How sex affects the sinus rhythm heartbeat.

Background: There is increasing awareness of sex-specific differences in epidemiology and pathophysiology of atrial fibrillation (AF). It is, however, unknown whether males and females differ in atrial electrophysiological properties during sinus rhythm (SR). The aim of this study was therefore to investigate sex-based (regional) differences in electrophysiological properties during SR of the right (RA) and left (LA) atrium including Bachmanns Bundle (BB) and pulmonary vein region (PVA). Methods: Intra-operative, high resolution mapping during SR was performed in 53 matched females with males (without a history of AF), to measure lines of conduction block (CB), continuous conduction delay and block (cCDCB), conduction velocities (CV), total atrial activation times (TAT), unipolar potential voltages and percentage of low voltage areas (LVA). Results: Compared to males, females have significantly 1) lower unipolar potential voltages and slower CV at both RA and BB, 2) more LVAs, CB and cCDCB lines and longer CB and cCDCB lines at the RA only (all P < 0.05). Conclusions: Electrophysiological properties of the atria during SR differ between males and females. These sex-based differences are particularly present at the RA and to a lesser degree at BB. In females, both the RA and BB contained more areas of conduction disorders and low voltage potentials. Future studies are required to investigate whether these areas play a role in sex-based differences in vulnerability to arrhythmias such as atrial fibrillation.

Impact of Obesity on Atrial Electrophysiological Substrate.

(1) Background. Obesity is a well-established worldwide recognised risk factor for atrial fibrillation (AF). Prior review papers reported on the associations between obesity and AF development, but not on the relation between obesity and atrial electrophysiology. We therefore conducted a systematic review to describe the current knowledge of the characteristics of the atrial electrophysiological substrate in obese individuals and how they relate to the development of AF. (2) Methods. A search was conducted in Pubmed, Embase, and the Cochrane Library for publications evaluating the impact of obesity on atrial electrophysiology, electrical substrates, and their relation to the development of AF. (3) Results. A systematic literature search retrieved 477 potential publications based on the inclusion criteria; 76 full-text articles were selected for the present systematic review. The literature demonstrated that obesity predisposes to not only a higher AF incidence but also to more extensive atrial electrophysiological abnormalities increasing susceptibility to AF development. (4) Conclusion. Obesity may predispose to an overall increase in atrial electropathology, consisting of an increase in the slowing of the conduction, conduction block, low-voltage areas, and complex fractionated electrograms. To determine the impact of obesity-induced atrial electrical abnormalities on the long-term clinical outcome, further prospective studies are mandatory.

The influence of sex on early post-operative atrial fibrillation after cardiac surgery.

BACKGROUND: Early post-operative atrial fibrillation (EPOAF) occurs more frequently in male (M) patients. However, most patients included in EPOAF studies were also M. The aim of the present study was to compare, in a matched M and F population, the occurrence of EPOAF episodes and EPOAF characteristics using continuous rhythm monitoring (CRM) during the first five post-operative days. METHODS: Our study population consisted of 30 F patients matched with 30 M patients admitted for elective cardiac surgery. After cardiac surgery, patients were continuously monitored for a maximum of 5 days, and the burden of EPOAF episodes was quantified. RESULTS: No significant differences in the onset, number, burden, total duration, shortest, median and longest EPOAF episode were detected between M and F patients. However, EPOAF occurred more frequently on the third post-operative day (F: 16 vs. M: 7; p = .013). CONCLUSIONS: Except for the occurrence of the EPOAF on the third post-operative day. EPOAF characteristics did not differ between M and F patients.

Low-voltage potentials contribute to postoperative atrial fibrillation development in obese patients.

BACKGROUND: Obesity predisposes to the development of atrial fibrillation (AF); however, the pathophysiology underlying this relation is only partly understood. OBJECTIVE: As low-voltage areas are considered indicators of the arrhythmogenic substrates promoting AF, our study aimed to compare the extensiveness of atrial low-voltage areas between obese and nonobese patients by using high-resolution epicardial mapping in order to identify predilection sites of low-voltage areas. METHODS: A total of 430 patients (131 (30%) obese and 299 (70%) nonobese) were matched resulting in 212 patients (body mass index [BMI] ≥30 kg/m2: n = 106; BMI <30 kg/m2: n = 106) undergoing cardiac surgery (mean age 63 ± 11 years; 161 male). All patients underwent epicardial mapping of the right atrium, Bachmann bundle (BB), and left atrium during sinus rhythm. Low-voltage potentials were defined as potentials with peak-to-peak amplitudes below the fifth percentile of all potential amplitudes obtained from nonobese patients. RESULTS: Compared with nonobese patients, obese patients have potentials with lower voltages (median of medians) (4.5 mV [0.4-16.2 mV] vs 5.5 mV [0.8-18.0 mV]; P < .001), especially at BB (4.1 mV [0.4-12.3 mV] vs 6.2 mV [1.0-14.3 mV]; P < .001) and left atrium (5.1 mV [0.5-10.1 mV] vs 6.2 mV [0.8-15.9 mV]; P = .003). The percentage of low-voltage potentials was higher in obese (median 3.6% [0.0%-77.1%]) than in nonobese (median 2.3% [0.0%-57.9%]) patients (P < .001), again at BB (obese: 2.9% [0.0%-77.1%] vs nonobese: 0.9% [0.0%-42.0%]; P < .001). Percentages of low-voltage potentials correlated with incidences of conduction block (P < .001), while BMI (P = .044) and low-voltage potentials (P = .001) were independent predictors for the incidence of early postoperative AF. CONCLUSION: Obesity may predispose to an overall decrease in atrial voltage and a higher percentage in low-voltage potentials. BB was a predilection area for low voltage within the atria of obese patients.

Heterogeneity in Conduction Underlies Obesity-Related Atrial Fibrillation Vulnerability.

BACKGROUND: Obese patients are more vulnerable to development of atrial fibrillation but pathophysiology underlying this relation is only partly understood. The aim of this study is to compare the severity and extensiveness of conduction disorders between obese patients and nonobese patients measured at a high-resolution scale. METHODS: Patients (N=212) undergoing cardiac surgery (male:161, 63±11 years) underwent epicardial mapping of the right atrium, Bachmann bundle, and left atrium during sinus rhythm. Conduction delay (CD) was defined as interelectrode conduction time of 7 to 11 ms and conduction block (CB) as conduction time ≥12 ms. Prevalence of CD/CB, continuous CDCB (cCDCB), length of CD/CB/cCDCB lines, and severity of CB were analyzed. RESULTS: In obese patients, the overall incidence of CD (3.1% versus 2.6%; P=0.002), CB (1.8% versus 1.2%; P<0.001), and cCDCB (2.6% versus 1.9%; P<0.001) was higher and CD (P=0.012) and cCDCB (P<0.001) lines are longer. There were more conduction disorders at Bachmann bundle and this area has a higher incidence of CD (4.4% versus 3.3%, P=0.002), CB (3.1% versus 1.6%, P<0.001), cCDCB (4.6% versus 2.7%, P<0.001) and longer CD (P<0.001) or cCDCB (P=0.017) lines. The severity of CB is also higher, particularly in the Bachmann bundle (P=0.008) and pulmonary vein (P=0.020) areas. In addition, obese patients have a higher incidence of early de-novo postoperative atrial fibrillation (P=0.003). Body mass index (P=0.037) and the overall amount of CB (P=0.012) were independent predictors for incidence of early postoperative atrial fibrillation. CONCLUSIONS: Compared with nonobese patients, obese patients have higher incidences of conduction disorders, which are also more extensive and more severe. These differences in heterogeneity in conduction are already present during sinus rhythm and may explain the higher vulnerability to atrial fibrillation of obese patients.

Impact of atrial programmed electrical stimulation techniques on unipolar electrogram morphology.

INTRODUCTION: Intra-atrial conduction abnormalities are associated with the development of atrial fibrillation (AF) and cause morphological changes of the unipolar atrial electrogram (U-AEGM). This study examined the impact of different atrial programmed electrical stimulation (APES) protocols on U-AEGM morphology to identify the most optimal APES protocol provoking conduction abnormalities. METHODS: APES techniques (14 protocols) were applied in 30 patients referred for an electrophysiology study, consisting of fixed rate, extra, and decremental stimuli at different frequencies. U-AEGM morphologies including width, amplitude, and fractionation for patients without (control group) and with a history of AF (AF group) were examined during APES. In addition, sinus rhythm (SR) U-AEGMs preceding different APES protocols were compared to evaluate the morphology stability over time. RESULTS: U-AEGM morphologies during SR before the APES protocols were comparable (all P > .396). Atrial refractoriness was longer in the AF group compared to the control group (298 ± 48 vs 255 ± 33 ms; P ≤ .020), but did not differ between AF patients with and without amiodarone therapy (278 ± 48 vs 311 ± 40 ms; P ≥ .126). Compared to the initial SR morphology, U-AEGM width, amplitude, and fractionation changed significantly during the 14 different APES protocols, particularly in the AF group. In both groups, U-AEGM changes in morphology were most pronounced during fixed-rate stimulation with extra stimuli (8S1-S2 = 400-250 ms). CONCLUSION: APES results in significant changes in U-AEGM morphology, including width, amplitude, and fractionation. The impact of APES differed between APES sequence and between patients with and without AF. These findings suggest that APES could be useful to identify AF-related conduction abnormalities in the individual patient.

The impact of obesity on early postoperative atrial fibrillation burden.

BACKGROUND: Obesity has been linked to the development of postoperative atrial fibrillation. This study is aimed at investigating the role of body mass index in the evolution of de novo, early postoperative atrial fibrillation by assessing differences between obese and nonobese patients undergoing cardiac surgery. METHODS: Patients with early de novo postoperative atrial fibrillation were included. Continuous cardiac rhythms were recorded during the first 5 postoperative days in obese (N = 67, 66 ± 9 years; 51 [76%] male) and nonobese (N = 89, 69 ± 9; 75 [84%] male) patients without a history of atrial fibrillation undergoing cardiac surgery. Postoperative atrial fibrillation burden was defined as the ratio between total duration of all atrial fibrillation episodes and total recording time (atrial fibrillation burden, %). RESULTS: A total of 1191 (median: 5/patient) postoperative atrial fibrillation episodes were identified in the obese group compared with 1218 (median: 4/patient) in the nonobese group. The median duration and number of prolonged (>60 minutes) postoperative atrial fibrillation episodes were higher in obese patients (250 vs 145 minutes, P = .003, and median of 2 vs 1 episode, P = .031). Obesity was associated with a larger early postoperative atrial fibrillation burden (obese patients: median, 7%; interquartile range, 2.5-19.7 vs nonobese patients: median, 3.2%; interquartile range, 0.5-8.8, P = .001) mainly on the third postoperative day (P = .021). CONCLUSIONS: Obesity predisposes to a larger number of prolonged atrial fibrillation episodes in the early postoperative period after cardiac surgery for coronary artery disease or valvular heart disease. The higher atrial fibrillation burden in the early postoperative period occurred particularly on the third day. Future studies will determine whether obesity prevention may play a key role in reducing the incidence of postoperative atrial fibrillation in patients undergoing cardiac surgery.

Unipolar atrial electrogram morphology from an epicardial and endocardial perspective.

BACKGROUND: Endo-epicardial asynchrony (EEA) and the interplay between the endocardial and epicardial layers could be important in the pathophysiology of atrial arrhythmias. The morphologic differences between epicardial and endocardial atrial electrograms have not yet been described, and electrogram morphology may hold information about the presence of EEA. OBJECTIVE: The purpose of this study was to directly compare epicardial to endocardial unipolar electrogram morphology during sinus rhythm (SR) and to evaluate whether EEA contributes to electrogram fractionation by correlating fractionation to spatial activation patterns. METHODS: In 26 patients undergoing cardiac surgery, unipolar electrograms were simultaneously recorded from the epicardium and endocardium at the inferior, middle, and superior right atrial (RA) free wall during SR. Potentials were analyzed for epi-endocardial differences in local activation time, voltage, RS ratio, and fractionation. The surrounding and opposite electrograms of fractionated deflections were evaluated for corresponding local activation times in order to determine whether fractionation originated from EEA. RESULTS: The superior RA was predisposed to delayed activation, EEA, and fractionation. Both epicardial and endocardial electrograms demonstrated an S-predominance. Fractionation was mostly similar between the 2 sides; however, incidentally deflections up to 4 mV on 1 side could be absent on the other side. Remote activation was responsible for most fractionated deflections (95%) in SR, of which 4% could be attributed to EEA. CONCLUSION: Local epi-endocardial differences in electrogram fractionation occur occasionally during SR but will likely increase during arrhythmias due to increasing EEA and (functional) conduction disorders. Electrogram fractionation can originate from EEA, and this study demonstrated that unipolar electrogram fractionation can potentially identify EEA.

Cardiotoxicity of anthracycline therapy: current perspectives.

Anthracyclines, especially doxorubicin and daunorubicin, are the drugs of first choice in the treatment of patients with hematologic malignancies, soft-tissue sarcomas, and solid tumors. Unfortunately, the use of anthracyclines is limited by their dose-dependent and cumulative cardiotoxicity. The molecular mechanism responsible for anthracycline-induced cardiotoxicity remains poorly understood, although experimental and clinical studies have shown that oxidative stress plays the main role. Hence, antioxidant agents, especially dexrazoxane, and also other drug classes (statins, ß-blockers) proved to have a beneficial effect in protecting against anthracycline-induced cardiotoxicity. According to previous clinical trials, the major high-risk factors for anthracycline-induced cardiotoxicity are age, body weight, female gender, radiotherapy, and other diseases such as Down syndrome, familial dilated cardiomyopathy, diabetes and hypertension. Consequently, further studies are needed to elucidate the molecular pathogenesis of anthracycline-induced cardiotoxicity and also to discover new cardioprotective agents against anthracycline-induced cardiotoxicity.

Effect of garlic on plasma lipoprotein(a) concentrations: A systematic review and meta-analysis of randomized controlled clinical trials.

OBJECTIVES: Garlic can play an essential role in the prevention of atherosclerosis, but the research addressing the effect of garlic on the concentration of lipoprotein(a) [Lp(a)] has not been fully demonstrated. The aim of this study was to assess the effect of garlic on plasma Lp(a) concentrations through systematic review of literature and meta-analysis of available randomized controlled trials. METHODS: The literature search included SCOPUS, PubMed-Medline, ISI Web of Science, and Google Scholar databases up to March 10, 2015 to identify randomized controlled trials investigating the effect of garlic on plasma Lp(a) concentrations. Two independent reviewers extracted data on study characteristics, methods, and outcomes. Overall, the effect of garlic on plasma Lp(a) levels was reported in six trials. RESULTS: Meta-analysis did not suggest a significant alteration in plasma Lp(a) levels after garlic consumption (weighted mean difference [WMD] = 16.86%; 95% confidence interval, -4.59 to 38.31; P = 0.124). This result was robust in the leave-one-out sensitivity analysis. When the studies were categorized according to the duration of supplementation, there was no effect in the subgroup of trials lasting ≤12 wk (WMD = 2.01%; 95% CI, -14.67 to 18.68; P = 0.813) but a significant elevation of plasma Lp(a) concentrations was found in trials lasting >12 wk (WMD = 54.59%; 95% CI, 30.47-78.71; P < 0.001). Random-effects meta-regression suggested an inverse association between the changes in plasma concentrations of Lp(a) and duration of supplementation (slope 1.71; 95% CI, 0.46-2.97; P = 0.007). CONCLUSIONS: The present meta-analysis did not suggest a significant effect of garlic supplementation on the reduction of Lp(a) levels.

The impact of statin therapy on plasma levels of von Willebrand factor antigen. Systematic review and meta-analysis of randomised placebo-controlled trials.

Increased plasma levels of von Willebrand factor antigen (vWF:Ag) are associated with high risk of coronary artery disease. The effect of statin therapy on vWF:Ag levels remains uncertain. Therefore the aim of this meta-analysis was to evaluate the effect of statin therapy on vWF:Ag Levels. A systematic multiple-database search was carried out to identify randomized controlled trials (RCTs) that investigated the effect of statins on plasma vWF:Ag levels. Random-effect meta-analysis of 21 treatment arms revealed a significant decrease in plasma vWF:Ag levels following statin therapy (SMD: -0.54, 95 %CI: -0.87, -0.21, p=0.001). In subgroup analyses, the greatest effect was observed with simvastatin (SMD: -1.54, 95 %CI: -2.92, -0.17, p=0.028) and pravastatin (SMD: -0.61, 95 %CI: -1.18, -0.04, p=0.035), but not with fluvastatin (SMD: -0.34, 95 %CI: -0.69, 0.02, p=0.065), atorvastatin (SMD: -0.23, 95 %CI: -0.57, 0.11, p=0.179) and rosuvastatin (SMD: -0.20, 95 % CI: -0.71, 0.30, p=0.431). The lowering effect of statins on plasma vWF:Ag levels was greater in the subset of studies lasting ≥ 12 weeks (SMD: -0.70, 95 %CI: -1.19, -0.22, p=0.005) compared with that of studies lasting < 12 weeks (SMD: -0.34, 95 %CI: -0.67, 0.003, p=0.052). Finally, low-intensity statin therapy was not associated with a significant reduction in vWF:Ag levels (SMD: -0.28, 95 %CI: -0.82, 0.27, p=0.320), but a significant effect was observed in high-intensity statin trials (SMD: -0.66, 95 %CI: -1.07, -0.24, p=0.002). This meta-analysis of available RCTs demonstrates a significant reduction in plasma vWF:Ag levels following statin therapy.

Effects of flaxseed supplements on blood pressure: A systematic review and meta-analysis of controlled clinical trial.

BACKGROUND & AIMS: Many experimental and clinical trials suggested that flaxseed might be a potent antihypertensive, but the evidences concerning the effects of flaxseed supplements on blood pressure (BP) has not been fully conclusive. We aimed to assess the impact of the effects of flaxseed supplements on blood pressure through systematic review of literature and meta-analysis of available randomized controlled trials (RCTs). METHODS: The literature search included PUBMED, Cochrane Library, Scopus, and EMBASE up to February 2015 to identify RCTs investigating the effect of flaxseed supplements on plasma blood pressure. Effect size was expressed as weighed mean difference (WMD) and 95% confidence interval (CI). RESULTS: 15 trials (comprising 19 treatment arms) with 1302 participants were included in this meta-analysis. Random-effects meta-analysis suggested significant reductions in both systolic BP (SBP) (WMD: -2.85 mmHg, 95%CI: -5.37 to -0.33, p = 0.027) and diastolic BP (DBP) (WMD: -2.39 mmHg, 95%CI: -3.78 to -0.99, p = 0.001) following supplementation with flaxseed products. When the studies were stratified according to their duration, there was a greater effect on both SBP and DBP in the subset of trials with ≥12 weeks of duration (WMD: -3.10 mmHg, 95%CI: -6.46 to 0.27, p = 0.072 and -2.62 mmHg, 95%CI: -4.39 to -0.86, p = 0.003, respectively) vs the subset lasting <12 weeks (WMD: -1.60 mmHg, 95%CI: -5.44 to 2.24, p = 0.413, and -1.74 mmHg, 95%CI: -4.41 to 0.93, p = 0.202, respectively). Another subgroup analysis was performed to assess the impact of flaxseed supplement type on BP. Reduction of SBP was significant with flaxseed powder (WMD: -1.81 mmHg, 95% CI: -2.03 to -1.59, p < 0.001) but not oil (WMD: -4.62 mmHg, 95%CI: -11.86 to 2.62, p = 0.211) and lignan extract (WMD: 0.28 mmHg, 95% CI: -3.49 to 4.04, p = 0.885). However, DBP was significantly reduced with powder and oil preparations (WMD: -1.28 mmHg, 95% CI: -2.44 to -0.11, p = 0.031, and -4.10 mmHg, 95%CI: -6.81 to -1.39, p = 0.003, respectively), but not with lignan extract (WMD: -1.78 mmHg, 95% CI: -4.28 to 0.72, p = 0.162). CONCLUSIONS: This meta-analysis of RCTs showed significant reductions in both SBP and DBP following supplementation with various flaxseed products.

Impact of statin therapy on coronary plaque composition: a systematic review and meta-analysis of virtual histology intravascular ultrasound studies.

BACKGROUND: Virtual histology intravascular ultrasound (VH-IVUS) imaging is an innovative tool for the morphological evaluation of coronary atherosclerosis. Evidence for the effects of statin therapy on VH-IVUS parameters have been inconclusive. Consequently, we performed a systematic review and meta-analysis to investigate the impact of statin therapy on plaque volume and its composition using VH-IVUS. METHODS: The search included PubMed, Cochrane Library, Scopus and Embase (through 30 November 2014) to identify prospective studies investigating the effects of statin therapy on plaque volume and its composition using VH-IVUS. RESULTS: We identified nine studies with 16 statin treatment arms and 830 participants. There was a significant effect of statin therapy in reducing plaque volume (standardized mean difference (SMD): -0.137, 95 % confidence interval (CI): -0.255, -0.019; P = 0.023), external elastic membrane volume (SMD: -0.097, 95 % CI: -0.183, -0.011; P = 0.027) but not lumen volume (SMD: -0.025, 95 % CI: -0.110, +0.061; P = 0.574). There was a significant reduction in fibrous plaque volume (SMD: -0.129, 95 % CI: -0.255, -0.003; P = 0.045) and an increase of dense calcium volume (SMD: +0.229, 95 % CI: +0.008, +0.450; P = 0.043), while changes in fibro-fatty (SMD: -0.247, 95 % CI: -0.592, +0.098; P = 0.16) and necrotic core (SMD: +0.011, 95 % CI: -0.144, +0.165; P = 0.892) tissue volumes were not statistically significant. CONCLUSIONS: This meta-analysis indicates a significant effect of statin therapy on plaque and external elastic membrane volumes and fibrous and dense calcium volumes. There was no effect on lumen volume, fibro-fatty and necrotic tissue volumes.

Effects of supplementation with green tea catechins on plasma C-reactive protein concentrations: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Promising experimental and clinical trials suggest that green tea decreases the inflammatory process in cardiometabolic diseases, but evidence from epidemiologic studies about the effects on plasma C-reactive protein (CRP) seems inconsistent and ambiguous. Therefore, the aim of this meta-analysis was to evaluate the effects of green tea supplementation on plasma CRP concentrations. METHODS: We searched selected database up to October 26, 2014 to identify randomized controlled trials (RCTs) investigating the effects of green tea supplementation on plasma CRP concentrations. Two independent reviewers extracted data on study characteristics, methods, and outcomes. RESULTS: Meta-analysis of data from 11 RCTs arms did not indicate a significant effect of supplementation with green tea catechins on plasma CRP concentrations (weighted mean difference [WMD], 0.085 mg/L; 95% confidence interval [CI], -0.225 to 0.395; P = 0.592). This effect size was robust in sensitivity analysis and omission of each individual study did not have a significant effect. The nonsignificant effects of green tea catechins on plasma CRP concentrations were also observed in subgroups of studies with green tea supplementation with a duration of <8 wk (WMD, 0.029 mg/L; 95% CI, -0.229 to 0.286; P = 0.828) and ≥8 wk (WMD, 0.099 mg/L; 95% CI, -0.555 to 0.754; P = 0.766). Likewise, there was no significant effect in subgroups of studies with total catechins doses <400 mg/d (WMD, 0.073 mg/L; 95% CI, -0.251 to 0.398; P = 0.658) and ≥400 mg/d (WMD, 0.213 mg/L; 95% CI, -0.148 to 0.574; P = 0.247). The effect sizes were not significant after stratification of studies to those recruiting healthy subjects (WMD, -0.028 mg/L; 95% CI, -0.216 to 0.160; P = 0.769), and those recruiting participants with cardiometabolic diseases (WMD, 0.260 mg/L; 95% CI, -0.815 to 1.334; P = 0.636). CONCLUSIONS: This meta-analysis of data from 11 RCT arms did not indicate a significant effect of supplementation with green tea catechins on plasma CRP concentrations. Furthermore, well-designed trials are necessary to validate these results.

Tibolone decreases Lipoprotein(a) levels in postmenopausal women: A systematic review and meta-analysis of 12 studies with 1009 patients.

INTRODUCTION: Circulating lipoprotein (a) (Lp(a)) is a recognized risk factor for cardiovascular disease (CVD). Tibolone, a synthetic steroid, may lower Lp(a) levels; however, evidence of the effects of tibolone on Lp(a) still remain to be defined. Therefore, we investigated the effects of tibolone treatment on circulating Lp(a) levels in postmenopausal women. METHODS: The search included PUBMED, Web of Science, Scopus, and Google Scholar (up to January 31st, 2015) to identify controlled clinical studies investigating the effects of oral tibolone treatment on Lp(a) levels in postmenopausal women. Random-effects meta-regression was performed using unrestricted maximum likelihood method for the association between calculated weighted mean difference (WMD) and potential moderators. RESULTS: Meta-analysis of data from 12 trials (16 treatment arms) suggested a significant reduction of Lp(a) levels following tibolone treatment (WMD: -25.28%, 95% confidence interval [CI]: -36.50, -14.06; p < 0.001). This result was robust in the sensitivity analysis and its significance was not influenced after omitting each of the included studies from the meta-analysis. When the studies were categorized according to the tibolone dose, there were consistent significant reductions of Lp(a) in the subsets of studies with doses <2.5 mg/day (WMD: -17.00%, 95%CI: -30.22, -3.77; p < 0.012) and 2.5 mg/day (WMD: -29.18%, 95%CI: -45.02, -13.33; p < 0.001). Likewise, there were similar reductions in the subsets of trials with follow-up either <24 months (WMD: -26.79%, 95%CI: -38.40, -15.17; p < 0.001) or ≥24 months (WMD: -23.10%, 95%CI: -40.17, -6.03; p = 0.008). CONCLUSIONS: This meta-analysis shows that oral tibolone treatment significantly lowers circulating Lp(a) levels in postmenopausal women. Further studies are warranted to explore the mechanism of this effect and the potential value and place of tibolone or its analogues in the treatment of elevated Lp(a) in individuals at risk of CVD.

Statin therapy and plasma coenzyme Q10 concentrations--A systematic review and meta-analysis of placebo-controlled trials.

Statin therapy may lower plasma coenzyme Q10 (CoQ10) concentrations, but the evidence as to the significance of this effect is unclear. We assessed the impact of statin therapy on plasma CoQ10 concentrations through the meta-analysis of available RCTs. The literature search included selected databases up to April 30, 2015. The meta-analysis was performed using either a fixed-effects or random-effect model according to I(2) statistic. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). The data from 8 placebo-controlled treatment arms suggested a significant reduction in plasma CoQ10 concentrations following treatment with statins (WMD: -0.44 µmol/L, 95%CI: -0.52, -0.37, p<0.001). The pooled effect size was robust and remained significant in the leave-one-out sensitivity analysis. Subgroup analysis suggested that the impact of statins on plasma CoQ10 concentrations is significant for all 4 types of statins studied i.e. atorvastatin (WMD: -0.41 µmol/L, 95%CI: -0.53, -0.29, p<0.001), simvastatin (WMD: -0.47 µmol/L, 95% CI: -0.61, -0.33, p<0.001), rosuvastatin (WMD: -0.49 µmol/L, 95%CI: -0.67, -0.31, p<0.001) and pravastatin (WMD: -0.43 µmol/L, 95%CI: -0.69, -0.16, p=0.001). Likewise, there was no differential effect of lipophilic (WMD: -0.43 µmol/L, 95%CI: -0.53, -0.34, p<0.001) and hydrophilic statins (WMD: -0.47 µmol/L, 95%CI: -0.62, -0.32, p<0.001). With respect to treatment duration, a significant effect was observed in both subsets of trials lasting <12 weeks (WMD: -0.51 µmol/L, 95%CI: -0.64, -0.39, p<0.001) and ≥12 weeks (WMD: -0.40 µmol/L, 95%CI: -0.50, -0.30, p<0.001). The meta-analysis showed a significant reduction in plasma CoQ10 concentrations following treatment with statins. Further well-designed trials are required to confirm our findings and elucidate their clinical relevance.

Statin therapy reduces plasma endothelin-1 concentrations: A meta-analysis of 15 randomized controlled trials.

OBJECTIVE: Raised plasma endothelin-1 (ET-1) levels may be a risk factor for vascular dysfunction and cardiovascular (CV) disease. This meta-analysis assessed the effect of statins on circulating ET-1 concentrations. METHODS AND RESULTS: The search included PUBMED, Cochrane Library, Web of Science, Scopus, and EMBASE up to September 30, 2014 to identify randomized controlled trials (RCTs) with ET-1 measurement during statin therapy. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Data from 15 RCTs showed that statin therapy significantly reduces plasma ET-1 concentrations (WMD: -0.30 pg/mL, 95%CI: -0.47, -0.13; p < 0.01). This effect was robust in sensitivity analysis, and not largely affected by the duration of statin therapy (<12 weeks - WMD: -0.51 pg/mL, 95%CI: -0.89, -0.14, p < 0.01; >12 week -WMD: -0.19 pg/mL, 95%CI: -0.36, -0.02; p < 0.05) or by dose of statins (<40 mg/day - WMD: -0.27 pg/mL, 95%CI: -0.49, -0.05; p = 0.01; >40 mg/day - WMD: -0.38 pg/mL, 95%CI: -0.68, -0.08; p = 0.01). Lipophilic (atorvastatin, simvastatin, fluvastatin, and cerivastatin - WMD: -0.34 pg/mL, 95%CI: -0.55, -0.13; p < 0.01), but not a hydrophilic statin (pravastatin - WMD: -0.18 pg/mL, 95%CI: -0.44 -0.08; p > 0.05) had a significant effect in promoting ET-1 reduction. CONCLUSIONS: Statin therapy significantly reduces circulating ET-1 concentrations, regardless of treatment duration or dose of statins. This effect of statins may be influenced by statin lipophilicity. There is a need to establish whether lowering ET-1 levels has a beneficial effect on CV events.

A systematic review and meta-analysis of the effect of statins on plasma asymmetric dimethylarginine concentrations.

The impact of statin therapy on plasma asymmetric dimethylarginine (ADMA) levels has not been conclusively studied. Therefore the aim of the meta-analysis was to assess the effect of statins on circulating ADMA levels. We searched selected databases (up to August 2014) to identify randomized controlled trials (RCTs) that investigate the effect of statins on plasma ADMA concentrations. A weighted meta-regression (WMD) using unrestricted maximum likelihood model was performed to assess the impact of statin dose, duration of statin therapy and baseline ADMA concentrations as potential variables on the WMD between statin and placebo group. In total, 1134 participants in 9 selected RCTs were randomized; 568 were allocated to statin treatment and 566 were controls. There was a significant reduction in plasma ADMA concentrations following statin therapy compared with placebo (WMD: -0.104 µM, 95% confidence interval: -0.131 to -0.077, Z = -7.577, p < 0.0001). Subgroups analysis has shown a significant impact of hydrophilic statins (WMD: -0.207 µM, 95%CI: -0.427 to +0.013, Z = -7.250, p < .0001) and a non-significant effect of hydrophobic statins (WMD: -0.101 µM, 95%CI: -0.128 to -0.074, Z = -1.845, p = 0.065). In conclusion, this meta-analysis of available RCTs showed a significant reduction in plasma ADMA concentrations following therapy with hydrophilic statins.

Association between statin use and plasma D-dimer levels. A systematic review and meta-analysis of randomised controlled trials.

D-dimers, specific breakdown fragments of cross-linked fibrin, are generally used as circulating markers of activated coagulation. Statins influence haemostatic factors, but their effect on plasma D-dimer levels is controversial. Therefore, the aim of this meta-analysis was to evaluate the association between statin therapy and plasma D-dimer levels. We searched PubMed, Web of Science, Cochrane Library, Scopus and EMBASE (up to September 25, 2014) to identify randomised controlled trials (RCTs) investigating the impact of statin therapy on plasma D-dimer levels. Two independent reviewers extracted data on study characteristics, methods and outcomes. Meta-analysis of data from nine RCTs with 1,165 participants showed a significant effect of statin therapy in reducing plasma D-dimer levels (standardised mean difference [SMD]: -0.988 µg/ml, 95 % confidence interval [CI]: -1.590 - -0.385, p=0.001). The effect size was robust in sensitivity analysis and omission of no single study significantly changed the overall estimated effect size. In the subgroup analysis, the effect of statins on plasma D-dimer levels was significant only in the subsets of studies with treatment duration ≥ 12 weeks (SMD: -0.761 µg/ml, 95 %CI: -1.163- -0.360; p< 0.001), and for lipophilic statins (atorvastatin and simvastatin) (SMD: -1.364 µg/ml, 95 % CI: -2.202- -0.526; p=0.001). Hydrophilic statins (pravastatin and rosuvastatin) did not significantly reduce plasma D-dimer levels (SMD: -0.237 µg/ml, 95 %CI: -1.140-0.665, p=0.606). This meta-analysis of RCTs suggests a decrease of plasma D-dimer levels after three months of statin therapy, and especially after treatment with lipophilic statins. Well-designed trials are required to validate these results.

Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel.

Statins are one of the most commonly prescribed drugs in clinical practice. They are usually well tolerated and effectively prevent cardiovascular events. Most adverse effects associated with statin therapy are muscle-related. The recent statement of the European Atherosclerosis Society (EAS) has focused on statin-associated muscle symptoms (SAMS), and avoided the use of the term 'statin intolerance'. Although muscle syndromes are the most common adverse effects observed after statin therapy, excluding other side effects might underestimate the number of patients with statin intolerance, which might be observed in 10 - 15% of patients. In clinical practice, statin intolerance limits effective treatment of patients at risk of, or with, cardiovascular disease. Knowledge of the most common adverse effects of statin therapy that might cause statin intolerance and the clear definition of this phenomenon is crucial to effectively treat patients with lipid disorders. Therefore, the aim of this position paper was to suggest a unified definition of statin intolerance, and to complement the recent EAS statement on SAMS, where the pathophysiology, diagnosis and the management were comprehensively presented.