Alterations in Myocardial Function and Electrocardiology in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy with a highly variable phenotype. The assessment of arrhythmogenic potential in HCM patients and identification of early signs of the disease in relatives of HCM patients is challenging. The aim of this thesis was to characterize the mechanical and electrical changes in the left ventricle of carriers of either the MYBPC3-Q1061X or TPM1-D175N mutation for hypertrophic cardiomyopathy and to identify novel imaging and electrocardiographic parameters with the potential to enhance sudden cardiac death risk stratification and follow-up. A total of 140 subjects carrying a pathogenic variant for HCM were recruited for these studies from three centers in Finland, divided into two groups: those with left ventricular hypertrophy (G+/LVH+ n = 98) and those without hypertrophy (G+/LVH- n = 42). We studied the association of ventricular arrhythmias on 24h ambulatory electrocardiograms to 2D strain echocardiographic findings and cardiac magnetic resonance imaging variables in 31 G+/LVH+ HCM patients. Mechanical dispersion was significantly increased in HCM patients with episodes of ventricular arrhythmia on ambulatory ECGs and was a better predictor of these episodes than global longitudinal strain or late gadolinium enhancement. Mechanical dispersion may be a useful marker of arrhythmogenic potential in HCM patients. We evaluated conventional and novel ECG parameters in the whole cohort of mutation carriers. An abnormal ECG was present in 97% of G+/LVH+ and 86% of G+/LVH- subjects. The combination criteria of RV1RV3 + Q waves and septal remodeling identified G+/LVH- subjects with a 64% sensitivity and 97% specificity. The proposed novel ECG criteria may increase the efficacy of using electrocardiography in identification of G+/LVH- subjects. A group of 46 HCM patients was assessed with a 24h ambulatory ECG with comprehensive repolarization analysis and these findings were compared with imaging findings. Rate adapted QTe interval was prolonged in HCM patients. Maximal wall thickness was associated with longer maximal QTe and median T wave peak to T wave end interval. HCM patients with late gadolinium enhancement had a steeper QTe/RR slope compared to HCM patients without LGE and control subjects. The presence of LGE may independently affect the repolarization dynamics in HCM. The metabolome of carriers of the MYBPC3-Q1061X mutation was investigated with comprehensive laboratory assays. 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.Hypertrofinen kardiomyopatia (HCM) on yleisin perinnöllinen sydänlihassairaus. Sairauteen liittyy äkkikuoleman riski osalla potilaista. Tämän riskin arvioiminen on tunnetusti vaikeaa myös moderneilla riskinarviomenetelmillä ja tarve diagnostisille työkaluille, jotka tätä parantaisivat, on ilmeinen. Taudin periytyvyyden arvioimiseksi tarvitaan geenidiagnostiikan lisäksi hyviä menetelmiä varhaisten tautimuotojen havaitsemiseen seurannan kohdentamiseksi. Tämän väitöskirjan tavoite on ollut sydänlihaksen mekaanisten ja sähköisten muutosten arvioiminen ja parempien diagnostisen työkalujen löytäminen rytmihäiriöriskin ja sairauden esimuutosten todentamiseen. Potilasmateriaali koostui 140 suomalaisesta, jotka kantavat joko MYBPC3-Q1061X tai TPM1-D175N geenimutaatiota, jotka aiheuttavat hypertrofista kardiomyopatiaa. Potilaat jaettiin kahteen ryhmään: Ensimmäisessä ryhmässä olivat mutaatiokantajat, joilla todettiin vasemman kammion seinämähypertrofia eli hypertrofinen kardiomyopatia (n = 98) ja toisessa ryhmässä mutaatiokantajat, joilla ei ole hypertrofiaa (n = 42). Ensimmäisessä osatyössä tutkittiin lyhyiden kammioarytmioiden esiintymisen korrelaatiota kuvantamislöydöksiin 31:llä HCM-potilaalla. Totesimme ultraäänitutkimuksella mitatun mekaanisen dispersion olevan selvästi suurentunut HCM-potilailla, joilla esiintyi kammioarytmioita holter-seurannassa. Mekaaninen dispersio ennusti rytmihäiriöitä paremmin kuin pitkittäinen strain ultraäänessä tai jälkitehostuma MRI:ssä. Toisessa osatyössä kartoitimme koko mutaatiokantajakohortin EKG-löydöksiä ja niiden yhteyttä kuvantamislöydöksiin. Ehdottamamme uudet EKG-parametrit RV1RV3 ja väliseinän uudelleenmuovautuminen olivat hyvin spesifejä mutaatiokantajille ja erottelivat hyvin ei-hypertrofiset mutaatiokantajat kontrolliryhmästä. Yhdistelemällä näitä uusia EKG-löydöksiä vanhojen hyväksi havaittujen mittausten kanssa päästiin aikaisempaa parempaan erottelukykyyn ei-hypertrofisten mutaatiokantajien ja kontrolliryhmän välillä. Käyttämällä uusia EKG-löydöksiä voidaan yksilöiden seurantaa mahdollisesti kohdentaa paremmin. Kolmannessa osatyössä tutkimme holter-rytminseurannan repolarisaatiomuutosten yhteyttä kuvantamislöydöksiin 46:lla HCM-potilaalla. Totesimme QT-ajan olevan pidentynyt HCM-potilailla ja se piteni progressiivisesti matalammilla syketaajuuksilla suhteessa terveisiin verrokkeihin. QT-ajan pitenemä oli yhteydessä vasemman kammion seinämäpaksuuteen. Potilailla, joilla oli myöhäistehostumaa vasemmassa kammiossa, oli jyrkempi QT/RR kulmakerroin. Myöhäistehostuma voi olla itsenäinen tekijä repolarisaatiomuutoksissa ja vaikuttaa tätä kautta myös rytmihäiriöherkkyyteen. HCM-potilaiden metabolomia ei ole juurikaan aikaisemmin tutkittu. Selvitimme laajalla analyysillä HCM-potilaiden metabolomista profiilia. Löydöksenä oli haaraketjuisten aminohappojen, triglyseridien ja fosfolipidien konsentraatiomuutoksia verrattuna terveisiin kontrolleihin. Nämä muutokset assosioituivat kuvantamislöydöksiin eli taudin vaikeusasteeseen

Cause-Specific Mortality of Patients With Atrial Septal Defect and Up to 50 Years of Follow-Up

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

Features of liver tissue remodeling in intestinal failure during and after weaning off parenteral nutrition

Background. Intestinal failure is associated frequently with liver injury, which persists after weaning off parenteral nutrition. We compared features of liver remodeling in intestinal failure during and after weaning off parenteral nutrition. Methods. Liver biopsies and serum samples were obtained from 25 intestinal failure patients at a median age of 9.7 years (interquartile range: 4.6-18) and from age-matched control patients. Seven patients had been receiving parenteral nutrition for 53 months (22-160), and 18 patients had been weaned off parenteral nutrition 6.3 years (2.4-17) earlier, after having received parenteral nutrition for 10 months (3.3-34). Expression of alpha smooth muscle actin, collagen 1, proinflammatory cytokines, growth factors, and matrix metalloproteinases (MMPs) was measured. Results. Significant increases in immunohistochemical expression of alpha-smooth muscle actin and collagen 1 were observed predominantly in portal areas and were similar to increases seen in patients currently receiving parenteral nutrition and in patients weaned off parenteral nutrition. Gene and protein expressions of alpha-smooth muscle actin and collagen were interrelated. Gene expression of ACTA2, encoding alpha-smooth muscle actin, was increased only in patients who were receiving parenteral nutrition currently. Comparable upregulation of interleukin-1 (alpha and beta), epidermal growth factor, integrin-beta 6, and MMP9 gene expression was observed in both patient groups, irrespective of whether they were receiving parenteral nutrition currently. Liver expression and serum levels of TIMP1 and MMP7 were increased only in the patients on parenteral nutrition currently but were not increased after weaning off parenteral nutrition. Conclusion. Intestinal failure is characterized by abnormal activation of hepatic myofibroblast and accumulation of collagen both during and after weaning off parenteral nutrition. Persistent transcriptional upregulation of proinflammatory and fibrogenic cytokines after weaning off parenteral nutrition suggests that factors other than parenteral nutrition may contribute to intestinal failure associated liver disease.Peer reviewe

Anemia and low-grade inflammation in pediatric kidney transplant recipients

Anemia and low-grade inflammation are reported to be associated with impaired long-term graft outcome in renal transplant (RTx) recipients. In this study, hemoglobin (Hb) and inflammation marker levels were correlated with measured glomerular filtration rate (GFR) in 128 pediatric RTx recipients over a median follow-up period of 10 years. Serum levels of erythropoietin (EPO), hepcidin-25, high-sensitivity C-reactive protein (CRP) (hsCRP) and interleukin-6 (IL-6) were analyzed by enzyme-linked immunosorbent assays, and GFR was analyzed by Cr-51-EDTA clearance. The median levels of Hb (115 g/L), hsCRP (0.4 mg/L) and IL-6 (1.4 pg/mL) and the median erythrocyte sedimentation rate (ESR; 19 mm/h) remained stable after the first post-operative year. However, approximately half of the patients had a normocytic, normochromic anemia, and one-third had elevated levels of hsCRP (> 1 mg/L) and ESR (> 25 mm/h), indicating continuous low-grade inflammation. Low Hb levels preceded increased fibrosis in protocol biopsies taken at 1.5 and 3 years after transplantation and preceded decreased GFR by several years. Hb levels showed an inverse correlation with EPO levels (r = -0.206, p = 0.038) and ESR (r = -0.369, p <0.001), but not with hepcidin-25, hsCRP or IL-6 levels. The levels of the major inflammatory markers IL-6 and hsCRP did not show a significant correlation with GFR at either the early maintenance phase or later. In the multivariable analysis, low Hb levels performed better than any other marker with respect to predicting concomitant and subsequent GFR. Anemia, but not elevated inflammatory indices, was associated with poor concomitant and subsequent graft function during a 10-year follow-up in pediatric RTx patients.Peer reviewe

Non-invasive dye dilution method for measuring an atrial septal defect shunt size

Aims Objective of this study was to evaluate the feasibility of the non-invasive dye dilution method to quantify shunt size related to atrial septal defects (ASD). The diagnostic accuracy of shunt size determination in ASD's has been suboptimal with common non-invasive methods. We have previously developed a cost-effective and time-effective non-invasive dye dilution method. In this method, the indocyanine green solution is injected into the antecubital vein and the appearance of the dye is detected with an earpiece densitometer. Methods and results We studied 192 patients with an ASD. Mean pulmonary blood flow/systemic blood flow (Qp/Qs) was measured with dye dilution technique and compared with following methods: Fick's invasive oximetry (n=49), transoesophageal echocardiography (TEE) measuring ASD size (n=143) and cardiac MR (CMR) (n=9). For the first 49 patients, Qp/Qs was 2.05 +/- 0.70 with the Fick's invasive oximetry and 2.12 +/- 0.68 with dye dilution method with an excellent correlation between the two methods (R=0.902, p Conclusion The dye dilution method with earpiece densitometer recording is a clinically feasible and reliable method to assess shunt size in ASDs.Peer reviewe

Divergent expression of liver transforming growth factor superfamily cytokines after successful portoenterostomy in biliary atresia

Background: Pathogenesis of progressive liver fibrosis in biliary atresia after successful portoenterostomy remains unclear. We related hepatic expression of transforming growth factor beta (TGF-beta) superfamily cytokines to histologic liver injury after successful portoenterostomy. Methods: Enrolled in our study were 28 patients with biliary atresia who had liver biopsies obtained during and after successful portoenterostomy, which normalized serum bilirubin ( Results: After median follow-up of 3.0 years, histologic cholestasis resolved, whereas fibrosis had progressed only in isolated biliary atresia. Liver protein expression of transforming growth factor beta 1 and connective tissue growth factor (P Conclusion: These findings support a central role of transforming growth factor beta superfamily in mediating continuing liver fibrogenesis after successful portoenterostomy. Transforming growth factor beta pathway cytokines responded divergently to clearance of jaundice, which was reflected by differential progression of fibrosis between syndromic and isolated patients. (C) 2018 Elsevier Inc. All rights reserved.Peer reviewe

Noninvasive Evaluation of Liver Fibrosis and Portal Hypertension After Successful Portoenterostomy for Biliary Atresia

We investigated noninvasive follow-up markers for histologic liver fibrosis and portal hypertension (PH) in patients with biliary atresia after successful portoenterostomy (PE). Among children with bilirubin 11 mu mol/L in the youngest tertile (AUROC, 0.91; P 80 mu mol/L in the middle tertile (AUROC, 0.81; P = 0.009), and liver stiffness was >24 kPa in the oldest age tertile (AUROC, 0.96; P = 0.002). Conclusion: After successful PE, development of PH associates with progression of liver fibrosis and can be accurately detected by APRI and stiffness. Liver stiffness most accurately identified cirrhosis in older children, whereas biochemical markers of cholestasis closely reflected histologic cirrhosis in younger children.Peer reviewe

Expression of 6 Biomarkers in Liver Grafts After Pediatric Liver Transplantation : Correlations with Histology, Biochemistry, and Outcome

Background: Subclinical graft inflammation and fibrosis after pediatric liver transplantation (LT) are common. Biomarkers are needed that precede and are associated with these changes and graft outcome. Material/Methods: We evaluated immunohistochemical expression of 6 biomarkers [alpha-smooth muscle actin (alpha-SMA), collagen I, decorin, vimentin, P-selectin glycoprotein ligand-1 (PSGL-1), and CD34] in biopsies taken intraoperatively at LT (baseline) (n=29) and at 11.3 years after LT (first follow-up) (n=51). Liver biochemistry and graft histology were assessed at the first follow-up and at final assessment (19.6 years after LT) (n=48). Second follow-up biopsies for histology were available from 24 patients. The immunostainings were correlated with liver histology, biochemistry, and outcome at these time-points. Results: Baseline levels of the biomarkers were unrelated to presence of fibrosis at follow-up. Increased a-SMA, collagen I levels, decorin, and vimentin were associated with simultaneous fibrosis at the first follow-up (p=0.001-0.027). Increased SMA, collagen I, decorin, vimentin, PSGL-1, and CD34 expression at first follow-up were associated with simultaneous portal inflammation (p=0.001-0.025). alpha-SMA, decorin, and vimentin expression were increased in patients without fibrosis at the first follow-up but who developed fibrosis in second follow-up (p=0.014 p=0.024 and p=0.024). Significant fibrosis (F2) and markedly increased alpha-SMA, collagen I, decorin, and vimentin levels at first follow-up were associated with suboptimal liver status at the final assessment (p=0.002-0.042). Conclusions: The expression of the biomarkers at LT was unrelated to later development of graft fibrosis. alpha-SMA, decorin, and vimentin were associated with later graft fibrosis and suboptimal liver status.Peer reviewe