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Background: Patients with diabetes have increased rates of major adverse cardiac events (MACEs). We hypothesized that this is explained by diabetes-associated differences in coronary plaque morphology and lipid content. Methods: In PROSPECT II (Providing Regional Observations to Study Predictors of Events in the Coronary Tree), 898 patients with acute myocardial infarction with or without ST-segment elevation underwent 3-vessel quantitative coronary angiography and coregistered near-infrared spectroscopy and intravascular ultrasound imaging after successful percutaneous coronary intervention. Subsequent MACEs were adjudicated to either treated culprit lesions or untreated nonculprit lesions. This substudy stratified patients by diabetes status and assessed baseline culprit and nonculprit prevalence of high-risk plaque characteristics defined as maximum plaque burden ≥70% and maximum lipid core burden index ≥324.7. Separate covariate-adjusted multivariable models were performed to identify whether diabetes was associated with nonculprit lesion–related MACEs and high-risk plaque characteristics. Results: Diabetes was present in 109 of 898 patients (12.1%). During a median 3.7-year follow-up, MACEs occurred more frequently in patients with versus without diabetes (20.1% versus 13.5% [odds ratio (OR), 1.94 (95% CI, 1.14–3.30)]), primarily attributable to increased risk of myocardial infarction related to culprit lesion restenosis (4.3% versus 1.1% [OR, 3.78 (95% CI, 1.12–12.77)]) and nonculprit lesion–related spontaneous myocardial infarction (9.3% versus 3.8% [OR, 2.74 (95% CI, 1.25–6.04)]). However, baseline prevalence of high-risk plaque characteristics was similar for patients with versus without diabetes concerning culprit (maximum plaque burden ≥70%: 90% versus 93%, P =0.34; maximum lipid core burden index ≥324.7: 66% versus 70%, P =0.49) and nonculprit lesions (maximum plaque burden ≥70%: 23% versus 22%, P =0.37; maximum lipid core burden index ≥324.7: 26% versus 24%, P =0.47). In multivariable models, diabetes was associated with MACEs in nonculprit lesions (adjusted OR, 2.47 [95% CI, 1.21–5.04]) but not with prevalence of high-risk plaque characteristics (adjusted OR, 1.21 [95% CI, 0.86–1.69]). Conclusions: Among patients with recent myocardial infarction, both treated and untreated lesions contributed to the diabetes-associated ≈2-fold increased MACE rate during the 3.7-year follow-up. Diabetes-related plaque characteristics that might underlie this increased risk were not identified by multimodality imaging. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02171065.

Introduction: Sex differences have been poorly studied in patients with right-sided heart valve disease. The principal aim of the current study was to explore the impact of sex differences on right ventricular (RV) hemodynamics and all-cause mortality in patients with moderate or severe tricuspid regurgitation (TR). Methods: This is a retrospective study of 209 patients with significant TR. All patients were clinically profiled at baseline and underwent a transthoracic echocardiogram. The cohort was followed up for clinical events for a median duration of 80 months (mean ± SD 69.4 ± 33.4 months). Results: There were 117 women with a mean (± SD) age of 72.6 ± 13 years and 92 men with a mean (± SD) age of 70.8 ± 15.8 years. There were no sex differences between the individual measures of RV systolic function (tricuspid annular plane systolic excursion [TAPSE], systolic pulmonary artery pressure, and RV S’), but overall RV systolic dysfunction (TAPSE p = 0.002). There was no difference in all-cause mortality between women and men (Log-Rank p = 0.528). Age and increased RV WT were independent predictors of all-cause mortality both in women (hazard ratio [HR] 2.61) and men (HR 3.01). Conclusions: In this cohort of patients with significant TR, women more frequently had preserved RV systolic function than men. There was no sex-difference in all-cause mortality. An increased RV WT and higher age were independent predictors of all-cause mortality in both women and men.

Background: We aim to explore the determinants of right ventricular wall tension (RV base-to-apex length multiplied by systolic pulmonary artery pressure [RV WT] and association with all-cause mortality in patients with moderate-to-severe tricuspid regurgitation. Materials & methods: Of total, 180 patients (71 ± 15 years, 54% females) were included. An increased RV WT was defined as >3300 mmHg x mm. Results: Patients with increased RV WT (n = 85, 47%) were more likely to be male and taller than patients with normal RV WT. In a multivariable-adjusted model, increased RV WT was associated with a 2.6-fold higher risk of all-cause mortality (HR: 2.59, 95% CI: 1.65–4.06). Conclusion: In patients with significant tricuspid regurgitation, an increased RV WT was common, and associated with a 2.6-fold higher risk of all-cause mortality. Male sex was the only independent determinant.

BACKGROUND: Primary percutaneous coronary intervention with implantation of a metallic drug-eluting stent (DES) is the standard treatment for patients presenting with ST-elevation myocardial infarction (STEMI). Implantation of a bioresorbable scaffold (BRS) during STEMI represents a novel strategy without intravascular metal.OBJECTIVE: The aim of the study was to investigate 12-month healing response in an STEMI population after implantation of either the Absorb BRS or Xience DES (Abbott Vascular, USA).METHODS: The present trial was a prospective, randomized, controlled, nonblinded, noninferiority study with planned inclusion of 120 patients with STEMI. Patients were randomly assigned 1:1 to treatment with Absorb BRS or Xience DES. Implantation result and healing response were evaluated by angiography and optical coherence tomography (OCT) at baseline and 12-month follow-up. The primary endpoint was minimum flow area (MFA) assessed at 12 months. Coronary stent healing index (CSHI) was calculated from OCT images.RESULTS: Out of 66 included patients, 58 had follow-up OCT after 12 months, and 49 entered matched analysis. One death occurred in each group; none were stent-related. MFA was 5.13 ± 1.70 mm2 (95% CI, 4.44-5.82) in the BRS group compared with 6.30 ± 2.49 mm2 (95% CI, 5.22-7.37) (P = 0.06) in the DES group. Noninferiority could not be evaluated. CSHI for both groups had a median score of 3.CONCLUSION: The DES group performed numerically better in primary and secondary endpoints, but the CSHI showed good stent healing in both groups.

BackgroundUsing contemporary data from NORIC (Norwegian Registry of Invasive Cardiology) we investigated the predictive value of patient age and time from ECG diagnosis to sheath insertion (ECG‐2‐sheath) in primary percutaneous coronary intervention for ST‐segment–elevation myocardial infarction (STEMI).Methods and ResultsData from 11 226 patients collected from all centers offering 24/7/365 primary percutaneous coronary intervention service were explored. For patients aged Pvalue 80 years and mortality at 30 days, mortality was 10.5% and 17.7% for Restricted mean survival gains during median 938 days of follow‐up in patients with ECG‐2‐sheath time ConclusionsTime from ECG‐diagnosis to sheath insertion is strongly correlated with mortality. This applies especially to octogenarians who derive the most in terms of absolute mortality reduction.RegistrationURL:https://helsedata.no/en/forvaltere/norwegian‐institute‐of‐public‐health/norwegian‐registry‐of‐invasive‐cardiology/.

Background Low-dose dobutamine stress echocardiography (DSE) is indicated in patients with low flow (stroke volume index [SVi] 2) low gradient (mean pressure gradient 20% increase in SVi) and severity grade of AS. Severe AS is defined by a mean pressure gradient of 40 mmHg occurring at any time during the test when aortic valve area remains 2. Case presentation This case report highlights the utility of mitral annular systolic velocity (S′) by tissue Doppler imaging and peak LV outflow tract (LVOT) velocity as markers of LV intrinsic contractile function during DSE in a patient with low flow low gradient AS and reduced EF prior to transcatheter aortic valve implantation (TAVI). Conclusions Mitral annular S′ and peak LVOT velocities are reliable markers of LV intrinsic contractile function and should be incorporated into routine low-dose DSE.

Background Dobutamine stress echocardiography is an established diagnostic modality for assessing myocardial ischaemia in patients with known or suspected coronary artery disease. Dobutamine infusion causes dose-dependent increase in heart rate and contractility. However, in some cases, it induces paradoxical sinus deceleration, whose underlying mechanism and clinical significance are not fully understood. Case summary We present episodes of paradoxical sinus deceleration observed during dobutamine stress echocardiography in six (four males and two females) patients and described its patterns of occurrence and clinical and echocardiographic characteristics. Discussion Paradoxical sinus deceleration occurred mostly at maximal dobutamine infusion was accompanied with a decline in blood pressure and resolved spontaneously following cessation of dobutamine infusion. Individuals experiencing paradoxical sinus deceleration had in common abnormal left ventricle geometry but differed with regard to age, sex, and cardiometabolic risk factors.

Patient-centered health care emphasizes shared decision-making (SDM), incorporating both clinical evidence and patient preferences and values. SDM is important in heart valve disease, both because there might be more than one treatment option and due to the importance of adherence after intervention. We aimed to describe patient information and involvement in decision-making about care and recording of patient-reported outcome measures (PROMs) in valve interventions. The opinion piece and recommendations are based upon literature review and our own experience from specialist valve clinics. Before a valve intervention, adequate patient information, discussion of the various treatment options and exploring patient preferences, in line with the concept of SDM, may improve post-intervention quality of life. After intervention, patients with prosthetic heart valves require adequate counseling and close follow-up to make them more confident and competent to manage their own health, as well as to maintain the efficacy of treatment provided. PROMs inform SDM before and improve care after valve intervention, focusing on outcomes beyond mortality and morbidity. SDM may improve post-intervention quality of life. Formal PROMs questionnaires inform SDM, quantify patient centered changes and should be used more often in clinical practice and research. A thorough assessment of baseline frailty status in patients scheduled for valve intervention is essential and may affect postoperative outcome.

Aims To assess characteristics and outcome of patients treated with Impella for acute myocardial infarction (AMI) complicated by severe cardiogenic shock (CS) or cardiac arrest (CA). Methods and results From 2008 through 2017, 92 patients with AMI complicated by CS were treated with Impella. Survival varied according to clinical presentation. Patients in cardiogenic shock without CA had a 75% 30-day survival. Patients with CA and return of spontaneous circulation (ROSC) had a 43% survival and those with CA and ongoing cardio-pulmonary resuscitation (CPR) had a 6% 30-day survival. Age, pre-existing hypertension, coronary disease, ventilatory support and use of adrenergic agents were associated with worse prognosis. Complications were predominantly access site related. Conclusions In this registry of patients with AMICS treated with Impella, hypertension and older age were found to be negatively predictive for survival. Patients without CA had the highest 30-day survival. In patients with ROSC, survival was strongly related to age and comorbidity. Patients with ongoing CPR had very high mortality.

Left ventricular (LV) strain on the electrocardiogram (ECG) (down-sloping, convex ST-segment depression with asymmetric T-wave inversion in leads V5 and V6) reflects fibrosis as a result of subendocardial ischemia. It is associated with a significantly increased risk of cardiovascular events independent of the presence of LV hypertrophy on the echocardiogram or cardiac magnetic resonance (CMR) scan. Ongoing studies of early aortic valve replacement in asymptomatic patients with severe aortic stenosis are using ECG changes as a marker of possible fibrosis shown by midwall late gadolinium enhancement on CMR. However, until these studies report, it is still reasonable to respond to LV strain on the ECG by tightening control of systemic hypertension and consider intervention in cases where indications are otherwise in borderline.

Introduction If reperfusion can be performed within 120 minutes, pPCI is the ESC guideline recommended treatment in patients with ST-elevation myocardial infarction (STEMI). Aims Historically, prognosis is dependent on time from diagnosis to reperfusion in patients with STEMI. We sought to investigate this in a contemporary patient population by assessing mortality as function of time from ECG diagnosis to sheath insertion in the Norwegian registry for invasive cardiology (NORIC). Methods NORIC, which is a part of the Norwegian Cardiovascular Disease Registry, is a national, mandatory and non-consensual person-identifiable health registry. Data from NORIC were linked with the National Population Register. Data were registered from 1st of January 2013 to 31st of June 2019. Results During this period complete data were available for n=5754 patients with 526 events. ECG diagnosis to sheath insertion was a predictor of mortality with the 4th (>106 min) vs 1st quartile ( Nationally 62% percent of the patients received pPCI within the ESC recommended 90 minutes from ECG-diagnosis with large geographical variation (range 38–89%). Nationally 80% received pPCI within 115 minutes (range 75–202 minutes). Conclusion In a contemporary STEMI population, time from ECG diagnosis to sheath insertion is a strong predictor for mortality in patients admitted for pPCI for STEMI. However, the data also demonstrate large variations between different geographical health regions in Norway that should be addressed. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Haukeland University Hospital

Symptomatic severe pulmonary vein stenosis (PVS) after catheter ablation of atrial fibrillation (AF) is a rare but well-recognized complication. Treatment options include pulmonary vein angioplasty with or without drug eluting balloons or angioplasty with stent implantation. The treatment of choice is unclear. In our center, pulmonary vein stenting is the treatment of choice for significantly stenotic veins. We present the long-term clinical outcome of 9 patients treated with stent implantation. Between 2001 and 2015, 3048 patients with AF were treated with catheter ablation at our institution, of which 9 developed symptomatic PVS. A total of 11 PVS were treated. Pre-procedural imaging (CT, MR, transesophageal echocardiography, angiography) was performed in all patients. Mean time from ablation to stenting was 18 months. Three patients had recurrent pneumonia and the remaining reduced functional capacity (NYHA 2). All patients were in functional capacity NYHA 1 (p

Aims Established surgical scores have limitations in delineating risk among candidates for transcatheter aortic valve implantation (TAVI). Assessment of frailty might help to estimate the mortality risk and identify patients likely to benefit from treatment. The aim of the study was to develop a frailty score to guide the decision for TAVI. Methods and results We conducted a prospective observational study in patients ≥70 years referred for TAVI during 2011–15. A Heart Team had declined the patients for open heart surgery due to high risk but accepted them for TAVI. Prior to the procedure, a geriatric assessment (GA) was performed. Based on this, an 8-element frailty score with a 0–9 (least frail–most frail) scale was developed. A total of 142 patients, 54% women, mean age 83 (standard deviation 4) years, with severe and symptomatic aortic stenosis were assessed. All-cause 2 year mortality was 11%. The novel GA frailty score predicted 2-year mortality in Cox analyses, also when adjusted for age, gender, and logistic EuroSCORE [hazard ratio (HR) 1.75, 95% confidence interval (CI): 1.28–2.42, P < 0.001]. A receiver operating characteristic (ROC) curve analysis indicated that a GA frailty score cut-off at ≥4 predicted 2-year mortality with a specificity of 80% (95% CI: 73–86%) and a sensitivity of 60% (95% CI: 36–80%). The area under the curve was 0.81 (95% CI 0.71–0.90). Conclusion A novel 8-element GA frailty score identified gradations in survival in patients declined for open heart surgery. Patients with higher GA frailty scores had significantly higher 2-year mortality after TAVI.

Plasma choline has been associated with cardiovascular disease and nonalcoholic steatohepatitis.We sought to study relations of plasma choline and its metabolite betaine to long-term risk of acute myocardial infarction (AMI) and all-cause mortality according to smoking status, in patients undergoing coronary angiography for stable angina pectoris.Samples were obtained before angiography from 2568 patients who were subsequently randomized in the Western Norway B-Vitamin Intervention Trial (WENBIT). Hazard ratios (HR) were calculated using multivariate Cox-regression and p-values were reported for trends over quartiles.Plasma concentrations of choline, but not betaine, were lower in smokers, and choline was positively associated with C-reactive protein and troponin T in nonsmokers, but not in smokers (p for interaction0.03). During a follow up of 4.8 ± 1.4 (mean ± SD) years, 8.3% suffered from AMI and 6.1% died. In the total population, choline was not associated with AMI or all-cause mortality. However, comparing the highest vs. the lowest quartiles, plasma choline was associated with increased risk of AMI in nonsmokers (HR 2.63, 95% CI 1.56 to 5.51; p for trend = 0.013) and no risk in smokers (p for interaction 0.001). Plasma choline significantly improved discrimination and reclassification when added to established cardiovascular risk factors. Plasma betaine was not associated with either endpoint.In patients with stable angina pectoris, elevated plasma choline is associated with elevated troponin levels and increased risk of AMI in nonsmokers. These results motivate further research into the relation between choline metabolism, smoking, and atherothrombosis.

Background Plasma concentration of total homocysteine is associated with risk of cardiovascular disease in epidemiological studies. We wanted to examine the effects of B-vitamin therapy, which may lower total homocysteine, on coronary flow and vascular function in patients with established coronary artery disease (CAD). Methods Forty patients with stable CAD, mean (standard deviation) aged 57.8 (9.0) years, recruited into the Western Norway B-Vitamin Intervention Trial, were randomly assigned to daily oral treatment with 0.8mg of folic acid and 0.4mg of vitamin B12 or placebo, and 40mg of vitamin B6 or placebo, using a 22 factorial design. At baseline, and after 9 and 24 months, coronary blood flow was assessed by coronary angiography and Doppler flow-wire measurements during intracoronary infusion of saline (basal), incremental doses of acetylcholine, adenosine, and nitroglycerin. Results We found a significant increase in basal (P

Objective— Interferon γ (IFN-γ) is centrally involved in atherosclerosis-related inflammation, but its activity cannot be reliably assessed by systemic measurements. In activated macrophages, IFN-γ stimulates production of neopterin and conversion of tryptophan to kynurenine. We evaluated the relationships of plasma neopterin and plasma kyunernine:tryptophan ratio (KTR) to long-term prognosis in patients with stable angina pectoris and angiographically verified significant coronary artery disease. Methods and Results— Samples were obtained from 2380 patients with a mean age of 63.7 years; 77.3% were men. During a median follow-up of 56 months, 10.8% of patients experienced a major coronary event (MCE), and 9.5% died. For MCE, each SD increment of neopterin and KTR (logarithmically transformed) was associated with multivariable adjusted hazard ratios and 95% CIs of 1.28 (1.10 to 1.48) and 1.28 (1.12 to 1.48), respectively. The corresponding hazard ratios (95% CIs) for all-cause mortality were 1.40 (1.21 to 1.62) (neopterin) and 1.23 (1.06 to 1.43) (KTR). Conclusion— In patients with stable angina pectoris, systemic markers of IFN-γ activity, plasma neopterin, and plasma KTR provide similar risk estimates for MCE and mortality. Our results support experimental data linking IFN-γ to acute atherosclerotic complications.

Objectives Osteoprotegerin (OPG) is a member of the tumor necrosis factor superfamily with pleiotropic effects on bone metabolism, endocrine function and the immune system. Circulating OPG levels are elevated in cardiovascular disease (CVD). We assessed serum OPG as predictor of long-term prognosis in patients with suspected stable angina pectoris (SAP) undergoing elective coronary angiography. Methods Samples were obtained from 1025 patients (median [25th, 75th percentile] age 62 [54, 70] years, 71.9% men). At inclusion, 43.2% of patients had single or double vessel disease, whereas 34.3% had triple vessel disease. Results During a median follow-up of 73 months, 11.0% of patients died, 5.9% died from CVD and 10.0% experienced an acute myocardial infarction (MI). In univariable analyses, strong associations were observed between OPG concentrations and all-cause mortality, CVD mortality and the incidence of MI (fatal or nonfatal). However, adjustment for conventional risk factors attenuated the risk estimates which were no longer significant, except for the subgroup with levels above the 90th percentile. For decile 10 versus deciles 1–9 of serum OPG, the following multivariable hazard ratios (95% confidence intervals) were observed: All-cause mortality: 1.94 (1.18, 3.18), p = 0.01; CVD mortality: 2.29 (1.16, 4.49), p = 0.02; and MI: 1.76 (1.02, 3.06), p = 0.04. Conclusion In patients with SAP, elevated serum OPG is associated with increased risk of all-cause mortality, CVD mortality and MI, but independent effects are mainly confined to levels above the 90th percentile.

AIMS: We hypothesized that the plaque composition and plaque type classification differs between acute coronary syndrome (ACS) and stable angina (SA) patients. METHODS AND RESULTS: We analyzed culprit lesion (CL) and nonculprit lesion (NCL) of ACS patients compared with target lesion (TL) and nontarget lesion (NTL) of SA patients by intravascular ultrasound radio frequency analysis in 874 lesion segments of 424 patients (ACS: 193 patients/SA: 231 patients). Comparing all lesion segments in ACS and SA patients did not show significant differences in absolute or relative plaque composition. However, necrotic core area was larger in CL versus TL (0.9+/-0.7 vs. 0.7+/-0.5 mm, P=0.005) and all plaque components were significantly higher in CL compared with NCL and TL compared with NTL, respectively. A higher amount of thin cap fibroatheroma lesions (15.2 vs. 5.1%, P

Quantitative contrast stress echocardiography (CSE) can assess regional myocardial perfusion. The aim of this study was to evaluate the performance of quantitative CSE in the detection of restenosis after percutaneous coronary intervention (PCI).Thirty-three patients with stable coronary artery disease, scheduled for PCI, underwent CSE and quantitative coronary angiography (QCA) before and 9 months after PCI. Regional myocardial perfusion was analysed blinded to QCA results. QCA identified 38 significant stenoses (or =50% diameter reduction). Before PCI, perfusion during stress was significantly reduced in regions supplied by stenotic arteries; blood flow velocity (Deltabeta) -3.9 (-9.0 to 0.5) s(-1), perfusion rate (DeltaA x beta) -175.0 (-518.0 to 58.5) s(-1), and refilling time (Deltart) 210 (-22 to 452)ms, compared with the perfusion increase seen in regions supplied by non-stenotic arteries; Deltabeta 1.6 (-0.7 to 4.4) s(-1), DeltaA x beta 151.7 (-67.0 to 300.5) s(-1), and Deltart -47 (-195 to 89) ms, all P0.05. At follow-up, regional stress-induced perfusion improved in 29 regions with successful PCI; Deltabeta 0.1 (-2.7 to 3.6), DeltaA x beta 30.5 (-133.3 to 232.1), and Deltart -99 (-247 to 125), all Por = 0.01, although there was no improvement in nine regions with restenosis; Deltabeta 0.9 (-1.5 to 5.3), DeltaAxbeta 65.7 (-40.8 to 412.6), and Deltart -79 (-268 to 163), P = NS.Quantitative CSE has the potential to detect angiographically significant coronary artery stenoses as well as angiographic success after PCI.

Background: Myocardial contrast stress echocardiography (stress MCE) is a novel method for diagnosing coronary artery disease (CAD). Few studies have compared the diagnosis of ischemia by stress MCE to angiographic CAD. Methods: Dobutamine stress MCE and SonoVue contrast infusion were performed before an elective percutaneous coronary intervention in 37 patients (8 women) aged 45–75 years with symptomatic CAD and at least one significant coronary artery stenosis measured by quantitative coronary angiography (QCA). The total and regional perfusion and wall motion (WM) were scored as normal or abnormal and attributed to the three main epicardial coronary arteries using a 17-segment left ventricular model. Results: An intermediate stress level was obtained in 29 (78%) patients, and 2 (5%) patients obtained peak stress. A perfusion defect was detected in 92% and WM abnormality in 57% of the patients at peak stress (P < 0.01). By perfusion, 70% of stenoses were both detected and correctly anatomically located, compared to 42% by WM (P < 0.01). All 21 patients with multivessel disease and/or proximal left anterior descending (LAD) stenosis measured by QCA were identified by stress-induced perfusion defects, while only 11 of them were identified by WM abnormalities (P < 0.01). Conclusion: Perfusion scoring is superior to WM scoring during stress MCE for diagnosing significant CAD in patients obtaining intermediate stress level, in particular, when multivessel disease or proximal LAD stenosis is present.

Background— Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is expressed abundantly in the necrotic core of coronary lesions, and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture. Methods and Results— This study compared the effects of 12 months of treatment with darapladib (an oral Lp-PLA 2 inhibitor, 160 mg daily) or placebo on coronary atheroma deformability (intravascular ultrasound palpography) and plasma high-sensitivity C-reactive protein in 330 patients with angiographically documented coronary disease. Secondary end points included changes in necrotic core size (intravascular ultrasound radiofrequency), atheroma size (intravascular ultrasound gray scale), and blood biomarkers. Background therapy was comparable between groups, with no difference in low-density lipoprotein cholesterol at 12 months (placebo, 88±34 mg/dL; darapladib, 84±31 mg/dL; P =0.37). In contrast, Lp-PLA 2 activity was inhibited by 59% with darapladib ( P P =0.22) or plasma high-sensitivity C-reactive protein ( P =0.35). In the placebo-treated group, however, necrotic core volume increased significantly (4.5±17.9 mm 3 ; P =0.009), whereas darapladib halted this increase (−0.5±13.9 mm 3 ; P =0.71), resulting in a significant treatment difference of −5.2 mm 3 ( P =0.012). These intraplaque compositional changes occurred without a significant treatment difference in total atheroma volume ( P =0.95). Conclusions— Despite adherence to a high level of standard-of-care treatment, the necrotic core continued to expand among patients receiving placebo. In contrast, Lp-PLA 2 inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability. These findings suggest that Lp-PLA 2 inhibition may represent a novel therapeutic approach.

Background: Inflammation is important in the pathogenesis of atherosclerosis. Polymorphisms of Fc receptors for IgG (FcγR) are associated with modifying effects of several infectious and autoimmune diseases. We have assessed the relationship between polymorphisms in three different FcγR genes and coronary artery disease (CAD). Methods and results: We genotyped for the FcγRIIA-R/H131, the FcγRIIIB-Na1/Na2, and the FcγRIIIA-F/V158 polymorphisms in 882 patients undergoing diagnostic coronary angiography. Significant CAD was defined as ≥50% lumen diameter stenosis in at least one coronary artery. In the analysis, no association was found between the FcγRIIA and FcγRIIIB genotypes and CAD, whereas the FcγRIIIA genotype was strongly related. Compared to those being heterozygous, or homozygous for the F allele, patients homozygous for the V allele had significantly reduced risk: OR, 0.53; (CI, 0.32–0.90). Additional adjustment for classical risk factors and sedimentation rate did not affect the results. The V/V genotype was also inversely related to the extent of CAD defined as no CAD, single, double or triple vessel disease ( P trend=0.002). Conclusions: Our data provide evidence for an association between FcγRIIIA allelic variants and coronary atherosclerosis. Genetic variation in this IgG-receptor may influence the clearance of antibodies by monocyte-derived macrophages involved in the pathogenesis of CAD.

Objective— Betaine is a substrate in the betaine–homocysteine methyltransferase reaction, converting homocysteine to methionine. There are only sparse data on plasma betaine as a determinant of the plasma total homocysteine (tHcy) concentration. Methods and Results— Ninety patients undergoing coronary angiography were randomized into 4 groups administered oral: (1) folic acid (0.8 mg), vitamin B12 (0.4 mg), and vitamin B6 (40 mg); (2) folic acid and vitamin B12; (3) vitamin B6 alone; or (4) placebo. Nonfasting blood samples were collected at baseline and 3, 14, and 28 days and 3, 6, and 12 months after treatment start. A 4-hour methionine-loading test (0.1 g/kg) was performed at baseline and after 3 months. At baseline, median (interquartile range) plasma betaine was 36.9 μmol/L (range: 30.3 to 46.8) and was increased by 15% after methionine loading. The postmethionine load (PML) increase in tHcy was inversely related to plasma betaine (β=−0.29, P =0.02) and even more strongly to PML betaine (β=−0.47, P P =0.007). Conclusions— Plasma betaine is a strong determinant of the PML increase in tHcy in subjects not supplemented with B-vitamins.

Total plasma homocysteine (tHcy) is an independent risk factor for coronary artery disease, and tHcy is lowered by B vitamins. To assess the effect of homocysteine-lowering B-vitamin treatment on angiographic progression of coronary artery disease, this substudy of the Western Norway B Vitamin Intervention Trial (WENBIT) included patients who had undergone percutaneous coronary intervention. The patients were randomized to daily oral treatment with folic acid, vitamin B(12), and vitamin B(6) or placebo in a 2 x 2 factorial design. The coronary angiograms obtained at baseline and follow-up were evaluated. The primary angiographic end points were the changes in minimum lumen diameter and diameter stenosis. A total of 348 subjects (288 men) with a mean +/- SD age of 60 +/- 10.2 years were followed up for a median of 10.5 months (twenty-fifth, seventy-fifth percentile 9.2, 11.8). The baseline median plasma tHcy level was 10.0 mumol/L (twenty-fifth, seventy-fifth percentile 8.1, 11.0), and treatment with folic acid/vitamin B(12) lowered the tHcy levels by 22%. At follow-up, we found 309 lesions with a significant decrease from baseline in the minimum lumen diameter of a mean of -0.16 +/- 0.4 mm and an increase in the diameter stenosis of 4.4 +/- 0.7%. Treatment with folic acid/vitamin B(12) or vitamin B(6) was not associated with a change in diameter stenosis or minimum lumen diameter. In a post hoc analysis, folic acid/vitamin B(12) treatment was significantly associated with rapid progression (odds ratio 1.84, 95% confidence interval 1.07 to 3.18). In conclusion, vitamin B treatment showed no beneficial effect on the angiographic progression of coronary artery disease, and the post hoc analyses suggested that folic acid/vitamin B(12) treatment might promote more rapid progression.