Peter Penson

Evidence-based assessment of lipoprotein(a) as a risk biomarker for cardiovascular diseases – some answers and still many questions

Abstract The present article is aimed at outlining the current state of knowledge regarding the clinical value of lipoprotein(a) (Lp(a)) as a marker of cardiovascular disease (CVD) risk by summarizing the results of recent clinical studies, meta-analyses and systematic reviews. The literature supports the predictive value of Lp(a) on CVD outcomes, although the effect size is modest. Lp(a) would also appear to have an effect on cerebrovascular outcomes, however the effect appears even smaller than that for CVD outcomes. Consideration of apolipoprotein(a) (apo(a)) isoforms and LPA genetics in relation to the simple assessment of Lp(a) concentration may enhance clinical practice in vascular medicine. We also describe recent advances in Lp(a) research (including therapies) and highlight areas where further research is needed such as the measurement of Lp(a) and its involvement in additional pathophysiological processes.

Does vitamin D supplementation alter plasma adipokines concentrations? A systematic review and meta-analysis of randomized controlled trials.

We aimed to elucidate the role of vitamin D supplementation on adipokines through a systematic review and a meta-analysis of randomized placebo-controlled trials (RCTs). The search included PUBMED, Scopus, Web of Science and Google Scholar through July 1st, 2015. Finally we identified 9 RCTs and 484 participants. Meta-analysis of data from 7 studies did not find a significant change in plasma adiponectin concentrations following vitamin D supplementation (mean difference [MD]: 4.45%, 95%CI: -3.04, 11.93, p=0.244; Q=2.18, I(2)=0%). In meta-regression, changes in plasma adiponectin concentrations following vitamin D supplementation were found to be independent of treatment duration (slope: 0.25; 95%CI: -0.69, 1.19; p=0.603) and changes in serum 25-hydroxy vitamin D [25(OH)D] levels (slope: -0.02; 95%CI: -0.15, 0.12; p=0.780). Meta-analysis of data from 6 studies did not find a significant change in plasma leptin concentrations following vitamin D supplementation (MD: -4.51%, 95%CI: -25.13, 16.11, p=0.668; Q=6.41, I(2)=21.97%). Sensitivity analysis showed that this effect size is sensitive to one of the studies; removing it resulted in a significant reduction in plasma leptin levels (MD: -12.81%, 95%CI: -24.33, -1.30, p=0.029). In meta-regression, changes in plasma leptin concentrations following vitamin D supplementation were found to be independent of treatment duration (slope: -1.93; 95%CI: -4.08, 0.23; p=0.080). However, changes in serum 25(OH)D were found to be significantly associated with changes in plasma leptin levels following vitamin D supplementation (slope: 1.05; 95%CI: 0.08, 2.02; p=0.033). In conclusion, current data did not indicate a significant effect of vitamin D supplementation on adiponectin and leptin levels.

Evaluating bempedoic acid for the treatment of hyperlipidaemia

ABSTRACT Introduction: Despite the effectiveness of statins in the treatment of lipid disorders, residual risk still exists, and hitherto studies where additional drugs were added to statin therapy have been mainly negative or the outcomes were very modest. Therefore there is still a need for new and effective oral agents in the combination therapy of lipid disorders. Areas covered: The review covers the current state of knowledge on the mechanism of action of bempedoic acid (ETC-1002) and results from recent clinical studies. Expert opinion: ETC-1002 is a novel oral lipid-lowering therapy. The reduction of both low-density lipoprotein cholesterol (LDL-C) and high sensitivity C-reactive protein (hsCRP) demonstrated by ETC-1002 in clinical trials suggests that agent may have the potential for CV risk reduction. Adverse effects of current lipid-lowering agents can be dose-limiting, and combination approaches to lipid-lowering may often be utilized for optimal CV risk reduction. Because of this, new lipid-modulating drugs are urgently required. ETC-1002 has a unique mechanism of action (adenosine triphosphate-citrate lyase inhibition). It has been shown to be safe in combination with statins as well as ezetimibe, and appears to effectively lower LDL-C and has the potential to reduce the risk of muscle-related adverse events, which can limit the utilization and effectiveness of statin therapy.

The role of nutraceuticals in the prevention of cardiovascular disease

Cardiovascular disease (CVD) ranks among the most common health-related and economic issues worldwide. Dietary factors are important contributors to cardiovascular risk, either directly, or through their effects on other cardiovascular risk factors including hypertension, dyslipidemia and diabetes mellitus. Nutraceuticals are natural nutritional compounds, which have been shown to be efficacious in preventative medicine or in the treatment of disease. Several foods and dietary supplements have been shown to protect against the development of CVD. The aim of this review is to present an update on the most recent evidence relating to the use of nutraceuticals in the context of the prevention and treatment of CVD.

The sirtuin family members SIRT1, SIRT3 and SIRT6: Their role in vascular biology and atherogenesis

The sirtuins, silent mating-type information regulation 2 (SIRTs), are a family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases with important roles in regulating energy metabolism and senescence. Activation of SIRTs appears to have beneficial effects on lipid metabolism and antioxidants, prompting investigation of the roles of these proteins in atherogenesis. Although clinical data are currently limited, the availability and safety of SIRT activators such as metformin and resveratrol provide an excellent opportunity to conduct research to better understand the role of SIRTs in human atherosclerosis. Encouraging observations from preclinical studies necessitate rigorous large, prospective, randomized clinical trials to determine the roles of SIRT activators on the progression of atherosclerosis and ultimately on cardiac outcomes, such as myocardial infarction and mortality.

Association between telomere length and complete blood count in US adults

Introduction Telomere length (TL) is related to age-related health outcomes, but little is known about the relationship between TL and complete blood count (CBC) parameters. We aimed to determine the relationship between TL and CBC in a sample of healthy US adults. Material and methods Participants in the National Health and Nutrition Examination Survey (NHANES) recruited between 1999 and 2002 who had essential data on total CBC and TL were studied. We computed age- and race-adjusted mean values for total CBC using analysis of covariance (ANCOVA). All statistical analyses accounted for the survey design and sample weights by using SPSS Complex Samples v22.0 (IBM Corp, Armonk, NY). Results Of the 8892 eligible participants, 47.8% (n = 4123) were men. The mean age was 41.8 years overall, 41.0 years in men and 42.6 in women (p = 0.238). The sex-stratified ANCOVA showed no significant difference in the total CBC across TL quartiles (all p > 0.05) in both sexes. In the adjusted model, there was a significant negative relationship with monocyte count (β = –0.051, 95% CI: –0.422; –0.142), mean cell hemoglobin (β = –0.051, 95% CI: –0.038; –0.011) and red cell distribution width (β = –0.031, 95% CI: –0.054; –0.003), while there was a significant positive relationship with basophil ratio (β = 0.046, 95% CI: 0.049–0.171). Conclusions These results support the possibility that telomere attrition may be a marker for reduced proliferative reserve in hematopoietic progenitor cells.

The effect of statins on cardiovascular outcomes by smoking status: A systematic review and meta-analysis of randomized controlled trials

&NA; Smoking is an important risk factor for cardiovascular disease (CVD) morbidity and mortality. The impact of statin therapy on CVD risk by smoking status has not been fully investigated. Therefore we assessed the impact of statin therapy on CVD outcomes by smoking status through a systematic review of the literature and meta‐analysis of available randomized controlled trials (RCTs). The literature search included EMBASE, ProQuest, CINAHL and PUBMED databases to 30 January 2016 to identify RCTs that investigated the effect of statin therapy on cumulative incidence of major CVD endpoints (e.g. non‐fatal myocardial infarction, revascularization, unstable angina, and stroke). Relative risks (RR) ratios were calculated from the number of events in different treatment groups for both smokers and non‐smokers. Finally 11 trials with 89,604 individuals were included. The number of smokers and non‐smokers in the statin groups of the analyzed studies was 8826 and 36,090, respectively. The RR for major CV events was 0.73 (95% confidence interval [CI]: 0.67–0.81; p < 0.001) in nonsmokers and 0.72 (95%CI: 0.64–0.81; p < 0.001) in smokers. Moderate to high heterogeneity was observed both in non‐smokers (I2 = 77.1%, p < 0.001) and in smokers (I2 = 51.6%, p = 0.024) groups. Smokers seemed to benefit slightly more from statins than non‐smokers according to the number needed to treat (NNT) analysis (23.5 vs 26.8) based on RRs applied to the control event rates. The number of avoided events per 1000 individuals was 42.5 (95%CI: 28.9–54.6) in smokers and 37.3 (95%CI: 27.2–46.4) in non‐smokers. In conclusion, this meta‐analysis suggests that the effect of statins on CVD is similar for smokers and non‐smokers, but in terms of NNTs and number of avoided events, smokers seem to benefit more although non‐significantly.

Relationship between long noncoding RNAs and physiological risk factors of cardiovascular disease

Long noncoding ribonucleic acids (lncRNAs) are an important category of noncoding RNAs that play crucial roles in controlling the expression of genes in health and in a range of illnesses including cardiovascular disease. A large body of genetic, experimental, and epidemiologic evidence suggests roles for an increasing number of lncRNAs in the regulation of metabolism, lipid profile, inflammation, and glucose metabolism in type II diabetes. Importantly, it has been suggested that lncRNAs can regulate chromatin alteration, messenger RNA stability, microRNA action, and can control transcription factors. We aimed to highlight emerging concepts, based on the most current knowledge, regarding the roles of lncRNA in the regulation of cardiovascular risk factors such as lipid profile, glucose homeostasis, and inflammation.

Effects of pentoxifylline on inflammatory markers and blood pressure: a systematic review and meta-analysis of randomized controlled trials

Introduction: Pentoxifylline is a xanthine derivative with potential cardiovascular benefits. Aim: To evaluate the impact of pentoxifylline on blood pressure (BP) and plasma TNF-&agr;, C-reactive protein (CRP) and IL-6 through a systematic review and meta-analysis of randomized controlled trials. Methods: The protocol was registered (PROSPERO: CRD42016035988). The search included PUBMED, ProQuest, Scopus and EMBASE until 1 September 2015 to identify trials reporting BP or inflammatory markers during pentoxifylline therapy. Quantitative data synthesis was performed using a random-effects model, with weighted mean difference (WDF) and 95% confidence intervals (CIs) as summary statistics. Results: Fifteen studies (16 treatment arms) were found to be eligible for inclusion. Meta-analysis did not suggest any effect of pentoxifylline on either SBP or DBP. Pentoxifylline treatment was associated with a significant reduction in plasma concentrations of TNF-&agr; (WDF: −1.03 pg/ml, 95% CI: −1.54, −0.51; P < 0.001, 11 treatment arms) and CRP (WDF: −1.39 mg/l, 95% CI: −2.68, −0.10; P = 0.034, five treatment arms). No alteration in plasma IL-6 concentration was observed. The impact of pentoxifylline on plasma TNF-&agr; levels was found to be positively associated with treatment duration (slope: 0.031; 95% CI: 0.004, 0.057; P = 0.023) but independent of pentoxifylline dose (slope: −0.0003; 95% CI: −0.002, 0.001; P = 0.687). Conclusion: Pentoxifylline did not alter BP or plasma IL-6 concentration, but significantly reduced circulating TNF-&agr; and CRP concentrations.

Does coffee consumption alter plasma lipoprotein(a) concentrations? A systematic review

ABSTRACT Coffee consumption alters plasma lipid and cholesterol concentrations, however, its effects on lipoprotein(a) (Lp(a)) have received little study. The aim of this PRISMA compliant systematic review was to examine the role of coffee on serum Lp(a). This study was prospectively registered (PROSPERO 2015:CRD42015032335). PubMed, Scopus, Web of Science and Cochrane Central were searched from inception until 9th January 2016 to detect trials and epidemiological studies investigating the impact of coffee on serum Lp(a) concentrations in humans. We identified six relevant publications describing nine experimental trials of various designs. There were a total of 640 participants across all studies and experimental groups. In short-term controlled studies, consumption of coffee, or coffee diterpenes was associated with either a reduction in serum Lp(a) of ≤11 mg/dL (6 trials, 275 participants), or no effect (2 trials, 56 participants). Conversely, one cross-sectional study with 309 participants showed serum Lp(a) was elevated in chronic consumers of boiled coffee who had a median Lp(a) of 13.0 mg/dL (range 0–130) compared with consumers of filtered coffee who had median Lp(a) 7.9 mg/dL (range 0–144). The effect of coffee on Lp(a) is complex and may follow a biphasic time-course. The type of coffee and the method of preparation appear to be important to determining the effect on Lp(a).