side effects. However, long-term studies with large sample sizes are required to evaluate its effect on cardiovascular events and mortality.