Single blind, multicentre, randomized, controlled trial testing the effects of a novel nutraceutical compound on plasma lipid and cardiovascular risk factors: Results of the interim analysis.

BACKGROUND AND AIMS: The clustering of high levels of LDL cholesterol (LDL-C) and other risk factors represents a predisposing condition for atherosclerotic disease development. Cardiovascular prevention is based on effective control of these conditions. In adult subjects with mild hypercholesterolemia we compared in the real life the effects of a new combination of nutraceuticals on lipid and glucose metabolism and blood pressure with those of an established nutraceutical combination. METHOD AND RESULTS: This multicenter, controlled, randomized, single-blind trial was designed to compare the effect of Armolipid Plus® versus that of LopiGLIK® on lipid and glucose levels and blood pressure (BP) in subjects with mild hypercholesterolemia not on statin therapy. Primary outcome was the proportion of subjects achieving therapeutic targets of LDL-C (<130 mg/dl); secondary outcomes were the effects on HDL-C, glycated haemoglobin and insulin levels. Data from an overall sample of 359 adult individuals (age 55.2 ± 11.1 years, women 57.7%, LDL-C 157.3 ± 22.6 mg/dl, HDL-C 50.7 ± 13.0 mg/dl) are reported. 72% of subjects treated with LopiGLIK® and 43% treated with Armolipid Plus® achieved the primary endpoint (p < 0.0001). Both treatments reduced plasma levels of total and LDL-C and triglycerides (p < 0.001 for all comparisons). The treatments also reduced systolic and diastolic blood pressure, plasma levels of glycated haemoglobin, insulin and HOMA index. The changes induced by LopiGLIK® in all these metabolic parameters were greater than those obtained with Armolipid Plus®. CONCLUSIONS: The present analysis shows that LopiGLIK® may represent a more effective tool for clinical management of CV risk factors in subjects with mild hypercholesterolemia.

The possible role of chromosome X variability in hypertensive familiarity.

Familiarity participates in the pathogenesis of hypertension, although only recently, whole genome studies have proposed regions of the human genome possibly involved in the transmission of the hypertensive phenotype. Although studies have mainly focused on autosome, hitherto the influence of sex on familial transmission of hypertension has not been considered. We analysed the database of the Campania Salute Network of Hypertension center of the Federico II University Hospital of Naples (Italy), using dichotomous variables for paternal and maternal familiarity and gender (male and female) of 12 504 hypertensive patients (6868 males and 5636 females) and 6352 controls (3484 males and 2868 females), totaling 18 856 subjects. In the hypertensive group, familiarity was present in 75% of cases with odds of 3.77 and in only 26% of the normotensives with odds of 0.94. The odds ratio (OR) indicated that familiarity increases the risk of developing hypertension by 2.91 (95% confidence interval (CI)=2.67-3.17, P<0.001) times. Additionally, maternal familiarity was 37% (OR=3.01, 95% CI=2.66-3.41, P<0.001), paternal familiarity was 21% (OR=2.31, 95% CI=2.01-2.68, P<0.001) and the double familiarity was 17% (OR=3.45, 95% CI=2.87-4.01, P<0.001), thus suggesting a plausible association between maternal familiarity and development of hypertension; this finding was observed both in male and in female patients, although the phenomenon was larger in males. Given the dominance of maternal transmission in males, by genome-wide analysis of the X chromosome, we found two regions that were differently distributed in male hypertensives with maternal hypertension. Our data highlight the importance of genetic variants in the X chromosome to the maternal transmission of the hypertensive phenotype.

Identification of phenotypes at risk of transition from diastolic hypertension to isolated systolic hypertension.

Little is known about the potential progression of hypertensive patients towards isolated systolic hypertension (ISH) and about the phenotypes associated with the development of this condition. Aim of this study was to detect predictors of evolution towards ISH in patients with initial systolic-diastolic hypertension. We selected 7801 hypertensive patients free of prevalent cardiovascular (CV) diseases or severe chronic kidney disease and with at least 6-month follow-up from the Campania Salute Network. During 55±44 months of follow-up, incidence of ISH was 21%. Patients with ISH at the follow-up were significantly older (P<0.0001), had longer duration of hypertension, higher prevalence of diabetes and were more likely to be women (all P<0.0001). They exhibited higher baseline left ventricular mass index (LVMi), arterial stiffness (pulse pressure/stroke index), relative wall thickness (RWT) and carotid intima-media thickness (IMT; all P<0.001). Independent predictors of incident ISH were older age (odds ratio (OR)=1.14/5 years), female gender (OR=1.30), higher baseline systolic blood pressure (OR=1.03/5 mm Hg), lower diastolic blood pressure (OR=0.89/5 mm Hg), longer duration of hypertension (OR=1.08/5 months), higher LVMi (OR=1.02/5 g m(-2.7)), arterial stiffness (OR=2.01), RWT (OR=1.02), IMT (OR=1.19 mm(-1); all P<0.0001), independently of antihypertensive treatment, obesity, diabetes and fasting glucose (P>0.05). Our findings suggest that ISH is a sign of aggravation of the atherosclerotic disease already evident by the target organ damage. Great efforts should be paid to prevent this evolution and prompt aggressive therapy for arterial hypertension should be issued before the onset of target organ damage, to reduce global CV risk.

Early effects of the antineoplastic agent salinomycin on mitochondrial function.

Salinomycin, isolated from Streptomyces albus, displays antimicrobial activity. Recently, a large-scale screening approach identified salinomycin and nigericin as selective apoptosis inducers of cancer stem cells. Growing evidence suggests that salinomycin is able to kill different types of non-stem tumor cells that usually display resistance to common therapeutic approaches, but the mechanism of action of this molecule is still poorly understood. Since salinomycin has been suggested to act as a K(+) ionophore, we explored its impact on mitochondrial bioenergetic performance at an early time point following drug application. In contrast to the K(+) ionophore valinomycin, salinomycin induced a rapid hyperpolarization. In addition, mitochondrial matrix acidification and a significant decrease of respiration were observed in intact mouse embryonic fibroblasts (MEFs) and in cancer stem cell-like HMLE cells within tens of minutes, while increased production of reactive oxygen species was not detected. By comparing the chemical structures and cellular effects of this drug with those of valinomycin (K(+) ionophore) and nigericin (K(+)/H(+) exchanger), we conclude that salinomycin mediates K(+)/H(+) exchange across the inner mitochondrial membrane. Compatible with its direct modulation of mitochondrial function, salinomycin was able to induce cell death also in Bax/Bak-less double-knockout MEF cells. Since at the concentration range used in most studies (around 10 µM) salinomycin exerts its effect at the level of mitochondria and alters bioenergetic performance, the specificity of its action on pathologic B cells isolated from patients with chronic lymphocytic leukemia (CLL) versus B cells from healthy subjects was investigated. Mesenchymal stromal cells (MSCs), proposed to mimic the tumor environment, attenuated the apoptotic effect of salinomycin on B-CLL cells. Apoptosis occurred to a significant extent in healthy B cells as well as in MSCs and human primary fibroblasts. The results indicate that salinomycin, when used above µM concentrations, exerts direct, mitochondrial effects, thus compromising cell survival.

Primary prevention with statins and incident diabetes in hypertensive patients at high cardiovascular risk.

BACKGROUND AND AIMS: The ESC/ESH guidelines for arterial hypertension recommend using statins for patients with high cardiovascular (CV) risk for both secondary and primary prevention. A recent meta-analysis, combining previous studies on statins, concluded that they are associated with a 9% increased risk of incident type 2 diabetes mellitus (DM). There is no information on whether statins increase incidence of DM in primary prevention. METHOD AND RESULTS: We evaluated risk of incident DM in relation to statin prescription in 4750 hypertensive, non-diabetic outpatients (age 58.57 ± 9.0 yrs, 42.3% women), from the CampaniaSalute Network, without chronic kidney disease more than grade 3, free of prevalent CV disease and with at least 12 months of follow-up. DM was defined according to ADA criteria. At the end of follow-up period (55.78 ± 42.5 months), 676 patients (14%) were on statins. These patients were older (62.54 ± 7.3 vs 57.91 ± 9.1 yrs; p < 0.0001), more often female (49% vs 41.2%; p = 0.0001), with higher initial total cholesterol (217.93 ± 44.3 vs 205.29 ± 36.6 mg/dl), non-HDL cholesterol (167.16 ± 44.5 vs 155.18 ± 36.7 mg/dl) and triglycerides (150.69 ± 85.2 vs 130.98 ± 72.0 mg/dl; all p < 0.0001) than patients no taking statins, without other differences in clinical and laboratory characteristics. At the end of follow-up, prevalence of DM was 18.1% among patients on statins and 7.2% among those without lipid-lowering therapy (p < 0.0001). However, incident DM was 10.2% in patients on statins and 8.7% in those free of statin therapy (NS). CONCLUSION: In real-life outpatient environment, statin prescription for primary prevention is not associated with increased risk of incident DM.

beta-Blockade and increased dyslipidemia in patients bearing Glu27 variant of beta2 adrenergic receptor gene.

In this study, the effects of polymorphisms of the beta(2) and beta(3) adrenergic receptor genes on the occurrence of dyslipidemia and diabetes mellitus in hypertensive patients treated with beta-blockers (atenolol or metoprolol) were evaluated. Patients who gave written informed consent were asked to return for blood sampling for estimation of serum glucose, total cholesterol, HDL, triglycerides and for genotype determination. Genotyping analysis was performed by PCR-RFLP assay. In patients bearing beta(2)AR Glu27 or the beta(3)AR Arg64 variant there was a larger occurrence of hypertriglyceridemia, alone or in combination with elevated cholesterol levels. Furthermore, the beta(2)AR Glu27 variant significantly associates with hypetriglyceridemia in a cumulative fashion. The risk to develop this side effect after beta-blockade was four-fold higher in patients homozygous for the beta(2)AR Glu27 variant as compared to beta(2)AR27Gln allele. This result allows the identification of patients at high risk to develop metabolic complications to chronic beta-blockade treatment.

Leptin induces direct vasodilation through distinct endothelial mechanisms.

In this study, we reveal that leptin evokes an acute hypotensive effect in 6-hydroxydopamine sympathectomized rats (response to maximal leptin dose, mean blood pressure: from 92 +/- 4 to 78 +/- 2 mmHg, P < 0.01). This hemodynamic effect is related to a direct action of the hormone on vascular tone, since in aortic and mesenteric rings increasing doses of leptin evoke a dose-dependent vasorelaxation (aorta: from 3 +/- 1 to 36 +/- 3, n = 15; mesenteric: from 6 +/- 1 to 30 +/- 5, n = 10), which is impaired by endothelial denudation. In particular, leptin-evoked vasorelaxation is impaired by nitric oxide synthase inhibition in aorta (delta% of maximal response: from 36 +/- 3 to 3 +/- 1, P < 0.01) and by endothelium-derived hyperpolarizing factor (EDHF) inhibition in mesenteric arteries (delta% of maximal response: from 30 +/- 5 to 7 +/- 2, P < 0.01), suggesting that vasorelaxation evoked by leptin is heterogeneous and related to the vascular bed. Finally, the inhibition of nitric oxide synthase by NG-nitro-L-arginine-methyl ester does not modify blood pressure response to leptin, suggesting a predominant role of the EDHF mechanism in the hypotensive effect of leptin.