Integrin mediated adhesion of mononuclear cells from patients with familial hypercholesterolemia

BACKGROUND: Low-density lipoproteins (LDL) can induce the adhesion of monocytes to endothelial cells. Monocytes of patients with familial hypercholesterolemia (FH) are exposed to high concentrations of LDL, and it has been reported that adhesiveness of these cells in hypercholesterolemic patients is enhanced. We investigated whether LFA-1 or VLA-4 mediated adhesion is altered in FH patients and whether HMG-CoA reductase inhibitors influence this adhesion. PATIENTS AND METHODS: LFA-1 and VLA-4 mediated adhesion to ICAM-1 and VCAM-1 coated beads was investigated using freshly isolated monocytes and T-lymphocytes from patients with homozygous FH, heterozygous FH (before and after cholesterol lowering treatment), and from controls. In addition, the expression of beta1- and beta2-integrins on these cells was determined. RESULTS: Both LFA-1 and VLA-4 mediated adhesion and integrin expression of monocytes and CD3+ cells from patients with homozygous FH and heterozygous FH was similar to that of monocytes from a control population. Treatment with HMG-CoA reductase inhibitors did not affect the adherence to ICAM-1 or VCAM-1, and did not influence the expression of integrins. CONCLUSIONS: In contrast to studies by others, we demonstrated in the present study that the actual LFA-1 and VLA-4 mediated adhesion of T-lymphocytes and monocytes is not altered in patients with FH.     

The long-term efficacy and safety profile of barnidipine

Two multicentre trials have investigated the efficacy and tolerability of treatment with once-daily barnidipine, in patients with mild to moderate essential hypertension. The long-term efficacy and safety of barnidipine were demonstrated in a long-term, multicentre, open-label study. In total, 106, 79 and 32 patients were followed for the first, second and third year, respectively. Patients received barnidipine at a dose titrated to achieve a sitting DBP > or = 90 mmHg or a decrease in sitting BDP > or = 10 mmHg. If necessary, another antihypertensive agent was added to achieve normalisation of blood pressure. In the first year, normalisation of blood pressure was achieved in 91% of patients. This was maintained in 91% and 81% of patients in the second and third years, respectively. At the end of treatment in both years, over 60% of patients remained on barnidipine monotherapy (10 or 20 mg/day). A low incidence of adverse events possibly or probably related to barnidipine (10 or 20 mg/day) monotherapy was reported in the first and second years with headache, peripheral oedema and palpitations the most commonly reported. In the third year of follow-up, only one adverse event, an ECG abnormality, was considered to be possibly related to the study medication. The effective 24 hour control of blood pressure with barnidipine monotherapy was confirmed in a randomised, double-blind, placebo-controlled, cross-over study of 20 patients. These patients were given 6 week regimens of both barnidipine (20 mg/day) and placebo. Office and 24 hour ambulatory blood pressures were recorded at the end of each treatment phase. Barnidipine lowered blood pressure to a significantly greater extent than placebo both at night and during the day. Adverse events were classified as mild or moderate and fewer adverse events were reported with barnidipine treatment compared with placebo. Barnidipine monotherapy (20 mg/day) is safe and effective in providing 24 hour control of blood pressure. Furthermore, the efficacy and tolerability of barnidipine monotherapy (10 or 20 mg/day) are maintained for at least 2 years.     

Serum HER2 levels are increased in patients with chronic heart failure

BACKGROUND: The use of trastuzumab, an antibody against the human epidermal growth factor receptor 2 (HER2), in patients with HER2 positive metastatic breast cancer, is related to cardiotoxicity. AIMS: To investigate whether serum HER2 is increased in heart failure patients and related to disease severity. METHODS: Serum HER2, plasma tumor necrosis factor (TNF)-alpha and its soluble (s) receptors (sTNF-R1 and 2) were determined with ELISA in chronic heart failure patients and age and gender-matched healthy controls. RESULTS: Serum HER2 was higher (P=0.013) in 50 heart failure patients (18 female; median age 57 (range 33-77) years), mean 12.1+/-S.D. 2.3 ng/mL, than in 15 controls, 10.4+/-2.6 ng/mL. Serum HER2 levels correlated inversely with left ventricular ejection fraction (P=0.037) and were highest among NYHA class III patients, followed by NYHA class II patients and controls (P=0.029, Kruskal-Wallis test). STNF-R1 (P<.001) and sTNF-R2 (P=0.015) were higher in patients than controls, and correlated positively with HER2 (P=0.027 and P=0.036, respectively). CONCLUSIONS: Serum HER2 levels are increased in chronic heart failure patients. Further research is necessary to determine whether HER2 plays a role in the pathophysiology of heart failure.     

Prognosis of metastatic breast cancer: are there differences between patients with de novo and recurrent metastatic breast cancer?

Background:

We aimed to determine the prognostic impact of time between primary breast cancer and diagnosis of distant metastasis (metastatic-free interval, MFI) on the survival of metastatic breast cancer patients.

Methods:

Consecutive patients diagnosed with metastatic breast cancer in 2007–2009 in eight hospitals in the Southeast of the Netherlands were included and categorised based on MFI. Survival curves were estimated using the Kaplan–Meier method. Cox proportional hazards model was used to determine the prognostic impact of de novo metastatic breast cancer vs recurrent metastatic breast cancer (MFI ⩽24 months and >24 months), adjusted for age, hormone receptor and HER2 status, initial site of metastasis and use of prior (neo)adjuvant systemic therapy.

Results:

Eight hundred and fifteen patients were included and divided in three subgroups based on MFI; 154 patients with de novo metastatic breast cancer, 176 patients with MFI <24 months and 485 patients with MFI >24 months. Patients with de novo metastatic breast cancer had a prolonged survival compared with patients with recurrent metastatic breast cancer with MFI <24 months (median 29.4 vs 9.1 months, P<0.0001), but no difference in survival compared with patients with recurrent metastatic breast cancer with MFI >24 months (median, 29.4 vs 27.9 months, P=0.73). Adjusting for other prognostic factors, patients with MFI <24 months had increased mortality risk (hazard ratio 1.97, 95% CI 1.49–2.60, P<0.0001) compared with patients with de novo metastatic breast cancer. When comparing recurrent metastatic breast cancer with MFI >24 months with de novo metastatic breast cancer no significant difference in mortality risk was found. The association between MFI and survival was seen irrespective of use of (neo)adjuvant systemic therapy.

Conclusion:

Patients with de novo metastatic breast cancer had a significantly better outcome when compared with patients with MFI <24 months, irrespective of the use of prior adjuvant systemic therapy in the latter group. However, compared with patients with MFI >24 months, patients with de novo metastatic breast cancer had similar outcome.     

Prognostic value of plasma erythropoietin on mortality in patients with chronic heart failure

OBJECTIVES: This study aimed to investigate the prognostic importance of plasma erythropoietin (EPO) levels in chronic heart failure (CHF) patients. BACKGROUND: Anemia is common and is associated with an impaired survival in patients with CHF. Erythropoietin is a hematopoietic growth factor, upregulated in anemic conditions. Little is known about the pathophysiology of anemia in CHF and the prognostic importance of plasma EPO levels in CHF patients. METHODS: In 74 patients with CHF (age, 61 +/- 2 years; left ventricular ejection fraction, 0.31 +/- 0.01; peak oxygen consumption, 19.1 +/- 0.6 [mean +/- SEM]) and in 15 control patients, hemoglobin levels and plasma concentrations of EPO and brain natriuretic peptide were measured. RESULTS: During a mean follow-up of 3.0 years (range, 2.3 to 5.3 years), 22 patients (30%) died. Anemia was present in 24% of the patients. Multivariate analysis showed that plasma EPO (p = 0.026) and hemoglobin levels (p = 0.005) were independent predictors of survival in this CHF population. We observed only a mild inverse correlation between the logarithm of EPO and hemoglobin levels (r2 = 0.08, p = 0.02) in CHF patients, whereas the control group showed a clear significant inverse correlation (r2 = 0.44, p = 0.007). CONCLUSIONS: Elevated plasma EPO levels are associated with an impaired prognosis independent of hemoglobin levels and other established markers of CHF severity. Furthermore, in the CHF patients, EPO levels poorly correlate with the hemoglobin levels, in contrast with the control group.     

Long-term safety and efficacy of high-dose atorvastatin treatment in patients with familial hypercholesterolemia

In the 2-year Atorvastatin versus Simvastatin on Atherosclerosis Progression extension study, patients with familial hypercholesterolemia who continued to take atorvastatin 80 mg for an additional 2 years had complete arrest of the progression of mean carotid intima-media thickness (0.89 mm at the start vs 0.90 mm at the end of the study, p = 0.58). In contrast, patients previously taking simvastatin 40 mg had significant regression of intima-media thickness (0.95 mm at the start vs 0.92 mm at the end of the study, p = 0.01). Therefore, both placebo- and statin-treated patients with familial hypercholesterolemia are best treated with high-dose atorvastatin, a therapeutic regimen that induces atherosclerosis regression and is safe and well tolerated over a 4-year period.