Bráður nýrnaskaði eftir hjartaskurðaðgerðir: tíðni, áhættuþættir, tengsl við aðra fylgikvilla við og eftir skurðaðgerð, lifun og langtímaáhrif á nýrnastarfsemi

In line with advances in surgery, perioperative care, and intensive care, the outcome in patients treated for cardiovascular disease has improved. Open-heart surgery is common in most western countries and, in line with the general ageing of populations, the frequency of these procedures is expected to increase in the coming decades. Patients who undergo cardiac surgery often have complex medical problems that predispose them to a range of surgical complications. Among the most common postoperative complications are arrhythmias, most often atrial fibrillation, and bleeding. Acute kidney injury (AKI) is also a common and often serious complication―as well as being a strong risk factor for worse postoperative outcome and increased mortality after surgery. However, many previous studies have suffered from a lack of data on baseline kidney function before AKI as well as selective patient cohorts. Approximately 250 open-heart surgeries are performed annually in Iceland. However, there has been a lack of data on the incidence and risk factors for AKI following heart surgery. The aim of the studies in this thesis was to evaluate the incidence of AKI using internationally validated criteria. Furthermore, we wanted to examine the association between AKI and other postoperative complications, and also long-term outcome, mainly regarding kidney function and survival. In that context, we particularly examined the effect of recovery of renal function on long-term outcome. Data were gathered from comprehensive nationwide databases that contained detailed information on all patients who underwent heart surgery in Iceland from 2001 through 2015. Information on kidney function, both pre- and postoperatively, was recorded in a thorough manner, as it is a prerequisite for reliable evaluation of AKI. The studies showed that the incidence of AKI after cardiac surgery in Iceland was relatively low compared to neighboring countries. In line with previous studies, the preoperative condition of patients was shown to be associated with the incidence of AKI. Advanced age, reduced preoperative kidney function, higher preoperative risk assessment scores, a higher body mass index, and more complex surgery were found to be independent predictors of the development of AKI. AKI was significantly associated with worse postoperative outcome, as reflected by higher rates of various postoperative complications when compared to patients with normal kidney function postoperatively. Atrial fibrillation, diagnosed in almost half of the patients, was the most common postoperative complication following surgical myocardial revascularization and aortic valve replacement in Iceland. Furthermore, the incidence of atrial fibrillation was higher in patients who sustained AKI than in those who did not. As in the case of AKI, the independent predictors of atrial fibrillation were advanced age, more complex surgery, and higher preoperative risk assessment scores. The diagnosis of AKI was found to be associated with an increased need for renal replacement therapy and worse long-term kidney function. Also, AKI patients had significantly higher postoperative mortality and worse long-term survival, with survival being inversely correlated to the severity of AKI. Importantly, the majority of patients recovered their renal function after AKI. Although renal recovery was not a significant predictor of one-year survival, it was found to be associated with more favorable long-term survival. By using extensive comprehensive nationwide databases, it was possible to determine the incidence of AKI after open-heart surgery in Iceland and to define risk factors. Most patients who sustained AKI recovered their renal function and the rate of progression to end-stage renal disease was low. Although AKI appears to be associated with a worse postoperative outcome in patients, early detection of AKI and gaining a better understanding of the risk factors remain important steps in reducing the morbidity and mortality of patients diagnosed with AKI. It is to be hoped that a better understanding of these factors will help to improve the long-term prognosis in this patient group, leading to increased rates of renal recovery and reduced costs of treatment.Framfarir í skurðlækningum og gjörgæslu hafa leitt til bættrar meðferðar sjúklinga sem þjást af hjarta- og æðasjúkdómum. Í dag eru opnar hjartaaðgerðir algengar á Vesturlöndum og útlit er fyrir að þeim muni fjölga á komandi áratugum, samfara auknum fjölda aldraðra. Sjúklingar sem gangast undir opnar hjartaaðgerðir eru oft með flókin heilsufarsvandamál sem eykur tíðni fylgikvilla. Á meðal algengustu fylgikvilla eftir opnar hjartaaðgerðir eru hjartsláttaróregla, einkum gáttatif, og blæðingar. Bráður nýrnaskaði (BNS) er einnig algengur fylgikvilli eftir hjartaaðgerðir og tengist verri horfum sjúklinga eftir aðgerð. Skortur á gögnum um grunnstarfsemi nýrna hefur þó verið galli á mörgum fyrri rannsóknum sem auk þess hafa oft á tíðum skoðað mjög sérhæfða sjúklingahópa. Árlega eru framkvæmdar um 250 opnar hjartaaðgerðir á Íslandi og eru um 2/3 þeirra kransæðahjáveituaðgerðir. Markmið þessarar doktorsritgerðar var að meta tíðni og áhættuþætti BNS eftir hjartaaðgerðir á Íslandi en skort hefur á slíkar rannsóknir fram til þessa. Auk þess voru könnuð tengsl BNS og annarra fylgikvilla eftir opnar hjartaaðgerðir. Loks var samband BNS og langtíma skerðingar á nýrnastarfsemi rannsakað, þar með talið þörf á nýrnaskilunarmeðferð, sem og langtímalifun. Að lokum var sérstaklega lagt mat á hvaða áhrif bati á nýrnastarfsemi hefur á horfur sjúklinga sem hljóta BNS. Við rannsóknirnar var stuðst við gagnagrunna með ítarlegum upplýsingum um alla sjúklinga sem gengust undir hjartaaðgerð á Íslandi frá 2001-2015. Ber þar sérstaklega að nefna nákvæma skráningu á nýrnastarfsemi sjúklinga, bæði fyrir og eftir aðgerð, en þær upplýsingar eru forsenda til að geta lagt mat á tíðni og áhættuþætti BNS. Rannsóknirnar leiddu í ljós að tíðni BNS eftir hjartaaðgerðir er heldur lægri hér á landi samanborið við nágrannalönd okkar. Líktog aðrar rannsóknir hafa sýnt er BNS tengdur undirliggjandi ástandi sjúklinga og voru aldur, skerðing á nýrnastarfsemi fyrir aðgerð, hærri áhættustigun fyrir aðgerð, umfangsmeiri skurðaðgerð og hærri líkamsþyngdarstuðull sjálfstæðir áhættuþættir. Bráður nýrnaskaði tengdist verri horfum sjúklinga eftir aðgerð sem meðal annars endurspeglaðist í hærri tíðni ýmissa fylgikvilla. Gáttatif reyndist algengasti fylgikvillinn og greindist í nærri helmingi sjúklinga sem gengust ii undir kransæðahjáveitu- eða ósæðarlokuskiptaaðgerð á Landspítala. Auk þess kom í ljós að tíðni gáttatifs var marktækt aukin hjá sjúklingum sem fengu BNS. Eins og fyrir BNS, reyndust hærri aldur, umfang aðgerðar og hærri áhættustigun fyrir aðgerð vera sjálfstæðir áhættuþættir fyrir greiningu gáttatifis. Greining BNS tengdist einnig aukinni þörf á skammtíma nýrnaskilunarmeðferð og versnun á langtíma nýrnastarfsemi. Aukinheldur höfðu sjúklingar sem fengu BNS marktækt lakari lifun eftir aðgerð og reyndist langtímalifun í öfugu hlutfalli við alvarleika upphaflegs nýrnaskaða. Meirihluti sjúklinga virtist hinsvegar endurheimta nýrnastarfsemi eftir BNS í kjölfar aðgerðar. Bati á nýrnastarfsemi spáði ekki fyrir um eins árs lifun sjúklinga en hinsvegar lifðu sjúklingar sem náðu bata marktækt lengur en samanburðarhópur sem ekki náði bata. Með því að notast við yfirgripsmikla og nákvæma gagnagrunna, sem ná til heillar þjóðar, reyndist unnt að meta tíðni BNS og gáttatifs eftir opnar hjartaaðgerðir á Íslandi um leið og lifun og forspárþættir lifunar eftir þessar aðgerðir voru kannaðir. Flestir sjúklingar sem hlutu BNS endurheimtu nýrnastarfsemi og fáir hlutu endastigs nýrnabilun. Samt sem áður virðist BNS tengjast verri útkomu eftir hjartaaðgerð og ljóst er að úrræði skortir þegar greining BNS liggur fyrir. Snemmbúin greining BNS og kortlagning áhættuþátta á þó vonandi eftir að auka skilning okkar á BNS og hvernig fyrirbyggja má sjúkdóminn og að bæta horfur þessa sjúklingahóps

Acute kidney injury and outcome following aortic valve replacement for aortic stenosis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Most studies on acute kidney injury (AKI) following open-heart surgery have focused on short-term outcome following coronary artery bypass grafting. We reviewed the incidence, risk factors and outcome, including long-term survival, of AKI after aortic valve replacement (AVR) in a population-based cohort.A retrospective review of 365 patients who underwent AVR for aortic stenosis during 2002-2011 was made. AKI was defined according to the RIFLE criteria. All patients requiring dialysis were followed up in a centralized registry. Risk factors for AKI were analysed with univariable and multivariable analysis, and survival was graphically presented with the Kaplan-Meier method.The rate of AKI was 82/365 (22.5%); 40, 28 and 14 patients belonging to the Risk, Injury and Failure groups, respectively. Preoperatively, 37 (45.1%) AKI patients had reduced kidney function. Transfusion of red blood cells, obesity and prolonged cardiopulmonary bypass time were independent risk factors for AKI. Acute postoperative dialysis was required in 15 patients (4.1%), and 1 patient developed dialysis-dependent end-stage renal disease. Major postoperative complications were more common in the AKI group (65 vs 22%, P < 0.001). The 30-day mortality rate in the AKI group was 18%, as opposed to 2% in the non-AKI group (P < 0.001), with a 5-year survival rate of 66 vs 87%, respectively (P < 0.001). In multivariable analysis AKI was an independent predictor of operative mortality [odds ratio = 5.89, 95% confidence interval (CI) = 1.99-18.91] but not of long-term survival (hazard ratio = 1.44, 95% CI = 0.86-2.42).More than 1 in 5 patients (22.5%) who underwent AVR developed AKI postoperatively. AKI was associated with higher morbidity and was an independent predictor of operative mortality. However, AKI was not a determinant of long-term survival.Landspitali University Research Fund, University of Iceland Research Fund, Helga Gudmundsdottir and Sigurlidi Kristjansson Memorial Fund

Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation

Source at https://doi.org/10.1038/s42003-018-0068-9. Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in RPL3L, the first ribosomal gene implicated in atrial fibrillation to our knowledge. Analysis of 167 RNA samples from the right atrium reveals that the splice-donor variant in RPL3L results in exon skipping. We also observe an association with a missense variant in MYZAP (OR = 1.38), encoding a component of the intercalated discs of cardiomyocytes. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart

Genetic insight into sick sinus syndrome

Aims. The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results. We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1–1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10⁻²⁰), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion. We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS

Sequence variants with large effects on cardiac electrophysiology and disease.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadFeatures of the QRS complex of the electrocardiogram, reflecting ventricular depolarisation, associate with various physiologic functions and several pathologic conditions. We test 32.5 million variants for association with ten measures of the QRS complex in 12 leads, using 405,732 electrocardiograms from 81,192 Icelanders. We identify 190 associations at 130 loci, the majority of which have not been reported before, including associations with 21 rare or low-frequency coding variants. Assessment of genes expressed in the heart yields an additional 13 rare QRS coding variants at 12 loci. We find 51 unreported associations between the QRS variants and echocardiographic traits and cardiovascular diseases, including atrial fibrillation, complete AV block, heart failure and supraventricular tachycardia. We demonstrate the advantage of in-depth analysis of the QRS complex in conjunction with other cardiovascular phenotypes to enhance our understanding of the genetic basis of myocardial mass, cardiac conduction and disease

Genetics and epidemiology of mutational barcode-defined clonal hematopoiesis

Publisher Copyright: © 2023, The Author(s).Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome sequencing of 45,510 Icelandic and 130,709 UK Biobank participants combined with a mutational barcode method, we identified 16,306 people with CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates a dosage-dependent impact on risk of CH. CH associates with several smoking-related diseases. Contrary to published claims, we find no evidence that CH is associated with cardiovascular disease. We provide evidence that CH is driven by genes that are commonly mutated in myeloid neoplasia and implicate several new driver genes. The presence and nature of a driver mutation alters the risk profile for hematological disorders. Nevertheless, most CH cases have no known driver mutations. A CH genome-wide association study identified 25 loci, including 19 not implicated previously in CH. Splicing, protein and expression quantitative trait loci were identified for CD164 and TCL1A.Peer reviewe

Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadAims: To explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 genes, key regulators of intestinal absorption of dietary sterols. Methods and results: We examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL) cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genetic score of ABCG5/8 variants predicting 1 mmol/L increase in non-HDL cholesterol associates with two-fold increase in CAD risk [odds ratio (OR) = 2.01, 95% confidence interval (CI) 1.75-2.31, P = 9.8 × 10-23] compared with a 54% increase in CAD risk (OR = 1.54, 95% CI 1.49-1.59, P = 1.1 × 10-154) associated with a score of other non-HDL cholesterol variants predicting the same increase in non-HDL cholesterol (P for difference in effects = 2.4 × 10-4). Conclusions: Genetic variation in cholesterol absorption affects levels of circulating non-HDL cholesterol and risk of CAD. Our results indicate that both dietary cholesterol and phytosterols contribute directly to atherogenesis. Keywords: ABCG5/8; Absorption; Dietary cholesterol; Genetics; Phytosterols.Novo Nordisk Foundation University College London Hospital National Institute for Health Research Biomedical Research Centr

Genome-wide analysis yields new loci associating with aortic valve stenosis

Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 × 10−22) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 × 10−13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 × 10−10) and aortic root diameter (P = 1.30 × 10−8), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 × 10−3) and coronary artery disease (OR = 1.05, P = 9.3 × 10−5). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases