Browsing by Subject "HEART"

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  • 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.
  • Ekström, Kaj; Räisänen-Sokolowski, Anne; Lehtonen, Jukka; Nordenswan, Hanna-Kaisa; Mäyranpää, Mikko I.; Kupari, Markku (2020)
    Aims Cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) are inflammatory cardiomyopathies sharing histopathological and clinical features. Their differentiation is difficult and susceptible of confusion and apparent mistakes. The possibility that they represent different phenotypes of a single disease has been debated. Methods and results We made a retrospective audit of 73 cases of GCM diagnosed in Finland since the late 1980s. All available histological material was reanalyzed as were other examinations pertinent to the distinction between GCM and CS. Finding granulomas in or outside the heart was considered diagnostic of CS and exclusive of GCM. Altogether 45 of the 73 cases of GCM (62%) were reclassified as CS. In all except one case, this was based on finding sarcoid granulomas that either had been originally missed (n = 29) or misinterpreted (n = 11) or were found in additional posttransplant myocardial specimens (n = 3) or samples of extracardiac tissue (n = 1) accrued over the disease course. Supporting the reclassification, patients relocated to the CS group had less heart failure at presentation (prevalence 20% vs. 46%, P = 0.017) and better 1 year transplant-free survival (82% vs. 45%, P = 0.011) than patients considered to represent true GCM. Conclusions Recognizing granulomas in or outside the heart remains a challenge for the pathologist. Given that CS and GCM are considered distinct diseases and granulomas exclusive of GCM, many cases of GCM, if thoroughly scrutinized, may need reclassification as CS. However, whether CS and GCM are truly different entities or parts of a one-disease continuum has not yet been conclusively settled.
  • Dijkstra, M. H.; Pirinen, E.; Huusko, J.; Kivelä, R.; Schenkwein, D.; Alitalo, K.; Yla-Herttuala, S. (2014)
  • Blauw, Lisanne L.; Noordam, Raymond; Soidinsalo, Sebastian; Blauw, C. Alexander; Li-Gao, Ruifang; de Mutsert, Renee; Berbee, Jimmy F. P.; Wang, Yanan; van Heemst, Diana; Rosendaal, Frits R.; Jukema, J. Wouter; Mook-Kanamori, Dennis O.; Wurtz, Peter; van Dijk, Ko Willems; Rensen, Patrick C. N. (2019)
    According to the current dogma, cholesteryl ester transfer protein (CETP) decreases high-density lipoprotein (HDL)-cholesterol (C) and increases low-density lipoprotein (LDL)-C. However, detailed insight into the effects of CETP on lipoprotein subclasses is lacking. Therefore, we used a Mendelian randomization approach based on a genetic score for serum CETP concentration (rs247616, rs12720922 and rs1968905) to estimate causal effects per unit (mu g/mL) increase in CETP on 159 standardized metabolic biomarkers, primarily lipoprotein subclasses. Metabolic biomarkers were measured by nuclear magnetic resonance (NMR) in 5672 participants of the Netherlands Epidemiology of Obesity (NEO) study. Higher CETP concentrations were associated with less large HDL (largest effect XL-HDL-C, P = 6 x 10(-22)) and more small VLDL components (largest effect S-VLDL cholesteryl esters, P = 6 x 10(-6)). No causal effects were observed with LDL subclasses. All these effects were replicated in an independent cohort from European ancestry (MAGNETIC NMR GWAS; n similar to 20,000). Additionally, we assessed observational associations between ELISA-measured CETP concentration and metabolic measures. In contrast to results from Mendelian randomization, observationally, CETP concentration predominantly associated with more VLDL, IDL and LDL components. Our results show that CETP is an important causal determinant of HDL and VLDL concentration and composition, which may imply that the CETP inhibitor anacetrapib decreased cardiovascular disease risk through specific reduction of small VLDL rather than LDL. The contrast between genetic and observational associations might be explained by a high capacity of VLDL, IDL and LDL subclasses to carry CETP, thereby concealing causal effects on HDL.
  • Lehmonen, Lauri; Kaasalainen, Touko; Atula, Sari; Mustonen, Tuuli; Holmström, Miia (2019)
    Gelsolin (AGel) amyloidosis is a hereditary condition with common neurological effects. Myocardial involvement, especially strain, T1, or extracellular volume (ECV), in this disease has not been investigated before. Local myocardial effects and possible amyloid accumulation were the targets of interest in this study. Fifty patients with AGel amyloidosis were enrolled in the study. All patients underwent cardiovascular magnetic resonance imaging, including cine imaging, T1 mapping, tagging, and late gadolinium enhancement (LGE) imaging at 1.5 T. Results for volumetry, myocardial feature-tracking strain, rotation, torsion, native T1, ECV, and LGE were investigated. The population mean native T1 values in different segments of the left ventricle (LV) varied between 1003 and 1080 ms. Myocardial mean T1 was 1031 ± 37 ms. T1 was highest in the basal plane of the LV (1055 ± 40 ms), similarly to ECV (30.0% ± 4.4%). ECV correlated with native T1 in all LV segments (p 
  • Kiss, Jan; Stark, Christoffer; Nykaäen, Antti; Lemström, Karl (2020)
    Objectives. We present the outcome of the first 80 patients receiving a continuous flow left ventricular assist device at Helsinki University Hospital between December 2011 and November 2018. Design. This was a single-center retrospective study. We describe our patient management in detail. The primary end-points were death, heart transplantation, or pump explant. Data was reported in accordance with the Interagency Registry for Mechanical Circulatory Support protocol. All patients receiving an assist device during the study period were included in the data analysis. Results. Mean patient age was 53 +/- 12 years at implantation and 85% were male. Most patients suffered from dilated (48%), or ischemic (40%) cardiomyopathy. One-third of patients were bridged with venoarterial extracorporeal membrane oxygenation to assist device implantation. Implant strategy was bridge to transplant or bridge to decision in most patients (88%). Mean follow-up time on pump was 529 +/- 467 days. Survival was 98, 92, 85, 79 and 71% at 1, 3, 12, 24 and 36 months, respectively. Most common causes of death were multi-organ failure, right heart failure, or stroke. Only three patients (4%) had suspected pump thrombosis, two of which resolved with medical treatment and one resulting in death. Pump exchange or explant were not performed in a single patient. Neurological events occurred in 18%, non-disabling stroke in 8%, and fatal stroke in 4% of the patients. The incidence of device-related infection was 10%. Conclusions. Survival rates were good, although one third of patients were bridged with temporary circulatory support. We report a high level of freedom from pump thrombosis, fatal stroke, and driveline infection.
  • Lappalainen, Laura; Stenvall, Harriet; Lavikainen, Piia; Miettinen, Heikki; Martikainen, Janne; Sintonen, Harri; Tolppanen, Anna-Maija; Roine, Risto P.; Hartikainen, Juha (2021)
    Background Patient-reported outcome (PRO) instruments measure health gains, including changes in health-related quality of life (HRQoL). Previous studies have assessed the reliability and relationship of multiple HRQoL instruments in search of the optimal instrument for feasible measurement of PROs. Although the 15D instrument was shown to have the best sensitivity and construct validity among cardiac patients, it is unknown how well it captures relevant disease-specific information scores compared to instruments included in the International Consortium for Health Outcomes Measurement (ICHOM) standard set. The aim of this study was to investigate whether the disease-specific PRO instruments and a generic HRQoL instrument capture disease related symptoms in coronary artery disease (CAD) patients. Methods Health status and HRQoL were assessed with the instruments included in the ICHOM standard set: Seattle Angina Questionnaire short-form (SAQ-7), Rose Dyspnea Scale (RDS), two-item Patient Health Questionnaire (PHQ-2), and with the 15D HRQoL instrument at baseline and 1 year from the treatment in a university hospital setting. Spearman correlation and explanatory factor analysis were used to assess the relationship of baseline scores and 1-year change in scores of 297 patients. Results At baseline, the overall 15D score and SAQ-physical limitation (SAQ-PL), 15D "breathing" and SAQ-PL, as well as "breathing" and RDS showed moderately strong correlations. The factor interpreted to reflect "Breathing-related physical activity", based on high loadings of "breathing", RDS, SAQ-PL, "mobility", "vitality", and "usual activities", explained 19.2% of the total variance. Correlations between 1-year changes in scores were fair. The factor of "Breathing-related physical activity", with significant loading of RDS, SAQ-PL, "breathing, "usual activities", "vitality", "sexual activity", "mobility", and disease-specific quality of life explained 20.5% of the total variance in 1-year change in scores. The correlation of angina frequency measured by SAQ-7 and the 15D instrument was poor. Conclusions The 15D detects dyspnea and depression similarly to RDS and PHQ-2 but not angina similarly to the SAQ-7. This may call for supplementing the 15D instrument with a disease-specific instrument when studying CAD patients.
  • Pöyhönen, Pauli; Kylmälä, Minna; Vesterinen, Paula; Kivistö, Sari; Holmström, Miia; Lauerma, Kirsi; Väänänen, Heikki; Toivonen, Lauri; Hänninen, Helena (2018)
    Background: Large myocardial infarction (MI) is associated with adverse left ventricular (LV) remodeling (LVR). We studied the nature of LVR, with specific attention to non-transmural MIs, and the association of peak CK-MB with recovery and chronic phase scar size and LVR. Methods: Altogether 41 patients underwent prospectively repeated cardiovascular magnetic resonance at a median of 22 (interquartile range 9-29) days and 10 (8-16) months after the first revascularized MI. Transmural MI was defined as >= 75% enhancement in at least one myocardial segment. Results: Peak CK-MB was 86 (40-216) mu g/L in median, while recovery and chronic phase scar size were 13 (3-23) % and 8 (2-19) %. Altogether 33 patients (81%) had a non-transmural MI. Peak CK-MB had a strong correlation with recovery and chronic scar size (r >= 0.80 for all, r >= 0.74 for non-transmural MIs; p <0.001). Peak CK-MB, recovery scar size, and chronic scar size, were all strongly correlated with chronic wall motion abnormality index (WMAi) (r >= 0.75 for all, r >= 0.73 for non-transmural MIs; p <0.001). There was proportional scar size and LV mass resorption of 26% (0-50%) and 6% (-2-14%) in median. Young age (<60 years, median) was associated with greater LV mass resorption (median 9% vs. 1%, p = 0.007). Conclusions: Peak CK-MB has a strong association with chronic scar size and wall motion abnormalities after revascularized non-transmural MI. Considerable infarct resorption happens after the first-month recovery phase. LV mass resorption is related to age, being more common in younger patients.
  • RIPTRANS Study Grp Collaborators; Uutela, Aki; Helanterä, Ilkka; Lemström, Karl; Passov, Arie; Syrjälä, Simo; Åberg, Fredrik; Mäkisalo, Heikki; Nordin, Arno; Lempinen, Marko; Sallinen, Ville (2020)
    Introduction Remote ischaemic preconditioning (RIPC) using a non-invasive pneumatic tourniquet is a potential method for reducing ischaemia-reperfusion injury. RIPC has been extensively studied in animal models and cardiac surgery, but scarcely in solid organ transplantation. RIPC could be an inexpensive and simple method to improve function of transplanted organs. Accordingly, we aim to study whether RIPC performed in brain-dead organ donors improves function and longevity of transplanted organs. Methods and analyses RIPTRANS is a multicentre, sham-controlled, parallel group, randomised superiority trial comparing RIPC intervention versus sham-intervention in brain-dead organ donors scheduled to donate at least one kidney. Recipients of the organs (kidney, liver, pancreas, heart, lungs) from a randomised donor will be included provided that they give written informed consent. The RIPC intervention is performed by inflating a thigh tourniquet to 300 mm Hg 4 times for 5 min. The intervention is done two times: first right after the declaration of brain death and second immediately before transferring the donor to the operating theatre. The sham group receives the tourniquet, but it is not inflated. The primary endpoint is delayed graft function (DGF) in kidney allografts. Secondary endpoints include short-term functional outcomes of transplanted organs, rejections and graft survival in various time points up to 20 years. We aim to show that RIPC reduces the incidence of DGF from 25% to 15%. According to this, the sample size is set to 500 kidney transplant recipients. Ethics and dissemination This study has been approved by Helsinki University Hospital Ethics Committee and Helsinki University Hospital's Institutional Review Board. The study protocol was be presented at the European Society of Organ Transplantation congress in Copenhagen 14-15 September 2019. The study results will be submitted to an international peer-reviewed scientific journal for publication.
  • Sysi-Aho, Marko; Koikkalainen, Juha; Seppanen-Laakso, Tuulikki; Kaartinen, Maija; Kuusisto, Johanna; Peuhkurinen, Keijo; Karkkainen, Satu; Antila, Margareta; Lauerma, Kirsi-Maria Susanna; Reissell, Eeva; Jurkko, Raija; Lotjonen, Jyrki; Heliö, Tiina; Oresic, Matej (2011)
  • Karhu, Suvi Tuuli; Välimäki, Mika Juhani; Jumppanen, Antti Mikael; Kinnunen, Sini Marketta; Pohjolainen, Lotta Matilda; Leigh, Robert Scott; Auno, Atte Samuli; Földes, Gábor; Boije af Gennäs, Per Gustav; Yli-Kauhaluoma, Jari Tapani; Ruskoaho, Heikki Juhani; Talman, Virpi (2018)
    Safety assessment of drug candidates in numerous in vitro and experimental animal models is expensive, time consuming and animal intensive. More thorough toxicity profiling already in the early drug discovery projects using human cell models, which more closely resemble the physiological cell types, would help to decrease drug development costs. In this study we aimed to compare different cardiac and stem cell models for in vitro toxicity testing and to elucidate structure-toxicity relationships of novel compounds targeting the cardiac transcription factor GATA4. By screening the effects of eight compounds at concentrations ranging from 10 nM up to 30 A mu M on the viability of eight different cell types, we identified significant cell type- and structure-dependent toxicity profiles. We further characterized two compounds in more detail using high-content analysis. The results highlight the importance of cell type selection for toxicity screening and indicate that stem cells represent the most sensitive screening model, which can detect toxicity that may otherwise remain unnoticed. Furthermore, our structure-toxicity analysis reveals a characteristic dihedral angle in the GATA4-targeted compounds that causes stem cell toxicity and thus helps to direct further drug development efforts towards non-toxic derivatives.
  • Lähteenvuo, Johanna; Hätinen, Olli-Pekka; Kuivanen, Antti; Huusko, Jenni; Paananen, Jussi; Lähteenvuo, Markku; Nurro, Jussi; Hedman, Marja; Hartikainen, Juha; Laham-Karam, Nihay; Mäkinen, Petri; Räsänen, Markus; Alitalo, Kari; Rosenzweig, Anthony; Ylä-Herttuala, Seppo (2020)
    VEGF-B gene therapy is a promising proangiogenic treatment for ischemic heart disease, but unexpectedly, we found that high doses of VEGF-B promote ventricular arrhythmias (VA).VEGF-B knockout, αMHC-VEGF-B transgenic mice, and pigs transduced intramyocardially with adenoviral (Ad)VEGF- B186 were studied.Immunostaining showed a 2-fold increase in the number of nerves (76 vs.39 in controls, nerves/field,p
  • Nissinen, T. A.; Degerman, J.; Räsänen, M.; Poikonen, A. R.; Koskinen, S.; Mervaala, E.; Pasternack, A.; Ritvos, O.; Kivela, R.; Hulmi, J. J. (2016)
    Doxorubicin is a widely used and effective chemotherapy drug. However, cardiac and skeletal muscle toxicity of doxorubicin limits its use. Inhibiting myostatin/activin signalling can prevent muscle atrophy, but its effects in chemotherapy-induced muscle wasting are unknown. In the present study we investigated the effects of doxorubicin administration alone or combined with activin receptor ligand pathway blockade by soluble activin receptor IIB (sACVR2B-Fc). Doxorubicin administration decreased body mass, muscle size and bone mineral density/content in mice. However, these effects were prevented by sACVR2B-Fc administration. Unlike in many other wasting situations, doxorubicin induced muscle atrophy without markedly increasing typical atrogenes or protein degradation pathways. Instead, doxorubicin decreased muscle protein synthesis which was completely restored by sACVR2B-Fc. Doxorubicin administration also resulted in impaired running performance without effects on skeletal muscle mitochondrial capacity/function or capillary density. Running performance and mitochondrial function were unaltered by sACVR2B-Fc administration. Tumour experiment using Lewis lung carcinoma cells demonstrated that sACVR2B-Fc decreased the cachectic effects of chemotherapy without affecting tumour growth. These results demonstrate that blocking ACVR2B signalling may be a promising strategy to counteract chemotherapy-induced muscle wasting without damage to skeletal muscle oxidative capacity or cancer treatment.
  • Stark, Christoffer K. -J.; Tarkia, Miikka; Kentala, Rasmus; Malmberg, Markus; Vahasilta, Tommi; Savo, Matti; Hynninen, Ville-Veikko; Helenius, Mikko; Ruohonen, Saku; Jalkanen, Juho; Taimen, Pekka; Alastalo, Tero-Pekka; Saraste, Antti; Knuuti, Juhani; Savunen, Timo; Koskenvuo, Juha (2016)
    The use of cardiopulmonary bypass (CPB) and aortic cross-clamping causes myocardial ischemia-reperfusion injury (I-RI) and can lead to reduced postoperative cardiac function. We investigated whether this injury could be attenuated by thymosin beta 4 (TB4), a peptide which has showed cardioprotective effects. Pigs received either TB4 or vehicle and underwent CPB and aortic cross-clamping for 60 min with cold intermittent blood-cardioplegia and were then followed for 30 h. Myocardial function and blood flow was studied by cardiac magnetic resonance and PET imaging. Tissue and plasma samples were analyzed to determine the amount of cardiomyocyte necrosis and apoptosis as well as pharmacokinetics of the peptide. In vitro studies were performed to assess its influence on blood coagulation and vasomotor tone. Serum levels of the peptide were increased after administration compared to control samples. TB4 did not decrease the amount of cell death. Cardiac function and global myocardial blood flow was similar between the study groups. At high doses a vasoconstrictor effect on mesentery arteries and a vasodilator effect on coronary arteries was observed and blood clot firmness was reduced when tested in the presence of an antiplatelet agent. Despite promising results in previous trials the cardioprotective effect of TB4 was not demonstrated in this model for global myocardial I-RI.
  • Jorgenrud, Benedicte; Jalanko, Mikko; Helio, Tiina; Jaaskelainen, Pertti; Laine, Mika; Hilvo, Mika; Nieminen, Markku S.; Laakso, Markku; Hyotylainen, Tuulia; Oresic, Matej; Kuusisto, Johanna (2015)
    Aims Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are the most common genetic cause of hypertrophic cardiomyopathy (HCM) worldwide. The molecular mechanisms leading to HCM are poorly understood. We investigated the metabolic profiles of mutation carriers with the HCM-causing MYBPC3-Q1061X mutation with and without left ventricular hypertrophy (LVH) and non-affected relatives, and the association of the meta-bolome to the echocardiographic parameters. Methods and Results 34 hypertrophic subjects carrying the MYBPC3-Q1061X mutation, 19 non-hypertrophic mutation carriers and 20 relatives with neither mutation nor hypertrophy were examined using comprehensive echocardiography. Plasma was analyzed for molecular lipids and polar metabolites using two metabolomics platforms. Concentrations of branched chain amino acids, triglycerides and ether phospholipids were increased in mutation carriers with hypertrophy as compared to controls and non-hypertrophic mutation carriers, and correlated with echocardiographic LVH and signs of diastolic and systolic dysfunction in subjects with the MYBPC3-Q1061X mutation. Conclusions Our study implicates the potential role of branched chain amino acids, triglycerides and ether phospholipids in HCM, as well as suggests an association of these metabolites with remodeling and dysfunction of the left ventricle.
  • Wiberg, M.; Niskanen, J.E.; Hytönen, M.; Dillard, K.; Hagner, K.; Anttila, M.; Lohi, H. (2020)
    Introduction To describe unexpected sudden cardiac death (SCD) in young Leonbergers (