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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, p48 h vs. 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. Clin Chem Lab Med 2010;48:875–81.

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.

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.

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.

In the diagnosis of coronary artery disease (CAD) with Dobutamine Stress Echocardiography (DSE), regional wall motion abnormalities (RWMA) are assumed to indicate a perfusion deficit.For a more particular examination of RWMAs, we compared simultaneous echo-contrast (Optisone)-enhanced DSE (0-40 microg/kg Dobutamine, 16-segment- model) and MiBi-SPECT in a prospective double-blinded study design in 69 non-selected consecutive patients (44 male, 25 female, age 64+/-12 years). Additionally, all patients were examined by coronary-angiography. The prevalence of significant CAD (stenosis50% lumen diameter) was 52%. DSE had a sensitivity of 78% and a specificity of 66% for the detection of significant CAD with a positive and negative predictive value of 72 and 73%, respectively. Among 28 patients with significant CAD and positive DSE study (true positive), 78% displayed a corresponding perfusion deficit in MiBi-SPECT. Among 11 patients with a positive DSE study but no current significant coronary stenosis (false positive), 82% showed stress-induced RWMAs in the inferior/posterior region, 73% displayed left ventricular hypertrophy, 54% resting-ECG abnormalities and 45% resting-RWMA (3 previous MI, 2 previous CABG surgery). Among 8 patients with negative DSE study but significant coronary stenosis (false negative), 75% had a stenosis of the LCX, 63% displayed resting- WMA, 63% displayed left bundle branch block or ST-segment depression, 50% displayed only peripheral coronary stenosis, and DSE visualization was suboptimal in 38%.This prospective study in non-selected patients shows that the majority of RWMAs in DSE are matched to a perfusion deficit detectable by nuclear imaging. Nevertheless, pre-existing cardiac abnormalities may also lead to stress-induced RWMA not associated with a perfusion deficit or mask a perfusion deficit upon DSE. Particularly in patients with LV hypertrophy, resting-RWMA, bundle branch block or ST segment depression, the predictive value of DSE may, therefore, be limited.

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. © Springer-Verlag 2005.

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.

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 45%; BNP 139±27 pg/mL versus 75±6; NT-proBNP 816±237 pg/mL versus 243±20; both P P P

Eine 17-jahrige Patientin stellte sich mit epigastrischen Schmerzen mit Ausstrahlung in Thorax und Hals in der Notaufnahme vor. Bei der Patientin war ein langjahriger systemischer Lupus erythematodes (SLE) mit vorwiegender Nierenbeteiligung bekannt. Im Rahmen der Notfallbehandlung konnte ein akuter Hinterwandinfarkt bei koronarer Dreigefaserkrankung diagnostiziert werden. Therapeutisch wurde eine perkutane transluminale Koronarangioplastie mit Ballondilatation des Ramus marginalis sinister und des Ramus posterolateralis sinister durchgefuhrt. Nach 8 Wochen kam es zum erneuten akuten Koronarsyndrom. Ein Stent wurde implantiert, der nach 8 Wochen bereits wieder verschlossen war. In diesem Fallbericht wird das ungewohnlich fruhe Auftreten eines Myokardinfarkts und einer koronaren Dreigefaserkrankung bei einer jungen Patientin mit SLE vor dem Hintergrund der publizierten Literatur beschrieben und diskutiert, insbesondere da ursachlich sowohl eine Arteriosklerose als auch eine Arteriitis im Rahmen des SLE auftreten konnen.

The majority of patients with myocardial infarction (MI) and hypercholesterolaemia does not achieve guideline recommended low-density lipoprotein cholesterol (LDL) levels. Suboptimal dosages of statins explain this dilemma in most patients.We evaluated the relationship between statin treatment quality (optimal: LDL115 mg/dl, suboptimal: LDL/=115 mg/dl, no statin therapy despite hypercholesterolaemia) and the subsequent incidence of coronary events (coronary death, nonfatal MI, bypass surgery) over a 30 months follow-up in a large cohort of post MI patients with hypercholesterolaemia (n=2045). Analysis was performed in a nested case-control manner comparing 173 cases with a coronary event and 346 matched controls.Patients who developed a coronary event were treated optimally in 11.0%, suboptimally in 43.4% (p0.05 vs. optimal treatment) and were untreated in 45.7% (p0.001 vs. optimal treatment). Respective numbers in event-free patients were 21.4%, 47.7%, and 30.9%. After adjustment for most potential confounders, including all cardiovascular risk factors and medication, the relative risk of future non-fatal MI and coronary death associated with a suboptimal statin treatment was 2.02 (95% CI 1.04 to 4.18) compared to optimal statin treatment. Moreover, the statin equivalent dose in optimally treated individuals was significantly higher than in suboptimally treated individuals (0.85+/-0.03 vs. 0.78+/-0.02, p0.05).In this community-based study, a lipid lowering therapy with statins into the recommended target range of LDL levels may be associated with decreased cardiovascular risk compared to a statin therapy without titrating the LDL level below 115 mg/dl. Thus, the quality of statin treatment was identified as an independent predictor of coronary events in post MI patients.

Many studies have shown that the B-type natriuretic peptides (BNP and NT-proBNP) are proven diagnostic markers for heart failure due to left ventricular systolic dysfunction. The manner in which they are to be used is still being unravelled; most single centre studies have chosen the best concentration of the peptide on ROC analysis as their cut-point resulting in numerous different values for both BNP and NT-proBNP appearing in the literature. We report a different approach of defining an age and sex corrected abnormal concentration for NT-proBNP, derived from normal individuals within a large sample of 3051 subjects pooled from three European epidemiology studies and applying that to the entire population to detect HF and LVD. Three thousand and fifty one subjects were studied. Of these 10% (305) had significant LVD and 3.1% (94) had HF. The median concentrations of NT-proBNP (IQR) in normals, those with LVD and in heart failure subjects were 20 pg/ml (10.30), 117.3 pg/ml (28.145) and 269.6 pg/ml (54.323), P0.001, respectively. The area under the ROC curve for NT-proBNP for the detection of 'heart failure' was 0.85 and 0.69 for LVD. NT-proBNP was an independent predictor of the presence of HF on multivariate analysis. An abnormal NT-proBNP was defined as being95th centile for normals, age and sex corrected, and diagnosed HF with a sensitivity of 75% and a negative predictive value of 99%. In an additional analysis in a breathless subgroup of our population, in 30% a raised NT-proBNP concentration could be explained by HF due to LVD, in another 64% the high BNP level was associated with some other structural of functional cardiac abnormality or renal impairment. We were unable to assign a possible cause to the high NT-proBNP values in 5.9% of this breathless subgroup of the population. An abnormal NT-proBNP concentration is an accurate diagnostic test both for the exclusion of HF in the population and in ruling out LVD in breathless subjects. An elevated NT-proBNP merely indicates the presence of 'cardio-renal distress' and should prompt referral for further investigation.

Purpose. – Patients with an acute myocardial infarction (AMI) are of high risk to develop ischemia-induced ventricular arrhythmias, leading to sudden cardiac death (SCD) in about one third of all AMI patients. The individual susceptibility to ischemia-induced arrhythmias may be modified by polymorphisms in genes encoding ion channels. The cardiac ATP-dependent potassium channel (K ATP ) current is generated by ion channels encoded by the KCNJ11 gene and the SUR2a gene. Opening of the K ATP channel during ischemia results in action potential shortening in various studies and may therefore influence the outcome of AMI patients. Methods. – Using a three-primer strategy, we sequenced the complete coding and adjacent 5′ and 3′ sequences of the intronless KCNJ11 gene (1.3 kb) prospectively in two groups. Patients of group 1 ( n = 84) survived three or more transmyocardial infarctions without developing any ventricular arrhythmias. Patients of group 2 died suddenly from their first myocardial infarction ( n = 86), most of them witnessed SCDs. Results. – We identified a total of six known polymorphisms (K23E, A190A, L267V, L270V, I337V, and K281K) and two new polymorphisms (L267L, 3′UTR +62 G/A). The allele, genotype, and haplotype frequencies did not differ between the two groups. All polymorphisms were found to be in Hardy–Weinberg equilibrium. In addition, we identified two novel missense mutations in a highly conserved region of the gene in two patients of group 2 (P266T and R371H) with yet unknown functional consequences. Conclusion. – In this study of AMI patients, SCD was not related to polymorphisms in the KCNJ11 gene.

The heart rate turbulence (HRT) parameters were introduced for risk stratification of ventricular arrhythmias in postmyocardial infarction patients. However, the relationship of these parameters with other risk stratificators such as heart rate variability (HRV), repolarization parameters or left ventricular function is unknown. Furthermore, the influence of age and medication on HRT remains to be evaluated. Holter ECG's of 509 post‐MI patients (1–10 years after MI) were screened for single ventricular extrasystole. In 196 patients the parameters' turbulence onset (TO) and turbulence slope (TS) could be computed. A pathological TO (>0%) and TS ( 45%. In contrast, the percentage of pathological HRT was not different between patients with left ventricular hypertrophy (16 out of 59, 27%) compared to patients without LVH (38 out of 133, 28%). The HRT was pathological in 14 out of 24 patients with diabetes mellitus (58%) compared to 40 out of 172 (23%) normoglycemic patients (TO: −0.6 ± 3.1 vs. −2.5 ± 5.5, P < 0.02). HRT was similar in patients with ß‐blockers (n = 96) as in patients without ß‐blockers (n = 100). In stable post‐MI patients, HRT is influenced by age and left ventricular function and correlates with heart rate variability. Therapy with ß‐blockers has no influence on HRT, while diabetic patients may have an increased likelihood of pathological HRT.

The DD genotype of the angiotensin converting enzyme (ACE) polymorphism has been associated with myocardial infarction (MI). However, sample sizes of many case-control studies showing positive association were small and data were inconsistent. Furthermore, no family-based study is available. In a case-control study frequencies of the ACE genotypes were compared in 1319 unrelated patients with previous MI before 60 years of age (616 from the MONICA Augsburg region and 703 from rehabilitation centers in south Germany) and in 2381 population controls from the MONICA Augsburg study region). Furthermore, linkage and association of the ACE I/D polymorphism with MI were tested in 246 informative families using the sib-transmission/disequilibrium test (S-TDT). Overall, no excess of the D allele was found in MI patients (frequency 0.53 versus 0.57 in the general population; P=0.2). The ACE DD genotype was even slightly less frequent in groups with MI compared to the general population controls (0.26 versus 0.33 in women and 0.28 versus 0.33 in men). Similar results were also obtained in 247 men with low cardiovascular risk. In the family-based study, the frequency of the D allele was not different in siblings with or without previous MI (0.53 versus 0.50, respectively; S-TDT P=0.15) indicating no linkage or association of the D allele with MI. In a case-control study of MI patients and controls from the general population as well as a family study neither association nor linkage of the ACE D allele with MI was detected despite sample sizes that were among the largest samples studied so far.

Die koronare Herzerkrankung und der Herzinfarkt sind in unserer Gesellschaft die haufigsten Todesursachen, und auch in der heutigen Zeit endet jeder zweite Herzinfarkt todlich. Die traditionellen Risikofaktoren (arterielle Hypertonie, Hypercholesterinamie, Diabetes mellitus) erklaren die familiare Akkumulation der koronaren Herzerkrankung nicht vollstandig.

The G protein β 3 -subunit C825T polymorphism results in a truncated splice variant protein that is associated with enhanced transmembrane signaling, increased proliferative activity, and arterial hypertension. The aim of the present study was to further investigate the association of this polymorphism with left ventricular (LV) structure and function. A total of 2052 individuals from a large-scale population-based sample were investigated for the G protein β 3 -subunit C825T polymorphism and echocardiographic parameters of LV structure and function. Complete genotyping and echocardiographic data were available in 1720 individuals (829 men and 891 women). The mean LV mass indices in men with CC (n=384) and TT (n=84) genotypes were 98.3±1.2 g/m 2 and 100.0±2.8 g/m 2 , respectively ( P =0.64). In women, the corresponding values were 83.1±1.0 g/m 2 for the CC genotype (n=397) and 83.8±2.1 g/m 2 for the TT genotype (n=91, P =0.32). Likewise, LV dimensions or parameters of the diastolic function and serologic markers of LV mass were not associated with the C825T variant. Finally, multivariate analyses accounting for potentially confounding factors failed to show any influence of this polymorphism on echocardiographic parameters. In conclusion, we were not able to confirm the previously published associations of the G protein β 3 -subunit C825T polymorphism with LV structure and diastolic function.

N-terminal pro-brain natriuretic peptide (NT-proBNP) is increased early after acute myocardial infarction. We assessed the relationship of NT-proBNP with left ventricular function and mass as well as with renal function, hemodynamic, and anthropometric variables in 625 outpatients in the chronic phase after myocardial infarction and 465 siblings without infarction (control). NT-proBNP was measured by nonextracted, enzyme-linked, sandwich immunoassay. NT-proBNP was correlated with left ventricular ejection fraction, mass index, and renal function, in addition to infarction history, gender, and age, in univariate and multivariate analysis (all P P P

Masnahmen zur Sekundarpravention bei koronarer Herzerkrankung werden in Deutschland unzureichend umgesetzt. Wir untersuchten daher den Einfluss einer stationaren Rehabilitation auf die Umsetzung der aktuellen Leitlinien bei Patienten mit schwerer koronarer Herzerkrankung (KHK). Hierzu entwickelten wir ein Fall-Kontroll-Design in betroffenen Geschwisterpaaren, von denen ein Geschwister an der Rehabilitation teilnahm und das weitere Geschwister darauf verzichtete. In 15 kardialen Rehabilitationskliniken wurden durch Aktenstudium 1500 Familien identifiziert, in welchen zwei Geschwister eine dokumentierte schwere koronare Herzerkrankung, d.h. Zustand nach Herzinfarkt oder Zustand nach revaskularisierenden Masnahmen, aufwiesen. Aus dieser Gruppe liesen sich 268 Geschwisterpaare identifizieren, welche sich hinsichtlich einer Teilnahme an einer stationaren Rehabilitationsmasnahme diskordant verhielten. In diesen Geschwisterpaaren wurde im Durchschnitt 5,2 Jahre nach Herzinfarkt oder Revaskularisation ein standardisiertes Interview sowie eine Evaluation der Risikofaktoren durchgefuhrt. Wahrend sich die Geschwister zum Zeitpunkt der Manifestation der koronaren Herzerkrankung mit oder ohne konsekutive stationare Rehabilitation nicht unterschieden, fanden sich wahrend der Follow-up-Untersuchung bei Teilnehmern der stationaren Rehabilitation (Reha-Geschwister) eine signifikant haufigere Einnahme von antihypertensiver Medikation (92,2 vs. 82,1%, p

Aims In the general population, measures for secondary prevention of myocardial infarction are poorly utilized. Our aim was therefore to analyse whether post-myocardial infarction in-hospital rehabilitation and education programmes improve the subsequent utilization of preventive strategies. Methods and Results We screened 93500 patient charts in cardiac rehabilitation clinics to identify a myocardial infarction patient with a sibling, who likewise had a myocardial infarction prior to the age of 60 years but was discordant with respect to the participation in cardiac in-hospital rehabilitation. In 92 such sibling pairs the coronary risk profile was studied by standardized questionnaire, biochemical measurements and physical examination. At the time of the acute myocardial infarction, both groups showed an equal risk factor distribution. However, at follow-up (on average 5·5 years after myocardial infarction), rehabilitation-siblings presented with significantly lower systolic (137±2 vs 150±3mmHg, P

Aims Patients with arterial hypertension or hypercholesterolaemia may benefit from medical therapy for primary prevention of myocardial infarction. Preventive therapy may be particularly effective in individuals with a positive family history for myocardial infarction since such subjects are at high risk for coronary events. The objective of this population-based study was to analyse the risk profile as well as the current utilization of preventive strategies in asymptomatic siblings of patients with myocardial infarction. Methods and Results We studied siblings of 325 patients with premature myocardial infarction from the Augsburg MONICA myocardial infarction registry by standardized questionnaire, blood pressure recordings, and biochemical measurements. Out of 580 siblings, 510 were free of coronary heart disease symptoms. With multiple risk factors being present in most asymptomatic siblings, 29·4% of asymptomatic individuals had an estimated individual 10-year risk for a major cardiovascular event of ≥20%, or when projected to the age of 60. According to the guidelines of the European Societies of Cardiology, Atherosclerosis, and Hypertension (ESC/EAS/ESH) from 1994 (1998 guidelines in parenthesis) dietary and lifestyle interventions were indicated for arterial hypertension in 48·1% (43·0%) and/or for hypercholesterolaemia in 17·3% (78·8%). Drug treatment was indicated for arterial hypertension in 27·9% (30·6%) and for hypercholesterolaemia in 13·6% (19·1%) of asymptomatic siblings. Of those individuals with the respective indication, actual drug treatment was given for arterial hypertension in 91·5% (83·3%) and for hypercholesterolaemia in 46·4% (33·0%). However, treatment targets were reached in only 31·0% (28·2%) with arterial hypertension and in 7·2% (5·2%) with hypercholesterolaemia, respectively. Conclusions Most asymptomatic individuals with positive fraternal family history have more than one modifiable risk factor. Interestingly, a large number of these individuals appears to be under medical surveillance as many receive some sort of drug treatment. However, this therapy did not meet the treatment goals in the majority of those with arterial hypertension and/or hypercholesterolaemia. Thus, although individuals with a positive fraternal history for myocardial infarction can be easily identified, implementation of sufficient preventive strategies continues to be poor in a Western European country.

Objective: A polymorphism at position 825(C→T) of the G protein β3 ( GNB3 ) gene was found to be associated with enhanced transmembrane signalling as well as with an increased prevalence of arterial hypertension. The aim of the present study was to further investigate the association of the GNB3 C825T allele status with arterial hypertension in a large population-based sample and its association with specific end organ damage, i.e. myocardial infarction (MI). Methods: Individuals from a population-based sample ( n = 2052) and patients suffering from premature MI (age at first MI ≤60 years, n = 606) were studied by questionnaire as well as by physical examination and biochemical analyses. Results: In the population-based sample, the prevalence of arterial hypertension (blood pressure ≥160/95 mmHg and/or antihypertensive medication) was higher in individuals with the TT genotype (41.8%) as compared to heterozygote individuals (36.6%) or those with the CC genotype (32.75%) ( P = 0.02). This association was predominantly found in men. Moreover, men without antihypertensive medication carrying the TT genotype showed higher diastolic blood pressure than those carrying the CC genotype (86.5 vs. 83.7 mmHg, P = 0.04). However, the genotype distribution and the allele frequencies were similar in both, the population-based and the MI patient sample. Furthermore, neither the age at the time of MI nor the location of the MI were related to the genotype distribution. Similarly, gender and age stratified analyses did not show any association of the GNB3 genotype and MI. Conclusions: In male individuals from a large population-based sample, the T allele of the GNB3 polymorphism was associated with arterial hypertension. However, the effects of the GNB3 825T allele on blood pressure were small and did not translate to a clinically relevant increase of risk for MI.

Several reports indicate the benefit of ACE inhibitors for patients with left ventricular systolic dysfunction after acute myocardial infarction (MI). We sought to determine the implementation of the treatment guidelines in patient samples from the general population. Furthermore we aimed to identify patient characteristics associated with the use of ACE inhibitors. Screening of two MI-registries allowed the identification of 226 MI patients with left ventricular dysfunction. Patients were considered to be eligible for ACE inhibitor therapy when a EF < or = 40% was documented in the patient records of cardiac rehabilitation clinics (REG-MI, n = 147) or detected by standardised echocardiography (KORA, n = 78). On average 5.5 years following MI, a standardised questionnaire and a detailed medical history was obtained. Specifically, information was collected regarding current medication and potential contraindications for ACE inhibitors. MI patients with LV dysfunction received ACE inhibitors in 62% (REG-MI) and 45% (KORA). The doses prescribed were substantially smaller than target doses used in the large-scale studies (REG-MI: 40 +/- 4%, KORA: 23 +/- 3%, % of target doses). Only 13% (REG-MI) and 3% (KORA) received more than 50% of the target dosage. Additionally, actual doses of the most frequently used ACE inhibitors were significantly different (captopril: 23 +/- 2%, enalapril: 42 +/- 5% of target doses). The likelihood of receiving ACE inhibitors was significantly higher in patients with written recommendation for such medication (odds ratio 6.02, confidence interval 1.93-20.16) and in patients visiting cardiologists (odds ratio 3.69, confidence interval 1.26-11.07) as revealed by multivariate analysis of the REG-MI database. Despite national and international guidance, a large proportion of MI patients with left ventricular dysfunction is not receiving ACE inhibitors, and when used, the doses prescribed are markedly smaller than target doses used in clinical trials that established the utility of these drugs. Medical care by cardiologists and written recommendation of ACE inhibition in patient records were independent predictors of a more appropriate prescription of ACE inhibitors.

Objective: Genetic variants of the lipoprotein lipase gene have been associated with dyslipidemia and coronary artery disease. However, data have been inconsistent and are mainly based on selected predominantly male patient groups. Methods: We evaluated the influence of the HindIII restriction fragment length polymorphism on lipid levels in the general population (1361 participants of a large population-based survey from Augsburg, Germany; 50% women) as well as the association of this polymorphism with the risk of myocardial infarction (MI; genotype frequencies in 1159 patients with documented MI under 60 years of age). Results: In the population-based survey, a highly significant association between the frequent H2H2 genotype and unfavorable cholesterol subfraction levels was observed in men and in postmenopausal women whereas no significant association was observed in premenopausal women (uni- and multivariate analysis). Such unfavorable lipid levels in homozygotes for the H2 allele may be expected to be associated with a 19–25% increased risk to suffer from myocardial infarction (MI). Nevertheless, genotype and allele frequencies in the general population were not different from those in patients with previous MI (H2H2 genotype frequency 51.3% vs. 53.2%, respectively; P =0.63). Conclusion : This large study shows that the H2H2 genotype of the lipoprotein lipase gene polymorphism is associated with unfavorable lipid levels. Estrogen status may modulate this association in women. The effects of the genotype on lipid levels were apparently not strong enough to reveal a significant association with MI.

Background Published data regarding effects of growth hormone (GH) on the renin system are controversial. The aim of this study therefore was to evaluate the effects of GH on the renin system in normal rats and rats with myocardial infarction (MI). Methods Normal rats received 2, 5, or 10 IU GH/kg/day or vehicle subcutaneously for 4 weeks. Furthermore rats with MI were randomized to receive 2 IU GH/kg/day or vehicle for 4 weeks. Subdivision into MI groups (mild, moderate, and large) was by histological determination of infarct size. Renal renin gene expression was assessed by RNAase protection assay and plasma renin activity by radioimmunoassay. In addition, isolated mouse juxtaglomerular cells were exposed to GH for 20 h, and renin secretion rates were assessed. Results GH treatment in normal rats for 4 weeks increased body weight, and kidney weight to body weight ratio, but did not affect renin secretion and renal renin gene expression. In rats with large MI, renal renin gene expression increased about fourfold, but was unchanged in rats with small and moderate MI as compared to normal rats. In rats with MI, body weight decreased and this decrease was partially reversed by GH treatment. GH treatment did not change renal renin gene expression, and renin secretion in rats with MI. Renin secretion of isolated juxtaglomerular cells was unaffected by GH. Conclusions Our study demonstrates that GH treatment has no significant effect on renin secretion and on renal renin gene expression in normal rats and in rats with stimulated renin system due to MI in vivo. In isolated juxtaglomerular cells in vitro, renin secretion was also unaffected by GH.

Background The effects of hypoxia on renin secretion and renin gene expression have been controversial. In recent studies, we have demonstrated that acute hypoxia of 6 h duration caused a marked stimulation of renin secretion and renal renin gene expression. This hypoxia-induced stimulation of the renin-angiotensin system might contribute, for example, to the progression of chronic renal failure and to the development of hypertension in the sleep-apnoea syndrome. For this reason, we were interested in the more chronic effects of hypoxia on renal renin gene expression and its possible regulation. Methods Male rats were exposed to chronic normobaric hypoxia (10% O(2)) for 2 and 4 weeks. Additional groups of rats were treated with an endothelin ET(A) receptor antagonist, LU135252, or a NO donor, molsidomine, respectively. Systolic blood pressure and right ventricular pressures were measured. Renal renin, endothelin-1 and endothelin-3 gene expression were quantitated using RNAase protection assays. Results During chronic hypoxia, haematocrit increased to 72+/-2%, and right ventricular pressure increased by a mean of 26 mmHg. Renal renin gene expression was halved during 4 weeks of chronic hypoxia. This decrease was reversed by endothelin receptor blockade (105 or 140% of baseline values after treatment for weeks 3-4 or 1-4). Furthermore, there was a trend of increasing renal endothelin-1 gene expression (to 173% of baseline values) after 4 weeks of hypoxia. Systolic blood pressure increased moderately during 4 weeks of chronic hypoxia from 129+/-2 to 150+/-4 mmHg. This blood pressure increase was higher in rats treated for 4 weeks with an endothelin receptor antagonist (196+/-11 mmHg). Conclusions Chronic hypoxia (in contrast to acute hypoxia) suppresses renal renin gene expression. This inhibition presumably is mediated by endothelins.

Endothelin-1, -2 and -3 (ET-1, -2, -3) have suppressive effects on the renin system in different experimental in vitro models, whereas a modulation of renin secretion or renin gene expression by endothelins (ETs) in in vivo studies has not so far been found. In a recent study we observed a significant stimulation of the renin system by acute hypoxia over 6 h in rats. In the study reported here, we investigated the more chronic effects of hypoxia (10% O2 for 4 weeks) on renin gene expression and the influence of the ET system on its regulation. Renin mRNA levels decreased after 2 weeks of hypoxia to 76% of control and after 4 weeks to 49% of control (p < 0.05). Concomitant administration of the ET(A)-receptor antagonist LU135252 led to a significant increase in renin gene expression compared to control or hypoxia alone. ET-1 mRNA increased to 120% after 2 weeks and 173% after 4 weeks of hypoxia (NS), while ET-3 was not affected by hypoxia. We therefore conclude that ETs have a suppressive effect on renal renin gene expression in the setting of chronic hypoxia in rats in vivo.

Background: There is evidence from in vitro studies to suggest that the genes of platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) are, like the erythropoietin gene, regulated by oxygen tension. Hypoxia-induced stimulation of, for example, PDGF or VEGF might be involved in the pathogenesis of acute or chronic renal failure and in renal ‘inflammatory’ diseases (glomerulonephritis, vasculitis, allograft rejection). Methods: Male Wistar rats were exposed to chronic normobaric hypoxia (10% O2, 90% N2) for 4 weeks. Additional groups of rats were treated with the endothelin receptor antagonist LU13525 and the NO donor molsidomine. Renal mRNA levels of PDGF-A, PDGF-B, and VEGF were semiquantitated using RNase protection assays. Results: Renal gene expression of PDGF-A and PDGF-B was neither affected by 2 or 4 weeks of hypoxia nor by concomitant treatment with LU135252 or molsidomine. Chronic hypoxia did also not change VEGF gene expression; however, concomitant treatment with LU135252 increased all VEGF subtypes (188, 164, 120). Conclusions: The findings of the present study suggest that renal PDGF and VEGF gene expression in vivo during chronic hypoxia for 2 and 4 weeks is not sensitive to tissue hypoxia in contrast to cell culture experiments. During chronic hypoxia with concomitant blockade of endothelin receptors, all VEGF subtypes were increased, suggesting an inhibitory action of endothelins with regard to renal VEGF gene expression.

The aim of this study was to examine the effects of both angiotensin II type I receptor antagonism using losartan (LOS) and beta-receptor blockade by metoprolol (MP) in isoproterenol-induced cardiac injury in the rat. Two weeks after isoproterenol (ISO) application, 90 ISO and 30 control (CTRL) rats were examined. ISO rats were treated for two weeks with either LOS, MP, or vehicle (n = 30 each group). Compared to CTRL, ISO induced left ventricular hypertrophy (LVH), fibrosis, and overexpression of extracellular matrix proteins. LOS significantly attenuated these changes. MP only reduced LVH, but exerted no effect on structural alterations. LV end-diastolic and mean right atrial pressures were significantly increased in the ISO group and normalized in the LOS and MP group. Mean aortic blood flow velocity was significantly decreased in the ISO group and unaltered in the LOS and MP group versus CTRL. Blood pressure was decreased in ISO and LOS rats. MP treatment had no effect on blood pressure, but significantly lowered heart rate. Isoproterenol induced mild heart failure. Losartan and metoprolol applications in ISO-treated rats were highly effective in attenuating hemodynamic alterations and LVH. Early application of losartan 24 hours after isoproterenol-induced cardiac injury revealed significant beneficial effects on myocardial structure.

Left ventricular hypertrophy (LVH) is characterized by remodeling of both myocyte and interstitial compartments of the heart. The aim of this investigation was to study the effects of angiotensin converting enzyme (ACE) inhibition on alterations in the composition of the interstitium in chronic pressure-overload hypertrophy.LVH was induced in weanling rats by banding the ascending aorta. Animals with aortic banding received either vehicle (n = 20), hydralazine (20 mg/kg per day, n = 20), or the ACE inhibitor ramipril (10 mg/kg per day, n = 20) during weeks 6-12 after banding.Compared with sham-operated, untreated rats (n = 20), aortic-banded vehicle and hydralazine-treated rats displayed substantially increased left ventricular weights and myocyte diameters whereas ramipril significantly blunted the hypertrophic response at the myocyte level (each P0.001) as well as the increase in left ventricular weight (each P0.01). In addition, image analysis revealed a significant induction of perivascular and interstitial tissue accumulation in vehicle- and hydralazine-treated rats (2.5-fold, each P0.0001). In contrast, ramipril-treated rats displayed attenuated interstitial and perivascular fibrosis, both being significantly diminished compared with vehicle- and hydralazine-treated rats (each P0.001). Further, vehicle- and hydralazine-treated rats were characterized by elevated steady-state messenger (m)RNA levels of fibronectin (2.7- and 2.8-fold, P0.005), collagen I (2.0- and 1.8-fold, P0.0005), collagen III (both 2.2-fold, P0.001) and laminin B (1.6- and 1.6-fold, P0.005). In parallel, the corresponding immunohistochemical signals were markedly enhanced in these groups. In comparison, ramipril significantly blunted the induction of collagen I and III, laminin B and fibronectin at both the mRNA and protein levels. These morphological and molecular differences between the hydralazine and ramipril groups could not be attributed to differences in left ventricular-pressures, which were markedly elevated in all aortic stenosis rats (1.9-fold, each P0.001 versus sham). In fact, given that ramipril but not hydralazine blunted the hypertrophic response to pressure overload, the echocardiographic measurements revealed that left ventricular systolic wall stress was higher in the ramipril group (70 +/- 1 versus 34 +/- 0.7 kdyn/cm2; P0.02).ACE inhibition may limit both myocyte and interstitial remodeling despite ongoing cardiac pressure overload.

Schunkert H, Hense H-W, Brockel U, Luchner A, Muscholl M, Holmer SR, Danser AHJ, Mayer B, Riegger GAJ (University of Regensburg, Regensburg; University of Munster, Munster, Institut fur Epidemiologie, Munich-Neuherberg, Germany; Erasmus University, Rotterdam, The Netherlands). Differential effects of antihypertensive drugs on neurohormonal activation: insights from a population-based sample. J Intern Med 1998; 244: 109–19. Objectives The clinical course of hypertension or heart failure may be modified by the extent of concurrent neurohormonal activation. Factors that regulate neurohormones in patients with these conditions are complex. In the present study, we examined the relative contribution of antihypertensive therapy to the variability of neurohormonal levels in a well defined population based sample. Design and setting Cross-sectional study of a mixed urban and rural population. Subjects Middle-aged individuals (n= 646) were analysed in order to elucidate determinants of neurohormone levels by uni- and multivariate comparisons. The assessment included anthropometric, echocardiographic and, if appropriate, genotype information. Results The intake of antihypertensive drugs was related to significant alterations of neurohormone levels that, in part, exceeded the contribution of all other variables studied. Multivariate analyses revealed that renin levels were independently related to the intake of beta blockers (n= 80; –8.4 mU L−1; P= 0.001), angiotensin-converting enzyme (ACE)-inhibitors (n= 39; +15.9 mU L−1; P= 0.0001), diuretics (n= 62; +14.3 mU L−1; P= 0.0001), and calcium channel blockers (n= 45; +5.9 mU L−1; P= 0.05). Aldosterone levels were related to ACE-inhibition (–156.5 pmol L−1; P= 0.04) and diuretic treatment (+422.4 pmol L−1; P= 0.0001) in an opposite fashion whereas beta blockers and calcium channel blockers had no significant independent effects. The levels of the atrial natriuretic peptide were significantly related to the use of beta blockers (+3.9 pmol L−1; P= 0.002) and calcium channel blockers (+3.1 pmol L−1; P= 0.05). Finally, serum angiotensinogen levels and ACE activity were not found to be significantly affected by antihypertensive medication but were rather related to gender or genotype. Conclusions The data emphasize that antihypertensive treatment with different classes of drugs may modulate serum levels of neurohormones substantially resulting in distinct patterns of activation. These drug-related effects may require consideration when neurohormonal activation is of functional relevance or when neurohormones serve as prognostic predictors in patients with cardiovascular disorders.

Objective: Numerous studies support the concept that cardiac angiotensin-converting enzyme (ACE) is involved in the pathophysiology of left ventricular hypertrophy. However, the pulmonary vasculature is considered to be the most prominent site of ACE expression. We thus examined the tissue specificity of ACE regulation in rats with severe cardiac pressure overload hypertrophy in transition to cardiac failure with secondary pulmonary hypertension. Methods and Results: Rats were studied 12 weeks after banding of the ascending aorta (LVH, n =20) that resulted in a 1.7-fold increase in left ventricular (LV) to body weight ratio. In addition, as compared to sham-operated rats ( n =20), we observed in LVH rats a 1.6-fold increase in right ventricular (RV) to body weight ratio, the development of pulmonary hypertension, and elevated plasma renin activities. Moreover, ACE mRNA and activity levels were more than 2-fold higher in both hypertrophied ventricles ( P

Abstract The upregulation of left ventricular (LV) atrial natriuretic peptide (ANP) mRNA is a highly conserved marker of cardiac hypertrophy. The aim of this study was to further examine the pathway leading to ANP induction during pressure overload of the heart. Systolic wall stress was imposed acutely on isovolumetrically beating rat hearts in a Langendorff apparatus (ς=300×10 3 dyne/cm 2 ). Northern and Western blots revealed that elevated wall stress induced LV c- fos and c- jun mRNAs (3.5- and 3-fold, P P P P P cis acting elements. However, the transient nature of c- fos and c- jun upregulation also suggests that AP-1 is not the only mediator of ANP induction in LV hypertrophy.

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) 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 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. Clin Chem Lab Med 2010;48:121–8.

One of the abnormalities in end-stage human heart failure is desensitization of the beta-adrenergic signaling pathway, resulting in decreased adenylyl cyclase activity and cyclic adenosine 3',5'-monophosphate formation. This process includes changes in expression of receptors and G-protein alpha subunits. It was hypothesized that changes in the gene expression of G-protein beta subunits (Gbeta) and of adenylyl cyclase itself may contribute to the attenuation of activation of adenylyl cyclase.The hypothesis was tested by determining messenger RNA steady-state levels (Northern and slot-blot analyses) of adenylyl cyclase type V (a major isoform in adult myocardium) and Gbeta in the left ventricles of patients with terminal heart failure because of idiopathic dilated cardiomyopathy (n = 10) or ischemic heart disease (n = 7) and in the left ventricles of nonfailing donors (n = 5). Adenylyl cyclase type V messenger RNA was elevated by 85 +/- 25% in dilated cardiomyopathy and by 113 +/- 35% in ischemic heart disease (P.05 vs nonfailing hearts). In contrast, Gbeta messenger RNA was unchanged in cardiomyopathy (3.48 +/- 0.18 pg/microgram total RNA vs nonfailing hearts 3.99 +/- 0.46) and decreased in ischemic heart disease (2.43 +/- 0.26, P.01).The data indicate that gene expression of the major cardiac isoform of adenylyl cyclase (type V) seems increased in human end-stage heart failure. Therefore, attenuated adenylyl cyclase activity in this condition may not be the result of adenylyl cyclase messenger RNA downregulation. Similarly, the unchanged or decreased expression of Gbeta argues against changes in Gbeta contributing to this process.

Background Epidemiologic studies have shown that left ventricular hypertrophy is often found in the absence of an elevated cardiac workload. To investigate whether such hypertrophy is determined in...

Utilizing a combination of mechanical and chemical unilateral denervation, we have examined the relevance of renal innervation for the expression of renin in kidneys of adult rats. Renal denervation led to a reduction by 57 +/- 4% of renin-containing areas in denervated kidneys as quantitated by morphometry of kidney sections immunoreactive against a polyclonal antirenin antibody. Preprorenin mRNA content in the denervated kidneys fell to 46 +/- 7% of the contralateral innervated kidneys. Treatment of rats with the beta 1-adrenoreceptor antagonist metoprolol (100 mg.kg-1.day-1) for 2 days decreased renal renin mRNA levels to 71% of control levels. Unilateral renal denervation led to a further decrease of renin mRNA levels also in metoprolol-treated animals to 60% of the values found in the contralateral kidneys. Hypotensive hemorrhage led to a 1.4-fold increase of renin mRNA in the kidneys of sham-treated animals. In unilaterally denervated rats renin mRNA increased to levels similar to those in sham-operated animals in both denervated and in contralateral innervated kidneys in response to bleeding. As a consequence, the ratio of abundance of renin mRNA in the denervated to the innervated kidneys rose to 86 +/- 7%. Pretreatment of the animals with metoprolol, on the other hand, prevented the rise of renin mRNA in response to hypotensive hemorrhage. Our findings suggest that in the adult organism renal neural input significantly contributes to the expression of renin under basal conditions, while it appears to be of less importance for stimulation of renin gene expression by severe blood loss.

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.

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

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. © 2006 Lippincott Williams & Wilkins.

The MONICA/KORA surveys are characterized by a careful and broad investigation of multiple cardiovascular phenotypes. Particularly, repeated blinded measurements of blood pressure, comprehensive echocardiographic and electrocardiographic evaluations as well as differentiation between fat and fat-free body mass have led to manifold innovative observations. Specifically, genetic and serological markers of the renin angiotensin system could be associated with high blood pressure and left ventricular hypertrophy. The same applies to the importance of parameters of body composition as obesity and muscular mass. Moreover, the prevalence of heart failure in the general population could be determined for the first time in Germany. Additionally, the prevalence of left ventricular systolic and diastolic dysfunction could be obtained in the region of the survey, exemplarily for the Federal Republic of Germany. Finally, the surveys of the population random sample were used to define normal serum levels of natriuretic peptides. In summary, the evaluation of cardiovascular phenotypes in the MONICA/KORA surveys resulted in a -- in the European region unique -- documentation of cardiovascular functional parameters in the general population. Moreover, multiple epidemiological observations as to pathophysiologically relevant topics of heart and vascular diseases could be studied in extraordinary details.

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 whichor = 2 family members had severe CAD and 1 had myocardial infarction (MI) at60 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.

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 ( h 2 =0.49±0.12; P =0.01), coronary calcification ( h 2 =0.51±0.17; P =0.001), and ectatic coronary lesions ( h 2 =0.52±0.07; P =0.001). In contrast, no heritability was found for distal disease ( h 2 =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.

The BK (bradykinin) B2 receptor is the major cellular mediator of the effects of BK. A 9 bp deletion in the promoter of the receptor gene represents an allelic variant that is associated with enhanced mRNA expression levels. We tested whether this polymorphism is associated with the prevalence of MI (myocardial infarction) or with echocardiographically determined left ventricular function in post-MI patients. Patients with documented MI (n=484), matched controls and controls without evidence of coronary heart disease (n=1363) constituted cases and controls. MI patients and controls were carefully matched for age, gender and cardiovascular risk factors. Genotype distributions of the 9 bp insertion/deletion polymorphism were similar across the groups: −9/−9, −9/+9 and +9/+9 were 22.1, 49.5 and 28.5% in MI patients, and 23.0, 44.6 and 32.5% in matched control subjects respectively. The lack of association was also observed in selected subgroups, stratified by age, gender and cardiovascular risk factors. Furthermore, there was no relation between this polymorphism and left ventricular systolic function in post-MI patients. These findings indicate that the 9 bp insertion/deletion polymorphism of the BK B2 receptor gene is neither related to the prevalence of MI nor to left ventricular function after MI.

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.In a prospective study, 21 patients with stable CHF (NYHA functional class II-III, ejection fraction40%, 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.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; p0.05) and TNFalpha levels (1.51+/-0.49 vs. 0.64+/-0.15 pg/ml; p0.05) levels. In CHF patients, 3 month of beta-blockade lowered heart rate (84+/-14 vs. 68+/-12 bpm; p0.01), systolic (131+/-7 vs. 118+/-6 mm Hg; p0.01), and diastolic blood pressure (78+/-5 vs. 71+/-6 mm Hg; p0.01). 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.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.

Objectives: A higher incidence of pulmonary autograft dilatation is assumed in patients with ascending aortic dilatation and bicuspid aortic valve disease. To examine whether structural abnormalities are present in the ascending aorta as well as in the pulmonary trunk (PT) we specifically addressed molecular mechanisms and signalling pathways for aneurysm formation in ascending aortic aneurysms and PT of patients with different aortic valve pathology undergoing an extended Ross procedure. Methods: Wall segments resected from aortic aneurysms (20 patients, 7 bicuspid aortic valves BAV, and 13 tricuspid aortic valves TAV) and from PTs were submitted to analysis of leukocyte infiltration (immunohistochemistry), smooth muscle cell (SMC) apoptosis (in situ end-labelling of DNA-fragments TUNEL), and expression of death-promoting proteins perforin, granzyme B, Fas/FasL (immunoblotting). Results: Degenerative changes including rarefication and apoptosis of SMCs were significantly more severe in BAV than TAV disease (apoptotic index 9.2 ^ 3.2 vs. 11.9 ^ 6.2, P ¼ 0:02). Immunohistochemistry confirmed presence and activation of death-promoting mediators in aneurysmal tissue whereas pulmonary tissue displayed only few apoptotic cells, occasional Fas þ cells, rarely colocalized with FasL. By Western blot analysis extracts from BAV and TAV but not pulmonary artery wall contained appreciable amounts of perforin, granzyme B, and Fas/FasL. Conclusion: Aneurysm formation is associated with SMC apoptosis and local signal expression of activated cells in patients with bicuspid as well as TAV. The PT itself is not pathologically involved with only minor degenerative changes. Although the disease process in the aorta appeared to be more severe in patients with BAV, there was similarity of histological and molecular changes of the pulmonary artery wall in all patients. Dilation of the pulmonary autograft seems not to be the result of histopathological and biomolecular mechanisms in the PT. q 2004 Elsevier B.V. All rights reserved.

Background— In patients with chronic heart failure (CHF), central sleep apnea (CSA) and enhanced ventilatory response (V̇ e /V̇ co 2 slope) to exercise are common. Both breathing disorders alone indicate poor prognosis in CHF. Although augmented chemosensitivity to co 2 is thought to be one important underlying mechanism for both breathing disorders, it is unclear whether both breathing disorders are related closely in patients with CHF. Methods and Results— We investigated 20 CHF patients with clinically important CSA (apnea-hypopnea-index (AHI), number of episodes per hour ≥15) and 10 CHF patients without CSA. Patients with and without CSA did not differ with respect to exercise capacity (peak V̇ o 2 , 63.4±3.4% versus 60.8±4.4% of predicted value; P =0.746) and left ventricular ejection fraction (LVEF, 31±2% versus 31±3%; P =0.948). The AHI was not correlated with exercise capacity (peak V̇ o 2 , percent of predicted value; P =0.260) and LVEF (percent, P =0.886). In contrast, the positive correlation of the V̇ e /V̇ co 2 slope, determined by cardiopulmonary exercise testing, with the AHI was highly significant ( P e /V̇ co 2 slope was significantly increased in patients with CSA compared with those without CSA (29.7 versus 24.9; P Conclusions— The ventilatory response to exercise is significantly augmented in CHF patients with CSA compared with those without. In contrast to peak V̇ o 2 and LVEF, the V̇ e /V̇ co 2 slope is strongly related to the severity of CSA in patients with CHF, which underscores an augmented chemosensitivity to co 2 as a common underlying pathophysiological mechanism.

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 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.

Aims The prevalence of left ventricular diastolic abnormalities in the general population is largely unclear. Thus, the aim of this study was, firstly, to identify abnormal diastolic function by echocardiography in an age-stratified population-based European sample (MONICA Augsburg, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(n=1274\) \end{document}, 25 to 75 years, mean 51±14) and, secondly, to analyse clinical and anthropometric parameters associated with diastolic abnormalities. Methods and results The overall prevalence of diastolic abnormalities, as defined by the European Study Group on Diastolic Heart Failure (i.e. age dependent isovolumic relaxation time (92–105ms) and early (E-wave) and late (A-wave) left ventricular filling (E/A-ratio, 1–0.5)) was 11.1%. When only subjects treated with diuretics or with left atrial enlargement were considered (suggesting diastolic dysfunction) the prevalence was 3.1%. The prevalence of diastolic abnormalities varied according to age: from 2.8% in individuals aged 25–35 years to 15.8% among those older than 65 years \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \((P{

Background— Serum lipoprotein(a) [Lp(a)] concentration is largely determined by variability at the apolipoprotein(a) gene locus. Most prominent effects relate to polymorphisms in the promoter (a pentanucleotide [PN] repeat) and coding regions (a kringle IV [K4] repeat), the latter of which also affects Lp(a) particle size. The impact of these polymorphisms on cardiovascular risk is poorly understood. Methods and Results— We studied both polymorphisms and Lp(a) levels in 834 registry-based myocardial infarction (MI) patients (38% women) and 1548 population-based controls. Lp(a) concentrations were inversely related with the numbers of K4 and PN repeats. However, the effect of the PN polymorphism was restricted to subjects producing small Lp(a) particles (≤8 PN 66.1 mg/dL versus >8 PN 8.7 mg/dL; P P < 0.002) and in women with ≤8 PN repeats (OR 1.46, P =0.009). Interestingly, in women, the frequent haplotype with ≤8 PN and ≤22 K4 repeats, which is related to high levels of small Lp(a) particles, resulted in an elevated OR for MI (1.79; P =0.01) independently of Lp(a) serum concentration. Conclusions— The K4 and PN repeat polymorphisms largely explain the high variability of serum Lp(a) levels. A haplotype with ≤8 PN and ≤22 K4 repeats is characterized by high concentrations of small Lp(a) particles. Our observation that this haplotype was associated with MI independently of Lp(a) serum levels may suggest that Lp(a) particle size in addition to its concentration may modulate MI risk in women.