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  • Moilanen, Anne-Mari; Rysa, Jaana; Serpi, Raisa; Mustonen, Erja; Szabo, Zoltan; Aro, Jani; Napankangas, Juha; Tenhunen, Olli; Sutinen, Meeri; Salo, Tuula; Ruskoaho, Heikki (2012)
  • Lindbohm, Joni; Korja, Miikka; Jousilahti, Pekka; Salomaa, Veikko; Kaprio, Jaakko (2018)
    Background and aims: Studies report that both high and low total cholesterol (TC) elevates SAH risk. There are few prospective studies on high-density lipoproteins (HDL-C) and low-density lipoproteins (LDL-C), and apparently none concerns apolipoproteins A and B. We aimed to clarify the association between lipid profile and SAH risk. Methods: The National FINRISK study provided risk-factor data recorded at enrolment between 1972 and 2007. During 1.52 million person-years of follow-up until 2014, 543 individuals suffered from incident hospitalized SAH or outside-hospital-fatal SAH. Cox proportional hazards model was used to calculate the hazard ratios and multiple imputation predicted ApoA1, ApoB, and LDL-C values for cohorts from a time before apolipoprotein-measurement methods were available. Results: One SD elevation (1.28 mmol/l) in TC elevated SAH risk in men (hazard ratio (HR) 1.15 (95% CIs 1.00-1.32)). Low HDL-C levels increased SAH risk, as each SD decrease (0.37 mmol/l) in HDL-C raised the risk in women (HR 1.29 (95% CIs 1.07-1.55)) and men (HR 1.20 (95% CIs 1.14-1.27)). Each SD increase (0.29 g/l) in ApoA1 decreased SAH risk in women (HR 0.85 (95% CIs 0.74-0.97)) and men (HR 0.88 (95% CIs 0.76-1.02)). LDL-C (SD 1.07 mmol/l) and ApoB (SD 0.28 g/l) elevated SAH risk in men with HR 1.15 (95% CIs 1.01-1.31) and HR 1.26 (95% CIs 1.10-1.44) per one SD increase. Age did not change these findings. Conclusions: An adverse lipid profile seems to elevate SAH risk similar to its effect in other cardiovascular diseases, especially in men. Whether SAH incidence diminishes with increasing statin use remains to be studied. (C) 2018 Elsevier B.V. All rights reserved.
  • Inouye, Michael; Silander, Kaisa; Hämäläinen, Eija; Salomaa, Veikko; Harald, Kennet; Jousilahti, Pekka; Mannisto, Satu; Eriksson, Johan G.; Saarela, Janna; Ripatti, Samuli; Perola, Markus; van Ommen, Gert-Jan B.; Taskinen, Marja-Riitta; Palotie, Aarno; Dermitzakis, Emmanouil T.; Peltonen, Leena (2010)
  • Theelen, Thomas L.; Lappalainen, Jari P.; Sluimer, Judith C.; Gurzeler, Erika; Cleutjens, Jack P.; Gijbels, Marion J.; Biessen, Erik A. L.; Daemen, Mat J. A. P.; Alitalo, Kari; Yla-Herttuala, Seppo (2015)
    Objective: Angiopoietin-2 (Ang-2) blocking agents are currently undergoing clinical trials for use in cancer treatment. Ang-2 has also been associated with rupture-prone atherosclerotic plaques in humans, suggesting a role for Ang-2 in plaque stability. Despite the availability of Ang-2 blocking agents, their clinical use is still lacking. Our aim was to establish if Ang-2 has a role in atheroma development and in the transition of subclinical to clinically relevant atherosclerosis. We investigated the effect of antibody-mediated Ang-2 blockage on atherogenesis after in a mouse model of atherosclerosis. Methods: Hypercholesterolemic (low-density lipoprotein receptor(-/-) apolipoprotein B-100/100) mice were subjected to high-cholesterol diet for eight weeks, one group with and one group without Ang-2 blocking antibody treatment during weeks 4-8. To enhance plaque development, a peri-adventitial collar was placed around the carotid arteries at the start of antibody treatment. Aortic root, carotid arteries and brachiocephalic arteries were analyzed to evaluate the effect of Ang-2 blockage on atherosclerotic plaque size and stable plaque characteristics. Results: Anti-Ang-2 treatment reduced the size of fatty streaks in the brachiocephalic artery (-72%, p <0.05). In addition, antibody-mediated Ang-2 blockage reduced plasma triglycerides (-27%, p <0.05). In contrast, Ang-2 blockage did not have any effect on the size or composition (collagen content, macrophage percentage, adventitial microvessel density) of pre-existing plaques in the aortic root or collar-induced plaques in the carotid artery. Conclusions: Ang-2 blockage was beneficial as it decreased fatty streak formation and plasma triglyceride levels, but had no adverse effect on pre-existing atherosclerosis in hypercholesterolemic mice. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.
  • Sarikaya, Hakan; da Costa, Bruno R.; Baumgartner, Ralf W.; Duclos, Kathleen; Touze, Emmanuel; de Bray, Jean M.; Metso, Antti; Metso, Tiina; Arnold, Marcel; Arauz, Antonio; Zwahlen, Marcel; Jueni, Peter (2013)
  • Paukkunen, Mikko; Parkkila, Petteri; Hurnanen, Tero; Pankaala, Mikko; Koivisto, Tero; Nieminen, Tuomo; Kettunen, Raimo; Sepponen, Raimo (2016)
    The vibrations produced by the cardiovascular system that are coupled to the precordium can be noninvasively detected using accelerometers. This technique is called seismocardiography. Although clinical applications have been proposed for seismocardiography, the physiology underlying the signal is still not clear. The relationship of seismocardiograms of on the back-to-front axis and cardiac events is fairly well known. However, the 3-D seismocardiograms detectable with modern accelerometers have not been quantified in terms of cardiac cycle events. A major reason for this might be the degree of intersubject variability observed in 3-D seismocardiograms. We present a method to quantify 3-D seismocardiography in terms of cardiac cycle events. First, cardiac cycle events are identified from the seismocardiograms, and then, assigned a number based on the location in which the corresponding event was found. 396 cardiac cycle events from 9 healthy subjects and 120 cardiac cycle events from patients suffering from atrial flutter were analyzed. Despite the weak intersubject correlation of the waveforms (0.05, 0.27, and 0.15 for the x-, y-, and z-axes, respectively), the present method managed to find latent similarities in the seismocardiograms of healthy subjects. We observed that in healthy subjects the distribution of cardiac cycle event coordinates was centered on specific locations. These locations were different in patients with atrial flutter. The results suggest that spatial distribution of seismocardiographic cardiac cycle events might be used to discriminate healthy individuals and those with a failing heart.
  • Martiskainen, Mika; Oksala, Niku; Pohjasvaara, Tarja; Kaste, Markku; Oksala, Anni; Karhunen, Pekka J.; Erkinjuntti, Timo (2014)
  • Fischer, Krista; Kettunen, Johannes; Wurtz, Peter; Haller, Toomas; Havulinna, Aki S.; Kangas, Antti J.; Soininen, Pasi; Esko, Tonu; Tammesoo, Mari-Liis; Maegi, Reedik; Smit, Steven; Palotie, Aarno; Ripatti, Samuli; Salomaa, Veikko; Ala-Korpela, Mika; Perola, Markus; Metspalu, Andres (2014)
  • Kinnunen, Sini Marketta; Tölli, Marja Anneli; Välimäki, Mika Juhani; Gao, Erhe; Szabo, Zoltan; Rysä, Jaana; Almeida Ferreira, Monica Patricia; J. Ohukainen, Pauli; Serpi, Raisa; Correia, Alexandra; Makila, Ermei; Salonen, Jarno; Hirvonen, Jouni Tapio; Almeida Santos, Helder; Ruskoaho, Heikki Juhani (2018)
    Transcription factors are fundamental regulators of gene transcription, and many diseases, such as heart diseases, are associated with deregulation of transcriptional networks. In the adult heart, zinc-finger transcription factor GATA4 is a critical regulator of cardiac repair and remodelling. Previous studies also suggest that NKX2-5 plays function role as a cofactor of GATA4. We have recently reported the identification of small molecules that either inhibit or enhance the GATA4–NKX2-5 transcriptional synergy. Here, we examined the cardiac actions of a potent inhibitor (3i-1000) of GATA4–NKX2-5 interaction in experimental models of myocardial ischemic injury and pressure overload. In mice after myocardial infarction, 3i-1000 significantly improved left ventricular ejection fraction and fractional shortening, and attenuated myocardial structural changes. The compound also improved cardiac function in an experimental model of angiotensin II -mediated hypertension in rats. Furthermore, the up-regulation of cardiac gene expression induced by myocardial infarction and ischemia reduced with treatment of 3i-1000 or when micro- and nanoparticles loaded with 3i-1000 were injected intramyocardially or intravenously, respectively. The compound inhibited stretch- and phenylephrine-induced hypertrophic response in neonatal rat cardiomyocytes. These results indicate significant potential for small molecules targeting GATA4–NKX2-5 interaction to promote myocardial repair after myocardial infarction and other cardiac injuries.
  • Talman, Virpi; Kivelä, Milla Riikka (2018)
    The heart is a complex organ consisting of various cell types, each of which plays an important role in both physiological and pathophysiological conditions. The cells communicate with each other through direct cell-cell interactions and paracrine signaling, and both homotypic and heterotypic cell interactions contribute to the organized structure and proper function of the heart. Cardiomyocytes (CMs) and endothelial cells (ECs) are two of the most abundant cardiac cell types and they also play central roles in both cardiac remodeling and regeneration. The postnatal cell cycle withdrawal of CMs, which takes place within days or weeks after birth, represents the major barrier for regeneration in adult mammalian hearts, as adult CMs exhibit a very low proliferative capacity. Recent evidence highlights the importance of ECs not only as the most abundant cell type in the heart but also as key players in post-infarction remodeling and regeneration. In this MiniReview, we focus on blood vascular ECs and CMs and their roles and interactions in cardiac physiology and pathologies, with a special emphasis on cardiac regeneration. We summarize the known mediators of the bidirectional CM-EC interactions and discuss the related recent advances in the development of therapies aiming to promote heart repair and regeneration targeting these two cell types.
  • Pätilä , Tommi; Miyagawa, Shigeru; Imanishi, Yukiko; Fukushima, Satsuki; Siltanen, Antti; Mervaala, Eero; Kankuri, Esko; Harjula, Ari; Sawa, Yoshiki (2015)
    Although cell therapy of the failing heart by intramyocardial injections of myoblasts to results in regenerative benefit, it has also been associated with undesired and prospectively fatal arrhythmias. We hypothesized that intramyocardial injections of myoblasts could enhance inflammatory reactivity and facilitate electrical cardiac abnormalities that can be reduced by epicardial myoblast sheet delivery. In a rat model of ischemic heart failure, myoblast therapy either by intramyocardial injections or epicardial cell sheets was given 2 weeks after occlusion of the coronary artery. Ventricular premature contractions (VPCs) were assessed, using an implanted three-lead electrocardiograph at 1, 7, and 14 days after therapy, and 16-point epicardial electropotential mapping (EEPM) was used to evaluate ventricular arrhythmogenicity under isoproterenol stress. Cardiac functioning was assessed by echocardiography. Both transplantation groups showed therapeutic benefit over sham therapy. However, VPCs were more frequent in the Injection group on day 1 and day 14 after therapy than in animals receiving epicardial or sham therapy (p <0.05 and p <0.01, respectively). EEPM under isoproterenol stress showed macroreentry at the infarct border area, leading to ventricular tachycardias in the Injection group, but not in the myoblast sheet- or sham-treated groups (p = 0.045). Both transplantation types modified the myocardial cytokine expression profile. In animals receiving epicardial myoblast therapy, selective reductions in the expressions of interferon gamma, interleukin (IL)-1 beta and IL12 were observed, accompanied by reduced infiltration of inflammatory CD11b- and CD68-positive leukocytes, compared with animals receiving myoblasts as intramyocardial injections. Intramyocardial myoblast delivery was associated with enhanced inflammatory and immunomodulatory reactivity and increased frequency of VPCs. In comparison to intramyocardial injection, the epicardial route may serve as the preferred method of skeletal myoblast transplantation to treat heart failure.
  • Virtanen, Marianna; Elovainio, Marko; Josefsson, Kim; Batty, G. David; Singh-Manoux, Archana; Kivimaki, Mika (2017)
    Objective To examine coronary heart disease (CHD) and its risk factors as predictors of long-term trajectories of psychological distress from midlife to old age. Methods In the Whitehall II cohort study, 6890 participants (4814 men, 2076 women; mean age 49.5 years) had up to seven repeat assessments of psychological distress over 21 years (mean follow-up 19 years). CHD and its risk factors (lifestyle-related risk factors, diabetes, hypertension and cholesterol) were assessed at baseline. Group-based trajectory modelling was used to identify clusters of individuals with a similar pattern of psychological distress over time. Results We identified four trajectories of psychological distress over the follow-up: 'persistently low (69% of the participants), 'persistently intermediate' (13%), 'intermediate to low' (12%) and 'persistently high' (7%). The corresponding proportions were 60%, 16%, 13% and 11% among participants with CHD; 63%, 15%, 12% and 10% among smokers and 63%, 16%, 12% and 10% among obese participants. In multivariable adjusted multinomial regression analyses comparing other trajectories to persistently low trajectory, prevalent CHD was associated with intermediate to low (OR 1.70, 95% CI 1.08 to 2.68) and persistently high (OR 1.92, 95% CI 1.16 to 3.19) trajectories. Smoking (OR 1.33, 95% CI 1.07 to 1.64; OR 1.55, 95% CI 1.19 to 2.04) and obesity (OR 1.33, 95% CI 1.04 to 1.70; OR 1.47, 95% CI 1.07 to 2.01) were associated with persistently intermediate and persistently high trajectories, respectively. Conclusion CHD, smoking and obesity may have a role in the development of long-lasting psychological distress from midlife to old age.
  • Aula, Hanna; Skyttä, Tanja; Tuohinen, Suvi; Luukkaala, Tiina; Hämäläinen, Mari; Virtanen, Vesa; Raatikainen, Pekka; Moilanen, Eeva; Kellokumpu-Lehtinen, Pirkko-Liisa (2018)
    BackgroundRadiation-induced heart disease is mainly caused by activation of the fibrotic process. Transforming growth factor-beta 1 (TGF-1) and platelet-derived growth factor (PDGF) are pro-fibrotic mediators. The aim of our study was to evaluate the behavior of TGF-1 and PDGF during adjuvant radiotherapy (RT) for breast cancer and the association of these cytokines with echocardiographic changes.MethodsOur study included 73 women with early-stage breast cancer or ductal carcinoma in situ (DCIS) receiving post-operative RT but not chemotherapy. TGF-1 and PDGF levels in serum samples taken before and on the last day of RT were measured by an enzyme-linked immunosorbent assay. Echocardiography was also performed at same time points. Patients were grouped according to a15% worsening in tricuspid annular plane systolic excursion (TAPSE) and pericardium calibrated integrated backscatter (cIBS).ResultsIn all patients, the median TGF-1 decreased from 25.0 (IQR 21.1-30.3) ng/ml to 23.6 (IQR 19.6-26.8) ng/ml (p=0.003), and the median PDGF decreased from 18.0 (IQR 13.7-22.7) ng/ml to 15.6 (IQR 12.7-19.5) ng/ml (p
  • Eranti, Antti; Kerola, Tuomas; Aro, Aapo L.; Tikkanen, Jani T.; Rissanen, Harri A.; Anttonen, Olli; Junttila, M. Juhani; Knekt, Paul; Huikuri, Heikki V. (2016)
    Background: Diabetes predisposes to sudden cardiac death (SCD). However, it is uncertain whether greater proportion of cardiac deaths are sudden among diabetes patients than other subjects. It is also unclear whether the risk of SCD is pronounced already early in the course of the disease. The relationship of impaired glucose tolerance (IGT) and SCD is scarcely documented. Methods: A general population cohort of 10594 middle-aged subjects (mean age 44 years, 52.6 % male, follow-up duration 35-41 years) was divided into diabetes patients (n = 82), subjects with IGT (n = 3806, plasma glucose = 9.58 mmol/l in one-hour glucose tolerance test), and controls (n = 6706). Results: Diabetes patients had an increased risk of SCD after adjustment confounders (hazard ratio 2.62, 95 % confidence interval 1.46-4.70, p = 0.001) but risk for non-sudden cardiac death was similarly increased and the proportion of SCD of cardiac deaths was not increased. The SCD risk persisted after exclusion of subjects with baseline cardiac disease or non-fatal cardiac events during the follow-up. Subjects with IGT were at increased risk for SCD (univariate hazard ratio 1.51; 95 % confidence interval 1.31-1.74; p <0.001) and also for non-sudden cardiac deaths and non-fatal cardiac events but adjustments for other risk factors attenuated these effects. Conclusions: Diabetes was associated with increased risk of SCD but also the risk of non-sudden cardiac death was similarly increased. The proportion of cardiac deaths being sudden in subjects with diabetes was not increased. The higher SCD risk in diabetes patients was independent of known cardiac disease at baseline or occurrence of nonfatal cardiac event during the follow-up.
  • Karhu, S. Tuuli; Ruskoaho, Heikki; Talman, Virpi (2021)
    Cardiac fibrosis is characterized by accumulation and activation of fibroblasts and excessive production of extracellular matrix, which results in myocardial stiffening and eventually leads to heart failure. Although previous work suggests that protein kinase C (PKC) isoforms play a role in cardiac fibrosis and remodeling, the results are conflicting. Moreover, the potential of targeting PKC with pharmacological tools to inhibit pathologic fibrosis has not been fully evaluated. Here we investigated the effects of selected PKC agonists and inhibitors on cardiac fibroblast (CF) phenotype, proliferation, and gene expression using primary adult mouse CFs, which spontaneously transdifferentiate into myofibroblasts in culture. A 48-hour exposure to the potent PKC activator phorbol 12-myristate 13-acetate (PMA) at 10 nM concentration reduced the intensity of a-smooth muscle actin staining by 56% and periostin mRNA levels by 60% compared with control. The decreases were inhibited with the pan-PKC inhibitor Gö6983 and the inhibitor of classical PKC isoforms Gö6976, suggesting that classical PKCs regulate CF transdifferentiation. PMA also induced a 33% decrease in 5-bromo-2’-deoxyuridine–positive CFs, which was inhibited with Gö6983 but not with Gö6976, indicating that novel PKC isoforms (nPKCs) regulate CF proliferation. Moreover, PMA downregulated the expression of collagen-encoding genes Col1a1 and Col3a1 nPKC-dependently, showing that PKC activation attenuates matrix synthesis in CFs. The partial PKC agonist isophthalate derivative bis(1-ethylpentyl) 5-(hydroxymethyl)isophthalate induced parallel changes in phenotype, cell cycle activity, and gene expression. In conclusion, our results reveal distinct PKC-dependent regulation of CF transdifferentiation and proliferation and suggest that PKC agonists exhibit potential as an antifibrotic treatment.
  • FinnDiane Study Grp (2018)
    Aims/hypothesisThe aim of this study was to assess the potential dose-dependent effects of smoking on the risk of CHD, heart failure and stroke in individuals with type 1 diabetes.MethodsThe study included 4506 individuals with type 1 diabetes who were participating in the Finnish Diabetic Nephropathy (FinnDiane) study. Intensity of smoking was estimated by packs per day and cumulative smoking by pack-years. Cox regression analyses were used to estimate the risk of incident CHD, heart failure or stroke during follow-up.ResultsOne pack per day significantly increased the risk of incident CHD in current smokers compared with never smokers (HR 1.45 [95% CI 1.15, 1.84]), after adjustment for age, sex, HbA(1c), hypertension, duration of diabetes and BMI. The risk of CHD in former smokers was similar to the risk in never smokers. The risk of incident heart failure was 1.43 (95% CI 1.03, 1.97) in current smokers per one pack per day and 1.37 (95% CI 1.05, 1.77) in former smokers, while the risk of incident stroke was 1.70 (95% CI 1.26, 2.29) and 1.49 (95% CI 1.14, 1.93), respectively. After further adjustments for lipids, however, the difference in the risk of heart failure in current and former smokers was no longer significant. Cumulative smoking data were similar to smoking intensity data.Conclusions/interpretationThere is a dose-dependent association between smoking and cardiovascular disease in individuals with type 1 diabetes. In men in particular, the risk of incident stroke remains high even after smoking cessation and is increased in current and former smokers independently of other risk factors.
  • Ferreira, Mónica P. A.; Talman, Virpi; Torrieri, Giulia; Liu, Dongfei; Marques, Gonçalo; Moslova, Karina; Liu, Zehua; Pinto, João F.; Hirvonen, Jouni; Ruskoaho, Heikki; Santos, Hélder A. (2018)
    The inability of the heart to recover from an ischemic insult leads to the formation of fibrotic scar tissue and heart failure. From the therapeutic strategies under investigation, cardiac regeneration holds the promise of restoring the full functionality of a damaged heart. Taking into consideration the presence of vast numbers of fibroblasts and myofibroblasts in the injured heart, direct fibroblast reprogramming into cardiomyocytes using small drug molecules is an attractive therapeutic option to replenish the lost cardiomyocytes. Here, a spermine-acetalated dextran-based functional nanoparticle is developed for pH-triggered drug delivery of two poorly water soluble small molecules, CHIR99021 and SB431542, both capable of increasing the efficiency of direct reprogramming of fibroblast into cardiomyocytes. Upon functionalization with polyethylene glycol and atrial natriuretic peptide, the biocompatibility of the nanosystem is improved, and the cellular interactions with the cardiac nonmyocytes are specifically augmented. The dual delivery of the compounds is verified in vitro, and the compounds exerted concomitantly anticipate biological effects by stabilizing β-catenin (CHIR99021) and by preventing translocation of Smad3 to the nucleus of (myo)fibroblasts (SB431542). These observations highlight the potential of this nanoparticle-based system toward improved drug delivery and efficient direct reprogramming of fibroblasts into cardiomyocyte-like cells, and thus, potential cardiac regeneration therapy.
  • Abdollahi, Anna M.; Virtanen, Heli E. K.; Voutilainen, Sari; Kurl, Sudhir; Tuomainen, Tomi-Pekka; Salonen, Jukka T.; Virtanen, Jyrki K. (2019)
    Background: Epidemiologic studies suggest inverse associations between consumption of egg, a major source of dietary cholesterol, and stroke. However, the evidence of the relation remains limited, especially among carriers of apolipoprotein E4 (apoE4), which influences cholesterol metabolism. Objective: The aim of this study was to investigate associations of egg and cholesterol intakes with risk of stroke and with the major stroke risk factor, blood pressure, inmiddle-aged and older men from eastern Finland and whether apoE phenotype could modify these associations. Methods: A total of 1950 men aged 42-60 y in 1984-1989 were included at the baseline examinations of the prospective population-based Kuopio Ischaemic Heart Disease Risk Factor Study. Data on apoE phenotype were available for 1015 men. Dietary intakes were assessed with 4-d food records at baseline and incident stroke events were assessed by record linkage to hospital discharge registries. Cox proportional hazards regression analyses were used to estimate associations with stroke risk. Associations with baseline blood pressure were evaluated with ANCOVA. Results: During the mean +/- SD follow-up of 21.2 +/- 7.2 y, there were 217 incidences of any stroke: 166 of ischemic stroke and 55 of hemorrhagic stroke. Comparing the highest egg intake quartile with the lowest, the multivariable-adjusted HRs were 0.81 for total stroke (95% CI: 0.54, 1.23; P-trend = 0.32), 0.84 for ischemic stroke (95% CI: 0.53, 1.34; P-trend = 0.44), and 0.75 for hemorrhagic stroke (95% CI: 0.32, 1.77; P-trend = 0.40). The respective HRs for the highest cholesterol intake quartile compared with the lowest were 0.86 (95% CI: 0.57, 1.32; P-trend = 0.42), 0.74 (95% CI: 0.46, 1.20; P-trend = 0.32), and 1.10 (95% CI: 0.45, 2.66; P-trend = 0.75). Diastolic blood pressure was 1.6 mm Hg (P-trend = 0.04) lower in the highest egg intake quartile compared with the lowest, but there were no associations with systolic blood pressure or with cholesterol intake. ApoE phenotype (32% had apoE4 phenotype) did not modify the associations. Conclusion: Neither egg nor cholesterol intakes were associated with stroke risk in this cohort, regardless of apoE phenotype. This trial was registered at as NCT03221127.
  • Terho, Henri K.; Tikkanen, Jani T.; Kenttä, Tuomas V.; Junttila, Juhani M.; Aro, Aapo L.; Anttonen, Olli; Kerola, Tuomas; Rissanen, Harri A.; Knekt, Paul; Huikuri, Heikki V. (2018)
    Background: Abnormal 12 lead electrocardiogram (ECG) findings and proposing its ability for enhanced risk prediction, majority of the studies have been carried out with elderly populations with prior cardiovascular diseases. This study aims to denote the association of sudden cardiac death (SCD) and various abnormal ECG morphologies using middle-aged population without a known cardiac disease. Methods: In total, 9511 middle-aged subjects (mean age 42 +/- 8.2 years, 52% males) without a known cardiac disease were included in this study. Risk for SCD was assessed after 10 and 30-years of follow-up. Results: Abnormal ECG was present in 16.3% (N = 1548) of subjects. The incidence of SCD was distinctly higher among those with any ECG abnormality in 10 and 30-year follow-ups (1.7/1000 years vs. 0.6/1000 years, P <0.001; 3.4;1000 years vs. 1.9/1000 years, P <0.001). At 10-year point, competing risk multivariate regression model showed HR of 1.62 (95% CI 1.0-2.6, P = 0.05) for SCD in subjects with abnormal ECG. QRS duration 110 ms, QRST-angle > 100', left ventricular hypertrophy, and T-wave inversions were the most significant independent ECG risk markers for 10-year SCD prediction with up to 3-fold risk for SCD. Those with ECG abnormalities had a 1.3-fold risk (95% CI 1.07-1.57, P - 0.007) for SCD in 30-year follow-up, whereas QRST-angle > 100 degrees, LVH, ER 0.1 mV and 0.2 mV were the strongest individual predictors. Subjects with multiple ECG abnormalities had up to 6.6-fold risk for SCD (P <0.001). Conclusion: Several ECG abnormalities are associated with the occurrence of early and late SCD events in the middle-age subjects without known history of cardiac disease. (C) 2018 The Authors. Published by Elsevier B.V.
  • Backlund, Michael; Paukku, Kirsi; Kontula, Kimmo K.; Lehtonen, Jukka Y. A. (2016)
    As the formation of ribonucleoprotein complexes is a major mechanism of angiotensin II type 1 receptor (AT1R) regulation, we sought to identify novel AT1R mRNA binding proteins. By affinity purification and mass spectroscopy, we identified TIA-1. This interaction was confirmed by colocalization of AT1R mRNA and TIA-1 by FISH and immunofluorescence microscopy. In immunoprecipitates of endogenous TIA-1, reverse transcription-PCR amplified AT1R mRNA. TIA-1 has two binding sites within AT1R 3'-UTR. The binding site proximal to the coding region is glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-dependent whereas the distal binding site is not. TIA-1 functions as a part of endoplasmic reticulum (ER) stress response leading to stress granule (SG) formation and translational silencing. We and others have shown that AT1R expression is increased by ER stress-inducing factors. In unstressed cells, TIA-1 binds to AT1R mRNA and decreases AT1R protein expression. Fluorescence microscopy shows that ER stress induced by thapsigargin leads to the transfer of TIA-1 to SGs. In FISH analysis AT1R mRNA remains in the cytoplasm and no longer colocalizes with TIA-1. Thus, release of TIA-1-mediated suppression by ER stress increases AT1R protein expression. In conclusion, AT1R mRNA is regulated by TIA-1 in a ER stress-dependent manner.