Beta-receptor selectivity of carvedilol and metoprolol succinate in patients with heart failure (SELECT trial): a randomized dose-ranging trial.

STUDY OBJECTIVE: To determine whether metoprolol succinate (a beta(1)-selective beta-blocker) remains beta(1)-selective compared with carvedilol (a nonselective beta-blocker) during upward titration of doses in patients with American College of Cardiology (ACC) stage C heart failure. DESIGN: Prospective, randomized, parallel-arm study. Setting. General clinical research center. PATIENTS: Twenty-five beta-blocker-naïve adults with New York Heart Association functional classes II or III heart failure (i.e., ACC stage C). Intervention. Patients received either immediate-release carvedilol 3.125 mg twice/day or controlled-release metoprolol succinate 25 mg once/day; doses were titrated upward by doubling the dose every 2 weeks until reaching a maximum tolerated dose or a goal dose of carvedilol 25 mg twice/day and metoprolol 200 mg/day. Before each dose titration, terbutaline (a beta-receptor agonist) was infused at 6 mg/kg over 1 hour for determination of beta(2)-blockade. MEASUREMENTS AND MAIN RESULTS: Patients were studied at baseline and after each dose titration of metoprolol succinate (at 25, 50, 100, and 200 mg once/day) and immediate-release carvedilol (at 3.125, 6.25, 12.5, and 25 mg twice/day). Glucose and potassium concentrations were measured twice serially at baseline, every 10 minutes during infusion, every 15 minutes for the first hour after infusion, and every 30 minutes for the second hour after infusion. The median area under the concentration-time curve (AUC) was calculated for changes in glucose and potassium concentrations. As assessed by glucose AUC, there was no significant difference in the degree of beta(2)-blockade between metoprolol 200 mg and carvedilol 25 mg. In contrast to these data, the degree of beta(2)-blockade as assessed by potassium AUC was greater for carvedilol compared with metoprolol across all doses. CONCLUSION: In this ACC stage C heart failure population, carvedilol was nonselective at all clinically relevant doses, whereas metoprolol succinate was beta(1)-selective at low doses and became progressively nonselective at higher doses.

Achieving National Cholesterol Education Program goals in coronary artery disease.

National Cholesterol Education Program (NCEP) guidelines recommend low-density lipoprotein cholesterol (LDL-C) levels <100 mg/dL for patients with coronary artery disease (CAD) and lipid-lowering therapy if LDL-C remains >100-130 mg/dL after dietary intervention. Studies consistently report that the majority of CAD patients do not achieve NCEP goals in clinical practice; we sought to determine if our practice fared better. We performed a retrospective chart review of 600 CAD patients followed by cardiologists. The mean age was 69, and 66% of patients were male. Of persons with a cardiology clinic lipid profile (60%), most (76%) achieved an LDL-C <100 mg/dL; however, only 61% were treated to the NCEP secondary goal of non-HDL-C <130 mg/dL. Of patients not at an LDL-C goal, 81% were on lipid-lowering therapy, but only 18% were on maximal statin doses and 6% on combination therapy. We concluded that the majority of CAD patients have had recent lipid measurements and are treated according to NCEP guidelines, but many patients remain on suboptimal therapy.

Effect of Terplex/VEGF-165 gene therapy on left ventricular function and structure following myocardial infarction. VEGF gene therapy for myocardial infarction.

BACKGROUND: We used a novel lipopolymeric gene delivery system, TeplexDNA, to transfect myocardium with plasmid vascular endothelial growth factor-165 (pVEGF) and evaluated the ability of pVEGF to preserve left ventricular function and structure after coronary ligation in a rabbit model. METHODS: New Zealand white rabbits underwent circumflex coronary ligation after direct intramyocardial injection of either Terplex alone or Terplex + 50 microg pVEGF-165. Serial echocardiography and histologic studies were performed (n = 12/group). Mortality did not differ between groups. The data is reported as the mean +/- standard deviation. RESULTS: Over the 21 days following coronary ligation, pVEGF-165-treated animals demonstrated significant improvement in fractional shortening (20-25%, p = 0.02), long axis two-dimensional ejection fraction (42-51%, p=0.02) and short axis m-mode ejection fraction (46-54%, p = 0.02). No significant improvements were noted in the control group. VEGF-treated animals had a 50% increase in peri-infarct vessel density and a trend towards a smaller infarct size (20% vs. 29%, p = 0.10). In animals receiving pVEGF-165, the diastolic ventricular area increased from 1.87 +/- 0.24 cm2 prior to ligation to 2.19 +/- 0.23 cm2 at 21 days following ligation, compared to an increase from 1.84 +/- 0.38 to 2.54 +/- 0.55 cm2 over the same period in control animals (p = 0.03). Similarly, the systolic ventricular area in VEGF-165 animals increased from 1.06 +/- 0.26 cm2 prior to ligation to 1.50 +/- 0.29 cm2 at 21 days following ligation, compared to an increase from 1.16 +/- 0.30 to 1.86 +/- 0.43 cm2 over the same period in the control animals (p = 0.04). CONCLUSION: TerplexDNA mediated delivery of plasmid VEGF administered at the time of coronary occlusion improves left ventricular function and reduces left ventricular dilation following myocardial infarction.

Do associations with C-reactive protein and extent of coronary artery disease account for the increased cardiovascular risk of renal insufficiency?

OBJECTIVES: We sought to determine whether the association of higher C-reactive protein levels (CRP) and more extensive coronary artery disease (CAD) explains the high cardiovascular risk of renal insufficiency (RI). BACKGROUND: Renal insufficiency and renal failure (RF) have been associated with increased cardiovascular risk in several studies, and it has been suggested that this association may be due to higher CRP levels and greater extent of CAD. To what extent CRP or severity of CAD explains this risk is uncertain. METHODS: A total of 1,484 patients without myocardial infarction (MI) undergoing angiography were entered and followed for 3.0 +/- 1.6 years; RI and RF were defined as estimated glomerular filtration rates (GFR) of 30 to 60 and <30 ml/min; CRP was measured by immunoassay and > or = 1.0 mg/dl defined as elevated. A CAD score was determined by extent and severity of angiographic disease. Multivariate Cox regressions were performed using seven standard risk factors, homocysteine, GFR, CRP, and CAD score. RESULTS: Mean age was 64 years, and 67% were men; CAD was absent in 24%, mild in 11%, and severe (> or =70% stenosis) in 60%; CRP and CAD scores increased with declining renal function (median CRP: 1.2, 1.4, 2.2 mg/dl, p < 0.001 and CAD score: 8.1, 8.7, 9.3, p = 0.008 for no-RI, RI, and RF). During follow-up, 208 patients (15%) died or had nonfatal MI. Unadjusted hazard ratio (HR) for death/MI was 2.3 for RI and 5.1 for RF (p < 0.0001). Adjustment for CRP (HR, 2.2, 4.5), CAD score (HR, 2.1, 5.1), and all other risk factors (HR, 1.7, 4.5) had minimal or modest impact on RI and RF risk; HR increased to 5.4 (p < 0.001) for presence of both elevated CRP and RI/RF. CONCLUSIONS: Renal insufficiency, CRP, and angiographic CAD, although correlated, are largely independent predictors of cardiovascular risk, suggesting the importance of both inflammation and as yet undefined RI-related risk factors.

The role of infection in the pathogenesis of cardiovascular disease.

Atherosclerosis is a complex, multifactorial disease. Recently, research has intensified to identify the role of various infections in the pathogenesis of atherosclerosis. Specific agents have been proposed as direct initiators or accelerators of atherosclerosis, while other infectious agents have been proposed as accelerators of atherosclerosis through nonspecific stimulation of the inflammatory cascade. Recently, the total pathogen burden concept has suggested that while each specific infection contributes only slightly to the pathogenesis of atherosclerosis, the cumulative effects of infectious agents contribute greatly. Several randomized trials evaluating antibiotic therapy in the prevention of cardiovascular events have now been completed, although results have been conflicting. This manuscript summarizes current understanding of the role of infectious agents as a trigger of inflammation, as a contributor to atherosclerosis, and the potential role of antibiotic therapy in the treatment of atherosclerosis.

Role of inflammation in cardiovascular disease: how to use C-reactive protein in clinical practice.

Acute coronary syndromes, stroke, and sudden death are common complications of a disrupted atherosclerotic plaque. Unstable plaque is a result of multiple factors but is commonly characterized by an infiltrate of inflammatory cells. Medical research strongly supports a role for inflammation in the pathogenesis, progression, and disruption of atherosclerotic plaque. Medical science also has improved our understanding of the complex interactions between our environment and our immune, coagulation, and cardiovascular systems. Clinical studies have demonstrated systemic markers of inflammation to be strong predictors of clinical events, and specific treatments of atherosclerosis and its risk factors have been associated with reductions in inflammatory markers. The authors review the current understanding of the role of inflammation in the pathogenesis of atherosclerosis, the common inflammatory markers, and potential anti-inflammatory therapy. Among several potential circulating markers of vascular inflammation, high sensitivity C-reactive protein is best validated and standardized as a marker for cardiovascular risk assessment. Nevertheless, there remain many uncertainties in utilizing C-reactive protein in clinical practice. Here, the authors describe the central role of C-reactive protein in atherosclerosis, review the studies demonstrating predictive value of C-reactive protein, describe the factors requiring consideration when utilizing C-reactive protein, discuss clinical scenarios in which measurement of C-reactive protein may be helpful, and suggest ways to interpret and treat elevated C-reactive protein levels. Finally, the authors summarize future expectations for assessing and modulating the vascular inflammation to inhibit initiation and progression of the atherosclerotic process.

The role of inflammation and infection in the pathogenesis and evolution of coronary artery disease.

Inflammation plays a major role in the initiation and progression of coronary artery disease (CAD) and the precipitation of acute coronary events. However, the inflammatory triggers are poorly understood. Noninfectious stimuli undoubtedly play a role. Recently, chronic infection has been proposed as another inflammatory trigger. Histologically, unstable atherosclerotic plaque contains activated macrophages and T lymphocytes, adhesion molecules, chemokines and cytokines, matrix-degrading enzymes, and prothrombotic factors. Circulating inflammatory markers such as C-reactive protein, fibrinogen, and interleukins are increased in high-risk cohorts and predict future risk. Experimental models and human studies have supported a role of infection in the promotion of atherosclerosis. Although the independent predictive value of seropositivity to individual agents has varied, total pathogen burden, the sum of seropositivities to many bacterial and viral vectors, has been more consistent. Whether antibiotics or vaccines will be useful in CAD prevention remains to be shown. Meanwhile, therapies with proven vascular anti-inflammatory effects (eg, diet, exercise, smoking cessation, aspirin, statins) should be optimized.

C-reactive protein and angiographic coronary artery disease: independent and additive predictors of risk in subjects with angina.

OBJECTIVES: The objective of this study was to determine the prognostic value of C-reactive protein (CRP) independent of coronary angiographic findings. BACKGROUND: High sensitivity CRP, a marker of inflammation, predicts risk of cardiovascular events. However, it is uncertain whether it remains predictive once angiographic findings are considered. METHODS: A total of 2,554 patients with angina but without acute myocardial infarction (MI) were studied angiographically; 1,848 patients had coronary artery disease (CAD) and 706 patients did not. Coronary artery disease was quantified in five ways and combined for a CAD score. C-reactive protein was measured and patients were followed for up to five years for death or MI. RESULTS: C-reactive protein correlated with the extent of CAD, but correlation coefficients were low (0.02 to 0.08). Of angiographic measures, the CAD score best predicted future events (hazard ratio [HR] = 1.8 [1.2 to 2.6], p = 0.004, for CAD score > 4). C-reactive protein > or = 1.0 mg/dl was predictive in both patients without CAD (HR = 2.3 [0.9 to 5.5], p = 0.07) and with CAD (HR = 2.1 [1.5 to 3.1], p = 0.0001). Multivariate adjustment resulted in little change in HR. C-reactive protein retained predictive value within each quintile of CAD score. C-reactive protein and CAD independently and additively contributed to the risk prediction: low CRP and lowest CAD score was associated with lowest risk, and high CRP and highest CAD score was associated with the highest risk, with a 10-fold difference between extremes (2.5% vs. 24%). CONCLUSIONS: C-reactive protein correlates with extent of CAD, but the degree of correlation is low. Severity/extent of CAD and CRP are independent and additive predictors of risk. Therapy should target CRP-associated risk as well as angiographically evident stenosis.

Usefulness of high-sensitivity C-reactive protein in predicting long-term risk of death or acute myocardial infarction in patients with unstable or stable angina pectoris or acute myocardial infarction.

High-sensitivity C-reactive protein (CRP), proposed as a new coronary risk marker, may reflect either an acute phase reaction or the level of chronic inflammation. Thus, CRP may be less predictive of long-term outcomes when measured after acute myocardial infarction (AMI) than after unstable angina pectoris (UAP) or stable angina pectoris (SAP). A total of 1,360 patients with severe coronary artery disease (>/=1 stenosis >/=70%) had CRP levels obtained at angiography. Presenting diagnoses were SAP (n = 599), UAP (n = 442), or AMI (n = 319). During follow-up (mean 2.8 years), death or nonfatal AMI (D/AMI) occurred in 19.5%, 16.1%, and 17.2% (p = NS) with SAP, UAP, and AMI, respectively. Corresponding median CRP levels were 1.31, 1.27, and 2.50 mg/dl (p <0.001). For the overall cohort, increasing age, low ejection fraction, revascularization, and elevated CRP were the strongest of 6 independent predictors for D/AMI. Among those presenting with SAP, CRP levels above the first tertile were associated with an adjusted hazard ratio of 1.8 (95% confidence interval [CI] 1.2 to 2.8, p <0.009) for D/AMI. After UAP, the hazard ratio was 2.7 (95% CI 1.4 to 5.0, p <0.002). However, when measured during hospitalization for AMI, CRP was not predictive of long-term outcome (hazard ratio 1.0 [95 % CI 0.5 to 1.7] p = 0.86). In conclusion, predischarge CRP levels are higher after AMI than after UAP or SAP. However, whereas CRP is strongly predictive of long-term D/AMI for patients presenting with SAP or UAP, it is not predictive shortly after AMI, suggesting that measurements should be delayed until the acute phase reaction is over and levels have returned to baseline.