Actionable Genotypes and Their Association with Life Span in Iceland.

BACKGROUND: In 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 genes associated with diseases for which preventive or therapeutic measures are available. Evaluations of the association of actionable genotypes in these genes with life span are currently lacking. METHODS: We assessed the prevalence of coding and splice variants in genes on the ACMG Secondary Findings, version 3.0 (ACMG SF v3.0), list in the genomes of 57,933 Icelanders. We assigned pathogenicity to all reviewed variants using reported evidence in the ClinVar database, the frequency of variants, and their associations with disease to create a manually curated set of actionable genotypes (variants). We assessed the relationship between these genotypes and life span and further examined the specific causes of death among carriers. RESULTS: Through manual curation of 4405 sequence variants in the ACMG SF v3.0 genes, we identified 235 actionable genotypes in 53 genes. Of the 57,933 participants, 2306 (4.0%) carried at least one actionable genotype. We found shorter median survival among persons carrying actionable genotypes than among noncarriers. Specifically, we found that carrying an actionable genotype in a cancer gene was associated with survival that was 3 years shorter than that among noncarriers, with causes of death among carriers attributed primarily to cancer-related conditions. Furthermore, we found evidence of association between carrying an actionable genotype in certain genes in the cardiovascular disease group and a reduced life span. CONCLUSIONS: On the basis of the ACMG SF v3.0 guidelines, we found that approximately 1 in 25 Icelanders carried an actionable genotype and that carrying such a genotype was associated with a reduced life span. (Funded by deCODE Genetics-Amgen.).

Evaluation of Large-Scale Proteomics for Prediction of Cardiovascular Events.

Importance: Whether protein risk scores derived from a single plasma sample could be useful for risk assessment for atherosclerotic cardiovascular disease (ASCVD), in conjunction with clinical risk factors and polygenic risk scores, is uncertain. Objective: To develop protein risk scores for ASCVD risk prediction and compare them to clinical risk factors and polygenic risk scores in primary and secondary event populations. Design, Setting, and Participants: The primary analysis was a retrospective study of primary events among 13 540 individuals in Iceland (aged 40-75 years) with proteomics data and no history of major ASCVD events at recruitment (study duration, August 23, 2000 until October 26, 2006; follow-up through 2018). We also analyzed a secondary event population from a randomized, double-blind lipid-lowering clinical trial (2013-2016), consisting of individuals with stable ASCVD receiving statin therapy and for whom proteomic data were available for 6791 individuals. Exposures: Protein risk scores (based on 4963 plasma protein levels and developed in a training set in the primary event population); polygenic risk scores for coronary artery disease and stroke; and clinical risk factors that included age, sex, statin use, hypertension treatment, type 2 diabetes, body mass index, and smoking status at the time of plasma sampling. Main Outcomes and Measures: Outcomes were composites of myocardial infarction, stroke, and coronary heart disease death or cardiovascular death. Performance was evaluated using Cox survival models and measures of discrimination and reclassification that accounted for the competing risk of non-ASCVD death. Results: In the primary event population test set (4018 individuals [59.0% women]; 465 events; median follow-up, 15.8 years), the protein risk score had a hazard ratio (HR) of 1.93 per SD (95% CI, 1.75 to 2.13). Addition of protein risk score and polygenic risk scores significantly increased the C index when added to a clinical risk factor model (C index change, 0.022 [95% CI, 0.007 to 0.038]). Addition of the protein risk score alone to a clinical risk factor model also led to a significantly increased C index (difference, 0.014 [95% CI, 0.002 to 0.028]). Among White individuals in the secondary event population (6307 participants; 432 events; median follow-up, 2.2 years), the protein risk score had an HR of 1.62 per SD (95% CI, 1.48 to 1.79) and significantly increased C index when added to a clinical risk factor model (C index change, 0.026 [95% CI, 0.011 to 0.042]). The protein risk score was significantly associated with major adverse cardiovascular events among individuals of African and Asian ancestries in the secondary event population. Conclusions and Relevance: A protein risk score was significantly associated with ASCVD events in primary and secondary event populations. When added to clinical risk factors, the protein risk score and polygenic risk score both provided statistically significant but modest improvement in discrimination.

Multiomics study of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis and hepatocellular carcinoma, and integrated the findings with expression and proteomic data. For NAFL, we utilized 9,491 clinical cases and proton density fat fraction extracted from 36,116 liver magnetic resonance images. We identified 18 sequence variants associated with NAFL and 4 with cirrhosis, and found rare, protective, predicted loss-of-function variants in MTARC1 and GPAM, underscoring them as potential drug targets. We leveraged messenger RNA expression, splicing and predicted coding effects to identify 16 putative causal genes, of which many are implicated in lipid metabolism. We analyzed levels of 4,907 plasma proteins in 35,559 Icelanders and 1,459 proteins in 47,151 UK Biobank participants, identifying multiple proteins involved in disease pathogenesis. We show that proteomics can discriminate between NAFL and cirrhosis. The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options.

Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland.

Objective: Familial hypercholesterolemia (FH) is traditionally defined as a monogenic disease characterized by severely elevated LDL-C (low-density lipoprotein cholesterol) levels. In practice, FH is commonly a clinical diagnosis without confirmation of a causative mutation. In this study, we sought to characterize and compare monogenic and clinically defined FH in a large sample of Icelanders. Approach and Results: We whole-genome sequenced 49 962 Icelanders and imputed the identified variants into an overall sample of 166 281 chip-genotyped Icelanders. We identified 20 FH mutations in LDLR, APOB, and PCSK9 with combined prevalence of 1 in 836. Monogenic FH was associated with severely elevated LDL-C levels and increased risk of premature coronary disease, aortic valve stenosis, and high burden of coronary atherosclerosis. We used a modified version of the Dutch Lipid Clinic Network criteria to screen for the clinical FH phenotype among living adult participants (N=79 058). Clinical FH was found in 2.2% of participants, of whom only 5.2% had monogenic FH. Mutation-negative clinical FH has a strong polygenic basis. Both individuals with monogenic FH and individuals with mutation-negative clinical FH were markedly undertreated with cholesterol-lowering medications and only a minority attained an LDL-C target of <2.6 mmol/L (<100 mg/dL; 11.0% and 24.9%, respectively) or <1.8 mmol/L (<70 mg/dL; 0.0% and 5.2%, respectively), as recommended for primary prevention by European Society of Cardiology/European Atherosclerosis Society cholesterol guidelines. Conclusions: Clinically defined FH is a relatively common phenotype that is explained by monogenic FH in only a minority of cases. Both monogenic and clinical FH confer high cardiovascular risk but are markedly undertreated.

Immediate and long-term need for permanent cardiac pacing following aortic valve replacement.

Introduction: Atrioventricular (AV) node conduction disturbances are common following surgical aortic valve replacement (SAVR), and in some cases the patient needs a permanent pacemaker (PPM) implantation before discharge from hospital. Little is known about the long-term need for PPM and the PPM dependency of these individuals. We determined the incidence of PPM implantation before and after discharge in SAVR patients. Methods: We studied 557 consecutive patients who underwent SAVR for aortic stenosis in Iceland between 2002 and 2016. Timing and indication for PPM were registered, with a new concept, ventricular pacing proportion (VPP), defined as ventricular pacing ≥90% of the time, being used to approximate pacemaker dependency. The median follow-up time was 73 months. We plotted the cumulative incidence of pacemaker implantation, treating death as a competing risk. Results: Of the 557 patients, 22 (3.9%) received PPM in the first 30 days after surgery, most commonly for complete AV block (n = 14) or symptomatic bradycardia (n = 8); Thirty-eight other patients (6.8%) had a PPM implanted >30 days postoperatively, at a median of 43 months after surgery (range 0‒181), most often for AV block (n = 13) or sick-sinus syndrome (n = 10). The cumulative incidence of PPM implantation at 1, 5, and 10 years postoperatively was 5.0%, 9.2%, and 12.3%, respectively. During follow-up, 45.0% of the 60 patients had VPP ≥90%. Conclusion: The cumulative incidence of permanent pacemaker implantation following SAVR was about 12% at 10 years, with every other patient having VPP ≥90% during follow-up. This suggests that AV node conduction disturbances extend significantly beyond the perioperative period.

Sequence variant at 4q25 near PITX2 associates with appendicitis.

Appendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 × 10-11). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk.

Atrial fibrillation following cardiac surgery: risk analysis and long-term survival.

BACKGROUND: We studied potential risk factors for postoperative atrial fibrillation (POAF) in a large cohort of patients who underwent open-heart surgery, evaluating short- and long-term outcome, and we developed a risk-assessment model of POAF. METHODS: A retrospective study of 744 patients without prior history of AF who underwent CABG (n = 513), OPCAB (n = 207), and/or AVR (n = 156) at Landspitali Hospital in 2002-2006. Logistic regression analysis was used to study risk factors for POAF, comparing patients with and without POAF. RESULTS: The rate of POAF was 44%, and was higher following AVR (74%) than after CABG (44%) or OPCAB (35%). In general, patients with POAF were significantly older, were more often female, were less likely to be smokers, had a lower EF, and had a higher EuroSCORE. The use of antiarrythmics was similar in the groups but patients who experienced POAF were less likely to be taking statins. POAF patients also had longer hospital stay, higher rates of complications, and operative mortality (5% vs. 0.7%). In multivariate analysis, AVR (OR 4.4), a preoperative history of cardiac failure (OR 1.8), higher EuroSCORE (OR 1.1), and advanced age (OR 1.1) were independent prognostic factors for POAF. Overall five-year survival was 83% and 93% for patients with and without POAF (p <0.001). CONCLUSION: POAF was detected in 44% of patients, which is high compared to other studies. In the future, our assessment score will hopefully be of use in identifying patients at high risk of POAF and lower complications related to POAF.

Plasma n-3 and n-6 fatty acids and the incidence of atrial fibrillation following coronary artery bypass graft surgery.

BACKGROUND: The anti-inflammatory or anti-arrhythmic effects of n-3 long-chain polyunsaturated fatty acids (LC-PUFA) may decrease the risk of postoperative atrial fibrillation (POAF), but interventional studies have yielded conflicting results. We examined the association between n-3 LC-PUFA and n-6 LC-PUFA in plasma phospholipids (PL) and POAF in patients undergoing coronary artery bypass grafting (CABG). METHODS: A total of 125 patients undergoing CABG were enrolled in the study. The levels of fatty acids in PL were measured preoperatively and on the third postoperative day. The endpoint was defined as POAF lasting ≥5 min. The incidence of POAF was compared between quartiles of the level of each fatty acid in plasma PL by univariate and multivariable analysis. RESULTS: The incidence of POAF was 49·6%. By univariate analysis, the incidence of POAF increased significantly with each higher quartile of pre- and postoperative docosahexaenoic acid (DHA) and diminished significantly with each higher quartile of pre- and postoperative arachidonic acid (AA). For postoperative total n-3 LC-PUFA, there was a significant U-curve relationship where the second quartile had the lowest incidence of POAF or 25·8%. In multivariable analysis, this U-curve relationship between n-3 LC-PUFA levels and POAF risk was not significant, whereas the association between POAF and DHA or AA remained statistically significant. CONCLUSIONS: This study suggests that n-3 LC-PUFA supplements might prevent POAF in CABG patients with low baseline levels of these fatty acids in plasma PL, but may be harmful in those with high levels. AA may play an important role in electrophysiological processes.

EHRA Expert Consensus Statement on the management of cardiovascular implantable electronic devices in patients nearing end of life or requesting withdrawal of therapy.

The purpose of this Consensus Statement is to focus on implantable cardioverter-defibrillator (ICD) deactivation in patients with irreversible or terminal illness. This statement summarizes the opinions of the Task Force members, convened by the European Heart Rhythm Association (EHRA) and the Heart Rhythm Society (HRS), based on ethical and legal principles, as well as their own clinical, scientific, and technical experience. It is directed to all healthcare professionals who treat patients with implanted ICDs, nearing end of life, in order to improve the patient dying process. This statement is not intended to recommend or promote device deactivation. Rather, the ultimate judgement regarding this procedure must be made by the patient (or in special conditions by his/her legal representative) after careful communication about the deactivation's consequences, respecting his/her autonomy and clarifying that he/she has a legal and ethical right to refuse it. Obviously, the physician asked to deactivate the ICD and the industry representative asked to assist can conscientiously object to and refuse to perform device deactivation.

Does treatment with n-3 polyunsaturated fatty acids prevent atrial fibrillation after open heart surgery?

AIMS: To examine the effect of n-3 polyunsaturated fatty acid (PUFA) treatment on the incidence of post-operative atrial fibrillation (POAF). METHODS AND RESULTS: A prospective, randomized, double-blinded, placebo-controlled trial was conducted in patients admitted for coronary artery bypass grafting and/or valvular repair surgery. The patients received either n-3 PUFA capsules, containing a daily dose of 1240 mg eicosapentaenoic acid and 1000 mg docosahexaenoic acid, or olive oil capsules for 5-7 days prior to surgery and post-operatively until hospital discharge. The endpoint was POAF, defined as an episode detected by continuous electrocardiographic monitoring, lasting >5 min. A total of 170 patients were enrolled in the study, and 168 patients underwent surgery. Their median age was 67 (range 43-82) years, and 79.2% were males. There was no difference in baseline characteristics between the n-3 PUFA group (n = 83) and the placebo group (n = 85), and the incidence of POAF was 54.2 and 54.1% (P = 0.99), respectively. Factors associated with POAF included advanced age, peak post-operative C-reactive protein level, valvular surgery, lower body mass index, and non-smoking, but n-3 PUFA concentration in plasma lipids was not associated with POAF. CONCLUSION: There is no evidence for a beneficial effect of treatment with n-3 PUFA on the occurrence of POAF in patients undergoing open heart surgery.