Efficacy and safety of the dual L- and T-type calcium channel blocker, ACT-280778: a proof-of-concept study in patients with mild-to-moderate essential hypertension.

ACT-280778 is an oral, non-dihydropyridine, dual L-/T-type calcium channel blocker. This phase 2a, double-blind, randomized, placebo- and active-controlled study investigated the efficacy and safety of 10 mg ACT-280778. Patients with mild-to-moderate essential hypertension received once-daily placebo (n=53), ACT-280778 10 mg (n=52) or amlodipine 10 mg (n=54) for 4 weeks. The primary end point was the change from baseline to week 4 in placebo-adjusted mean trough sitting diastolic blood pressure (SiDBP) with ACT-280778. Tolerability was assessed by recording treatment-emergent adverse events (TEAEs). Baseline clinical characteristics were similar across groups. No significant difference was observed at week 4 in mean trough SiDBP between placebo (-9.9 (95% confidence limit (CL) -12.7, -7.0) mm Hg) and ACT-280778 (-9.5 (-12.4, -6.5) mm Hg; P=0.86); amlodipine reduced mean trough SiDBP by -16.8 (-19.0, -14.5) mm Hg, confirming assay validity. Change in mean PR interval at week 4 (pre-dose) differed between placebo (-1.0 (95% CL -4.4, 2.3) ms) and ACT-280778 (6.5 (3.5, 9.6) ms); amlodipine did not increase PR interval (1.1 (-1.6, 3.9) ms).Treatment-emergent adverse events (TEAE) frequency was 32.1% (placebo), 32.7% (ACT-280778) and 33.3% (amlodipine). The most common TEAEs were headache, peripheral edema, hypertension and second-degree atrioventricular block. ACT-280778 (10 mg) did not lower blood pressure in mild-to-moderate hypertension.

High dose treatment with angiotensin II receptor blocker in patients with hypertension: differential effect of tissue protection versus blood pressure lowering.

Aggressive inhibition of renin-angiotensin-aldosterone system may provide the best cardiovascular protection. We examined the effect of different doses of angiotensin II receptor blocker, Candesartan, on arterial elasticity, inflammatory and metabolic parameters in hypertensive patients with multiple cardiovascular risk factors. 69 hypertensive patients were randomized into three groups: group 1 included patients treated with high doses of Candesartan (32 mg), group 2 included patients treated with conventional doses of Candesartan (16 mg), group 3 included patients that received antihypertensive treatment other that angiotensin II type-1 receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs). Patients were evaluated for lipid profile, HbA1C, insulin, C-peptide, hs-CRP, aldosterone, renin and Homeostasis model assessment-insulin resistance (HOMA-IR). Arterial elasticity was evaluated using pulse wave contour analysis method (HDI CR 2000, Eagan, Minnesota). In patients treated with high doses of Candesartan: large artery elasticity index (LAEI) increased from 8.6+/-2.8 to 16.6+/-5.1 ml/mm Hg x 100 after 6 months of treatment (p<0.0001). Small artery elasticity index (SAEI) increased from 2.7+/-1.3 to 5.9+/-2.8 ml/mm Hg x 100 (p<0.0001). Systemic vascular resistance (SVR) decreased from 1881.5+/-527.5 to 1520.9+/-271.8 (p<0.0006). In patients treated with conventional doses of Candesartan: LAEI index increased from 11.0+/-3.5 to 14.4+/-3.2 ml/mm Hg x 100 (p<0.0001). SAEI increased during the study from 3.7+/-1.4 to 5.4+/-2.1 ml/mm Hg x 100 (p<0.0001). SVR decreased from 1699.8+/-327.6 to 1400.7+/-241 (p<0.0001). In the control group: neither LAE nor SAE improved during the treatment period. Although similar reduction in blood pressure was observed in all three groups, both LAE and SAE improved only in patients treated by ARBs. Treatment with high doses of Candesartan improves arterial stiffness to a greater extent than conventional doses of Candesartan, despite comparable changes in blood pressure.

Effect of long-term treatment with rosiglitazone on arterial elasticity and metabolic parameters in patients with Type 2 diabetes mellitus: a 2-year follow-up study.

AIMS: Thiazolidinediones may influence the atherogenic process by improving cardiovascular risk factors. The present study was designed to determine the long-term effect of rosiglitazone on arterial compliance and metabolic parameters in patients with Type 2 diabetes. METHODS: In an open-label, prospective study, 65 diabetic patients received rosiglitazone orally (4-8 mg/day) for 6 months. After 6 months, the patients continued an open follow-up study and were divided into two groups: group 1 included patients continuing rosiglitazone for 2 years, group 2 included patients discontinuing rosiglitazone and receiving other oral glucose-lowering agents. Lipid profile, glycated haemoglobin (HbA1c), insulin, C-peptide, fibrinogen, high-sensitivity-CRP and homeostasis model assessment-insulin resistance were measured. Arterial elasticity was assessed using pulse wave contour analysis. RESULTS: In patients treated with rosiglitazone for 2 years: the large artery elasticity index (LAEI) increased from 10.0 +/- 4.6 to 13.9 +/- 4.7 ml/mmHg x 100 after 2 years (P = 0.003). The small artery elasticity (SAEI) index increased significantly from 3.2 +/- 1.2 to 5.1 +/- 1.9 (P < 0.0001). In patients who discontinued rosiglitazone: LAEI did not change after 6 months, but decreased from 12.1 +/- 5.4 to 8.9 +/- 3.9 ml/mmHg x 10 (P < 0.0001) at the end of 2 years. SAEI increased during the first 6 months of treatment, from 3.9 +/- 1.8 to 5.1 +/- 1.5 ml/mmHg x 100 (P < 0.0001) and decreased after discontinuation of rosiglitazone (P = 0.042). CONCLUSIONS: Prolonged treatment with rosiglitazone improved arterial elasticity. However, significant deterioration in LAEI and SAEI was observed in patients who discontinued rosiglitazone. The beneficial vascular effect of rosiglitazone on arterial elasticity was independent of glycaemic control.

C-reactive protein distribution and correlates among men and women with chronic coronary heart disease.

BACKGROUND: C-reactive protein (CRP) elevated in inflammation is associated with atherosclerotic disease. We describe the distribution of CRP and its association with coronary heart disease (CHD) risk factors in a large CHD patient group. METHODS: This analysis comprises 2,723 male and 256 female CHD patients, included in the Bezafibrate Infarction Prevention (BIP) study. High sensitive CRP levels were determined in frozen plasma samples. RESULTS: CRP distribution, was normalized upon log transformation. Levels among women were higher than in men in the entire group (4.4 vs. 3.5 mg/l) and in each age group. Co-morbidities, smoking, lower education level, and use of cardiovascular drugs, were associated with elevated CRP levels in both sexes. The correlation between CRP and body mass index (BMI), insulin and glucose was stronger among women. The explained variability in CRP level was larger in women (20%) compared to men (13%). Among women, BMI explained 10% of CRP variability, whereas the contribution of each variable among men was significantly smaller. CONCLUSIONS: Among men and women with CHD, CRP level was correlated with traditional risk factors and to a lesser degree to manifestation of CHD. BMI is the main contributor to CRP variability, explained by these factors among women.

Long-term thyrotropin-suppressive therapy with levothyroxine impairs small and large artery elasticity and increases left ventricular mass in patients with thyroid carcinoma.

BACKGROUND: Exogenous subclinical hyperthyroidism, caused by long-term thyrotropin (TSH)-suppressive treatment with levothyroxine (LT(4)), is associated with several cardiovascular abnormalities. In order to assess the effect of long-term thyroid hormone-suppressive therapy on the blood vessels and myocardium, we determined the arterial elasticity, using the pulse wave contour analysis. METHODS AND RESULTS: Twenty-six athyreotic patients receiving TSH-suppressive LT(4) therapy for periods ranging from 3 to 21 years at a mean daily dose of 2.25 +/- 0.5 microg/kg per day were included in the study. Twenty six age- and gender-matched healthy subjects served as controls. Arterial elasticity of large and small arteries was evaluated using pulse wave contour analysis method (HDI CR 200, Eagen, MN). Cardiac structure was assessed by two-dimensional echocardiography. We found decreased large artery elasticity in subclinical hyperthyroidism (sHT) patients compared to controls (14.14 +/- 3.38 versus 10.53 +/- 2.43 L/mm Hg x 100, p < 0.000). Small artery elasticity was also lower in patients than in controls (5.42 +/- 1.82 versus 4.30 +/- 1.75 mL/mm Hg x 100, p < 0.056). The echocardiographic data showed significantly increased left ventricular (LV) mass index (101.90 +/- 18.61 versus 88.03 +/- 22.01 g/m(2), p < 0.049) and interventricular septum thickness (10.61 +/- 1.46 versus 9.11 +/- 1.13 mm, p < 0.002) in LT(4)-treated patients compared to controls. CONCLUSIONS: We found impaired vascular elasticity of large and small arteries and increased LV mass in patients receiving long-term TSH-suppressive therapy with LT(4).

The effect of a rapid weight loss induced by laparoscopic adjustable gastric banding on arterial stiffness, metabolic and inflammatory parameters in patients with morbid obesity.

OBJECTIVE: To determine the effect of drastic weight loss on arterial compliance, inflammatory and metabolic parameters in patients with morbid obesity with and without cardiovascular risk factors who underwent laparoscopic adjustable gastric banding (LAGB). DESIGN: Open prospective study, morbidly obese subjects divided into low- and high-risk group were evaluated before and 4 months after LAGB. SUBJECTS: Forty-one Caucasian subjects aged between 16 and 55 years, with morbid (grade 3) obesity (20 low- risk and 21 high-risk subjects) who underwent LAGB and completed a 16-week follow-up. MEASUREMENTS: Patients were evaluated at baseline and 4 months after LAGB for body mass index (BMI), arterial blood pressure (BP), metabolic factors including lipid profile, HbA1C, insulin, C-peptide, fibrinogen, hs-C reactive protein (CRP) and Homeostasis model assessment-insulin resistance (HOMA-IR). Arterial elasticity of large and small arteries was evaluated using pulse-wave contour analysis method (HDI CR 2000, Eagan, Minnesota) at baseline and after 4 months. RESULTS: Body mass index reduction induced by LABG, from 43.55+/-5.11 to 35.10+/-4.87 in low-risk patients and from 42.90+/-3.22 to 35.00+/-3.24 in high-risk patients, significantly improved small artery elasticity (SAE) from 6.30+/-2.74 to 7.25+/-1.85, in morbidly obese patients with multiple cardiovascular risk factors (high-risk group). Improvement in SAE was accompanied by improvement of arterial BP, glucose and lipid metabolism, and reduction of CRP values. CONCLUSION: Although dramatic weight reduction induced by surgical intervention was associated with similar changes in body weight and significant improvement of metabolic and inflammatory parameters in two groups of obese patients, SAE improved only in high-risk patients.

Glucagon does not affect catecholamine release in primary cultures of bovine adrenal chromaffin cells.

OBJECTIVE: Human pheochromocytoma tumor cells express glucagon receptors, and bolus i.v. glucagon injection rapidly increases plasma epinephrine levels, suggesting that glucagon can directly stimulate adrenomedullary secretion. In this study, we tested whether the catecholamine secretory response to glucagon was present in bovine chromaffin cells or exclusive to the tumor cells. DESIGN AND METHODS: Adrenomedullary cells were cultured in 24-well plates (10(6) cells per well). After 48-72 hours, wells were incubated for 1-20 minutes with (1) incubation medium (control), (2) catecholamine secretagogues (nicotine or potassium ion), or (3) glucagon (10(-8) to 10(-5) M). After incubation, catecholamine contents in medium and cells were assayed by high-pressure liquid chromatography with electrochemical detection. Fractional release rates of epinephrine, norepinephrine, and dopamine were calculated and compared to controls. Reverse-transcriptase PCR was performed to compare expression of mRNA of the glucagon receptor in chromaffin cells and pheochromocytoma cells. RESULTS: Nicotine and potassium evoked time-dependent release of epinephrine, norepinephrine, and dopamine. Glucagon did not affect catecholamine secretion at any concentration. Reverse-transcriptase PCR failed to detect mRNA for glucagon receptor in bovine adrenomedullary cells, but did detect it in human pheochromocytoma cells. CONCLUSIONS: In contrast to pheochromocytoma tumor cells, bovine adrenomedullary chromaffin cells do not express the glucagon receptor, and therefore do not secrete catecholamines in response to glucagon.

TNFalpha stimulated ATP-sensitive potassium channels and attenuated deoxyglucose and Ca uptake of H9c2 cardiomyocytes.

Tumor necrosis factor (TNFalpha) is an inflammatory cytokine that induces programmed cell death in a variety of tissue types, including the heart. Recent experimental data suggest that the TNF expressed within the myocardium in response to environmental injury plays an important role in initiating homeostatic response. The effect of TNFalpha (10-50 ng/mL) was studied on (86)Rb efflux, (3)H-deoxyglucose uptake, or (45)Ca uptake in H9c2 cardiomyocytes. TNFalpha stimulated (86)Rb efflux from cultures, while 2 micro M glibenclamide blocker of ATP-sensitive potassium channels or 20 micro M zvad-fmk caspase inhibitor attenuated this effect. TNFalpha also depressed the stimulatory effect of 80 mM KCl on (45)Ca uptake in the cardiomyocytes. TNFalpha inhibited the stimulatory effect of 100 nM insulin on (3)H-deoxyglucose uptake. Our findings further suggest that TNFalpha mediated adaptive and protective effects in the heart during a brief environmental injury.

Treatment with atorvastatin improves small artery compliance in patients with severe hypercholesterolemia.

BACKGROUND: We studied the effect of atorvastatin on arterial compliance in patients with severe hypercholesterolemia. METHODS: Seventeen patients with low-density lipoprotein cholesterol levels above 170 mg/dL, were included in the study, none of whomever received hypolipidemic medication or had other risk factors. Patients were followed for five visits, every 4 weeks. RESULTS: After 20 weeks of treatment, lipid profile improved significantly. Large artery elasticity index did not change significantly, but small artery elasticity index increased by 21% (4.6+/-0.5 to 5.6+/-0.9, P < .01). Although none of our patients suffered from hypertension, both systolic and diastolic blood pressure (BP) decreased significantly (6 mm Hg and 3 mm Hg, respectively). CONCLUSIONS: We conclude that atorvastatin improves the elasticity of small arteries and reduces systolic and diastolic BP in patients with severe hypercholesterolemia.

Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study.

OBJECTIVE: This study investigated whether treatment with the anti-tumor necrosis factor-alpha monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/mL. DESIGN: Multicenter, double-blind, randomized, placebo-controlled study. SETTING: Eighty-four intensive care units in academic medical centers in Europe and Israel. PATIENTS: A total of 944 septic patients were screened and stratified by the results of a rapid qualitative immunostrip test for serum IL-6 concentrations. Patients with a positive test kit result indicating IL-6 concentrations of >1000 pg/mL were randomized to receive either afelimomab (n = 224) or placebo (n = 222). Patients with a negative IL-6 test (n = 498) were not randomized and were followed up for 28 days. INTERVENTIONS: Treatment consisted of 15-min infusions of 1 mg/kg afelimomab or matching placebo every 8 hrs for 3 days. Standard surgical and intensive care therapy was otherwise delivered. MEASUREMENTS AND MAIN RESULTS: The study was terminated prematurely after an interim analysis estimated that the primary efficacy end points would not be met. The 28-day mortality rate in the nonrandomized patients (39.6%, 197 of 498) was significantly lower (p <.001) than that found in the randomized patients (55.8%, 249 of 446). The mortality rates in the IL-6 test kit positive patients randomized to afelimomab and placebo were similar, 54.0% (121 of 224) vs. 57.7% (128 of 222), respectively. Treatment with afelimomab was not associated with any particular adverse events. CONCLUSIONS: The IL-6 immunostrip test identified two distinct sepsis populations with significantly different mortality rates. A small (3.7%) absolute reduction in mortality rate was found in the afelimomab-treated patients. The treatment difference did not reach statistical significance.