[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.

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.

Smoking denial in cardiovascular disease studies.

Assessment of self-reported smoking behavior in cardiovascular studies may lead to inaccurate measures of nicotine exposure. A more objective measurement of nicotine exposure can be done by measurement of plasma cotinine levels. The aim of the present study was to define the rate of discordance between the self-reported smoking behavior and biochemically defined smoking status. Data from 3,316 patients hospitalized for coronary angiography, who completed a questionnaire on smoking behavior, were analyzed. As a biochemical assessment of smoking status we used a cut-off serum cotinine level of 15 µg/l. Smoking denial, defined as a discrepancy between high cotinine levels and self-reported never- or ex-smoking status, was observed in 3.7 % of the study participants. In a logistic regression analysis with a step-wise inclusion of sex, age, CAD, previous MI, and educational level, only male sex (odds ratio male/female: 2.00, 95 % CI 1.22-3.33; p = 0.007) and age (odds ratio per year: 0.79, 95 % confidence interval 0.66-0.94, p = 0.008) were associated with smoking denial. In conclusion, a misclassification rate of 3.7 % in the evaluation of such an important risk factor may lead to blurred effects and favor false negative results. The results of the present study substantiate the importance of biochemical markers for smoking assessment in cardiovascular studies.

The fatty liver index is associated with increased mortality in subjects referred to coronary angiography.

BACKGROUND AND AIMS: Fatty liver index (FLI), a surrogate parameter for nonalcoholic fatty liver disease, is an emerging risk factor for cardiovascular diseases and mortality. We aimed to evaluate whether FLI is associated with all-cause, cardiovascular, and non-cardiovascular mortality as well as fatal cancer in a cohort of subjects routinely referred to coronary angiography. METHODS AND RESULTS: FLI was calculated using BMI (body mass index), waist circumference (WC), triglycerides (TG) and gamma-glutamyl transferase (GGT) in 3270 subjects who were referred to coronary angiography (1997-2000). The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes, cardiovascular causes, non-cardiovascular causes, and fatal cancer. After a median follow-up time of 7.7 years, 740 subjects (22.6%) had died. There were 437 deaths due to cardiovascular disease and 303 deaths due to non-cardiovascular disease. Age-, sex-, and BMI-adjusted HRs (with 95% confidence intervals) for all-cause, cardiovascular, and non-cardiovascular mortality in the highest compared to the lowest FLI quartile were 2.56 (1.90-3.43; p < 0.001), 2.17 (1.47-3.22; p < 0.001), and 3.49 (2.16-5.66; p < 0.001), respectively. In age-, sex-, and BMI-adjusted analyzes, we found no significant association of FLI with fatal cancer. Multivariate adjusted HRs for all-cause, cardiovascular, non-cardiovascular mortality, and fatal cancer in the highest compared to the lowest FLI quartile were 2.17 (1.58-2.99; p < 0.001), 1.64 (1.07-2.51; p = 0.023), 3.72 (2.22-6.24; p < 0.001), and 2.33 (1.01-5.41; p = 0.048) respectively. CONCLUSION: In subjects referred to coronary angiography, high FLI levels are independently associated with increased all-cause, cardiovascular, and non-cardiovascular mortality as well as fatal cancer.

Association of bone turnover markers with mortality in men referred to coronary angiography.

UNLABELLED: We aimed to examine the association of fatal events with osteocalcin (OC) and beta-crosslaps (ß-CTX) levels in men. We observed a U-shaped association of OC and ß-CTX levels with fatal events in a large cohort of men at high cardiovascular risk. INTRODUCTION: Accumulating evidence suggests an association of low OC levels with metabolic disturbances. Whether OC levels are related to fatal events is, however, less clear. Further, high ß-CTX levels are linked to increased mortality. We aimed to examine the association of fatal events with both OC and ß-CTX in men. METHODS: We measured OC and ß-CTX in 2,271 men referred to coronary angiography (1997-2000). RESULTS: We observed a U-shaped association of OC and ß-CTX with fatal events. Crude hazard ratios (HRs) for all-cause and non-cardiovascular mortality in the highest OC quintile were 1.38 (1.04-1.83) and 1.47 (0.89-2.40), respectively, and 2.11 (1.61-2.75) and 2.06 (1.29-3.29) for men in the lowest compared to the third OC quintile. In multivariate-adjusted models, HRs for all-cause, and non-cardiovascular mortality in the lowest OC quintile were 1.63 (1.23-2.16) and 1.79 (1.10-2.92), respectively, compared to the third OC quintile, whereas the association of high OC with mortality lost its significance. Crude and multivariate-adjusted HRs for cardiovascular mortality in the lowest OC quintile compared to the third OC quintile were 2.08 (1.49-2.90) and 1.74 (1.24-2.46), respectively. Moreover, high as well as low ß-CTX levels were independently associated with all-cause (quintile 1 vs. quintile 3: HR 1.42 (1.05-1.92); quintile 5 vs. quintile 3: HR 1.79 (1.31-2.45)) and cardiovascular mortality (quintile 1 vs. quintile 3: HR 1.55 (1.05-2.28); quintile 5 vs. quintile 3: HR 1.85 (1.23-2.77)). CONCLUSIONS: We observed a U-shaped association of OC and ß-CTX with fatal events in a large cohort of men at high cardiovascular risk.

Uric acid is predictive of cardiovascular mortality and sudden cardiac death in subjects referred for coronary angiography.

BACKGROUND AND AIMS: High serum uric acid (SUA) is suggested to be causally involved in the pathogenesis of vascular disease. The present study aimed to investigate whether SUA independently predicts all-cause mortality, cardiovascular mortality and sudden cardiac death in subjects scheduled for coronary angiography. METHODS AND RESULTS: We studied participants of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. A total of 3245 individuals were included in the analysis. There was a follow-up for all-cause mortality, cardiovascular mortality, and sudden cardiac death with a mean (±standard deviation) duration of 7.3 (±2.3) years. Sex-specific quartiles of SUA were established and multivariate statistical models were used. A total of 730 deaths occurred during the follow-up. Among these, 473 (64.8%) were accounted for by cardiovascular diseases. Sudden cardiac death occurred in 184 (25.2%) cases. Adjusting for sex and age subjects in the fourth SUA quartile had increased all-cause (hazard ratio (HR) = 1.68, p < 0.001) and cardiovascular (HR = 2.00, p < 0.001) mortality compared to individuals in the first quartile. Furthermore, high SUA was a risk factor for sudden cardiac death (HR = 2.27, p < 0.001). These associations remained significant including cardiovascular risk factors and the severity of coronary atherosclerosis as covariates in the models. After additional adjustment for medication use statistical significance for the association between the SUA quartiles and all-cause mortality disappeared. CONCLUSION: High SUA independently indicates increased risk for cardiovascular and sudden cardiac death in subjects referred for coronary angiography.

High estradiol levels are associated with increased mortality in older men referred to coronary angiography.

There is evidence showing an important role of estrogens in men's health. We aimed to evaluate whether estradiol levels are associated with overall mortality and specific fatal events.We measured estradiol levels in 2,078 men who were routinely referred for coronary angiography (1997-2000).The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes, from cardiovascular and non-cardiovascular causes including cancer according to estradiol levels.Multivariable HRs (with 95% confidence intervals) for all-cause, non-cardiovascular, and cancer mortality were 1.43 (1.08-1.91), 2.11 (1.34-3.34), and 2.27 (1.00-5.19), respectively, in the fourth estradiol quartile as compared to the first. There was no significant association of estradiol levels with cardiovascular mortality. In multivariate adjusted analyses, higher estradiol levels in men were significantly associated with prevalent strokes, peripheral vascular disease, and carotid artery stenosis compared to lower estradiol levels.High levels of estradiol are associated with all-cause and non-cardiovascular mortality in a large cohort of older men referred to coronary angiography. Further studies are warranted to confirm our results and to elucidate the underlying mechanisms.

Sex steroids and mortality in men referred for coronary angiography.

OBJECTIVE: Accumulating evidence suggests that sex steroids are associated with various chronic diseases. We aimed at evaluating whether total testosterone (TT), free testosterone (FT) and sex hormone-binding globulin (SHBG) are associated with all-cause mortality and specific fatal events. DESIGN, SETTING AND PARTICIPANTS: We measured TT and SHBG levels in 2078 men who were routinely referred for coronary angiography (1997-2000). FT was calculated according to Vermeulen. MEASUREMENTS: The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes, from cardiovascular and non-cardiovascular causes and from cancer according to SHBG, FT and TT. RESULTS: Multivariable-adjusted HRs (with 95% confidence intervals) in the fourth compared to the first SHBG quartile for all-cause, non-cardiovascular and cancer mortality were 1·61 (1·16-2·23), 2·44 (1·39-4·28), and 2·86 (1·03-7·32), respectively. There was no significant association of SHBG levels with cardiovascular mortality. All-cause mortality was significantly reduced per 1 SD increase in FT in the multivariate-adjusted analyses [0·49 (0·30-0·81)]. We observed no significant associations of FT with cardiovascular and cancer mortality, and TT levels were not independently related to any fatal events. CONCLUSION: High levels of SHBG are associated with adverse health outcomes in a large cohort of older men referred for coronary angiography. Further studies are warranted to confirm our results and to elucidate the underlying mechanisms for our findings.

[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.

Effect of HMG CoA reductase inhibitors on low-density lipoprotein cholesterol and C-reactive protein: systematic review and meta-analysis.

OBJECTIVE: HMG CoA reductase inhibitors (statins) have been claimed to decrease C-reactive protein (CRP), independent of their effect on low-density lipoprotein cholesterol (LDL-C). We conducted a systematic review and meta-analysis to investigate whether a relationship between the average effect of statins on LDL-C and CRP exists. DATA SOURCES: The literature search of the Medline and Cochrane databases between 1980 and August 2007 yielded 65 statin intervention studies with 94 treatment arms involving 16,260 patients reporting changes in both LDL-C and CRP. DATA EXTRACTION AND STATISTICAL METHOD: From each study relative changes in LDL-C and CRP were extracted. Random effects meta-analysis was used to obtain pooled summary estimates of the average study specific LDL-C and CRP reductions, in total and stratified by dose and type of statin. Weighted correlation analysis and metaregression analysis was used to investigate the relationship between the LDL-C and CRP changes adjusted for baseline values, type of statin and dose. RESULTS: Pooled summary estimates of statin-induced changes in LDL-C and CRP levels were -34.7% (95% CI: -37.7% to -31.8%) and -30.8% (95% CI: -39.4% to -22.3%), respectively. We found a positive correlation between the average LDL-C and CRP reduction (r = 0.49, p = 0.010) which increased when adjusting for pre-treatment concentrations (r = 0.79, p < 0.001). The effect of statins on CRP were strongly related to the changes in LDL-C and baseline concentrations, independent of the type and dose of statin used. CONCLUSION: Our meta-analysis shows a strong correlation between statin-induced reductions in LDL-C and CRP, which has not been evident from individual studies. Measuring CRP in addition to LDL-C in the monitoring of statin treatment is currently not warranted.

[Lowering LDL cholesterol. How much is enough?]. / Senkung des LDL-Cholesterins. Wie viel ist gut genug?

Reducing cholesterol and LDL cholesterol (LDL-C) is one of the few clearly demonstrated principles in the prevention and treatment of arteriosclerosis. LDL-C reduction over a number of years to ca. 70 mg/dl can reduce the risk of coronary events by about two thirds. Lipid lowering pharmacotherapy is the more effective the higher the individual risk of the patient is. The therapeutic decision is based on the total risk of the patient. For coronary patients after acute coronary syndrome and/or with diabetes mellitus, a reduction of LDL-C to 70 mg/dl is justified. For patients with "stable" coronary heart disease, a LDL-C level of 100 mg/dl or less should be strived for. Whether diabetes mellitus always indicates a "coronary risk equivalent" and thus justifies a reduction in LDL-C to 100 ml/dl or less, is questionable.