Dynamic changes in N-terminal pro-brain natriuretic peptide in acute coronary syndromes treated with percutaneous coronary intervention: a marker of ischemic burden, reperfusion and outcome.

BACKGROUND: Whereas N-terminal pro-brain natriuretic peptide (NT-proBNP) is approved for risk stratification of patients with acute coronary syndromes (ACS), short-term temporal changes in NT-proBNP concentrations and the optimal time points for sampling are not clear. The purpose of this study was to better define the short-term changes in NT-proBNP in relation to clinical presentation, reperfusion and prognostic value in patients with ACS, as well as to identify the optimum time points for sampling. METHODS: We studied daily plasma concentrations of NT-proBNP in 133 unselected patients with myocardial infarction (n=65), stable coronary artery disease (CAD, n=46) and no CAD (n=22) who underwent coronary angiography. RESULTS: Patients with non-ST-elevation myocardial infarction (NSTEMI) presented with markedly higher NT-proBNP than patients with ST-elevation myocardial infarction (STEMI) [1305 (741-3208) ng/L vs. 170 (70-424) ng/L, p<0.001]. Also, time to presentation from onset of pain was much longer in NSTEMI as compared to STEMI (>48 h vs. <6 h, p<0.001). Patients with NSTEMI also presented with higher NT-proBNP as compared with CAD [224 (98-732) ng/L] and no CAD [47 (26-102) ng/L; p<0.001, NSTEMI vs. both]. Following successful percutaneous coronary intervention [thrombolysis in myocardial infarction (TIMI) 3-flow established], NT-proBNP increased markedly within 24 h in patients with STEMI [718 (379-1338) ng/L, p<0.01 vs. 0 h], whereas no change in NT-proBNP was noted in patients with NSTEMI [1190 (1010-2024) ng/L, p=0.88 vs. 0 h]. In both STEMI and NSTEMI, NT-proBNP decreased significantly 96 h after successful reperfusion [STEMI -52%, 372 (189-610) ng/L, p<0.05; NSTEMI -52%, 613 (365-724) ng/L, p<0.05]. Unsuccessful reperfusion (TIMI<3) was associated with unchanged or increased NT-proBNP. NT-proBNP at 96 h and peak NT-proBNP further displayed a strong correlation with cardiac troponin T (r=0.64 and r=0.54, p<0.001), a marker of infarct size, and NT-proBNP at 96 h was a strong predictor of long-term prognosis (hazard ratio 7.29, p=0.025). CONCLUSIONS: In patients with NSTEMI, NT-proBNP may be increased as high as concentrations usually associated with acute congestive heart failure despite the absence of clinical signs. In contrast, patients with STEMI and short time to presentation may present with completely normal NT-proBNP, but dramatic short-term increases following reperfusion. NT-proBNP reflects ischemic burden, reperfusion success and prognosis, and the current data support repetitive sampling in patients with ACS.

Improvement of the cardiac marker N-terminal-pro brain natriuretic peptide through adjustment for renal function: a stratified multicenter trial.

BACKGROUND: N-terminal-pro brain natriuretic peptide (NT-proBNP) is a useful cardiac marker that is also influenced by renal dysfunction. It was our objective to assess the relationship between NT-proBNP concentrations in plasma and worsening renal function, and to attempt adjustment of NT-proBNP for renal dysfunction in a prospective, stratified multi-center study. METHODS: We stratified 203 male patients according to their cardiac status and the estimated glomerular filtration rate (eGFR). Cardiac disease was assessed by medical history, physical examination and standardized echocardiography. Patients were stratified according to the following: absence of cardiac history and abnormalities (control, CTRL, n=66), cardiac history without left ventricular hypertrophy (LVH) or left ventricular systolic dysfunction (LVD) (history, n=30), LVH without systolic dysfunction (LVH, n=68), and LVD [ejection fraction (EF) <40%, LVD, n=39]. Renal disease was stratified according to the eGFR: 15-30 mL/min (n=52), 31-75 mL/min (n=99), and >75 mL/min (n=52). RESULTS: NT-proBNP was correlated with eGFR in the entire study population and for all levels of cardiac disease (all p<0.01). Regression analysis allowed adjustment of NT-proBNP for eGFR in a continuous manner, and this adjustment significantly improved the predictive value (receiver operating characteristic curve for symptomatic LVD from 0.80 to 0.86, p<0.01; sensitivity from 74% to 83% and specificity from 68% to 79%). CONCLUSIONS: NT-proBNP correlates inversely and significantly with eGFR throughout all levels of cardiac strata. We propose for the first time a continuous adjustment algorithm which markedly improves the predictive values of NT-proBNP in male patients with impaired renal function.

No association of two functional polymorphisms in human ALOX15 with myocardial infarction.

The 12/15-lipoxygenase plays a janus-role in inflammation with pro-inflammatory and anti-inflammatory effects in cell systems and even opposite effects on atherosclerosis in two different animal species. Screening of the human 15-lipoxygenase (ALOX15) gene detected a polymorphic C to T substitution at position c.-292, which led to three times higher ALOX15 activity in macrophages and showed a trend to be atheroprotective in a small case-control study for coronary artery disease (CAD). A second polymorphism at position c.1693C>T leading to an T560M exchange and an inactive enzyme was recently associated with increased CAD. We now investigated whether these polymorphisms or a certain haplotype of ALOX15 are associated with myocardial infarction (MI) in a case-control subset from the population-based MONIKA/KORA cohort S3. Six polymorphisms in ALOX15 were analyzed in 2629 participants to cover all major haplotypes with a frequency higher than 1% in the Caucasian population. None of the polymorphism was associated with MI but a rare ALOX15 haplotype showed a significant protective effect on the risk for MI (p=0.03). However, none of the polymorphisms or haplotypes was associated with CRP levels. These data suggest that ALOX15 may play a less prominent role during later stages of atherosclerosis involving atherothrombotic mechanisms than eventually during early plaque development.

Head-to-head comparison of BNP and IL-6 as markers of clinical and experimental heart failure: Superiority of BNP.

Activation of BNP and IL-6 are hallmarks of left ventricular (LV) dysfunction and congestive heart failure (CHF). To assess the relative activation of BNP and IL-6 in clinical and experimental heart failure, we performed a human study in which plasma N-terminal proBNP (NT-proBNP) and IL-6 were measured in a large group of patients in the chronic phase after myocardial infarction (MI) and an animal study in which LV gene expression of BNP and IL-6 was assessed in rapid ventricular pacing-induced heart failure. In the human study, NT-proBNP and IL-6 were measured by non-extracted, enzyme-linked immunoassay in 845 subjects (n=468 outpatients after MI, MONICA MI register Augsburg; and 377 siblings without MI, control). NT-proBNP (295+/-23pg/mL vs. CTRL 84+/-8, P<0.05) and IL-6 (2.7+/-0.1pg/mL vs. CTRL 2.1+/-0.1, P<0.05) were both elevated in subjects with MI. These increases were particularly pronounced in the presence of concomitant CHF (both P<0.01 vs. CTRL) and LV dysfunction (EF<45%, both P<0.05 vs. CTRL). However, NT-proBNP was significantly correlated with several cardiac structural and functional parameters (EF, LVMI, history of MI, CHF symptoms; all P<0.05) upon regression analysis whereas IL-6 was only correlated with history of MI (P<0.001). Accordingly, MI subjects with symptomatic LV dysfunction were detected by NT-proBNP with a greater sensitivity, specificity, and ROC-area (85%, 88%, and 0.87, respectively) as compared to IL-6 (69%, 53%, and 0.67, respectively). In the animal study, IL-6 and BNP expression were both significantly elevated in CHF (both P<0.05) but with a much greater absolute activation of BNP. In addition, BNP mRNA expression displayed a stronger inverse correlation with LV function (r=-0.74; P<0.001) than IL-6 (r=-0.53; P=0.001) and was a markedly more sensitive and specific molecular marker of LV dysfunction (sensitivity 91%, specificity 100%, ROC-area 0.94) than IL-6 (sensitivity 74%, specificity 83%, ROC-area 0.87). Our animal study provides evidence that IL-6 expression is activated in heart failure but to a significantly lesser degree than that of BNP. Both the stronger expression of BNP and the better correlation with LV function provide the molecular basis for a diagnostic superiority of NT-proBNP in clinical LV dysfunction and heart failure.

Association between arterial pressure and coronary artery calcification.

OBJECTIVES: Coronary artery calcification (CAC) determined by electron beam computed tomography is a predictor of future cardiovascular events. This study investigates conditions affecting CAC severity in patients with coronary artery disease (CAD) undergoing coronary angiography. METHODS: Presence and degree of CAC were assessed angiographically in 877 CAD patients grouped into no visible CAC (n = 333), mild to moderate CAC (n = 321), and severe CAC (n = 223). Regression analyses investigated relationships between CAC and demographic data, cardiovascular risk factors, and coronary anatomy. RESULTS: Prevalences of hypertension and systolic blood pressure (SBP) values were higher in individuals with CAC (moderate CAC: 49.5%, 137.5 +/- 18.6 mmHg; severe CAC: 58.3%, 142.1 +/- 20.4 mmHg) compared to individuals with CAD but no CAC (42.0%, 134.0 +/- 18.4 mmHg; both P < 0.001). Likewise, pulse pressure was significantly elevated with increasing degree of CAC (no CAC, 52.3 +/- 13.6 mmHg vs moderate CAC, 55.7 +/- 14.4 mmHg vs severe CAC, 59.1 +/- 15.4 mmHg; P < 0.001). Further determinants of CAC were age, positive family history for CAC and severity of CAD. No differences in CAC severity were found in relation to body mass index, low-density lipoprotein-cholesterol, diabetes, and smoking habits. In multivariate analysis, CAC was independently related to age, SBP or pulse pressure, respectively, positive family history for CAC, and the severity of CAD. CONCLUSIONS: Of the cardiovascular risk factors, SBP and pulse pressure display the strongest relationship with angiographic detection of CAC. Mechanistic studies need to clarify whether hypertension causes CAC, or whether coronary calcium deposition serves as a marker for a higher degree of vascular calcification and, thus, impaired vascular compliance and higher blood pressure levels.

A locus on chromosome 10 influences C-reactive protein levels in two independent populations.

High sensitivity C-reactive protein (hsCRP) is an independent risk factor for cardiovascular disease, such as stroke or coronary artery disease. Genetic factors influence significantly the inter-individual variability of hsCRP. The aim of this study was to identify genomic regions influencing hsCRP levels. A genome scan was performed in two independent studies of Caucasian populations, namely 513 Western-European families ascertained for myocardial infarction (n = 1,406) and 120 French-Canadian families diagnosed with hypertension (n = 758). In the myocardial infarction families, 31% of the inter-individual variation of hsCRP levels was explained by genetic factors (P = 0.0000015) and loci influencing hsCRP were identified on chromosomes 10 (at 141 cM) and 5 (at 150 cM) with multipoint LOD scores of 3.15 and 2.23, respectively. An additional suggestive signal was detected on chromosome 2 in subset analyses. A similar degree of heritability has been observed in a second independent population of French-Canadian hypertensive families for hsCRP (30%) and linkage results for chromosome 10 were confirmed with maximum LOD score of 2.7. We identified a chromosomal region in two independent populations which influences hsCRP in addition to several unique regions. This provides targets for the identification of genes involved in the regulation of hsCRP and the development and progression of vascular disease, including stroke.

The common Y402H variant in complement factor H gene is not associated with susceptibility to myocardial infarction and its related risk factors.

Recently, the genetic variant Y402H in the CFH (complement factor H) gene was associated with an increased risk for MI (myocardial infarction) in a prospective Caucasian cohort. In another nested case-control study, however, the CFH-Y402H variant did not carry susceptibility to MI. The aim of the present study was to test for an association between the CFH-Y402H variant and MI in a large case-control sample with a familial background for CAD (coronary artery disease). A total of 2161 individuals from the German MI family study were studied by questionnaire, physical examination and biochemical analyses. MI patients (n=1188; 51.4+/-8.6 years at first MI) were recruited from families with at least two members affected by MI and/or severe CAD. Spouses, sisters-in-law and brothers-in-law respectively, without MI/CAD were included as unaffected controls (n=973; 56.9+/-9.8 years). Genotyping was performed using a TaqMan assay. The common Y402H variant in the CFH gene was not associated with classical cardiovascular risk factors (diabetes, hypercholesterolaemia, hypertension, obesity, smoking and C-reactive protein serum levels). No association was found between the CFH-Y402H variant and susceptibility to MI. Separate analyses in both men and women revealed no gender-specific influence of the gene variant on cardiovascular risk factors or MI. This investigation was unable to replicate the association between the common CFH-Y402H variant and susceptibility to MI in our large Caucasian population which is enriched for genetic factors. We conclude that the CFH-Y402H variant has no relevant risk-modifying effect in our population.

Impact of diabetes on QT dynamicity in patients with and without myocardial infarction: The KORA Family Heart Study.

INTRODUCTION: Patients with diabetes mellitus (DM) have an unfavorable prognosis after myocardial infarction (MI), partially due to a higher risk of sudden cardiac death (SCD). QT dynamicity is an independent predictor of SCD in post-MI patients. However, the effects of diabetes on QT dynamicity in patients with MI have not been described. METHODS: We studied 468 survivors of MI (67 with DM) from the population-based MONICA registry (KORA Family Heart Study), Augsburg, Germany, by standardized questionnaire, anthropometry, electrocardiogram (ECG), 30-minute-Holter-ECG-recordings and echocardiography. In addition, 422 siblings without prior MI (22 with DM) were studied by the same protocol. RESULTS: Among post-MI patients, the QT/RR slope was significantly steeper in diabetics than in nondiabetics (0.096 +/- 0.057 vs 0.077 +/- 0.045; P = 0.002). Likewise, among siblings without MI, the QT/RR slope was steeper in diabetics than in nondiabetics (0.104 +/- 0.053 vs 0.080 +/- 0.042; P = 0.008). The association of DM with steeper QT/RR slope remained significant in multivariate models in post-MI patients (beta: -0.14; P = 0.004) as well as in individuals without MI (beta: -0.10; P = 0.047). CONCLUSIONS: In a large population of survivors of MI and unaffected siblings, patients and siblings presenting with DM exhibited an abnormal QT rate-dependence, compared with individuals without DM in both groups. Thus, diabetes itself may be a major determinant of ventricular arrhythmias, independently of a previous MI. These observations might in part explain the higher incidence of sudden cardiac death and ventricular arrhythmias in patients with DM.

Association of a functional polymorphism in the CYP4A11 gene with systolic blood pressure in survivors of myocardial infarction.

OBJECTIVE: Survivors of myocardial infarction (MI) are known to have a high prevalence of arterial hypertension which, at the same time, imposes a major risk to such patients. Genetic variants of the arachidonic acid monooxygenase CYP4A11 may result in decreased synthesis of 20-hydroxyeicostatetraenoic acid (20-HETE), experimental hypertension and elevated blood pressure levels in humans. The present study aimed to investigate the impact of the functionally relevant T8590C polymorphism of this gene on blood pressure and the prevalence of hypertension in MI patients. METHODS: Survivors of MI from the MONICA Augsburg MI registry (n = 560) were studied after a mean of 5.6 years after the acute event. Participants were examined by standardized anthropometric and echocardiographic measurements, as well as genotyping for CYP4A11 T8590C allele status. RESULTS: Genotype frequencies in MI patients (TT = 71.8%, CT = 26.2%, CC = 2.0%) did not differ from those in population-based controls (n = 1363; TT = 75.4%, CT = 22.5% and CC = 2.1%, P = 0.22). MI survivors with the CC genotype displayed higher systolic blood pressure levels (CC: 143.4 +/- 4.9 mmHg versus CT: 134.5 +/- 1.3 mmHg and TT: 131.1 +/- 0.8 mmHg; P = 0.02) and a non-significant trend towards higher diastolic blood pressure levels (CC: 88.4 +/- 3.0 mmHg versus CT: 84.9 +/- 0.8 mmHg and TT: 83.9 +/- 0.5 mmHg; P = 0.17) in multivariate models. Accordingly, the C allele was related to elevated odds ratios for hypertension in a recessive [4.14; 95% confidence interval (CI) = 1.07-15.96, P = 0.04] and in a dominant model (1.50; 95% CI = 1.03-2.20, P = 0.04), respectively. No blood pressure-independent association of the T8590C polymorphism with echocardiographic parameters of left ventricular function and/or geometry was found. CONCLUSION: The data obtained in the present study strengthen the evidence of an association of the CYP4A11 T8590C polymorphism with blood pressure levels and hypertension prevalence. Particularly, the risk of arterial hypertension is substantially higher in MI patients homozygous for the CC allele. By contrast, no evidence was obtained for an association between this genotype and MI.

Association of the metabolic syndrome with early coronary disease in families with frequent myocardial infarction.

This study examined the extent to which the metabolic syndrome (MS) augments the risk for major cardiovascular events in healthy patients with a strong genetic background for coronary artery disease (CAD). In a prospective cohort study, we examined 1,316 patients without previously diagnosed CAD or diabetes mellitus. Patients were participants of the Regensburg Myocardial Infarction Family Study, in which > or = 2 family members had severe CAD and 1 had myocardial infarction (MI) at < 60 years of age. During a 2-year follow-up, the incidence of first cardiovascular events (MI, revascularization, and cardiac death) was compared between those with and without the MS at baseline. In all previously unaffected family members, the presence of MS increased the hazard ratio for first manifestation of CAD by a factor of 1.9 (p = 0.030), which resulted in an event rate of 7.1% during follow-up. Specifically in young patients (< or = 50 years old, n = 422), we identified the MS as a major event predictor that conferred a 5.8-fold increased relative risk for first cardiovascular events compared with patients without the MS (95% confidence interval 1.4 to 23.8, p = 0.015, event rate 6.2%). Remarkably, of the individual MS components, obesity was strongly associated with incident MI (relative risk 4.4, 95% confidence interval 1.5 to 13.0, p = 0.007). Thus, the MS strongly predicts cardiac morbidity and mortality in healthy patients with a family background of CAD.

Association of angiotensin-converting enzyme 2 (ACE2) gene polymorphisms with parameters of left ventricular hypertrophy in men. Results of the MONICA Augsburg echocardiographic substudy.

Angiotensin-converting enzyme (ACE) activity is considered to be of major importance for the conversion of angiotensin (Ang) I to Ang II. Recently, a second ACE, named ACE2, has been identified. Experimental data provide evidence that ACE2 might be involved in modulating cardiac structure and function. In the present explorative study, we assessed whether polymorphisms in the ACE2 gene are related to echocardiographically determined parameters of left ventricular mass, structure or function in the general population. Five intronic single nucleotide polymorphisms (SNPs) were genotyped using the 5'-exonuclease activity (TaqMan) assay in the echocardiographic substudy of the third MONICA Augsburg survey. As ACE2 is located on the X chromosome, women and men were analysed separately. Four SNPs showed high pairwise linkage disequilibrium (rs4646156, rs879922, rs4240157 and rs233575). The minor alleles of these four SNPs were associated with higher left ventricular mass index (LVMI) and higher septal wall thickness (SWT) in men. Likewise, male carriers of a common haplotype (frequency 29.9%) consisting of the minor alleles of these four SNPs displayed higher values for LVMI and SWT than non-carriers (LVMI: TGGC 98.8+/-1.52 vs non-TGGC 94.8+/-0.99 g/m(2), p=0.027; SWT: TGGC 11.5+/-0.14 vs non-TGGC 11.1+/-0.09 mm, p=0.019). Furthermore, this haplotype was associated with an increased odds ratio (OR) for left ventricular hypertrophy (OR 3.10, p=0.006). In women, similar but less pronounced and consistent trends were observed. No association was observed between any of these SNPs and parameters of left ventricular systolic or diastolic function nor with blood pressure levels. This study provides evidence that genetic variants in the ACE2 gene may be associated with left ventricular mass, SWT and left ventricular hypertrophy in hemizygous men.

Association of the T8590C polymorphism of CYP4A11 with hypertension in the MONICA Augsburg echocardiographic substudy.

Genetic variants of the arachidonic acid monooxygenase CYP4A11 result in decreased synthesis of 20-hydroxyeicostatetraenoic acid and experimental hypertension. Moreover, in humans, the T8590C polymorphism of CYP4A11 displayed association with arterial hypertension. The aim of the present study was to further investigate this association in a large population-based sample. Therefore, the participants of the echocardiographic substudy of the third MONICA (MONitoring trends and determinants In CArdiovascular disease) survey (n=1397) were studied by standardized anthropometric, echocardiographic, and biochemical measurements as well as genotyping for CYP4A11 T8590C allele status. Individuals with the CC genotype have higher systolic (CC 141.4+/-3.17 mm Hg versus CT 134.2+/-0.97 mm Hg and TT 134.3+/-0.53 mm Hg; P=0.03) and diastolic blood pressure levels (CC 85.4+/-2.06 mm Hg versus CT 80.3+/-0.63 mm Hg and TT 80.7+/-0.34 mm Hg; P=0.02). Accordingly, the odds ratio (adjusted for age, body mass index, and gender) of the CC genotype versus the CT and TT genotypes for hypertension was 3.31 (95% confidence interval [CI]), 1.38 to 7.96; P=0.016) in the entire study population, with similar trends in men (4.30 [95% CI, 1.08 to 17.15]) and women (2.93 [95% CI, 0.88 to 9.84]). Consistent with the renal effects of the gene, no blood pressure-independent association between the T8590C polymorphism and echocardiographic parameters of left ventricular function and geometry was found. In conclusion, our data strengthen the association between the T8590C polymorphism of CYP4A11 and hypertension and suggest a recessive mode of inheritance. In contrast, we found no blood pressure-independent modulatory effect of CYP4A11 T8590C on cardiac size, structure, and function.

Functional improvement in heart failure patients treated with beta-blockers is associated with a decline of cytokine levels.

BACKGROUND: In patients with severe heart failure (CHF), chronically elevated cytokine levels document a systemic inflammation. Experimental data suggest that activation of the beta-adrenergic system may participate in this inflammatory response. Herein, we studied as to whether beta-adrenergic blockade on top of standard CHF therapy affects plasma cytokine levels (interleukin-6 [IL-6] and tumor necrosis factor alpha [TNFalpha]). Moreover, we studied if beta-blocker related changes of these cytokines correspond to changes in left ventricular (LV) function and exercise capacity. METHODS: In a prospective study, 21 patients with stable CHF (NYHA functional class II-III, ejection fraction <40%, mean age 57.6+/-12.4 years) were treated with captopril (100-150 mg/day), furosemide (40-120 mg/day), and/or digoxin (0.1-0.2 mg/day) for at least 1 month before they entered a 4 week run-in period in which dosages were kept unchanged. Metoprololsuccinate was administered in increasing dosages (up to 190 mg/day) for the following 3 months. Clinical, echocardiographic, spiroergometric, and biochemical changes were assessed at the start and the end of the run-in period as well as after 3 month of beta-blockade. RESULTS: As compared to 210 healthy volunteers, CHF patients, prior to beta-blockade, presented with markedly elevated IL-6 (8.9+/-9.9 vs. 2.1+/-0.5 pg/ml; p<0.05) and TNFalpha levels (1.51+/-0.49 vs. 0.64+/-0.15 pg/ml; p<0.05) levels. In CHF patients, 3 month of beta-blockade lowered heart rate (84+/-14 vs. 68+/-12 bpm; p<0.01), systolic (131+/-7 vs. 118+/-6 mm Hg; p<0.01), and diastolic blood pressure (78+/-5 vs. 71+/-6 mm Hg; p<0.01). Spiroergometric determined VO2 max (17.8+/-4.5 vs. 19.8+/-4.3 ml/min kg; p=0.013) increased significantly during 3 month of beta-blockade. Moreover, LV functional parameters tended to improve but the interindividual response varied and changes were non-significant. Interestingly, IL-6 levels decreased markedly during beta-blockade (8.9+/-9.9 vs. 4.5+/-3.1 pg/ml; p=0.036), whereas TNFalpha levels remained unchanged. Moreover, significant positive correlations were found between decrease of IL-6 levels and left ventricular end diastolic diameters (r2=0.59; p=0.012), whereas an inverse correlation was found between the decrease of IL-6 and the increase of VO2 max (r2=0.54; p=0.037), respectively. CONCLUSION: In heart failure patients, beta-blockade may lower IL-6 but not TNFalpha levels. Changes of IL-6 during beta-blockade may be related to changes of LV function and geometry.

NT-ProBNP in outpatients after myocardial infarction: interaction between symptoms and left ventricular function and optimized cut-points.

BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-proBNP) allows us to rule out left ventricular dysfunction (LVD) in the general population at a recommended cut-off concentration of 125 pg/mL. It was our objective to reassess this cut-point in outpatients after myocardial infarction. METHODS AND RESULTS: NT-proBNP was assessed in 418 randomly selected outpatients who had experienced myocardial infarction and 352 siblings who had not experienced myocardial infarction (control). Left ventricular ejection fraction (LVEF) and mass-index (LVMI) were assessed by echocardiography. NT-proBNP was elevated in outpatients after myocardial infarction (mean [+/-SEM], 305 +/- 25 pg/mL vs control, 84 +/- 8 pg/mL; P < .01) and was correlated inversely with LVEF ( P < .001). When patients were stratified according to the presence or absence of heart failure, NT-proBNP was elevated significantly throughout all LVEF strata (each P < .05). On regression analysis, NT-proBNP was correlated independently with LVEF, LVMI, heart failure, and glomerular filtration rate (all P < .01). In patients with heart failure, the optimal cut-point for the detection of an LVEF <35% was 348 pg/mL (sensitivity 80%; specificity 69%) and for the detection of an LVEF <45% was 260 pg/mL (sensitivity 60%; specificity 60%). The relative risk for LVD in the presence of elevated NT-proBNP increased from 2.7 to 7.7 (EF < 35%) and from 1.4 to 2.4 (EF < 45%) when these cut-points were applied instead of the 125 pg/mL cut-point. An LVEF of <35% could be ruled out in symptomatic outpatients after myocardial infarction with a negative predictive value of 97% (cut-point 348 pg/mL) and in asymptomatic outpatients after myocardial infarction with a negative predictive value of 98% (cut-point 157 pg/mL). CONCLUSION: NT-proBNP is higher in outpatients after myocardial infarction than in the general population. In symptomatic patients, a cut-point of 348 pg/mL yields satisfactory sensitivity and specificity for the detection of significant LVD (EF < 35%). Furthermore, significant LVD can be virtually ruled out in symptomatic and asymptomatic outpatients after myocardial infarction at below-threshold concentrations.

C-reactive protein as predictor of death in end-stage diabetic nephropathy: role of peripheral arterial disease.

BACKGROUND: Patients with diabetes type 2 receiving dialysis therapy have a poor survival prognosis, mainly due to cardiovascular events. Increased C-reactive protein (CRP) levels, important in atherosclerosis, are associated with an increased risk for cardiovascular events. However, to date no study has shown the predictive value of CRP in relation to peripheral arterial disease stage. METHODS: We enrolled all 445 prevalent patients with diabetic nephropathy receiving maintenance hemodialysis in 30 centers in Southern Germany from August 1999 to January 2000 for prospective study until December 2003. At inclusion, CRP and a complete clinical phenotype, including peripheral arterial disease Fontaine Stage were determined. The primary end point was all-cause mortality. RESULTS: A total of 305 (68.5%) patients died. An increased log CRP at study inclusion was significantly associated with an increase in hazard ratio (HR) by multivariate Cox regression for all-cause (HR = 1.5, P= 0.002) and cardiac death (HR = 1.76, P= 0.02) in the entire collective. This result was applicable only to patients with peripheral arterial disease Fontaine stage IV (N= 190, multivariate HR = 1.75 for all-cause mortality, P= 0.006). Possibly due to inadequate power, we observed only an insignificant trend for CRP as predictor of all-cause death in patients without peripheral arterial disease or with less severe forms of peripheral arterial disease (HR = 1.36, P= 0.08). CONCLUSION: In contrast to patients with peripheral arterial disease stage IV, patients with less severe atherosclerosis and elevated CRP are, if any, at less risk for cardiovascular mortality, possibly due to the difference in extent of affected vasculature and thus activated platelets and coagulation. Before judging the predictive value of CRP for mortality, peripheral vessel status should be determined.

Effect of compensated renal dysfunction on approved heart failure markers: direct comparison of brain natriuretic peptide (BNP) and N-terminal pro-BNP.

Brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are markers of heart failure. Although renal dysfunction may increase plasma concentrations, the magnitude of this effect has not been assessed in a head-to-head comparison between the clinically approved tests. We assessed the effect of compensated renal dysfunction on BNP (Triage BNP; Biosite) and NT-proBNP (elecsys proBNP; Roche) in 469 randomly selected stable outpatients after myocardial infarction (MI; Monitoring Trends and Determinants in Cardiovascular Diseases [MONICA] register Augsburg) who were characterized with respect to renal function (glomerular filtration rate [GFR]; Cockroft method) and left ventricular (LV) ejection fraction (EF) and mass (2D echocardiography). BNP and NT-proBNP were elevated in MI patients with LV dysfunction (LVD; EF <35%) compared with MI patients with preserved EF ( >45%; BNP 139+/-27 pg/mL versus 75+/-6; NT-proBNP 816+/-237 pg/mL versus 243+/-20; both P <0.03). Among all MI patients, the prevalence of renal dysfunction (GFR <85 mL/min) was 24%. BNP and NT-proBNP were significantly elevated in MI patients with renal dysfunction (BNP 132+/-17 pg/mL versus 68+/-4 without renal dysfunction; NT-proBNP 535+/-80 pg/mL versus 232+/-19; both P <0.05), and both markers were correlated with GFR in univariate and multivariate analyses (all P <0.01). When binary cut-off values were stratified according to the absence or presence of renal dysfunction (BNP 75 pg/mL and 125 pg/mL, respectively; NT-proBNP 100 pg/mL and 350 pg/mL, respectively), the predictive power of both markers for the detection of LVD increased substantially. BNP and NT-proBNP are almost similarly influenced by mild-to-moderate renal dysfunction. Renal dysfunction is a potential cause of elevated marker concentrations in the absence of LVD, and cut-off concentrations should be stratified according to renal function.

[Acute coronary syndrome in a 17-year-old female with systemic lupus erythematosus]. / Akutes Koronarsyndrom bei einer 17-jährigen Patientin mit systemischem Lupus erythematodes.

CASE REPORT: A 17-year-old female was admitted to the hospital with epigastric pain radiating into the chest and neck. The patient had a known, long-standing history of systemic lupus erythematosus (SLE) with predominantly renal involvement. Diagnostic examinations including left heart catheterization showed acute myocardial infarction based on a coronary three-vessel disease. Percutaneous transluminal coronary angioplasty (PTCA) with dilatation of the left marginal branch and the left posterolateral branch was performed. 8 weeks after PTCA, the patient was admitted again showing occlusion of the same coronary artery. A coronary stent was implanted which, after 8 weeks, also showed signs of occlusion. This case report describes premature myocardial infarction in a young woman with SLE and addresses and discusses the problem that myocardial infarction in SLE can be caused by atherosclerosis and/or arteritis of the coronary arteries.

Distinct heritable patterns of angiographic coronary artery disease in families with myocardial infarction.

BACKGROUND: Coronary artery disease (CAD) and myocardial infarction (MI) are significantly determined by genetic background. Whether distinct angiographic features of CAD are affected by inherited factors has never been investigated. Thus, we analyzed comprehensively the extent to which various aspects of CAD, including disease severity, distribution of lesions, presence of coronary calcification, morphology of stenoses, and anatomic characteristics, are under genetic control. METHODS AND RESULTS: We retrospectively studied the coronary angiograms of 882 siblings with CAD from 401 families. These families were ascertained through index patients defined by MI before the age of 60 years and at least 1 sibling with MI or coronary revascularization procedures. Heritability calculations were performed with variance-component analysis. Additionally, recurrence risks to siblings were analyzed. Traditional cardiovascular risk factors and age at the first coronary event displayed significant heritable components. After adjustment for age and sex, significant heritabilities were identified for proximal stenoses, in particular, left main CAD (h2=0.49+/-0.12; P=0.01), coronary calcification (h2=0.51+/-0.17; P=0.001), and ectatic coronary lesions (h2=0.52+/-0.07; P=0.001). In contrast, no heritability was found for distal disease (h2=0.05+/-0.19; NS), the pattern of coronary arterial blood supply, or the number of diseased vessels. Calculation of recurrence risks in siblings largely confirmed the heritability estimates. CONCLUSIONS: Distinct morphological characteristics associated with CAD show different degrees of heritability. Notably, the most hazardous localizations, like left main or proximal disease, display a high heritability. In contrast, some features of coronary morphology, such as distal disease, do not appear to be markedly influenced by heritable factors.

No association of interleukin-6 gene polymorphism (-174 G/C) with myocardial infarction or traditional cardiovascular risk factors.

BACKGROUND: Recently, a polymorphism at position -174 (G>C) of the interleukin-6 (IL-6) promoter was found to be associated with an increased prevalence of myocardial infarction (MI). The aim of the present study was to further investigate the association of the IL-6 -174 G/C allele status with specific end organ damage, i.e. myocardial infarction in large population-based samples. METHODS: Individuals from two Bavarian samples of MI patients (total n=1322) and the population-based Augsburg MONICA survey (1023 unselected controls) were studied by questionnaire, physical examination, echocardiographical assessment and biochemical analyses. The -174 G/C polymorphism was genotyped using a newly established PCR-RFLP. IL-6 levels were measured in a subset of 574 MI patients. RESULTS: In the population-based sample, the IL-6 genotype was neither associated with traditional cardiovascular risk factors (systolic and diastolic blood pressure, total cholesterol, HDL and LDL cholesterol, body mass index, diabetes mellitus) nor with cardiac structural or functional parameters (left ventricular mass index, ejection fraction, diastolic inflow pattern). Moreover, the genotype distribution of the -174 G/C polymorphism was not different in MI patients (GG: 34.1%; GC: 47.4%; CC: 18.5%) and population-based controls (GG: 32.4%; GC: 48.8%; CC: 18.9%) (p=0.67). IL-6 levels were neither related to the -174 G/C polymorphism (p=0.29) nor to ACE-inhibitor treatment (2.16 with vs. 2.09 pg/ml without ACE-inhibitor, p=0.27). However, patients receiving statins displayed significantly lower IL-6 levels (1.83 vs. 2.32 pg/ml in the group without statins, p<0.0001). CONCLUSIONS: This extensive investigation failed to obtain evidence that the IL-6 -174 G/C promoter polymorphism affects traditional cardiovascular risk factors or the prevalence of myocardial infarction in a Caucasian sample.