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BACKGROUND: Chronic total occlusions (CTO) are frequent among patients with coronary artery disease. Revascularization with percutaneous coronary intervention (PCI) is safe and feasible in experienced hands. However, randomized data are needed to demonstrate symptomatic as well as prognostic effect of CTO-PCI compared to optimal medical therapy alone.METHODS AND DESIGN: This trial aims to evaluate the effect of CTO PCI in patients with a CTO lesion and target vessel diameter ≥ 2.5 mm, and myocardial ischemia in the relevant territory. First, all patients are subjected to optimal medical therapy (OMT) for at least for 3 months and non-CTO lesions are managed according to guidelines. Subsequently, prior to randomization myocardial ischemia and quality of life (Seattle Questionnaire (SAQ)) is assessed. Patients are divided into two cohorts based on their SAQ score and randomized to either OMT alone or OMT and CTO-PCI. Cohort A is defined as Low- or asymptomatic patients with a quality-of-life score > 60 and/or CCS class < 2, and more than 10 % ischemia in the left ventricle (LV). Cohort B is symptomatic patients with a quality-of-life score < 60 or CCS class angina > 1 and at least ischemia in 5% of the LV. The primary end-point in cohort A is a composite of major adverse cardiac and cerebral events, hospitalization for heart failure and malignant ventricular arrhythmias. The primary endpoint in cohort B is difference in quality of life 6 months after randomization.IMPLICATIONS: This trial is designed to investigate if CTO-PCI improves QoL and MACCE. Both positive and negative outcome of the trial will affect future guidelines and recommendations on how to treat patients with CTO.

BACKGROUND CONTEXT: Both lumbar disc herniation in the general population and lower back pain in the pregnant population are known to be common conditions. The physiological and anatomical of the mother predispose to increased strain of the lumbar disc, while pregnancy may promote caution in physicians contemplating surgical care. PURPOSE: We aimed to report the incidence of lumbar discectomy during pregnancy and 12 months post-partum in Finland between 1999 and 2017. STUDY DESIGN: Retrospective register-based cohort study. PATIENT SAMPLE: Using nationwide data from the Finnish Care Register for Health Care and the Finnish Medical Birth Register, all women aged 15 to 49 years with a lumbar discectomy or pregnancy ending in delivery from 1st January, 1999 to 31st December, 2017 were included. OUTCOME MEASURES: Incidence rates and their 95% confidence intervals were calculated for lumbar discectomy. Incidence rate ratios (IRR) were calculated between the study population and the control population. The effect of smoking on surgery risk was reported using odds ratios. METHODS: A retrospective statistical analysis was performed to identify patients undergoing lumbar discectomy during pregnancy or the first 12 months after delivery. Incidence rates were compared to the age-adjusted values of the age-matched female general population. The effect of smoking on the risk of lumbar discectomy was analysed using age-adjusted odds ratios. RESULTS: In total, 91 discectomies were performed during pregnancy and 508 within 12 months post-partum. The total incidence of lumbar discectomy during pregnancy was 11 operations per 100 000 person-years with an incidence rate ratio (IRR) of 0.2 (95% CI 0.1 to 0.2) when compared to the age-adjusted female general population. Women with active smoking before pregnancy were at a higher risk for lumbar discectomy during pregnancy (OR 2.0, 95% CI 1.2 to 3.2). Caesarean section was more common after lumbar discectomy (22%). No perinatal mortality was observed. During the first year post-partum the rate of lumbar discectomy increased to 47 per 100 000 person-years with an IRR of 0.7 (95% CI 0.6 to 0.8). 90-day reoperation rates were higher than in the general population with an IRR of 1.7 (95% CI 1.1 to 2.7). CONCLUSIONS: Lumbar discectomy during pregnancy is rare, but smoking increases the risk. Lumbar discectomy during pregnancy seems to be safe for the neonate. Post-partum incidences increased towards the end of the first year, but remained below the rates in the general population with a higher risk for short-term reoperation. publishedVersion

Background: The QT interval in the electrocardiogram (ECG) is a fundamental risk measure for arrhythmic adverse cardiac events. However, the QT interval depends on the heart rate and must be corrected accordingly. The present QT correction (QTc) methods are either simple models leading to under- or overcorrection, or impractical in requiring long-term empirical data. In general, there is no consensus on the best QTc method. Objective: We introduce a model-free QTc method—AccuQT—that computes QTc by minimizing the information transfer from R-R to QT intervals. The objective is to establish and validate a QTc method that provides superior stability and reliability without models or empirical data. Methods: We tested AccuQT against the most commonly used QT correction methods by using long-term ECG recordings of more than 200 healthy subjects from PhysioNet and THEW databases. Results: AccuQT overperforms the previously reported correction methods: the proportion of false-positives is reduced from 16% (Bazett) to 3% (AccuQT) for the PhysioNet data. In particular, the QTc variance is significantly reduced and thus the RR-QT stability is increased. Conclusion: AccuQT has significant potential to become the QTc method of choice in clinical studies and drug development. The method can be implemented in any device recording R-R and QT intervals. publishedVersion

Aim: To compare 4D flow magnetic resonance imaging (MRI) and 2D phase contrast (PC) MRI when evaluating bicuspid (BAV) and tricuspid (TAV) aortic valves. Materials and Methods: A total of 83 subjects (35 BAV, 48 TAV) were explored with 4D flow and 2D PC MRI. Systolic peak velocity, peak flow and regurgitation fraction were analysed at two pre-defined aortic levels (aortic root, mid-tubular). Furthermore, the two methods of 4D flow analysis (Heart and Artery) were compared. Results: Correlation between the 2D PC MRI and 4D flow MRI derived parameters ranged from moderate (R=0.58) to high (R=0.90). 4D flow MRI yielded significantly higher peak velocities in the tubular aorta in both groups. Regarding the aortic root, peak velocities were significantly higher in the TAV group with 4D flow MRI, but in the BAV group 4D flow MRI yielded non-significantly lower values. Findings on peak flow differences between the two modalities followed the same pattern as the differences in peak velocities. 4D flow MRI derived regurgitation fraction values were lower in both locations in both groups. Interobserver agreement for different 4D flow MRI acquired parameters varied from poor (ICC=0.07) to excellent (ICC=1.0) in the aortic root, and it was excellent in the tubular aorta (ICC=0.8-1.0). Conclusion: 4D flow MRI seems to be accurate in comparison to 2D PC MRI in normal aortic valves and in BAV with mild to moderate stenosis. However, the varying interobserver reproducibility and impaired accuracy at higher flow velocities should be taken into account in clinical practice when using the 4D flow method. publishedVersion

Background: In patients with some cardiovascular disease conditions, slightly elevated body mass index (BMI) is associated with a lower mortality risk (termed “obesity paradox”). It is uncertain, however, if this obesity paradox exists in patients who have had invasive cardiology procedures. We evaluated the association between BMI and mortality in patients who underwent coronary angiography. Methods: We utilised the KARDIO registry, which comprised data on demographics, prevalent diseases, risk factors, coronary angiographies, and interventions on 42,636 patients. BMI was categorised based on WHO cut-offs or transformed using P-splines. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated for all-cause mortality. Results: During a median follow-up of 4.9 years, 4688 all-cause deaths occurred. BMI was nonlinearly associated with mortality risk: compared to normal weight category (18.5–25 kg/m2), the age-adjusted HRs (95% CIs) for all-cause mortality were 1.90 (1.49, 2.43), 0.96 (0.92, 1.01), 1.04 (0.99, 1.09), 1.08 (0.96, 1.20), and 1.45 (1.22, 1.72) for underweight (40 kg/m2), respectively. The corresponding multivariable adjusted HRs (95% CIs) were 2.00 (1.55, 2.58), 0.92 (0.88, 0.97) 1.01 (0.95, 1.06), 1.10 (0.98, 1.23), and 1.49 (1.26, 1,78), respectively. Conclusions: In patients undergoing coronary angiography, underweight and obesity class III are associated with increased mortality risk, and the lowest mortality was observed in the preobesity class. It appears the obesity paradox may be present in patients who undergo invasive coronary procedures. publishedVersion

Introduction: The electrocardiographic interpretation of end conduction delay (ECD) in the right ventricular branch of the heart has already generated some hypotheses that this right branch is not single, as anatomically demonstrated, and can be divided into distinct terminal branches when we analyze tracings through the vectorcardiogram. Methods: There were 227 electrocardiograms selected, with typical characteristics defined as ECD of patients from the electrocardiography service of the Centro Universitário Saúde ABC, of both sexes, in the age range of 18 to 87 years, with varied ethnicities, weight and height, with cardiovascular risk factors or without them. We performed vectorcardiograms in these patients to observe the behavior of the final portion of electrical conduction. Results: Analyzing the vectorcardiographic tracings of patients who presented ECD in electrocardiogram, we confirmed in the recording by the frontal plane, the presence of ECD but recorded in three distinct regions; 103 patients in the right upper quadrant between -120° and -150°, 45 patients in the right lower quadrant between +170° and -170°, and medial, and 79 patients in the right lower quadrant between +110° and + 140°. Conclusion: Electrical depolarization of the heart in the right ventricle in electrocardiographic tracings apparently records typical alterations that we can diagnose as depolarization of a single bundle; but when we performed vectorcardiograms, we recorded three distinct zones of right ventricular depolarization with delay; i.e., three distinct sectors of right ventricle free wall delay, such as type I (upper), type II (lower) and type III (medial). publishedVersion

Myocardial sleeves around pulmonary veins (PVs) are highly innervated structures with heterogeneous morphological and electrophysiological characteristics. Autonomic nerve dysfunction in the myocardium may be associated with an increased risk of cardiovascular morbidity and mortality. This article studied autonomic neural remodeling in myocardial sleeves around PVs and atrial-PV ostia with immunohistochemical and morphometric methods with clinicopathological correlations. PVs were collected from 37 and atrial-PV ostia from 17 human autopsy hearts. Immunohistochemical analysis was performed using antibodies against tyrosine hydroxylase (TH), choline acetyltransferase (CHAT), and growth-associated protein 43 (GAP43). In the PV cohort, subjects with immediate cardiovascular cause of death had significantly decreased sympathetic nerve density in fibro-fatty tissue vs those with non-cardiovascular cause of death (1624.53 vs 2522.05 µm2/mm2, p=0.038). In the atrial-PV ostia cohort, parasympathetic nerve density in myocardial sleeves was significantly increased in subjects with underlying cardiovascular cause of death (19.48 µm2/mm2) than subjects with underlying non-cardiovascular cause of death with no parasympathetic nerves detected ( p=0.034). Neural growth regionally varied in sympathetic nerves and was present in most of the parasympathetic nerves. Heterogeneous autonomic nerve distribution and growth around PVs and atrial-PV ostia might play a role in cardiovascular morbidity and mortality. No association in nerve density was found with atrial fibrillation.

Background: Cardiac sarcoidosis (CS) predisposes to sudden cardiac death (SCD). Guidelines for implantable cardioverter defibrillators (ICDs) in CS have been issued by the Heart Rhythm Society in 2014 and the American College of Cardiology/American Heart Association/Heart Rhythm Society consortium in 2017. How well they discriminate high from low risk remains unknown. Methods: We analyzed the data of 398 patients with CS detected in Finland from 1988 through 2017. All had clinical cardiac manifestations. Histological diagnosis was myocardial in 193 patients (definite CS) and extracardiac in 205 (probable CS). Patients with and without Class I or IIa ICD indications at presentation were identified, and subsequent occurrences of SCD (fatal or aborted) and sustained ventricular tachycardia were recorded, as were ICD indications emerging first on follow-up. Results: Over a median of 4.8 years, 41 patients (10.3%) had fatal (n=8) or aborted (n=33) SCD, and 98 (24.6%) experienced SCD or sustained ventricular tachycardia as the first event. By the Heart Rhythm Society guideline, Class I or IIa ICD indications were present in 339 patients (85%) and absent in 59 (15%), of whom 264 (78%) and 30 (51%), respectively, received an ICD. Cumulative 5-year incidence of SCD was 10.7% (95% CI, 7.4%–15.4%) in patients with ICD indications versus 4.8% (95% CI, 1.2%–19.1%) in those without (χ 2 =1.834, P =0.176). The corresponding rates of SCD were 13.8% (95% CI, 9.1%–21.0%) versus 6.3% (95% CI, 0.7%–54.0%; χ 2 =0.814, P =0.367) in definite CS and 7.6% (95% CI, 3.8%–15.1%) versus 3.3% (95% CI, 0.5%–22.9%; χ 2 =0.680, P =0.410) in probable CS. In multivariable regression analysis, SCD was predicted by definite histological diagnosis ( P =0.033) but not by Class I or IIa ICD indications ( P =0.210). In patients without ICD indications at presentation, 5-year incidence of SCD, sustained ventricular tachycardia, and emerging Class I or IIa indications was 53% (95% CI, 40%–71%). By the American College of Cardiology/American Heart Association/Heart Rhythm Society guideline, all patients with complete data (n=245) had Class I or IIa indications for ICD implantation. Conclusions: Current ICD guidelines fail to distinguish a truly low-risk group of patients with clinically manifest CS, the 5-year risk of SCD approaching 5% despite absent ICD indications. Further research is needed on prognostic factors, including the role of diagnostic histology. Meanwhile, all patients with CS presenting with clinical cardiac manifestations should be considered for an ICD implantation.

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology. Xiang Zhu is supported by the Stein Fellowship from Stanford University and Institute for Computational and Data Sciences Seed Grant from The Pennsylvania State University. C.D.B. is supported by the NIH (R01-HL133218). Funding for the Global Lipids Genetics Consortium was provided by the NIH (R01-HL127564). This research was conducted using the UK Biobank Resource under application number 24460. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by awards 2I01BX003362-03A1 and 1I01BX004821-01A1. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. We thank Bethany Klunder for administrative support. Study-specific acknowledgments are provided in the supplemental information.

Objectives: The authors aimed to investigate the impact of severe bleeding and use of red blood cell (RBC) transfusion on the development of postoperative stroke after surgical (SAVR) and transcatheter aortic valve replacement (TAVR), taken from the FinnValve registry. Design: Nationwide, retrospective observational study. Setting: Five Finnish university hospitals participated in the registry. Participants: A total of 6,463 patients who underwent SAVR (n = 4,333) or TAVR (n = 2,130). Interventions: Patients who underwent TAVR or SAVR with a bioprosthesis with or without coronary revascularization. Measurements and Main Results: The incidence of postoperative stroke after SAVR was 3.8%. In multivariate analysis, the number of trans-fused RBC units (odds ratio [OR], 1.098; 95% confidence interval [CI], 1.064-1.133) was one of the independent predictors of postoperative stroke. The incidence of stroke increased, along with the severity of perioperative bleeding, according to the European Coronary Artery Bypass Grafting (E-CABG) bleeding grades were as follows: grade 0, 2.2% (reference group); grade 1, 3.4% (adjusted OR, 1.841; 95% CI, 1.105-3.066); grade 2, 5.5% (adjusted OR, 3.282; 95% CI, 1.948-5.529); and grade 3, 14.8% (adjusted OR, 7.103; 95% CI, 3.612-13.966). The inci-dence of postoperative stroke after TAVR was 2.5%. The number of transfused RBC units was an independent predictor of stroke after TAVR (adjusted OR, 1.155; 95% CI, 1.058-1.261). The incidence of postoperative stroke increased, along with the severity of perioperative bleeding, as stratified by the E-CABG bleeding grades: E-CABG grade 0, 1.7%; grade 1, 5.3% (adjusted OR, 1.270; 95% CI, 0.532-3.035); grade 2, 10.0% (adjusted OR, 2.898; 95% CI, 1.101-7.627); and grade 3, 30.0% (adjusted OR, 10.706; 95% CI, 2.389-47.987). Conclusions: Perioperative bleeding requiring RBC transfusion and/or reoperation for intrathoracic bleeding is associated with an increased risk of postoperative stroke after SAVR and TAVR. Patient blood management and meticulous preprocedural planning and operative technique aiming to avoid significant perioperative bleeding may reduce the risk of cerebrovascular complications. (C) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Introduction: There are several potential causes of QRS-axis deviation in the ECG, but there is limited data on the prognostic significance of QRS-axis deviation in ACS patients. Subjects and methods: We evaluated the long-term prognostic significance of acute phase frontal plane QRS-axis deviation and its shift during hospital stay in ACS patients. A total of 1026 patients who met the inclusion criteria were divided into three categories: normal (n = 823), left (n = 166) and right/extreme axis (n = 37). Results: The median survival time was 9.0 years (95% CI 7.9—10.0) in the normal, 3.6 years (95% CI 2.4—4.7) in the left and 1.3 years (95% CI 0.2—2.4) in the right/extreme axis category. Both short and long-term all-cause mortality was lowest in the normal axis category and highest in the right/extreme axis category. Compared to normal axis, both admission phase QRS-axis deviation groups were independently associated with a higher risk of all-cause mortality. When including left ventricular hypertrophy in the ECG, only the right/extreme axis retained its statistical significance (aHR 1.76; 95% CI 1.16—2.66, p = 0.007). Axis shift to another axis category had no effect on mortality. Conclusion: In ACS patients, acute phase QRS-axis deviation was associated with higher risk of all-cause mortality. Among the axis deviation groups, right/extreme QRS-axis deviation was the strongest predictor of mortality in the multivariable analysis. Further studies are required to investigate to what extent this association is caused by pre-existing or by ACS-induced axis deviations. QRS-axis shift during hospital stay had no effect on all-cause mortality. publishedVersion

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases; it is primarily caused by mutations in sarcomeric genes. However, HCM is also associated with mutations in non-sarcomeric proteins and a Finnish founder mutation for HCM in non-sarcomeric protein junctophilin-2 (JPH2) has been identified. This study aimed at assessing the issue of modelling the rare Finnish founder mutation in cardiomyocytes (CMs) differentiated from iPSCs; therefore, presenting the same cardiac abnormalities observed in the patients. To explore the abnormal functions in JPH2-HCM, skin fibroblasts from a Finnish patient with JPH2 p.(Thr161Lys) were reprogrammed into iPSCs and further differentiated into CMs. As a control line, an isogenic counterpart was generated using the CRISPR/Cas9 genome editing method. Finally, iPSC-CMs were evaluated for the morphological and functional characteristics associated with JPH2 mutation. JPH2-hiPSC-CMs displayed key HCM hallmarks (cellular hypertrophy, multi-nucleation, sarcomeric disarray). Moreover, JPH2-hiPSC-CMs exhibit a higher degree of arrhythmia and longer action potential duration associated with slower inactivation of calcium channels. Functional evaluation supported clinical observations, with differences in beating characteristics when compared with isogenic-hiPSC-CMs. Thus, the iPSC-derived, disease-specific cardiomyocytes could serve as a translationally relevant platform to study genetic cardiac diseases. publishedVersion

Brugada syndrome is an inherited cardiac arrhythmia disorder that is mainly associated with mutations of the cardiac voltage-gated sodium channel alpha subunit 5 (SCN5A) gene. The clinical symptoms include ventricular fibrillation and an increased risk of sudden cardiac death. Human-induced pluripotent stem cell (hiPSC) lines were derived from symptomatic and asymptomatic individuals carrying the R1913C mutation in the SCN5A gene. The present work aimed to observe the phenotype-specific differences in hiPSC-derived cardiomyocytes (CMs) obtained from symptomatic and asymptomatic mutation carriers. In this study, CM electrophysiological properties, beating abilities and calcium parameters were measured. Mutant CMs exhibited higher average sodium current densities than healthy CMs, but the differences were not statistically significant. Action potential durations were significantly shorter in CMs from the symptomatic individual, and a spike-and-dome morphology of action potential was exclusively observed in CMs from the symptomatic individual. More arrhythmias occurred in mutant CMs at single cell and cell aggregate levels compared with those observed in wild-type CMs. Moreover, there were no major differences in ionic currents or intracellular calcium dynamics between the CMs of asymptomatic and symptomatic individuals after the administration of adrenaline and flecainide.In conclusion, mutant CMs were more prone to arrhythmia than healthy CMs but did not explain why only one of the mutation carriers was symptomatic.

Brugada syndrome (BrS) is an inherited clinicalelectrocardiographic arrhythmic entity with an autosomal dominant genetic pattern of inheritance or de novo variant. The syndrome has low worldwide prevalence, but is endemic in Southeast Asian countries (Thailand, Philippines and Japan). The BrS is a subtle structural heart disease (SHD), and the diagnosis is only possible when the so-called type 1 Brugada ECG pattern is spontaneously present or induced for example with fever. Repolarization-depolarization disturbances in BrS patients can be caused by genetic mutations, abnormal neural crest cell migration, low expression of connexin-43 gap junction protein, or connexome disturbances. A recent autopsy study revealed increase in biventricular collagen with myocardial fibrosis when compared with control subjects although the main affected cardiac territory is the right ventricular outflow tract (RVOT). In this location, there is abnormally low expression of significant connexin-43 gap junction responsible for the electro-vectorcardiographic manifestations of terminal QRS conduction delay in the right standard precordial leads (V1-V2), high right precordial leads (V1H-V2H), as well as in the unipolar aVR lead (“the forgotten lead”). Based on their location, these leads reflect the electrical activity of the RVOT. publishedVersion

Objectives. Quality of life (QoL) is possibly the most important variable for the patient when subjective results of heart procedures are evaluated. The purpose of this study was to analyze the change in the quality of life 1 year after surgical aortic valve replacement (SAVR). Design. A Finnish single-center prospective cohort intervention study was performed from 2013 to 2018. QoL was assessed with the EQ-5D-3L VAS questionnaire before surgery and 6 and 12 months after surgery. We used univariate analysis to assess the change in the number of people experiencing problems and logistic regression analysis to assess the patients’ characteristics on the change in QoL. Results. At one year follow-up, patients’ quality of life improved in all EQ-5D dimensions. The greatest decreases in patients experiencing problems 12 months after surgery occurred in the dimension “mobility” (–24.1% change in reporting problems, p

In this article, we consider data complexity in the context of calcium transient signal data collected from induced pluripotent stem cell-derived cardiomyocytes. We present a novel way to measure data complexity based on the nearest neighbour searching method. Data complexity here is seen as overlapping and mixed data classes in addition to a relatively great number of data cases. Complexity affects classification results, which were run with nearest neighbour searching, feedforward artificial neural networks and random forests for seven genetic cardiological disease classes and healthy controls. The data are obtained from individuals carrying mutations for genetic cardiac diseases with induced pluripotent stem cell (iPSC) technology and the diseases include hypertrophic cardiomyopathy with two different founder gene mutations, dilated cardiomyopathy, long QT syndrome type 1 and 2, Brugada syndrome, a severe genetic ventricular arrhythmia (CPVT) and healthy controls. The data are from calcium transients from spontaneously beating iPSC-derived cardiomyocytes cultured in a biotechnology laboratory. When the genotype of the iPSC-derived cardiomyocytes is the same as the donor of the tissue sample and based on the characteristics of the calcium transients, it was possible to classify the seven diseases and healthy controls with machine learning. Peak data first detected before actual pre-processing from calcium transient signals corresponded to beats (repeating excitation–contraction coupling) of induced stem cell-derived cardiomyocytes and formed the basis of classification. During pre-processing of the calcium transient signals, we found that such techniques among others as even strong outlier cleaning or class size balancing by generating artificial cases improved only slightly or not at all classification accuracies. Therefore, the current data set was sufficiently complicated for our data complexity study. Random forests produced the best classification accuracies, 68% for all eight classes. publishedVersion

The COVID-19 pandemic caused by the novel coronavirus SARS-CoV-2 continues to have a major impact on health and social systems around the world. The COVID-19 and influenza manifest themselves in a similar way, causing respiratory diseases that can present asymptomatically, as well as from the cold to severe respiratory problems until death. The form of transmission is similar, through contact with droplets or particles of saliva and secretions, which implies preventive actions that involve the same hygiene measures, use of masks and the need to cough using the elbow or disposable tissues. This characterizes a syndemic. It becomes necessary to monitor these diseases so that there are parameters for better decisionmaking on the appropriate clinical management of these respective diseases publishedVersion Non

With over 17 million annual deaths, cardiovascular diseases (CVDs) dominate the cause of death statistics. CVDs can deteriorate the quality of life drastically and even cause sudden death, all the while inducing massive healthcare costs. This work studied state-of-the-art deep learning techniques to predict increased risk of death in CVD patients, building on the electronic health records (EHR) of over 23,000 cardiac patients. Taking into account the usefulness of the prediction for chronic disease patients, a prediction period of six months was selected. Two major transformer models that rely on learning bidirectional dependencies in sequential data, BERT and XLNet, were trained and compared. To our knowledge, the presented work is the first to apply XLNet on EHR data to predict mortality. The patient histories were formulated as time series consisting of varying types of clinical events, thus enabling the model to learn increasingly complex temporal dependencies. BERT and XLNet achieved an average area under the receiver operating characteristic curve (AUC) of 75.5% and 76.0%, respectively. XLNet surpassed BERT in recall by 9.8%, suggesting that it captures more positive cases than BERT, which is the main focus of recent research on EHRs and transformers. publishedVersion

Background: Preoperative esophageal stenting is proposed to have a negative effect on outcomes. The aim was to compare a 5-year survival in patients undergoing esophagectomy for esophageal cancer with and without preoperative esophageal stent in a population-based nationwide cohort from Finland. The secondary outcome was 90-day mortality. Methods: This study included curatively intended esophagectomies for esophageal cancer in Finland between 1999 and 2016, with follow-up until December 31, 2019. Cox proportional hazards models provided hazard ratios (HRs) with 95% confidence intervals (CIs) of overall 5-year and 90-day mortality. Model 1 was adjusted for age, sex, year of the surgery, comorbidities, histology, pathological stage, and neoadjuvant therapy. Model 2 included also albumin level and BMI. Result: Of 1064 patients, a total of 134 patients underwent preoperative stenting and 930 did not. In both adjusted models 1 and 2, higher 5-year mortality was seen in patients with preoperative stent with HRs of 1.29 (95% CI 1.00–1.65) and 1.25 (95% CI 0.97–1.62), respectively, compared to no stenting. The adjusted HR of 90-day mortality was 2.49 (95% CI 1.27–4.87) in model 1 and 2.49 (95% CI 1.25–4.99) in model 2. When including only neoadjuvant-treated patients, those with preoperative stent had a 5-year survival of 39.2% compared to 46.4% without stent (adjusted HR 1.34, 95% CI 1.00–1.80), and a 90-day mortality rate of 8.5% and 2.5% (adjusted HR 3.99, 95% CI 1.51–10.50). Discussion: This nationwide study reports worse 5-year and 90-day outcomes in patients with preoperative esophageal stent. Since residual confounding remains possible, observed difference could be only an association rather than the cause. publishedVersion

AimsThe aim was to validate the performance of a monitoring system consisting of a wrist-worn device and a data management cloud service intended to be used by medical professionals in detecting atrial fibrillation (AF).MethodsThirty adult patients diagnosed with AF alone or AF with concomitant flutter were recruited. Continuous photoplethysmogram (PPG) and intermittent 30 s Lead I electrocardiogram (ECG) recordings were collected over 48 h. The ECG was measured four times a day at prescheduled times, when notified due to irregular rhythm detected by PPG, and when self-initiated based on symptoms. Three-channel Holter ECG was used as the reference.ResultsThe subjects recorded a total of 1,415 h of continuous PPG data and 3.8 h of intermittent ECG data over the study period. The PPG data were analyzed by the system’s algorithm in 5-min segments. The segments containing adequate amounts, at least ~30 s, of adequate quality PPG data for rhythm assessment algorithm, were included. After rejecting 46% of the 5-min segments, the remaining data were compared with annotated Holter ECG yielding AF detection sensitivity and specificity of 95.6 and 99.2%, respectively. The ECG analysis algorithm labeled 10% of the 30-s ECG records as inadequate quality and these were excluded from the analysis. The ECG AF detection sensitivity and specificity were 97.7 and 89.8%, respectively. The usability of the system was found to be good by both the study subjects and the participating cardiologists.ConclusionThe system comprising of a wrist device and a data management service was validated to be suitable for use in patient monitoring and in the detection of AF in an ambulatory setting.Clinical Trial Registration: ClinicalTrials.gov/, NCT05008601.

Summary: Little is known about survival after proximal humerus fracture. In this manuscript, we found the mortality to be high (almost four times higher than in age- and sex-matched controls). While frailty hip fracture has gained attention, we hope our manuscript will shed light on frailty proximal humerus fracture patients. Introduction: Proximal humerus fractures (PHF) are common and occur mostly after the 6th decade of life. While mortality following PHF has been reported previously, mortality data after longer follow-up on a national level is lacking. Methods: We obtained data from the Swedish Hospital Discharge Register (SHDR), on all adult patients (≥ 18 years) with a diagnosis of PHF (S42.2, S42.20, or S42.21) for the period between 2001 and 2016. We used the Swedish Cause of Death Register (SCDR) to investigate mortality in the fracture cohort. We compared the mortality of fracture patients with age- and sex-matched population-based mortality data obtained from Statistics Sweden. Results: A total of 147 692 PHF patients were identified, with a male to female ratio of 1:3. The mean age was 69 years (range, 18 to 111). Most patients were treated non-surgically (n = 126,487, 86%). The crude mortality rate was 2.2% at 1 month, 4.1% at 3 months, 8.5% at 12 months, and 24% at 48 months after sustaining a PHF. Mortality increased with age; however, the standardized mortality rate (SMR) was highest among young patients. SMR was 5.4 in the 18- to 39-year age group, 3.9 in the 40- to 64-year age group, 1.8 in the 65–79-year age group, and 1.2 in the ≥ 80-year-old population. The age-adjusted SMR was 3.9 in the whole adult PHF population. Conclusion: The mortality rate and SMR suggest that PHF patients are heterogeneous. Some older PHF patients may benefit from specialized care (e.g., orthogeriatric), and this should be evaluated in future studies. publishedVersion

Transcatheter (TC) atrial septal defect (ASD) closure has been the mainstay of therapy for secundum-type ASDs for over 20 years. This nationwide cohort evaluated the long-term outcome of transcatheter-closed ASDs. The study enrolled every transcatheter ASD closure performed in Finland from 1999 to 2019. Five age, sex, and municipality-matched controls per ASD patient were gathered from the general population. The median follow-up period was 5.9 years (range 0–20.8). We used the hospital discharge register to gather all hospital visits and diagnoses. Closure complications and echocardiographic changes were collected from the electronic health records. Transcatheter ASD closure was performed in 1000 patients (68.5% females) during the study period. The median (range) age at the time of the procedure was 37.9 (1.8–87.5) years. ASD patients had an increased risk for new-onset atrial fibrillation (RR 2.45, 95% CI: 1.84–3.25), migraine (RR 3.61, 95% CI: 2.54–5.14), ischemic heart disease (RR 1.73, 95% CI: 1.23–2.45), ventricular fibrillation/tachycardia (RR 3.54 (95% CI: 1.48–8.43) and AV conduction disorder (RR 3.60, 95% CI: 1.94–6.70) compared to the control cohort. Stroke risk was not increased (RR 1.36, 95% CI: 0.91–2.03). Adverse events occurred in 6.3% (n = 63) of the patients, including four erosions and ten device embolizations. After TC closure of ASD, patients had a higher risk of new-onset atrial fibrillation and migraine than controls without ASD. As novel findings, we found an increased risk for ischemic heart disease, AV conduction disorders, and ventricular fibrillation/tachycardia.Key messagesEven though patients have an excellent overall prognosis after percutaneous ASD closure, the increased incidence of major comorbidities like atrial fibrillation and heart failure prompts more thorough lifelong follow-up.This study’s novel findings revealed the increased risk for ischemic heart disease, AV conduction disorders, or ventricular tachycardia/fibrillation during the follow-up.Major complications after the closure are rare; erosion is seen in 0.4% of the patients and embolization in 1.0% of the patients. Even though patients have an excellent overall prognosis after percutaneous ASD closure, the increased incidence of major comorbidities like atrial fibrillation and heart failure prompts more thorough lifelong follow-up. This study’s novel findings revealed the increased risk for ischemic heart disease, AV conduction disorders, or ventricular tachycardia/fibrillation during the follow-up. Major complications after the closure are rare; erosion is seen in 0.4% of the patients and embolization in 1.0% of the patients.

Background: In young patients, up to 40% of ischemic strokes remain cryptogenic despite modern-day diagnostic work-up. There are limited data on blood pressure (BP) behavior in these patients. Thus, we aimed to compare ambulatory blood pressure (ABP) profiles between young patients with a recent cryptogenic ischemic stroke (CIS) and stroke-free controls. Patients and Methods: In this substudy of the international multicenter case–control study SECRETO (NCT01934725), 24-hour ambulatory blood pressure monitoring (ABPM) was performed in consecutive 18–49-year-old CIS patients and stroke-free controls. The inclusion criteria were met by 132 patients (median age, 41.9 years; 56.1% males) and 106 controls (41.9 years; 56.6% males). We assessed not only 24-hour, daytime, and nighttime ABP but also hypertension phenotypes and nocturnal dipping status. Results: 24-hour and daytime ABP were higher among controls. After adjusting for relevant confounders, a non-dipping pattern of diastolic blood pressure (DBP) was associated with CIS in the entire sample (odds ratio, 3.85; 95% confidence interval, 1.20–12.42), in participants without antihypertensives (4.86; 1.07–22.02), and in participants without a patent foramen ovale (PFO) (7.37; 1.47–36.81). After excluding patients in the first tertile of the delay between the stroke and ABPM, a non-dipping pattern of DBP was not associated with CIS, but a non-dipping pattern of both systolic BP and DBP was (4.85; 1.37–17.10). In participants with a PFO and in those without hypertension by any definition, no associations between non-dipping patterns of BP and CIS emerged. Conclusions: Non-dipping patterns of BP were associated with CIS in the absence of a PFO but not in the absence of hypertension. This may reflect differing pathophysiology underlying CIS in patients with versus without a PFO. Due to limitations of the study, results regarding absolute ABP levels should be interpreted with caution.Key Messages Nocturnal non-dipping patterns of blood pressure were associated with cryptogenic ischemic stroke except in participants with a patent foramen ovale and in those without hypertension by any definition, which may indicate differing pathophysiology underlying cryptogenic ischemic stroke in patients with and without a patent foramen ovale. It might be reasonable to include ambulatory blood pressure monitoring in the diagnostic work-up for young patients with ischemic stroke to detect not only the absolute ambulatory blood pressure levels but also their blood pressure behavior. publishedVersion

The typical ECG changes in tetralogy of Fallot are right axis deviation, large R waves in the anterior precordial leads and large S waves in the lateral precordial leads. We present a patient with extreme deviation of the frontal QRS axis between −90° and ± 180°. The child underwent open heart surgery twice before one year of age and a third time at nine years of age. The axis change persisted into adulthood. publishedVersion

acceptedVersion

We aimed to investigate a hypothesised association between daily mean temperature and the risk of surgery for acute type A aortic dissection (ATAAD). For the period of 1 January 2005 until 31 December 2019, we collected daily data on mean temperatures and date of 2995 operations for ATAAD at 10 Nordic cities included in the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) collaboration. Using a two-stage time-series approach, we investigated the association between hot and cold temperatures relative to the optimal temperature and the rate of ATAAD repair in the selected cities. The relative risks (RRs) of cold temperatures (≤−5°C) and hot temperatures (≥21°C) compared to optimal temperature were 1.47 (95% CI: 0.72–2.99) and 1.43 (95% CI: 0.67–3.08), respectively. In line with previous studies, we observed increased risk at cold and hot temperatures. However, the observed associations were not statistically significant, thus only providing weak evidence of an association. publishedVersion

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry metaanalysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) R01HL127564 R01HL142711, Wellcome Trust 201543/B/16/Z 202802/Z/16/Z, European Commission HEALTH-F2-2013-601456 608765 786833, TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation NNF15CC0018486, American Diabetes Association 1-19-ICTS-068, Academy of Finland 312062 Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, Finnish innovation fund Sitra (EW) Finska Lakaresallskapet, American Heart Association 15POST24470131 17POST33650016, University of Bristol NIHR Biomedical Research Centre BRC-1215-2001, MRC & WT 217065/Z/19/Z, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_UU_00011, CRUK Integrative Cancer Epidemiology Programme C18281/A19169, Medical Research Council UK (MRC) MC_UU_00011/1, UK National Institute for Health Research Academic Clinical Fellowship, American Heart Association 18CDA34110116, Miguel Servet contract from the ISCIII Spanish Health Institute CP17/00142, European Social Fund (ESF), Westlake Education Foundation, British Heart Foundation FS/14/66/3129 Z01HG200362 R01HL142302 R01HL105756

Background Patients with severe aortic stenosis and left ventricular systolic dysfunction have a poor prognosis, and this may result in inferior survival also after aortic valve replacement. The outcomes of transcatheter and surgical aortic valve replacement were investigated in this comparative analysis. Methods The retrospective nationwide FinnValve registry included data on patients who underwent transcatheter or surgical aortic valve replacement with a bioprosthesis for severe aortic stenosis. Propensity score matching was performed to adjust the outcomes for baseline covariates of patients with reduced (≤ 50%) left ventricular ejection fraction. Results Within the unselected, consecutive 6463 patients included in the registry, the prevalence of reduced ejection fraction was 20.8% (876 patients) in the surgical cohort and 27.7% (452 patients) in the transcatheter cohort. Reduced left ventricular ejection fraction was associated with decreased survival (adjusted hazards ratio 1.215, 95%CI 1.067–1.385) after a mean follow-up of 3.6 years. Among 255 propensity score matched pairs, 30-day mortality was 3.1% after transcatheter and 7.8% after surgical intervention (p = 0.038). One-year and 4-year survival were 87.5% and 65.9% after transcatheter intervention and 83.9% and 69.6% after surgical intervention (restricted mean survival time ratio, 1.002, 95%CI 0.929–1.080, p = 0.964), respectively. Conclusions Reduced left ventricular ejection fraction was associated with increased morbidity and mortality after surgical and transcatheter aortic valve replacement. Thirty-day mortality was higher after surgery, but intermediate-term survival was comparable to transcatheter intervention. Trial registration The FinnValve registry ClinicalTrials.gov Identifier: NCT03385915.

BACKGROUND: Sudden cardiac arrests (SCA) and sudden cardiac deaths (SCD) are believed to account for a large proportion of deaths due to cardiovascular causes. The purpose of this study is to provide comprehensive information on the epidemiology of SCAs and SCDs after acute coronary syndrome. METHODS: The incidence of SCA (including SCDs) was studied retrospectively among 10,316 consecutive patients undergoing invasive evaluation for acute coronary syndrome (ACS) between 2007 and 2018 at Tays Heart Hospital (sole provider of specialized cardiac care for a catchment area of over 0.5 million residents). Baseline and follow-up information was collected by combining information from the hospital's electronic health records, death certificate data, and a full-disclosure review of written patient records and accounts of the circumstances leading to death. RESULTS: During twelve years of follow-up, the cumulative incidence of SCAs (including SCDs) was 9.8% (0.8% annually) and that of SCDs 5.4% (0.5% annually). Cumulative incidence of SCAs in patients with ST-elevation myocardial infarction, non-ST-elevation myocardial infarction and unstable angina pectoris were: 11.9%,10.2% and 5.7% at twelve years. SCAs accounted for 30.5% (n = 528/1,732) of all deaths due to cardiovascular causes. The vast majority of SCAs (95.6%) occurred in patients without implantable cardioverter defibrillator (ICD) devices or among patients with no recurrent hospitalizations for coronary artery disease (89.1%). CONCLUSIONS: SCAs accounted for less than a third of all deaths due to cardiovascular causes among patients with previous ACS. Incidence of SCA is highest among STEMI and NSTEMI patients. After the hospital discharge, most of SCAs happen to NSTEMI patients. publishedVersion

The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

Ischemic heart disease is the most common cardiovascular disease and a major burden for healthcare worldwide. However, its pathophysiology is still not fully understood, and human-based models for disease mechanisms and treatments are needed. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to model acute ischemia-reperfusion in our novel cell culture assembly. The assembly enables exchange of oxygen partial pressure for the cells within minutes, mimicking acute ischemic event. In this study, hypoxia was induced using 0% O2 gas for three hours and reoxygenation with 19% O2 gas for 24 hours in serum- and glucose-free medium. According to electrophysiological recordings, hypoxia decreased the hiPSC-CM-beating frequency and field potential (FP) amplitude. Furthermore, FP depolarization time and propagation slowed down. Most of the electrophysiological changes reverted during reoxygenation. However, immunocytochemical staining of the hypoxic and reoxygenation samples showed that morphological changes and changes in the sarcomere structure did not revert during reoxygenation but further deteriorated. qPCR results showed no significant differences in apoptosis or stress-related genes or in the expression of glycolytic genes. In conclusion, the hiPSC-CMs reproduced many characteristic changes of adult CMs during ischemia and reperfusion, indicating their usefulness as a human-based model of acute cardiac ischemia-reperfusion.

Background and aims: A deep sternal wound infection is a life-threatening complication after cardiac surgery. This study was conducted to describe the mortality associated with postoperative deep sternal wound infections after cardiac surgery and to find risk factors linked to increased mortality in 1 year follow-up. Material and Methods: A total of 7973 open-heart surgeries were performed at Tampere University Hospital. Deep sternal wound infection patients were identified, their 1-year mortality status was recorded, and the related risk factors were analyzed. Results: We detected a total of 129 (1.6%) postoperative deep sternal wound infection patients. The 1-year mortality associated with a postoperative deep sternal wound infection was 20.2%. No preoperative or perioperative, statistically significant factors associated with increased 1-year mortality were found. A prolonged stay in an intensive care unit after surgery as well as stroke, delirium, wound secretion, and co-infection were associated with increased 1-year mortality. Conclusion: The risk factors found for increased 1-year mortality were all postoperative. The quality of surgical treatment as well as precise postoperative care and evaluation remain the most important factors to decrease later mortality due to deep sternal wound infections.

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM. Published version The Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) supported the meta-analysis—Project-ID 387509280—SFB1350 (Subproject C6 to I.M.H.). A.M.H., B.R., and R.T. were supported by VACSR&D MVP grant CX001897. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by VACSR&D MVP grant CX001897 (A.M.H.). This publication does not represent the views of the Department of Veteran Affairs or the United States Government. We conducted this research using the UK Biobank resource under the application number 20272.

Background and purpose — Smoking weakens bone health and increases the risk of fractures. We investigated the incidence of fractures in smoking, fertile-aged women and compared it with that of non-smoking, fertile-aged women using data from nationwide registers. Patients and methods — We conducted a retrospective register-based nationwide cohort study from 1998 to 2018. We identified all women smoking during pregnancy from the Medical Birth Register and compared these with non-smok-ers. We gathered fractures for both groups from the Care Register for Health Care. Pregnancies with missing smoking or socioeconomic status were excluded. A Cox regression model was used to analyze adjusted hazard ratios (aHR) with 95% confidence intervals (CI) for fractures during the 5-year follow-up starting from delivery. The model was adjusted for the age of the mother at the time of delivery and socioeconomic status. Results — The smoking group included 110,675 pregnancies and the non-smoking group 628,085 pregnancies. The overall fracture rate was higher in smokers after 1-year follow-up (aHR 1.7, CI 1.5–2.0) and 5-year follow-up (aHR 1.7, CI 1.6–1.8). After 5-year follow-up, the fracture rates for polytraumas (aHR 2.3, CI 1.4–3.7), inpatient admitted fractures (aHR 2.0, CI 1.7–2.4), and non-admitted fractures (aHR 1.8, CI 1.7–1.9) were all higher among smoking women. Conclusion — Smoking in fertile-aged women was associated with a higher risk of fractures during the 1-year and 5-year follow-up after giving birth, also after adjusting for age and socioeconomic status. Whether the increased fracture risk is caused by direct effects of smoking on bone health or riskier behavior remains uncertain. publishedVersion

Objective Acute volume overload (AVO) induces early ischemia-like changes in intramyocardial arteries. We investigated whether the Factor Xa (FXa) inhibitor apixaban interacts with the myocardium early after AVO. Methods Fifty-five syngeneic Fisher rats underwent surgical abdominal aortocaval fistula to induce AVO. Among them, 17 rats were treated with apixaban (10 mg/kg/day). The myocardial outcome was studied using histological analysis and by measuring atrial natriuretic peptide (ANP) and matrix metalloprotease 9 (MMP9) gene expression. Results After 3 days, the total number of intramyocardial arteries was significantly increased in the AVO+apixaban (AVO+A) group compared with that in the AVO group (12.0 ± 1.2 and 10.2 ± 1.5, point score units, respectively). In the AVO+A group, there were significantly more edematous nuclei in myocardial arteries in the right and left ventricle compared with that in the AVO group. ANP and MMP9 expression levels continued to increase significantly in the AVO+A group compared with those in the AVO group. Conclusion Apixaban interacts with intramyocardial arteries in the left and right ventricles after AVO and ANP and MMP9 expression levels increased. Thus, the myocardial effect of Factor Xa inhibition needs to be monitored after AVO.

Sex differences exist in the structure and function of human heart. The patterns of ventricular repolarization in normal electrocardiograms (ECG) differ in men and women: men ECG pattern displays higher T-wave amplitude and increased ST angle. Generally, women have longer QT duration because of reduced repolarization reserve, and thus, women are more susceptible for the occurrence of torsades de pointes associated with drugs prolonging ventricular repolarization. Sex differences are also observed in the prevalence, penetrance and symptom severity, and also in the prognosis of cardiovascular disease. Generally, women live longer, have less clinical symptoms of cardiac diseases, and later onset of symptoms than men. Sex hormones also play an important role in regulating ventricular repolarization, suggesting that hormones directly influence various cellular functions and adrenergic regulation. From the clinical perspective, sex-based differences in heart physiology are widely recognized, but in daily practice, cardiac diseases are often underdiagnosed and untreated in the women. The underlying mechanisms of sex differences are, however, poorly understood. Here, we summarize sex-dependent differences in normal cardiac physiology, role of sex hormones, and differences in drug responses. Furthermore, we also discuss the importance of human induced pluripotent stem cell-derived cardiomyocytes in further understanding the mechanism of differences in women and men. publishedVersion

Publisher Copyright: © 2022, The Author(s). Previous studies have demonstrated that environmental and temporal factors may affect the incidence of acute type A aortic dissection (ATAAD). Here, we aimed to investigate the hypothesis that national holidays and weekends influence the incidence of surgery for ATAAD. For the period 1st of January 2005 until 31st of December 2019, we investigated a hypothesised effect of (country-specific) national holidays and weekends on the frequency of 2995 surgical repairs for ATAAD at 10 Nordic cities included in the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) collaboration. Compared to other days, the number of ATAAD repairs were 29% (RR 0.71; 95% CI 0.54–0.94) lower on national holidays and 26% (RR 0.74; 95% CI 0.68–0.82) lower on weekends. As day of week patterns of symptom duration were assessed and the primary analyses were adjusted for period of year, our findings suggest that the reduced surgical incidence on national holidays and weekends does not seem to correspond to seasonal effects or surgery being delayed and performed on regular working days.

The aim of the present study was to investigate the levels of YKL-40 during and after coronary artery bypass grafting surgery (CABG) and to establish possible connections between YKL-40 and markers of oxidative stress, inflammation, and myocardial injury. Patients undergoing elective CABG utilizing cardiopulmonary bypass (CPB) were recruited into the study. Blood samples were collected at the onset of anesthesia, during surgery and post-operatively. Levels of YKL-40, 8-isoprostane, interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1) and troponin T (TnT) were measured by immunoassay. YKL-40 levels increased significantly 24 h after CPB. Positive correlation was seen between post-operative TnT and YKL-40 levels (r = 0.457, p = 0.016) and, interestingly, baseline YKL-40 predicted post-operative TnT increase (r = 0.374, p = 0.050). There was also a clear association between YKL-40 and the chemotactic factors MCP-1 (r = 0.440, p = 0.028) and IL-8 (r = 0.484, p = 0.011) linking YKL-40 to cardiac inflammation and fibrosis following CABG. The present results show, for the first time, that YKL-40 is associated with myocardial injury and leukocyte-activating factors following coronary artery bypass surgery. YKL-40 may be a factor and/or biomarker of myocardial inflammation and injury and subsequent fibrosis following heart surgery.

BACKGROUND: Coronary artery disease (CAD) frequently coexists with severe aortic valve stenosis (AS) in patients planned for transcatheter aortic valve implantation (TAVI). How to manage CAD in this patient population is still an unresolved question. In particular, it is still not known whether fractional flow reserve (FFR) guided revascularization with percutaneous coronary intervention (PCI) is superior to medical treatment for CAD in terms of clinical outcomes. STUDY DESIGN: The third Nordic Aortic Valve Intervention (NOTION-3) Trial is an open-label investigator-initiated, multicenter multinational trial planned to randomize 452 patients with severe AS and significant CAD to either FFR-guided PCI or medical treatment, in addition to TAVI. Patients are eligible for the study in the presence of at least 1 significant PCI-eligible coronary stenosis. A significant stenosis is defined as either FFR ≤0.80 and/or diameter stenosis >90%. The primary end point is a composite of first occurring all-cause mortality, myocardial infarction, or urgent revascularization (PCI or coronary artery bypass graft performed during unplanned hospital admission) until the last included patient have been followed for 1 year after the TAVI. SUMMARY: NOTION-3 is a multicenter, multinational randomized trial aiming at comparing FFR-guided revascularization vs medical treatment of CAD in patients with severe AS planned for TAVI. publishedVersion

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ObjectivesMental health conditions (MHCs) have been associated with undertreatment of unrelated medical conditions, but whether patients with MHCs face disparities in receiving rhythm control therapies for atrial fibrillation (AF) is currently unknown. We assessed the hypothesis that MHCs are associated with a lower use of antiarrhythmic therapies (AATs).DesignA nationwide retrospective registry-based cohort study.SettingThe Finnish AntiCoagulation in Atrial Fibrillation cohort included records on all patients with AF in Finland during 2007–2018 identified from nationwide registries covering all levels of care as well as drug purchases. MHCs of interest were diagnosed depression, bipolar disorder, anxiety disorder, schizophrenia and any MHC.ParticipantsWe identified 239 222 patients (mean age 72.6±13.2 years; 49.8% women) with incident AF, in whom the prevalence of any MHC was 19.9%.OutcomesPrimary outcome was use of any AAT, including cardioversion, catheter ablation, and fulfilled antiarrhythmic drug (AAD) prescription.ResultsLower overall use of any AAT emerged in patients with any MHC than in those without MHC (16.9% vs 22.9%, pConclusionsAmong patients with AF, a clear disparity exists in AAT use between those with and without MHCs.Trial registration numberClinicalTrials Identifier:NCT04645537; ENCePP Identifier: EUPAS29845.

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

Background: No population-based studies comparing long-term survival after transhiatal esophagectomy (THE) and transthoracic esophagectomy (TTE) exist. This study aimed to compare the 5-year survival of esophageal cancer patients undergoing THE or TTE in a population-based nationwide setting. Methods: This study included all curatively intended THE and TTE for esophageal cancer in Finland during 1987–2016, with follow-up evaluation until 31 December 2019. Cox proportional hazard models provided hazard ratios (HRs) with 95% confidence intervals (CIs) of 5-year and 90-day mortality. The results were adjusted for age, sex, year of operation, comorbidities, histology, neoadjuvant treatment, and pathologic stage. Results: A total of 1338 patients underwent THE (n = 323) or TTE (n = 1015). The observed 5-year survival rate was 39.3% after THE and 45.0% after TTE (p = 0.072). In adjusted model 1, THE was not associated with greater 5-year mortality (HR 0.99; 95% CI 0.82–1.20) than TTE. In adjusted model 2, including T stage instead of pathologic stage, the 5-year mortality hazard rates after THE (HR 0.87, 95% CI 0.72–1.05) and TTE were comparable. The 90-day mortality rate for THE was higher than for TTE (adjusted HR 0.72; 95% CI 0.45–1.14). In subgroup analyses, no differences between THE and TTE were observed in Siewert II gastroesophageal junction cancers, esophageal cancers, or pN0 tumors, nor in the comparison of THE and TTE with two-field lymphadenectomy. The sensitivity analysis, including patients with missing patient records, who underwent surgery during 1996–2016 mirrored the main analysis. Conclusions: This Finnish population-based nationwide study suggests no difference in 5-year or 90-day mortality after THE and TTE for esophageal cancer. publishedVersion

We describe two patient cases with acute coronary syndrome (ACS) and broad QRS in the acute phase electrocardiogram (ECG). The patients' ECG findings resembled left bundle branch block (LBBB), but with atypical features. Broad QRS not fulfilling the criteria for LBBB or right bundle branch block (RBBB) is diagnosed as non-specific intraventricular conduction delay (NSIVCD). The case report deals with the challenges of predicting acute coronary occlusion in patients with NSIVCD in their acute phase ECG. In one of the cases, the ECG changed from typical LBBB to NSIVCD or atypical LBBB with the development of systolic dysfunction and clinical heart failure. publishedVersion

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) hold great potential in the cardiovascular field for human disease modeling, drug development, and regenerative medicine. However, multiple hurdles still exist for the effective utilization of hiPSC-CMs as a human-based experimental platform that can be an alternative to the current animal models. To further expand their potential as a research tool and bridge the translational gap, we have generated a cardiac-specific hiPSC reporter line that differentiates into fluorescent CMs using CRISPR-Cas9 genome editing technology. The CMs illuminated with the mScarlet fluorescence enable their non-invasive continuous tracking and functional cellular phenotyping, offering a real-time 2D/3D imaging platform. Utilizing the reporter CMs, we developed an imaging-based cardiotoxicity screening system that can monitor distinct drug-induced structural toxicity and CM viability in real time. The reporter fluorescence enabled visualization of sarcomeric disarray and displayed a drug dose–dependent decrease in its fluorescence. The study also has demonstrated the reporter CMs as a biomaterial cytocompatibility analysis tool that can monitor dynamic cell behavior and maturity of hiPSC-CMs cultured in various biomaterial scaffolds. This versatile cardiac imaging tool that enables real time tracking and high-resolution imaging of CMs has significant potential in disease modeling, drug screening, and toxicology testing. Graphical abstract

Background The incidences of spine fractures and fusion surgeries have increased. A few studies have reported an increased rate of caesarean sections (CS) in women who have undergone spine surgery but have not reported on the health of neonates. Objective We report the incidence of spine fractures, spine fracture surgeries and fusion surgery for other reasons and the effect of these injuries and procedures on later pregnancy outcomes in Finland. Methods Data on all fertile-aged women (1998–2018) who had undergone spine fracture or spine fusion surgery were retrieved from the Care Register for Healthcare and combined with data from the National Medical Birth Register. Women with spine fracture or spine surgery before pregnancy were compared with women without previous spine fracture or surgery. We calculated incidences of spine fracture, spine fracture surgery and fusion surgery for other reasons with 95% confidence intervals (CI). We used multivariable logistic regression to evaluate CS and neonatal health. Results are reported as adjusted odds ratios (AOR). Results The main finding of our study was the increasing incidence (156%) of spine fusion surgeries for other reasons in fertile-aged women. A total CS rate (including elective and unplanned CS) in the spine fracture group was 19.7% (AOR 1.26, CI 1.17–1.34), in fusion surgery for other reasons group 25.3% (AOR 1.37, CI 1.30–1.49) and 15.9% in the control group. The rate for neonates requiring intensive care in the spine fracture group was 12.2% (AOR 1.18, CI 1.08–1.29), in fusion surgery for other reasons group 13.6% (AOR 1.12, CI 1.02–1.23) and 10.0% in the control group. Conclusions The incidence of fusion surgery for other reasons increased during our study period. The rate of CS was higher in women with preceding spine fracture or fusion surgery. Our results suggest that vaginal delivery after fractures of the spine is both possible and safe for mother and neonate.

BACKGROUND: The outcome in patients after surgery for acute type A aortic dissection without replacement of the part of the aorta containing the primary tear is undefined.METHODS: Data of 1122 patients who underwent surgery for acute type A aortic dissection in eight Nordic centers from Jan 2005 to Dec 2014 were retrospectively analyzed. The patients with primary tear location either unfound, unknown, not confirmed or not recorded (n=243, 21.7%) were excluded from the analysis. The patients were divided into two groups according to whether the aortic reconstruction encompassed the portion of the primary tear (TR group, n=730) or not (TNR group, n=149). The restricted mean survival time ratios adjusted for patient characteristics and surgical details between the groups were calculated for all-cause mortality and aortic reoperation-free survival. The median follow-up time was 2.57 (inter-quartile range 0.53-5.30) years.RESULTS: For the majority of the patients in the TR group, the primary tear was located in the ascending aorta (83.6%). The reconstruction encompassed both aortic root and the aortic arch in 7.4% in the TR group as compared with 0.7% in the TNR patients (PCONCLUSIONS: Primary tear resection alone does not determine the mid-term outcome after surgery for acute type A aortic dissection.

Background and Objective The newer adenosine diphosphate (ADP) receptor blockers ticagrelor and prasugrel are superior to clopidogrel in the long-term management of acute coronary syndrome (ACS). We evaluated the acute performance (prehospital loading) of these ADP receptor blockers in a primary percutaneous coronary intervention (PCI) for an ST-elevation myocardial infarction (STEMI). Methods In a retrospective, single-center registry study, data on all STEMI patients admitted for their first primary PCI between January 2007 and April 2020 were analyzed (n = 3218). The three ADP receptor blockers were mainly used during consecutive periods (clopidogrel 2007–2010, prasugrel 2011–2014, and ticagrelor 2014–2020), and were compared with risk factor-adjusted multivariate logistic regression for acute 3- and 7-day mortality and culprit artery flow before and after PCI. Results Of the 3218 total patients, 47.6% (n = 1532) were treated with ticagrelor, 22.1% (n = 711) were treated with prasugrel, and 30.3% (n = 975) were treated with clopidogrel. The use of ticagrelor or prasugrel as opposed to clopidogrel was associated with better culprit artery flow before PCI (odds ratio [OR] 1.21 for moderate or good flow, 95% confidence interval [CI] 1.03–1.42, p = 0.022), as well as lower acute mortality (OR 0.66 for 3-day mortality, 95% CI 0.46–0.95, p = 0.025; and OR 0.71 for 7-day mortality, 95% CI 0.52–0.98, p = 0.039). The results in regard to acute mortality were highlighted among patients with short treatment delays (disappearing with longer treatment delays; p

Background Radiation therapy (RT) results in myocardial changes consisting of diffuse fibrosis, which may result in changes in diastolic function. Objectives The aim of this study was to explore RT-associated changes in left ventricular (LV) diastolic function. Methods Sixty chemotherapy-naive patients with left-sided, early-stage breast cancer were studied with speckle tracking echocardiography at 3 time points: prior to, immediately after, and 3 years after RT. Global and regional early diastolic strain rate (SRe) were quantified, as were parameters of systolic function. Results Regional changes in SRe, particularly the apical and anteroseptal segments, were observed over time and were more evident than global changes. The apical SRe declined from a median of 1.24 (interquartile range: 1.01 to 1.39) s-1 at baseline to 1.02 (interquartile range: 0.79 to 1.15) s-1 at 3 years of follow-up (p < 0.001). This decline was associated with the left ventricular maximal radiation dose (β = 0.36, p = 0.007). The global SRe was, Central Illustration

Objectives. Mediastinal chest tubes are considered to be a significant factor causing postoperative pain after cardiac surgery. The aim of the study was to ascertain whether the duration of mediastinal drainage is associated with postoperative pain and opioid consumption. Design. A total of 468 consecutive patients undergoing cardiac surgery at the Tampere University Hospital between December 2015 and August 2016 were retrospectively analyzed. The first 252 patients were treated according to short and the following 216 patients according to extended drainage protocol, in which the mediastinal chest tubes were habitually removed on the first and second postoperative day, respectively. The oxycodone hydrochloride consumption, as well as daily mean pain scores assessed by numeric/visual rating scales, were compared between the groups. Results. The mean daily pain scores and cumulative opioid consumption were similar in both groups. Patients with reduced ejection fraction, diabetes, and peripheral vascular disease reported lower initial pain scores. The median cumulative oxycodone hydrochloride consumption did not differ according to the drainage protocol but was higher in males, smokers, and after aortic surgery. In contrast, patients with advanced age, hypertension, and peripheral vascular disease had lower consumption. In multivariable analysis, male sex and aortic surgery were associated with higher and advanced age with lower opioid use. Conclusions. The length of mediastinal chest tube drainage is not associated with the amount of postoperative pain or need for opioids after cardiac surgery. Male sex and aortic surgery were associated with higher and advanced age with lower overall opioid consumption. publishedVersion