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.
Because of their good tolerability and their positive effect on lipid parameters and clinical outcomes, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have become the drugs of first choice for the management of dyslipidemia. Pitavastatin is the newest member in the statin family and received Food and Drug Administration approval for oral use in August 2009. Compared to other statins such as atorvastatin, simvastatin and pravastatin at specific doses, pitavastatin dosed at 1 to 4 mg daily showed similar efficacy in lowering low-density lipoprotein cholesterol (LDL-C) and altering other lipid parameters according to a number of studies. In addition, pitavastatin demonstrated cholesterol-lowering efficacy in special populations such as the elderly, patients with diabetes, and patients with higher cardiovascular risk. Because pitavastatin is minimally metabolized by the cytochrome P-450 isoenzymes, it is associated with a lower frequency of drug-drug interactions, and this may be a desirable characteristic of pitavastatin. Beneficial effects, such as reductions of coronary plaque volume and fibrofatty composition, have also been observed with pitavastatin. Thus far, the safety profile of pitavastatin is favorable and appears to be similar to those of other statins. Given its encouraging pharmacokinetic and pharmacodynamic characteristics, pitavastatin is likely to be a good alternative to other more established statins. The pharmacologic and pharmacokinetic properties of pitavastatin are reviewed in this article.
Cardiac natriuretic peptides are a family of structurally related peptides that are important in sodium and volume homeostasis. They consist of atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide and are elevated in patients with left ventricular dysfunction. In contrast with vasoconstrictive hormones, such as norepinephrine, angiotensin II, and arginine vasopressin, which worsen the physiological milieu in patients with left ventricular dysfunction and heart failure, the natriuretic peptides ameliorate these effects by promoting natriuresis, diuresis, peripheral vasodilation, and by inhibiting the renin-angiotensin system. The serum levels of the natriuretic peptides correlate with the severity of heart failure and appear to have prognostic value. The present article reviews the biochemistry, molecular biology, and physiology of natriuretic peptides and their pathophysiological link to heart failure. The therapeutic uses of natriuretic peptides are also reviewed. This includes the use of intravenous nesiritide, a synthetic human brain natriuretic peptide, and the recently developed vasopeptidase inhibitors which are designed to inhibit the degradation of natriuretic peptides.
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.
Inflammation contributes to the pathogenesis of coronary heart disease and elevated serum levels of C-reactive protein (CRP) are independently associated with increased coronary risk. This study assessed whether there were differences in the effects on CRP and high-density lipoprotein (HDL) cholesterol levels among patients treated with three common statins. In a prospective, observational study, 80 dyslipidemic adults without evidence of cardiovascular disease were treated with 10 mg atorvastatin (A), 20 mg simvastatin (S), or 40 mg pravastatin (P) daily. CRP and lipid profiles were assayed before and after 12 weeks of therapy; in 21 patients, CRP levels were also measured after 1 and 4 weeks. The three treatment groups experienced comparable reductions in CRP (A: 33%, S: 42%, and P: 30%) and statistically insignificant changes in HDL cholesterol levels. CRP began to decrease after 1 week of treatment, and decreased further at 4 and 12 weeks of therapy. The change in the log-transformed CRP concentration correlated with the change in the log-transformed LDL cholesterol concentration. Subjects had similar baseline CRP levels, lipid profiles, and coronary risk factors. The authors conclude that at doses achieving similar reductions in LDL cholesterol, the three statins were associated with comparable decreases in CRP without significant changes in HDL cholesterol levels. The correlation between the reductions in CRP and LDL cholesterol differs from the findings of other published studies, and should prompt further investigation of the mechanism by which statins reduce CRP.
In the left ventricle subjected to pressure overload activity, the antioxidant enzymes increased at the hyperfunctional stage. During the transition to heart failure, these enzymes are down-regulated, oxidative stress increases, and apoptosis progresses. Maladaptative activation of the antioxidant enzymes at an early stage may contribute to the intrinsic vulnerability of right ventricle to pressure overload. The authors studied changes in expression and activity of the enzymes manganese and copper-zinc superoxide dismutases, glutathione peroxidase, and catalase in the right ventricle of rat following induction of pulmonary hypertension by injection of monocrotaline. Increase in the manganese superoxide dismutase was delayed to the late failing stage, activity of glutathione peroxidase was depressed throughout, and only catalase was activated at the early stage before returning to control levels. This inability to activate antioxidant enzymes may contribute to the deleterious consequences of pressure overload on right ventricle systolic function.
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.
The authors reviewed the available data on the relationship between hypocholesterolemia and anemia with various etiologies. The data were collected from sources identified by a MEDLINE search of English-language literature published between 1966 and 2001 and bibliographies of relevant articles. The study selection included primary research articles, metaanalyses, and abstracts concerning the relation between hypocholesterolemia and anemia. Textbooks, meeting proceedings, and reference lists were also searched. Despite differences in study design, a relation was found between hematocrit and serum cholesterol levels and between hemoglobin and cholesterol levels. Further studies are required to determine the exact etiology and clinical significance of these findings.
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.
Cardiac chest pain is accompanied by oxidative stress, which generates alkanes and other volatile organic compounds (VOCs). These VOCs are excreted in the breath and could potentially provide a rational diagnostic marker of disease. The breath methylated alkane contour (BMAC), a 3-dimensional surface plot of C4-C20 alkanes and monomethylated alkanes, provides a comprehensive set of markers of oxidative stress. In this pilot study, we compared BMACs in patients with unstable angina pectoris and in healthy volunteers. Breath VOCs were analyzed in 30 patients with unstable angina confirmed by coronary angiography and in 38 age-matched healthy volunteers with no known history of heart disease (mean age +/- SD, 62.7 +/- 12.3 years and 62.5 +/- 10.0, not significant). BMACs in both groups were compared to identify the combination of VOCs that provided the best discrimination between the 2 groups. Forward stepwise entry discriminant analysis selected 8 VOCs to construct a predictive model that correctly classified unstable angina patients with sensitivity of 90% (27 of 30) and specificity of 73.7% (28 of 38). On cross-validation, sensitivity was 83.3% (25 of 30) and specificity was 71.1% (27 of 38). We conclude that the breath test distinguished between patients with unstable angina and healthy control subjects.
