[Congenital disorders of lipoprotein metabolism]. / Angeborene Störungen im Lipoproteinstoffwechsel.

Congenital disorders of lipid metabolism are caused by a wide range of variants of the genes for receptors, apolipoproteins, enzymes, transfer factors, and cellular cholesterol transporters. Clinically most relevant are autosomal dominant familial hypercholesterolemia (FH) and familial combined hyperlipoproteinemia (FCHL). FH has a prevalence of 1:250. It is due to mutations of the low density lipoprotein (LDL) receptor, less often to mutations of the apolipoprotein B (APOB), the proprotein convertase subtilisin/kexin type 9 (PCSK9), or the signal transducing adapter family member 1 (STAP1). FH often leads to early atherosclerosis. Its diagnosis can definitely be made only by molecular genetic testing. The detection of mutations of the LDLR, APOB, or PCSK9 is an indicator for extremely high cardiovascular risk, independently of the concentration of LDL cholesterol. FCHL is also common (1:100) and is seen in about 10% of patients with early myocardial infarction. It is produced by combinations of frequent genetic variants affecting triglycerides and LDL cholesterol. Other monogenic hyperlipoproteinemias (HLP) affect the catabolism of chylomicrons (familial chylomicronemia) or of remnants of triglyceride-rich lipoproteins (type III hyperlipoproteinemia). Multiple hereditary disorders in HDL metabolism - with a broad spectrum of clinical significance - are known. Currently, second generation sequencing methods are used to simultaneously analyze multiple disease-causing genes. This approach cost-neutrally provides additional information such as the genetic risk of atherosclerosis and predisposition to statin intolerance.

Independent associations of vitamin D metabolites with anemia in patients referred to coronary angiography: the LURIC study.

PURPOSE: Anemia and vitamin D deficiency are both frequent in adult patients. Whether low vitamin D metabolite levels are an independent risk factor for different subtypes of anemia remains to be studied in detail. METHODS: In 3299 patients referred for coronary angiography, we investigated the association of 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D [1,25(OH)2D] with anemia [hemoglobin (Hb) <12.5 g/dl] of specific subtypes. RESULTS: Compared with patients with 25OHD levels in the adequate range (50-125 nmol/l), patients with deficient 25OHD concentrations (<30 nmol/l; 33.6 % of patients) had 0.6 g/dl lower Hb levels. Hb values were 1.3 g/dl lower in patients with 1,25(OH)2D levels <40 pmol/l (5.4 % of patients), compared with patients in the highest 1,25(OH)2D category (>70 pmol/l). Of the participants, 16.7 % met the criteria for anemia. In multivariate-adjusted regression analyses, the odds ratios for anemia in the lowest 25OHD and 1,25(OH)2D categories were 1.52 (95 % CI 1.15-2.02) and 3.59 (95 % CI 2.33-5.52), compared with patients with 25OHD levels in the adequate range and patients with 1,25(OH)2D levels >70 pmol/l. The probability of anemia was highest in patients with combined 25OHD and 1,25(OH)2D deficiency [multivariable-adjusted odds ratio 5.11 (95 % CI 2.66-9.81)]. Patients with anemia of chronic kidney disease had the highest prevalence of 25OHD deficiency and 1,25(OH)2D concentrations of <40 pmol/l. CONCLUSIONS: Low 25OHD and 1,25(OH)2D concentrations are independently associated with anemia. Patients with poor kidney function are most affected. Interventional trials are warranted to prove whether administration of plain or activated vitamin D can prevent anemia.

[Clinical importance of HDL cholesterol]. / Klinische Bedeutung des HDL-Cholesterins.

BACKROUND: Each year 16-17 million determinations of high-density lipoprotein cholesterol (HDL-C) are conducted and interpreted in Germany. Recently acquired data have led to a fundamental reassessment of the clinical significance of HDL-C. METHOD: This review article is based on a selective literature search. RESULTS: Low HDL­C levels usually indicate an increased cardiovascular risk, particularly in primary prevention but the epidemiological relationship between HDL­C and the risk is complex. The HDL plays a role in the back transport and excretion of cholesterol; however, the biological functions of HDL are dependent on the protein and lipid composition, which is not reflected by the HDL­C concentration. If the composition of HDL is pathologically altered it can also exert negative vascular effects. CONCLUSION: Compared with low-density lipoprotein cholesterol (LDL-C), HDL­C is of secondary importance for cardiovascular risk stratification and the calculation of the LDL-C:HDL­C ratio is not useful for all patients. Low HDL­C levels should prompt a search for additional metabolic and inflammatory pathologies. An increase in HDL­C through lifestyle changes (e.g. smoking cessation and physical exercise) has positive effects and is recommended; however, HDL­C is currently not a valid target for drug therapy.

Saturated fatty acids are not off the hook.

A recent meta-analysis by Chowdhury et al. (2014) has disclaimed the association between coronary artery diseases and either circulating blood levels or the intake of total saturated fatty acids (SFA). Scrutiny revealed that two of the eight studies included in the meta-analysis focused on the proportion of pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) and their impact on cardiovascular disease (CVD) risk. These odd-chain fatty acids are markers for milk or ruminant fat intake. Both studies indicated inverse associations between milk-fat intake and first-ever myocardial infarction. Neither of the two studies described the association between total circulating blood SFA on coronary outcomes. In contrast to the cardioprotective effects of dairy consumption, we expected that an elevated intake of palmitic acid (C16:0) and stearic acid (C18:0) de novo may raise CVD risk. Thus, it is of particular importance to differentiate the effects of individual circulating SFA on cardiovascular outcomes. Excluding the studies that evaluated the association of fatty acids from milk fat and cardiovascular outcomes revealed a positive association of total SFA blood levels and coronary outcome (RR 1.21, CI 1.04-1.40). Therefore, results obtained from studies of C15:0 and C17:0 cannot be mixed with results from studies of other SFA because of the opposite physiological effects of regular consumption of foods rich in C16:0 and C18:0 compared to high intake of milk or ruminant fat. In our opinion, it is vital to analyze the impact of individual SFA on CVD incidence in order to draw prudent conclusions.

Alterations in the coagulation system of active smokers from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

Smoking is an important and preventable risk factor of cardiovascular diseases with effects on blood coagulation. Our aim was to analyze the influence of smoking on coagulation parameters. Concentrations or activities of blood coagulation factors were compared in 777 active smokers and 1,178 lifetime non-smokers of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. The association with mortality was examined using Cox regression. The findings show that AS had a tendency toward thrombosis. They displayed significantly higher values for fibrinogen, soluble fibrinogen, factor XIII, and tissue factor pathway inhibitor; whereas FVII, FVIII, FXII, von Willebrand factor (vWF), and thrombomodulin were decreased. The Cox regression analysis showed fibrinogen, FVIII, vWF, thrombomodulin, and tissue factor pathway inhibitor to be independent risk factors for mortality in active smokers with hazard ratios of 1.16 (95% CI: 1.02-1.31), 1.40 (1.22-1.59), 1.37 (1.22-1.56), 1.19 (1.07-1.31), and 1.22 (1.06-1.40) per increase of one standard deviation. We conclude that active smokers have an increased thrombogenic potential associated with significant changes in the coagulation system. Individual parameters of the coagulation system are independent predictors of mortality. Therefore, parameters of the coagulation system, apart from other risk factors for cardiovascular disease (e.g., lipids or life-style) should be determined for risk prediction in active smokers.

C-reactive protein and lipoprotein-associated phospholipase A2 in smokers and nonsmokers of the Ludwigshafen Risk and Cardiovascular Health study.

Measurement of high sensitivity CRP (hsCRP) and lipoprotein-associated phospholipase A2 (LpPLA2) provides information on systemic inflammation and stability of atherosclerotic plaques. Data analyzing the effect of smoking on these parameters are sparse. The aim of our study was the analysis of these parameters in active smokers and never-smokers. The study included 777 smokers and 1,178 never-smokers, of whom 221 and 302 died during a follow-up, respectively. The values of LpPLA2 and hsCRP were significantly higher in smokers than in never-smokers. Mortality was highest in smokers and never-smokers with elevation of both biomarkers. Multivariate adjusted hazard ratios for patients in the highest tertile of both hsCRP and LpPLA2 compared with patients in the lowest tertile of both markers were 1.85 (1.04-3.28) in never-smokers and 1.94 (1.10-3.45) in smokers. Our data confirmed the predictive value of hsCRP and LpPLA2. However, there were a relevant number of patients with an increase of only one of these parameters. Therefore, beside other risk factors for cardiovascular disease, both parameters should be determined at least in high risk patients.

Evolving biomarkers improve prediction of long-term mortality in patients with stable coronary artery disease: the BIO-VILCAD score.

OBJECTIVE: Algorithms to predict the future long-term risk of patients with stable coronary artery disease (CAD) are rare. The VIenna and Ludwigshafen CAD (VILCAD) risk score was one of the first scores specifically tailored for this clinically important patient population. The aim of this study was to refine risk prediction in stable CAD creating a new prediction model encompassing various pathophysiological pathways. Therefore, we assessed the predictive power of 135 novel biomarkers for long-term mortality in patients with stable CAD. DESIGN, SETTING AND SUBJECTS: We included 1275 patients with stable CAD from the LUdwigshafen RIsk and Cardiovascular health study with a median follow-up of 9.8 years to investigate whether the predictive power of the VILCAD score could be improved by the addition of novel biomarkers. Additional biomarkers were selected in a bootstrapping procedure based on Cox regression to determine the most informative predictors of mortality. RESULTS: The final multivariable model encompassed nine clinical and biochemical markers: age, sex, left ventricular ejection fraction (LVEF), heart rate, N-terminal pro-brain natriuretic peptide, cystatin C, renin, 25OH-vitamin D3 and haemoglobin A1c. The extended VILCAD biomarker score achieved a significantly improved C-statistic (0.78 vs. 0.73; P = 0.035) and net reclassification index (14.9%; P < 0.001) compared to the original VILCAD score. Omitting LVEF, which might not be readily measureable in clinical practice, slightly reduced the accuracy of the new BIO-VILCAD score but still significantly improved risk classification (net reclassification improvement 12.5%; P < 0.001). CONCLUSION: The VILCAD biomarker score based on routine parameters complemented by novel biomarkers outperforms previous risk algorithms and allows more accurate classification of patients with stable CAD, enabling physicians to choose more personalized treatment regimens for their patients.

Copper, ceruloplasmin, and long-term cardiovascular and total mortality (the Ludwigshafen Risk and Cardiovascular Health Study).

BACKGROUND: Copper and its main transport protein ceruloplasmin have been suggested to promote the development of atherosclerosis. Most of the data come from experimental and animal model studies. Copper and mortality have not been simultaneously evaluated in patients undergoing coronary angiography. METHODS AND RESULTS: We examined whether serum copper and ceruloplasmin concentrations are associated with angiographic coronary artery disease (CAD) and mortality from all causes and cardiovascular causes in 3253 participants of the Ludwigshafen Risk and Cardiovascular Health Study. Age and sex-adjusted hazard ratios (HR) for death from any cause were 2.23 (95% CI, 1.85-2.68) for copper and 2.63 (95% CI, 2.17-3.20) for ceruloplasmin when we compared the highest with the lowest quartiles. Corresponding hazard ratios (HR) for death from cardiovascular causes were 2.58 (95% CI, 2.05-3.25) and 3.02 (95% CI, 2.36-3.86), respectively. Further adjustments for various risk factors and clinical variables considerably attenuated these associations, which, however, were still statistically significant and the results remained consistent across subgroups. CONCLUSIONS: The elevated concentrations of both copper and ceruloplasmin are independently associated with increased risk of mortality from all causes and from cardiovascular causes.

[High-density lipoprotein (HDL) and cholesteryl ester transfer protein (CETP): role in lipid metabolism and clinical meaning]. / High-density-Lipoproteine und Cholesterinester-Transferprotein: Rolle im Lipidstoffwechsel und klinische Bedeutung.

Large epidemiological studies have consistently shown that plasma levels of high-density lipoprotein (HDL) correlate inversely with cardiovascular risk. The apparent cardioprotective role of HDL has primarily been attributed to its participation in reverse cholesterol transport (RCT) but there is also substantial evidence that supports the concept of HDL and apoA-I preventing oxidative damage, inhibiting systemic inflammation, promoting vascular integrity and preventing thrombosis. Besides conventional therapy to increase HDL like physical exercise, weight loss and dietary changes new strategies to intervene at various steps of its metabolism have been proposed and are in development. One of the most promising approaches is inhibiting cholesteryl ester transfer protein (CETP)which plays a central role in RCT by transferring cholesteryl esters from HDL to apoB containing lipoproteins in exchange for triglycerides. The failure of the CETP inhibitor torcetrapib, however, to cause any benefit on cardiovascular outcomes despite significantly increased HDL levels in several clinical trials casted doubts upon the concept of CETP inhibition. Meanwhile, off target toxicity could be shown for torcetrapib and a new generation of CETP inhibitors stands ready to be tested in large clinical trials. This article describes the formation and remodeling of HDL, how HDL is thought to be beneficial for the vasculature and what options we have today to increase HDL levels with a special focus on CETP inhibition.