Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease

Perioperative bleeding and use of blood products in coronary artery bypass grafting

Abstract Coronary artery disease (CAD) is the leading cause of death in developed countries. In patients with complex CAD, coronary artery bypass grafting (CABG) remains the preferred treatment as it can provide long-lasting results. However, CABG carries a significant risk of excessive perioperative bleeding and other complications, which may deteriorate the prognosis. Transfusion of blood products is generally used to compensate blood loss. However, both bleeding and blood transfusions have been shown to be associated with an adverse outcome. This cohort study aimed to clarify the impact of perioperative bleeding and the use of different blood products in the development of perioperative complications in 2,764 patients undergoing isolated CABG. The universal definition of perioperative bleeding classification (UDPB) was employed to stratify the severity of bleeding. Additionally, the impact of storage time of transfused red blood cells (RBCs) on the outcome was investigated. Increased UDPB classes, particularly classes 3 and 4, were associated with significantly poorer immediate and late outcome. RBC transfusion in patients who underwent elective off-pump CABG was independently associated with increased troponin I release indicating myocardial injury. Prolonged storage duration of transfused RBCs did not affect immediate and late outcome of patients with moderate bleeding. The most remarkable risk factors for stroke after off-pump CABG were any degree of atherosclerosis of the ascending aorta as well as transfusion of platelets and/or solvent/detergent-treated plasma. The UDPB classification appears to be a promising research tool to stratify the severity of perioperative bleeding and to assess its prognostic impact after coronary surgery. Prevention of major bleeding that leads to blood transfusion may protect from myocardial injury and stroke and possibly result in better early and late outcomes. Patients with a diseased ascending aorta could be considered at high risk of stroke because of their risk of generalized atherosclerosis. In case of mildly diseased aorta, the “no-touch” aorta policy should be considered with the intention of preventing postoperative stroke.Tiivistelmä Sepelvaltimotauti on yleisin kuolinsyy kehittyneissä maissa. Potilailla, joilla on vaikea monen suonen tai vasemman sepelvaltimon päärungon tauti, sepelvaltimoiden ohitusleikkaus on edelleen paras hoitovaihtoehto, koska sillä pystytään saavuttamaan pitkäkestoisia tuloksia. Kuitenkin ohitusleikkaukseen liittyy suuri riski leikkauksen aikaiselle tai jälkeiselle verenvuodolle ja muille haittatapahtumille, jotka osaltaan huonontavat potilaan ennustetta. Vuodon hoitona käytetään yleisesti verensiirtoa. Kuitenkin on osoitettu, että sekä verenvuoto että verituotteiden anto lisäävät riskiä komplikaatioille. Tämän kohorttitutkimuksen tavoitteena oli selvittää tarkemmin leikkauksen yhteydessä ilmenevän vuodon ja siihen liittyvän verensiirron vaikutuksia leikkauksen jälkeisten haittatapahtumien kehittymiseen 2764 ohitusleikatulla potilaalla. Universal Definition of Perioperative Bleeding (UDPB) -luokitusta käytettiin vuodon vaikeusasteen luokittelemiseen. Lisäksi tutkittiin siirrettyjen punasolujen varastointiajan vaikutusta potilaan ennusteeseen. Korkeammat UDPB-luokat, erityisesti luokat 3 ja 4, liittyivät merkittävästi huonompaan lyhyen ja pitkän aikavälin ennusteeseen. Potilailla, joille oli tehty kiireetön ohitusleikkaus ilman sydän-keuhkokoneen käyttöä, punasolujen anto oli itsenäinen riskitekijä suurentuneelle troponiini I -päästölle eli sydänlihasvauriolle. Pidentynyt punasolujen varastointiaika ei ollut yhteydessä lyhyen tai pitkän aikavälin ennusteeseen potilailla, jotka olivat vuotaneet kohtalaisesti. Merkittävimmät riskitekijät ilman sydän-keuhkokonetta tehdyn leikkauksen jälkeiselle aivoinfarktille olivat minkä tahansa asteinen nousevan aortan ateroskleroosi sekä verihiutaleiden ja/tai jääplasman anto. UDPB-luokitus vaikuttaa lupaavalta tutkimustyökalulta verenvuodon vaikeusasteen luokitteluun. Lisäksi sitä voidaan käyttää vuodon ennusteellisen vaikutuksen arvioimiseen ohitusleikkauksen jälkeen. Runsaan verenvuodon ja siihen liittyvän verensiirron ehkäiseminen saattaa suojata potilasta sydänlihasvauriolta ja aivoinfarktilta ja mahdollisesti johtaa parempaan lyhyen ja pitkän aikavälin ennusteeseen. Potilaita, joilla on nousevan aortan ateroskleroosi, voisi pitää suuressa aivoinfarktiriskissä yleisen ateroskleroosiriskin vuoksi. Potilailla, joilla on lieväkin nousevan aortan ateroskleroosi, tulisi harkita aortan jättämistä pihdittämättä aivoinfarktin ehkäisemiseksi

The effect of preoperative anemia on the outcome after coronary surgery

Abstract Background: Preoperative anemia is associated with increased morbidity and mortality after cardiac surgery. Since anemia is ultimately treated with red blood cell transfusions, we investigated the independent impact of anemia and transfusion on the outcome after coronary artery bypass grafting (CABG). Methods: This study included 2761 consecutive patients who underwent isolated CABG. Anemia was defined as hemoglobin <12.0 g/dL in women and <13.0 g/dL in men. The main outcomes were 30-day and late mortality. Results: Patients with preoperative anemia had an increased prevalence of significant comorbidities and were associated with higher unadjusted risk of early and late adverse events. Propensity score matching resulted in 560 pairs with similar baseline and operative characteristics. In these matched pairs, anemic patients had an increased risk of late all-cause death (P = 0.047) and acute kidney injury (P < 0.0001). However, when adjusted for the severity of perioperative bleeding, preoperative anemia was not associated with an increased mortality risk (HR 1.10, 95% CI 0.86–1.39). Instead, this regression model showed that the European CABG registry (E-CABG) bleeding classification was an independent predictor of late mortality (compared to grade 0: grade 1, HR 1.93, 95% CI 1.37–2.73, grade 2, HR 2.19, 95% CI 1.50–3.18, grade 3, HR 5.59, 95% CI 3.34–9.39, P < 0.0001). Conclusions: When adjusted for important baseline characteristics and operative factors as well as for the severity of perioperative bleeding and the amount of transfused blood products, anemia was not associated with an increased risk of adverse events. Increased exposure to blood transfusion among anemic patients may be the determinant of their poorer late survival

Outcome after procedures for retained blood syndrome in coronary surgery

Abstract OBJECTIVES: Incomplete drainage of blood from around the heart and lungs can lead to retained blood syndrome (RBS) after cardiac surgery. The aim of this study was to assess the incidence of and the outcome after procedures for RBS in patients undergoing isolated coronary artery bypass grafting (CABG). METHODS: A total of 2764 consecutive patients who underwent isolated CABG from 2006 to 2013 were investigated retrospectively. Patients undergoing any procedure for RBS were compared with patients who did not undergo any procedure for RBS. Multivariate analyses were performed to assess the impact of procedures for RBS on the early outcome. RESULTS: A total of 254 patients (9.2%) required at least one procedure for RBS. Multivariate analysis showed that RBS requiring a procedure for blood removal was associated with significantly increased 30-day mortality [8.3% vs 2.7%, odds ratio (OR) 2.11, 95% confidence interval (95% CI) 1.15–3.86] rates. Procedures for RBS were independent predictors of the need for postoperative antibiotics (51.6% vs 32.1%, OR 2.08, 95% CI 1.58–2.74), deep sternal wound infection/mediastinitis (6.7% vs 2.2%, OR 3.12, 95% CI 1.72–5.66), Kidney Disease: Improving Global Outcomes acute kidney injury (32.7% vs 15.3%, OR 2.50, 95% CI 1.81–3.46), length of stay in the intensive care unit (mean 8.3 vs 2.0 days, beta 1.74, 95% CI 1.45–2.04) and composite major adverse events (21.3% vs 6.9%, OR 3.24, 95% CI 2.24–4.64). These findings were also confirmed in a subgroup of patients with no pre- or postoperative unstable haemodynamic conditions. CONCLUSION: RBS requiring any procedure for blood removal from pericardial and pleural spaces is associated with an increased risk of severe complications after isolated CABG

Transfusion and blood stream infections after coronary surgery

Abstract The aim of this study was to evaluate the impact of blood transfusion on bloodstream infections. This study included 2764 patients who underwent isolated coronary artery bypass grafting. Blood cultures were drawn in 27.9% of patients and were positive in 3.5% of them. Blood transfusion before blood cultures were drawn (4.7% vs 1.2%, odds ratio 3.75, 95% confidence interval 1.11–12.67) and deep sternal wound infection/mediastinitis (20.0% vs 2.8%, odds ratio 7.43, 95% confidence interval 2.72–20.32) were independent predictors of a positive postoperative blood culture. Positive blood culture increased the risk of 5-year mortality (among patients with blood cultures drawn: 44.7% vs 19.6%, adjusted hazard ratio 2.10, 95% confidence interval 1.18–3.71). Exposure to blood products may increase the risk of bloodstream infection after cardiac surgery. Positive blood cultures after coronary artery bypass grafting are associated with poor late survival. These findings require validation in prospective studies

Meta-analysis of the sources of bleeding after adult cardiac surgery

Abstract Objective: The aim of this study was to pool data on the proportion and prognostic impact of sources of bleeding in patients requiring re-exploration after adult cardiac surgery. Design: Systematic review of the literature and meta-analysis. Setting: Multistitutional study. Measurements and Main Results: A literature review was performed to identify studies published since 1990 evaluating the outcome after reoperation for bleeding or tamponade after adult cardiac surgery. Eighteen studies including 5,1497 patients fulfilled the selection criteria. Reoperation for bleeding/tamponade was performed in 2,455 patients (4.6%; 95% confidence interval [CI] 3.9%–5.2%, I² 92%). These had a significantly higher risk of in-hospital/30-day mortality compared with patients not reoperated for bleeding (pooled rates: 9.3% v 2.3%; risk ratio 3.30; 95% CI 2.52–4.32; I² 47%; 8 studies; 25,463 patients). Surgical sites of bleeding were identified in 65.7% of cases (95% CI 58.3%–73.2%; I² 94%), cardiac site bleeding in 40.9% of cases (95% CI 29.7%–52.0%; I² 94%), and mediastinal/sternum site bleeding in 27.0% of cases (95% CI 16.8%–37.3%; I² 94%). The main sites of bleeding were the body of the graft (20.2%), the sternum (17.0%), vascular sutures (12.5%), the internal mammary artery harvest site (13.0%), and anastomoses (9.9%). In metaregression, surgical site bleeding was associated with a lower risk of in-hospital/30-day mortality compared with diffuse bleeding (p = 0.003). Conclusions: Surgical site bleeding is identified in two-thirds of patients undergoing re-exploration after adult cardiac surgery. Meticulous surgical technique and systematic intraoperative checking of potential surgical sites of bleeding at the time of the original cardiac surgery may reduce the risk of such a severe complication

Meta-analysis of the outcome after postcardiotomy venoarterial extracorporeal membrane oxygenation in adult patients

Abstract Objective: This study was planned to pool existing data on outcome and to evaluate the efficacy of postcardiotomy venoarterial extracorporeal membrane oxygenation (VA-ECMO) in adult patients. Design: Systematic review of the literature and meta-analysis. Setting: Multi-institutional study. Participants: Adult patients with acute heart failure immediately after cardiac surgery. Interventions: VA-ECMO after cardiac surgery. Studies evaluating only heart transplant patients were excluded from this analysis. Measurements and Main Results: A literature search was performed to identify studies published since 2000. Thirty-one studies reported on 2,986 patients (mean age, 58.1 years) who required postcardiotomy VA-ECMO. The weaning rate from VA-ECMO was 59.5% and hospital survival was 36.1% (95% CI 31.5–40.8). The pooled rate of reoperation for bleeding was 42.9%, major neurological event 11.3%, lower limb ischemia 10.8%, deep sternal wound infection/mediastinitis 14.7%, and renal replacement therapy 47.1%. The pooled mean number of transfused red blood cell units was 17.7 (95% CI 13.3–22.1). The mean stay in the intensive care unit was 13.3 days (95% CI 10.2–16.4). Survivors were significantly younger (mean, 55.7 v 63.6 years, p = 0.015) and their blood lactate level before starting VA-ECMO was lower (mean, 7.7 v 10.7 mmol/L, p = 0.028) than patients who died. One-year survival rate was 30.9% (95% CI 24.3–37.5). Conclusions: Pooled data showed that VA-ECMO may salvage one-third of patients unresponsive to any other resuscitative treatment after adult cardiac surgery

Comparison of survival of transfemoral transcatheter aortic valve implantation versus surgical aortic valve replacement for aortic stenosis in low-risk patients without coronary artery disease

Abstract Increasing data support transcatheter aortic valve implantation (TAVI) as a valid option over surgical aortic valve replacement (SAVR) in the treatment for severe aortic stenosis (AS) also in patients with low operative risk. However, limited data exist on the outcome of TAVI and SAVR in low-risk patients without coronary artery disease (CAD). The FinnValve registry included data on 6463 patients who underwent TAVI or SAVR with bioprosthesis between 2008 and 2017. Herein, we evaluated the outcome of low operative risk as defined by STS-PROM score <3% and absence of CAD, previous stroke and other relevant co-morbidities. Only patients who underwent TAVI with third-generation prostheses and SAVR with Perimount Magna Ease or Trifecta prostheses were included in this analysis. The primary endpoints were 30-day and 3-year all-cause mortality. Overall, 1,006 patients (175 TAVI patients and 831 SAVR patients) met the inclusion criteria of this analysis. Propensity score matching resulted in 140 pairs with similar baseline characteristics. Among these matched pairs, 30-day mortality was 2.1% in both TAVI and SAVR cohorts (p = 1.00) and 3-year mortality was 17.0% after TAVI and 14.6% after SAVR (p = 0.805). Lower rates of bleeding and atrial fibrillation, and shorter hospital stay were observed after TAVI. The need of new permanent pacemaker implantation and the incidence of early stroke did not differ between groups. In conclusion, TAVI using third-generation prostheses achieved similar early and mid-term survival compared with SAVR in low-risk patients without CAD