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Circulation Feb 2020Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition...
BACKGROUND
Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required.
METHODS
Utilizing an evidence-based framework, 3 gene curation teams blinded to each other's work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams.
RESULTS
Of 17 genes reported as being causative for LQTS, 9 () were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes () were curated as definitive genes for typical LQTS. Another 4 genes () were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene () had moderate level evidence for causing LQTS.
CONCLUSIONS
More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.
Topics: Atrioventricular Block; Evidence-Based Medicine; Female; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Humans; Long QT Syndrome; Male; Multicenter Studies as Topic
PubMed: 31983240
DOI: 10.1161/CIRCULATIONAHA.119.043132 -
Frontiers in Cardiovascular Medicine 2023Atrioventricular block (AVB) is a serious complication following coronary artery bypass grafting (CABG) surgery, and its high-grade form may necessitate the implantation... (Review)
Review
BACKGROUND AND OBJECTIVES
Atrioventricular block (AVB) is a serious complication following coronary artery bypass grafting (CABG) surgery, and its high-grade form may necessitate the implantation of a permanent pacemaker (PPM). AVB is associated with increased morbidity and mortality rates. This study aims to estimate the incidence of AVB and subsequent PPM implantation after isolated CABG surgery.
MATERIAL AND METHODS
We searched electronic databases of PubMed, Embase, and Scopus from inception to 18 November 2022. Clinical trials and observational studies reporting the incidence of post-CABG AVB or subsequent PPM implantation in adult patients were included. The total incidence for all included outcomes was calculated using the inverse variance method, and the statistic was reported to evaluate the heterogeneity of studies.
RESULTS
A total of 28 studies met the inclusion criteria. Four studies [3 cohorts, 1 randomized controlled trial (RCT)] reported AVB without specifying its type; one (cohort) reported different degrees of AVB, 20 (12 cohorts, 8 RCTs) reported complete heart block (CHB) (or AVB requiring temporary pacing), and nine (8 cohorts, 1 RCT) reported the number of PPM inserted due to AVB. The pooled incidence of AVB, CHB (or AVB requiring temporary pacing), and PPM due to AVB was 1.16%, 1.73%, and 0.58%, respectively. Meta-regression analysis revealed that age, gender, diabetes, hypertension, hyperlipidemia, or smoking were not significantly associated with AVB, CHB, or PPM implantation.
CONCLUSION
This study highlights the incidence of AVB and the need for PPM implantation following CABG surgery. The findings emphasize the importance of postoperative monitoring and surveillance to improve patient outcomes.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022377181, identifier PROSPERO CRD42022377181.
PubMed: 37593149
DOI: 10.3389/fcvm.2023.1225833 -
Pediatric Cardiology Dec 2023Pacing indications in children are clearly defined, but whether an epicardial (EPI) or an endocardial (ENDO) pacemaker performs better remains to be elucidated. This... (Meta-Analysis)
Meta-Analysis Review
Pacing indications in children are clearly defined, but whether an epicardial (EPI) or an endocardial (ENDO) pacemaker performs better remains to be elucidated. This systematic review and meta-analysis aimed to directly compare the incidence of pacemaker (PM) lead-related complications, mortality, hemothorax and venous occlusion between EPI and ENDO in children with atrioventricular block (AVB) or sinus node dysfunction (SND). Literature search was conducted in MEDLINE (via PubMed), Scopus by ELSEVIER, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and OpenGrey databases until June 25, 2022. Random-effects meta-analyses were performed to assess the pacing method's effect on lead failure, threshold rise, post-implantation infection and battery depletion and secondarily on all-cause mortality, hemothorax and venous occlusion. Several sensitivity analyses were also performed. Of 22 studies initially retrieved, 18 were deemed eligible for systematic review and 15 for meta-analysis. Of 1348 pediatric patients that underwent EPI or ENDO implantation, 542 (40.2%) had a diagnosis of congenital heart disease (CHD). EPI was significantly associated with higher possibility of PM-lead failure [pooled odds ratio (pOR) 3.00, 95% confidence interval (CI) 2.05-4.39; I = 0%]; while possibility for threshold rise, post-implantation infection and battery depletion did not differ between the PM types. Regarding the secondary outcome, the mortality rates between EPI and ENDO did not differ. In sensitivity analyses the results were consistent results between the two PM types. The findings suggest that EPI may be associated with increased PM-lead failure compared to ENDO while threshold rise, infection, battery depletion and mortality rates did not differ.
Topics: Child; Humans; Atrioventricular Block; Sick Sinus Syndrome; Cardiac Pacing, Artificial; Hemothorax; Treatment Outcome; Pacemaker, Artificial; Postoperative Complications; Vascular Diseases
PubMed: 37480376
DOI: 10.1007/s00246-023-03213-x -
Frontiers in Medicine 2022To evaluate the evidence regarding the prevalence and risk of bundle branch block (BBB), atrioventricular block (AVB) and pacemaker implantation (PMI) in patients with...
OBJECTIVE
To evaluate the evidence regarding the prevalence and risk of bundle branch block (BBB), atrioventricular block (AVB) and pacemaker implantation (PMI) in patients with spondyloarthritis compared to a control group without spondyloarthritis.
METHODS
A systematic review of the literature was performed using Pubmed (Medline), EMBASE (Elsevier) and Cochrane Library (Wiley) databases until December 2021. The prevalence and risk for AVB, BBB and PMI were analyzed. Cohort, case control and cross-sectional studies in patients ≥18 years meeting the classification criteria for spondyloarthritis were included. The Odds ratio (OR), risk ratio (RR), or Hazard ratio (HR) and prevalence difference were considered as outcomes. Data was synthesized in a previously defined extraction form which included a risk of bias assessment using the Newcastle-Ottawa Scale.
RESULTS
In total, eight out of 374 studies were included. None of the studies provided results regarding the risk of low grade AVB and BBB in SpA patients. Only indirect results comparing prevalences from low to medium quality studies were found. According to population based registries, the sex and age adjusted HR of AVB was 2.3 (95% CI 1.6-3.3) in ankylosing spondylitis, 2.9 (95% CI 1.8-4.7) in undifferentiated spondyloarthritis and 1.5 (95% CI 1.1 a 1.9) in psoriatic arthritis. The absolute risk for AVB was 0.4% (moderate to high; 95% CI 0.34%-0.69%) for AS, 0.33% (moderate to high; 95% CI 0.21%-0.53%) for uSpA and 0.34% (moderate to high; 95% CI 0.26%-0.45%) for PsA.The RR for PMI in AS patients was 1.3 (95% CI 1.16-1.46) for groups aged between 65 and 69 years, 1.33 (95% CI 1.22-1.44) for 70-75 years, 1.24 (95% CI 1.55-1.33) for 75-79 years and 1.11 (95% CI 1.06-1.17) for groups older than 80 years. The absolute risk for PMI in AS patients was 0.7% (moderate to high risk; 95% CI 0.6-0.8%) for groups aged between 65-69, 1.44% (high risk; 95% CI 1.33-1.6%) for 70-75 years, 2.09% (high risk; 95% CI 2.0-2.2%) for 75-79 years and 4.15% (high risk; 95% CI 4.0-4.3%) for groups older than 80 years.
CONCLUSIONS
Very few cases of low grade AVB and BBB were observed in observational studies. No study evaluated association measures for low grade AVB and BBB but the differences of prevalence were similar in SpA and control groups even though studies lacked the power to detect statistical differences. According to population based registries there was an approximately two fold-increased risk of high grade AVB in SpA patients. RR for PMI was higher in younger age groups.
PubMed: 35402464
DOI: 10.3389/fmed.2022.851483 -
Health Technology Assessment... Aug 2015Bradycardia [resting heart rate below 60 beats per minute (b.p.m.)] can be caused by conditions affecting the natural pacemakers of the heart, such as sick sinus... (Review)
Review
BACKGROUND
Bradycardia [resting heart rate below 60 beats per minute (b.p.m.)] can be caused by conditions affecting the natural pacemakers of the heart, such as sick sinus syndrome (SSS) and atrioventricular (AV) blocks. People suffering from bradycardia may present with palpitations, exercise intolerance and fainting. The only effective treatment for patients suffering from symptomatic bradycardia is implantation of a permanent pacemaker.
OBJECTIVE
To appraise the clinical effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber atrial pacemakers for treating symptomatic bradycardia in people with SSS and no evidence of AV block.
DATA SOURCES
All databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Health Technology Assessment database, NHS Economic Evaluations Database) were searched from inception to June 2014.
METHODS
A systematic review of the clinical and economic literature was carried out in accordance with the general principles published by the Centre for Reviews and Dissemination. Randomised controlled trials (RCTs) evaluating dual-chamber and single-chamber atrial pacemakers and economic evaluations were included. Pairwise meta-analysis was carried out. A de novo economic model was developed.
RESULTS
Of 493 references, six RCTs were included in the review. The results were predominantly influenced by the largest trial DANPACE. Dual-chamber pacing was associated with a statistically significant reduction in reoperation [odds ratio (OR) 0.48, 95% confidence interval (CI) 0.36 to 0.63] compared with single-chamber atrial pacing. The difference is primarily because of the development of AV block requiring upgrade to a dual-chamber device. The risk of paroxysmal atrial fibrillation was also reduced with dual-chamber pacing compared with single-chamber atrial pacing (OR 0.75, 95% CI 0.59 to 0.96). No statistically significant difference was found between the pacing modes for mortality, heart failure, stroke, chronic atrial fibrillation or quality of life. However, the risk of developing heart failure may vary with age and device. The de novo economic model shows that dual-chamber pacemakers are more expensive and more effective than single-chamber atrial devices, resulting in a base-case incremental cost-effectiveness ratio (ICER) of £6506. The ICER remains below £20,000 in probabilistic sensitivity analysis, structural sensitivity analysis and most scenario analyses and one-way sensitivity analyses. The risk of heart failure may have an impact on the decision to use dual-chamber or single-chamber atrial pacemakers. Results from an analysis based on age (> 75 years or ≤ 75 years) and risk of heart failure indicate that dual-chamber pacemakers dominate single-chamber atrial pacemakers (i.e. are less expensive and more effective) in older patients, whereas dual-chamber pacemakers are dominated by (i.e. more expensive and less effective) single-chamber atrial pacemakers in younger patients. However, these results are based on a subgroup analysis and should be treated with caution.
CONCLUSIONS
In patients with SSS without evidence of impaired AV conduction, dual-chamber pacemakers appear to be cost-effective compared with single-chamber atrial pacemakers. The risk of developing a complete AV block and the lack of tools to identify patients at high risk of developing the condition argue for the implantation of a dual-chamber pacemaker programmed to minimise unnecessary ventricular pacing. However, considerations have to be made around the risk of developing heart failure, which may depend on age and device.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42013006708.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Atrial Fibrillation; Bradycardia; Cost-Benefit Analysis; Heart Failure; Humans; Markov Chains; Models, Econometric; Pacemaker, Artificial; Quality of Life; Randomized Controlled Trials as Topic; Sick Sinus Syndrome
PubMed: 26293406
DOI: 10.3310/hta19650 -
Frontiers in Cardiovascular Medicine 2022Although right ventricular pacing (RVP) is recommended by most of the guidelines for atrioventricular block, it can cause electrical and mechanical desynchrony, impair...
A systematic review and Bayesian network meta-analysis comparing left bundle branch pacing, his bundle branch pacing, and right ventricular pacing for atrioventricular block.
BACKGROUND
Although right ventricular pacing (RVP) is recommended by most of the guidelines for atrioventricular block, it can cause electrical and mechanical desynchrony, impair left ventricular function, and increase the risk of atrial fibrillation. Recently, the His-Purkinje system pacing, including His bundle pacing (HBP) and left bundle branch pacing (LBBP), has emerged as a physiological pacing modality. However, few studies have compared their efficacy and safety in atrioventricular block (AVB).
METHODS AND RESULTS
The PubMed, Web of Science, Cochrane Library, and ScienceDirect databases were searched for observational studies and randomized trials of patients with atrioventricular block requiring permanent pacing, from database inception until 10 January 2022. The primary outcomes were complications and heart failure hospitalization. The secondary outcomes included changes in left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDD), pacing parameters, procedure duration, and success rate. After extracting the data at baseline and the longest follow-up duration available, a pairwise meta-analysis and a Bayesian random-effects network meta-analysis were performed. Odds ratios (ORs) with 95% confidence intervals (CIs) or 95% credible intervals (CrIs) were calculated for dichotomous outcomes, whereas mean differences (MDs) with 95% CIs or 95% CrIs were calculated for continuous outcomes. Seven studies and 1,069 patients were included. Overall, 43.4% underwent LBBP, 33.5% HBP, and 23.1% RVP. Compared with RVP, LBBP and HBP were associated with a shorter paced QRS duration and a more preserved LVEF. HBP significantly increased the pacing threshold and reduced the R-wave amplitude. There was no difference in the risk of complications or the implant success rate. The pacing threshold remained stable during follow-up for the three pacing modalities. The pacing impedance was significantly reduced in HBP, while a numerical but non-significant pacing impedance decrease was observed in both LBBP and RVP. LBBP was associated with an increased R-wave amplitude during follow-up.
CONCLUSION
In this systematic review and network meta-analysis, HBP and LBBP were superior to RVP in paced QRS duration and preservation of LVEF for patients with atrioventricular block. LBBP was associated with a lower pacing threshold and a greater R-wave amplitude than HBP. However, the stability of the pacing output of LBBP may be a concern. Further investigation of the long-term efficacy in left ventricular function and the risk of heart failure hospitalization is needed.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=315046], identifier [CRD42022315046].
PubMed: 36386361
DOI: 10.3389/fcvm.2022.939850 -
Health Technology Assessment... Nov 2005To estimate the effectiveness and cost-effectiveness of dual-chamber pacemakers versus single-chamber atrial or single-chamber ventricular pacemakers in the treatment of... (Review)
Review
The effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation.
OBJECTIVES
To estimate the effectiveness and cost-effectiveness of dual-chamber pacemakers versus single-chamber atrial or single-chamber ventricular pacemakers in the treatment of bradycardia due to sick sinus syndrome (SSS) or atrioventricular block (AVB).
DATA SOURCES
Electronic databases and relevant Internet sites. Contact with device manufacturers and experts in the field.
REVIEW METHODS
A systematic review was carried out of randomised controlled trials (RCTs). The quality of selected studies was appraised using standard frameworks. Meta-analyses, using random effects models, were carried out where appropriate. Limited exploration of heterogeneity was possible. Critical appraisal of economic evaluations was carried out using two frameworks. A decision-analytic model was developed using a Markov approach, to estimate the cost-effectiveness of dual-chamber versus ventricular or atrial pacing over 5 and 10 years as cost per quality-adjusted life-year (QALY). Uncertainty was explored using one-way and probabilistic sensitivity analyses.
RESULTS
The searches retrieved a systematic review of effectiveness and cost-effectiveness published in 2002, four parallel group RCTs and 28 cross-over trials. Dual-chamber pacing was associated with lower rates of atrial fibrillation, particularly in SSS, than ventricular pacing, and prevents pacemaker syndrome. Higher rates of atrial fibrillation were seen with dual-chamber pacing than with atrial pacing. Complications occurred more frequently in dual-chamber pacemaker insertion. The cost of a dual-chamber system, over 5 years, including cost of complications and subsequent clinical events in the population, was estimated to be around 7400 pounds. The overall cost difference between single and dual systems is not large over this period: around 700 pounds more for dual-chamber devices. The cost-effectiveness of dual-chamber compared with ventricular pacing was estimated to be around 8500 pounds per QALY in AVB and 9500 pounds in SSS over 5 years, and around 5500 pounds per QALY in both populations over 10 years. Under more conservative assumptions, the cost-effectiveness of dual-chamber pacing is around 30,000 pounds per QALY. The probabilistic sensitivity analysis showed that, under the base-case assumptions, dual-chamber pacing is likely to be considered cost-effective at levels of willingness to pay that are generally considered acceptable by policy makers. In contrast, atrial pacing may be cost-effective compared with dual-chamber pacing.
CONCLUSIONS
Dual-chamber pacing results in small but potentially important benefits in populations with SSS and/or AVB compared with ventricular pacemakers. Pacemaker syndrome is a crucial factor in determining cost-effectiveness; however, difficulties in standardising diagnosis and measurement of severity make it difficult to quantify. Dual-chamber pacing is in common usage in the UK. Recipients are more likely to be younger. Insufficient evidence is currently available to inform policy on specific groups who may benefit most from pacing with dual-chamber devices. Further important research is underway. Outstanding research priorities include the economic evaluation of UKPACE studies of the classification, diagnosis and utility associated with pacemaker syndrome and evidence on the effectiveness of pacemakers in children.
Topics: Age Factors; Bradycardia; Cost-Benefit Analysis; Decision Support Techniques; Heart Block; Humans; Markov Chains; Pacemaker, Artificial; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Sick Sinus Syndrome
PubMed: 16266560
DOI: 10.3310/hta9430 -
Acta Obstetricia Et Gynecologica... Jul 2018The aim of this study was to explore the effect of maternal fluorinated steroid therapy on fetuses affected by second-degree immune-mediated congenital atrioventricular... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
The aim of this study was to explore the effect of maternal fluorinated steroid therapy on fetuses affected by second-degree immune-mediated congenital atrioventricular block.
MATERIAL AND METHODS
Studies reporting the outcome of fetuses with second-degree immune-mediated congenital atrioventricular block diagnosed on prenatal ultrasound and treated with fluorinated steroids compared with those not treated were included. The primary outcome was the overall progression of congenital atrioventricular block to either continuous or intermittent third-degree congenital atrioventricular block at birth. Meta-analyses of proportions using random effect model and meta-analyses using individual data random-effect logistic regression were used.
RESULTS
Five studies (71 fetuses) were included. The progression rate to congenital atrioventricular block at birth in fetuses treated with steroids was 52% (95% confidence interval 23-79) and in fetuses not receiving steroid therapy 73% (95% confidence interval 39-94). The overall rate of regression to either first-degree, intermittent first-/second-degree or sinus rhythm in fetuses treated with steroids was 25% (95% confidence interval 12-41) compared with 23% (95% confidence interval 8-44) in those not treated. Stable (constant) second-degree congenital atrioventricular block at birth was present in 11% (95% confidence interval 2-27) of cases in the treated group and in none of the newborns in the untreated group, whereas complete regression to sinus rhythm occurred in 21% (95% confidence interval 6-42) of fetuses receiving steroids vs. 9% (95% confidence interval 0-41) of those untreated.
CONCLUSIONS
There is still limited evidence as to the benefit of administered fluorinated steroids in terms of affecting outcome of fetuses with second-degree immune-mediated congenital atrioventricular block.
Topics: Atrioventricular Block; Disease Progression; Female; Fetal Diseases; Glucocorticoids; Humans; Pregnancy; Ultrasonography, Prenatal
PubMed: 29512819
DOI: 10.1111/aogs.13338 -
CJC Open Feb 2024High-grade atrioventricular block (HGAVB) is common after transcatheter aortic valve implantation (TAVI), often necessitating permanent pacemaker (PPM) implantation.... (Review)
Review
BACKGROUND
High-grade atrioventricular block (HGAVB) is common after transcatheter aortic valve implantation (TAVI), often necessitating permanent pacemaker (PPM) implantation. Delayed HGAVB has varying definitions but typically refers to onset 48 hours after TAVI or following discharge and may cause syncope and sudden cardiac death. This review estimates the incidence of delayed HGAVB and identifies limitations of current literature.
METHODS
A systematic review was performed of the following online databases: Medline, Cochrane, Web of Science, and Scopus. Studies that labelled the outcome of "delayed" or "late" atrioventricular block after TAVI were included; patients with previous PPM or aortic valve surgery were excluded. Initial search yielded 775 studies, which, after screening, was narrowed to 19 studies.
RESULTS
Nineteen studies with 14,898 patients were included. Mean age was 81.7 years, and 46.3% were male. Mean Society of Thoracic Surgeons (STS) score was 5.6%, and 31.3% of patients had known atrial fibrillation. The most common access site was transfemoral (84.8%), whereas balloon-expandable valves were used in 62.1%, self-expanding valves in 34.0%, and mechanically expanding valves in 3.9% of cases. The incidence of delayed HGAVB ranged from 1.7% to 14.6%, with significant methodologic heterogeneity noted among the included studies.
CONCLUSIONS
Delayed HGAVB is a common and potentially serious complication of TAVI, with similar risk factors to acute HGAVB. With a move toward an early discharge strategy post-TAVI, further prospective study of delayed HGAVB is warranted to improve understanding of predisposing factors, incidence, timing, and implications.
PubMed: 38585677
DOI: 10.1016/j.cjco.2023.10.003 -
Heart (British Cardiac Society) May 2016First-degree atrioventricular block is frequently encountered in clinical practice and is generally considered a benign process. However, there is emerging evidence that... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
First-degree atrioventricular block is frequently encountered in clinical practice and is generally considered a benign process. However, there is emerging evidence that prolonged PR interval may be associated with adverse outcomes. This study aims to determine if prolonged PR interval is associated with adverse cardiovascular outcomes and mortality.
METHODS
We searched MEDLINE and EMBASE for studies that evaluated clinical outcomes associated with prolonged and normal PR intervals. Relevant studies were pooled using random effects meta-analysis for risk of mortality, cardiovascular mortality, heart failure, coronary heart disease, atrial fibrillation and stroke or transient ischaemic attack (TIA). Sensitivity analyses were performed considering the population type and the use of adjustments.
RESULTS
Our search yielded 14 studies that were undertaken between 1972 and 2011 with 400,750 participants. Among the studies that adjusted for potential confounders, the pooled results suggest an increased risk of mortality with prolonged PR interval risk ratio (RR) 1.24 95% CI 1.02 to 1.51, five studies. Prolonged PR interval was associated with significant risk of heart failure or left ventricular dysfunction (RR 1.39 95% CI 1.18 to 1.65, three studies) and atrial fibrillation (RR 1.45 95% CI 1.23 to 1.71, eight studies) but not cardiovascular mortality, coronary heart disease or myocardial infarction or stroke or TIA. Similar observations were recorded when limited to studies of first-degree heart block.
CONCLUSIONS
Data from observational studies suggests a possible association between prolonged PR interval and significant increases in atrial fibrillation, heart failure and mortality. Future prospective studies are needed to confirm the relationships reported, consider possible mechanisms and define the optimal monitoring strategy for such patients.
Topics: Adult; Aged; Aged, 80 and over; Atrioventricular Block; Brugada Syndrome; Cardiac Conduction System Disease; Female; Humans; Male; Middle Aged; Observational Studies as Topic; Prognosis
PubMed: 26879241
DOI: 10.1136/heartjnl-2015-308956