Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Comparison of two bioelectrical impedance devices and dual-energy X-ray absorptiometry to evaluate body composition in heart failure.

BACKGROUND: The utilisation of bioelectrical impedance analysis (BIA) in heart failure can be affected by many factors and its applicability remains controversial. The present study aimed to verify the adequacy of single-frequency BIA (SF-BIA) and multifrequency BIA (MF-BIA) compared to dual-energy x-ray absorptiometry (DEXA) for evaluating body composition in outpatients with heart failure. METHODS: In this cross-sectional study, 55 patients with stable heart failure and left ventricle ejection fraction ≤45% were evaluated for fat mass percentage, fat mass and fat-free mass by DEXA and compared with the results obtained by SF-BIA (single frequency of 50 kHz) and MF-BIA (frequencies of 20 and 100 kHz). RESULTS: MF-BIA and DEXA gave similar mean values for fat mass percentage, fat mass and fat-free mass, whereas values from SF-BIA were significantly different from DEXA. Both SF-BIA and MF-BIA measures of body composition correlated strongly with DEXA (r > 0.8; P < 0.001), except for fat mass assessed by SF-BIA, which showed a moderate correlation (r = 0.760; P < 0.001). MF-BIA also showed a better agreement with DEXA by Bland-Altman analysis in all measurements. However, both types of equipment showed wide limits of agreement and a significant relationship between variance and bias (Pitmans's test P > 0.05), except MF-BIA for fat-free mass. CONCLUSIONS: Compared with DEXA, MF-BIA showed better accuracy than SF-BIA, although both types of equipment showed wide limits of agreement. The BIA technique should be used with caution, and regression equations might be useful for correcting the observed variations, mainly in extreme values of body composition.

Upregulation of fibronectin synthesis by interleukin-1 beta in coronary artery smooth muscle cells is associated with the development of the post-cardiac transplant arteriopathy in piglets.

We previously described in piglets after heterotopic cardiac transplantation the early development of a coronary arteriopathy characterized by increased immunostaining for fibronectin and interleukin-1 beta (IL-1 beta) in the vessel wall. The objective of this study was to culture smooth muscle cells from donor and host coronary arteries in these piglets to determine whether donor cells produce more fibronectin than host cells as judged by increased protein and mRNA levels, and whether IL-1 beta may be regulating this increase by an autocrine mechanism involving increased production of the cytokine. We documented increased donor coronary artery smooth muscle cell fibronectin protein synthesis and mRNA compared to host. By using neutralizing antibodies to IL-1 beta, fibronectin protein synthesis and mRNA levels were reduced in donor cells to the levels observed in the host cells and a similar reduction in synthesis was observed with the IL-1 receptor antagonist. Immunoprecipitation of newly synthesized IL-1 beta revealed increased endogenous levels in donor compared to host cells. We therefore suggest in the coronary arteriopathy a pathophysiologic mechanism whereby IL-1 beta-mediated increased fibronectin synthesis may promote lymphocyte trapping and migration of medial smooth muscle cells leading to progressive intimal thickening associated with the post-cardiac transplant coronary arteriopathy.

The role of adrenergic receptor polymorphisms in heart failure.

The main function of the cardiac adrenergic system is to regulate cardiac work both in physiologic and pathologic states. A better understanding of this system has permitted the elucidation of its role in the development and progression of heart failure. Regardless of the initial insult, depressed cardiac output results in sympathetic activation. Adrenergic receptors provide a limiting step to this activation and their sustained recruitment in chronic heart failure has proven to be deleterious to the failing heart. This concept has been confirmed by examining the effect of beta-blockers on the progression of heart failure. Studies of adrenergic receptor polymorphisms have recently focused on their impact on the adrenergic system regarding its adaptive mechanisms, susceptibilities and pharmacological responses. In this article, we review the function of the adrenergic system and its maladaptive responses in heart failure. Next, we discuss major adrenergic receptor polymorphisms and their consequences for heart failure risk, progression and prognosis. Finally, we discuss possible therapeutic implications resulting from the understanding of polymorphisms and the identification of individual genetic characteristics.

Abnormalities in intramyocardial arteries detected in cardiac transplant biopsy specimens and lack of correlation with abnormal intracoronary ultrasound or endothelial dysfunction in large epicardial coronary arteries.

OBJECTIVES: We sought to determine whether abnormalities in small intramyocardial vessels could be detected on routine cardiac transplant biopsy specimens and whether these features correlate with intimal thickening by intracoronary ultrasound and endothelial dysfunction in large epicardial vessels. BACKGROUND: Variability in clinical presentation of allograft vasculopathy suggests differential involvement of large and small vessels. Intracoronary ultrasound and endothelial function studies detect large-vessel abnormalities but may not reflect changes in small intramyocardial arteries. The latter could be detected in routine cardiac biopsy specimens by histologic and immunohistochemical studies. METHODS: Thirty-nine cardiac transplant recipients underwent intracoronary ultrasound and acetylcholine studies 5 to 7 days after endomyocardial biopsy. Biopsy tissue was evaluated for coronary artery endothelial plumping and intimal thickening and increased immunostaining for fibronectin, tumor necrosis factor-alpha and receptor for hyaluronan-mediated motility. Large-vessel disease was assessed by calculating an average intimal index from intracoronary ultrasound of the left anterior descending coronary artery. Endothelial function was determined by quantitative coronary analysis after acetylcholine challenge. RESULTS: Coronary arteries were found in the biopsy tissue of 30 (76%) of the 39 patients who formed the study group. Fourteen of 30 patients had abnormal histologic findings. Immunohistochemical analysis for fibronectin, possible in 20 of 30 patients, was positive in 14 (70%) of 20 and correlated with abnormal histologic findings (p = 0.01). Immunostaining was positive for tumor necrosis factor-alpha and receptor for hyaluronan-mediated motility in 12 (40%) and 13 (43%) of 30 patients, respectively. All patients had intimal thickening by intracoronary ultrasound, but intimal index did not correlate significantly with small-artery disease by histologic or immunohistochemical analysis. Large-vessel endothelial dysfunction in 13 patients (43%) did not correlate with either abnormal ultrasound findings or small-vessel disease. CONCLUSIONS: Intramyocardial arteries are readily observed in biopsy specimens from cardiac transplant recipients and provide useful information about allograft vasculopathy. Lack of correlation between intramyocardial and epicardial vessel disease suggests discordant progression of allograft vasculopathy.

Increased plasma levels of endothelin 1 and von Willebrand factor in patients with type 2 diabetes and dyslipidemia.

OBJECTIVE: Endothelial markers endothelin 1 (ET-1) and von Willebrand factor (vWF) were assessed in patients with type 2 diabetes and dyslipidemia and in patients with hypercholesterolemia. RESEARCH DESIGN AND METHODS: In this case-control study, plasma ET-and vWF levels were measured by enzyme-linked immunosorbent assay in 35 normoalbuminuric type 2 diabetic patients with dyslipidemia (56+/-5 years), in 21 nondiabetic patients with hypercholesterolemia (52+/-7 years), and in 19 healthy control subjects (45+/-4 years). All of the individuals were normotensive and nonsmokers. Urinary albumin was measured by immunoturbidimetry. RESULTS: ET-1 levels were higher (P<0.0001) in type 2 diabetic dyslipidemic patients (1.62+/-0.73 pg/ml) than in both nondiabetic hypercholesterolemic patients (0.91+/-0.73 pg/ml) and control subjects (0.69+/-0.25 pg/ml). vWF levels were significantly increased (P = 0.02) in type 2 diabetic (185.49+/-72.1%) and hypercholesterolemic (163.29+/-50.7%) patients compared with control subjects (129.70+/-35.2%). In the multiple linear regression analysis. ET-1 was significantly associated (adjusted r2 = 0.42) with serum triglyceride levels (P<0.001), age (P<0.01), insulin sensitivity index (P<0.02), and albuminuria levels (P<0.04). vWF levels were associated (adjusted r2 = 0.22) with albuminuria (P<0.001), fibrinogen levels (P<0.02), and BMI (P<0.03). CONCLUSIONS: Compared with hypercholesterolemic patients, type 2 diabetic patients with dyslipidemia have increased levels of ET-1 and vWF which may indicate more pronounced endothelial injury. These findings appear to be related to components of the insulin resistance syndrome.

Increased expression of tumor necrosis factor-alpha in diabetic macrovasculopathy.

Large vessel disease, a common feature of diabetes mellitus, appears to run an aggressive course, but its cellular and molecular aspects remain partially elucidated. Although in common atherosclerosis and especially in other forms of accelerated vasculopathy, immunoinflammatory mechanisms participate in the disease process, it is unclear whether this is present in diabetic vasculopathy. We hypothesized that diabetic macrovasculopathy, compared with classical atherosclerosis, is associated with increased immunoinflammatory features and matrix accumulation. In this study, vessel segments obtained after lower-limb amputation for advanced atherosclerotic disease, from type 2 diabetic patients (n = 20; 68.9+/-10.9 years) and nondiabetic patients (n = 16; 67.1+/-14.6 years) were analyzed. Histological characteristics (extent of intimal proliferation, cellularity, and fibrosis) were semiquantitatively graded in the two lesion types. Using immunohistochemistry, the presence of T cells and macrophages, accumulation of fibronectin, and expression of tumor necrosis factor-alpha was also assessed. Histological features of these advanced atherosclerotic lesions were similar in the two lesions examined. By immunohistochemistry, a similar pattern of T-cell and macrophage infiltration and fibronectin accumulation was observed. Nevertheless, increased expression of tumor necrosis factor-alpha was observed in diabetic lesions (13/19 patients had positive staining), whereas only 2 of 16 lesions from nondiabetic patients had positive staining (p < 0.003), with an odds ratio of 15.17 (confidence interval 2.12-139.5). These data suggest that increased expression of tumor necrosis factor-alpha observed in the diabetic lesions may reflect an enhanced inflammatory activity associated with the development of vascular lesions in type 2 diabetic patients.

Myocardial vacuolization, a marker of ischemic injury, in surveillance cardiac biopsies posttransplant: Correlations with morphologic vascular disease and endothelial dysfunction.

Allograft vasculopathy (AV) causes intimal thickening with progressive luminal obstruction, endothelial dysfunction, and abnormal vasomotion. Subendocardial vacuolization indicating ongoing ischemia was observed at autopsy in transplanted hearts with severe AV. Whether myocyte vacuolization can be observed with lesser degrees of AV in cardia transplant patients has not been reported. Thirty-nine cardiac transplant patients without flow-limiting disease in large epicardial arteries underwent invasive assessment of AV. Eight to 10 segments of the left anterior descending artery were analyzed by intracoronary ultrasound, and an average intimal index was calculated. Endothelial response to acetylcholine was assessed with serial quantitative angiography. Endomyocardial biopsies taken 5 to 7 days prior to the invasive studies were histopathologically reviewed for the presence of small intramyocardial arteries and myocyte vacuolization. Myocyte vacuolization was evident in biopsies from 20 patients (51%). Intramyocardial arteries were observed in 30 cases (76%); 14 had abnormal arteries. All patients had some degree of intimal thickening by intracoronary ultrasound, and 7 (17 %) had severely abnormal average intimal index (>0.2). Endothelial dysfunction was present in 23 patients (58%). Vacuolization failed to show an association with abnormal small artery histology or large epicardial artery ultrasound disease. However, a significant association between vacuolization and endothelial dysfunction was observed (p = 0.05). Myocyte vacuolization, possibly indicating ischemic injury, is common in biopsies from cardiac transplant patients and is associated with abnormal acetylcholine response in large epicardial arteries. We speculate that myocyte vacuolization may be caused at least in part by impaired coronary flow associated with endothelial dysfunction.

Analysis of atherosclerotic plaques obtained by coronary atherectomy: Foam cells correlated positively with subsequent restenosis.

Restenosis following coronary intervention is a complex process the mechanisms of which remains mostly unknown. Tissue obtained by atherectomy is an important means to study restenosis. Previous studies on atherectomy-retrieved tissue have not identified histologic features that correlate with restenosis. We performed an histopathologic evaluation on atherosclerotic plaque tissue obtained by atherectomy from 58 patients, all of whom had a 6-month angiographic follow-up. We identified macrophages and lymphocytes and localized tumor necrosis factor-α expression in the tissue by immunohistochemistry. Histopathology was correlated with late angiographic outcomes. Of 10 histologic features evaluated in the plaque tissue, only the presence of foam cells, identified in paraffin sections, correlated positively with restenosis (p = 0.04). Immunohistochemistry showed that macrophages (p = .07), tumor necrosis factor-α (p = .07), and lymphocytes (p = .14) were more prominent, but not significantly so, in lesions from patients with foam cells and restenosis than in lesions from patients without foam cells or restenosis. Thus the presence of foam cells in primary lesions obtained by atherectomy as identified in paraffin-embedded tissue appears to be a marker for restenosis.

Histological and immunohistochemical characteristics of eccentric coronary artery lesions retrieved by atherectomy from cardiac transplant recipients.

The lesions of cardiac allograft vasculopathy are thought to be strongly related to an immune inflammatory process. Little is known about the biology of these eccentric lesions. However, transplant patients may present with focal disease. Coronary atherectomy provides a unique opportunity to study these clinically relevant lesions in surviving transplant patients. In this series we characterized the features of four lesions (two restenotic and two primary) from three cardiac transplant recipients who underwent coronary atherectomy. The histologic characteristics of the lesions were analyzed and immunohistochemistry was used to assess qualitatively the presence of specific markers of inflammation and the extracellular matrix component fibronectin. Histology showed cholesterol clefts, calcium deposits, and foam cells with low to moderate cellularity and moderate to high fibrosis. Interleukin (IL)-1ß was present in two lesions, but tumor necrosis factor (TNF)-α was absent. The adhesion molecules intercellular adhesion molecule (ICAM)-1 and vascular cellular adhesion molecule (VCAM)-1 and the integrins α5ß1 and α4 were present in all lesions. There was mild to moderate accumulation of fibronectin. Thus, atheroscleroticlike features were present with only low to moderate degrees of immune inflammation. Our findings suggest that eccentric focal plaques in cardiac allograft vasculopathy are less likely to be primarily related to a prominent immune inflammatory process and are similar to atherosclerosis. We speculate that these eccentric lesions that resemble atherosclerosis may be more related to the conventional risk factors for coronary artery disease frequently seen in this population.

Circulating endothelin-1 and tumor necrosis factor-alpha: early predictors of mortality in patients with septic shock.

OBJECTIVES: To determine the predictive value of early determination of tumor necrosis factor (TNF)-alpha, TNF-alpha 1 and 2 soluble receptors (sTNFR1 and sTNFR2) and endothelin-1 (ET-1) for mortality in patients with septic shock. DESIGN: Prospective study. SETTING: Intensive care unit of a university hospital. PATIENTS: Twenty-one patients with septic shock. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Patients with septic shock had a pulmonary artery catheter inserted and blood samples drawn at time zero, 6, 12 and 24 h, simultaneously with hemodynamic assessments. Plasma levels of all markers were measured by ELISA. All patients were followed up to hospital discharge or death. Age and APACHE II scores were significantly higher in nonsurvivors (n = 11) than in survivors (n = 10). Hemodynamic assessments did not aid in the discrimination between the two groups of patients (P > 0.05). Levels of TNF-alpha were higher in nonsurvivors than in survivors at all time-points. sTNFR1 and sTNFR2 were also significantly elevated in nonsurvivors, but not in all measurements. Endothelin-1, however, was significantly higher in nonsurvivors than in survivors only at 6 h (P = 0.02). When both TNF-alpha and ET-1 were increased at early time-points, the best predictive values for mortality were obtained [positive and negative predictive values of 72 and 100% at 6 h, odds ratio 3.0, 95% CI (1.2-7.6)]. CONCLUSIONS: Increased levels of TNF-alpha were consistently higher at all time-points in nonsurvivors with septic shock. ET-1 levels, however, appeared also to be an early and sensitive predictor of mortality. Very early determination of TNF-alpha and ET-1 in septic shock may help to identify patients at higher risk for adverse outcome.

Association between early detection of soluble TNF-receptors and mortality in burn patients.

OBJECTIVES: To describe early sequential profiling of circulating levels of tumor necrosis factor alpha (TNF-alpha), TNF-1 and TNF-2 soluble receptors (sTNFR1 and sTNFR2), and of endothelin (ET-1) in patients with severe burn injury, and its association with mortality. DESIGN: Prospective study. SETTING: Intensive Care Burn Unit at a community hospital. PATIENTS: Twenty patients with total burn surface area (TBSA)> or = 30%. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Patients were enrolled within 6 h from the injury. Blood samples were drawn at zero, 6, 12, and 24 h for sequential ELISA measurement of plasma marker levels. Data are expressed as mean+/-SD. Age, TBSA, and inhalation injury were not significantly different between survivors ( n=9; 30+/-13 years, TBSA 40+/-12%) and nonsurvivors ( n=11, 38+/-15 years, TBSA 56+/-20%). sTNFR1 levels were increased in nonsurvivors (2937+/-1676 pg/ml; 4548+/-1436 pg/ml) as compared to survivors (1313+/-561 pg/ml; 2561+/-804 pg/ml) at 6 h and 24 h, respectively ( P=0.01 and 0.002). sTNFR2 levels were significantly increased in nonsurvivors (4617+/-1,876 pg/ml vs 2611+/-1,326 pg/ml) only at 6 h ( P=0.015). TNF-alpha and ET-1 levels were not different between nonsurvivors and survivors. After adjustment for TBSA, sTNFR1 and sTNFR2 remained significantly higher in nonsurvivors. CONCLUSION: Early and progressive increase in sTNFR1 and sTNFR2 levels is associated with higher risk for poor outcome in severely burned patients.

Increased plasma levels of soluble vascular cellular adhesion molecule-1 in patients with chest pain and angiographically normal coronary arteries.

AIMS: To assess plasma levels of vascular cellular adhesion molecule-1, a marker of endothelial dysfunction, in patients presenting with coronary syndromes submitted to coronary angiography. METHODS AND RESULTS: Plasma levels of soluble vascular cellular adhesion molecule-1 were measured by enzymatic immunoabsorbent assay in eight patients with angina-like chest pain and angiographically normal coronary arteries; in 14 patients with stable angina and in 18 patients with unstable angina, both with coronary lesions by angiography, and in 10 healthy volunteers. Levels of soluble vascular cellular adhesion molecule-1 were higher in unstable angina patients (1777+/-161 SE pg ml(-1)) compared to patients with stable angina (1178+/-206 SE pg ml(-1), P<0.05). Moreover, patients with angina-like chest pain and normal coronary arteries had significantly higher soluble vascular cellular adhesion molecule-1 levels (2307+/-295 SE pg ml(-1)) compared to stable angina patients (P<0.05), but similar levels compared to unstable angina patients. Patient groups had higher values of soluble vascular cellular adhesion molecule-1 compared to the control group (734+/-97 SE pg ml(-1)). CONCLUSIONS: Increased levels of soluble vascular cellular adhesion molecule-1 are associated with coronary artery disease in patients with anatomically established lesions. In patients free of flow-limiting lesions and angina-like chest pain, high levels of this marker may indicate endothelial dysfunction.

Cytokines and troponin-I in cardiac dysfunction after coronary artery grafting with cardiopulmonary bypass.

OBJECTIVE: The association between cytokines and troponin-I with cardiac function after cardiac surgery with cardiopulmonary bypass remains a topic of continued investigation. METHODS: Serial measurements, within 24h following surgery, of tumor necrosis factor-alpha, its soluble receptors, and troponin-I were performed in patients with normal ejection fraction undergoing coronary artery bypass grafting. Ejection fraction was measured by radioisotopic ventriculography preoperatively, at 24h and at day 7 postoperatively. RESULTS: Of 19 patients studied (59+/-8.5 years), 10 (group 1) showed no changes in ejection fraction, 53+/-8% to 55+/-7%, and 9 (group 2) had a decrease in ejection fraction, 60+/-11% to 47+/-11% (p=0.015) before and 24h after coronary artery bypass grafting, respectively. All immunological variables, except tumor necrosis factor-alpha soluble receptor I at 3h postoperation (5.5+/- 0.5 in group 1 versus 5.9+/-0.2 pg/ml in group 2; p=0.048), were similar between groups. Postoperative troponin-I had an inverse correlation with ejection fraction at 24h (r= -0.44). CONCLUSIONS: Inflammatory activity, assessed based on tumor necrosis factor-alpha and its receptors, appears to play a minor role in cardiac dysfunction after cardiac surgery. Troponin I levels are inversely associated with early postoperative ejection fraction.

Plasma levels of immunoinflammatory markers in De Novo coronary atherosclerosis and coronary restenosis postangioplasty.

OBJECTIVE: To compare circulating plasma levels of immunoinflammatory markers in patients with known de novo coronary artery disease and patients with postangioplasty restenosis. METHODS: Using enzymatic immunoabsorbent assay, we measured plasma levels of soluble interleukin-2 receptosr, tumor necrosis factor alpha, and soluble tumor necrosis alpha receptors I and II in 11 patients with restenosis postcoronary angioplasty (restenosis group), in 10 patients with primary atherosclerosis (de novo group) who were referred for coronary angiography because of stable or unstable angina, and in 9 healthy volunteers (control group). Levels of soluble interleukin-2 receptors were significantly higher in the de novo group compared with that in the restenosis and control groups. Levels were also higher in the restenosis group compared with that in the control group. Plasma levels of tumor necrosis alpha and receptor levels were significantly higher in the de novo group compared to with that in the restenosis and control groups, but levels in the restenosis group were not different from that in the controls. CONCLUSION: Coronary artery disease, either primary or secondary to restenosis, is associated with significant immunoinflammatory activity, which can be assessed by examining the extent of circulating plasma levels of inflammatory markers. Moreover, patients with de novo lesions appear to have increased inflammatory activity compared with patients with restenosis.

Impact of beta-2 Thr164Ile and combined beta-adrenergic receptor polymorphisms on prognosis in a cohort of heart failure outpatients.

Genetic polymorphisms of adrenergic receptors (ARs) have been associated with the development, progression, and prognosis of patients with heart failure (HF), with few data for the Brazilian population. We evaluated the role of the beta2-AR Thr164Ile polymorphism at codon 164 on prognosis in a prospective study on 315 adult Brazilian HF patients, predominantly middle-aged Caucasian men in functional class I-II, with severe left ventricular systolic dysfunction. Genomic DNA was extracted from peripheral blood and beta2-AR164 genotypes were detected by PCR followed by restriction fragment length analysis. During a median follow-up of 3 years, 95 deaths occurred and 57 (60%) were HF-related. Unexpectedly, Ile164 carriers (N = 12) had no HF-related events (log-rank P value = 0.13). Analysis using genotype combination with beta1-AR polymorphisms at codons 49 and 389 identified patients with favorable genotypes (Thr164Ile of beta2-AR, Gly49Gly of beta1-AR and/or Gly389Gly of beta1-AR), who had lower HF-related mortality (P = 0.01). In a Cox proportional hazard model adjusted for other clinical characteristics, having any of the favorable genotypes remained as independent predictor of all-cause (hazard ratio (HR): 0.41, 95%CI: 0.17-0.95) and HF-related mortality (HR: 0.12, 95%CI: 0.02-0.90). These data show that the beta2-AR Thr164Ile polymorphism had an impact on prognosis in a Brazilian cohort of HF patients. When combined with common beta1-AR polymorphisms, a group of patients with a combination of favorable genotypes could be identified.