Microaxial Flow Pump or Standard Care in Infarct-Related Cardiogenic Shock.

BACKGROUND: The effects of temporary mechanical circulatory support with a microaxial flow pump on mortality among patients with ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock remains unclear. METHODS: In an international, multicenter, randomized trial, we assigned patients with STEMI and cardiogenic shock to receive a microaxial flow pump (Impella CP) plus standard care or standard care alone. The primary end point was death from any cause at 180 days. A composite safety end point was severe bleeding, limb ischemia, hemolysis, device failure, or worsening aortic regurgitation. RESULTS: A total of 360 patients underwent randomization, of whom 355 were included in the final analysis (179 in the microaxial-flow-pump group and 176 in the standard-care group). The median age of the patients was 67 years, and 79.2% were men. Death from any cause occurred in 82 of 179 patients (45.8%) in the microaxial-flow-pump group and in 103 of 176 patients (58.5%) in the standard-care group (hazard ratio, 0.74; 95% confidence interval [CI], 0.55 to 0.99; P = 0.04). A composite safety end-point event occurred in 43 patients (24.0%) in the microaxial-flow-pump group and in 11 (6.2%) in the standard-care group (relative risk, 4.74; 95% CI, 2.36 to 9.55). Renal-replacement therapy was administered to 75 patients (41.9%) in the microaxial-flow-pump group and to 47 patients (26.7%) in the standard-care group (relative risk, 1.98; 95% CI, 1.27 to 3.09). CONCLUSIONS: The routine use of a microaxial flow pump with standard care in the treatment of patients with STEMI-related cardiogenic shock led to a lower risk of death from any cause at 180 days than standard care alone. The incidence of a composite of adverse events was higher with the use of the microaxial flow pump. (Funded by the Danish Heart Foundation and Abiomed; DanGer Shock ClinicalTrials.gov number, NCT01633502.).

Patients with autoimmune liver disease have glucose disturbances that mechanistically differ from steatotic liver disease.

Autoimmune liver diseases are associated with an increased risk of diabetes, yet the underlying mechanisms remain unknown. In this cross-sectional study, we investigated the glucose-regulatory disturbances in patients with autoimmune hepatitis (AIH, n = 19), primary biliary cholangitis (PBC, n = 15), and primary sclerosing cholangitis (PSC, n = 6). Healthy individuals (n = 24) and patients with metabolic dysfunction-associated steatotic liver disease (MASLD, n = 18) were included as controls. Blood samples were collected during a 120-min oral glucose tolerance test. We measured the concentrations of glucose, C-peptide, insulin, glucagon, and the two incretin hormones, glucose insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We calculated the homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin resistance (Matsuda index), insulin clearance, and insulinogenic index. All patient groups had increased fasting plasma glucose and impaired glucose responses compared with healthy controls. Beta-cell secretion was increased in AIH, PBC, and MASLD but not in PSC. Patients with AIH and MASLD had hyperglucagonemia and hepatic, as well as peripheral, insulin resistance and decreased insulin clearance, resulting in hyperinsulinemia. Patients with autoimmune liver disease had an increased GIP response, and those with AIH or PBC had an increased GLP-1 response. Our data demonstrate that the mechanism underlying glucose disturbances in patients with autoimmune liver disease differs from that underlying MASLD, including compensatory incretin responses in patients with autoimmune liver disease. Our results suggest that glucose disturbances are present at an early stage of the disease.NEW & NOTEWORTHY Patients with autoimmune liver disease but without overt diabetes display glucose disturbances early on in their disease course. We identified pathophysiological traits specific to these patients including altered incretin responses.

Long-term outcomes after coronary intervention with biodegradable polymer stents in patients with acute coronary syndromes.

BACKGROUND: Patients with acute coronary syndromes (ACS) may have worse outcomes after percutaneous coronary intervention compared to patients without ACS. AIMS: To compare 5-year efficacy and safety outcomes in patients with and without ACS treated with biodegradable polymers, the ultrathin strut sirolimus-eluting Orsiro stent (O-SES) or the biolimus-eluting Nobori stent (N-BES). METHODS: The Scandinavian Organisation for Randomized Trials with Clinical Outcome VII is a randomized trial comparing O-SES and N-BES in an all-comer setting. Of 2525 patients, 1329 (53%) patients had ACS and 1196 (47%) patients were without ACS. Endpoints were target lesion failure (TLF) (a composite of cardiac death, target lesion myocardial infarction, or target lesion revascularization) and definite stent thrombosis within 5 years. RESULTS: At 5-year follow-up, TLF did not differ significantly between patients with and without ACS (12.3% vs. 13.2%; rate ratio (RR) 1.00; 95% confidence interval (CI): 0.70-1.44), whereas the risk of definite stent thrombosis was increased in patients with ACS (2.3% vs. 1.3; RR: 2.01 [95% CI: 1.01-3.98]). In patients with ACS, the rate of TLF was similar between O-SES and N-BES (12.4% vs. 12.3%; RR: 1.02; 95% CI: 0.74-1.40). The reduced risk of definite stent thrombosis in O-SES treated ACS patients within the first year (0.2% vs. 1.6%; RR: 0.12; 95% CI: 0.02-0.93) was not maintained after 5 years (1.8% vs. 2.7%; RR: 0.77; 95% CI: 0.37-1.63). CONCLUSION: Patients with ACS had an increased risk of stent thrombosis regardless of the stent type used. Long-term outcomes were similar for ACS patients treated with O-SES or N-BES at 5 years.

Targeted metabolomics reveals plasma short-chain fatty acids are associated with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: Alterations in the production of short-chain fatty acids (SCFAs) may reflect disturbances in the gut microbiota and have been linked to metabolic dysfunction-associated steatotic liver disease (MASLD). We assessed plasma SCFAs in patients with MASLD and healthy controls. METHODS: Fasting venous blood samples were collected and eight SCFAs were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). Relative between-group differences in circulating SCFA concentrations were estimated by linear regression, and the relation between SCFA concentrations, MASLD, and fibrosis severity was investigated using logistic regression. RESULTS: The study includes 100 patients with MASLD (51% with mild/no fibrosis and 49% with significant fibrosis) and 50 healthy controls. Compared with healthy controls, MASLD patients had higher plasma concentrations of propionate (21.8%, 95% CI 3.33 to 43.6, p = 0.02), formate (21.9%, 95% CI 6.99 to 38.9, p = 0.003), valerate (35.7%, 95% CI 4.53 to 76.2, p = 0.02), and α-methylbutyrate (16.2%, 95% CI 3.66 to 30.3, p = 0.01) but lower plasma acetate concentrations (- 30.0%, 95% CI - 40.4 to - 17.9, p < 0.001). Among patients with MASLD, significant fibrosis was positively associated with propionate (p = 0.02), butyrate (p = 0.03), valerate (p = 0.03), and α-methylbutyrate (p = 0.02). Six of eight SCFAs were significantly increased in F4 fibrosis. CONCLUSIONS: In the present study, SCFAs were associated with MASLD and fibrosis severity, but further research is needed to elucidate the potential mechanisms underlying our observations and to assess the possible benefit of therapies modulating gut microbiota.

Impact of acute coronary syndrome on clinical outcomes after revascularization with the dual-therapy CD34 antibody-covered sirolimus-eluting Combo stent and the sirolimus-eluting Orsiro stent.

OBJECTIVES: To compare the efficacy and safety of the dual-therapy CD34 antibody-covered sirolimus-eluting Combo stent (DTS) and the sirolimus-eluting Orsiro stent (O-SES) in patients with and without acute coronary syndrome (ACS) included in the SORT OUT X study. BACKGROUND: The incidence of target lesion failure (TLF) after treatment with modern drug-eluting stents has been reported to be significantly higher in patients with ACS when compared to patients without ACS. Whether the results from the SORT OUT X study apply to patients with and without ACS remains unknown. METHODS: In total, 3146 patients were randomized to stent implantation with DTS (n = 1578; ACS: n = 856) or O-SES (n = 1568; ACS: n = 854). The primary end point, TLF, was a composite of cardiac death, target-lesion myocardial infarction (MI), or target lesion revascularization (TLR) within 1 year. RESULTS: At 1 year, the rate of TLF was higher in the DTS group compared to the O-SES group, both among patients with ACS (6.7% vs. 4.1%; incidence rate ratio: 1.65 [95% confidence interval, CI: 1.08-2.52]) and without ACS (6.0% vs. 3.2%; incidence rate ratio: 1.88 [95% CI: 1.13-3.14]). The differences were mainly explained by higher rates of TLR, whereas rates of cardiac death and target lesion MI did not differ significantly between the two stent groups in patients with or without ACS CONCLUSION: Compared to the O-SES, the DTS was associated with a higher risk of TLF at 12 months in patients with and without ACS. The differences were mainly explained by higher rates of TLR.

Randomized Clinical Comparison of the Dual-Therapy CD34 Antibody-Covered Sirolimus-Eluting Combo Stent With the Sirolimus-Eluting Orsiro Stent in Patients Treated With Percutaneous Coronary Intervention: The SORT OUT X Trial.

BACKGROUND: Target lesion failure remains an issue with contemporary drug-eluting stents. Thus, the dual-therapy sirolimus-eluting and CD34+ antibody-coated Combo stent (DTS) was designed to further improve early healing. This study aimed to investigate whether the DTS is noninferior to the sirolimus-eluting Orsiro stent (SES) in an all-comers patient population. METHODS: The SORT OUT X (Combo Stent Versus Orsiro Stent) trial, was a large-scale, randomized, multicenter, single-blind, 2-arm, noninferiority trial with registry-based follow-up. The primary end point target lesion failure was a composite of cardiac death, myocardial infarction, or target lesion revascularization within 12 months, analyzed using intention-to-treat. The trial was powered for assessing target lesion failure noninferiority of the DTS compared with the SES with a predetermined noninferiority margin of 0.021. RESULTS: A total of 3146 patients were randomized to treatment with the DTS (1578 patients; 2008 lesions) or SES (1568 patients; 1982 lesions). At 12 months, intention-to-treat analysis showed that 100 patients (6.3%) assigned the DTS and 58 patients (3.7%) assigned the SES met the primary end point (absolute risk difference, 2.6% [upper limit of 1-sided 95% CI, 4.1%]; P (noninferiority)=0.76). The SES was superior to the DTS (incidence rate ratios for target lesion failure, 1.74 [95% CI, 1.26-2.41]; P=0.00086). The difference was explained mainly by a higher incidence of target lesion revascularization in the DTS group compared with the SES group (53 [3.4%] vs. 24 [1.5%]; incidence rate ratio, 2.22 [95% CI, 1.37-3.61]; P=0.0012). CONCLUSIONS: The DTS did not confirm noninferiority to the SES for target lesion failure at 12 months in an all-comer population. The SES was superior to the DTS mainly because the DTS was associated with an increased risk of target lesion revascularization. However, rates of death, cardiac death, and myocardial infarction at 12 months did not differ significantly between the 2 stent groups. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03216733.

Impact of diabetes on 1-year clinical outcome in patients undergoing revascularization with the BioFreedom stents or the Orsiro stents from the SORT OUT IX trial.

This sub-study of the SORT OUT IX trial sought to compare clinical outcomes between patients with diabetes randomized to implantation of either the polymer-free biolimus A9-coated BioFreedom stent (BF-BES) or the ultra-thin strut, biodegradable polymer sirolimus-eluting Orsiro stent (O-SES). Patients with diabetes have an increased risk of target lesion failure (TLF) after percutaneous coronary intervention (PCI). The impact of different stent types in patients with diabetes is still discussed. A total of 607 of the 3151 patients (19.3%) enrolled in the SORT OUT IX study had diabetes. Randomization was stratified by patients with/without diabetes; 304 received BF-BES and 303 O-SES. The primary endpoint was TLF, which was a composite of cardiac death, myocardial infarction (not related to other than the index lesion) and target lesion revascularization (TLR) within 1 year. After 1 year, patients with diabetes had higher TLF (7.2% vs. 3.7%, incidence rate ratio [IRR]: 1.65; 95% confidence interval [CI]: 1.08-2.50), than patients without diabetes. TLF did not differ significantly between BF-BES and O-SES in patients with diabetes (8.2% vs. 6.3%, IRR: 1.17; 95% CI: 0.63-2.20). In patients with diabetes, cardiac death occurred in 2.3% of BF-BES and in 3.6% of O-SES (IRR: 0.58; 95% CI: 0.23-1.45) and TLR occurred in 5.3% and 2.3% of BF-BES and O-SES, respectively (IRR: 2.12; 95% CI: 0.81-5.56). Definite stent thrombosis rates of 1.3% were found in both stent types. Patients with diabetes had higher 1-year TLF rate after PCI compared to patients without diabetes, whereas TLF did not differ significantly between the two stent types BF-BES and O-SES in patients with diabetes.

Influence of fractional flow reserve on grafts patency: Systematic review and patient-level meta-analysis.

OBJECTIVE: To investigate the impact of invasive functional guidance for coronary artery bypass graft surgery (CABG) on graft failure. BACKGROUND: Data on the impact of fractional flow reserve (FFR) in guiding CABG are still limited. METHODS: Systematic review and individual patient data meta-analysis were performed. Primary objective was the risk of graft failure, stratified by FFR. Risk estimates are reported as odds ratios (ORs) derived from the aggregated data using random-effects models. Individual patient data were analyzed using mixed effect model to assess relationship between FFR and graft failure. This meta-analysis is registered in PROSPERO (CRD42020180444). RESULTS: Four prospective studies comprising 503 patients referred for CABG, with 1471 coronaries, assessed by FFR were included. Graft status was available for 1039 conduits at median of 12.0 [IQR 6.6; 12.0] months. Risk of graft failure was higher in vessels with preserved FFR (OR 5.74, 95% CI 1.71-19.29). Every 0.10 FFR units decrease in the coronaries was associated with 56% risk reduction of graft failure (OR 0.44, 95% CI 0.34 to 0.59). FFR cut-off to predict graft failure was 0.79. CONCLUSION: Surgical grafting of coronaries with functionally nonsignificant stenoses was associated with higher risk of graft failure.

Impact of diabetes on clinical outcomes after revascularization with the dual therapy CD34 antibody-covered sirolimus-eluting Combo stent and the sirolimus-eluting Orsiro stent.

OBJECTIVES: To compare the efficacy and safety of the dual therapy CD34 antibody-covered sirolimus-eluting Combo stent (DTS) and the sirolimus-eluting Orsiro stent (SES) in patients with and without diabetes mellitus (DM) included in the Scandinavian Organization for Randomized Trials with Clinical Outcome (SORT OUT) X study. BACKGROUND: The incidence of target lesion failure (TLF) after treatment with modern drug-eluting stents has been reported to be significantly higher in patients with DM when compared to patients without DM. Thus, whether the results from the SORT OUT X study apply to patients with and without DM remains unknown. METHODS: In total 3146 patients were randomized to stent implantation with DTS (n = 1578; DM: n = 279) or SES (n = 1568; DM: n = 271). The primary end point, TLF, was a composite of cardiac death, target-lesion myocardial infarction (MI), or target lesion revascularization (TLR) within 1 year. RESULTS: At 1 year, the rate of TLF was increased in the DTS group compared to the SES group, both among patients with DM (9.3% vs. 4.8%; risk difference: 4.5%; incidence rate ratio: 1.99, 95% confidence interval [CI]: 1.02-3.90) and without DM (5.7% vs. 3.5%; incidence rate ratio: 1.67, 95% CI: 1.15-2.42). The differences were mainly explained by higher rates of TLR. CONCLUSION: Compared to the SES, the DTS was associated with an increased risk of TLF at 12 months in patients with and without DM. The differences were mainly explained by higher rates of TLR, whereas rates of cardiac death and target lesion MI did not differ significantly between the two stent groups in patients with or without DM.

Randomized Comparison of the Polymer-Free Biolimus-Coated BioFreedom Stent With the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Orsiro Stent in an All-Comers Population Treated With Percutaneous Coronary Intervention: The SORT OUT IX Trial.

BACKGROUND: In patients with increased bleeding risk, the biolimus A9-coated BioFreedom stent, a stainless steel drug-coated stent free from polymer, has shown superiority compared with a bare-metal stent. The aim of this study was to investigate whether the BioFreedom stent is noninferior to a modern ultrathin strut biodegradable polymer cobalt-chromium sirolimus-eluting Orsiro stent in an all-comers patient population treated with percutaneous coronary intervention. METHODS: The SORT OUT IX trial (Scandinavian Organization for Randomized Trials With Clinical Outcome IX), was a large-scale, registry-based, randomized, multicenter, single-blind, 2-arm, noninferiority trial. The primary end point, major adverse cardiovascular events, was defined as the composite of cardiac death, myocardial infarction not related to any segment other than the target lesion, or target lesion revascularization within 1 year, analyzed by intention-to-treat. The trial was powered to assess noninferiority for major adverse cardiovascular events of the BioFreedom stent compared with the Orsiro stent with a predetermined noninferiority margin of 0.021. RESULTS: Between December 14, 2015 and April 21, 2017, 3151 patients were assigned to treatment with the BioFreedom stent (1572 patients, 1966 lesions) or to the Orsiro stent (1579 patients, 1985 lesions). Five patients were lost to follow-up because of emigration (99.9% follow-up rate). Mean age was 66.3±10.9, diabetes mellitus was seen in 19.3% of patients, and 53% of the patients had acute coronary syndromes. At 1 year, intention-to-treat analysis showed that 79 (5.0%) patients, who were assigned the BioFreedom stent, and 59 (3.7%), who were assigned the Orsiro stent, met the primary end point (absolute risk difference 1.29% [upper limit of one-sided 95% CI 2.50%]; Pnoninferiority=0.14). Significantly more patients in the BioFreedom stent group had target lesion revascularization than those in the Orsiro stent group (55 [3.5%] vs 20 [1.3%], rate ratio 2.77 [95% CI, 1.66-4.62]; P<0.0001). CONCLUSIONS: The biolimus A9-coated BioFreedom polymer-free stent did not meet criteria for noninferiority for major adverse cardiovascular events at 12 months when compared with the ultrathin strut biodegradable polymer sirolimus-eluting Orsiro stent in an all-comers population Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02623140.

Predictors of 10-Year Stent-Related Adverse Outcomes after Coronary Drug-Eluting Stent Implantation: The Importance of Stent Size.

INTRODUCTION: The predictors of stent treatment failure and their importance 10 years after treatment with drug-eluting stents (DESs) have not been reported in detail. METHODS: Data were retrieved from the SORT-OUT II database encompassing 2,849 non-left main coronary lesions in 2,073 unselected all-comer patients treated with first-generation DES and followed clinically for 10 years. Stent treatment failure (STF) was defined as definite or probable stent thrombosis, target lesion revascularization (TLR), or >70% restenosis left untreated. Target lesion failure (TLF) was defined as cardiac death, target vessel myocardial infarction, or TLR. Characteristics predicting higher hazard ratios (HRs) were identified by the multivariate Cox regression analysis. RESULTS: A stent diameter ≤2.5 versus ≥3.5 mm had STF 23.3 versus 11.8% and TLF 27.9 versus 18.8%. Stent length <20 versus >40 mm had STF 13.0 versus 29.0% and TLF 18.7 versus 34.6%. In multivariate analysis, decreasing stent diameter (HR: 1.24 [3.0 mm] to 2.12 [2.25 mm], reference ≥3.5 mm) and increasing stent length (HR: 1.15 [20-30 mm] to 2.07 [>40 mm], reference <20 mm) predicted STF together with diabetes (HR: 1.31), previous revascularization (HR: 1.31), restenotic (HR: 2.25), bifurcation (HR: 1.45), and chronically occluded lesions (HR: 1.54). A predictive score (PS) was calculated for each lesion from the HRs for the predictors present. The 10-year rates of STF were 10% in lesions with a PS ≤ 1.5 and 37% in those with PS ≥ 3.5. CONCLUSIONS: Ten-year outcomes show large variations depending on the stent size and a few patient and lesion characteristics. The calculation of a PS from these unambiguous variables may be used to improve the risk estimate in individual lesions and patients.

Coronary Artery Healing Process after Bioresorbable Scaffold in Patients with Non-ST-Segment Elevation Myocardial Infarction: Rationale, Design, and Methodology of the HONEST Study.

BACKGROUND: Bioresorbable scaffolds (BRSs) is a relatively new approach in treating coronary artery stenosis. The initial results of the first commercially available scaffolds consisting of a backbone of poly-L-lactide raised safety concerns related to delayed resorption and healing. The magnesium alloy-based scaffold degrades via bio-corrosion within months, whereas it often takes several years for polymer scaffolds to degrade. The aim of the study was to assess the healing stage by optical coherence tomography (OCT) after 6 months in patients with non-ST-segment elevation myocardial infarct (NSTEMI) randomized to OCT or angiography-guided percutaneous coronary intervention with implantation of a magnesium sirolimus-eluting Magmaris scaffold (Magmaris; Biotronik, Bülach, Switzerland). METHODS: We analyzed the healing process by comparing OCT at baseline and after 6 months. Five stages of healing were defined with stage 1 being the least healed and stage 5 demonstrating complete resorption and healing with no visible scaffold/remnant. The primary end point is a calculated healing score that is based on 5 subtypes of healing stage: (1) malapposed, (2) uncovered with no detection of smooth surface tissue on top of struts or remnants, (3) covered protruding, (4) covered embedded, and (5) complete healing with a smooth neointimal surface and no sign of struts or visible remnants assessed by OCT 6 months after the index procedure. RESULTS: The impact of OCT-guided compared to angiography-guided scaffold implantation will be illuminated. CONCLUSION: The present study will provide new information on midterm healing properties of the magnesium BRS in patients with NSTEMI.

Plasma proteome profiling discovers novel proteins associated with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) affects 25% of the population and can progress to cirrhosis with limited treatment options. As the liver secretes most of the blood plasma proteins, liver disease may affect the plasma proteome. Plasma proteome profiling of 48 patients with and without cirrhosis or NAFLD revealed six statistically significantly changing proteins (ALDOB, APOM, LGALS3BP, PIGR, VTN, and AFM), two of which are already linked to liver disease. Polymeric immunoglobulin receptor (PIGR) was significantly elevated in both cohorts by 170% in NAFLD and 298% in cirrhosis and was further validated in mouse models. Furthermore, a global correlation map of clinical and proteomic data strongly associated DPP4, ANPEP, TGFBI, PIGR, and APOE with NAFLD and cirrhosis. The prominent diabetic drug target DPP4 is an aminopeptidase like ANPEP, ENPEP, and LAP3, all of which are up-regulated in the human or mouse data. Furthermore, ANPEP and TGFBI have potential roles in extracellular matrix remodeling in fibrosis. Thus, plasma proteome profiling can identify potential biomarkers and drug targets in liver disease.

Rationale and design of DanGer shock: Danish-German cardiogenic shock trial.

OBJECTIVE: The DanGer Shock trial test the hypothesis that left ventricular (LV) mechanical circulatory support with Impella CP transvalvular microaxial flow pump improves survival in patients with ST segment elevation acute myocardial infarction complicated by cardiogenic shock (AMICS) compared to conventional guideline-driven treatment. This paper describes the rationale and design of the randomized trial, in addition to the baseline characteristics of the population screened and enrolled so far. METHODS: The DanGer Shock study is a prospective, multicenter, open-label trial in patients with AMICS randomized 1:1 to Impella CP or current guideline-driven therapy with planned enrollment of 360 patients. Patients comatose after out of hospital cardiac arrest are excluded. Eligible patients are randomized immediately following shock diagnosis. Among patients randomized to receive Impella CP, the device is placed prior to angioplasty. The primary endpoint is all-cause mortality at 180 days. Baseline characteristics of patients screened and randomized in the DanGer Shock as of June 2018 are compared with 2 contemporary AMICS studies. RESULTS: As of end of June 2018, 314 patients were screened and 100 patients were randomized. Patients had median arterial lactate of 5.5 mmol/L (interquartile range 3.7-8.8 mmol/L), median systolic blood pressure of 76 mmHg (interquartile range 70-88 mmHg), and median LV ejection fraction of 20% (interquartile range 10%-30%). CONCLUSION: The DanGer Shock trial will be the first adequately powered randomized trial to address whether mechanical circulatory LV support with Impella CP can improve survival in AMICS. Baseline characteristics of the first 100 randomized patients indicate a population in profound cardiogenic shock.

Impact of diabetes on clinical outcomes after revascularization with sirolimus-eluting and biolimus-eluting stents with biodegradable polymer from the SORT OUT VII trial.

OBJECTIVES: In this substudy of the SORT OUT VII trial, the clinical outcomes among patient with diabetes mellitus treated with Orsiro sirolimus-eluting stent (O-SES; Biotronik, Bülach, Switzerland) or Nobori biolimus-eluting stent (N-BES; Terumo, Tokyo, Japan) were compared. BACKGROUND: Diabetes is associated with increased risk of target lesion failure (TLF) after percutaneous coronary intervention. METHODS: In total, 2525 patients were randomized to stent implantation with O-SES (n = 1261, diabetes: n = 236) or N-BES (n = 1264, diabetes: n = 235). The primary endpoint, TLF, was a composite of cardiac death, target-lesion myocardial infarction (MI), or target lesion revascularization (TLR) within 2 years. RESULTS: At 2 year, TLF did not differ between O-SES vs N-BES in diabetic (9.3% vs 9.4%; RR 0.98, 95% CI 0.54-1.78) patients. The individual components of the primary endpoint did not differ among stent type. In diabetics, cardiac death occurred in 3% of O-SES-treated and in 3.8% of N-BES-treated patients (RR 0.77, 95% CI 0.29-2.08), MI occurred in 3.0% of O-SES-treated and in 3.8% of N-BES-treated patients (RR 0.76, 95% CI 0.28-2.06) and TLR occurred in 5,5% of O-SES-treated and in 6.0% of N-BES-treated patients (RR 0.91, 95% CI 0.43-1.95). CONCLUSION: TLF did not differ between O-SES- and N-BES-treated diabetic patients.

Hyperglucagonemia correlates with plasma levels of non-branched-chain amino acids in patients with liver disease independent of type 2 diabetes.

Patients with type 2 diabetes (T2D) and patients with nonalcoholic fatty liver disease (NAFLD) frequently exhibit elevated plasma concentrations of glucagon (hyperglucagonemia). Hyperglucagonemia and α-cell hyperplasia may result from elevated levels of plasma amino acids when glucagon's action on hepatic amino acid metabolism is disrupted. We therefore measured plasma levels of glucagon and individual amino acids in patients with and without biopsy-verified NAFLD and with and without type T2D. Fasting levels of amino acids and glucagon in plasma were measured, using validated ELISAs and high-performance liquid chromatography, in obese, middle-aged individuals with I) normal glucose tolerance (NGT) and NAFLD, II) T2D and NAFLD, III) T2D without liver disease, and IV) NGT and no liver disease. Elevated levels of total amino acids were observed in participants with NAFLD and NGT compared with NGT controls (1,310 ± 235 µM vs. 937 ± 281 µM, P = 0.03) and in T2D and NAFLD compared with T2D without liver disease (1,354 ± 329 µM vs. 511 ± 235 µM, P < 0.0001). Particularly amino acids with known glucagonotropic effects (e.g., glutamine) were increased. Plasma levels of total amino acids correlated to plasma levels of glucagon also when adjusting for body mass index (BMI), glycated hemoglobin (HbA1c), and cholesterol levels (ß = 0.013 ± 0.007, P = 0.024). Elevated plasma levels of total amino acids associate with hyperglucagonemia in NAFLD patients independently of glycemic control, BMI or cholesterol - supporting the potential importance of a "liver-α-cell axis" in which glucagon regulates hepatic amino acid metabolism. Fasting hyperglucagonemia as seen in T2D may therefore represent impaired hepatic glucagon action with increasing amino acids levels. NEW & NOTEWORTHY Hypersecretion of glucagon (hyperglucagonemia) has been suggested to be linked to type 2 diabetes. Here, we show that levels of amino acids correlate with levels of glucagon. Hyperglucagonemia may depend on hepatic steatosis rather than type 2 diabetes.

Effects of glucagon-like peptide-1 on glucagon secretion in patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: We evaluated the glucagon-suppressive effect of glucagon-like peptide-1 (GLP-1) and its potential effects on endogenous glucose production and whole body lipolysis in non-diabetic patients with non-alcoholic fatty liver disease (NAFLD). METHODS: On two separate days, 10 non-diabetic patients with liver biopsy-verified NAFLD (NAFLD activity score 2.5±1.0) and 10 matched controls underwent 2h intravenous infusions of GLP-1 (0.8 pmol×kg(-1)×min(-1)) and placebo. Since GLP-1-mediated glucagon suppression has been shown to be glucose-dependent, plasma glucose was clamped at fasting level during the first hour, and then raised and clamped at 'postprandial level' (fasting plasma glucose level plus 3 mmol/L) for the remaining hour. We evaluated relative plasma levels of glucagon, endogenous glucose production and whole body lipolysis rates with stable isotopes and respiratory quotient using indirect calorimetry. RESULTS: Compared to controls, patients with NAFLD were insulin resistant (homeostasis model assessment (HOMA(IR)): 3.8±2.2 vs. 1.6±1.5, p=0.003) and had fasting hyperglucagonaemia (7.5±5.3 vs. 5.8±1.5 mmol/L, p=0.045). Similar relative glucagon suppression was seen in both groups during GLP-1 infusion at fasting (-97±75 vs. -93±41 pmol/L×min(-1)p=0.566) and 'postprandial' plasma glucose levels (-108±101 vs. -97±53 pmol/L×min(-1), p=0.196). Increased insulinotropic effect of GLP-1 was observed in NAFLD patients. No effect of GLP-1 on endogenous glucose production was observed in any of the groups. CONCLUSIONS: Patients with NAFLD exhibited fasting hyperglucagonaemia, but intact GLP-1-mediated glucagon suppression independently of plasma glucose concentrations. Preserved glucagonostatic effect and increased insulinotropic effects of GLP-1 in NAFLD may be important to maintain normo-glycaemia in these patients.

Zotarolimus-eluting durable-polymer-coated stent versus a biolimus-eluting biodegradable-polymer-coated stent in unselected patients undergoing percutaneous coronary intervention (SORT OUT VI): a randomised non-inferiority trial.

BACKGROUND: New-generation drug-eluting coronary stents have reduced the risk of coronary events, especially in patients with complex disease or lesions. To what extent different stent platforms, polymers, and antiproliferative drugs affect outcomes, however, is unclear. We investigated the safety and efficacy of a third-generation stent by comparing a highly biocompatible durable-polymer-coated zotarolimus-eluting stent with a biodegradable-polymer-coated biolimus-eluting stent. METHODS: This open-label, randomised, multicentre, non-inferiority trial was done at three sites across western Denmark. All patients who presented with stable coronary artery disease or acute coronary syndromes and at least one coronary artery lesion (more than 50% stenosis) from March, 2011, to August, 2012, were assessed for eligibility. Patients were randomly assigned in a 1:1 ratio to receive either the durable-polymer zotarolimus-eluting stent or the biodegradable-polymer biolimus-eluting stent. The primary endpoint was a composite of safety (cardiac death and myocardial infarction not clearly attributable to a non-target lesion) and efficacy (target-lesion revascularisation) at 12 months, analysed by intention to treat. The trial was powered to assess non-inferiority of durable-polymer zotarolimus-eluting stent compared with the biodegradable-polymer biolimus-eluting stent with a predetermined non-inferiority margin of 0·025. This trial is registered with ClinicalTrials.gov, number NCT01956448. FINDINGS: Of 7103 screened, 1502 patients with 1883 lesions were assigned to receive the durable-polymer zotarolimus-eluting stent and 1497 patients with 1791 lesions to receive the biodegradable-polymer biolimus-eluting stent. 79 (5·3%) and 75 (5·0%) patients, respectively, met the primary endpoint (absolute risk difference 0·0025, upper limit of one-sided 95% CI 0·016%; p=0·004). The individual components of the primary endpoint did not differ significantly between stent types at 12 months. INTERPRETATION: The durable-polymer-coated zotarolimus-eluting stent was non-inferior to the biodegradable-polymer-coated biolimus-eluting stent in unselected patients. FUNDING: Medtronic Cardiovascular and Biosensors Interventional Technologies.

Influence of multivessel disease with or without additional revascularization on mortality in patients with ST-segment elevation myocardial infarction.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI), timely reperfusion with primary percutaneous coronary intervention (PCI) is the preferred treatment. In primary PCI patients with multivessel disease, it is unclear whether culprit vessel PCI only is the preferred treatment. We compared mortality among (1) STEMI patients with single-vessel disease and those with multivessel disease and (2) multivessel disease patients with and without additional revascularization of nonculprit lesions within 2 months after the index PCI. METHODS: From January 2002 to June 2009, all patients presenting with STEMI and treated with primary PCI were identified from the Western Denmark Heart Registry, which covers a population of 3.0 million. The hazard ratio (HR) for death was estimated using a Cox regression model, controlling for potential confounding. RESULTS: The study cohort consisted of 8,822 patients: 4,770 (54.1%) had single-vessel disease and 4,052 (45.9%) had multivessel disease. Overall, 1-year cumulative mortality was 7.6%, and 7-year cumulative mortality was 24.0%. Multivessel disease was associated with higher 7-year mortality (adjusted HR 1.45 [95% CI 1.30-1.62], P < .001). Among patients with multivessel disease, lack of additional revascularization beyond the culprit lesion was associated with higher 7-year mortality (adjusted HR 1.50 [95% CI 1.25-1.80], P < .001). In patients with multivessel disease who underwent additional revascularization, 7-year mortality (adjusted HR 1.01 [95% CI 0.84-1.22], P = .89) was similar compared to patients with single-vessel disease. CONCLUSION: In STEMI patients, multivessel disease was associated with a higher mortality compared to single-vessel disease. In multivessel disease patients, additional revascularization was associated with a higher survival compared with culprit vessel PCI only.

Influence of gastrointestinal factors on glucose metabolism in patients with cirrhosis.

BACKGROUND AND AIM: The impaired glucose tolerance in cirrhosis is poorly understood. We evaluated the influence of gastrointestinal-mediated glucose disposal and incretin effect in patients with cirrhosis. METHODS: Non-diabetic patients with Child-Pugh A or B cirrhosis (n = 10) and matched healthy controls (n = 10) underwent a 50-g oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose infusion. We presented data as median ± interquartile range and compared groups using non-parametric analysis of variance. RESULTS: Patients with cirrhosis were glucose intolerant compared with healthy controls (4-h OGTTAUC : 609 ± 458 vs 180 ± 155 min × mmol/L; P = 0.005), insulin resistant (homeostatic model assessment for insulin resistance: 3.7 ± 4.9 vs 2.6 ± 1.4; P = 0.014) and had fasting hyperglucagonemia (8 ± 3 vs 3 ± 4 pmol/L; P = 0.027). Isoglycemia was achieved using 35 ± 12 g of intravenous glucose in patients with cirrhosis compared with 24 ± 10 g in healthy controls (P = 0.003). The gastrointestinal-mediated glucose disposal was markedly lower in patients with cirrhosis (30 ± 23 vs 52 ± 20%; P = 0.003). Despite higher levels of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide patients with cirrhosis had reduced incretin effect (35 ± 44 vs 55 ± 30%; P = 0.008). CONCLUSION: Impaired gastrointestinal-mediated glucose disposal and reduced incretin effect may contribute to the glucose intolerance seen in patients with cirrhosis.