First-line trastuzumab plus epirubicin and cyclophosphamide therapy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: cardiac safety and efficacy data from the Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial.

PURPOSE: A high incidence of congestive heart failure (CHF) has been observed in patients with metastatic breast cancer (MBC) receiving doxorubicin-based chemotherapy and trastuzumab. The Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial evaluated trastuzumab plus cyclophosphamide and the less cardiotoxic anthracycline epirubicin. PATIENTS AND METHODS: This prospective trial combined a phase I dose-finding stage with a phase II randomized stage. In total, 120 patients with human epidermal growth factor receptor 2 (HER2) -positive MBC and adequate cardiac function received first-line trastuzumab (4 mg/kg intravenous loading dose, then 2 mg/kg every week) plus cyclophosphamide (600 mg/m(2)) and either epirubicin 60 mg/m(2) (HEC-60) or 90 mg/m(2) (HEC-90) for six cycles, followed by trastuzumab monotherapy until progression. Sixty patients with HER2-negative disease received epirubicin (90 mg/m(2)) and cyclophosphamide (EC-90) alone. The primary end point was dose-limiting cardiotoxicity (DLC). RESULTS: Incidence of DLC was 5.0%, 1.7%, and 0% in the HEC-90, HEC-60, and EC-90 arms, respectively. All DLC events were manageable. There were no cardiac-related deaths. Other adverse-event profiles were comparable across the three arms, except febrile neutropenia, which was reported in 10% of the HEC-90 arm compared with 3% of the other arms. Tumor response rates were 57%, 60%, and 25% in the HEC-60, HEC-90, and EC-90 arms, respectively; median time to progression was 12.5, 10.1, and 7.6 months, respectively. CONCLUSION: The HEC regimen is a promising treatment option for patients with HER2-positive MBC. The lower incidence of DLC with HEC, compared with the historic incidence associated with trastuzumab plus doxorubicin, supports further evaluation of the regimen, especially in adjuvant or neoadjuvant settings.

Left atrial size by planimetry is superior to M-mode diameter: biochemical calibration by atrial and brain natriuretic peptide.

BACKGROUND: Left atrial (LA) size is routinely assessed by M-mode on echocardiography. Recently, a superiority of apical measures of LA size has been suggested, but no biochemical calibration has been attempted yet. The aim of the current study was to compare echocardiographic parameters of LA size through biochemical calibration with the natriuretic peptides atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). METHODS: A total of 610 middle-aged (50-67 years) subjects from a population-based sample (MONICA Augsburg, Germany) were characterized with respect to LA area and volume from the apical two-chamber (2C) and four-chamber (4C) views in addition to M-mode echocardiography. ANP and BNP concentrations were determined by radioimmunoassay. RESULTS: A significant correlation to ANP and BNP was present with all measures on LA size. The univariate correlation was lowest with M-mode diameter (r = 0.11 with ANP; r = 0.09 with BNP, both P < .03), whereas 2C volume displayed the closest correlation (r = 0.20 with ANP and r = 0.28 with BNP, both P < .001) and even slightly exceeded 2C area, 4C volume, and 4C area. 2C volume further displaced LV systolic function, mass index, and heart rate as statistically significant predictors of ANP (P < .001) and BNP (P < .001) on adjusted regression analysis, whereas M-mode diameter was displaced as a significant predictor of ANP and BNP (P = not significant). CONCLUSIONS: The current population-based echocardiographic study allows new insight into the value of different measures of LA size. The closer association between natriuretic peptide concentrations and parameters derived from planimetry and volumetry suggests a superiority of these parameters LA diameter. LA volumetry should be included in routine echocardiography for optimized assessment of LA size.

Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial.

PURPOSE: The purpose of this analysis was to investigate trastuzumab-associated cardiac adverse effects in breast cancer patients after completion of (neo)adjuvant chemotherapy with or without radiotherapy. PATIENTS AND METHODS: The Herceptin Adjuvant (HERA) trial is a three-group, multicenter, open-label randomized trial that compared 1 or 2 years of trastuzumab given once every 3 weeks with observation in patients with HER-2-positive breast cancer. Only patients who after completion of (neo)adjuvant chemotherapy with or without radiotherapy had normal left ventricular ejection fraction (LVEF > or = 55%) were eligible. A repeat LVEF assessment was performed in case of cardiac dysfunction. RESULTS: Data were available for 1,693 patients randomly assigned to 1 year trastuzumab and 1,693 patients randomly assigned to observation. The incidence of trastuzumab discontinuation due to cardiac disorders was low (4.3%). The incidence of cardiac end points was higher in the trastuzumab group compared with observation (severe congestive heart failure [CHF], 0.60% v 0.00%; symptomatic CHF, 2.15% v 0.12%; confirmed significant LVEF drops, 3.04% v 0.53%). Most patients with cardiac dysfunction recovered in fewer than 6 months. Patients with trastuzumab-associated cardiac dysfunction were treated with higher cumulative doses of doxorubicin (287 mg/m(2) v 257 mg/m(2)) or epirubicin (480 mg/m(2) v 422 mg/m(2)) and had a lower screening LVEF and a higher body mass index. CONCLUSION: Given the clear benefit in disease-free survival, the low incidence of cardiac adverse events, and the suggestion that cardiac dysfunction might be reversible, adjuvant trastuzumab should be considered for treatment of breast cancer patients who fulfill the HERA trial eligibility criteria.

Coronary endothelial vasomotor function and vascular remodeling in heart transplant recipients randomized for tacrolimus or cyclosporine immunosuppression.

OBJECTIVES: This study aimed to compare changes in coronary endothelial function, systemic endothelin-1 (ET-1) levels, and vascular remodeling in heart transplant recipients randomized to cyclosporin A (CyA) or tacrolimus (Tac) immunosuppression. BACKGROUND: Functional endothelial abnormalities and intimal thickening are sensitive measures of early cardiac allograft vasculopathy (CAV). METHODS: The randomized, prospective study was performed in two groups of 22 patients, maintained on Tac or CyA and mycophenolate mofetil immunosuppression, 1 and 12 months after heart transplantation. We investigated epicardial luminal diameter, coronary blood flow velocity, and ET-1 plasma levels at 1 and 12 months after transplantation. Structural coronary alterations were determined using intravascular ultrasound. RESULTS: Epicardial vasomotor function at baseline and during follow-up was comparable between the groups. Deterioration of microvascular endothelial function during follow-up was significantly enhanced in the CyA versus Tac group (p < 0.05). Circulating ET-1 concentration increased in the CyA group but significantly decreased over time in the Tac group (CyA +17% vs. Tac -25%; p < 0.05). The time-dependent increase in mean intimal area was significantly enhanced in the CyA versus Tac group, whereas the vessel area significantly increased during follow-up in the Tac compared with the CyA group. CONCLUSIONS: Epicardial endothelial function is comparable between CyA- and Tac-treated patients. Microvascular endothelial function deteriorates more in CyA-treated patients, a finding that correlates with enhanced ET-1 concentration and an increased intimal area during follow-up. The mean vessel area in the Tac group increased over time, indicating positive vascular remodeling. Tac is superior to CyA with respect to microvascular endothelial function, intimal thickening, and vascular remodeling.

Relation of the G protein beta3-subunit polymorphism with left ventricle structure and function.

The G protein beta3-subunit C825T polymorphism results in a truncated splice variant protein that is associated with enhanced transmembrane signaling, increased proliferative activity, and arterial hypertension. The aim of the present study was to further investigate the association of this polymorphism with left ventricular (LV) structure and function. A total of 2052 individuals from a large-scale population-based sample were investigated for the G protein beta3-subunit C825T polymorphism and echocardiographic parameters of LV structure and function. Complete genotyping and echocardiographic data were available in 1720 individuals (829 men and 891 women). The mean LV mass indices in men with CC (n=384) and TT (n=84) genotypes were 98.3+/-1.2 g/m2 and 100.0+/-2.8 g/m2, respectively (P=0.64). In women, the corresponding values were 83.1+/-1.0 g/m2 for the CC genotype (n=397) and 83.8+/-2.1 g/m2 for the TT genotype (n=91, P=0.32). Likewise, LV dimensions or parameters of the diastolic function and serologic markers of LV mass were not associated with the C825T variant. Finally, multivariate analyses accounting for potentially confounding factors failed to show any influence of this polymorphism on echocardiographic parameters. In conclusion, we were not able to confirm the previously published associations of the G protein beta3-subunit C825T polymorphism with LV structure and diastolic function.

Prognostic value of 2D echocardiography in patients presenting with acute chest pain and non-diagnostic ECG for ST-elevation myocardial infarction.

The purpose of the present study was to test the hypothesis that early detection of regional wall motion abnormalities (WMA) by 2D echocardiography (ECHO) accurately predicts further cardiac events in patients presenting with acute chest pain. A prospective analysis was performed in subjects admitted with the first presentation of acute chest pain and a non-diagnostic ECG for acute ST-elevation myocardial infarction. Patients with known coronary artery disease were excluded. All subjects were contacted by phone for a 30days follow-up regarding cardiac events defined as PCI/CABG, AMI, and death. In 132 consecutive patients (89 male, 43 female) complete data sets consisting of case history (H; abnormal: typical angina), ECG (abnormal: ST-depression, T-inversion, atypical ST-elevation, LBBB), serum markers (TnI; abnormal: elevation of troponin I=0.5 ng/ml), ECHO (abnormal: WMA) and follow-up were available. In 45 patients, 60 cardiac events occurred (three deaths, 24 AMI, 33 PCI/CABG). Positive (PPV; %) and negative predictive values (NPV; %) of ECHO were superior to all other diagnostic tests (P<0.05 each) for adverse cardiac events, evolving AMI or death, and superior to history and ECG for later need of revascularisation (PCI/ACVB). Multivariate analysis revealed that WMA in ECHO predict cardiac events independently of age, gender, and the common combination of investigations (H/ECG/TnI). A significant independent impact of ECHO was also determined for the prediction of AMI/death or PCI/CABG. The study shows that early 2D echocardiography provides superior prognostic information concerning the risk of subsequent complications in patients with acute chest pain and a non-diagnostic ECG for ST-elevation-AMI.

Gender-specific differences of cardiac remodeling in subjects with left ventricular dysfunction: a population-based study.

BACKGROUND: Recent studies suggest that female gender is associated with a lower prevalence and a more benign prognosis of heart failure. In the current population-based study, it was our objective to evaluate the implications of gender on the association between impaired left ventricular (LV) function and mass as well as neurohumoral activation. METHODS AND RESULTS: A total of 1883 subjects (992 female, 891 male) of two MONICA surveys in Augsburg, Germany, were analyzed. Participants of one of these surveys were additionally characterized with respect to neurohormonal activation. As compared to men, women were characterized by a slightly higher LV ejection fraction (EF, Teichholz-Method, 65.4 +/- 0.3% vs. 63.4 +/- 0.3, P<0.01) and a markedly lower LV mass index (LVMI 81 +/- 1 g/m(2) vs. 96 +/- 1, P<0.01). As compared to men with normal LV function, those with LV dysfunction (EF below mean minus two standard deviations, S.D.) were characterized by significantly increased LV mass (LVMI +48%, P<0.01), plasma BNP (+373%, P<0.01) and ANP (+57%, P<0.01), while no significant changes were observed in women (LVMI +3%, BNP +48%, ANP +27%, all P=n.s). Only a small subgroup of women with severe LVD (EF below mean - 3 S.D.) was characterized by significantly increased LV mass (LVMI +23%, P<0.05 vs. control and LVD), however, this increase was less pronounced as compared to men with severe LVD (LVMI +46%, P<0.01 vs. control). Gender-specific differences between LV function and structure were also confirmed by multivariate analysis. While LVMI was independently and significantly correlated with EF in male subjects in addition to systolic blood pressure, age, and body mass index (all P<0.01), these parameters displaced EF as a predictor of LVMI in female subjects. CONCLUSIONS: Men with moderate or severe LV dysfunction are characterized by an increase in both LV mass and cardiac natriuretic peptide plasma concentrations. In contrast, LV mass and natriuretic peptide concentrations increase to a lesser extent and only with severe LV dysfunction in women. These observational data suggest gender-specific control of myocardial adaptations to hemodynamic overload and a more rapid induction of LV hypertrophy during myocardial dysfunction in male subjects.