A Clinical Perspective on Arsenic Exposure and Development of Atherosclerotic Cardiovascular Disease.

Cardiovascular risk has traditionally been defined by modifiable and non-modifiable risk factors, such as tobacco use, hyperlipidemia, and family history. However, chemicals and pollutants may also play a role in cardiovascular disease (CVD) risk. Arsenic is a naturally occurring element that is widely distributed in the Earth's crust. Inorganic arsenic (iAs) has been implicated in the pathogenesis of atherosclerosis, with chronic high-dose exposure to iAs (> 100 µg/L) being linked to CVD; however, whether low-to-moderate dose exposures of iAs (< 100 µg/L) are associated with the development of CVD is unclear. Due to limitations of the existing literature, it is difficult to define a threshold for iAs toxicity. Studies demonstrate that the effect of iAs on CVD is far more complex with influences from several factors, including diet, genetics, metabolism, and traditional risk factors such as hypertension and smoking. In this article, we review the existing data of low-to-moderate dose iAs exposure and its effect on CVD, along with highlighting the potential mechanisms of action.

The Role of Nitrates in the Management of Stable Ischemic Heart Disease: A Review of the Current Evidence and Guidelines.

Coronary artery disease is the leading cause of mortality in the United States and can result in significant morbidity. In particular, stable ischemic heart disease (SIHD) is a condition that affects nearly 9 million individuals in the United States alone, with substantial annual health care costs related to recurrent medical visits and chronic disease management. Nitrates form a cornerstone of SIHD management by reducing myocardial oxygen consumption and increasing exercise capacity by several mechanisms, including increasing epicardial blood flow through vasodilation and decreased vascular resistance, blunting coronary steal, and reducing preload. Yet the role of nitrates may be underappreciated in clinical practice and their utilization may be limited due to concerns of tolerance to treatment, a lack of randomized data validating their ability to prevent adverse cardiovascular events, and the pervasive use of percutaneous interventions without robust attempts at implementing optimal medical therapy. In this review, we discuss both the recent ACC/AHA/ACP/AATS/PCNA/SCAI/STS and European Society of Cardiology guidelines, with a particular focus on indications, contraindications, and future directions of nitrate therapy in SIHD.

Conservative versus invasive stable ischemic heart disease management strategies: what do we plan to learn from the ISCHEMIA trial?

Over the past decade, landmark randomized clinical trials comparing initial management strategies in stable ischemic heart disease (SIHD) have demonstrated no significant reduction in 'hard' end points (all-cause mortality, cardiac death or myocardial infarction) with one strategy versus another. The main advantage derived from early revascularization is improved short-term quality of life. Nonetheless, questions remain regarding how best to manage SIHD patients, such as whether a high-risk subgroup can be identified that may experience a survival or myocardial infarction benefit from early revascularization, and if not, when should diagnostic catheterization and revascularization be performed. The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial is designed to address these questions by randomizing SIHD patients with at least moderate ischemia to an initial conservative strategy of optimal medical therapy or an initial invasive strategy of optimal medical therapy plus cardiac catheterization and revascularization.

Revascularization options in stable coronary artery disease: it is not how to revascularize, it is whether and when to revascularize.

Patients with acute coronary syndromes and severe multivessel or left main coronary artery disease have better outcomes when prompt revascularization is performed in addition to optimal medical therapy (OMT). However, in patients with stable ischemic heart disease, randomized strategy trials have revealed equipoise between initial strategies of OMT alone and OMT plus revascularization. Conducted in diverse stable ischemic heart disease patient populations and throughout the spectrum of atherosclerotic and ischemic burden, the RITA-2, MASS II, COURAGE, BARI 2D and FAME 2 trials demonstrate that OMT alone and OMT plus revascularization yield similar outcomes with respect to mortality and myocardial infarction. What remains unclear is whether there may be one or more subsets of patients with stable ischemic heart disease in whom revascularization may be associated with a reduction in mortality or myocardial infarction, which is to be addressed in the ongoing ISCHEMIA trial.

Mechanisms of action for arsenic in cardiovascular toxicity and implications for risk assessment.

The possibility of an association between inorganic arsenic (iAs) exposure and cardiovascular outcomes has received increasing attention in the literature over the past decade. The United States Environmental Protection Agency (US EPA) is currently revising its Integrated Risk Assessment System (IRIS) review of iAs, and one of the non-cancer endpoints of interest is cardiovascular disease (CVD). Despite the increased interest in this area, substantial gaps remain in the available information, particularly regarding the mechanism of action (MOA) by which iAs could cause or exacerbate CVD. Few studies specifically address the plausibility of an association between iAs and CVD at the low exposure levels which are typical in the United States (i.e., below 100 µg As/L in drinking water). We have conducted a review and evaluation of the animal, mechanistic, and human data relevant to the potential MOAs of iAs and CVD. Specifically, we evaluated the most common proposed MOAs, which include disturbance of endothelial function and hepatic dysfunction. Our analysis of the available evidence indicates that there is not a well-established MOA for iAs in the development or progression of CVD. Few human studies of the potential MOAs have addressed plausibility at low doses and the applicability of extrapolation from animal studies to humans is questionable. However, the available evidence indicates that regardless of the specific MOA, the effects of iAs on physiological processes at the cellular level appear to operate via a threshold mechanism. This finding is consistent with the lack of association of CVD with iAs exposure in humans at levels below 100 µg/L, particularly when considering important exposure and risk modifiers such as nutrition and genetics. Based on this analysis, we conclude that there are no data supporting a linear dose-response relationship between iAs and CVD, indicating this relationship has a threshold.

Evaluation of the stable coronary artery disease patient: anatomy trumps physiology.

The past decade has been associated with profound progress in both the assessment and treatment of stable ischemic heart disease (SIHD) patients. The many randomized clinical trials, observational studies, and post hoc analyses continue to elucidate the role of coronary anatomy and ischemic burden in treating our patients in routine clinical practice, with the preponderance of the current scientific evidence base suggesting that coronary anatomy does indeed trump physiology in predicting future coronary events in SIHD patients. However, the many clinical studies and post hoc analyses, while provocative, are relatively underpowered; therefore, an important question remains as to whether anatomic burden or ischemic burden can most reliably identify patients who would derive clinical benefits from an initial invasive strategy, regardless of prognostic value.