Although there have been many significant advances over the last 50 years with regards to anticoagulant therapy, warfarin remains the definitive standard for the long-term prevention of thromboembolic events in many patients at risk for these complications. Although effective, warfarin has a narrow therapeutic window, necessitating frequent laboratory monitoring for anticoagulant effect. Ximelagatran is an investigational anticoagulant that directly inhibits thrombin, unlike heparin or warfarin, which are indirect inhibitors. Although indirect thrombin inhibitors are mainly only effective at inhibiting circulating thrombin, direct thrombin inhibitors are able to inhibit both free and clot-bound thrombin, thereby producing more effective anticoagulation. Ximelagatran is the first orally available direct thrombin inhibitor to reach phase 3 clinical trials. Ximelagatran is a prodrug for the active metabolite melagatran, and has been demonstrated to have a relatively wide therapeutic window in terms of bleeding and antithrombotic effect compared with warfarin. Clinical studies have demonstrated ximelagatran to be comparable in efficacy to warfarin and low-molecular-weight heparins (LMWH) for prophylaxis of venous thromboembolism, comparable to warfarin for stroke prevention in the setting of atrial fibrillation, and, when combined with aspirin, possible more effective than aspirin alone at preventing major adverse cardiovascular events in patients with a recent myocardial infarction. Adverse effects with ximelagatran primarily involve bleeding complications, which are more frequent than with placebo, but appear comparable to those occurring with standard anticoagulant treatment (ie, warfarin and LMWH). Ximelagatran has also been demonstrated to cause transient increases in liver enzymes, the significance of which will need to be addressed in ongoing phase 3 studies. Should ongoing trials prove ximelagatran to have at least similar therapeutic efficacy and safety as warfarin, ximelagatran may become a first-line anticoagulant due to its ease of administration and lack of a need for drug monitoring. The results of these trials are eagerly awaited in helping to defining the place in therapy for this promising new agent.

Long-term weight reduction remains the ultimate objective and challenge of obesity management. Few long-term dietary or pharmacointervention studies have been conducted and there is a critical need for long-range treatment strategies that are effective, safe, and acceptable. The authors conducted a retrospective cohort analysis of 21 euglycemic, hyperinsulinemic women with progressive, refractory, midlife weight gain (Syndrome W) who had previously lost weight (> or =10% reduction from baseline) with a comprehensive 1-year treatment program that included metformin and a hypocaloric, carbohydrate-modified (low-glycemic index) diet, as well as, other lifestyle modifications. The goal of the analysis was to determine long-term efficacy of the composite intervention using NHLBI criteria for weight stabilization, weight regain < or =3 kg (6.6 lb) in 2 years. Of a total of 26 consecutive women with Syndrome W who achieved goal weight during a 3-year period (1998-2001), 21 women (mean [standard error] age, 55.2 [2.4] years; mean body mass index, 34.2 [1.3] kg/m(2)) continued metformin and returned for annual follow-up visits. Weight maintenance was observed at the final (2-4 year) follow-up visit in 19/21 (90.5%) of women. Mean final follow-up weight (77.5 [2.8] kg) correlated highly with mean weight at 1-year protocol completion (77.2 [2.7] kg), (correlation coefficients r(xy) and sigma(xy) = 0.96, P = 0.000), demonstrating long-term weight reduction in the surveillance phase. Significant and robust decrements in fasting insulin (-28.4% [8.1%] to -43.4% [3.7%]) were observed at all follow-up visits (P < or = 0.002). This preliminary case series suggests that metformin may be an effective long-term adjunct to dietary and other interventions in the treatment of obesity in hyperinsulinemic patients. A randomized clinical trial of the dual regimen should be considered in nondiabetic women with midlife weight gain and hyperinsulinemia (Syndrome W) and, quite possibly, in additional euglycemic overweight and obese subjects with documented hyperinsulinemia and other portentous features of the Metabolic Syndrome.

Humanistic qualities of integrity, respect and compassion are important components of medical education. Studies, however, suggest that students may not perceive their faculty physicians as humanistic. Knowing how the perception of humanistic qualities varies by training level may offer insight on how we teach humanism. In this study, the authors compared humanistic quality scores of fourth-year medical students, internal medicine residents, and attending physicians on a general medicine ward of a teaching hospital. A validated nursing survey to assess humanistic qualities among physicians was distributed to randomly selected nurses on the medicine wards. The survey measured physician relationships with other medical staff, the patient, and family members. Each item was scored on a 5-point Likert scale. Composite scores for physician to staff relationships and physician to patient/family relationships, as well as an overall evaluation score, were compared across levels of physician training. A t test was done to determine statistical significance across training levels. No statistically significant differences were found between internal medicine residents and attending physicians. Subinterns appear to have better perceived qualities of humanism compared with resident and attending physicians. Because resident and attending physicians play an important role in medical education, efforts should be made to improve the perceived humanistic qualities of both resident and attending physicians.

Carotid angioplasty-stenting (CAS) was attempted in 78 carotid arteries in 74 patients (45 men and 29 women) with occlusive internal carotid arterial disease and was technically successful in 77 of 78 arteries (99%). Of 77 arteries with successful CAS, 58 (75%) were asymptomatic, 15 (20%) were associated with transient ischemic attacks or amaurosis, and 4 (5%) were associated with prior stroke. Of 77 arteries with successful CAS, 34 (44%) were associated with prior carotid endarterectomy with recurrence of occlusive carotid disease, and 43 arteries (56%) were associated with primary CAS. Sixty-eight of 74 patients (92%) who underwent CAS had high-risk features. Cerebral protection was given to 22 of 74 patients (30%). None of the 74 patients (0%) died of CAS. Minor stroke developed in 3 of 74 patients (4%). These data show that CAS is effective for treating symptomatic and asymptomatic patients with occlusive carotid arterial disease.

Inhaled nitric oxide (NO) has emerged as a promising pulmonary vasodilator to treat pulmonary hypertension associated with heart disease and ventilation/perfusion mismatching. However, the pharmacokinetics of inhaled NO still remains obscure and its cardiopulmonary selectivity appears to be increasingly under debate. In the present study measured NO content and levels of cyclic guanosine 3',5'monophosphate (cGMP), a mediator of NO-induced vasodilation, in a variety of organs from rats subjected to NO inhalation. Electron spin resonance spectroscopy associated to a spin trapping technique using N-methyl D-glucamine dithiocarbamate (FeMGD) was used to directly quantify NO levels in the lung, kidney, liver, aorta, and heart from anesthetized Wistar rats subjected to various doses (0, 20, 50, 100, or 200 ppm) and various times (0, 30, 45, or 75 minutes) of inhaled NO. Inhaled NO at a dose of 100 and 200 ppm significantly increased the NO-FeMGD complex in all organs studied. An increase of cGMP was detected in the lung and the aorta after inhaled NO for 45 minutes at the dose of 50 ppm. No changes in NO levels and its metabolites were shown between 30 and 75 minutes of inhaled NO. The results show that inhaled NO at a dose of 100 ppm or more increases NO levels in other organs beside the lung, strongly suggesting that inhaled NO would be more than a pulmonary vasodilator and its selectivity remains to be reconsidered when used for therapeutic purposes.

The adenosine A(1)/A(2) receptor agonist AMP 579 has been reported to protect the heart against infarction even when administered after the onset of ischemia. The present study explored both the timing and the duration of treatment required to limit infarct size in in situ rabbit hearts subjected to 30 min of regional ischemia and 3 hours of reperfusion. In groups 1 and 2, AMP 579 was infused from 10 min before reperfusion and continued for either 30 or 40 min. In group 3, AMP 579 was begun at the onset of reperfusion and continued for 70 min. In group 4, AMP 579 was also infused for 70 min but begun 10 min after reperfusion. In untreated hearts 36.4 +/- 3.1% of the risk zone infarcted. Protection was observed only in hearts having a 70-minute infusion of AMP 579 starting at reperfusion (13.0 +/- 1.9%, P < 0.05). Therefore, AMP 579 must be present at the moment of reperfusion and have a continued presence of more than 30 min thereafter to protect. Importantly, because AMP 579 can protect when administered up to the time of reperfusion, it likely prevents a reperfusion injury, and, therefore, has impressive clinical potential.

Arrhythmogenic right ventricular dysplasia (ARVD) is a form of cardiomyopathy characterized by fibrofatty infiltration of the right ventricle that leads to cardiac arrhythmias, usually sustained ventricular tachycardia or ventricular fibrillation. ARVD typically becomes recognized in young adults. The authors report a case of an octogenarian in whom third-degree atrioventricular block, low cardiac output syndrome, and failure to capture the pacer stimuli developed. ARVD was diagnosed at autopsy based on fibrofatty replacement of the right ventricle. To date, this case represents the oldest patient ever diagnosed with ARVD reported in the literature.

Aldosterone has been implicated for many years as an important substance in the pathogenesis of heart disease. Elevated aldosterone concentrations have been documented in patients with hypertension and heart failure, leading to the use of aldosterone antagonists for the treatment of these conditions. Spironolactone has been used for nearly 2 decades for the treatment of hypertension, and more recently, has become a standard agent for the treatment of systolic heart failure. Spironolactone, however, is a nonselective antagonist of the aldosterone receptor, binding also to other steroid receptors and causing a significant percentage of patients to have sex hormone-related adverse effects such as gynecomastia. Eplerenone is the first of a new class of drugs known as selective aldosterone receptor antagonists, which selectively block the aldosterone receptor with minimal effect at other steroid receptors, thereby minimizing many of the hormonal side effects seen with spironolactone. Eplerenone has been shown to be beneficial both as monotherapy and combination therapy for lowering elevated blood pressure in patients with hypertension. The antihypertensive efficacy of eplerenone is roughly similar to that of other antihypertensive agents, although in 1 study black patients responded better with eplerenone than losartan. In addition, eplerenone has demonstrated some renoprotective effects in diabetic patients with hypertension. Recently, eplerenone was shown to significantly reduce mortality and cardiovascular morbidity in post-myocardial infarction patients with systolic heart failure currently taking standard heart failure medications. Eplerenone is generally well tolerated, although hyperkalemia with this agent is of some concern. Eplerenone is metabolized by CYP3A4 and administration with potent inhibitors of this enzyme is contraindicated because of the risk of hyperkalemia. In summary, eplerenone has proven to be beneficial in treating hypertension and post-myocardial infarction heart failure. Its exact place in therapy will in large part be determined by its cost and whether or not future studies will be able to demonstrate a clinical benefit of this agent over spironolactone or other currently available treatments.

Valvular involvement is the most encountered form of heart disease in systemic lupus erythematosus (SLE). Immunoglobulin and complement deposition in the valvular structure will subsequently lead to Libman-Sacks vegetations, valve thickening, and valve regurgitation. Valvular stenosis is rarely seen. Involvement of the mitral valve is most frequently encountered. Valve disease for most patients is mild and asymptomatic, but patients in whom severe mitral regurgitation develops will present with symptoms of congestive heart failure. A heart murmur will be heard in almost all patients with moderate or severe regurgitation. Transesophageal echocardiography is the most sensitive method to detect the valvular involvement. The valvular changes, the hemodynamic status, or the symptomatology have been shown to progress, remain stable, or sometimes improve. Severe regurgitation, infective endocarditis, and thromboembolic events (mostly stroke or transitory ischemic attacks) are complications of valvular involvement in SLE. In treatment of these patients, prophylaxis of infectious endocarditis, selective antiaggregant and anticoagulant medication, and valve replacement are currently offered. The role of corticosteroid treatment is still unclear in the outcome of SLE valvulopathy.

The concept of a "high-risk" carotid endarterectomy patient has been suggested in an effort to justify the application of carotid angioplasty and stenting outside of clinical trials. Contemporary results of carotid endarterectomy in this subgroup of patients would argue against the existence of a high-risk patient. Until randomized prospective trials establish the role of carotid angioplasty and stenting in carotid bifurcation disease, this new technology should be restricted to recurrent and radiation-induced disease.

Recent studies indicate an expansion of the population eligible for primary prevention of coronary artery disease with lipid-lowering therapy. This change has led to the unnecessary treatment of many individuals and an overall decreased effectiveness of medication with potentially significant side effects. If instead, the asymptomatic population is screened for the presence of early coronary artery disease (CAD), lipid lowering can be targeted to those who can truly benefit. The prevalence of asymptomatic CAD in men older than 50 years of age approaches 20% and arteriography is currently the best available test to identify these men. The approximate complication rate of arteriography in such a population (1 or 2 per 10,000) approaches that of other screening tests. Although insufficient data exists for formal cost analysis, approximations indicate significant savings for arteriographically targeted treatment of at-risk asymptomatic individuals. The authors show that coronary arteriography is a potentially safe and cost-effective method of screening an asymptomatic adult population for presence of early CAD, allowing for the targeting of lipid lowering to those who can benefit most from this therapy.

The direct correlation between glucose levels and cardiovascular disease in individuals with type 2 diabetes can now be applied to individuals that share an abnormal metabolic milieu similar to that found in central obesity, the metabolic syndrome, and type 2 diabetes. Premature macrovascular complications with a very high morbidity and mortality rate can be found in these nondiabetic populations. The typical phenotype has visceral or central obesity, excess of free fatty acids, insulin resistance, increased insulin secretion, and hypertension. A more complex metabolic-cardiovascular syndrome develops that includes dyslipidemia, abnormal production of cytokines, chronic inflammatory state, and abnormal coagulation. The interplay of all these cardiovascular risk factors is responsible for the accelerated atherosclerotic process. The different terminologies used for populations sharing this common ground for premature cardiovascular disease now generally accepted as the metabolic syndrome, are also discussed. Aggressive insulin treatment during acute illness in individuals with the abnormal metabolic milieu is beneficial. Insulin treatment is changing from using insulin as a hormone to treat only severe hyperglycemia, to a new paradigm using insulin in high doses as a drug. Aggressive insulin regimens should be used to treat only minimal elevations of blood glucose or to prevent hyperglycemia. The newly observed properties of insulin are reviewed which include suppression of inflammatory cytokines and adhesion molecules, improved hemostasis, and other cardiac beneficial effects. The concomitant administration of intravenous glucose and insulin permits the administration of higher insulin doses that can result in improved outcome due to its nonglycemic-related benefits. The use of aggressive insulin therapy requires both better and more cost-effective algorithms to successfully treat this high-risk population during acute illness.

The authors investigated the association of transesophageal echocardiographic findings with the site of arterial occlusion in patients who underwent transesophageal echocardiography because of thromboembolic stroke and in whom the site of arterial occlusion was diagnosed by computerized axial tomography. The study population included 101 patients (mean age 59 +/- 15 years) with thromboembolic stroke and 101 randomly selected age-matched and sex-matched control without stroke. Transesophageal echocardiographic findings that were significantly higher in the patients with thromboembolic stroke than in the control group were vegetations on the aortic or mitral valve (9% versus 1%, P < 0.01), left atrial or left atrial thrombus or spontaneous echocardiographic contrast (20% versus 6%, P < 0.005), thrombus on a prosthetic valve or in the left ventricle (4% versus 0%, P < 0.05), and atherosclerosis in the thoracic aorta (37% versus 21%, P < 0.02). A higher prevalence of atherosclerosis in the thoracic aorta was found in patients with lacunar infarction compared with patients with middle cerebral artery occlusion (67% versus 25%, P < 0.02), as well as a higher prevalence of vegetations on the aortic or mitral valve in patients with occlusion of 2 arteries compared with patients with vertebrobasilar artery occlusion (28% versus 0%, P < 0.05).

The main objective of this study was to determine if physicians perceive that extracardiac or nonclinical factors such as patients' financial status, lifestyle, or trust in the physician impact coronary revascularization decisions. A self-administered questionnaire was developed and mailed to a random sample of 1200 family physicians, internists, cardiologists, and cardiothoracic surgeons who were active members of well-respected medical organizations in the United States. Survey questions were rated on a 4- and 5-point Likert scale to determine whether physicians perceive that nonclinical factors impede or facilitate coronary revascularization, respectively. The survey response rate was 70%. Family physicians were most likely to perceive that unhealthy lifestyle (51%), financial barriers (48%), and lack of social support (31%) probably or definitely precluded revascularization. White physicians (52%) were more likely to perceive that distrust in the physician affected revascularization, compared with black (33%), Hispanic (38%) and Asian (40%) physicians. Mean responses regarding how often (1 = rarely to 5 = most of the time) nonclinical factors facilitate revascularization revealed that women and Hispanic physicians were more likely to perceive male patients had easier access to the procedure (mean response, 2.8 for women versus 2.1 for men; 2.8 for Hispanics versus 2.4 for blacks and 2.1 for whites). Physicians perceived that nonclinical factors influence decision making for coronary revascularization. What needs to be further explored is whether such factors affect actual patient outcomes or contribute to disparities in the utilization of cardiac interventions.