Associations of Polymorphisms in the Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha Gene With Subsequent Coronary Heart Disease: An Individual-Level Meta-Analysis.

Background: The knowledge of factors influencing disease progression in patients with established coronary heart disease (CHD) is still relatively limited. One potential pathway is related to peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A), a transcription factor linked to energy metabolism which may play a role in the heart function. Thus, its associations with subsequent CHD events remain unclear. We aimed to investigate the effect of three different SNPs in the PPARGC1A gene on the risk of subsequent CHD in a population with established CHD. Methods: We employed an individual-level meta-analysis using 23 studies from the GENetIcs of sUbSequent Coronary Heart Disease (GENIUS-CHD) consortium, which included participants (n = 80,900) with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. Three variants in the PPARGC1A gene (rs8192678, G482S; rs7672915, intron 2; and rs3755863, T528T) were tested for their associations with subsequent events during the follow-up using a Cox proportional hazards model adjusted for age and sex. The primary outcome was subsequent CHD death or myocardial infarction (CHD death/myocardial infarction). Stratified analyses of the participant or study characteristics as well as additional analyses for secondary outcomes of specific cardiovascular disease diagnoses and all-cause death were also performed. Results: Meta-analysis revealed no significant association between any of the three variants in the PPARGC1A gene and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline: rs8192678, hazard ratio (HR): 1.01, 95% confidence interval (CI) 0.98-1.05 and rs7672915, HR: 0.97, 95% CI 0.94-1.00; rs3755863, HR: 1.02, 95% CI 0.99-1.06. Similarly, no significant associations were observed for any of the secondary outcomes. The results from stratified analyses showed null results, except for significant inverse associations between rs7672915 (intron 2) and the primary outcome among 1) individuals aged ≥65, 2) individuals with renal impairment, and 3) antiplatelet users. Conclusion: We found no clear associations between polymorphisms in the PPARGC1A gene and subsequent CHD events in patients with established CHD at baseline.

Genome-wide analysis identifies novel susceptibility loci for myocardial infarction.

AIMS: While most patients with myocardial infarction (MI) have underlying coronary atherosclerosis, not all patients with coronary artery disease (CAD) develop MI. We sought to address the hypothesis that some of the genetic factors which establish atherosclerosis may be distinct from those that predispose to vulnerable plaques and thrombus formation. METHODS AND RESULTS: We carried out a genome-wide association study for MI in the UK Biobank (n∼472 000), followed by a meta-analysis with summary statistics from the CARDIoGRAMplusC4D Consortium (n∼167 000). Multiple independent replication analyses and functional approaches were used to prioritize loci and evaluate positional candidate genes. Eight novel regions were identified for MI at the genome wide significance level, of which effect sizes at six loci were more robust for MI than for CAD without the presence of MI. Confirmatory evidence for association of a locus on chromosome 1p21.3 harbouring choline-like transporter 3 (SLC44A3) with MI in the context of CAD, but not with coronary atherosclerosis itself, was obtained in Biobank Japan (n∼165 000) and 16 independent angiography-based cohorts (n∼27 000). Follow-up analyses did not reveal association of the SLC44A3 locus with CAD risk factors, biomarkers of coagulation, other thrombotic diseases, or plasma levels of a broad array of metabolites, including choline, trimethylamine N-oxide, and betaine. However, aortic expression of SLC44A3 was increased in carriers of the MI risk allele at chromosome 1p21.3, increased in ischaemic (vs. non-diseased) coronary arteries, up-regulated in human aortic endothelial cells treated with interleukin-1ß (vs. vehicle), and associated with smooth muscle cell migration in vitro. CONCLUSIONS: A large-scale analysis comprising ∼831 000 subjects revealed novel genetic determinants of MI and implicated SLC44A3 in the pathophysiology of vulnerable plaques.

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data.

BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

Model selection for metabolomics: predicting diagnosis of coronary artery disease using automated machine learning.

MOTIVATION: Selecting the optimal machine learning (ML) model for a given dataset is often challenging. Automated ML (AutoML) has emerged as a powerful tool for enabling the automatic selection of ML methods and parameter settings for the prediction of biomedical endpoints. Here, we apply the tree-based pipeline optimization tool (TPOT) to predict angiographic diagnoses of coronary artery disease (CAD). With TPOT, ML models are represented as expression trees and optimal pipelines discovered using a stochastic search method called genetic programing. We provide some guidelines for TPOT-based ML pipeline selection and optimization-based on various clinical phenotypes and high-throughput metabolic profiles in the Angiography and Genes Study (ANGES). RESULTS: We analyzed nuclear magnetic resonance-derived lipoprotein and metabolite profiles in the ANGES cohort with a goal to identify the role of non-obstructive CAD patients in CAD diagnostics. We performed a comparative analysis of TPOT-generated ML pipelines with selected ML classifiers, optimized with a grid search approach, applied to two phenotypic CAD profiles. As a result, TPOT-generated ML pipelines that outperformed grid search optimized models across multiple performance metrics including balanced accuracy and area under the precision-recall curve. With the selected models, we demonstrated that the phenotypic profile that distinguishes non-obstructive CAD patients from no CAD patients is associated with higher precision, suggesting a discrepancy in the underlying processes between these phenotypes. AVAILABILITY AND IMPLEMENTATION: TPOT is freely available via http://epistasislab.github.io/tpot/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Subsequent Event Risk in Individuals With Established Coronary Heart Disease.

BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events.

BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk. METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD. RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09). CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Biomarker Glycoprotein Acetyls Is Associated With the Risk of a Wide Spectrum of Incident Diseases and Stratifies Mortality Risk in Angiography Patients.

BACKGROUND: Integration of systems-level biomolecular information with electronic health records has led to recent interest in the glycoprotein acetyls (GlycA) biomarker-a serum- or plasma-derived nuclear magnetic resonance spectroscopy signal that represents the abundance of circulating glycated proteins. GlycA predicts risk of diverse outcomes, including cardiovascular disease, type 2 diabetes mellitus, and all-cause mortality; however, the underlying detailed associations of GlycA's morbidity and mortality risk are currently unknown. METHODS: We used 2 population-based cohorts totaling 11 861 adults from the Finnish general population to test for an association with 468 common incident hospitalization and mortality outcomes during an 8-year follow-up. Further, we utilized 900 angiography patients to test for GlycA association with mortality risk and potential utility for mortality risk discrimination during 12-year follow-up. RESULTS: New associations with GlycA and incident alcoholic liver disease, chronic renal failure, glomerular diseases, chronic obstructive pulmonary disease, inflammatory polyarthropathies, and hypertension were uncovered, and known incident disease associations were replicated. GlycA associations for incident disease outcomes were in general not attenuated when adjusting for hsCRP (high-sensitivity C-reactive protein). Among 900 patients referred to angiography, GlycA had hazard ratios of 4.87 (95% CI, 2.45-9.65) and 5.00 (95% CI, 2.38-10.48) for 12-year risk of mortality in the fourth and fifth quintiles by GlycA levels, demonstrating its prognostic potential for identification of high-risk individuals. When modeled together, both hsCRP and GlycA were attenuated but remained significant. CONCLUSIONS: GlycA was predictive of myriad incident diseases across many major internal organs and stratified mortality risk in angiography patients. Both GlycA and hsCRP had shared and independent contributions to mortality risk, suggesting chronic inflammation as an etiological factor. GlycA may be useful in improving risk prediction in specific disease settings.

Genome-wide association study pinpoints a new functional apolipoprotein B variant influencing oxidized low-density lipoprotein levels but not cardiovascular events: AtheroRemo Consortium.

BACKGROUND: Oxidized low-density lipoprotein may be a key factor in the development of atherosclerosis. We performed a genome-wide association study on oxidized low-density lipoprotein and tested the impact of associated single-nucleotide polymorphisms (SNPs) on the risk factors of atherosclerosis and cardiovascular events. METHODS AND RESULTS: A discovery genome-wide association study was performed on a population of young healthy white individuals (N=2080), and the SNPs associated with a P<5×10(-8) were replicated in 2 independent samples (A: N=2912; B: N=1326). Associations with cardiovascular endpoints were also assessed with 2 additional clinical cohorts (C: N=1118; and D: N=808). We found 328 SNPs associated with oxidized low-density lipoprotein. The genetic variant rs676210 (Pro2739Leu) in apolipoprotein B was the proxy SNP behind all associations (P=4.3×10(-136), effect size=13.2 U/L per allele). This association was replicated in the 2 independent samples (A and B, P=2.5×10(-47) and 1.1×10(-11), effect sizes=10.3 U/L and 7.8 U/L, respectively). In the meta-analyses of cohorts A, C, and D (excluding cohort B without angiographic data), the top SNP did not associate significantly with the age of onset of angiographically verified coronary artery disease (hazard ratio=1.00 [0.94-1.06] per allele), 3-vessel coronary artery disease (hazard ratio=1.03 [0.94-1.13]), or myocardial infarction (hazard ratio=1.04 [0.96-1.12]). CONCLUSIONS: This novel genetic marker is an important factor regulating oxidized low-density lipoprotein levels but not a major genetic factor for the studied cardiovascular endpoints.

High-throughput quantification of circulating metabolites improves prediction of subclinical atherosclerosis.

AIMS: High-throughput metabolite quantification holds promise for cardiovascular risk assessment. Here, we evaluated whether metabolite quantification by nuclear magnetic resonance (NMR) improves prediction of subclinical atherosclerosis in comparison to conventional lipid testing. METHODS AND RESULTS: Circulating lipids, lipoprotein subclasses, and small molecules were assayed by NMR for 1595 individuals aged 24-39 years from the population-based Cardiovascular Risk in Young Finns Study. Carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis, was measured in 2001 and 2007. Baseline conventional risk factors and systemic metabolites were used to predict 6-year incidence of high IMT (≥ 90 th percentile) or plaque. The best prediction of high intima-media thickness was achieved when total and HDL cholesterol were replaced by NMR-determined LDL cholesterol and medium HDL, docosahexaenoic acid, and tyrosine in prediction models with risk factors from the Framingham risk score. The extended prediction model improved risk stratification beyond established risk factors alone; area under the receiver operating characteristic curve 0.764 vs. 0.737, P =0.02, and net reclassification index 17.6%, P =0.0008. Higher docosahexaenoic acid levels were associated with decreased risk for incident high IMT (odds ratio: 0.74; 95% confidence interval: 0.67-0.98; P = 0.007). Tyrosine (1.33; 1.10-1.60; P = 0.003) and glutamine (1.38; 1.13-1.68; P = 0.001) levels were associated with 6-year incident high IMT independent of lipid measures. Furthermore, these amino acids were cross-sectionally associated with carotid IMT and the presence of angiographically ascertained coronary artery disease in independent populations. CONCLUSION: High-throughput metabolite quantification, with new systemic biomarkers, improved risk stratification for subclinical atherosclerosis in comparison to conventional lipids and could potentially be useful for early cardiovascular risk assessment.

Common variation in the ADAM8 gene affects serum sADAM8 concentrations and the risk of myocardial infarction in two independent cohorts.

OBJECTIVE: The single nucleotide polymorphism (SNP) rs2995300 in the metalloproteinase-disintegrin gene ADAM8 has been shown to affect the areas of complicated coronary plaques and the risk of fatal myocardial infarction (MI) in men. This study was set up to further investigate the role of ADAM8 in MI. AIM: To investigate the possible association of the ADAM8 SNPs rs2995300 and rs2275725 with ADAM8 mRNA levels, serum soluble ADAM8 (sADAM8) concentrations, and MI risk. METHODS: Samples from the Finnish cardiovascular study (FINCAVAS, N=2156) and the angiography and genes study (ANGES, N=1000) were genotyped. Serum sADAM8 concentrations were determined with ELISA (N=443). ADAM8 mRNA levels in atherosclerotic plaques were analysed from the tampere vascular study (TVS, N=53) samples. RESULTS: A significantly increased MI risk for carriers of the rs2995300C allele and the rs2275725 A allele was revealed in the meta-analysis of the ANGES and FINCAVAS patient data (OR=1.42, P<0.001 and OR=1.43, P<0.001). The risk increase was comparable to that caused by smoking in these cohorts. The risk allele carriers also had higher sADAM8 serum concentrations. CONCLUSIONS: The risk alleles of the investigated ADAM8 SNPs were associated with elevated sADAM8 serum levels and MI risk. The present results implicate ADAM8 in the development of CVDs and suggest its prognostic and therapeutic potential.

Short stature is associated with coronary heart disease: a systematic review of the literature and a meta-analysis.

AIMS: The aim of this study was to assess the relationship between short stature and coronary heart disease (CHD) morbidity and mortality. METHODS AND RESULTS: We performed a systematic search from MEDLINE, PREMEDLINE, and All EBM Reviews as well as from a reference list of relevant articles. We used SPICO (Study design, Patient, Intervention, Control-intervention, Outcome) criteria. The methodological quality of studies was analysed by modified Borghoust criteria. From a total of 1907 articles, we selected 52 studies comprising population-based follow-up studies and patient cohorts followed after a CHD event, as well as case-control studies with height either as a continuous or categorical variable, totalling 3 012 747 individuals. The short ones were below 160.5 cm and tall ones over 173.9 cm on average. Among the shortest height category, the relative risks were 1.35 (95% CI 1.25-1.44) for all-cause mortality, 1.55 (1.37-1.74) for all cardiovascular disease (CVD) mortality, 1.49 (1.33-1.67) for CHD, and 1.52 (1.28-1.81) for myocardial infarction when compared with those within the highest height category. The mean relative risk was 1.46 (1.37-1.55). Short stature was associated with increased cardiovascular morbidity and mortality in both genders. CONCLUSION: The relationship between short stature and CVD appears to be a real one. On the basis of comparison, adults within the shortest category had an approximately 50% higher risk of CHD morbidity and mortality than tall individuals.

The anti-inflammatory effect of bradykinin preconditioning in coronary artery bypass grafting (bradykinin and preconditioning).

OBJECTIVE: The present study was designed to investigate the cardioprotective effect of exogenous administration of bradykinin (BK) in cardiac surgery. METHODS: Forty-one patients who were scheduled for isolated coronary artery bypass grafting (CABG) were randomized into Control group and BK group. BK patients received 25 microg bradykinin infusion for 7 minutes before the cardiopulmonary bypass (CPB). Release of cardiac specific troponin I (TnI) and creatine kinase cardiac isoenzyme (CK-MB) was recorded. Perioperative circulating cytokine interleukin (IL)-6, 8 and 10 were measured. RESULTS: There was no significant difference in TnI between groups. However, BK patients released significantly less CK-MB than the controls (p =0.043). Systemic plasma levels of IL-6, IL-8 and IL-10 increased significantly after reperfusion in both groups as compared with baseline (p <0.05). The ratio of IL-8 to IL-10 was significantly lower in BK groups than in controls (p =0.03). CONCLUSIONS: We conclude that exogenous administration of BK prior to CPB in CABG patients attenuates ischemic myocardial injury. It also shifts the circulating inflammatory cytokine balance towards the anti-inflammatory direction.

Diagnostic performance of plasma high sensitive C-reactive protein in detecting three-vessel coronary artery disease: modification by apolipoprotein E genotype.

OBJECTIVES: Plasma high sensitive C-reactive protein (hsCRP) concentration is an important clinical test of systemic inflammation and, like apoE epsilon4 allele, an important risk factor of coronary artery disease (CAD). We investigated whether the diagnostic performance of plasma hsCRP in detecting severe 3-vessel CAD may be modified by apoE epsilon4 carrier status. METHODS: The study population (Angiography and Genes Study) comprised 485 Finnish subjects (336 men and 149 women, mean age 64.0+/-1.0) undergoing coronary angiography. ApoE genotypes were determined by the PCR-based method and by hsCRP using an automatic analyser. RESULTS: The diagnostic performance of hsCRP concentration in distinguishing 3-vessel CAD from its less widespread forms (non-3-vessel CAD) was assessed by receiver operating characteristic curve (ROC) analysis separately in apoE epsilon4 non-carriers and epsilon4 carriers. ROC analysis showed that hsCRP predicted 3-vessel CAD in apoE epsilon4 non-carriers (AUC 0.646; SE 0.035; p = 0.0001; 95 % CI 0.578-0.714) but not in epsilon4 carriers (AUC 0.518; SE 0.049; p = 0.719; 95 % CI 0.422-0.615). Multinomial logistic regression analysis revealed a significant (p<0.05) apoE epsilon4 group versus hsCRP group (<1.0 mg/L/>or=1.0 mg/L) interaction in relation to incidence of 3-vessel CAD. In apoE epsilon4 non-carriers, high hsCRP (>or=1.0 mg/L) was significantly (OR 2.1; 95 % CI 1.233-3.562; p = 0.006) associated with high incidence of 3-vessel CAD after adjustment for major CAD risk factors. CONCLUSION: The diagnostic performance of hsCRP in distinguishing 3-vessel CAD from less extensive forms of coronary atherosclerosis is more accurate in a group of subjects without the apoE epsilon4 allele than in patients with it.

Economic evaluation of drug-eluting stents: a systematic literature review and model-based cost-utility analysis.

OBJECTIVES: The aim of this study was to systematically review economic analyses comparing drug-eluting stents (DES) to bare metal stents (BMS) in patients who undergo percutaneous coronary intervention to form an overall view about cost-effectiveness of DES and to construct a simple decision analysis model to evaluate the cost-utility of DES. METHODS: Electronic databases searched from January 2004 to January 2006 were Cochrane Database of Systematic Reviews; DARE, HTA, EED (NHS CRD); MEDLINE(R) In-Process, Other Non-Indexed Citations, MEDLINE(R). References of the papers identified were checked. We included randomized controlled trials (RCT) or model-based cost-effectiveness analyses comparing DES to BMS in patients with coronary artery disease. The methodological quality of the papers was assessed by Drummond's criteria. Baseline characteristics and results of the studies were extracted and data synthesized descriptively. A decision tree model was constructed to evaluate the cost-utility of DES in comparison to BMS, where health-related quality of life was measured by the 15D. RESULTS: We identified thirteen good-quality economic evaluations. In two of these based on RCTs, DES was found cost-effective. In six studies, it was concluded that DES might probably be a cost-effective strategy in some circumstances, but not as a single strategy, and four studies concluded that DES is not cost-effective. One study did not draw a clear conclusion. In our analysis, the overall incremental cost-effectiveness ratio was Euros 98,827 per quality-adjusted life-years gained. Avoiding one revascularization with DES would cost Euros 4,794, when revascularization with BMS costs Euros 3,260. CONCLUSIONS: The evidence is inconsistent of whether DES would be a cost-effective treatment compared with BMS in any healthcare system where evaluated. A marked restenosis risk reduction should be achieved before use of DES is justifiable at present prices. When considering adoption of a new health technology with a high incremental cost within a fixed budget, opportunity cost in terms of untreated patients should be seriously considered as a question of collective ethics.

Effectiveness and safety of endoscopic thoracic sympathectomy for excessive sweating and facial blushing: a systematic review.

OBJECTIVES: Despite controversies, endoscopic thoracic sympathectomy (ETS) has been used as a treatment for excessive sweating of hands and face and for facial blushing. This study aims to evaluate the effectiveness of ETS for the current indications in a systematic review. METHODS: Controlled clinical trials and cohort studies with more than 100 patients were included. Abstracts were searched from MEDLINE and CCTR from 1966 to June 2004. Two reviewers extracted the data and assessed study quality. Data on effectiveness and safety were synthesized qualitatively. RESULTS: We did not find any controlled clinical trials. Fifteen prospective studies were included. The internal and external quality of these studies were poor overall. Follow-up was commonly less than 2 years, during which time excessive sweating and facial blushing seemed to decrease among most patients. Immediate complications related to thoracoscopy occurred in up to 10 percent of patients. Compensatory sweating below breast level was reported in up to 90 percent of the patients. Other common side effects included dryness of face and hands, gustatory sweating, and neuralgic pain. Several other less common side effects were reported. CONCLUSIONS: The evidence of the effectiveness of ETS is weak due to a lack of randomized trials. The intervention leads to severe immediate complications in some of the patients, and to persistent side-effects for many of the patients.

Reanalysis of systematic reviews: the case of invasive strategies for acute coronary syndromes.

OBJECTIVES: The objective of this study was to collect all systematic reviews on invasive strategies for acute coronary syndromes (ACS) and reanalyze the data in these reviews to reach combined estimates, as well as to make predictions on the effectiveness and risk of harm so as to facilitate relevant decision making in health care. METHODS: The data sources used were the following electronic databases, searched from 1994 to September 2004: Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials; DARE, HTA, EED (NHS CRD); MEDLINE In-Process, Other Non-Indexed Citations, MEDLINE, and PubMed (2000 to 2004). References to the identified systematic reviews were checked. An ancillary search to identify recent randomized controlled trials (RCTs) covering the period from January 2003 to January 2006 was done in MEDLINE(R). We included systematic reviews of RCTs on patients with ACS. In unstable angina and non-ST-elevation myocardial infarction (UA/NSTEMI), eligible reviews had to compare early routine invasive strategy with early selective invasive strategy. In ST-elevation myocardial infarction (STEMI), a comparison between primary percutaneous coronary intervention (PCI) and thrombolytic therapy was required. The methodological quality of the reviews was assessed, and a standardized data extraction form was used. Results for the main outcomes of the RCTs in the reviews were reanalyzed. An additional search of those RCTs not included in the meta-analyses was performed for UA/NSTEMI and short-term morality data on STEMI. Bayesian models were constructed to estimate the uncertainty about a possible treatment effect and to make predictions and probability statements. Main results are based on these analyses. Mortality was considered as the primary outcome measure. RESULTS: One systematic review on invasive strategies was identified for UA/NSTEMI and nine on invasive strategies for STEMI. Five reviews of the latter that were published after the year 2000 were included for the final analysis. The median quality score was 10.5 (range, 7-13; n = 6) on a scale from 0 to 18 points. An updated literature search identified one further RCT on UA/NSTEMI. Regarding NSTEMI and mortality, the average risk difference favoring an early invasive treatment strategy compared with early conservative strategy was .6 percent (95 percent credible interval [CrI], -2.1 to 1.0). Predicted risk (relative risk/risk difference scales) of doing harm was 26.7/26.6 percent. Regarding STEMI and mortality, the absolute risk reduction in favor of primary PCI over thrombolysis was 4.1 percent (95 percent CrI, -7.1 to -1.1) when PCI was compared with streptokinase and 1.2 percent (95 percent CrI, -2.7 to .2) when compared with fibrin-specific thrombolytics. Predicted risk of harm was 8.9/5.3 percent and 8.0/13.3 percent, respectively. CONCLUSIONS: There seems to be at present no solid evidence for survival benefit on early invasive strategy for UA/NSTEMI as a broad diagnostic group, and the risk of doing harm should be considered. Also, the evidence for PCI to decrease early mortality after STEMI is scanty. Estimations of predicted harm may further aid decisions on whether to implement the new treatment over the old one. It may also give an additional dimension for interpreting the results of any meta-analysis.

Overview of systematic reviews on invasive treatment of stable coronary artery disease.

OBJECTIVES: The aim of the study was to evaluate the validity of the systematic reviews as a source of best evidence and to present and interpret the evidence of the systematic reviews on effectiveness of surgery and percutaneous interventions for stable coronary artery disease. METHODS: Electronic databases were searched without language restriction from January 1966 to March 2004. The databases used included the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, DARE, the Health Technology Assessment Database, MEDLINE(R), MEDLINE(R) In-Process & Other Non-Indexed Citations. We included systematic reviews of randomized clinical trials on patients with stable coronary heart disease undergoing percutaneous coronary intervention or coronary artery bypass surgery in comparison with medical treatment or a comparison between invasive techniques. At least one of the following outcomes had to be reported: death, myocardial infarction, angina pectoris, revascularization. The methodological quality was assessed using a modified version of the scale devised by Oxman and Guyatt (1991). A standardized data-extraction form was used. The method used to evaluate clinical relevance was carried out with updated method guidelines from the Cochrane Back Research Group. Quantitative synthesis of the effectiveness data is presented. RESULTS: We found nineteen systematic reviews. The median score of validity was 13 points (range, 6-17 points), with a maximum of 18 points. Coronary artery bypass surgery gives better relief of angina, and the need for repeated procedures is reduced after bypass surgery compared with percutaneous interventions. There is inconsistent evidence as to whether bypass surgery improves survival compared with percutaneous intervention. A smaller need for repeated procedures exists after bare metal stent and even more so after drug-eluting stent placement than after percutaneous intervention without stent placement. However, according to the current evidence, these treatment alternatives do not differ in terms of mortality or myocardial infarction. CONCLUSIONS: We found some high-quality systematic reviews. There was evidence on the potential of invasive treatments to provide symptomatic relief. Surgery seems to provide a longer-lasting effect than percutaneous interventions with bare metal stents or without stents. Evidence in favor of drug-eluting stents so far is based on short-term follow-up and mostly on patients with single-vessel disease.

Apolipoprotein E polymorphism is not a predictor for repeated coronary artery bypass surgery.

OBJECTIVES: Factors leading to the occlusion of coronary grafts are diverse and may at least partially be inherited. We aimed to study the possible genetic predisposition and especially the role of apoE epsilon4 allele as a risk factor for repeated coronary artery bypass grafting (CABG) in a case-control setting. DESIGN: All patients (n=184) who underwent repeated CABG between 1990 and 1998 were identified in the computed registry of the Department of Cardiothoracic Surgery in Tampere University Hospital. Age, sex and operation date matched controls with first time CABG were selected from the same registry. DNA samples were collected by sample stick sent via the mail for buccal smear. The final analysis included 137 surviving matched pairs. RESULTS: In patients <62 years of age (median age), family history emerged as the only significant (OR=3.4; 95% CI=1.5-7.8, p=0.004) predictor for repeated surgery. Among older patients, repeated CABG was no longer predicted by family history but by hypercholesterolemia (OR=2.1; 95% CI=1.1-4.0, p=0.027), modified by apoE genotype. CONCLUSIONS: Our results suggest that medium-term survivors after redo CABG have a strong genetic predisposition unrelated to hypercholesterolemia or apoE genotype, leading to more severe coronary artery disease at earlier age. In the older age group, redo coronary artery bypass surgery is associated with hypercholesterolemia, which, although modified by apoE genotype, may mainly be due to other genetic or acquired factors.

Positive family history of coronary atherosclerosis and serum triglycerides may predict repeated coronary artery bypass surgery.

OBJECTIVE: Cardiovascular risk factor profile of patients in need of repeated coronary artery bypass surgery (redo CABG) seldom differ from patients having only single coronary artery bypass surgery (CABG). The aim of this study was to analyse the influence of positive family history for coronary artery disease in respect to redo CABG vs CABG in a case-control setting. DESIGN: One hundred and eighty four patients undergoing redo CABG between 1990-1998 were identified from the computed registry of the Department of Cardiothoracic Surgery in Tampere University Hospital. One hundred and eighty four age, gender and operation date matched patients with CABG were selected for control. RESULTS: According to chi-square analysis, positive family history for coronary artery disease was more common in Study group, 60.4% versus 49.5% (p<0.05). Preoperative systolic blood pressure was 135.5+/-1.4 mmHg versus 133.5+/-1.5 mmHg (ns), preoperative diastolic blood pressure was 81.2+/-0.8 mmHg versus 82.8+/-0.9 mmHg (ns), serum total cholesterol was 5.8+/-0.1 mmol/L versus 6.6+/-1.2 mmol/L and preoperative blood glucose was 5.6+/-0.2 mmol/L versus 5.3+/-0.2 mmol/L (ns) in Controls and Study group, respectively. However, serum triglyceride level was significantly higher in Study group 2.8+/-0.2 mmol/L versus 2.0+/-0.1 mmol/L (p<0.000). In regression analysis, only positive family history (OR=2.4; 95% CI=1.1-5.1; p<0,02) and high serum triglyceride level (>or=2 mmol/L, OR=1.6; 95% CI=1.2-2.2; p<0,02) were independent predictors for redo CABG. CONCLUSION: According to this study, positive family history for coronary atherosclerosis at the presence of high serum triglyceride level is significantly predicting the need for future redo CABG as compared with age, gender and operation time matched controls of CABG.

Continuous pleural lavage may decrease postoperative morbidity in patients undergoing thoracotomy for stage 2 thoracic empyema.

OBJECTIVE: To assess the impact of postoperative continuous pleural lavage (PCPL) after thoracotomy for the treatment of stage 2 pleural empyema in relation to postoperative length of stay and morbidity. METHODS: Stage 2 pleural empyema was diagnosed with computer tomography. Conservative treatment including antibiotics and pleural aspiration was introduced. 89 patients treated for stage 2 pleural empyema by thoracotomy, pleural discharge evacuation and irrigation after pleural decortication were identified after unsuccessful conservative treatment for 10 days. Whenever pleural discharge remained opaque after operation, PCPL was administered daily through the cranial chest tube and discharge evacuated through the caudal pleural suction (10-15 mmHg) tube. Risk factors related to pleural pus and patient outcome were sought for. RESULTS: Seventy-seven out of 89 patients (86.5%) had clear empyema discharge immediately after pleural decortication and irrigation. Pleural discharge remained opaque despite surgery in 12 out of 89 patients (13.5%) and PCPL was introduced. Presence of a combination of risk factors for pleural empyema, such as dental caries, alcohol abuse or previous inflammatory reaction, was predictive for persistence of opaque pleural discharge after operation (P<0.05). Need for re-thoracotomies (in 11 cases, P=ns) and postoperative deaths (P<0.05) were related with patients who did not have PCPL. The length of the hospital treatment was 20.1+/-3.1 (days+/-SEM) among patients with PCPL and 19.2+/-1.8 without PCPL before possible re-thoracotomy, respectively (P=ns). CONCLUSIONS: Early postoperative (1 day-11 months) mortality was statistically associated with patients having fibrinopurulent empyema but no PCPL. PCPL is a feasible method to clear pleural pus discharge without prolongation of hospitalization and may be recommended after thoracotomy for patients with fibrinopurulent stage 2 empyema.