Giuliana Mombelli

Nutraceutical approach to moderate cardiometabolic risk: results of a randomized, double-blind and crossover study with Armolipid Plus.

BACKGROUND Primary cardiovascular prevention may be achieved by lifestyle/nutrition improvements and specific drugs, although a relevant role is now emerging for specific functional foods and nutraceuticals. OBJECTIVES The aim of this study was to evaluate the usefulness of a nutraceutical multitarget approach in subjects with moderate cardiovascular risk and to compare it with pravastatin treatment. SUBJECTS Thirty patients with moderate dyslipidemia and metabolic syndrome (according to the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults) were included in an 8-week randomized, double-blind crossover study and took either placebo or a nutraceutical combination that contained red yeast rice extract, berberine, policosanol, astaxanthin, coenzyme Q10, and folic acid (Armolipid Plus). Subsequently, they were subjected to another 8-week treatment with pravastatin 10 mg/d. This dosage was selected on the basis of its expected -20% efficacy in reducing low-density lipoprotein-cholesterol. RESULTS Treatment with Armolipid Plus led to a significant reduction of total cholesterol (-12.8%) and low-density lipoprotein-cholesterol (-21.1%), similar to pravastatin (-16% and -22.6%, respectively), and an increase of high-density lipoprotein-cholesterol (4.8%). Armolipid Plus improved the leptin-to-adiponectin ratio, whereas adiponectin levels were unchanged. CONCLUSIONS These results indicate that this nutraceutical approach shows a lipid-lowering activity comparable to pravastatin treatment. Hence, it may be a safe and useful option, especially in conditions of moderate cardiovascular risk, in which a pharmacologic intervention may not be appropriate.

Clinical response to statins: Mechanism(s) of variable activity and adverse effects

Abstract Statins represent a major advance in the treatment of hypercholesterolemia, a significant risk factor for atherosclerosis. There is, however, notable interindividual variation in the cholesterolemic response to statins, and the origin of this variability is poorly understood; pharmacogenetics has attempted to determine the role of genetic factors. Myopathy, further, has been reported in a considerable percentage of patients, but the mechanisms underlying muscle injury have yet to be fully characterized. Most statins are the substrates of several cytochrome P450s (CYP). CYP polymorphisms may be responsible for variations in hypolipidemic activity; inhibitors of CYPs, e.g. of CYP3A4, can significantly raise plasma concentrations of several statins, but consequences in terms of clinical efficacy are not uniform. Pravastatin and rosuvastatin are not susceptible to CYP inhibition but are substrates of the organic anion-transporting polypeptide (OATP) 1B1, encoded by the SLCO1B1 gene. Essentially all statins are, in fact, substrates of membrane transporters: SLCO1B1 polymorphisms can decrease the liver uptake, as well as the therapeutic potential of these agents, and may be linked to their muscular side-effects. A better understanding of the mechanisms of statin handling will help to minimize adverse effects and interactions, as well as to improve their lipid-lowering efficiency.

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders

Objective: To validate new mitochondrial myopathy serum biomarkers for diagnostic use. Methods: We analyzed serum FGF21 (S-FGF21) and GDF15 from patients with (1) mitochondrial diseases and (2) nonmitochondrial disorders partially overlapping with mitochondrial disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in mitochondrial disease and (4) analyzed S-Fgf21 and skeletal muscle Fgf21 expression in 6 mouse models with different muscle-manifesting mitochondrial dysfunctions. Results: We report that S-FGF21 consistently increases in primary mitochondrial myopathy, especially in patients with mitochondrial translation defects or mitochondrial DNA (mtDNA) deletions (675 and 347 pg/mL, respectively; controls: 66 pg/mL, p < 0.0001 for both). This is corroborated in mice (mtDNA deletions 1,163 vs 379 pg/mL, p < 0.0001). However, patients and mice with structural respiratory chain subunit or assembly factor defects showed low induction (human 335 pg/mL, p < 0.05; mice 335 pg/mL, not significant). Overall specificities of FGF21 and GDF15 to find patients with mitochondrial myopathy were 89.3% vs 86.4%, and sensitivities 67.3% and 76.0%, respectively. However, GDF15 was increased also in a wide range of nonmitochondrial conditions. Conclusions: S-FGF21 is a specific biomarker for muscle-manifesting defects of mitochondrial translation, including mitochondrial transfer-RNA mutations and primary and secondary mtDNA deletions, the most common causes of mitochondrial disease. However, normal S-FGF21 does not exclude structural respiratory chain complex or assembly factor defects, important to acknowledge in diagnostics. Classification of evidence: This study provides Class III evidence that elevated S-FGF21 accurately distinguishes patients with mitochondrial myopathies from patients with other conditions, and FGF21 and GDF15 mitochondrial myopathy from other myopathies.

Statin Muscle Toxicity and Genetic Risk Factors

Hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) can cause skeletal muscle toxicity; the risk of toxicity is elevated by drug interactions and pharmacogenetic factors that increase the concentration of statins in plasma. The genetic basis of statin-related muscle disorders is largely unknown. Statins are substrates for several membrane transporters that may mediate drug interactions. Potent inhibitors of cytochrome P450 (CYP450) especially CYP3A4, can significantly increase the plasma concentrations of the active forms of atorvastatin, lovastatin and simvastatin. Fluvastatin, which is metabolized by CYP2C9, is less prone to pharmacokinetic interactions, while pravastatin and rosuvastatin are not susceptible to any CYP inhibition. OATP1B1 can decrease the hepatic uptake of many statins, as well as the therapeutic index of these agents. Polymorphisms of CYP450 enzymes, SLCO1B1, ABCB1, and COQ2 gene, can induce statin intolerance. This review summarized the principal relations known between statin myotoxicity and genetic risk factors.

Considering gender in prescribing statins: what do physicians need to know?

Abstract Numerous clinical studies with objectives such as mortality and morbidity of cardiovascular (CV) have reported the benefit of treatment for dyslipidemia with lipid-lowering therapy, in particular using the statins. But the trials conducted in past years did not consider the gender differences of statin effect, because women were poorly represented. All the results in terms of response, efficacy, reduction of LDL cholesterol and CV risk in primary and secondary prevention refer to men. In these recent years, it emerges the need to consider the different lipoprotein profile during lifetime and CV risk between men and women. Furthermore it is necessary to consider that, in patients with coronary artery disease, the lipid goal achieved is different between the two genders. Finally, we have to evaluate the side effects mostly present in women. In conclusion, there is a different prescription of these treatments in particular in the dosage used, that it is insufficient in women with cardiovascular disease. More recently it has emerged the exigency to use new guidelines that clearly indicate how should be the medical care, therefore, the specific way to treat men and women.

Influence of body variables in the development of metabolic syndrome—A long term follow-up study

Objectives The body variable associated with the diagnosis of Metabolic Syndrome (MetS) is an elevated waist circumference (WC), although a number of other variables have been suggested. Among these, an elevated waist-to-height ratio (WHtR), ie a value higher than 0.5, that may identify abnormality, independently from height. An elevated WHtR provided the best correlation with MetS in a prior study in a large Italian population. In order to assess the validity of this conclusion, a long-term follow-up study re-examined this population, also in order to detect possible associations with cardiovascular (CV) risk. Methods and results 1,071 subjects with a complete follow-up of over 6 years were evaluated with a comparative assessment of the three anthropometric variables, namely WHtR, WC and body mass index (BMI). WHtR≥ 0.5 had the highest sensitivity for the identification of MetS, both in males and females (94.1% and 86.7% respectively). WHtR was of reduced specificity, occurring, yet less frequently (17.7% in males and 30% in females), in patients without MetS. By contrast, enlarged WC occurred with a lower frequency in male patients who developed MetS (30.2%) whereas in females, frequency was higher than in males (69.3%). Finally, a BMI≥ 25 kg/m2 had intermediate sensitivity and specificity regardless of gender. WC showed the highest odds ratio (2.62, 95%CI: 1.18–5.78) for the prediction of CV occurrence. Conclusion The present study confirms WHtR as an excellent screening tool in identifying MetS carriers, but, different from reports in other countries, it shows a lower specificity in our population.

Systematic Lab Knowledge Integration for Management of Lipid Excess in High-Risk Patients: Rationale and Design of the SKIM LEAN Project

SKIM LEAN aims at exploiting Electronic Health Records (EHRs) to integrate knowledge derived from routine laboratory tests with background analysis of clinical databases, for the identification and early referral to specialist care, where appropriate, of patients with hypercholesterolemia, who may be inadequately controlled according to their cardiovascular (CV) risk level. SKIM LEAN addresses gaps in care that may occur through the lack of coordination between primary and specialist care, incomplete adherence to clinical guidelines, or poor patient’s compliance to the physician’s prescriptions because of comorbidities or drug side effects. Key project objectives include: 1) improved health professionals’ competence and patient empowerment through a two-tiered educational website for general practitioners (GPs) and patients, and 2) implementation of a hospital-community shared care pathway to increase the proportion of patients at high/very-high CV risk (Familial Hypercholesterolemia, previous CV events) who achieve target LDL cholesterol (LDL-C) levels. Thanks to a close collaboration between clinical and information technology partners, SKIM LEAN will fully exploit the value of big data deriving from EHRs, and filter such knowledge using clinically-derived algorithms to risk-stratify patients. Alerts for GPs will be generated with interpreted test results. GPs will be able to refer patients with uncontrolled LDL-C within the shared pathway to the lipid or secondary prevention outpatient clinics of NIG hospital. Metrics to verify the project achievements include web-site visits, the number of alerts generated, numbers of patients referred by GPs, the proportion of secondary prevention patients who achieve LDL-C 50% decrease from baseline.

Left main coronary wall thickness correlates with the carotid intima media thickness and may provide a new marker of cardiovascular risk

Evaluation of carotid intima media thickness (C-IMT) by ultrasound is a well-established non-invasive tool to assess cardiovascular (CV) risk. Novel equipment has made evaluation easier, although still operator-sensitive, and with normal values not always transferable outside of the cohort of origin. Parallel evaluations with coronary calcium score (CCS) by computed tomography have been carried out, but there is no consensus on which is the technique that provides the most reliable data. Visualization of coronary wall thickness is presently achievable by transthoracic echography (TTE), a procedure carried out in real time with little cost. It is repeatable, does not expose the patient to radiation risk and, in preliminary studies, correlates with coronary events over a prolonged period of time. The present report was aimed at comparing, in a continued series of 301 individuals, C-IMT with the wall thickness of the left main coronary (LMCWT), determined by TTE. All evaluated patients were individuals referred to the Lipid Clinic, in whom C-IMT measurements are routinely carried out. Of these patients, 58% were on drug treatment, predominantly statins (32%), followed by ezetimibe (11%), fibrates (8%), Proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies (2.3%) and nutraceuticals (14%). All participants signed an informed consent form and the procedures were approved by the Institutional Review Board. C-IMTs were measured with the electronic caliper of the MYLAB 70 XVG with a linear LA332 Probe (ESAOTE, Italy). The protocol requires determination of the mean C-IMTs of near and far walls of the right and left common carotids, bifurcations and internal carotids in three different projections, i.e. evaluating 36 segments per patient. C-IMTmean, an index of the extent of carotid atherosclerosis, is the average of C-IMTs at all the considered locations; conversely, C-IMTmax, representing an index of plaques, rather than of generalized wall thickening, is the single highest C-IMT. Coronary echography was carried out by the use of EPIQ 7C with an X5-1 Probe (Philips). The LMC was identified by evaluating projections from scanning, superior to the aortic valve. TTE visualization of the proximal LMCallows recording of the thickness of the LMCanterior (LMCaWT) and posterior walls (LMCpWT) together with the lumen diameter and percentage stenosis. Significant correlations for test–retest variability in the single operator were found: r1⁄4 0.81 and r1⁄4 0.85 for LMCaWT and LMCpWT, respectively. A comparative evaluation of C-IMTmax and LMCpWT in two participating patients is given in Figure 1(a) and (b). Patients were predominantly males (231 vs 70 females), women being older (median age 60 vs 51 years for males; Table 1). By assessing C-IMT variables and LMC thicknesses and widths, Spearman partial correlation coefficients, adjusted for age and body mass index (BMI), showed significant correlations (all p< 0.0001) between C-IMTmean (r1⁄4 0.31), C-IMTmax (r1⁄4 0.31) and C-IMTmean max (r1⁄4 0.33) with LMCpWT. Weaker correlations were found with the anterior wall thickness (r1⁄4 0.25, 0.23 and 0.25, respectively; all

Indicators of Cardiovascular Risk in Metabolic Syndrome: Long Term Follow-up in Italian Patients

BACKGROUND Cardiovascular risk (CV) factors associated with the metabolic syndrome (MetS) may vary in different populations. In some, hypertension may be the major determinant, in others are low high-density lipoprotein cholesterol (HDL-C), high triglycerides, or another component. SUBJECTS AND METHODS Subjects included in this analysis were identified in 2006, among those attending the Lipid Clinic of the Niguarda Hospital, and followed up through to 2013. Patient characteristics (including the occurrence of CV events) were obtained from electronic medical records. MetS was diagnosed according to the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) guidelines. The carotid intima media thickness (cIMT) was also followed in these patients over the years. RESULTS After 7 years a total of 858 subjects had a complete follow-up; 271 of those had MetS. Patients developing a CV event showed elevated baseline cIMT (e.g. cIMTmax ≥ 2.4 mm in males and ≥ 2.2 mm in females); moreover the cIMT in MetS patients was higher at baseline and the rise over 7 years was larger compared with patients without MetS. By examining each body variable for MetS we found that a waist to height ratio (WHtR) ≥ 0.5 was present in nearly all subjects with a CV event. CONCLUSION The follow-up data of a series of Italian patients with and without MetS, clearly indicates that the former have a raised cIMT and their arterial IMT progression is greater and the presence of a larger WHtR is apparently linked to a higher incidence of CV events.

Potential of PCSK9 as a new target for the management of LDL cholesterol

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