New Insights into Uric Acid Metabolism in the Pathophysiology of Ischaemic Heart Disease.

To the Editor: Recently, an update from the Framingham study could not find uric acid to be an independent risk factor for cardiovascular disease.1 While serum uric acid levels correlated significantly with the risk for cardiovascular events and mortality in women, this relationship became insignificant after factoring for 11 additional variables including hypertension, body mass index, and diuretic use.1 Both the authors1 and an accompanying editorial2 interpreted these findings as showing that uric acid is not a true risk factor for cardiovascular disease and that it should not be routinely measured to assess cardiovascular risk. The careful analysis of the Framingham study is to be commended, but one must be cautious in the interpretation of the findings. While some epidemiologic studies such as the current one have not been able to show uric acid to be an independent risk factor for cardiovascular disease, other studies using multivariate analyses3 4 5 6 came to an opposite conclusion. Another recently completed study, the Worksite,7 also found uric acid to be an independent risk factor for cardiovascular events and mortality, especially in women. One might look for subtle explanations to account for the differences in these various studies, as Culleton et al1 have attempted, but most of the studies examined the very same variables. A more central issue is whether one should interpret the finding that a risk factor is not statistically independent to mean that it should not be considered biologically important. We would argue that this is not true in several situations. First, if the risk factors are causally linked, then one may not be able to show that they are independent of each other. For example, although smoking is a risk factor for mortality, it might no longer be independent if it is …

Introduction

In the current issue of Circulation , Anker and colleagues1 report that elevated levels of uric acid (UA) predict mortality and the need for heart transplantation in patients with congestive heart failure (HF). Serum concentrations of UA added important prognostic information alone and when combined with measures of cardiac function (ejection fraction) and patient functional status (maximal oxygen consumption with exercise) and were independent of renal function, serum sodium, serum urea, diuretic usage, and patient age. Receiver operating curve analysis identified a cutoff of 585 μmol/L (9.8 mg/dL) as the best mortality predictor. This finding is not only potentially of value in patient management but also raises extremely interesting questions regarding the pathophysiological underpinnings of this finding. See p 1991 A consideration of the mechanism of UA production and metabolism offers insight into the relationship between UA levels and HF outcomes. Indeed, accumulating data support the idea that UA, in addition to being a potentially valuable prognostic marker, possesses specific toxic or other properties that could contribute to HF pathophysiology. Moreover, UA levels may reflect xanthine oxidase (XO) pathway activity, which has the potential to contribute to the progression of left ventricular dysfunction by interfering with myocardial energetics2 and myofilament calcium sensitivity.3 UA is a metabolic byproduct of purine metabolism (Figure). Serum UA may increase in the failing circulation because of increased generation, decreased excretion, or a combination of the 2 factors. There are several possible contributors to increased UA production in HF, including increased abundance and activity of XO,4 increased conversion of …

Editorial: Modifying Cardiovascular Risk Factors: Newer Advances in Cardiovascular Metabolism and Diagnostic Technologies.

Hippocrates would not be surprised to read that persons with gout had higher mortality, and particularly cardiovascular-related mortality, than persons without gout.1 On the other hand, he might well have been bemused, nearly 2500 years after he described the syndrome, that this made news. Article p 894 He should not have been. All too often, rigorous examination debunks conventional wisdom. Reassuringly, in this case, Drs Choi and Curhan found evidence to support long-standing belief. These dedicated and productive students of the pathogenesis and natural history of gout have here reported empiric data from the 51 000 male nonphysician health professionals who participated in the Health Professions Follow-up Study. From initial examination in 1986 through nearly 600 000 person-years of follow-up, 5825 deaths occurred, of which 2132 were cardiovascular and 1576 were ascribed to coronary heart disease, rates that attest to the generally good health of the group. The ≈6% prevalence of gout, at baseline, in men in their mid-50s, who mirror the general US population in body mass index, reported history of hypertension, hypercholesterolemia, and diabetes mellitus, was higher than expected. Interim biennial questionnaires identified incident cases of gout. Participants with gout were both more likely to report coronary heart disease (CHD) at baseline and, regardless of CHD status, more likely than gout-free persons to have cardiovascular disease (CVD) risk factors. Results were presented after stratification by CHD status at baseline. As expected, the incidence of all-cause and CHD mortality was much greater in those with than in those without prevalent CHD. The adjusted increased relative risk of those with gout (compared with those without) for all-cause, CVD, and CHD mortality was ≈25%. The single exception was a near doubling of increased relative risk of CHD mortality among those free of CHD at baseline. Neither the inclusion of incident …

Low serum levels of high-density lipoprotein (HDL) are commonly encountered in patients with coronary artery disease (CAD). An example of this type of patient is a 42-year-old white man with a history of sudden-onset angina secondary to a 90% obstructive lesion along the proximal left anterior descending coronary artery. The family history was significant for his father, who died of a myocardial infarction (MI) at age 44 years. The patient underwent percutaneous transluminal angioplasty with stenting but developed in-stent restenosis. He underwent cutting balloon angioplasty and brachytherapy and was asymptomatic for approximately 6 months. The stent then developed a high-grade occlusion with recurrence of angina, and the patient required single-vessel bypass surgery. The patient’s baseline serum lipid profile revealed low-density lipoprotein (LDL) 128 mg/dL, HDL 27 mg/dL, and triglycerides 92 mg/dL. His lipoprotein(a), C-reactive protein, and homocysteine levels were normal. He was not hypertensive, had no impairment of glycemic control, and did not smoke. With a combination of simvastatin 40 mg and niacin (Niaspan; Kos Pharmaceuticals) 1000 mg daily, the patient’s lipid profile improved, with LDL 78 mg/dL, HDL 43 mg/dL, and triglycerides 60 mg/dL. Follow-up stress testing demonstrated normal myocardial perfusion, and the patient has been asymptomatic for 2 years. With few exceptions, low HDL is an independent risk factor for CAD in case-control and prospective observational studies. In contrast, high HDL levels are associated with longevity and are protective against the development of atherosclerotic disease. In the Framingham Study, risk for CAD increases sharply as HDL levels fall progressively below 40 mg/dL.1 In the Quebec Cardiovascular Study, for every 10% reduction in HDL, risk for CAD increased 13%.2 Many clinicians believe that low HDL is associated with increased CAD risk because it is a marker for hypertriglyceridemia and elevated remnant particle concentrations. The Prospective Cardiovascular Munster …

Epidemiological studies have established a strong association between hypertension and coronary artery disease (CAD). Hypertension is a major independent risk factor for the development of CAD, stroke, and renal failure. The optimal choice of antihypertensive agents remains controversial, and there are only partial answers to important questions in the treatment of hypertension in the prevention and management of ischemic heart disease (IHD), such as: ● What are the appropriate systolic blood pressure (SBP) and diastolic blood pressure (DBP) targets in patients at high risk of developing CAD or in those with established CAD? ● Are the beneficial effects of treatment simply a function of blood pressure (BP) lowering, or do particular classes of drugs have uniquely protective actions in addition to lowering BP? ● Are there antihypertensive drugs that have shown particular efficacy in the primary and secondary prevention of IHD? ● Which antihypertensive drugs should be used in patients who have established CAD with stable or unstable angina pectoris, in those with non–ST-elevation myocardial infarction (NSTEMI), and in those with ST-elevation myocardial infarction (STEMI)?

Epidemiological studies have established a strong association between hypertension and coronary artery disease (CAD). Hypertension is a major independent risk factor for the development of CAD, stroke, and renal failure. The optimal choice of antihypertensive agents remains controversial, and there are only partial answers to important questions in the treatment of hypertension in the prevention and management of ischemic heart disease (IHD), such as: This scientific statement summarizes the published data relating to the treatment of hypertension in the context of CAD prevention and management and attempts, on the basis of the best available evidence, to develop recommendations that will be appropriate for both BP reduction and the management of CAD in its various manifestations. Where data are meager or lacking, the writing group has proposed consensus recommendations, with all of the reservations that that term implies and with the hope that large gaps in our knowledge base will be filled in the near future by data from well-designed prospective clinical trials. All of the discussion and recommendations refer to adults. The writing committee has not addressed hypertension or IHD in the pediatric age group. Also, there is no discussion of the different …

1. Relationship Between Hypertension and CAD e437 2. Prevention of Cardiovascular Events in Patients With Hypertension and CAD e443 3. BP Goals e445 4. Management of Hypertension in Patients With CAD and Stable Angina e449 5. Management of Hypertension in Patients With ACS e451

Waist Circumference, Visceral Obesity, and Cardiovascular Risk

Usefulness of Brachial Artery Flow-Mediated Dilation to Predict Long-Term Cardiovascular Events in Subjects Without Heart Disease

Microalbuminuria

To the Editor: The adipocyte secreted protein, adiponectin, is of particular interest in metabolic and vascular disease because of its close associations with insulin sensitivity and obesity.1 Lower levels of adiponectin are associated with later development of type 2 diabetes.2 Recent observations from the Health Professionals Follow-Up Study3 suggest that lower adiponectin concentrations might also be associated with incident myocardial infarction, findings in keeping with prior observations in patients with end-stage renal failure.4 We examined prospective relationships of adiponectin to vascular disease in a case–control series selected from the Strong Heart Study (SHS). The SHS is the largest study of cardiovascular disease in American Indians, a group at particular risk of obesity and type 2 diabetes and in whom an increasing incidence of coronary heart disease (CHD) is seen.5 Cases and controls were selected from the SHS cohort.6 The SHS recruited 4549 volunteers of American Indian heritage from 3 geographic areas (Arizona, North and South Dakota, and Oklahoma).6 Volunteers (59% female) were invited to a study examination on three occasions (SH1, 1988 to 1992; SH2, 1993 to 1995; SH3, 1997 to 1999) and remained under continued surveillance for development of vascular disease as described previously.7,8 Because of availability of plasma samples, baseline data for this study were taken from the second examination (SH2), and participants with prevalent cardiovascular disease at SH2 (definite CHD and stroke), …

A global epidemiological transition in the prevalence of noncommunicable diseases is taking place due to the emergence of behavioral and metabolic risk factors. A renewed interest in the role of serum uric acid as a risk factor has been generated and a crossover from rheumatology to composite of cardiovascular disorders is taking place. Hyperuricemia (HU) is defined as serum urate level > 6.8 mg/dl that is, the limit of urate solubility at physiological temperature and pH. The prevalence of HU and its complications have increased globally in the past decades. It is an indicator of a widespread transition in lifestyle. The positive association between serum uric acid and hypertension, coronary artery disease, stroke, heart failure, renal failure, and preeclampsia has been recognized. Evidence suggests that elevated serum uric acid is strongly associated with and predictive of insulin resistance and metabolic syndrome. The role of HU in the pathogenesis of cardiovascular and renal diseases involves effects on the endothelial function, oxidative metabolism, and platelet aggregation. Among the constellation of established atherosclerotic cardiovascular risk factors HU has an additive or synergistic impact on the outcomes. As an independent risk factor for cardiovascular and related diseases, the role of HU has been extensively debated for many years. Besides being a biomarker and risk factor, HU is also emerging a target for the prevention of atherosclerotic cardiovascular diseases. In most of the patients, with asymptomatic HU, treatment is not advocated to reduce cardiovascular risk. Currently, no guidelines and recommendations have been updated in the pharmacological management of asymptomatic HU. It will be particularly important to design large, long-term studies that would determine the effects of urate-lowering therapy on cardiovascular disease.

The article summarizes mechanisms, linking hyperuricemia, the elevated serum levels of uric acid (UA), and atrial fibrillation (AF), the most frequent cardiac arrhythmia. The actuality of the problem is explained by the fact that UA is considered as an independent risk marker of AF closely associated with the onset and subsequent persistence of AF as well as by the AF increased risk in males and females with hyperuricemia. It has been shown how hyperuricemia, combined with other AF risk factors, contributeы to the development of arrhythmia, as well as the role of hyperuricemia, oxidative stress and renin‑angiotensin system (RAS) activation in the AF pathogenesis. The consideration have been given to the hyperuricemia association with a prevalence of AF among the patients with carbohydrate exchange disorders such as metabolic syndrome and type 2 diabetes mellitus as well as to the relationship between hyperuricemia and endothelial vascular dysfunction, oxidative stress, high blood concentration of systemic inflammatory markers and insulin resistance (IR). Some mechanisms of hyperuricemia participation in cardiac remodeling as a risk factor of AF are adduced. In particular, the relationship between hyperuricemia and left atrial (LA) size that could be mediated through systemic inflammation and IR is discussed. A significance of a direct impaired action of UA on LA cardiomyocytes resulted in their structural and ionic remodeling is shown. The role of xanthinoxidase (XO) activation in initiation of oxidative stress and inflammation in cardiomyocytes and endothelial cells is discussed. All these mechanisms are emphasized to be able to shorten a potential of action of atrial cardiomyocytes as well as to reduce a threshold of re‑entry mechanism initiation and to promote an appearance of the first and the following AF episodes. An important place in the review is taken for an intracellular UA and its cellular transporters in the context of their participation in pathogenesis of AF. The possibilities of drug hyperuricemia correction have been described in regards the reduction of AF risk, in particular, the role of reducing of the oxidative stress intensity with the use of xanthine oxidase inhibitor allopurinol, the inhibitor of NADPH oxidase apocynin, the antioxidant N‑acetylcysteine in the reduction of the risk of onset and subsequent recurrences of AF episodes, and transition of arrhythmia in the persistent form. Some perspectives of probenecid (an inhibitor of UA intracellular transporter activity) usage in the reduction of AF risk due to such of its mechanisms as a reduction of intracellular UA accumulation and antiapoptotic action as well as an ability of this agent to inhibit a locally activated oxidative stress and locally activated tissue RAS are discussed. A significance of the further detailed study of pathophysiological mechanisms of AF in hyperuricemia is emphasized for elaboration of the most effective practical recommendations in prevention of this arrhythmia in persons with UA exchange disorders.