Arnold von Eckardstein

High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport

The incidence of coronary heart disease (CHD) was assessed via the Prospective Cardiovascular Münster (PROCAM) study in 19,698 volunteer subjects aged between 16 and 65 years. An adequate incidence of atherosclerotic CHD was only found in male subjects greater than 40 years of age. The analysis and subsequent 6 year follow-up period was, therefore, confined to 4559 male participants aged 40-64 years. In the follow-up period, 186 study participants developed atherosclerotic CHD (134 definite non-fatal myocardial infarctions (MIs) and 52 definite atherosclerotic CHD deaths including 21 sudden cardiac deaths and 31 fatal MIs). Univariate analysis revealed a significant association between the incidence of atherosclerotic CHD and high-density lipoprotein cholesterol (P < 0.001), which remained after adjustment for other risk factors.

High Density Lipoproteins and Arteriosclerosis Role of Cholesterol Efflux and Reverse Cholesterol Transport

High density lipoprotein (HDL) cholesterol is an important risk factor for coronary heart disease, and HDL exerts various potentially antiatherogenic properties, including the mediation of reverse transport of cholesterol from cells of the arterial wall to the liver and steroidogenic organs. Enhancement of cholesterol efflux and of reverse cholesterol transport (RCT) is considered an important target for antiatherosclerotic drug therapy. Levels and composition of HDL subclasses in plasma are regulated by many factors, including apolipoproteins, lipolytic enzymes, lipid transfer proteins, receptors, and cellular transporters. In vitro experiments as well as genetic family and population studies and investigation of transgenic animal models have revealed that HDL cholesterol plasma levels do not necessarily reflect the efficacy and antiatherogenicity of RCT. Instead, the concentration of HDL subclasses, the mobilization of cellular lipids for efflux, and the kinetics of HDL metabolism are important determinants of RCT and the risk of atherosclerosis.

HDL and arteriosclerosis: beyond reverse cholesterol transport

The inverse correlation between serum levels of high density lipoprotein (HDL) cholesterol and the risk of coronary heart disease, the protection of susceptible animals from atherosclerosis by transgenic manipulation of HDL metabolism, and several potentially anti-atherogenic in vitro-properties have made HDL metabolism an interesting target for pharmacological intervention in atheroslcerosis. We have previously reviewed the concept of reverse cholesterol transport, which describes both the metabolism and the classic anti-atherogenic function of HDL (Arterioscler. Thromb. Vasc. Biol. 20 2001 13). We here summarize the current understanding of additional biological, potentially anti-atherogenic properties of HDL. HDL inhibits the chemotaxis of monocytes, the adhesion of leukocytes to the endothelium, endothelial dysfunction and apoptosis, LDL oxidation, complement activation, platelet activation and factor X activation but also stimulates the proliferation of endothelial cells and smooth muscle cells, the synthesis of prostacyclin and natriuretic peptide C in endothelial cells, and the activation of proteins C and S. These anti-inflammatory, anti-oxidative, anti-aggregatory, anti-coagulant, and pro-fibrinolytic activities are exerted by different components of HDL, namley apolipoproteins, enzymes, and even specific phospholipids. This complexity further emphasizes that changes in the functionality of HDL rather than changes of plasma HDL-cholesterol levels determine the anti-atherogenicity of therapeutic alterations of HDL metabolism.

Hypertriglyceridemia and elevated lipoprotein (a) are risk factors for major coronary events in middle-aged men

Cardiovascular risk factors were analyzed in 4,849 male participants, aged 40 to 65 years, in an 8-year follow-up of the Münster Heart Study (Prospective Cardiovascular Münster Study; PROCAM). One hundred eighty-one definite nonfatal myocardial infarctions, 49 fatal myocardial infarctions, and 28 sudden cardiac deaths were observed. Multiple logistic function analysis confirmed that age, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, cigarette smoking, diabetes mellitus, angina pectoris, and family history of myocardial infarction were important cardiovascular risk factors. Interestingly, this analysis revealed a significant and independent association between serum levels of triglycerides and the incidence of major coronary events. The relation between lipoprotein(a) [Lp(a)] levels and the occurrence of major coronary events was analyzed in a subgroup of 878 men. Thirty-three probands with major coronary events had significantly higher geometric mean levels of Lp(a) than 828 men who did not experience major coronary events (0.09 vs 0.05 g/L; p <0.011). Thus, in addition to established risk for factors, serum levels of triglycerides and Lp(a) are sensitive indicators of increased risk major coronary events.

Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease

Therapies that raise levels of HDL, which is thought to exert atheroprotective effects via effects on endothelium, are being examined for the treatment or prevention of coronary artery disease (CAD). However, the endothelial effects of HDL are highly heterogeneous, and the impact of HDL of patients with CAD on the activation of endothelial eNOS and eNOS-dependent pathways is unknown. Here we have demonstrated that, in contrast to HDL from healthy subjects, HDL from patients with stable CAD or an acute coronary syndrome (HDLCAD) does not have endothelial antiinflammatory effects and does not stimulate endothelial repair because it fails to induce endothelial NO production. Mechanistically, this was because HDLCAD activated endothelial lectin-like oxidized LDL receptor 1 (LOX-1), triggering endothelial PKCβII activation, which in turn inhibited eNOS-activating pathways and eNOS-dependent NO production. We then identified reduced HDL-associated paraoxonase 1 (PON1) activity as one molecular mechanism leading to the generation of HDL with endothelial PKCβII-activating properties, at least in part due to increased formation of malondialdehyde in HDL. Taken together, our data indicate that in patients with CAD, HDL gains endothelial LOX-1- and thereby PKCβII-activating properties due to reduced HDL-associated PON1 activity, and that this leads to inhibition of eNOS-activation and the subsequent loss of the endothelial antiinflammatory and endothelial repair-stimulating effects of HDL.

Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are Improved After Extended-Release Niacin Therapy

Background— High-density lipoprotein (HDL)–raising therapies are currently under intense evaluation, but the effects of HDL may be highly heterogeneous. We therefore compared the endothelial effects of HDL from healthy subjects and from patients with type 2 diabetes mellitus and low HDL (meeting the criteria for metabolic syndrome), who are frequently considered for HDL-raising therapies. Moreover, in diabetic patients, we examined the impact of extended-release (ER) niacin therapy on the endothelial effects of HDL. Methods and Results— HDL was isolated from healthy subjects (n=10) and patients with type 2 diabetes (n=33) by sequential ultracentrifugation. Effects of HDL on endothelial nitric oxide and superoxide production were characterized by electron spin resonance spectroscopy analysis. Effects of HDL on endothelium-dependent vasodilation and early endothelial progenitor cell–mediated endothelial repair were examined. Patients with diabetes were randomized to a 3-month therapy with ER niacin (1500 mg/d) or placebo, and endothelial effects of HDL were characterized. HDL from healthy subjects stimulated endothelial nitric oxide production, reduced endothelial oxidant stress, and improved endothelium-dependent vasodilation and early endothelial progenitor cell–mediated endothelial repair. In contrast, these beneficial endothelial effects of HDL were not observed in HDL from diabetic patients, which suggests markedly impaired endothelial-protective properties of HDL. ER niacin therapy improved the capacity of HDL to stimulate endothelial nitric oxide, to reduce superoxide production, and to promote endothelial progenitor cell–mediated endothelial repair. Further measurements suggested increased lipid oxidation of HDL in diabetic patients, and a reduction after ER niacin therapy. Conclusions— HDL from patients with type 2 diabetes mellitus and metabolic syndrome has substantially impaired endothelial-protective effects compared with HDL from healthy subjects. ER niacin therapy not only increases HDL plasma levels but markedly improves endothelial-protective functions of HDL in these patients, which is potentially more important. Clinical Trial Registration— clinicaltrials.gov. Identifier: NCT00346970.

Inflammatory Markers at the Site of Ruptured Plaque in Acute Myocardial Infarction Locally Increased Interleukin-6 and Serum Amyloid A but Decreased C-Reactive Protein

Background—Acute myocardial infarction (AMI) is associated with inflammation. However, it remains unclear whether it originates from the ruptured plaque or represents a systemic process. Methods and Results—In 42 patients with AMI, a balloon-based embolization protection device and aspiration catheter (PercuSurge) were used during acute coronary interventions. Samples from the site of the ruptured plaque were taken under distal balloon occlusion. Systemic samples were taken from the aorta. Sera, plaques, and thrombi were analyzed for inflammatory markers and lipoproteins. Systemic levels of C-reactive protein (CRP), interleukin-6 (IL-6), and serum amyloid A (SAA) in the aorta amounted to 3.0 mg/L, 5.0 ng/L, and 22.1 mg/L, respectively (interquartile ranges [IQRs], 1.1 to 7.4 mg/L, 5.0 to 6.5 ng/L, and 13.9 to 27.0 mg/L, respectively). In blood surrounding ruptured plaques, local levels of IL-6 (8.9 ng/L; IQR, 5.0 to 16.9 ng/L) and SAA (24.3 mg/L; IQR, 16.3 to 44.0 mg/L) were significantly higher, whereas CRP levels (2.5 mg/L; IQR, 0.9 to 7.7 mg/L) were decreased compared with the aorta (all P<0.0001). The coronary levels of IL-6 determined in vivo showed biological activity in vitro. Harvested thrombus contained CD68-positive monocytes expressing IL-6 and showed extracellularly and intracellularly positive staining for SAA, whereas CRP was found exclusively in the cytoplasm of phagocyting white blood cells. Conclusions—Coronary levels of IL-6 and SAA at the site of plaque rupture were increased relative to the systemic circulation, indicating local production of biologically active inflammatory mediators. In contrast, CRP was locally decreased, at least in part by uptake by the phagocyting cells, suggesting a systemic origin of the protein.

Multimodal perioperative management--combining thoracic epidural analgesia, forced mobilization, and oral nutrition--reduces hormonal and metabolic stress and improves convalescence after major urologic surgery.

We sought in this prospective study to use a multimodal approach to reduce stress and improve recovery in patients undergoing major surgery. During an initial study period, 30 patients were randomly allocated to receive general anesthesia (GA; Group 1) or a combination of GA and intraoperative thoracic epidural analgesia (TEA; Group 2) when undergoing radical cystectomy. Parenteral nutrition was provided for 5 days after surgery. During the second period, 15 patients were treated with a multimodal approach (Group 3) consisting of intraoperative GA and TEA, postoperative patient-controlled TEA, early oral nutrition, and enforced mobilization. Data for plasma and urine catecholamines, plasma cortisol, the nitrogen balance, the postoperative inflammatory nutrition index, pain relief, fatigue, sleep, overnight recovery, recovery of bowel function, and mobilization were recorded up to the fifth postoperative day. Plasma concentrations of catecholamines and cortisol were comparable in all patients, but those in Group 3 had lower levels of urinary catecholamine excretion. Protein intake was more effective with parenteral nutrition. Nitrogen balances were less negative, and the postoperative inflammatory nutrition index score increased significantly in the traditional groups but not in Group 3. Multimodally treated patients reported less fatigue and better overnight recovery. Along with improved pain relief, recovery of bowel function, and ambulation, there were no differences in the postoperative complication rates among the three groups. The multimodal approach reduced stress and improved metabolism and recovery after radical cystectomy.

Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk.

OBJECTIVES This prospective population study was conducted to assess the role of elevated lipoprotein(a) [Lp(a)] as a coronary risk factor. BACKGROUND The role of elevated Lp(a) as a risk factor for coronary heart disease is controversial. In addition, little attention has been paid to the interaction of Lp(a) with other risk factors. METHODS A total of 788 male participants of the Prospective Cardiovascular Münster (PROCAM) study aged 35 to 65 years were followed for 10 years. Both Lp(a) and traditional cardiovascular risk factors (e.g., age, low density lipoprotein [LDL] cholesterol, high density lipoprotein [HDL] cholesterol, triglycerides, systolic blood pressure, cigarette smoking, diabetes mellitus, angina pectoris, and family history of myocardial infarction) were evaluated in 44 men who suffered from myocardial infarction, and in 744 men who survived without major coronary events or stroke. A multiple logistic function algorithm was used to estimate global cardiovascular risk by the combined effects of traditional risk factors. RESULTS Overall, the risk of a coronary event in men with an Lp(a) > or =0.2 g/liter was 2.7 times that of men with lower levels (95% confidence interval [CI]: 1.4 to 5.2). This increase in risk was most prominent in men with LDL cholesterol level > or =4.1 mmol/liter (relative risk [RR]: 2.6; 95% CI: 1.2 to 5.7), with HDL cholesterol < or =0.9 mmol/liter (RR 8.3; 95% CI: 2.0 to 35.5), with hypertension (RR 3.2; 95% CI: 1.4 to 7.2), or within the two highest global risk quintiles (relative risk: 2.7; 95% CI: 1.3 to 5.7). CONCLUSIONS Lp(a) increases the coronary risk, especially in men with high LDL cholesterol, low HDL cholesterol, hypertension and/or high global cardiovascular risk.

Altered Activation of Endothelial Anti- and Proapoptotic Pathways by High-Density Lipoprotein from Patients with Coronary Artery Disease Role of High-Density Lipoprotein–Proteome Remodeling

Background— Endothelial dysfunction and injury are thought to play an important role in the progression of coronary artery disease (CAD). High-density lipoprotein from healthy subjects (HDLHealthy) has been proposed to exert endothelial antiapoptotic effects that may represent an important antiatherogenic property of the lipoprotein. The present study therefore aimed to compare effects of HDLCAD and HDLHealthy on the activation of endothelial anti- and proapoptotic pathways and to determine which changes of the lipoprotein are relevant for these processes. Methods and Results— HDL was isolated from patients with stable CAD (HDLsCAD), an acute coronary syndrome (HDLACS), and healthy subjects. HDLHealthy induced expression of the endothelial antiapoptotic Bcl-2 protein Bcl-xL and reduced endothelial cell apoptosis in vitro and in apolipoprotein E–deficient mice in vivo. In contrast, HDLsCAD and HDLACS did not inhibit endothelial apoptosis, failed to activate endothelial Bcl-xL, and stimulated endothelial proapoptotic pathways, in particular, p38-mitogen-activated protein kinase–mediated activation of the proapoptotic Bcl-2 protein tBid. Endothelial antiapoptotic effects of HDLHealthy were observed after inhibition of endothelial nitric oxide synthase and after delipidation, but not completely mimicked by apolipoprotein A-I or reconstituted HDL, suggesting an important role of the HDL proteome. HDL proteomics analyses and subsequent validations and functional characterizations suggested a reduced clusterin and increased apolipoprotein C-III content of HDLsCAD and HDLACS as mechanisms leading to altered effects on endothelial apoptosis. Conclusions— The present study demonstrates for the first time that HDLCAD does not activate endothelial antiapoptotic pathways, but rather stimulates potential endothelial proapoptotic pathways. HDL-proteome remodeling plays an important role for these altered functional properties of HDL. These findings provide novel insights into mechanisms leading to altered vascular effects of HDL in coronary disease.