Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease.

BACKGROUND: Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease. METHODS: We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability. RESULTS: We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10(-3)). CONCLUSIONS: ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.).

A meta-analysis of specifically designed randomized trials of sirolimus-eluting versus paclitaxel-eluting stents in diabetic patients with coronary artery disease.

BACKGROUND: There is an ongoing debate on the optimal drug-eluting stent (DES) in diabetic patients with coronary artery disease. We addressed this issue by making a synthesis of the available evidence on the relative long-term efficacy and safety of sirolimus-eluting stent (SES) and paclitaxel-eluting stent (PES) in these patients. METHODS: Individual patient data were analyzed from 6 randomized trials specifically designed to compare SES with PES in diabetic patients. In total, 1183 patients were followed up for a median of 3.9 years (25th, 75th percentiles 3.4-4.5 years). The primary efficacy end point was target lesion revascularization (TLR). The composite of death and myocardial infarction (MI) was the primary safety end point. Stent thrombosis was a secondary end point. Overall hazard ratios (HRs) with 95% CIs were calculated as summary estimates. RESULTS: No significant heterogeneity was seen across the 6 randomized trials for all analyzed events. Sirolimus-eluting stent was associated with a significant reduction in the risk of TLR (HR 0.65 [0.47-0.91], P = .01). No significant differences were observed regarding the risk of death or MI (HR 1.04 [0.74-1.45], P = .83) and stent thrombosis (HR 1.00 [0.31-3.30], P = .67). Mortality was also not affected by the type of DES (HR 0.95 [0.65-1.39], P = .79). CONCLUSIONS: In diabetic patients with coronary artery disease, SES leads to a sustained reduction in the risk of TLR compared with PES. Both these DES types are, however, comparable with respect to the risk of stent thrombosis, MI, or death over long-term follow-up.

Comparison of paclitaxel- and sirolimus-eluting stents in everyday clinical practice: the SORT OUT II randomized trial.

CONTEXT: Approval of drug-eluting coronary stents was based on results of relatively small trials of selected patients; however, in routine practice, stents are used in a broader spectrum of patients. OBJECTIVE: To compare the first 2 commercially available drug-eluting stents-sirolimus-eluting and paclitaxel-eluting-for prevention of symptom-driven clinical end points, using a study design reflecting everyday clinical practice. DESIGN, SETTING, AND PATIENTS: Randomized, blinded trial conducted August 2004 to January 2006 at 5 university hospitals in Denmark. Patients were 2098 men and women (mean [SD] age, 63.6 [10.8] years) treated with percutaneous coronary intervention (PCI) and randomized to receive either sirolimus-eluting (n = 1065) or paclitaxel-eluting (n = 1033) stents. Indications for PCI included ST-segment elevation myocardial infarction (STEMI), non-STEMI or unstable angina pectoris, and stable angina. MAIN OUTCOME MEASURES: The primary end point was a composite clinical end point of major adverse cardiac events, defined as either cardiac death, acute myocardial infarction, target lesion revascularization, or target vessel revascularization. Secondary end points included individual components of the composite end point, all-cause mortality, and stent thrombosis. RESULTS: The sirolimus- and the paclitaxel-eluting stent groups did not differ significantly in major adverse cardiac events (98 [9.3%] vs 114 [11.2%]; hazard ratio, 0.83 [95% confidence interval, 0.63-1.08]; P = .16) or in any of the secondary end points. The stent thrombosis rates were 27 (2.5%) and 30 (2.9%) (hazard ratio, 0.87 [95% confidence interval, 0.52-1.46]; P = .60), respectively. CONCLUSION: In this practical randomized trial, there were no significant differences in clinical outcomes between patients receiving sirolimus- and paclitaxel-eluting stents. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00388934.

Ten-year clinical outcome of patients treated with a drug-eluting stent in the proximal left anterior descending artery segment compared with patients stented in other non-left main coronary segments.

AIMS: The aim of the study was to determine whether patients treated with drug-eluting stents in the proximal left anterior descending artery (LAD) carried a different long-term prognosis from patients treated in other coronary artery segments. METHODS AND RESULTS: Ten-year clinical outcome expressed as all-cause mortality and major adverse cardiac events (MACE: cardiac death, acute myocardial infarction, or target vessel revascularisation) was determined for 1,479 patients with a single non-left main coronary stenosis treated with a first-generation drug-eluting stent in the SORT OUT II trial. The outcome of patients treated with stents in the proximal LAD (n=365) was compared with that of patients treated in a non-proximal LAD segment (n=1,114). Follow-up was 99.3% complete. All-cause mortality was 24.9% in the proximal LAD group vs. 26.3% in the non-proximal LAD group (p=0.60). MACE occurred less frequently in the proximal LAD group, 24.6% vs. 31.0% with a hazard ratio of 0.77 (95% confidence interval [CI]: 0.61-0.97, p=0.024). After multivariate analysis which included baseline characteristics that were unevenly distributed between the groups, the hazard ratio for MACE was 0.82 (95% CI: 0.65-1.03, p=0.09). CONCLUSIONS: Patients treated with a drug-eluting stent in the proximal LAD have similar, if not better, long-term clinical outcome compared with patients stented in other coronary artery segments.

10-Year Clinical Outcome After Randomization to Treatment by Sirolimus- or Paclitaxel-Eluting Coronary Stents.

BACKGROUND: First-generation drug-eluting coronary stents (DES) were introduced in 2003 to 2004, and their use resulted in a considerable reduction in the development of in-stent restenosis at the cost of an increased risk of late stent thromboses. OBJECTIVES: This study followed clinical outcomes of patients included in a large randomized trial for 10 years to enable detection of late changes in annual event rates that could necessitate medical attention. METHODS: A total of 2,098 unselected all-comer patients (50% with acute coronary syndrome) were randomly assigned to have a first-generation DES implanted. This study recorded the occurrence of a major adverse cardiac event (MACE) assessed as the composite of cardiac death, myocardial infarction, and target vessel revascularization. Stent thromboses were also assessed. RESULTS: Of the 2,098 unselected patients, 73.1% were still alive after 10 years. During the follow-up period, MACE occurred in 346 (32.5%) in the group receiving a sirolimus-eluting stent and in 342 (33.1%) in the group receiving a paclitaxel-eluting stent (hazard ratio: 0.96; 95% confidence interval: 0.83 to 1.11; p = 0.60), with a steady annual rate of 2.6% after the first year. Definite, probable, and possible stent thrombosis appeared in 279 patients (13.3%), with no difference between stent types and with a steady annual rate of 1.3% after the first year. CONCLUSIONS: Among the surviving patients, the long-term annual MACE rate and the stent thrombosis rate appeared constant for both stent types, with no apparent late changes. Although there is no need for extraordinary medical attention for these patients, the absence of declines in annual event rates calls for continuous surveillance. (Danish Organization on Randomized Trials With Clinical Outcome II [SORT OUT II]; NCT00388934).

Stent thrombosis is the primary cause of ST-segment elevation myocardial infarction following coronary stent implantation: a five year follow-up of the SORT OUT II study.

BACKGROUND: The widespread use of coronary stents has exposed a growing population to the risk of stent thrombosis, but the importance in terms of risk of ST-segment elevation myocardial infarctions (STEMIs) remains unclear. METHODS: We studied five years follow-up data for 2,098 all-comer patients treated with coronary stents in the randomized SORT OUT II trial (mean age 63.6 yrs. 74.8% men). Patients who following stent implantation were readmitted with STEMI were included and each patient was categorized ranging from definite- to ruled-out stent thrombosis according to the Academic Research Consortium definitions. Multivariate logistic regression was performed on selected covariates to assess odds ratios (ORs) for definite stent thrombosis. RESULTS: 85 patients (4.1%), mean age 62.7 years, 77.1% men, were admitted with a total of 96 STEMIs, of whom 60 (62.5%) had definite stent thrombosis. Notably, definite stent thrombosis was more frequent in female than male STEMI patients (81.8% vs. 56.8%, p =  .09), and in very late STEMIs (p = 0.06). Female sex (OR 3.53 [1.01-12.59]) and clopidogrel (OR 4.43 [1.03-19.01]) was associated with increased for definite stent thrombosis, whereas age, time since stent implantation, use of statins, initial PCI urgency (STEMI [primary PCI], NSTEMI/unstable angina [subacute PCI] or stable angina [elective PCI]), and glucose-lowering agents did not seem to influence risk of stent thrombosis. CONCLUSION: In a contemporary cohort of coronary stented patients, stent thrombosis was evident in more than 60% of subsequent STEMIs.

Anthracycline-induced cardiomyopathy: favourable effects of cardiac resynchronization therapy.

We report a case of severe refractory congestive heart failure after anthracycline chemotherapy in a patient with a narrow QRS interval on the electrocardiogram and echocardiographic evidence of left ventricular dyssynchrony, where cardiac resynchronization therapy resulted in normalization of left ventricular ejection fraction and marked symptomatic relief.