The cardioprotective effects of adenosine-induced cardioplegic arrest versus saline in aortic valve replacement patients: A randomized controlled trial.

BACKGROUND AND AIMS: Adenosine is a widely used potent cardioprotective drug, but the effect of an adenosine bolus in initial cardioplegia on cardioprotection in aortic valve replacement (AVR) patients has not been demonstrated. The aim of this double-blind randomized clinical trial was to compare intra-aortic adenosine bolus with saline on the postoperative myocardial function in patients undergoing AVR. METHODS: Aortic valve stenosis patients scheduled for elective or urgent AVR surgery were randomized to receive either a 20 mg (4 mL) single dose of adenosine or a saline into the ascending aorta during the first cardioplegia infusion. The primary outcome was cardiac index (CI (L/min/m2) at four timepoints (before incision, after weaning from cardiopulmonary bypass (CPB), at 7 p.m. on the operation day, and at 6 a.m. the next morning). Secondary outcomes included left ventricular stroke work index, right ventricular stroke work index, and myocardial biomarkers at the same timepoints. RESULTS: Between November 2015 and March 2018, 45 patients were recruited, 23 in the adenosine group and 22 in the placebo group. The last follow-up date was 17 March 2018. There were no statistically significant differences in CI (mean differences with 95% confidence interval (95% CI): 0.09 L/min/m2 at baseline (-0.20 to 0.38), -1.39 L/min/m2 (-3.47 to 0.70) at post-CPB, -0.39 L/min/m2 (-0.78 to 0.004) at 7 p.m., and -0.32 L/min/m2 (-0.68 to 0.05) at 6 a.m., (p = 0.066)), right ventricular stroke work index, (p = 0.24), or cardiac biomarkers between the groups. Left ventricular stroke work index was lower in the adenosine group (-3.66 gm/m2 (-11.13 to 3.81) at baseline, -17.42 gm/m2 (-37.81 to 2.98) at post-CPB, -3.36 gm/m2 (-11.10 to 4.38) at 7 p.m., and -3.77 gm/m2 (-10.19 to 2.66) at 6 a.m. (p = 0.021)). CONCLUSIONS: There were no differences between 20 mg adenosine bolus and saline in the first cardioplegia infusion in CI improvement in AVR surgery for aortic valve stenosis.EudraCT number: 2014-001382-26.

High-dose adenosine versus saline-induced cardioplegic arrest in coronary artery bypass grafting: A randomized double-blind clinical feasibility trial.

BACKGROUND AND OBJECTIVE: In this clinical trial, we evaluated if a short-acting nucleoside, adenosine, as a high-dose bolus injection with blood cardioplegia induces faster arrest and provides better myocardial performance in patients after bypass surgery for coronary artery disease. METHODS: Forty-three patients scheduled for elective or urgent coronary artery bypass grafting were prospectively recruited in two-arm 1:1 randomized parallel groups to either receive 20 mg of adenosine (in 21 patients) or saline (in 22 patients) into the aortic root during the first potassium-enriched blood cardioplegia infusion. The main outcomes of the study were ventricular myocardial performance measured with cardiac index, right ventricular stroke work index, and left ventricular stroke work index at predefined time points and time to asystole after a single bolus injection of adenosine. Conventional myocardial biomarkers were compared between the two groups at predefined time points as secondary endpoints. Electrocardiographic data and other ad hoc clinical outcomes were compared between the groups. RESULTS: Compared with saline, adenosine reduced the time to asystole (68 (95% confidence interval (95% CI) = 37-100) versus 150 (95% CI = 100-210) seconds, p = 0.005). With myocardial performance, the results were inconclusive, since right ventricular stroke work index recovered better in the adenosine group (p = 0.008), but there were no significant overall differences in cardiac index and left ventricular stroke work index between the groups. Only the post-cardiopulmonary bypass cardiac index was better in the adenosine group (2.3 (95% CI = 2.2-2.5) versus 2.1 (95% CI = 1.9-2.2) L/min/m2, p = 0.016). There were no significant differences between the groups in cardiac biomarker values. CONCLUSIONS: A high dose adenosine bolus at the beginning of the first cardioplegia infusion resulted in significantly faster asystole in coronary artery bypass grafting patients but enhanced only partially the ventricular performance.EudraCT number: 2014-001382-26. https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-001382-26/FI.

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.

A randomized trial comparing inspiratory training and positive pressure training in immediate lung recovery after minor pleuro-pulmonary surgery.

BACKGROUND: Two respiratory physiotherapy modalities were compared in a randomized controlled trial on patients undergoing minor pleuro-pulmonary surgery. METHODS: Forty-five patients were randomly allocated into positive expiratory pressure (PEP) therapy (n=23) and inspiratory muscle training (IMT) groups (n=22). Individualized group specific physiotherapeutic guidance was administered preoperatively, and once a day postoperatively. Patients also performed independent exercises and kept a logbook. Pain was assessed on a numerical reference scale (NRS). Volumetric pulmonary function values and walking distance were recorded preoperatively, and on first (POD1) and second postoperative days (POD2). Pre- and postoperative values were compared using two-way repeated measures analysis of variance. RESULTS: Patient characteristics and pleuro-pulmonary interventions were similar between the groups. Thoracotomy was performed in 14/45 and video assisted surgery (VATS) in 31/45 of cases. Preoperative volumetric pulmonary functions were normal or slightly decreased in 29/45, and fell significantly (P<0.001) on the first postoperative day (POD1) and improved but remained significantly lower on the second postoperative day. The recovery of mean FEV1, FIV1 and FIVC values was greater in the IMT than in the PEP group between POD1 and POD2, but without significant difference. The corresponding relative to preoperative values were higher in the IMT group, with a significant difference in FEV1 (P=0.045). Also relative PEF and FIV1 values seemed to be slightly higher in the IMT compared to the PEP group, but not significantly. Average NRS values for pain were lower in the IMT group (P=0.010) but only on POD1. Air leak was noted in 4/45 patients, two in each group, on POD1, and two in PEP groups and one in IMT group on POD2. Mean measured walking distances between groups did not differ. Mean hospital stay was 4 days in the PEP group and 3 days in the IMT group. There was no hospital mortality. CONCLUSIONS: Pulmonary function values decreased significantly after minor lung resections, supporting rehabilitative respiratory physiotherapy to avoid postoperative pulmonary complications (PPCs). Both PEP and IMT training were well tolerated and equally efficient when comparing spirometry values at three time points. IMT appeared advantageous regarding relative FEV1 recovery and immediate postoperative pain.

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.

Risk of symptomatic venous thromboembolism after abdominal aortic aneurysm repair in long-term follow-up of 1021 consecutive patients.

OBJECTIVE: Venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism (PE), is an infrequent but consequential and potentially preventable complication after major surgical procedures. The aim of the study was to describe the long-term occurrence of symptomatic VTE in patients undergoing abdominal aortic aneurysm (AAA) repair and to ascertain patient-specific risk factors as well as to compare the rate with that of a reference population. METHODS: The study included all patients who had undergone endovascular or open AAA repair, both elective and urgent/acute cases, at the Tampere University Hospital (Finland) between February 2001 and December 2016; 59% of patients had undergone endovascular and 41% open repair, and 23% of all cases had required urgent or emergency treatment. Information about later treatment episodes for symptomatic VTE and survival data were obtained from national registries. The reference population was obtained from national registries with a random sample of inhabitants matched for age, sex, and location of residence with a 4:1 ratio and was analyzed similarly. RESULTS: Altogether, 1021 patients and 4065 controls were included (88% male; median age, 74 years in both groups). The high-risk period for VTE lasted for approximately 3 months, and during that time, its occurrence was highest in patients with coronary disease (2.5%), after open repair (2.4%), and in an urgent or emergency setting (2.6%), whereas the rate was low after endovascular aneurysm repair (1.0%). The cumulative incidence of VTE at 3 months, 1 year, 3 years, and 5 years was 1.1%, 1.6%, 2.7%, and 4.5% in patients and 0.1%, 0.3%, 1.0%, and 1.8% in the reference population, respectively (P < .001 each). Most VTE events were PE in the patient group. The 5-year mortality rates were 37.9% in patients and 23.8% in controls (P < .001). CONCLUSIONS: The incidence of symptomatic VTE, particularly PE, after AAA repair is significant, in both short-term and long-term follow-up. Open surgery, acute setting, and concomitant coronary disease appear to increase the risk.

Pleural infection-an indicator of morbidity and increased burden on health care.

OBJECTIVES: Patients with pleural infections frequently have several comorbidities and inferior long-term survival. We hypothesized that these patients represent a vulnerable cohort with high rates of hospitalization and frequent use of healthcare services. This study aims to ascertain the need for and causes of treatment episodes after pleural infections during long-term follow-up. METHODS: Patients treated for pleural infections at Tampere University Hospital between January 2000 and December 2008 (n = 191, 81% males, median age 58 years) were included and compared to a demographically matched population-based random sample of 1910 controls. Seventy percent of the pleural infections were caused by pneumonias and 80% of the patients underwent surgery. Information regarding later in-hospital periods and emergency room and out-patient clinic visits, as well as survival data, was obtained from national registries and compared between patients and controls. RESULTS: Patients treated for pleural infections had significantly higher rates of hospitalizations (8.19 vs 2.19), in-hospital days (88.5 vs 26.6), emergency room admissions (3.18 vs 1.45), out-patient clinic visits (41.1 vs 11.8) and procedures performed (1.26 vs 0.55) per 100 patient-months when compared to controls during 5-year follow-up, in addition to having increased mortality (30% vs 11%), P-value <0.00001 each. Particularly, episodes due to respiratory and digestive diseases, malignancies and mental disorders were more frequent. The patients' comorbidities, such as alcoholism or chronic pulmonary disease, were associated with more frequent use of healthcare services. CONCLUSIONS: Patients treated for pleural infections have high rates of hospitalizations, emergency room admissions and out-patient clinic visits during follow-up.

Early postoperative statin administration does not affect the rate of atrial fibrillation after cardiac surgery.

OBJECTIVES: Postoperative atrial fibrillation is the most frequent complication after cardiac surgery, and the use of statins in preventing them is being extensively studied. The aim of this study was to investigate whether a pause in the administration of statins affects the occurrence of atrial fibrillation after cardiac surgery in a prospective randomized and controlled setting. METHODS: A total of 301 patients without chronic atrial fibrillation with prior statin medication scheduled for elective or urgent cardiac surgery involving the coronary arteries and/or heart valves were prospectively recruited and randomized for statin re-initiation on either the first (immediate statin group) or the fifth (late statin group) postoperative day, using the original medication and dosage. The immediate statin group comprised 146 patients and the late statin group 155 patients. Except for a somewhat higher rate of males (85% vs 73%, P = 0.016) in the immediate statin group, the baseline characteristics and the distribution of procedures performed within the groups were comparable. The occurrence of postoperative atrial fibrillation and the clinical course of the patients were compared between the groups. RESULTS: The incidence of atrial fibrillation was 46% and the median delay after surgery before the onset of atrial fibrillation was 3 days in both groups (P = NS). No differences were observed in the frequency of the arrhythmia in any subgroup analyses or in other major complications or clinical parameters. No adverse effects related to early statin administration were detected. CONCLUSIONS: Early re-initiation of statins does not appear to affect the occurrence of postoperative atrial fibrillation. CLINICAL TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT)-2016-001655-44.

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.

Incidence, presentation and risk factors of late postoperative pericardial effusions requiring invasive treatment after cardiac surgery.

OBJECTIVES: Occurrence and risk factors of late postoperative pericardial effusions requiring invasive treatment, i.e. pretamponade and tamponade, following cardiac surgery are incompletely described in current literature. The purpose of this study was to define the incidence and presentation of late pretamponade and tamponade as well as to outline significant predisposing factors. METHODS: A cohort of 1356 consecutive cardiac surgery patients treated in a tertiary academic centre between January 2013 and December 2014 was followed up for 6 months after surgery. Pericardial effusion was considered late when presenting after the 7th postoperative day. The incidence, timing and risk factors, as well as symptoms and clinical findings associated with late pretamponade and tamponade in patients surviving at least 7 days was analysed. RESULTS: Of 1308 patients included in the analysis, 81 (6.2%) underwent invasive treatment for late postoperative pericardial effusion, 27 (2.1%) for pretamponade and 54 (4.1%) for tamponade, respectively, with a median delay of 11 (range 8-87) days after the primary operation. Haemodynamic instability was present in 34.6%, signs of cardiac chamber compression in 54.3% and subjective symptoms, mostly dyspnoea, in 56.8% of patients, respectively. Treated patients were younger, had lower EuroSCORE-II rating, less coronary disease, better cardiac function, higher preoperative haemoglobin values and had mostly undergone elective surgery involving cardiac valves. In multivariable analysis, independent risk factors were single valve surgery and high preoperative haemoglobin level, whereas age 60-69 years was associated with lower risk. CONCLUSIONS: Younger, generally healthier patients undergoing valve surgery are at greatest risk for developing late tamponade or pretamponade.

Effect of family history on the risk of varicose veins is affected by differential misclassification.

OBJECTIVE: We assessed differential misclassification in self-reported family history of varicose veins by comparing consistency of subject's own varicose vein status and the consistency of information on varicose veins in family members. STUDY DESIGN AND SETTING: A population-based cohort study of 4,903 middle-aged residents of the city of Tampere, Finland. A questionnaire was used at entry and at the end of the 5-year follow-up. RESULTS: The estimated prevalence of positive family history of varicose veins varied depending on subject's own varicose veins from odds ratio (OR) 0.14 (95% confidence interval [CI]=0.01-0.58), in those with varicose veins reported in the first but not the second survey to OR 6.0 (95% CI=2.0-47.8), in those with varicose veins reported in the second survey but not in the first. The incidence of varicose veins varied from 0.4 (95% CI=0.1-1.4) to 4.1 (95% CI=2.1-7.1) (per 100 person-years) depending how the proband memorized the family history. CONCLUSION: Results on the effect of family history on varicose veins are subject to bias, which reduces the credibility of the reports proposing a strong hereditary component of varicose veins.

Effect of family history on the incidence of varicose veins: a population-based follow-up study in Finland.

In the literature, the estimates of high risk of family history for varicose veins are based on prevalence rates from cross-sectional studies. The purpose of this study was to compare such prevalence rates with incidence rates from our longitudinal follow-up study to find out whether there is a difference due to the methodology. A validated questionnaire was used in 3 middle-aged cohorts (n = 6874) in Tampere, Finland. Positive family history was more common both in men (prevalence odds ratio 6.6; 95% confidence interval, 4.7-9.3) and women (4.9; 95% confidence interval, 4.0-6.0) with varicose veins compared to those without. However, positive family history was linked much less with the incidence of varicose veins than the prevalence of varicose veins in women (incidence odds ratio 1.8; 95% confidence interval, 1.1-2.8) and men 1.4 (95% confidence interval, 0.7-2.6). There is likely to be a hereditary component of varicose veins, but it is substantially less than usually proposed in literature.

Persons with varicose veins have a high subsequent incidence of arterial disease: a population-based study in Tampere, Finland.

The aim of this population research was to find out the risk of arterial disease (defined as angina pectoris, myocardial infarction, peripheral occlusive arterial disease, and cerebrovascular disease) and hypertension in persons with varicose veins. A 5-year follow-up study was conducted in Tampere, Finland. A validated questionnaire was used in 3 middle-aged cohorts (40, 50, and 60 year olds) in a general population of 6,874. In the follow-up study, 71% (n = 4,903) replied. The incidence of arterial disease and hypertension was studied in those with varicose veins and those without at the entry to the study. During the follow-up, new arterial disease occurred significantly more often in individuals with varicose veins. The incidence odds ratio was 2.0 (95% confidence interval, 1.5-2.7; n = 3,032), but the incidence odds ratio of new hypertension was 1.0 (95% confidence interval, 0.8-1.3; n = 2,915). Varicose veins are a risk indicator of arterial disease but not of hypertension. Varicose veins likely do not cause arterial disease, but they may have common causes that, however, are not related with hypertension.

Risk indicators for varicose veins in forty- to sixty-year-olds in the Tampere varicose vein study.

The objectives of the study were to discover the main determinants for the prevalence of varicose veins in a general population, and to assess the possibilities for prevention of this common surgical disease. Varicose veins were evaluated in three defined cohorts of 3284 men and 3590 women aged 40, 50, and 60 years by using a validated questionnaire. The response rate was 75% among men and 86% among women, and varicose veins were determined by self-assessment. Increasing age, female sex, childbirths, standing posture at work, higher weight or height, and positive family history were significantly associated with varicose veins in a univariate analysis. These factors were further taken into a multivariate logistic regression analysis, and female gender (adjusted odds ratio, OR 2.2), increasing age (OR 2.2-2.8), a reported positive family history for varicose veins (OR 4.9), increasing number of births (OR 1.2-2.8), standing posture at work (OR 1.6), and higher weight (OR 1.2) and height (OR 1.4) were found to independent and significant risk indicators of varicose veins. Increasing age, positive family history of varicose veins, and child-births in women were the most important factors in terms of population etiologic fractions. Familial predisposition and pregnancy-related factors bear important associations with varicose veins. Thus prevention of varicose veins appears to be difficult. Varicose veins are nonlethal and, therefore, higher age is related to higher prevalence.