Pia Lundman

MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction

Antigen presentation to T cells by MHC molecules is essential for adaptive immune responses. To determine the exact position of a gene affecting expression of MHC molecules, we finely mapped a previously defined rat quantitative trait locus regulating MHC class II on microglia in an advanced intercross line. We identified a small interval including the gene MHC class II transactivator (Mhc2ta) and, using a map over six inbred strains combined with gene sequencing and expression analysis, two conserved Mhc2ta haplotypes segregating with MHC class II levels. In humans, a –168A → G polymorphism in the type III promoter of the MHC class II transactivator (MHC2TA) was associated with increased susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction, as well as lower expression of MHC2TA after stimulation of leukocytes with interferon-γ. We conclude that polymorphisms in Mhc2ta and MHC2TA result in differential MHC molecule expression and are associated with susceptibility to common complex diseases with inflammatory components.

Mild-to-moderate hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentrations of asymmetric dimethylarginine.

OBJECTIVES The aim of this study was to investigate endothelial function and common carotid intima-media thickness (IMT) in healthy young men with mild-to-moderate hypertriglyceridemia. Plasma asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, was measured to further elucidate the mechanisms involved. BACKGROUND Hypertriglyceridemia is a risk factor for coronary heart disease although the mechanisms behind the increased risk remain to be defined. Acute elevation of plasma triglycerides induced by an intravenous fat load is associated with impaired endothelial function. The results of studies examining acute effects induced by a high-fat meal or effects of chronic hypertriglyceridemia on endothelial function are more inconsistent. METHODS Flow-mediated vasodilation and nitroglycerin-induced vasodilation of the brachial artery and common carotid IMT were measured noninvasively by ultrasound technique in 15 hypertriglyceridemic (HTG) subjects and 15 matched controls, mean age 34 years. Plasma concentrations of ADMA were measured by high-performance liquid chromatography. RESULTS Flow-mediated vasodilation was decreased in the HTG group (p < 0.0001), whereas nitroglycerin-induced vasodilation and carotid IMT did not differ significantly. Asymmetric dimethylarginine concentrations were higher in the HTG group (p < 0.05). CONCLUSIONS Hypertriglyceridemia in young men is associated with endothelial dysfunction and increased plasma concentration of ADMA but not with increased IMT of the common carotid artery. The corollary is that chronic hypertriglyceridemia results in endothelial dysfunction, possibly due to increased ADMA concentration, and that endothelial dysfunction might precede increased IMT among the early manifestations of atherosclerosis.

Transient Triglyceridemia Decreases Vascular Reactivity in Young, Healthy Men Without Risk Factors for Coronary Heart Disease

BACKGROUND Hypertriglyceridemia is now accepted as a risk factor for coronary heart disease, although the mechanism behind the increased risk is not well understood. The present study was undertaken to investigate the effects of triglyceridemia on endothelial function, because impaired endothelial function is considered a marker of atherogenesis. METHODS AND RESULTS Flow- and nitroglycerin-induced dilatation of the brachial artery was investigated noninvasively by high-resolution ultrasound technique in seven young, healthy men without risk factors for coronary heart disease. Transient triglyceridemia was induced by infusion of a triglyceride emulsion, Intralipid, which raised free fatty acid concentrations twofold and triglyceride levels fourfold. Flow-induced vasodilatation decreased from 7.1+/-3.0% to 1.6+/-2.6% (P<.0002), whereas nitroglycerin-induced vasodilatation decreased from 20.5+/-5.8% to 11.5+/-3.2% (P<.002) before and after 1 hour of infusion of Intralipid, respectively. CONCLUSIONS Transient triglyceridemia decreases vascular reactivity, presumably by both endothelium-dependent and endothelium-independent mechanisms.

Influence of Renal Function on the Effects of Early Revascularization in Non-ST-Elevation Myocardial Infarction Data From the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART)

Background— It is unknown whether patients with non–ST-elevation myocardial infarction derive a similar benefit from an early invasive therapy at different levels of renal function. Methods and Results— A total of 23 262 consecutive non–ST-elevation myocardial infarction patients ≤80 years old were included in a nationwide coronary care unit register between 2003 and 2006. Glomerular filtration rate (eGFR) was estimated with the Modification of Diet in Renal Disease Study formula. Patients were divided into medically or invasively treated groups if revascularized within 14 days of admission. A propensity score for the likelihood of invasive therapy was calculated. A Cox regression model with adjustment for propensity score and discharge medication was used to assess the association between early revascularization and 1-year mortality across renal function stages. There was a gradient, with significantly fewer patients treated invasively with declining renal function: eGFR ≥90 mL · min−1 · 1.73 m−2, 62%; eGFR 60 to 89 mL · min−1 · 1.73 m−2, 55%; eGFR 30 to 59 mL · min−1 · 1.73 m−2, 36%; eGFR 15 to 29 mL · min−1 · 1.73 m−2, 14%; and eGFR <15 mL · min−1 · 1.73 m−2/dialysis, 15% (P<0.001). After adjustment, the overall 1-year mortality was 36% lower (hazard ratio 0.64, 95% confidence interval 0.56 to 0.73, P<0.001) with an invasive strategy. The magnitude of survival difference was similar in normal-to-moderate renal function groups. The lower mortality observed with invasive therapy declined with lower renal function, with no difference in mortality in patients with kidney failure (eGFR <15 mL · min−1 · 1.73 m−2) or in those receiving dialysis (hazard ratio 1.61, 95% confidence interval 0.84 to 3.09, P=0.15). Conclusions— Early invasive therapy is associated with greater 1-year survival in patients with non–ST-elevation myocardial infarction and mild-to-moderate renal insufficiency, but the benefit declines with lower renal function, and is less certain in those with renal failure or on dialysis.

Serum matrix metalloproteinase-3 concentration is influenced by MMP-3 )1612 5A/6A promoter genotype and associated with myocardial infarction

Objectives.  Matrix metalloproteinase‐3 (MMP‐3) is implicated in the formation of atherosclerotic plaques, and the MMP‐3 −1612 5A/6A polymorphism is associated with myocardial infarction (MI) and stable coronary artery disease (CAD). The present study examined whether the −1612 5A/6A polymorphism in the promoter region of the MMP‐3 gene influences serum concentrations of MMP‐3 and whether serum concentrations of MMP‐3 are related to extent of coronary atherosclerosis and risk of MI.

Persistent lipid abnormalities in statin-treated patients and predictors of LDL-cholesterol goal achievement in clinical practice in Europe and Canada

Background: The prevalence of persistent lipid abnormalities in patients receiving statins in primary and secondary care is needed to formulate recommendations for future treatment. Studies associating cardiovascular risk factors with lipid target goal achievement are lacking. Design: A cross-sectional, observational study that assessed the prevalence of persistent dyslipidemia in patients treated with statins and analyzed predictors of lipid target achievement. Methods: Serum lipid values of 22,063 statin-treated patients were studied in the context of their cardiovascular risk factors, and the potency and composition of their lipid-lowering treatment. European Society of Cardiology recommendations were used to classify patient risk, and to define LDL-cholesterol goal and normal levels for HDL-cholesterol and triglycerides. Results: Overall, 48.2% of patients did not achieve the therapeutic goal for LDL-cholesterol, either as a single lipid anomaly or associated with low HDL-cholesterol, elevated triglycerides, or both. Lack of goal achievement was more prevalent among low-risk patients (55.8%) than high-risk patients (46.8%). Serum LDL-cholesterol levels were lower in high-risk patients. Predictors associated with LDL-cholesterol goal achievement were higher statin dose (odds ratio (OR): 0.35), specialist treatment (OR: 0.74), or combined lipid-lowering therapy (OR: 0.80). Conclusions: Nearly half of statin-treated patients missed their therapeutic LDL-cholesterol goal, highlighting a gap between recommendations and clinical practice. Better achievement of LDL-cholesterol therapeutic goal was found among patients at high cardiovascular risk, those on high statin doses or using combination therapy, and patients managed by specialists. Results suggest that residual dyslipidemia in statin-treated patients at low cardiovascular risk may be reduced by increasing statin dose.

Human Evidence That the Cystatin C Gene Is Implicated in Focal Progression of Coronary Artery Disease

Objective—Overexpression of elastolytic cysteine and aspartic proteases, known as cathepsins, is implicated in atherogenesis. The potential significance of imbalance in expression between cathepsins and their inhibitor cystatin C in cardiovascular disease has been highlighted by the demonstration of cystatin C deficiency in human atherosclerosis and abdominal aortic aneurysms. Methods and Results—We identified and characterized physiologically relevant polymorphisms in the promoter region of the cystatin C gene that influence cystatin C production and used these polymorphisms as a tool to examine the significance of cystatin C in coronary atherosclerosis in vivo in humans. Seven polymorphisms, all in strong-linkage disequilibrium, were identified in the cystatin C gene, of which 2 promoter polymorphisms (−82G/C and −78T/G) were functional in vitro in electromobility shift and transient transfection assays. Genotyping of 1105 individuals (237 survivors of a first myocardial infarction before age 60 and 2 independent groups comprising a total of 868 healthy individuals) revealed that the plasma cystatin C concentration was significantly lower in carriers of the mutant haplotype. Furthermore, the mutant haplotype was associated with a higher average number of stenoses per coronary artery segment in unselected postinfarction patients (N=237) undergoing routine coronary angiography. Conclusions—These results provide human evidence for an important role of cystatin C in coronary artery disease.

Relation between renal function, presentation, use of therapies and in-hospital complications in acute coronary syndrome: data from the SWEDEHEART register.

Abstract.  Szummer K, Lundman P, Jacobson SH, Schön S, Lindbäck J, Stenestrand U, Wallentin L, Jernberg T, for SWEDEHEART. (Karolinska Institute, Karolinska University Hospital, Stockholm; Karolinska Institute, Danderyd Hospital, Danderyd; Ryhov County Hospital, Jönköping; University Hospital, Uppsala and University Hospital, Linköping; Sweden) Relation between renal function, presentation, use of therapies and in‐hospital complications in acute coronary syndrome: data from the SWEDEHEART register. J Intern Med 2010; 268:40–49.

Acute hypertriglyceridaemia in humans increases the triglyceride content and decreases the anti-inflammatory capacity of high density lipoproteins

INTRODUCTION Post-prandial hypertriglyceridaemia is a risk factor for cardiovascular disease, although the underlying mechanisms remain unclear. High density lipoproteins (HDL) have been shown to be atheroprotective, in part through attenuation of vascular inflammation. In this study, the influence of acute hypertriglyceridaemia on the composition and anti-inflammatory properties of HDL was investigated. METHODS Eight fasting healthy male subjects (34+/-2 years) received 20% Intralipid (15 mg/kg/h) or saline, on separate occasions in random order. At baseline and 60 min post-infusion, the total HDL fraction was isolated and its chemical composition determined. HDL were added to TNF-alpha stimulated human coronary artery endothelial cells and VCAM-1 and ICAM-1 expression was determined by flow cytometry. RESULTS Serum triglyceride (97.4+/-8.5mg/dL baseline, 283.2+/-35.4 mg/dL post-infusion, p<0.001) and HDL triglyceride content (3.8+/-0.5% HDL mass baseline, 5.3+/-0.9% HDL mass post-infusion, p<0.05) increased significantly after Intralipid infusion. HDL post-Intralipid were significantly less anti-inflammatory compared with control (e.g. at 8 microM apoA-I, %VCAM-1 expression 54+/-5 post-saline, 73+/-4 post-Intralipid, p=0.01; %ICAM-1 expression 94+/-1 post-saline, 99.4+/-0.6 post-Intralipid, p<0.01). There was also a significant correlation between HDL triglyceride content and VCAM-1 expression (R=0.70, p=0.005); as well as between plasma triglyceride levels and both VCAM-1 (R=0.71, p<0.005) and ICAM-1 expression (R=0.80, p<0.005). CONCLUSION Acute hypertriglyceridaemia, simulating the post-prandial state, results in triglyceride-rich HDL with impaired anti-inflammatory capacity.

Accumulation of Apolipoprotein C-I–Rich and Cholesterol-Rich VLDL Remnants During Exaggerated Postprandial Triglyceridemia in Normolipidemic Patients With Coronary Artery Disease

BACKGROUND Exaggerated postprandial triglyceridemia is common in normolipidemic patients with coronary artery disease (CAD). Alterations in the composition of triglyceride-rich lipoproteins (TRLs) are likely to underlie this metabolic disturbance. However, the composition of very-low-density lipoproteins (VLDLs), which are the most abundant postprandial TRLs, has never been defined in CAD patients. METHODS AND RESULTS We examined postprandial changes in the number and composition of VLDLs in middle-aged, normolipidemic CAD patients and control subjects. TRLs from 14 patients and 14 control subjects aged 45 to 55 years were subfractionated by density gradient ultracentrifugation into Svedberg flotation rate (Sf) fractions >400, 60 to 400, and 20 to 60. The VLDLs were separated from chylomicron remnants by immunoaffinity chromatography. In CAD patients, the postprandial concentrations of triglycerides and large (Sf 60 to 400) VLDL particles were elevated. In addition, their postprandial large VLDLs were enriched in apolipoprotein (apo) C-I and their postprandial small (Sf 20 to 60) VLDL remnants were enriched with apo C-I and cholesterol. CONCLUSIONS Perturbed handling of postprandial triglycerides in normolipidemic CAD patients involves the accumulation of apo C-I-rich large VLDL particles and the generation of small, apo C-I- and cholesterol-rich VLDL remnants.