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AbstractBackground Transcatheter (TC) atrial septal defect (ASD) closure has been the mainstay of therapy for secundum-type ASDs for over 20 years.Aims This nationwide cohort evaluated the long-term outcome of transcatheter-closed ASDs.Methods 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.Results 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.Conclusion 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.

Background: The underlying risk factors for young-onset cryptogenic ischaemic stroke (CIS) remain unclear. This multicentre study aimed to explore the association between heavy alcohol consumption and CIS with subgroup analyses stratified by sex and age., Methods: Altogether, 540 patients aged 18-49 years (median age 41; 47.2% women) with a recent CIS and 540 sex-matched and age-matched stroke-free controls were included. Heavy alcohol consumption was defined as >7 (women) and >14 (men) units per week or at least an average of two times per month ≥5 (women) and ≥7 (men) units per instance (binge drinking). A conditional logistic regression adjusting for age, sex, education, hypertension, cardiovascular diseases, diabetes, hypercholesterolaemia, current smoking, obesity, diet and physical inactivity was used to assess the independent association between alcohol consumption and CIS., Results: Patients were twice as more often heavy alcohol users compared with controls (13.7% vs 6.7%, p<0.001), were more likely to have hypertension and they were more often current smokers, overweight and physically inactive. In the entire study population, heavy alcohol consumption was independently associated with CIS (adjusted OR 2.11; 95% CI 1.22 to 3.63). In sex-specific analysis, heavy alcohol consumption was associated with CIS in men (2.72; 95% CI 1.25 to 5.92), but not in women (1.56; 95% CI 0.71 to 3.41). When exploring the association with binge drinking alone, a significant association was shown in the entire cohort (2.43; 95% CI 1.31 to 4.53) and in men (3.36; 95% CI 1.44 to 7.84), but not in women., Conclusions: Heavy alcohol consumption, particularly binge drinking, appears to be an independent risk factor in young men with CIS., Competing Interests: Competing interests: JP: shareholder of Olvi Oyj. TT: has served/serves on scientific advisory boards for Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Inventiva and Portola Pharm., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Approximately 7.6 million individuals experience a new ischemic stroke each year, and roughly 25% of all ischemic strokes are cardiogenic in origin, carrying a high risk of recurrence, death, and disability. To prevent future ischemic strokes, especially in younger individuals, it is crucial to detect and treat direct and indirect cardioembolic sources., Summary: Cardiac imaging is a rapidly evolving field, and post-stroke cardiac imaging is no longer limited to echocardiography but also includes other imaging techniques, such as cardiac magnetic resonance imaging and cardiac computed tomography. Clinicians must be familiar with numerous cardiac and systemic disorders related to stroke and consider the possibilities that imaging diagnostics have to offer. Additional diagnostic tests, such as pre- and transcranial ultrasound with a bubble test, can also increase the diagnostic accuracy for detecting right-left shunt embolisms. Moreover, a patent foramen ovale (PFO) has traditionally been considered as a minor or uncertain risk factor for ischemic stroke. However, PFO-associated strokes are a distinct category among the cardioembolic sources, as in most cases, we do not assume that the thrombus has been developed in situ in the PFO structure or elsewhere intracardially, rather, the PFO merely acts as a mediator for a paradoxical, venous embolism. The article has two parts: Part I, the heart-brain axis, describes multimodality cardiac imaging in the assessment of cardioembolic sources of ischemic stroke, with a special focus on disorders that traditionally have received little attention in the literature. Part II discusses the brain-heart axis, namely, when acute cerebrovascular events lead to cardiac dysfunction, for example, neurogenic stunned myocardium and Takotsubo syndrome., Key Messages: Advances in cardiovascular imaging have significantly enhanced the detection of cardiac disorders associated with stroke. Clinicians involved in post-stroke workup need to be aware of the capabilities of different imaging modalities to ensure high diagnostic accuracy in order to effectively treat and prevent stroke recurrence., (© 2025 The Author(s). Published by S. Karger AG, Basel.)

Missing teeth have been linked to incident cardiovascular disease, diabetes, and all-cause mortality. Our previous study revealed that signs of oral infections and inflammatory conditions (i.e., periodontal disease and dental caries) are associated with disadvantageous features of circulating metabolites. This study investigates whether missing teeth and tooth loss, the end points of these diseases, are associated with similar metabolic features. The 2 Finnish population-based studies Health-2000 ( n = 6,197) and FINRISK-97 ( n = 6,050) were included, as was Parogene ( n = 465), a cohort of patients with an indication for coronary angiography. The number of teeth was recorded in clinical examinations. Serum concentrations of 157 metabolites were determined by a nuclear magnetic resonance spectroscopy-based method. Health-2000 participants ( n = 3,371) provided follow-up serum samples, and 1,186 of them participated in a repeated oral examination 11 y after the baseline. Linear regression models adjusted for age, sex, smoking, body mass index, and diabetes were fitted to the number of teeth and metabolite measures. The results from the separate cohorts were combined in a fixed-effects meta-analysis. We also analyzed whether the number of teeth at baseline and tooth loss during follow-up were associated with changes in metabolite concentrations. Missing teeth were associated with increased very-low-density lipoprotein-related measures and triglyceride concentrations, as well as with decreased high-density lipoprotein parameters and small particle size. Missing teeth also had an association with low levels of unsaturated fatty acids (FAs), including omega-3 and omega-6 FAs, and elevated proportions of monounsaturated and saturated FAs. The number of teeth at baseline predicted changes in several concentrations, such as measures related to intermediate-density lipoprotein, low-density lipoprotein, and FAs, but no associations with tooth loss during the 11-y follow-up were observed. To conclude, missing teeth are associated with adverse metabolic features characterized by systemic inflammation and several risk factors for cardiometabolic diseases., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Although the incidence and case fatality (CF) of acute myocardial ischaemic syndrome (AMIS) have declined in recent decades, some studies have suggested a potential stagnation in this decline. We examined if a similar development in AMIS trends can be observed in Finland from 1996 to 2021 among persons aged 35-74 years., Methods: We linked Finnish country-wide Hospital Discharge- and Causes of Death- Registers covering the first non-fatal and fatal myocardial ischaemic events (total 69 906 442 person-years at risk). We analyzed the incidence, mortality, and 28-day CF and their trends using negative binomial, Poisson, segmented and logistic regression adjusting for age and sex., Results: The analysis consisted of 186 489 non-fatal and 72 907 fatal myocardial ischaemic events. AMIS incidence declined in men (annual percentage change (APC) -2.0%) and in older women (APC of 55-64 years -1.5%; 65-74 years -3.3%) during the study period. However, the incidence decline slowed down over the last decade in oldest age groups and stopped overall in women. Incidence was unchanged during the study period in younger women aged 35-54 years. AMIS mortality and CF declined (APC of mortality in men -4.4%; in women -5.0%; APC of CF in men -2.7%; in women -3.3%)., Conclusions: AMIS mortality declined in all groups, but the decline in AMIS incidence slowed down and even stopped in women. Incidence was unchanged during the study period in women aged 35-54 years. These results emphasize the need for further efforts in prevention of cardiovascular disease, particularly in young and middle-aged women.

Dilated cardiomyopathy (DCM) is a heart muscle disease that represents an important cause of morbidity and mortality, yet causal mechanisms remain largely elusive. Here, we perform a large-scale genome-wide association study and multitrait analysis for DCM using 9,365 cases and 946,368 controls. We identify 70 genome-wide significant loci, which show broad replication in independent samples and map to 63 prioritized genes. Tissue, cell type and pathway enrichment analyses highlight the central role of the cardiomyocyte and contractile apparatus in DCM pathogenesis. Polygenic risk scores constructed from our genome-wide association study predict DCM across different ancestry groups, show differing contributions to DCM depending on rare pathogenic variant status and associate with systolic heart failure across various clinical settings. Mendelian randomization analyses reveal actionable potential causes of DCM, including higher bodyweight and higher systolic blood pressure. Our findings provide insights into the genetic architecture and mechanisms underlying DCM and myocardial function more broadly., Competing Interests: Competing interests: P.T.E. has received sponsored research support from Bayer AG, IBM Health, Bristol Myers Squibb and Pfizer; he has consulted for Bayer AG, Novartis and MyoKardia. K.G.A. has received sponsored research support from Sarepta Therapeutics and Bayer AG, and reports a research collaboration with Novartis. Y.M.P. is involved in the development of therapies for DCM as an advisor to Forbion and Medical Director at ARMGO pharma and CMO at Phlox Therapeutics. P.C. reports personal fees for consultancies, outside the present work, for Amicus, OWKIN, Pfizer and SANOFI. J.S.W. has received research support from Bristol Myers Squibb, and has acted as a consultant for MyoKardia, Pfizer, Foresite Labs, Health Lumen and Tenaya Therapeutics. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Objective: Biallelic titin truncating variants (TTNtv) have been associated with a wide phenotypic spectrum, ranging from complex prenatal muscle diseases with dysmorphic features to adult-onset limb-girdle muscular dystrophy, with or without cardiac involvement. Given the size and complexity of TTN, reaching an unequivocal molecular diagnosis and precise disease prognosis remains challenging., Methods: In this case series, 12 unpublished cases and one already published case with biallelic TTNtv were collected from multiple international medical centers between November 2022 and September 2023. TTN mutations were detected through exome or genome sequencing. Information about familial and personal clinical history was collected in a standardized form. RNA-sequencing and analysis of TTN exon usage were performed on an internal sample cohort including postnatal skeletal muscles, fetal skeletal muscles, postnatal heart muscles, and fetal heart muscles. In addition, publicly available RNA-sequencing data was retrieved from ENCODE., Results: We generated new RNA-seq data on TTN exons and identified genotype-phenotype correlations with prognostic implications for each titinopathy patient (whether worsening or improving in prenatal and postnatal life) using percentage spliced in (PSI) data for the involved exons. Interestingly, thanks to exon usage, we were also able to rule out a titinopathy diagnosis in one prenatal case., Interpretation: This study demonstrates that exon usage provides valuable insights for a more exhaustive clinical interpretation of TTNtv; additionally, it may serve as a model for implementing personalized medicine in many other genetic diseases, since most genes undergo alternative splicing., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Although knowledge of the role of the oral microbiome in ischemic stroke is steadily increasing, little is known about the multikingdom microbiota interactions and their consequences. We enrolled participants from a prospective multicentre case-control study and investigated multikingdom microbiome differences using saliva metagenomic datasets ( n  = 308) from young patients diagnosed with cryptogenic ischemic stroke (CIS) and age- and sex-matched stroke-free controls. Differentially abundant taxa were identified using Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC2). Functional potential was inferred using HUMANn3. Our findings revealed significant differences in the composition and functional capacity of the oral microbiota associated with CIS. We identified 51 microbial species, including 47 bacterial, 3 viral, and one fungal species associated with CIS in the adjusted model. Co-abundance network analysis highlighted a more intricate microbial network in CIS patients, indicating potential interactions and co-occurrence patterns among microbial species across kingdoms. The results of our metagenomic analysis reflect the complexity of the oral microbiome, with high diversity and multikingdom interactions, which may play a role in health and disease., Competing Interests: The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Society for Microbial Ecology.)

Periodontitis is associated with an increased risk of ischemic stroke, and the risk may be particularly high among young people with unexplained stroke etiology. Thus, we investigated in a case-control study whether periodontitis or recent invasive dental treatments are associated with young-onset cryptogenic ischemic stroke (CIS). We enrolled participants from a multicenter case-control SECRETO study including adults aged 18 to 49 y presenting with an imaging-positive first-ever CIS and stroke-free age- and sex-matched controls. Thorough clinical and radiographic oral examination was performed. Furthermore, we measured serum lipopolysaccharide (LPS) and lipotechoic acid (LTA) levels. Multivariate conditional regression models were adjusted for stroke risk factors, regular dentist visits, and patent foramen ovale (PFO) status. We enrolled 146 case-control pairs (median age 41.9 y; 58.2% males). Periodontitis was diagnosed in 27.5% of CIS patients and 20.1% of controls ( P < 0.001). In the fully adjusted models, CIS was associated with high periodontal inflammation burden (odds ratio [OR], 95% confidence interval) with an OR of 10.48 (3.18-34.5) and severe periodontitis with an OR of 7.48 (1.24-44.9). Stroke severity increased with the severity of periodontitis, having an OR of 6.43 (1.87-23.0) in stage III to IV, grade C. Invasive dental treatments performed within 3 mo prestroke were associated with CIS, with an OR of 2.54 (1.01-6.39). Association between CIS and invasive dental treatments was especially strong among those with PFO showing an OR of 6.26 (1.72-40.2). LPS/LTA did not differ between CIS patients and controls but displayed an increasing trend with periodontitis severity. Periodontitis and recent invasive dental procedures were associated with CIS after controlling for multiple confounders. However, the role of bacteremia as a mediator of this risk was not confirmed., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A. Saraste discloses fees for consultancy or lectures from Abbott, Astra Zeneca, Bayer, Novartis, and Pfizer outside the current study. Other authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To elucidate the risk and temporal relationship of cardiovascular (CV) comorbidities in rheumatic diseases., Methods: Patients in the FinnGen study diagnosed between 2000 and 2014 with seropositive (n = 2368) or seronegative (n = 916) rheumatoid arthritis (RA), ankylosing spondylitis (AS, n = 715), psoriatic arthritis (PsA, n = 923), systemic lupus erythematosus (SLE, n = 190), primary Sjogren's syndrome (pSS, n = 412) or gout (n = 2034) were identified from healthcare registries. Each patient was matched based on age, sex, and birth region with twenty controls without any rheumatic conditions. Overall risk ratios (RR) were calculated by comparing the prevalence of seven CV diseases between patients and controls. Logistic regression models were used for estimating odds ratios (OR) for CV comorbidities before and after the onset of rheumatic diseases., Results: The RR for 'any CVD' varied from 1.14 (95 % confidence interval [CI] 1.02-1.26) in PsA to 2.05 (95 % CI 1.67-2.52) in SLE. Patients with SLE or gout demonstrated over two-fold risks for several CV comorbidities. Among CV comorbidities, venous thromboembolism (VTE) showed the highest effect sizes in several rheumatic diseases. The ORs for CV comorbidities were highest within one year before and/or after the onset of the rheumatic disease. However, in gout the excess risk of CV disease was especially high before gout diagnosis., Conclusions: The risk of CV comorbidities was elevated in all studied rheumatic diseases, with highest risks observed in SLE and gout. The risk for CV diseases was highest immediately before and/or after rheumatic disease diagnosis, highlighting the increased risk for CV comorbidities across all rheumatic diseases very early on the disease course., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hanna-Kaisa Aaramaa: a lecture fee from Novartis and support for attending rheumatological congresses from UCB Pharma and Medac. Pia Isomäki: honoraria for honoraria for educational events from Abbvie, Galapagos and Pfizer; consultant of Galapagos, Eli Lilly, Pfizer, ViforPharma. Anne M Kerola: speaker fees from Boehringer-Ingelheim and Sanofi; advisory boards of Pfizer, Gilead and Boehringer-Ingelheim; and congress sponsorship from Pfizer, Abbvie and Mylan. Antti Palomäki: consulting fees from Pfizer, Abbvie and Amgen, lecture fees from Boehringer-Ingelheim, Pfizer and Sanofi, and travel expenses from Novartis. Kari K Eklund: lecture fees from Celltrion, Novartis and MSD, and consulting fees from SOBI., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Gingivitis, i.e. inflammation of the gums, is often induced by dentalplaque. However, its exact link to the oral microbiota remains unclear., Methods: In a case-control study involving 120 participants, comprising 60 cases and 60 controls (mean age (SD) 36.6 (7.6) years; 50% males), nested within a prospective multicentre cohort study, we examined theoral microbiome composition of gingivitis patients and their controlsusing shotgun metagenomic sequencing of saliva samples. Participants underwent clinical and radiographic oral health examinations, including bleeding on probing (BOP), at six tooth sites. BOP ≥33%was considered 'generalized gingivitis/initial periodontitis'(GG/IP), and BOP <33% as 'healthy and localized gingivitis'(H/LG). Functional potential was inferred using HUMANn3., Results: GG/IP exhibited an increase in the abundance of Actinomyces, Porphyromonas, Aggregatibacter, Corynebacterium, Olsenella, and Treponema , whereas H/LG exhibited an increased abundance of Candidatus Nanosynbacter . Nineteen bacterial species and fourmicrobial functional profiles, including L-methionine, glycogen, andinosine-5'-phosphate biosynthesis, were associated with GG/IP. Constructing models with multiple markers resulted in a strong predictive value for GG/IP, with an area under the curve (ROC) of 0.907 (95% CI: 0.848-0.966)., Conclusion: We observed distinct differences in the oral microbiome between the GG/IP and H/LG groups, indicating similar yet unique microbial profiles and emphasizing their potential role in progression of periodontal diseases., Competing Interests: No potential conflict of interest was reported by the authors., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Incidence of cryptogenic ischemic stroke (CIS) in young adults is increasing. Early left atrial (LA) myopathy might be 1 of the underlying mechanisms, but this has only been scarcely explored., Objectives: The purpose of this study was to assess the association between increased LA stiffness and CIS in young adults., Methods: In the multicenter SECRETO (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome) study, LA function was analyzed by speckle tracking echocardiography in 150 CIS patients (aged 18-49 years) and 150 age- and sex-matched controls. Minimum and maximum LA volumes, LA reservoir and contractile strain were measured. LA stiffness was calculated by the ratio: mitral peak E-wave velocity divided by mitral annular e' velocity (E/e')/LA reservoir strain and considered increased if ≥0.22. Increased LA volumes, LA stiffness, and/or reduced LA strain indicated LA myopathy. Logistic regression was used to determine the relation between LA stiffness and CIS and the clinical variables associated with LA stiffness., Results: Increased LA stiffness was found in 36% of patients and in 18% of controls ( P  < 0.001). Increased LA stiffness was associated with a 2.4-fold (95% CI: 1.1-5.3) higher risk of CIS after adjustment for age, sex, comorbidities, and echocardiographic confounders ( P  = 0.03). In patients, obesity, pre-CIS antihypertensive treatment, older age, and lower LA contractile strain were all related to increased LA stiffness (all P  < 0.05)., Conclusions: LA myopathy with increased LA stiffness and impaired LA mechanics more than doubles the risk of CIS in patients under the age of 50 years. This provides new insights into the link between LA dysfunction and CIS at young ages. (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome [SECRETO]; NCT01934725)., Competing Interests: The SECRETO study has been funded by the 10.13039/501100002341Academy of Finland under grant numbers 318075 and 322656, Helsinki and Uusimaa Hospital District (TYH2018318), and 10.13039/501100006306Sigrid Juselius Foundation. Dr Cramariuc has received clinical researcher funds and open project support from the Regional Health Authorities in Western Norway (project numbers F-12557 and F-12615). Dr Sarkanen has received grant number 322663 from the Academy of Finland. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.PERSPECTIVESCOMPETENCY IN MEDICAL KNOWLEDGE: Young adults with increased LA stiffness have significantly higher risk of CIS independent of LA size and in the absence of atrial fibrillation. TRANSLATIONAL OUTLOOK: Patients with premature LA disease may benefit from early intervention, like antithrombotic therapy. This should be further investigated in clinical studies addressing preventive and therapeutic interventions in young patients at high risk of ischemic stroke., (© 2024 The Authors.)

Background and Aims: Hydroxychloroquine (HCQ) has a variable effect on cholesterol synthesis. To clarify this, we assessed the effect of HCQ on the cholesterol-synthesis pathway in individuals with low and high cholesterol absorption efficiency., Method: A total of 53 acute myocardial infarction patients with a constant statin dose randomized to receive HCQ or placebo for six months in a double-blind manner, were classified further into low (n = 26) and high (n = 27) cholesterol absorbers based on the median baseline serum cholestanol level. Serum lipids and biomarkers of cholesterol synthesis (squalene, lanosterol, zymostenol, desmosterol, and lathosterol) and absorption efficiency (sitosterol and cholestanol), were measured at baseline and one-, six-, and 12-month follow-up visits., Results: In low cholesterol absorbers, serum cholesterol concentration and cholesterol synthesis and absorption biomarkers did not differ between the HCQ and placebo groups. At one month, high cholesterol absorbers with HCQ had lower serum cholesterol concentration and serum lanosterol to cholesterol ratio in comparison to the placebo group (HCQ 3.18 ± 0.62 vs. placebo 3.71 ± 0.65, p = 0.042, and HCQ 10.4 ± 2.55 vs. placebo 13.1 ± 2.36, p = 0.008, respectively). At 12 months, serum desmosterol to cholesterol ratio was lower in HCQ users (HCQ 47.1 ± 7.08 vs. placebo 59.0 ± 13.1, p = 0.011)., Conclusions: HCQ affects the cholesterol-synthesis pathway in high cholesterol absorbers. It reduces serum lanosterol and desmosterol ratios and consequently serum cholesterol concentration possibly by inhibiting the activity of lanosterol synthase as described earlier in vitro studies., Trial Registration: ClinicalTrials.gov Identifier: NCT02648464., (© 2024 The Authors.)

Bone marrow mononuclear cells (BMMCs) have been evaluated for their ability to improve cardiac repair and benefit patients with severe ischemic heart disease and heart failure. In our single-center trial in 2006-2011 we demonstrated the safety and efficacy of BMMCs injected intramyocardially in conjunction with coronary artery bypass surgery. The effect persisted in the follow-up study 5 years later. In this study, we investigated the efficacy of BMMC therapy beyond 10 years. A total of 18 patients (46%) died during over 10-years follow-up and 21 were contacted for participation. Late gadolinium enhancement cardiac magnetic resonance imaging (CMRI) and clinical evaluation were performed on 14 patients, seven from each group. CMRIs from the study baseline, 1-year and 5-years follow-ups were re-analyzed to enable comparison. The CMRI demonstrated a 2.1-fold larger reduction in the mass of late gadolinium enhancement values between the preoperative and the over 10-years follow-up, suggesting less scar or fibrosis after BMMC treatment (- 15.1%; 95% CI - 23 to - 6.7% vs. - 7.3%; 95% CI - 16 to 4.5%, p = 0.039), compared to placebo. No differences in mortality or morbidity were observed. Intramyocardially injected BMMCs may exert long-term benefits in patients with ischemic heart failure. This deserves further evaluation in patients who have received BMMCs in international clinical studies over two decades., (© 2024. The Author(s).)

Objectives: Long-term results after sinus venosus defect (SVD) closure are sparse and many studies lack a proper control cohort. This nationwide cohort evaluated the long-term outcome after SVD surgery., Methods: The study enrolled every surgical SVD correction from the nationwide hospital discharge registry (FHDR) and surgical registries of two tertiary centers. Patients with more complex congenital heart defects were excluded. Surgeries were performed from 1969 to 2019. Five sex and birth-year-matched controls per SVD patient were gathered from the general population., Results: In total, 182 surgical SVD corrections were performed during the study period. The median age at the time of surgery was 8.3 years (range 0.06-75.7), and the majority (77.5%, n = 141) were under 18 years old. The median follow-up period was 18 years (range 0.1-53). There was no significant difference in mortality during the follow-up (logrank p = 0.62, MRR 0.78, 95% CI: 0.30-2.0). However, SVD patients had elevated risk for new-onset atrial fibrillation (RR 4.9, 95% CI: 2.2-10.9), heart failure (RR 4.0, 95% CI: 1.2-13.2), ischemic heart disease (4.3, 95% CI, 1.5-11.7), migraine (RR 3.6, 95% CI: 1.5-9.1) and sick sinus syndrome, II- or III-degree AV-block or pacemaker implantation (RR 11.3, 95% CI: 2.9-43.8)., Conclusion: Young patients with SVD have an excellent survival prognosis after the surgery. Risk for sick sinus syndrome or conduction disorders, atrial fibrillation, and heart failure remains elevated in the long-term follow-up., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Patent foramen ovale (PFO) closure is traditionally guided by transoesophageal echocardiography (TEE) under general anaesthesia, which prolongs procedure duration and increases costs and risks. A transnasal echocardiography with a microTEE-probe (microTNE) is tolerated under conscious sedation and offers an effective alternative to TEE. The aim of this study was to compare the feasibility, safety and time expenditure of PFO closure using conventional TEE versus microTNE guidance., Methods: Consecutive patients assigned for PFO losure in Helsinki University Hospital from 2003 to 2021 were included in the study (n=336). TEE with general anaesthesia was used until November 2018 (n=167) while microTNE-guided PFO closure (n=169) under conscious sedation was the principal method thereafter. Patients were followed for 3 months after PFO closure., Results: The microTNE-route success rate was 97.2% vs TEE 100% (p=0.06) and procedure success rate was 97.7% with microTNE and 96.0% with TEE-guidance (p=0.54). The procedure time was significantly shorter with microTNE 21±7 min than with TEE 30±13 min (p<0.001). At the beginning of microTNE era, nasal bleeding complication was quite frequent; however, overall complication rates were equal between the groups. However, C reactive protein (CRP) increase was significantly milder with microTNE than TEE 1.0±2.9 vs 3.0±4.0 mg/L (p<0.001). An increase in CRP was independently associated with procedure type (p=0.004) and time (p=0.003)., Conclusions: MicroTNE is a feasible and safe alternative for PFO closure guidance. MicroTNE under conscious sedation shortens procedure duration and induces a milder inflammatory reaction than conventional TEE under general anaesthesia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Systemic metabolic signatures of oral diseases have been rarely investigated, and prospective studies do not exist. We analyzed whether signs of current or past infectious/inflammatory oral diseases are associated with circulating metabolites. Two study populations were included: the population-based Health-2000 ( n = 6,229) and Parogene ( n = 452), a cohort of patients with an indication to coronary angiography. Health-2000 participants ( n = 4,116) provided follow-up serum samples 11 y after the baseline. Serum concentrations of 157 metabolites were determined with a nuclear magnetic resonance spectroscopy-based method. The associations between oral parameters and metabolite concentrations were analyzed using linear regression models adjusted for age, sex, number of teeth, smoking, presence of diabetes, and education (in Health-2000 only). The number of decayed teeth presented positive associations with low-density lipoprotein diameter and the concentrations of pyruvate and citrate. Negative associations were found between caries and the unsaturation degree of fatty acids (FA) and relative proportions of docosahexaenoic and omega-3 FAs. The number of root canal fillings was positively associated with very low-density lipoprotein parameters, such as diameter, cholesterol, triglycerides, and number of particles. Deepened periodontal pockets were positively associated with concentrations of cholesterol, triglycerides, pyruvate, leucine, valine, phenylalanine, and glycoprotein acetyls and negatively associated with high-density lipoprotein (HDL) diameter, FA unsaturation degree, and relative proportions of omega-6 and polyunsaturated FAs. Bleeding on probing (BOP) was associated with increased concentrations of triglycerides and glycoprotein acetyls, as well as decreased proportions of omega-3 and omega-6 FAs. Caries at baseline predicted alterations in apolipoprotein B-containing lipoproteins and HDL-related metabolites in the follow-up, and both caries and BOP were associated with changes in HDL-related metabolites and omega-3 FAs in the follow-up. Signs of current or past infectious/inflammatory oral diseases, especially periodontitis, were associated with metabolic profiles typical for inflammation. Oral diseases may represent a modifiable risk factor for systemic chronic inflammation and thus cardiometabolic disorders., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ceramides and other sphingolipids are implicated in vascular dysfunction and inflammation. They have been suggested as potential biomarkers for hypertension. However, their specific association with hypertension prevalence and onset requires further investigation. This study aimed to identify specific ceramide and phosphatidylcholine species associated with hypertension prevalence and onset. The 2002 FINRISK (Finnish non-communicable risk factor survey) study investigated the association between coronary event risk scores (CERT1 and CERT2) and hypertension using prevalent and new-onset hypertension groups, both consisting of 7722 participants, over a span of 10 years. Ceramide and phosphatidylcholine levels were measured using tandem liquid chromatography-mass spectrometry. Ceramide and phosphatidylcholine ratios, including ceramide (d18:1/18:0), ceramide (d18:1/24:1), phosphatidylcholine (16:0/16:0), and the ratio of ceramide (d18:1/18:0)/(d18:1/16:0), are consistently associated with both prevalence and new-onset hypertension. Ceramide (d18:1/24:0) was also linked to both hypertension measures. Adjusting for covariates, CERT1 and CERT2 showed no-longer-significant associations with hypertension prevalence, but only CERT2 predicted new-onset hypertension. Plasma ceramides and phosphatidylcholines are crucial biomarkers for hypertension, with imbalances potentially contributing to its development. Further research is needed to understand the underlying mechanisms by which ceramides will contribute to the development of hypertension.

Background: Coronary computed tomography angiography is increasingly used as the first-line test for suspected coronary artery disease. Its overuse in a low pretest probability (PTP) population may lead to low diagnostic yield without change in patient management. We evaluated the clinical consequences of the updated 2019 European Society of Cardiology (ESC) chronic coronary syndromes guidelines' PTP estimation and whether imaging could be safely deferred in patients with a low PTP., Methods and Results: This retrospective cohort included all 1753 consecutive patients who underwent coronary computed tomography angiography for suspected coronary artery disease at Helsinki University Hospital between 2009 and 2017. PTP was calculated according to the 2013 and 2019 ESC guidelines. The overall mortality, cardiac deaths, myocardial infarctions, and hospitalizations for unstable angina were acquired from national registry data for 1 to 10 years of follow-up (median, 4 years). Updated 2019 ESC guidelines classified 72% of the patients as having low PTP, whose imaging could have been deferred. The revascularization rate (4.7%) and annual cardiac mortality (0.4%) were low in the 857 patients reclassified from the recommendation to test, according to the 2013 ESC guideline, to deferral of coronary computed tomography angiography, according to the new 2019 guideline., Conclusions: The updated 2019 ESC guideline PTP score aids clinicians in safely preventing the overuse of cardiac imaging in patients deemed at low PTP of coronary artery disease. Diagnostic yield, revascularization rate, and cardiac mortality are low in patients with low pretest risk.

Background . It has been unclear whether simple atrial septal defect (ASD) is an independent risk factor for infective endocarditis (IE). This study aimed to untangle the risk of endocarditis in a large nationwide cohort. Methods . We acquired data from the Finnish hospital discharge register on all individuals with ASD diagnosis from 1969 to 2019. Patients with complex congenital cardiac abnormalities were ruled out. Five individualized controls from the general population were matched to the ASD patient's birth year, sex, and residence at the index date. All the patients with ICD-8, -9, or -10 diagnosis codes for IE were gathered from the hospital discharge registry. Results . Altogether, 8322 patients with ASD and 39,237 individualized controls were enrolled in the study. Median follow-up was 21.6 years (IQR 11.8-36.9) from the first hospital contact. In total, 24 (16 male) cases of infective endocarditis among ASD patients and 10 (8 male) cases among controls were diagnosed during the follow-up. The incidence of endocarditis was 0.11 per 1000 person-years in the patients with ASD and 0.011 per 1000 person-years in the controls. The adjusted risk ratio for endocarditis was 13.51 (95% CI: 6.20-29.46) in patients with ASD compared to the control cohort. Patients with ASD and endocarditis had higher long-term mortality than individualized control patients (MRR 2.25, 95% CI: 1.23-4.11). Conclusions . The incidence of IE in patients with ASD was higher than in the general population. Mortality associated with IE was higher in patients with ASD compared to controls.

Objectives. To compare long-term angina pectoris relief of successful versus failed percutaneous coronary intervention of chronic total occlusions (CTO PCI). Background. Previous studies demonstrate better short-term angina pectoris relief of CTO PCI than with optimal medical treatment (OMT), however, data on the long-term effects are lacking. Methods. 295 patients undergoing CTO PCI were analyzed retrospectively, with a follow-up evaluation of symptoms of angina pectoris and all-cause death one to four years after the intervention. The primary outcome was long-term relief of symptoms of angina pectoris. Secondary outcomes included a composite of major adverse cardiovascular events (MACE), including all-cause death, myocardial infarction, stroke, and later target vessel revascularization (TVR). At follow-up, patients were interviewed for symptoms of angina pectoris at 1, 6, 12, and 22 to 48 months after the intervention. Results. CTO PCI was successful in 225 (76%) patients and failed in 70 (24%) patients. Short-term (six months) relief of angina pectoris was observed in both groups, but only the successful CTO PCI group showed long-term relief. The Kaplan-Meier curves of all-cause death did not differ between the groups ( p  = .715). The final follow-up was a mean (range) of 37 (25 to 44) months after the intervention in the successful CTO PCI group, and 33 (28 to 48) months in the failed CTO PCI group. Conclusions. Successful CTO PCI is associated with better long-term relief of symptoms of angina pectoris compared to failed CTO PCI.

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 MessagesNocturnal 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.

Background: Left ventricle (LV) optimized views are routinely used for left atrial (LA) volume and strain measurements on 2D echocardiography. This might be a source of the error because of the variation of the angle between the left atrial and left ventricle long axes (LA-LV angle), leading to foreshortening of the LA., Methods: We investigated two novel parameters: the angle between the left atrial and left ventricle long axes (LA-LV angle) and its deviation from the 4-chamber plane. To accurately measure the angles in 3D space, these measurements were performed using 3D echocardiography. We developed a method for the measurement based on marking anatomic points of reference in the 3D echocardiogram and measuring the angles between these points. We used three types of phantoms made of wood and agar-agar to investigate the repeatability and reproducibility of these measurements and performed measurements on human subjects., Results: The ultrasound measurements were in excellent agreement with the true angles of the phantoms: LA-LV angle bias was .5 degrees (95% CI -1.8 to +2.7) in the wooden phantoms and 1.2 degrees (-.7 to +3.1) in the agar-agar phantoms, while the angle deviation from the 4-chamber plane was -.9 degrees (-4.3 to +4.1) in the wooden phantoms and .0 degrees (-3.3 to +3.3) in the agar-agar phantoms. The measurements demonstrated good repeatability and reproducibility (Pearson correlation coefficients ranging from .91 to .99). The measurements from human hearts showed good repeatability (Pearson correlation was .81 for repeated LA-LV angle measurements and .97 for repeated measurements of the deviation from the 4-chamber plane)., Conclusion: The measurement of the LA-LV angle is a feasible tool to investigate one eventual error of 2D echocardiography., (© 2023 The Authors. Echocardiography published by Wiley Periodicals LLC.)

Background: Amiodarone is an effective antiarrhythmic drug, which interferes with cholesterol synthesis. In the human body, it inhibits two enzymes in the cholesterol-synthesis pathway, followed by increases especially in serum desmosterol and zymostenol concentrations and a decrease in that of serum lathosterol., Objectives: We explored whether desmosterol and zymostenol accumulate also in myocardial tissue during amiodarone treatment., Methods: Thirty-three patients admitted for cardiac transplantation volunteered for the study. Ten patients were on amiodarone treatment (AD group) and 23 were not (control group). The groups were matched as regards demographic and clinical variables. Myocardial samples were obtained from the removed hearts from 31 patients. Cholesterol, non-cholesterol sterols and squalene were quantified by means of gas-liquid chromatography., Results: In serum and myocardium, desmosterol was 19- and 18-fold higher and zymostenol 4- and 2-fold higher in the AD group versus the control group (p < 0.001 for all). In contrast, myocardial cholesterol, squalene and lathosterol levels were lower in the AD group than in the control group (p < 0.05 for all). Levels of phytosterols and cholestanol were similar in the serum and myocardium in the two groups. Levels of myocardial and serum desmosterol, zymostenol, lathosterol and phytosterols correlated with each other in both groups (p < 0.05 for all)., Conclusion: Amiodarone treatment caused the accumulation of desmosterol and zymostenol in myocardium. In particular, myocardial desmosterol concentrations were substantially elevated, which may play a part in some of the therapeutic and adverse effects of amiodarone treatment., (© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Competing Interests: Disclosures None.

Our aim was to investigate in a real-life prospective patient cohort how CYP2C19 loss-of-function (LOF) variants and CYP2C19 inhibitor omeprazole or esomeprazole influence the incidence of cardiovascular events in patients using clopidogrel. Data based simultaneously on these factors are conflicting and sparse. A cohort of prospective patients (n = 1972) with acute coronary syndrome (n = 1302) or symptomatic chronic coronary disease (n = 656) was followed for 365 days after hospitalization with information on purchased prescription drugs, hospital discharge, death, and genotype for CYP2C19*2, CYP2C19*3, and CYP2C19*8 LOF variants. The primary study outcome measurement was cardiovascular death or recurring myocardial infarction or stroke. Altogether, 608 patients (30.8%) carried CYP2C19 LOF alleles. During the 365-day follow-up 252 patients (12.8%) had an ischemic vascular event. Cardiovascular events were significantly more frequent in carriers of CYP2C19 LOF alleles (14.8%, 95% confidence interval [CI], 11.7-17.8) than in non-carriers (10.8%, 95% CI, 9.0-12.6, p = 0.0159). Omeprazole or esomeprazole use was similar among LOF allele carriers (n = 131, 21.5%) and non-carriers (n = 250, 18.3%, p = 0.185). Cardiovascular events were significantly more common in a composite group consisting of all CYP2C19 LOF carriers regardless of proton pump inhibitor use status and non-carriers using omeprazole or esomeprazole than in non-carriers not using omeprazole or esomeprazole (14.8%, 95% CI, 12.2-17.3 vs. 9.9%, 95% CI, 8.0-11.9, p = 0.00173). We observed significantly more cardiovascular events in carriers of CYP2C19 LOF variants and in non-carriers using omeprazole or esomeprazole. For optimal patient care, both genetics and concomitant medication should be considered., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Lowering elevated low-density lipoprotein cholesterol (LDL-C) concentrations reduces the risk of atherosclerotic cardiovascular diseases (ASCVDs). However, increasing evidence suggests that cholesterol metabolism may also be involved in the risk reduction of ASCVD events. In this review, we discuss if the different profiles of cholesterol metabolism, with a focus on high cholesterol absorption, are atherogenic, and what could be the possible mechanisms. The potential associations of cholesterol metabolism and the risk of ASCVDs are evaluated from genetic, metabolic, and population-based studies and lipid-lowering interventions. According to these studies, loss-of-function genetic variations in the small intestinal sterol transporters ABCG5 and ABCG8 result in high cholesterol absorption associated with low cholesterol synthesis, low cholesterol elimination from the body, and a high risk of ASCVDs. In contrast, loss-of-function genetic variations in another intestinal sterol transporter, NPC1L1 result in low cholesterol absorption associated with high cholesterol synthesis, elevated cholesterol elimination from the body, and low risk of ASCVDs. Statin monotherapy is not sufficient to reduce the ASCVD risk in cases of high cholesterol absorption, and these individuals need combination therapy of statin with cholesterol absorption inhibition. High cholesterol absorption, i.e., >60%, is estimated to occur in approximately one third of a population, so taking it into consideration is important to optimise lipid-lowering therapy to prevent atherosclerosis and reduce the risk of ASCVD events., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Piia Simonen declares no conflicts of interest. Katariina Öörni is co-inventor of a patent on LDL aggregation. Juha Sinisalo has taken part in consultative, research and educational cooperation with several companies marketing cholesterol-lowering products. Timo Strandberg has taken part in consultative, research and educational cooperation with several companies marketing cholesterol-lowering products. Ingmar Wester is employed by Raisio Group plc. and own shares in the company. Helena Gylling has taken part in educational and consultative collaboration regarding human cholesterol metabolism with Raisio Group plc., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: To evaluate the effect of hydroxychloroquine (HCQ) on serum and lipoprotein lipids and serum biomarkers of cholesterol synthesis and absorption in myocardial infarction patients with a high-dose statin., Methods: Myocardial infarction patients (n = 59) with a constant statin dose were randomized to receive hydroxychloroquine 300 mg (n = 31) or placebo (n = 28) daily for six months and followed up for one year., Results: Statin reduced total-c (-26 ± 22% in hydroxychloroquine and -28 ± 19% in placebo group, P = 0.931), LDL-c (-38 ± 26% vs. -44 ± 23%, respectively, P = 0.299), and cholesterol synthesis biomarkers zymostenol, desmosterol, and lathosterol ratios from baseline to one year (e.g., serum lathosterol ratio -17 ± 45% vs. -15 ± 41%, respectively, P < 0.001 for both, P = 0.623 between groups). Compensatorily, cholesterol absorption increased during the intervention (e.g., serum campesterol ratio 125 ± 90% vs. 113 ± 72%, respectively, P < 0.001 for both, P = 0.488 between groups). Hydroxychloroquine did not affect cholesterol concentrations or cholesterol absorption. It prevented the statin-induced increase in cholesterol precursor, desmosterol ratio, from six months to one year in the hydroxychloroquine group (P = 0.007 at one year compared to placebo)., Conclusions: Combined with a high-dose statin, hydroxychloroquine had no additional effect on serum cholesterol concentration or cholesterol absorption. However, the findings suggest that hydroxychloroquine interferes with lanosterol synthesis, and thereafter, it temporarily interferes with the cholesterol synthesis pathway, best seen in halting the increase of the desmosterol ratio.Trial Registration ClinicalTrials.gov Identifier: NCT02648464., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Purpose: We evaluated the residual vascular and adipose tissue inflammation in patients with chronic coronary artery disease (CAD) using positron emission tomography (PET)., Methods: Our study population consisted of 98 patients with known CAD and 94 control subjects who had undergone 18 F-fluorodeoxyglucose ( 18 F-FDG) PET due to non-cardiac reasons. Aortic root and vena cava superior 18 F-FDG uptake were measured to obtain the aortic root target-to-background ratio (TBR). In addition, adipose tissue PET measurements were done in pericoronary, epicardial, subcutaneous, and thoracic adipose tissue. Adipose tissue TBR was calculated using the left atrium as a reference region. Data are presented as mean ± standard deviation or as median (interquartile range)., Results: The aortic root TBR was higher in CAD patients compared to control subjects, 1.68 (1.55-1.81) vs. 1.53 (1.43-1.64), p  < 0.001. Subcutaneous adipose tissue uptake was elevated in CAD patients 0.30 (0.24-0.35) vs. 0.27 (0.23-0.31), p  < 0.001. Metabolic activity of CAD patients and control subjects was comparable in the pericoronary (0.81 ± 0.18 vs. 0.80 ± 0.16, p  = 0.59), epicardial (0.53 ± 0.21 vs. 0.51 ± 0.18, p  = 0.38) and thoracic (0.31 ± 0.12 vs. 0.28 ± 0.12, p  = 0.21) adipose tissue regions. Aortic root or adipose tissue 18 F-FDG uptake was not associated with the common CAD risk factors, coronary calcium score, or aortic calcium score ( p value > 0.05)., Conclusion: Patients with a chronic CAD had a higher aortic root and subcutaneous adipose tissue 18 F-FDG uptake compared to control patients, which suggests residual inflammatory risk., Competing Interests: Competing InterestsValtteri Uusitalo had advisory board activity and lecture fees from Pfizer. Sini Toivonen, Miia Lehtinen, Peter Raivio, Juha Sinisalo and Antti Loimaala declare no conflict of interest., (© The Author(s) 2022.)

Background: Coarctation of the aorta (CoA), a congenital narrowing of the proximal descending thoracic aorta, is a relatively common form of congenital heart disease. Untreated significant CoA has a major impact on morbidity and mortality. In the past 3 decades, transcatheter intervention (TCI) for CoA has evolved as an alternative to surgery., Objectives: The authors report on all TCIs for CoA performed from 2000 to 2016 in 4 countries covering 25 million inhabitants, with a mean follow-up duration of 6.9 years., Methods: During the study period, 683 interventions were performed on 542 patients., Results: The procedural success rate was 88%, with 9% considered partly successful. Complications at the intervention site occurred in 3.5% of interventions and at the access site in 3.5%. There was no in-hospital mortality. During follow-up, TCI for CoA reduced the presence of hypertension significantly from 73% to 34%, but despite this, many patients remained hypertensive and in need of continuous antihypertensive treatment. Moreover, 8% to 9% of patients needed aortic and/or aortic valve surgery during follow-up., Conclusions: TCI for CoA can be performed with a low risk for complications. Lifetime follow-up after TCI for CoA seems warranted., Competing Interests: Funding Support and Author Disclosures This work was funded by the Swedish state under the ALF agreement (grant 236611) and the Swedish Heart-Lung Foundation (grant 20180644) and Forskningsstiftelsen vid kardiologiska sektionen SU/Ostra Hospital. This study received no financial or other industry support. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background This study aimed to evaluate the long-term mortality and cause-specific mortality of patients with atrial septal defect (ASD) in a nationwide cohort. Methods and Results All patients diagnosed with simple ASD in the hospital discharge registry from 1969 to 2019 were included in the study. Complex congenital defects were excluded. Each subject was matched with 5 controls according to sex, age, and municipality at the index time. Adjusted mortality risk ratios (MRRs) were calculated using Poisson regression models. The median follow-up time was 11.1 years. Patients with ASD had higher overall mortality during follow-up, with an adjusted MRR of 1.72 (95% CI, 1.61-1.83). Patients with closed ASDs also had higher total mortality (MRR, 1.29 [95% CI, 1.10-1.51]). However, no difference in mortality was detected if the defect was closed before the age of 30 (MRR, 1.58 [95% CI, 0.90-2.77]), and transcatheter closed defects had lower mortality than the control cohort (MRR, 0.65 [95% CI, 0.42-0.99]). Patients with ASD had significantly more deaths due to congenital malformations (MRR, 54.61 [95% CI, 34.03-87.64]), other diseases of the circulatory system (MRR, 2.90 [95% CI, 2.42-3.49]), stroke (MRR, 1.89 [95% CI, 1.52-2.33]), diseases of the endocrine (MRR, 1.88 [95% CI, 1.10-3.22]) and respiratory system (MRR, 1.71 [95% CI, 1.19-2.45]), ischemic heart disease (MRR, 1.62 [95% CI, 1.41-1.86]), and accidents (MRR, 1.41 [95% CI, 1.05-1.89]). Conclusions Patients with ASD had higher overall mortality compared with a matched general population cohort. Increased cause-specific mortality was seen in congenital malformations, stroke, and heart diseases.

Background: Statin medication improves the prognosis of patients with lower extremity artery disease (LEAD). Research has previously focused on patients with a lowered ankle brachial index (ABI) excluding patients with a normal or elevated ankle brachial index. The aim of this study was to analyze the impact of statin use on survival and cardiovascular mortality in patients with LEAD of different severity depicted by the ABI level. Patients and methods: 4128 ABI measurements by trained and experienced nurses between 2000 and 2009 were combined with medication data from the Social Insurance Institution and causes of death data from the national causes of death registry. End of follow-up was set at the end of 2014. The data of statin use included all statin medication with the Anatomical Therapeutic Chemical (ATC) classification codes between C10AA01 and C10AA08. Results: 1956 (47.4%) patients had statin medication. Statin use was associated with improved overall survival and amputation free survival (AFS) on all ABI levels. When adjusted for age, sex and diabetes the greatest overall survival benefit from statin use was for the patients with ABI>1.3 (hazard ratio, HR: 0.67, 95% CI: 0.48-0.94, p =0.020, reference group statin non-users) and ABI 0.9-1.3 (HR: 0.78, 95% CI: 0.65-0.94, p =0.008). In propensity score matched pairs statin treatment was associated with significantly lower all-cause mortality ( p< 0.0001), cardiovascular mortality ( p= 0.034), cerebrovascular mortality ( p= 0.003) and embolic stroke related mortality ( p= 0.001) in patients with ABI >1.3 or <0.9. Overall survival benefit was significant in females with ABI<0.5 and in males across several ABI levels. Conclusions: According to our study, statins seem to improve overall and amputation free survival regardless of ABI level. Statin use was associated with lower mortality from cerebrovascular disease, overall mortality and in the propensity score matched patients with ABI<0.9 or >1.3 with cardiovascular mortality.

Background: Clinical implications of different types of vascular calcification are poorly understood. The two most abundant forms of calcification, nodular and sheet calcification, have not been quantitatively analyzed in relation to the clinical presentation of lower extremity arterial disease (LEAD)., Methods: The study analyzed 51 femoral artery plaques collected during femoral endarterectomy, characterized by the presence of > 90% stenosis. Comprehensive clinical data was obtained from patient records, including magnetic resonance angiography (MRA) images, toe pressure and ankle brachial index measurements and laboratory values. The plaques were longitudinally sectioned, stained with Hematoxylin and Eosin and digitized in a deep learning platform for quantification of the relative area of nodular and sheet calcification to the plaque section area. A deep learning artificial intelligence algorithm was designed and independently validated to reliably quantify nodular calcification and sheet calcification. Vessel measurements and quantity of each calcification category was compared to the risk factors and clinical presentation., Results: On average, > 90% stenosed vessels contained 22.4 ± 12.3% of nodular and 14.5 ± 11.8% of sheet calcification. Nodular calcification area proportion in lesions with > 90% stenosis is associated with reduced risk of critically low toe pressure (< 30 mmHg) (OR = 0.910, 95% CI = 0.835-0.992, p < 0.05), severely lowered ankle brachial index (< 0.4) (OR = 0.912, 95% CI = 0.84-0.986, p < 0.05), and semi-urgent operation (OR = 0.882, 95% CI = 0.797-0.976, p < 0.05). Sheet calcification did not show any significant association., Conclusions: Large amount of nodular calcification is associated with less severe LEAD. Patients with nodular calcification may have better flow reserves despite local obstruction., (© 2022. The Author(s).)

The populational heterogeneity of a disease, in part due to comorbidity, poses several complexities. Individual comorbidity profiles, on the other hand, contain useful information to refine phenotyping, prognostication, and risk assessment, and they provide clues to underlying biology. Nevertheless, the spectrum and the implications of the diagnosis profiles remain largely uncharted. Here we mapped comorbidity patterns in 100 common diseases using 4-year retrospective data from 526,779 patients and developed an online tool to visualize the results. Our analysis exposed disease-specific patient subgroups with distinctive diagnosis patterns, survival functions, and laboratory correlates. Computational modeling and real-world data shed light on the structure, variation, and relevance of populational comorbidity patterns, paving the way for improved diagnostics, risk assessment, and individualization of care. Variation in outcomes and biological correlates of a disease emphasizes the importance of evaluating the generalizability of current treatment strategies, as well as considering the limitations that selective inclusion criteria pose on clinical trials., (© 2022. The Author(s).)

To elucidate underlying disease mechanisms, we compared transition of gadolinium-based contrast agent bolus in cardiac chambers in magnetic resonance imaging between young patents with cryptogenic ischemic stroke and stroke-free controls. We included 30 patients aged 18-50 years with cryptogenic ischemic stroke from the prospective Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers and Outcome (NCT01934725) study and 30 age- and gender-matched stroke-free controls. Dynamic contrast-enhanced T1-weighted first-pass perfusion images were acquired at 1.5 T and analyzed for transit time variables, area under curves, relative blood flow, and maximum and minimum enhancement rates in left atrial appendage, left atrium, and left ventricle. These data were compared with previously published left ventricular non-compaction data of the same study population. Arrival time of contrast agent bolus in superior vena cava was similar in patients and controls (6.7[2.0] vs. 7.1[2.5] cardiac cycles, P = 0.626). Arrival and peak times showed comparable characteristics in patients and controls (P > 0.535). The minimum enhancement rate of the left ventricle was lower in patients than in controls (- 28 ± 11 vs. - 36 ± 13 1/(cardiac cycle), P = 0.012). Area under curves, relative blood flow, and other enhancement rates showed no significant differences between patients and controls (P > 0.107). Relative blood flow of cardiac chambers correlated with non-compacted left ventricular volume ratio (P < 0.011). Our results indicate slower washout of contrast agent and blood flow stagnation in the left ventricle of young patients with cryptogenic ischemic stroke. The washout was associated with left ventricular non-compaction, suggesting conditions favoring formation of intraventricular thrombosis., (© 2022. The Author(s).)

Objective: Oxidized epitopes such as malondialdehyde-acetaldehyde (MAA) play a crucial role in the progression of atherosclerosis through activation of the humoral immune response. The exact mechanism of the association between atherosclerosis and periodontal diseases is not fully understood. The aim of the current study is to evaluate the association of oral humoral immune response to oxidized epitopes with parameters of periodontal disease., Materials and Methods: The Parogene cohort consist of patients who have undergone coronary angiography due to cardiac symptoms. In this study, 423 patients were randomly selected for an extensive oral examination. Salivary Immunoglobulin A to oxidized epitopes and bacterial antigens was determined by chemiluminescence immunoassay., Results: In a binary logistic regression model adjusted with periodontal disease confounders, periodontal pocket depth (PPD) 4-5 mm associated with salivary IgA antibodies to MAA-LDL (p = 0.034), heat shock protein 60 of Aggregatibacter actinomycetemcomitans (p = 0.045), Porphyromonas gingivalis (p = 0.045), A. actinomycetemcomitans (p = 0.005), P. intermedia (p = 0.020), and total IgA (p = 0.003)., Conclusions: The current study shows the association of salivary IgA to MAA-LDL with PPD 4-5 mm in a cohort of patients with chronic coronary artery disease. Humoral immune cross-reactivation to oxidized epitopes such MAA-LDL could partly explain the link of periodontitis with systemic diseases., (© 2021 The Authors. Oral Diseases published by Wiley Periodicals LLC.)

Background: In our recent genome-wide association study, we found that genetic polymorphisms in the complement factor H (CFH) gene and S100A gene region are strongly associated with serum matrix metalloproteinase 8 (MMP-8) concentration and the release of MMP-8 from neutrophils. As MMP-8 is centrally involved in the pathogenesis of periodontitis, we aimed to evaluate the presence of genetic polymorphisms of S100A8/A9/A12, MMP8, and CFH in periodontitis. In addition, we studied whether polymorphisms of these genes affect the concentrations of S100A8, S100A12, MMP-8, or complement activation marker in saliva., Methods: We genotyped four single-nucleotide polymorphisms (SNPs, rs1560833 in S100A8/A9/A12, rs11225395 in MMP8, rs800292 in CFH, and rs1061170 in CFH) and measured salivary concentrations of S100A8, S100A12, MMP-8, and terminal complement complex (TCC) in the Parogene cohort (n = 508). The cohort was composed of patients with an indication to coronary angiography and all underwent a clinical and radiographic oral examination., Results: CFH polymorphisms rs800292 and rs1061170 were associated with periodontal parameters. None of the polymorphisms showed association with salivary proteins. However, salivary concentrations of S100A8, S100A12, MMP-8, and TCC were strongly associated with the number of periodontal pockets and alveolar bone loss., Conclusion: Interestingly, genetic variants of CFH, MMP8, and S100A8/A9/A12 gene regions did not affect salivary levels of measured proteins. However, saliva levels of S100A8, S100A12, MMP-8, and TCC, and CFH polymorphisms were associated with clinical and radiographic signs of periodontitis. Our study further supports the observations that any dysregulation of complement may increase the risk of inflammatory disorders, such as periodontitis., (© 2022 The Authors. Journal of Periodontology published by Wiley Periodicals LLC on behalf of American Academy of Periodontology.)

Hyperactive poly(ADP-ribose) polymerases (PARP) promote ischemic heart failure (IHF) after myocardial infarction (MI). However, the role of tankyrases (TNKSs), members of the PARP family, in pathogenesis of IHF remains unknown. We investigated the expression and activation of TNKSs in myocardium of IHF patients and MI rats. We explored the cardioprotective effect of TNKS inhibition in an isoproterenol-induced zebrafish HF model. In IHF patients, we observed elevated TNKS2 and DICER and concomitant upregulation of miR-34a-5p and miR-21-5p in non-infarcted myocardium. In a rat MI model, we found augmented TNKS2 and DICER in the border and infarct areas at the early stage of post-MI. We also observed consistently increased TNKS1 in the border and infarct areas and destabilized AXIN in the infarct area from 4 weeks onward, which in turn triggered Wnt/β-catenin signaling. In an isoproterenol-induced HF zebrafish model, inhibition of TNKS activity with XAV939, a TNKSs-specific inhibitor, protected against ventricular dilatation and cardiac dysfunction and abrogated overactivation of Wnt/β-catenin signaling and dysregulation of miR-34a-5p induced by isoproterenol. Our study unravels a potential role of TNKSs in the pathogenesis of IHF by regulating Wnt/β-catenin signaling and possibly modulating miRNAs and highlights the pharmacotherapeutic potential of TNKS inhibition for prevention of IHF.

Background and Purpose: We aimed to assess the association between covert atherosclerosis, arterial stiffness, and early-onset cryptogenic ischemic stroke (CIS) in a prospective case-control study., Methods: We enrolled 123 young CIS patients (median age 41 years; 42% women) and 123 age- and sex-matched controls. Carotid intima-media thickness (CIMT), Augmentation Index (AIx), central pulse wave velocity (PWV), and subendocardial viability ratio (SEVR) were compared between patients and controls. Conditional logistic regression was used adjusting for age, systolic blood pressure, diastolic blood pressure, current smoking, total cholesterol/high-density lipoprotein cholesterol (Total-C/HDL-C) ratio, and glycated albumin to assess the independent association between CIMT, arterial stiffness and CIS., Results: Patients with higher CIMT and PWV were older, more often men and they had more frequently well-documented risk factors, lower HDL and higher Total-C/HDL-C ratio compared to other tertiles. In univariate comparisons, we found no differences between patients and controls regarding CIMT, AIx, or PWV. In the entire cohort, patients had a significantly lower SEVR compared to controls (146.3%, interquartile range [IQR] 125.7-170.3 vs. 158.0%, IQR 141.3-181.0, P=0.010). SEVR was lower also in women compared to their controls (132.0%, IQR 119.4-156.1 vs. 158.7%, IQR 142.0-182.8, P=0.001) but no significant difference appeared between male patients and male controls. However, after adjusting for comorbidities and laboratory values these significant differences were lost (odds ratio [OR] 1.52, 95% confidence interval [CI] 0.47-4.91) in the entire cohort and OR 3.89, 95% CI 0.30-50.80 in women)., Conclusions: Higher CIMT and PWV were associated to higher age, male sex, and several well-documented cardiovascular risk factors. However, in this study we could not prove that either covert atherosclerosis or arterial stiffness contribute to pathogenesis of early-onset CIS., Competing Interests: Declaration of Competing Interest D.G. has received lecture or advisory honoraria from AstraZeneca, Boehringer Ingelheim, Fresenius, GE Healthcare, and Novo Nordisk, and support to attend medical meetings from CVRx and Sanofi Aventis, T.T.: Academic grants from European Union, Finnish Academy of Sciences, University of Gothenburg, Sahlgrenska University Hospital, Sigrid Juselius Foundation, and Wennerström's Foundation. Research contracts with Bayer, Boehringer Ingelheim, and Bristol Myers Squibb. Advisory board memberships: Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Portola Pharm. Other authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)