Renal denervation in patients who do not respond to cardiac resynchronization therapy

Cardiac resynchronization therapy (CRT) reduces the morbidity and mortality in advanced heart failure (HF) in about two-thirds of the patients. Approximately one-third of the patients do not respond to CRT. The overactivity of sympathetic nervous system is associated with advanced HF and deteriorates the hemodynamic state. We tested the hypothesis that controlling sympathetic overactivity by renal denervation (RDN) could be beneficial in nonresponders for CRT. In our HeartF-RDN study (ClinalTrials.gov. NCT02638324), RDN could not reverse the progression of HF in subjects with New York Heart Association Classification (NYHA) III-IV stage symptoms.Peer reviewe

Celiac disease antibody levels reflect duodenal mucosal damage but not clinical symptoms

Objectives: This study aimed to investigate, in a real-world population, whether the histological and clinical phenotype differ at baseline and during follow-up in patients with high and low CD (celiac disease) antibody titers. Materials and methods: The study cohort consisted of 96 consecutive patients diagnosed to have CD during the years 2010–2018. The clinical parameters, symptoms and laboratory results were registered and histomorphometry was analyzed from the available duodenal biopsies taken during the primary and follow-up esophageal-gastricduodenoscopies. Patients having immunoglobulin A transglutaminase antibody (tTG-ab) levels above 70 U/mL were classified as high titer patients. Results: Measured by the villous-crypt ratio, the duodenal mucosa was more severely damaged in the high tTG-ab group than in the low tTG-group at baseline (n = 70, 0.61 ± 0.63 vs. 1.02 ± 0.87, p =.003) and during the follow-up when the patients were on gluten-free diet (n = 27, 1.80 ± 0.72 vs. 2.35 ± 0.64, p =.041). Interestingly, the high tTG-ab group members had fewer gastrointestinal symptoms at baseline than those in the low tTG-ab group (43% vs. 68%, p =.013) but lower vitamin D levels (68 ± 34 nmol/L vs. 88 ± 29 nmol/L, p =.034) and more often microcytosis (28% vs. 10%, p =.040). During the follow-up, these differences were no longer detected. Conclusions: At baseline, CD patients with high tTG-ab have more severe duodenum injury and signs of malabsorption but fewer symptoms. After gluten-free diet has been initiated, the mucosal healing in the high tTG-ab group is prolonged, but symptoms and signs of malabsorption recover equally in both groups.acceptedVersionPeer reviewe

Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/allele) than common variants. Multiple rare, nonsense and missense variant associations were found in A2ML1 and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention

Non-alcoholic fatty liver disease (NAFLD):perspectives to etiology, complications and lipid metabolism

Abstract Obesity, insulin resistance, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) form a dangerous quartet which threatens human health all over the world. About 25% of adults around the world have NAFLD, which poses risks for cardiovascular and metabolic well-being and may develop into liver cirrhosis and hepatocellular carcinoma. Apart from lifestyle modification, treatment options for NAFLD are scarce. This thesis presents atrial fibrillation (AF) as a new complication of NAFLD among general population of 958 individuals aged 40-60 years participating in the OPERA study. Even after multiple-adjustments for confounding factors, ultrasound-based NAFLD predicted the development of AF during about 16 years of follow-up. Moreover, the association between AF and liver fibrosis in 76 individuals aged 64-82 years in a cross-sectional setting is presented. The thesis also shows that individuals with metabolic syndrome (MetS), with or without NAFLD, are at increased risk of cardiovascular events, T2D and the increase of left ventricular mass index in a study population of 958 individuals aged 40-60 years during a 20-year follow-up. In other words, NAFLD without MetS does not seem to expose to these three cardiometabolic complications. The thesis also shows that rifampicin-activated pregnane X receptor (PXR), a member of the nuclear receptor superfamily of ligand-activated transcription factors with several endobiotic and xenobiotic activators, increases serum levels of cholesterol, phospholipids and certain fatty acids, assessed by nuclear magnetic resonance metabolomics technique, in a randomized, open, placebo-controlled trial among 34 young and healthy individuals. These serum lipids are considered toxic lipids and capable of transforming hepatosteatosis into steatohepatitis and even more severe forms of NAFLD. Moreover, rifampicin-activated PXR has no effect on serum triglycerides, that are non-toxic lipids, or triglyceride accumulation in the liver, assessed by magnetic resonance imaging, in 15 young and healthy individuals. In conclusion, this thesis advances the knowledge in the pathogenesis, lipid metabolism, complications and heterogeneous nature of NAFLD. These may have implications for patient care and follow-up.Tiivistelmä Maailmanlaajuisesti noin 25% täysi-ikäisistä henkilöistä sairastaa alkoholinkäyttöön liittymätöntä rasvamaksaa. Sen tiedetään altistavan sydän- ja verisuonisairauksille, aineenvaihduntahäiriöille, maksakirroosille ja jopa maksasyövälle, mutta elämäntapahoitoa lukuun ottamatta hoitomahdollisuudet ovat toistaiseksi vähäisiä. Tässä väitöskirjassa osoitetaan ensimmäistä kertaa alkoholinkäyttöön liittymättömän rasvamaksan ennustavan itsenäisesti eteisvärinän ilmaantuvuutta noin 16 vuoden seurannan aikana 958 tavallisen keski-ikäisen ihmisen aineistossa osana OPERA-tutkimusta. Lisäksi väitöskirjassa osoitetaan maksan sidekudosmuodostuksen ja eteisvärinän välillä olevan yhteys poikkileikkausasetelmassa 76 iäkkään ihmisen muodostamassa aineistossa. Väitöstutkimuksessa havaittiin myös, että metabolista oireyhtymää sairastavilla henkilöillä on suurentunut tyypin 2 diabeteksen, sydän- ja verisuonisairauksien sekä vasemman kammion koon suurentumisen riski noin 20 vuoden seurannan aikana 958 tutkittavan henkilön aineistossa riippumatta siitä, onko heillä alkoholinkäyttöön liittymätön rasvamaksa. Toisin sanoen alkoholin käyttöön liittymätön rasvamaksa ilman metabolista oireyhtymää ei lisää edellä mainittujen kolmen sairauden riskiä. Väitöstutkimuksessa esitetään lisäksi, että rifampisiinilla aikaansaatu maksan pregnane X -reseptorin aktivaatio johtaa seerumin fosfolipidien, tiettyjen rasvahappojen sekä usean eri kolesterolityypin lisääntymiseen 34 terveen nuoren henkilön aineistossa. Kirjallisuudessa näiden seerumin rasva-aineiden on esitetty aiheuttavan alkoholin käyttöön liittymätöntä maksatulehdusta ja jopa rasvamaksan vakavimpia muotoja. Toisaalta rifampisiini ei lisännyt seerumin triglyseridipitoisuutta eikä aiheuttanut magneettitutkimuksella mitattuna triglyseridien kertymistä maksaan 15 terveen nuoren henkilön aineistossa. Tämä väitöstutkimus antaa lisätietoa rasvamaksan kehittymisestä, rasva-aineenvaihdunnasta ja komplikaatioista sekä korostaa rasvamaksan monimuotoista luonnetta. Nämä löydökset saattavat parantaa rasvamaksaa sairastavien henkilöiden hoitoa ja seurantaa

Non-Alcoholic Fatty Liver Disease as a Predictor of Atrial Fibrillation in Middle-Aged Population (OPERA Study).

Non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) are widespread diseases and have multiple common risk factors and comorbidities. No studies of association between ultrasonography-diagnosed NAFLD and AF exist in other than diabetic population. The goal of this prospective study was to study the value of NAFLD as a predictor of atrial fibrillation. This study had 958 subjects from the OPERA (Oulu Project Elucidating Risk of Atherosclerosis) cohort, and the mean follow-up time was 16.3 years. NAFLD was diagnosed if the subject had fatty liver in ultrasonography and no excess alcohol intake. AF was followed in the National Registers. In this study 249 subjects (26.0%) had NAFLD and 37 (14.9%) of these had AF whereas only 56 (7.9%) of those without NAFLD experienced AF during the follow-up time (p = 0.001). In the multiple Cox regression analysis including potential confounders (age, sex, study group, diabetes, body mass index (BMI), waist circumference, alcohol consumption, smoking, serum alanine aminotransferase concentration (ALT), systolic blood pressure, quick index, left ventricular mass index, left atrial diameter, coronary artery disease (CAD), atrial natriuretic peptide (ANP) and high sensitive C-reactive protein (hs-CRP)), NAFLD remained as an independent predictor of AF (Adjusted OR, 1.88 (95% Confidence interval (CI) 1.03-3.45)). In conclusion, our data shows that NAFLD is independently associated with the risk of AF

Metabolic syndrome but not genetic polymorphisms known to induce NAFLD predicts increased total mortality in subjects with NAFLD (OPERA study)

Abstract Metabolic syndrome (MetS) and genetic polymorphisms PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 are known inductors of non-alcoholic fatty liver disease (NAFLD). However, knowledge about how these affect the mortality of subjects with NAFLD is scarce. Therefore, we investigated the impact of MetS, PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 on overall and cardiovascular disease (CVD) specific mortality among subjects with or without NAFLD. NAFLD diagnosis was based on liver ultrasound at the baseline. After this and other comprehensive examinations, 958 middle-aged Finns, 249 with NAFLD, were followed for 21 years. The mortality data was gathered from the National Death Registry. After multiple adjustments, the NAFLD individuals with MetS had increased risk of overall mortality as compared to the NAFLD subjects without MetS [2.054 (1.011–4.173, p = 0.046)]. However, PNPLA3 rs738409 [1.049 (0.650–1.692, p =0 .844)], TM6SF2 rs58542926 [0.721 (0.369–1.411, p = 0.340)] or MBOAT7 rs641738 [0.885 (0.543–1.439, p = 0.621)] did not affect the overall mortality. MetS was also a marker of increased risk of CVD mortality (15% vs. 2%, p =0.013) while genetic polymorphisms did not affect CVD mortality. In conclusion, MetS, but not the gene polymorphisms studied, predicts increased overall and CVD-specific mortality among NAFLD subjects

Long-term metabolic fate and mortality in obesity without metabolic syndrome

Abstract Background: Obesity and metabolic syndrome (MetS) are known to expose to atrial fibrillation (AF), cardiovascular diseases (CVD) and mortality. Metabolically healthy obesity refers to obesity without MetS. This study aimed to investigate how obesity and MetS modify the risk of CVD, AF and mortality in very long-time follow-up. Methods: Finnish middle-aged subjects (n = 1045) were grouped into four subgroups according to the presence of obesity and MetS. CVD events and AF were followed for 24 years and total mortality for 30 years. Moreover, 600 available patients had a follow-up visit for metabolic examinations after approximately 22 years. Results: One-hundred and sixty-two (30%) subjects without obesity or MetS died during the follow-up. Ninety-two (17%) of the patients in this group had a CVD event and 58 (11%) were diagnosed with AF. As compared to them, obese subjects without MetS had similar metabolic fate and mortality (mortality 26 (38%), p = .143; CVD event 12 (18%), p = .858 and AF 7 (10%), p = .912, respectively), whereas subjects with obesity and MetS had greater mortality (102 (49%), p < .001), more CVD (71 (34%), p < .001) and AF (49 (23%), p < .001). Non-obese individuals with MetS had greater rates of mortality (96 (44%), p < .001) and CVD (80 (37%), p < .001), but not of AF (26 (12%), p = .606). Of the 40 subjects with obesity but without MetS at baseline and available for the follow-up visit, 15 (38%) were metabolically healthy at the follow-up visit. Conclusions: In the present long-term follow-up study, the presence of MetS, but not obesity only, implies a greater risk of mortality and CVD. The risk of AF is increased only in subjects with both obesity and MetS. However, obesity without MetS tends to progress eventually to obesity with MetS

Baseline characteristics of the study subjects (n = 958) according to the presence or absence of NAFLD.

<p>The values are means ± SD, absolute numbers with percentages or percentages alone. The medication data is expressed as number of subjects and percentages. Differences were tested by the ANOVA test for continuous variables and Pearson Chi-Squared test for categorical variables. ANP, atrial natriuretic peptide; hs-CRP, high-sensitive C-reactive protein; γ-GT, gamma-glutamyl transpeptidase; ALT, alanine aminotransferase; ACE, angiotensin converting enzyme.</p><p>Baseline characteristics of the study subjects (n = 958) according to the presence or absence of NAFLD.</p

Nonalcoholic fatty liver disease and its prognosis associates with shorter leucocyte telomeres in a 21-year follow-up study

Abstract Leucocyte telomere length (LTL) has been associated with nonalcoholic fatty liver disease (NAFLD), but the evidence is imperfect. Furthermore, liver fibrosis has been shown to correlate with mortality and recent studies have also found associations with LTL and fibrosis suggesting that LTL may have additional prognostic value in liver diseases. Our objective was to study the association of LTL and NAFLD and evaluate the association of LTL in prognosis of NAFLD subjects. Study subjects (n = 847) were middle-aged hypertensive patients. All participants were evaluated for NAFLD and their LTL was measured at baseline. Outcomes were obtained from Finnish Causes-of-Death Register and the Care Register for Health Care in Statistics Finland to the end of 2014. An inverse association with NAFLD prevalence and LTL length was observed (p &lt; .001 for trend). Shortest telomere tertile possessed statistically significantly more NAFLD subjects even with multivariate analysis (shortest vs. middle tertile HR 1.98 p = .006 and shortest vs. longest tertile HR 2.03 p = .007). For the study period, mortality of the study group showed statistically significant relation with telomere length in univariate but not for multivariate analysis. In subgroup analysis, LTL did not associate with prognosis of non-NAFLD subjects. However, LTL was inversely associated with overall mortality in the subjects with NAFLD in both univariate (HR 0.16 p = .007) and multivariate analysis (HR 0.20 p = .045). In middle-aged Caucasian cohort, shorter leucocyte telomeres associated independently with increased prevalence of NAFLD. Shorter LTL was not associated with mortality in non-NAFLD patients whereas it predicted mortality of NAFLD patients independently