Cardiometabolic Disease's Risk through Population Genetic Studies: Historical, Present and Future Resources of the Brisighella Biobank

Cardiovascular diseases (CVD) comprise the most common chronic disease worldwide. High lipid levels are a strong risk factor, making lipid-lowering statin therapy an important preventive measure. Here we explore the effects of common variants at the KIF6 and HMGCR loci on a range of cardio-metabolic traits and on response to statin therapy. While HMGCR is a well-established lipid-related locus, the role of KIF6 in response to statin therapy is controversial, and its contribution to related phenotype variability has not been clarified. We genotyped a coding KIF6 variant (p.W719R, rs20455) and two intronic ones in high LD to the former (rs9462535,rs9471077), as well as two non-coding variants in HMGCR (rs3761740 and rs3846662). Effects on 14 quantitative and 5 categorical cardiometabolic phenotypes including lipid-lowering therapy response were tested in a sample of 1,645 individuals from the Genetics in Brisighella Health Study (GBHS) from Italy and replicated in 10,662 individuals from the Estonian Genome Center (EGCUT). In GBHS the established HMGCR variant rs3846662 affects LDL cholesterol levels (P=8.5x10-4) while the intronic KIF6 variant rs9471077 modifies APOB levels (P=8.2x10-4). The latter association was confirmed in EGCUT. No significant association between KIF6 variants and response to statin therapy was observed. In the first genetic study involving GBHS we confirm the HMGCR effect on LDL-Cholesterol and demonstrate a novel KIF6 effect on APOB. The latter association needs to be evaluated for its predictive value for overall CVD risk and its potential contribution to stratified patient care

Nutraceuticals and cholesterol-lowering action

AbstractNutraceuticals play an important role in cardiovascular prevention in patients with dyslipidemia. Many scientific studies support the use of these substances alone or associated with other drugs in clinical practice. Specifically, monacolines, berberine, policosanol and gamma-oryzanol could significantly reduce cholesterolemia. However, there is still an insufficient number of studies demonstrating morbidity and mortality outcomes of nutraceuticals, nor are sufficient data regarding the use of nutraceuticals in different types of patients, on tolerability, safety, target population, modality and duration of use present in the literature

Circulating Levels of Proprotein Convertase Subtilisin/Kexin Type 9 and Arterial Stiffness in a Large Population Sample: Data From the Brisighella Heart Study

Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulating levels are significantly associated with an increased risk of cardiovascular events. This study aimed to evaluate the relationship between circulating levels of PCSK9 and arterial stiffness, an early instrumental biomarker of cardiovascular disease risk, in a large sample of overall healthy participants

High serum uric acid is associated to poorly controlled blood pressure and higher arterial stiffness in hypertensive subjects

Introduction Serum uric acid (SUA) has been associated to incident hypertension and increased risk of cardiovascular diseases. Materials and methods Among the 2191 subjects enrolled during the last population survey of the Brisighella Heart Study, we identified 146 new cases of arterial hypertension and 394 treated but uncontrolled hypertensive patients with different levels of SUA. Their hemodynamic characteristics have been compared with those of age- and sex-matched normotensive (N. 324) and controlled hypertensive (N. 470) subjects. Then, by logistic regression analysis, we evaluated which factors were associated with a worse BP control under pharmacological treatment. Results SUA levels were significantly higher in untreated hypertensive and uncontrolled hypertensive patients when compared to normotensives and controlled hypertensive patients. Pulse wave velocity (PWV) was significantly higher (p\uc2\ua0<\uc2\ua00.001) in undiagnosed and uncontrolled hypertensive patients, while controlled hypertensive patients had PWV values comparable to normotensive controls. A similar trend has been observed for the augmentation index (AI). A worse BP control was associated with SUA levels (OR 1277, 95% CI 1134\ue2\u80\u931600 per mg/dL), AI (OR 1066, 95%CI 1041\ue2\u80\u931092 per unit), and PWV (OR 1201, 95% CI 1089\ue2\u80\u931423, per m/s), but not with age, body mass index, nor estimated glomerular filtration rate. Conclusion Based on our data, SUA seems to be associated with an inadequate BP control in subjects treated with antihypertensive drugs, and subjects with both uncontrolled BP and relatively high SUA levels have also an increased arterial stiffness that (per se) could be a cause of worse BP control under treatment

LDL-oxidation, serum uric acid and pulse-wave velocity relationship in chronic kidney disease: Data from the Brisighella heart study cohort

Aim.The aim of our study was to evaluate the relationship between oxidized LDL (oxLDL), elevated Serum Uric Acid (SUA) and arterial stiffness in subjects with normal renal function compared with subjects with mild or moderate chronic kidney disease (CKD).Methods:We selected from the database of the Brisighella Heart Study 205 adult non-smokers subjects, in primary prevention for cardiovascular disease, with normal renal function (M: 99, F: 106), 118 age-matched subjects with mild CKD (M: 55; F: 63) and 94 with moderate CKD (M: 44; F: 50), all visited during the 2012 population survey. All subjects under- went a medical visit including the determination of LDL oxidative sus- ceptibility, oxLDL levels and arterial stiffness parameters such as Augmentation Index (AI) and Pulse Wave Velocity (PWV). Results: An univariate analysis revealed a direct correlation of PWV with t he main anthropometric, haemodynamic and laboratory values usually associated to higher arterial stiffness and a significant inverse correlation with LDL-C lag phase, HDL-C and apoAI (p&lt;0.05), either in subjects with normal renal function, or with mild or moderate CKD. In a stepwise multiple regression model we observed that in normal renal function and mild CKD groups the main predictors of PWV were age, Systolic Blood Pressure (SBP), ox-LDL, apoB and SUA (p&lt;0.05), while in moderate CKD group the main predictors were age, SBP and apoB, only (p&lt;0.05).Conclusions:In our population sample, SUA and oxLDL are signifcantly related to PWV in subjects with normal renal functions and with mild CKD, but not in subjects with more advanced CKD

Subjective effects of a combined lipid-lowering nutraceutical or ezetimibe on well-being and sexual performance in patients with perceived worsening of erectile function during statin treatment: a randomised clinical trial

Background Beyond clinical trial evidence, the perceived association of statin use and impotence in general practice is not infrequent and the most common associated consequence is the discontinuation of the statin treatment. Aim of the study To carry out a randomised clinical trial on Caucasian men refusing to continue statin therapy because of perceived worsening of erectile function in order to test the tolerability of alternative lipid-lowering strategies. Methods This is a single-blind, randomised clinical trial carried out on 50 moderately hypercholesterolaemic subjects (mean age: 54±6 years old) who voluntarily interrupted statin treatment because of self-reported erectile dysfunction (ED) during statin treatment, randomised to treatment with ezetimibe 10 mg or a combined lipid-lowering nutraceutical containing red yeast rice and berberine (3 mg monacolins and 500 mg per dose, respectively), to be taken as one dose per evening for 12 weeks. The effects of both treatments on ED and subjective well-being was tested by administrating, before and after 12 weeks of treatment, the International Index of Erectile Function (IIEF-5) and the Satisfaction Profile (SAT-P), and comparing the baseline hormonal level with the final one. Results After 12 weeks of treatment, both ezetimibe- and nutraceutical-treated patients experienced a significant improvement in low-density lipoprotein cholesterolaemia and triglyceridaemia (both p<0.05) and a significant increase in IIEF-5 score (p<0.05 for both). However, patients taking the nutraceutical experienced a more significant increase than the group taking ezetimibe (1.2±0.7 vs. 0.7±0.3, p=0.04). Both ezetimibe- and nutraceutical-treated subjects experienced a significant improvement in psychological performance-related SAT-P score, but the nutraceutical-treated group’s improvement was larger than that of the ezetimibe-treated group (+8±4 vs. +6±3, p<0.05). Moreover, only the nutraceutical-treated patients experienced a significant improvement in physical and social performance related SAT-P score compared to the baseline (+7±5 and 6±3, both p<0.05). Conclusion Our data support the use of alternative lipid-lowering strategies in patients refusing to continue statin consumption because of perceived worsening of erectile function

Serum Proinflammatory Chemokines in Healthy Elderly Taking or not Taking Simvastatin -Data from the Brisighella Heart Study

Background. Recent preclinical evidence and data from adult subjects suggests that statins could improve the proinflammatory profile of hypercholesterolemic subjects. Objectives. We aim to compare the serum levels of a set of proinflammatory chemokines in elderly statistical twins taking or not taking statins. Material and Methods. Among the historical cohort of the Brisighella Heart Study, we chose 40 healthy elderly subjects continuously treated with statins for at least 1 year and 40 cross-matched subjects not treated with statins (M : F = 1 : 1) characterized by similar age, body mass index (BMI), leisure-time and working activity, smoking habits, history of cardiovascular disease, systolic and diastolic blood pressure, fasting plasma glucose, plasma lipids, uric acid, and creatinine. Results. The proinflammatory chemokine serum level is similar in statin untreated and treated statistical twins. The OR to have a serum level of monocyte chemoattractant protein (MCP-1) lower than the 50th percentile of the distributionin statin-treated subjects compared to the statin untreated subjects is 0.669 (95% CI 0.193; 2.327), the ORfor interleukin-8 (IL-8) = 0.818 (95% CI 0.236; 2.835), the OR for \u3b3-interferon inducible protein-10 (IP-10) = 1.361(95% CI 0.358; 5.175), and for interleukin-18 (IL-18) = 0.545 (95% CI 0.155; 1.914). Conclusions. In relatively healthy, elderly subjects selected from a randomized general population sample, we did not observe differences in the serum levels of the selected set of proinflammatory chemokines in statin treated and untreated subjects with similar LDL-C level, suggesting that cholesterol reduction per se could be a main determinantof statin anti-inflammatory effect

Serum uric acid predicts incident metabolic syndrome in the elderly in an analysis of the Brisighella Heart Study

Several epidemiological studies report a positive correlation between hyperuricemia and metabolic syndrome (MetS) in adults, which hyperuricemic subjects seem to more easily develop. We aimed to verify if serum uric acid (SUA) concentrations were positively associated with MetS prevalence and middle-term (4-year) incidence in older overall healthy subjects. We also purposed to identify which SUA cut-off values could be functional in MetS diagnosis in addition to the traditionally used parameters. For this reason, we selected from the historical cohort of the Brisighella Heart Study 923 older healthy subjects repeatedly visited during the 2008 and 2012 population surveys. In our sample, MetS was more frequent for higher SUA concentrations rather than the population\u2019s mean in both men [OR = 2.12, 95%C.I.(1.55, 2.90)] and women [OR = 2.69,95%C.I.(1.91, 3.78)]. ROC analysis showed SUA was predictive of MetS in the whole population [AUC = 0.647, 95%C.I.(0.609, 0.686), P = 0.000001] and in both sex subgroups [men: AUC = 0.592, 95%C.I.(0.529, 654); P = 0.004; women: AUC = 0.758, 95%C.I.(0.711, 0.806), P &lt; 0.000001], even there were sex-related differences in the best cut-off values (5.5 mg/dL for men; 4.2 mg/dL for women). Prospectively, SUA appeared predictive of middle-term (4-year) MetS incidence in the whole population (AUC = 0.604, 95%C.I.[0.518, 0.690], P = 0.029, best cut-off value = 4.7 mg/dL) and in the female group (AUC = 0,641, 95%C.I.[0.519, 0.762], P = 0.039, best cut-off value = 3.9 mg/dL) though not in the male one (P &gt; 0.05). In conclusion, in our cohort, SUA is a frequent component of MetS, other than a middle-term predictor of newly diagnosed MetS in older women

Short-term effects of a combined nutraceutical of insulin-sensitivity, lipid level and indexes of liver steatosis: A double-blind, randomized, cross-over clinical trial

Abstract Background: Overweight subjects easily develop alterations of the glucose and lipid metabolism and are exposed to an increased cardiometabolic risk. This condition is potentially reversible through the improvement of dietary and behavioural habits. However, a well-assembled nutraceutical would be a useful tool to better improve the metabolic parameters associated to overweight and insulin resistance. Methods: To evaluate the effect of a combined nutraceutical containing berberine, chlorogenic acid and tocotrienols, we performed a double blind, cross-over designed trial versus placebo, in 40 overweight subjects with mixed hyperlipidaemia. After the first 8 weeks of treatment (or placebo), patients were asked to observe a 2-week washout period, and they were then assigned to the alternative treatment for a further period of 8 weeks. Clinical and laboratory data associated to hyperlipidaemia and insulin resistance have been obtained at the baseline, at the end of the first treatment period, after the washout, and again after the second treatment period. Results: Both groups experienced a significant improvement of anthropometric and biochemical parameters versus baseline. However, total cholesterol, LDL cholesterol, triglycerides, non-HDL cholesterol, fasting insulin, HOMA-IR, GOT and Lipid Accumulation Product decreased more significantly in the nutraceutical group versus placebo. Conclusions: This combination seems to improve a large number of metabolic and liver parameters on the short-term in overweight subjects. Further studies are needed to confirm these observations on the middle- and long-term