👤 K Aalto-Setälä

Modeling human cardiac diseases with induced pluripotent stem cells not only enables to study disease pathophysiology and develop therapies but also, as we have previously showed, it can offer a tool for disease diagnostics. We previously observed that a few genetic cardiac diseases can be separated from each other and healthy controls by applying machine learning to Ca For the current research, 419 hypertrophic cardiomyopathy (HCM) transient signals and 228 long QT syndrome (LQTS) transient signals were measured. HCM signals included data recorded from iPSC-CMs carrying either α-tropomyosin, i.e., TPM1 (HCMT) or MYBPC3 or myosin-binding protein C (HCMM) mutation and LQTS signals included data recorded from iPSC-CMs carrying potassium voltage-gated channel subfamily Q member 1 (KCNQ1) mutation (long QT syndrome 1 [LQT1]) or KCNH2 mutation (long QT syndrome 2 [LQT2]). The main objective was to study whether and how effectively HCMM and HCMT can be separated from each other as well as LQT1 from LQT2. After preprocessing those Ca We obtained excellent classification accuracies of 89% for HCM and even 100% for LQT at their best. The results indicate that the methods applied would be efficient for the identification of these genetic cardiac diseases. Show less

Nationwide large-scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. We sequenced 59 cardiomyopathy-associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most mutations were located in sarcomere genes (MYBPC3, MYH7, TPM1, and MYL2). Previously reported mutations by our study group (MYBPC3-Gln1061Ter, MYH7-Arg1053Gln, and TPM1-Asp175Asn) and a fourth major mutation MYH7-Val606Met accounted for 28.0% of cases. Mutations in GLA and PRKAG2 were found in three patients. Furthermore, we found 49 variants of unknown significance in 31 genes in 20.4% of cases. During a 6.7 ± 4.2 year follow-up, annual all-cause mortality in 482 index patients and their relatives with HCM was higher than that in the matched Finnish population (1.70 vs. 0.87%; P < 0.001). Sudden cardiac deaths were rare (n = 8). Systolic heart failure (hazard ratio 17.256, 95% confidence interval 3.266-91.170, P = 0.001) and maximal left ventricular wall thickness (hazard ratio 1.223, 95% confidence interval 1.098-1.363, P < 0.001) were independent predictors of HCM-related mortality and life-threatening cardiac events. The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation (12.9 vs. 3.5%, P < 0.001), but there was no difference in all-cause or HCM-related mortality between the two groups. Mortality due to HCM during 10 year follow-up among the 5.2 million population of Finland was studied from death certificates of the National Registry, showing 269 HCM-related deaths, of which 32% were sudden. We identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM-related mutations in non-sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM-related deaths annually. Show less

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease that affects the heart muscle with diverse clinical outcomes. HCM can cause sudden cardiac death (SCD) during or immediately after mild to rigorous physical activity in young patients. However, the mechanism causing SCD as a result of exercise remains unknown, but exercise-induced ventricular arrhythmias are thought to be responsible for this fatal consequence. To understand the disease mechanism behind HCM in a better way, we generated patient-specific induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from HCM patients carrying either the Show less

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease, which affects the structure of heart muscle tissue. The clinical symptoms include arrhythmias, progressive heart failure, and even sudden cardiac death but the mutation carrier can also be totally asymptomatic. To date, over 1400 mutations have been linked to HCM, mostly in genes encoding for sarcomeric proteins. However, the pathophysiological mechanisms of the disease are still largely unknown. Two founder mutations for HCM in Finland are located in myosin-binding protein C (MYBPC3-Gln1061X) and α-tropomyosin (TPM1-Asp175Asn) genes. We studied the properties of HCM cardiomyocytes (CMs) derived from patient-specific human induced pluripotent stem cells (hiPSCs) carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn mutation. Both types of HCM-CMs displayed pathological phenotype of HCM but, more importantly, we found differences between CMs carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn gene mutation in their cellular size, Ca(2+) handling, and electrophysiological properties, as well as their gene expression profiles. These findings suggest that even though the clinical phenotypes of the patients carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn gene mutation are similar, the genetic background as well as the functional properties on the cellular level might be different, indicating that the pathophysiological mechanisms behind the two mutations would be divergent as well. Show less

In the nationwide FinHCM Study including 306 Finnish patients with hypertrophic cardiomyopathy (HCM), we have previously identified two founder mutations in the alpha-tropomyosin (TPM1-D175N) and myosin-binding protein C (MYBPC3-Q1061X) genes, accounting for 18% of all cases. Objective. To screen additional mutations, previously identified in eastern Finnish cohorts with HCM, in the FinHCM Study population. Ten mutations in the beta-myosin heavy chain gene (MYH7), TPM1, and MYBPC3 were screened. MYH7-R1053Q was found in 17 of 306 patients (5.6%). No carriers of MYH7-R719W or N696S were found. A novel TPM1-D175G mutation was found in a single patient. MYBPC3 mutations were found in 14 patients: IVS5-2A-C in two, IVS14-13G-A in two, K811del in six, and A851insT in four patients. Altogether, a HCM-causing mutation was identified in 32 patients, accounting for 10.5% of all cases. In addition, two MYBPC3 variants R326Q and V896M with uncertain pathogenicity were found in eight and in 10 patients, respectively. Combining the present findings with our previous results, a causative mutation was identified in 28% of the FinHCM cohort. MYH7-R1053Q was the third most common mutation, and should be screened in all new cases of HCM in Finland. Show less

Hypertrophic cardiomyopathy (HCM) is predominantly caused by a large number of various mutations in the genes encoding sarcomeric proteins. However, two prevalent founder mutations for HCM in the alpha-tropomyosin (TPM1-D175N) and myosin-binding protein C (MYBPC3-Q1061X) genes have previously been identified in eastern Finland. To assess the prevalence of these founder mutations in a large population of patients with HCM from all over Finland. Patients and methods. We screened for two founder mutations (TPM1-D175N and MYBPC3-Q1061X) in 306 unrelated Finnish patients with HCM from the regions covering a population of ∼4,000,000. The TPM1-D175N mutation was found in 20 patients (6.5%) and the MYBPC3-Q1061X in 35 patients (11.4%). Altogether, the two mutations accounted for 17.9% of the HCM cases. In addition, 61 and 59 relatives of the probands were found to be carriers of TPM1-D175N and MYBPC3-Q1061X, respectively. The mutations showed regional clustering. TPM1-D175N was prevalent in central and western Finland, and MYBPC3-Q1061X in central and eastern Finland. The TPM1-D175N and MYBPC3-Q1061X mutations account for a substantial part of all HCM cases in the Finnish population, indicating that routine genetic screening of these mutations is warranted in Finnish patients with HCM. Show less

Apolipoprotein A-I/C-III/A-IV (apoA-I/C-III/A-IV) SstI and apolipoprotein B (apoB) XbaI polymorphisms have been shown to affect serum low-density lipoprotein (LDL) cholesterol concentrations in a sample of Finnish children. We studied whether these polymorphism are associated with carotid artery intima-media thickness (IMT), a marker of pre-clinical atherosclerosis, measured in the same subjects during their adulthood. A random sub-sample of 214 individuals from the "Cardiovascular Risk in Young Finns" study, for whom genotypes, cardiovascular risk factor data and carotid artery IMT measured in 2001 were available, were studied. Mean carotid IMT values increased according to the apoA-I/C-III/A-IV SstI genotype groups in the order of S1S1 (0.58+/-0.08 mm), S1S2 (0.61+/-0.08 mm), and S2S2 (0.70+/-0.16 mm, p=0.02, ANOVA). In multiple linear regression analysis after adjusting for age, sex and body mass index the mean IMT thickness among the S2 allele carriers was higher (p=0.02) compared to non-carriers. In logistic regression analysis the frequency of S2 allele carriers was higher among the high IMT group compared to the low IMT group (OR=4.02, CI: 1.68-9.61, p=0.002). No significant association between apoB XbaI polymorphism and carotid IMT was found. However, serum total and LDL cholesterol and apoB concentrations were significantly different among apoB genotype groups (p<0.001 for all traits). The apoA-I/C-III/A-IV SstI polymorphism is associated with carotid IMT in young Finns. Show less

In this report we present the genomic, cDNA, and predicted protein sequences for mouse apolipoproteins A-I and CIII, as well as sequence comparisons with other species. The genes for these apolipoproteins are within 2.5 kb of each other and convergently transcribed. The almost 9 kb of genomic sequence presented extends from 1298 bp 5' to the apolipoprotein A-I (Apoa-1) gene to 1249 bp 5' to the apolipoprotein CIII (Apoc-3) gene. The mouse Apoa-1 gene is 1.76 kb in length with four exons and three introns. The 5' flanking region contains TATA and CCAAT box sequences, an interferon responsive element homology, and potential binding sites for transcription factors CTF/NF1 and HNF4. Translation of the cDNA predicts that the mouse Apoa-1 primary transcript is 264 amino acids. The mouse Apoc-3 gene is 2.2 kb in length and also consists of four exons and three introns. The 5' flanking region contains TATA and CCAAT box sequences, RXR-1 and ARP-1 binding sites, and potential binding sites for transcription factors HNF4, NFkB, AP-1, and CTF/NF1. Translation of the cDNA predicts that the mouse Apoc-3 primary transcript is 99 amino acids. The clustering and genomic organization of the mouse Apoa-1 and Apoc-3 genes are similar to those of the rat and human genes. Significant sequence homologies between species exist for the proximal promoter and exonic regions of each gene, but not for the intronic or intergenic regions.(ABSTRACT TRUNCATED AT 250 WORDS) Show less