Browsing by Subject "HEART"

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  • Beauchamp, Philippe; Jackson, Christopher B.; Ozhathil, Lijo Cherian; Agarkova, Irina; Galindo, Cristi L.; Sawyer, Douglas B.; Suter, Thomas M.; Zuppinger, Christian (2020)
    Purpose: Both cardiomyocytes and cardiac fibroblasts (CF) play essential roles in cardiac development, function, and remodeling. Properties of 3D co-cultures are incompletely understood. Hence, 3D co-culture of cardiomyocytes and CF was characterized, and selected features compared with single-type and 2D culture conditions.Methods: Human cardiomyocytes derived from induced-pluripotent stem cells (hiPSC-CMs) were obtained from Cellular Dynamics or Ncardia, and primary human cardiac fibroblasts from ScienCell. Cardiac spheroids were investigated using cryosections and whole-mount confocal microscopy, video motion analysis, scanning-, and transmission-electron microscopy (SEM, TEM), action potential recording, and quantitative PCR (qPCR).Results: Spheroids formed in hanging drops or in non-adhesive wells showed spontaneous contractions for at least 1 month with frequent media changes. SEM of mechanically opened spheroids revealed a dense inner structure and no signs of blebbing. TEM of co-culture spheroids at 1 month showed myofibrils, intercalated disc-like structures and mitochondria. Ultrastructural features were comparable to fetal human myocardium. We then assessed immunostained 2D cultures, cryosections of spheroids, and whole-mount preparations by confocal microscopy. CF in co-culture spheroids assumed a small size and shape similar to the situation in ventricular tissue. Spheroids made only of CF and cultured for 3 weeks showed no stress fibers and strongly reduced amounts of alpha smooth muscle actin compared to early spheroids and 2D cultures as shown by confocal microscopy, western blotting, and qPCR. The addition of CF to cardiac spheroids did not lead to arrhythmogenic effects as measured by sharp-electrode electrophysiology. Video motion analysis showed a faster spontaneous contraction rate in co-culture spheroids compared to pure hiPSC-CMs, but similar contraction amplitudes and kinetics. Spontaneous contraction rates were not dependent on spheroid size. Applying increasing pacing frequencies resulted in decreasing contraction amplitudes without positive staircase effect. Gene expression analysis of selected cytoskeleton and myofibrillar proteins showed more tissue-like expression patterns in co-culture spheroids than with cardiomyocytes alone or in 2D culture.Conclusion: We demonstrate that the use of 3D co-culture of hiPSC-CMs and CF is superior over 2D culture conditions for co-culture models and more closely mimicking the native state of the myocardium with relevance to drug development as well as for personalized medicine.
  • Hänninen, Mikko; Jäntti, Toni; Tolppanen, Heli; Segersvärd, Heli; Tarvasmäki, Tuukka; Lassus, Johan; Vausort, Melanie; Devaux, Yvan; Sionis, Alessandro; Tikkanen, Ilkka; Harjola, Veli-Pekka; Lakkisto, Päivi (2020)
    Cardiogenic shock (CS) is a life-threatening emergency. New biomarkers are needed in order to detect patients at greater risk of adverse outcome. Our aim was to assess the characteristics of miR-21-5p, miR-122-5p, and miR-320a-3p in CS and evaluate the value of their expression levels in risk prediction. Circulating levels of miR-21-5p, miR-122-5p, and miR-320a-3p were measured from serial plasma samples of 179 patients during the first 5-10 days after detection of CS, derived from the CardShock study. Acute coronary syndrome was the most common cause (80%) of CS. Baseline (0 h) levels of miR-21-5p, miR-122-5p, and miR-320a-3p were all significantly elevated in nonsurvivors compared to survivors (p <0.05 for all). Above median levels at 0h of each miRNA were each significantly associated with higher lactate and alanine aminotransferase levels and decreased glomerular filtration rates. After adjusting the multivariate regression analysis with established CS risk factors, miR-21-5p and miR-320a-3p levels above median at 0 h were independently associated with 90-day all-cause mortality (adjusted hazard ratio 1.8 (95% confidence interval 1.1-3.0), p = 0.018; adjusted hazard ratio 1.9 (95% confidence interval 1.2-3.2), p = 0.009, respectively). In conclusion, circulating plasma levels of miR-21-5p, miR-122-5p, and miR-320a-3p at baseline were all elevated in nonsurvivors of CS and associated with markers of hypoperfusion. Above median levels of miR-21-5p and miR-320a-3p at baseline appear to independently predict 90-day all-cause mortality. This indicates the potential of miRNAs as biomarkers for risk assessment in cardiogenic shock.
  • Iborra-Egea, Oriol; Rueda, Ferran; Lakkisto, Päivi; Harjola, Veli-Pekka; Garcia-Garcia, Cosme; Bayes-Genis, Antoni (2019)
  • Becker, Anna; Backman, Janne T.; Itkonen, Outi (2020)
    Introduction: Life-long monitoring of immunosuppressive drugs (ISDs) in blood is essential after organ transplantation. However, the ISD concentrations vary depending on the assay employed. ISDs are strongly bound to cytoplasmic proteins in erythrocytes in circulation. Therefore, the relatively rapid sedimentation of blood cells in whole blood samples may affect the results when using liquid handling robots. Methods: We used 1115 blood samples from outpatients and ward patients with kidney (n = 373), liver (n = 101), heart (n = 29) and bone marrow (n = 155) transplant. Whole blood samples were pretreated by protein precipitation. Alternatively, the samples were hemolyzed by freezing prior to precipitation. ISDs were analyzed by a 2-plexing liquid chromatography tandem mass spectrometry (LC-MS/MS) assay and commercial chemiluminescent microparticle immunoassays (CMIA). Results: The difference between the two sample preparation practices was negligible (<2%). Overall, the measured ISD concentrations in patient samples were lower by LC-MS/MS than by CMIA. The difference was the largest (20.2%) and the smallest (9.1%) in samples from liver and from heart transplant patients, respectively. Conclusions: CMIA overestimates blood ISD concentrations as compared to LC-MS/MS. The extent of the difference was found to be organ transplant dependent. The ISDs can be quantitated either from intact or hemolyzed blood samples.
  • Dellgren, Goran; Lund, Thomas Kromann; Raivio, Peter; Leuckfeld, Inga; Svahn, Johan; Magnusson, Jesper; Riise, Gerdt C. (2020)
    Background A low level of evidence exists regarding the choice of calcineurin inhibitor (CNI) for immunosuppression after lung transplantation (LTx). Therefore, we designed a randomized clinical trial according to good clinical practice rules to compare tacrolimus with cyclosporine after LTx. Methods The ScanCLAD study is an investigator-initiated, pragmatic, controlled, randomized, open-label, multicenter study evaluating if an immunosuppressive protocol based on anti-thymocyte globulin (ATG) induction, once-daily tacrolimus dose, mycophenolate mofetil, and corticosteroid reduces the incidence of chronic lung allograft dysfunction (CLAD) after LTx, compared to a cyclosporine-based protocol with all other immunosuppressive and prophylactic drugs being identical between groups. All patients will be followed for 3 years to determine the main endpoint of CLAD. The study is designed for superiority, and power calculations show that 242 patients are needed. Also, the study is designed with more than 10 substudies addressing other important and unresolved issues in LTx. In addition, the ScanCLAD study enabled the synchronization of the treatment and follow-up protocols of the lung transplantation programs of all five Scandinavian lung transplantation centers. Planned Outcomes Recruitment started in 2016. At the end of April 2019, 227 patients were randomized. We anticipate the last patient to be randomized in autumn 2019, and thus the last patient visits will be in 2022. The ScanCLAD study is enrolling and investigates which CNI is to be preferred from a CLAD perspective after LTx. Trial Registry Number ScanCLAD trial registered at ClinicalTrials.gov before patient enrollment (NCT02936505). EUDRACT number 2015-004137-27.
  • Sarja, Henna; Anttila, Tuomas; Mustonen, Caius; Honkanen, Hannu-Pekka; Herajarvi, Johanna; Haapanen, Henri; Tuominen, Hannu; Miinalainen, Ilkka; Juvonen, Tatu; Anttila, Vesa (2017)
    Background: We hypothesized that diazoxide, a mitochondrial ATP-sensitive potassium channel opener, has cardioprotective effects during acute myocardial ischemia. Diazoxide is suggested to act through protein kinase Ce (PKC epsilon) activation. Methods: Twelve piglets were randomly assigned to receive intravenous infusion of diazoxide (3.5 mg/kg) with solvent or only solvent (6 animals per group) before cardiac ischemia. Myocardial ischemia was induced by occluding the left circumflex artery (LCX) for 40 minutes. The reperfusion and follow-up period lasted for three hours. Throughout the experiment hemodynamic measurements and blood samples were collected, and after the follow-up period the hearts were harvested for transmission electron microscopy (TEM) as well as histopathological and immunohistochemical analyses. Results: TEM showed less ischemic damage on a cellular level in the diazoxide group (P = .004) than in the control group. Creatinine kinase MB levels (Pt*g = .030) were lower, and oxygen consumption (Pt*g = .037) and delivery (Pg = .038) were higher in the diazoxide group compared to the controls. Conclusion: Diazoxide preserves myocardial cellular structure and cellular function, and thus it may have benefits in treating ischemic myocardial injury.
  • Rajendran, Jayasimman; Tomasic, Nikica; Kotarsky, Heike; Hansson, Eva; Velagapudi, Vidya; Kallijarvi, Jukka; Fellman, Vineta (2016)
    Mitochondrial disorders cause energy failure and metabolic derangements. Metabolome profiling in patients and animal models may identify affected metabolic pathways and reveal new biomarkers of disease progression. Using liver metabolomics we have shown a starvation-like condition in a knock-in (Bcs1l(c.232A>G)) mouse model of GRACILE syndrome, a neonatal lethal respiratory chain complex III dysfunction with hepatopathy. Here, we hypothesized that a high-carbohydrate diet (HCD, 60% dextrose) will alleviate the hypoglycemia and promote survival of the sick mice. However, when fed HCD the homozygotes had shorter survival (mean +/- SD, 29 +/- 2.5 days, n = 21) than those on standard diet (33 +/- 3.8 days, n = 30), and no improvement in hypoglycemia or liver glycogen depletion. We investigated the plasma metabolome of the HCD- and control diet-fed mice and found that several amino acids and urea cycle intermediates were increased, and arginine, carnitines, succinate, and purine catabolites decreased in the homozygotes. Despite reduced survival the increase in aromatic amino acids, an indicator of liver mitochondrial dysfunction, was normalized on HCD. Quantitative enrichment analysis revealed that glycine, serine and threonine metabolism, phenylalanine and tyrosine metabolism, and urea cycle were also partly normalized on HCD. This dietary intervention revealed an unexpected adverse effect of high-glucose diet in complex III deficiency, and suggests that plasma metabolomics is a valuable tool in evaluation of therapies in mitochondrial disorders.
  • Bhide, Amarnath; Räsänen, Juha; Huhta, Heikki; Junno, Juulia; Erkinaro, Tiina; Ohtonen, Pasi; Haapsamo, Mervi; Acharya, Ganesh (2017)
    We hypothesized that in near-term sheep fetuses, hypoxemia changes myocardial function as reflected in altered ventricular deformation on speckle-tracking echocardiography. Fetuses in 21 pregnant sheep were instrumented. After 4 d of recovery, fetal cardiac function was assessed by echocardiography at baseline, after 30 and 120 min of induced fetal hypoxemia and after its reversal. Left (LV) and right (RV) ventricular cardiac output and myocardial strain were measured. Baseline mean (standard deviation [ SD]) LV and RV global longitudinal strains were -18.7% (3.8) and -14.3% (5.3). Baseline RV global longitudinal and circumferential deformations were less compared with those of the left ventricle (p = 0.016 and p <0.005). LV, but not RV, global longitudinal strain was decreased (p = 0.003) compared with baseline with hypoxemia. Circumferential and radial strains did not exhibit significant changes. In the near-term sheep fetus, LV global longitudinal and circumferential strains are more negative than RV strains. Acute hypoxemia leads to LV rather than RV dysfunction as reflected by decreased deformation. (C) 2017 World Federation for Ultrasound in Medicine & Biology.
  • Nowak, Christoph; Salihovic, Samira; Ganna, Andrea; Brandmaier, Stefan; Tukiainen, Taru; Broeckling, Corey D.; Magnusson, Patrik K.; Prenni, Jessica E.; Wang-Sattler, Rui; Peters, Annette; Strauch, Konstantin; Meitinger, Thomas; Giedraitis, Vilmantas; Arnlov, Johan; Berne, Christian; Gieger, Christian; Ripatti, Samuli; Lind, Lars; Pedersen, Nancy L.; Sundstrom, Johan; Ingelsson, Erik; Fall, Tove (2016)
    Insulin resistance (IR) and impaired insulin secretion contribute to type 2 diabetes and cardiovascular disease. Both are associated with changes in the circulating metabolome, but causal directions have been difficult to disentangle. We combined untargeted plasma metabolomics by liquid chromatography/mass spectrometry in three non-diabetic cohorts with Mendelian Randomization (MR) analysis to obtain new insights into early metabolic alterations in IR and impaired insulin secretion. In up to 910 elderly men we found associations of 52 metabolites with hyperinsulinemic-euglycemic clamp-measured IR and/or beta-cell responsiveness (disposition index) during an oral glucose tolerance test. These implicated bile acid, glycerophospholipid and caffeine metabolism for IR and fatty acid biosynthesis for impaired insulin secretion. In MR analysis in two separate cohorts (n = 2,613) followed by replication in three independent studies profiled on different metabolomics platforms (n = 7,824 / 8,961 / 8,330), we discovered and replicated causal effects of IR on lower levels of palmitoleic acid and oleic acid. A trend for a causal effect of IR on higher levels of tyrosine reached significance only in meta-analysis. In one of the largest studies combining "gold standard" measures for insulin responsiveness with non-targeted metabolomics, we found distinct metabolic profiles related to IR or impaired insulin secretion. We speculate that the causal effects on monounsaturated fatty acid levels could explain parts of the raised cardiovascular disease risk in IR that is independent of diabetes development.
  • Bhide, Amarnath; Alanne, Leena; Rasanen, Juha; Huhta, Heikki; Junno, Juulia; Kokki, Merja; Erkinaro, Tiina; Ohtonen, Pasi; Haapsamo, Mervi; Acharya, Ganesh (2019)
    Sildenafil is a potential new treatment for placental insufficiency in human pregnancies as it reduces the breakdown of vasodilator nitric oxide. Pulmonary vasodilatation is observed in normoxemic fetuses following sildenafil administration. Placental insufficiency often leads to fetal hypoxemia that can cause pulmonary vasoconstriction and fetal cardiac dysfunction as evidenced by reduced isovolumic myocardial velocities. We tested the hypotheses that sildenafil, when given directly to the hypoxemic fetus, reverses reactive pulmonary vasoconstriction, increases left ventricular cardiac output by increasing pulmonary venous return, and ameliorates hypoxemic myocardial dysfunction. We used an instrumented sheep model. Fetuses were made hypoxemic over a mean (standard deviation) duration of 41.3 (9.5) minutes and then given intravenous sildenafil or saline infusion. Volume blood flow through ductus arteriosus was measured with an ultrasonic transit-time flow probe. Fetal left and right ventricular outputs and lung volume blood flow were calculated, and ventricular function was examined using echocardiography. Lung volume blood flow decreased and the ductus arteriosus volume blood flow increased with hypoxemia. There was a significant reduction in left ventricular and combined cardiac outputs during hypoxemia in both groups. Hypoxemia led to a reduction in myocardial isovolumic velocities, increased ductus venosus pulsatility, and reduced left ventricular myocardial deformation. Direct administration of sildenafil to hypoxemic fetus did not reverse the redistribution of cardiac output. Furthermore, fetal cardiac systolic and diastolic dysfunction was observed during hypoxemia, which was not improved by fetal sildenafil treatment. In conclusion, sildenafil did not improve pulmonary blood flow or cardiac function in hypoxemic sheep fetuses.
  • Zannas, Anthony S.; Jia, Meiwen; Hafner, Kathrin; Baumert, Jens; Wiechmann, Tobias; Pape, Julius C.; Arloth, Janine; Ködel, Maik; Martinelli, Silvia; Roitman, Maria; Roeh, Simone; Haehle, Andreas; Emeny, Rebecca T.; Iurato, Stella; Carrillo-Roa, Tania; Lahti, Jari; Räikkönen, Katri; Eriksson, Johan G.; Drake, Amanda J.; Waldenberger, Melanie; Wahl, Simone; Kunze, Sonja; Lucae, Susanne; Bradley, Bekh; Gieger, Christian; Hausch, Felix; Smith, Alicia K.; Ressler, Kerry J.; Mueller-Myhsok, Bertram; Ladwig, Karl-Heinz; Rein, Theo; Gassen, Nils C.; Binder, Elisabeth B. (2019)
    Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-kappa B-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-kappa B regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-kappa B. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-kappa B through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-kappa B signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.
  • Levy, Bruno; Clere-Jehl, Raphael; Legras, Annick; Morichau-Beauchant, Tristan; Leone, Marc; Frederique, Ganster; Quenot, Jean-Pierre; Kimmoun, Antoine; Cariou, Alain; Lassus, Johan; Harjola, Veli-Pekka; Meziani, Ferhat; Louis, Guillaume; Rossignol, Patrick; Duarte, Kevin; Girerd, Nicolas; Mebazaa, Alexandre; Vignon, Philippe (2018)
    BACKGROUND Vasopressor agents could have certain specific effects in patients with cardiogenic shock (CS) after myocardial infarction, which may influence outcome. Although norepinephrine and epinephrine are currently the most commonly used agents, no randomized trial has compared their effects, and intervention data are lacking. OBJECTIVES The goal of this paper was to compare in a prospective, double-blind, multicenter, randomized study, the efficacy and safety of epinephrine and norepinephrine in patients with CS after acute myocardial infarction. METHODS The primary efficacy outcome was cardiac index evolution, and the primary safety outcome was the occurrence of refractory CS. Refractory CS was defined as CS with sustained hypotension, end-organ hypoperfusion and hyperlactatemia, and high inotrope and vasopressor doses. RESULTS Fifty-seven patients were randomized into 2 study arms, epinephrine and norepinephrine. For the primary efficacy endpoint, cardiac index evolution was similar between the 2 groups (p = 0.43) from baseline (H0) to H72. For the main safety endpoint, the observed higher incidence of refractory shock in the epinephrine group (10 of 27 [37%] vs. norepinephrine 2 of 30 [7%]; p = 0.008) led to early termination of the study. Heart rate increased significantly with epinephrine from H2 to H24 while remaining unchanged with norepinephrine (p <0.0001). Several metabolic changes were unfavorable to epinephrine compared with norepinephrine, including an increase in cardiac double product (p = 0.0002) and lactic acidosis from H2 to H24 (p <0.0001). CONCLUSIONS In patients with CS secondary to acute myocardial infarction, the use of epinephrine compared with norepinephrine was associated with similar effects on arterial pressure and cardiac index and a higher incidence of refractory shock. (Study Comparing the Efficacy and Tolerability of Epinephrine and Norepinephrine in Cardiogenic Shock [OptimaCC]; NCT01367743) (J AmColl Cardiol 2018; 72: 173-82) (C) 2018 by the American College of Cardiology Foundation.
  • Herajarvi, Johanna; Anttila, Tuomas; Dimova, Elitsa Y.; Laukka, Tuomas; Myllymaki, Mikko; Haapanen, Henri; Olenchock, Benjamin A.; Tuominen, Hannu; Puistola, Ulla; Karihtala, Peeter; Kiviluoma, Kai; Koivunen, Peppi; Anttila, Vesa; Juvonen, Tatu (2017)
    Objectives. During aortic and cardiac surgery, risks for mortality and morbidity are inevitable. Surgical setups involving deep hypothermic circulatory arrest (DHCA) are effective to achieve organ protection against ischemic injury. The aim of this study was to identify humoural factors mediating additive protective effects of remote ischemic preconditioning (RIPC) in a porcine model of DHCA. Design. Twenty-two pigs were randomized into the RIPC group (n=11) and the control group (n=11). The RIPC group underwent four 5-minute hind limb ischemia-reperfusion cycles prior to cardiopulmonary bypass and DHCA. All animals underwent identical surgical procedures including 60min DHCA at 18 degrees C. Blood samples were collected from vena cava and sagittal sinus at several time points. After the 8-hour follow-up period, the brain, heart, and kidney tissue samples were collected for tissue analyses. Results. Serum levels of brain damage marker S100B recovered faster in the RIPC group, after 4hours of the arrest, (p
  • Lantto, Juulia; Erkinaro, Tiina; Haapsamo, Mervi; Huhta, Heikki; Voipio, Hanna-Marja; Hohimer, A. Roger; Davis, Lowell E.; Acharya, Ganesh; Räsänen, Juha (2019)
    The foramen ovale (FO) accounts for the majority of fetal left ventricular (LV) output. Increased right ventricular afterload can cause a redistribution of combined cardiac output between the ventricles. To understand the capability of the FO to increase its volume blood flow and thus LV output, we mechanically occluded the main pulmonary artery in seven chronically instrumented near-term sheep fetuses. We hypothesized that FO volume blood flow and LV output would increase during main pulmonary artery occlusion. Fetal cardiac function and haemodynamics were assessed by pulsed and tissue Doppler at baseline, 15 and 60 min after occlusion of the main pulmonary artery and 15 min after occlusion was released. Fetal ascending aorta and central venous pressures and blood gas values were monitored. Main pulmonary artery occlusion initially increased fetal heart rate (P <0.05) from [mean (SD)] 158 (7) to 188 (23) beats min(-1) and LV cardiac output (P <0.0001) from 629 (198) to 776 (283) ml min(-1). Combined cardiac output fell (P <0.0001) from 1524 (341) to 720 (273) ml min(-1). During main pulmonary artery occlusion, FO volume blood flow increased (P <0.001) from 507 (181) to 776 (283) ml min(-1). This increase was related to fetal tachycardia, because LV stroke volume did not change. Fetal ascending aortic blood pressure remained stable. Central venous pressure was higher (P <0.05) during the occlusion than after it was released. During the occlusion, fetal pH decreased and PCO2 increased. Left ventricular systolic dysfunction developed while LV diastolic function was preserved. Right ventricular systolic and diastolic function deteriorated after the occlusion. In conclusion, the FO has a limited capacity to increase its volume blood flow at near-term gestation.
  • Tikkanen-Dolenc, Heidi; Waden, Johan; Forsblom, Carol; Harjutsalo, Valma; Thorn, Lena M.; Saraheimo, Markku; Elonen, Nina; Rosengård-Bärlund, Milla; Gordin, Daniel; Tikkanen, Heikki O.; Groop, Per-Henrik; FinnDiane Study Grp (2017)
    Aims/hypothesis Cardiovascular disease (CVD) is the most common cause of premature death and disability among patients with type 1 diabetes. Diabetic nephropathy accounts for the increased cardiovascular morbidity and mortality of these patients. We recently showed that the intensity of exercise predicts the incidence and progression of diabetic nephropathy in patients with type 1 diabetes. Little is known about the relationship between physical activity and CVD. Therefore, we studied how physical activity affects the risk of CVD events in patients with type 1 diabetes. Methods A 10 year follow-up study including 2180 type 1 diabetes patients from the nationwide multicentre Finnish Diabetic Nephropathy Study (FinnDiane). Leisure time physical activity (LTPA) was assessed by a previously validated self-report questionnaire. A CVD event was defined as a verified myocardial infarction, coronary procedure or stroke. Patients were analysed separately for the risk of developing a first ever CVD event and for the risk of a recurrent CVD event following a baseline event. Results A total of 206 patients had an incident CVD event during follow-up. A higher total LTPA and higher intensity, frequency and duration of activity were associated with a lower risk of incident CVD events. The observed association between exercise frequency and incident CVD remained significant when adjusted for classic risk factors. Exercise intensity also had a borderline effect on the recurrence-free time in patients with a major CVD event at baseline. Conclusion/interprelation This study suggests that exercise, particularly high frequency and high intensity exercise, may reduce the risk of CVD events in patients with type 1 diabetes.
  • Pohl, Johannes; Golovko, Oksana; Carlsson, Gunnar; Örn, Stefan; Schmitz, Monika; Pashay Ahi, Ehsan (2021)
    Sewage effluent ozonation can reduce concentrations of chemical pollutants including pharmaceutical residues. However, the formation of potentially toxic ozonation byproducts (OBPs) is a matter of concern. This study sought to elucidate toxicity mechanisms of ozonated carbamazepine (CBZ), an anti-epileptic drug frequently detected in sewage effluents and surface water, in zebrafish embryos (Danio rerio). Embryos were exposed to ozonated and non-ozonated CBZ from 3 h post-fertilization (hpf) until 144 hpf. Embryotoxicity endpoints (proportion of dead and malformed embryos) were assessed at 24, 48, and 144 hpf. Heart rate was recorded at 48 hpf. Exposure to ozonated CBZ gave rise to cardiovascular-related malformations and reduced heart rate. Moreover, embryo-larvae exposed to ozonated CBZ displayed a lack of swim bladder inflation. Hence, the expression patterns of CBZ target genes involved in cardiovascular and embryonal development were investigated through a stepwise gene co-expression analysis approach. Two co-expression networks and their upstream transcription regulators were identified, offering mechanistic explanations for the observed toxicity phenotypes. The study presents a novel application of gene co-expression analysis elucidating potential toxicity mechanisms of an ozonated pharmaceutical with environmental relevance. The resulting data was used to establish a putative adverse outcome pathway (AOP).
  • Akinrinade, Oyediran; Ollila, Laura; Vattulainen, Sanna; Tallila, Jonna; Gentile, Massimiliano; Salmenpera, Pertteli; Koillinen, Hannele; Kaartinen, Maija; Nieminen, Markku S.; Myllykangas, Samuel; Alastalo, Tero-Pekka; Koskenvuo, Juha W.; Helio, Tiina (2015)
    Aims Genetic analysis among patients with dilated cardiomyopathy (DCM) is becoming an important part of clinical assessment, as it is in hypertrophic cardiomyopathy (HCM). The genetics of DCM is complex and therefore next-generation sequencing strategies are essential when providing genetic diagnostics. To achieve maximum yield, the diagnostic approach should include comprehensive clinical phenotyping combined with high-quality, high-coverage deep sequencing of DCM-associated genes and clinical variant classification as a basis for defining true yield in genetic testing. Our study has combined a novel sequencing strategy and clinical interpretation to analyse the yield and genotype-phenotype correlations among well-phenotyped Finnish DCM patients.Despite our increased understanding of the genetic basis of dilated cardiomyopathy (DCM), the clinical utility and yield of clinically meaningful findings of comprehensive next-generation sequencing (NGS)-based genetic diagnostics in DCM has been poorly described. We utilized a high-quality oligonucleotide-selective sequencing (OS-Seq)-based targeted sequencing panel to investigate the genetic landscape of DCM in Finnish population and to evaluate the utility of OS-Seq technology as a novel comprehensive diagnostic tool. Methods and results Using OS-Seq, we targeted and sequenced the coding regions and splice junctions of 101 genes associated with cardiomyopathies in 145 unrelated Finnish patients with DCM. We developed effective bioinformatic variant filtering strategy and implemented strict variant classification scheme to reveal diagnostic yield and genotype-phenotype correlations. Implemented OS-Seq technology provided high coverage of the target region (median coverage 410x and 99.42% of the nucleotides were sequenced at least 15x read depth). Diagnostic yield was 35.2% (familial 47.6% and sporadic 25.6%, P = 0.004) when both pathogenic and likely pathogenic variants are considered as disease causing. Of these, 20 (53%) were titin (TTN) truncations (non-sense and frameshift) affecting all TTN transcripts. TTN truncations accounted for 20.6% and 14.6% of the familial and sporadic DCM cases, respectively. Conclusion Panel-based, high-quality NGS enables high diagnostic yield especially in the familial form of DCM, and bioinformatic variant filtering is a reliable step in the process of interpretation of genomic data in a clinical setting.
  • Li, Chen; Stoma, Svetlana; Lotta, Luca A.; Warner, Sophie; Albrecht, Eva; Allione, Alessandra; Arp, Pascal P.; Broer, Linda; Buxton, Jessica L.; Da Silva Couto Alves, Alexessander; Deelen, Joris; Fedko, Iryna O.; Gordon, Scott D.; Jiang, Tao; Karlsson, Robert; Kerrison, Nicola; Loe, Taylor K.; Mangino, Massimo; Milaneschi, Yuri; Miraglio, Benjamin; Pervjakova, Natalia; Russo, Alessia; Surakka, Ida; van der Spek, Ashley; Verhoeven, Josine E.; Amin, Najaf; Beekman, Marian; Blakemore, Alexandra I.; Canzian, Federico; Hamby, Stephen E.; Hottenga, Jouke-Jan; Jones, Peter D.; Jousilahti, Pekka; Mägi, Reedik; Medland, Sarah E.; Montgomery, Grant W.; Nyholt, Dale R.; Perola, Markus; Pietiläinen, Kirsi H.; Salomaa, Veikko; Sillanpää, Elina; Suchiman, H. Eka; van Heemst, Diana; Willemsen, Gonneke; Agudo, Antonio; Boeing, Heiner; Boomsma, Dorret I.; Chirlaque, Maria-Dolores; Fagherazzi, Guy; Ferrari, Pietro; Franks, Paul; Gieger, Christian; Eriksson, Johan Gunnar; Gunter, Marc; Hägg, Sara; Hovatta, Iiris; Imaz, Liher; Kaprio, Jaakko; Kaaks, Rudolf; Key, Timothy; Krogh, Vittorio; Martin, Nicholas G.; Melander, Olle; Metspalu, Andres; Moreno, Concha; Onland-Moret, N. Charlotte; Nilsson, Peter; Ong, Ken K.; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Pedersen, Nancy L.; Penninx, Brenda W.J. H.; Quirós, J. Ramón; Jarvelin, Marjo Riitta; Rodríguez-Barranco, Miguel; Scott, Robert A.; Severi, Gianluca; Slagboom, P. Eline; Spector, Tim D.; Tjonneland, Anne; Trichopoulou, Antonia; Tumino, Rosario; Uitterlinden, André G.; van der Schouw, Yvonne T.; van Duijn, Cornelia M.; Weiderpass, Elisabete; Denchi, Eros Lazzerini; Matullo, Giuseppe; Butterworth, Adam S.; Danesh, John; Samani, Nilesh J.; Wareham, Nicholas J.; Nelson, Christopher P.; Langenberg, Claudia; Codd, Veryan (2020)
    Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) <0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
  • Helle, Emmi; Ampuja, Minna; Dainis, Alexandra; Antola, Laura; Temmes, Elina; Tolvanen, Erik; Mervaala, Eero; Kivelä, Riikka (2021)
    Cell-cell interactions are crucial for organ development and function. In the heart, endothelial cells engage in bidirectional communication with cardiomyocytes regulating cardiac development and growth. We aimed to elucidate the organotypic development of cardiac endothelial cells and cardiomyocyte and endothelial cell crosstalk using human induced pluripotent stem cells (hiPSC). Single-cell RNA sequencing was performed with hiPSC-derived cardiomyocytes (hiPS-CMs) and endothelial cells (hiPS-ECs) in mono- and co-culture. The presence of hiPS-CMs led to increased expression of transcripts related to vascular development and maturation, cardiac development, as well as cardiac endothelial cell and endocardium-specific genes in hiPS-ECs. Interestingly, co-culture induced the expression of cardiomyocyte myofibrillar genes and MYL7 and MYL4 protein expression was detected in hiPS-ECs. Major regulators of BMP- and Notch-signaling pathways were induced in both cell types in co-culture. These results reflect the findings from animal studies and extend them to human endothelial cells, demonstrating the importance of EC-CM interactions during development.