Norbert Katz

Arabinoxylan consumption decreases postprandial serum glucose, serum insulin and plasma total ghrelin response in subjects with impaired glucose tolerance

Objective:Arabinoxylan (AX) consumption is associated with metabolic improvement during diabetes and with modulation of ghrelin, an orexigenic gut hormone. The effect of AX consumption on ghrelin secretion in disturbed metabolic states is unknown. Therefore, we investigated the postprandial responses to AX consumption of serum glucose, insulin and triglycerides and plasma total and acylated ghrelin in subjects with impaired glucose tolerance (IGT).Design:Randomized, single-blind, controlled, crossover intervention trial.Subjects:Seven female and four male adults with IGT, aged 55.5 years, and body mass index (BMI) 30.1 kg/m2.Intervention:Subjects received either placebo or 15 g AX supplement for 6 weeks with a 6-week washout period in-between.Main outcome measurements:Postprandial responses of serum glucose, insulin and triglycerides, and plasma total and acylated ghrelin after a liquid meal challenge test (LMCT) measured at the beginning and at the end of the dietary intervention at −20, −5, 0, 15, 30, 45, 60, 90, 120, 150, 180, 210 and 240 min.Results:After LMCT, AX consumption resulted in lower postprandial responses in serum glucose, insulin and triglycerides (P<0.05). Compared to placebo, total plasma ghrelin was also reduced by 42±8 pg/ml (P<0.001) after AX consumption with no difference in plasma acylated ghrelin.Conclusion:AX consumption improved postprandial metabolic responses after an LMCT in subjects with IGT and reduced total ghrelin response. However, acylated ghrelin responses were unchanged, suggesting that the acylated ghrelin-mediated orexigenic regulation is not improved as only total plasma ghrelin decreased.Sponsorship:Federal Ministry of Education and Research Germany (PTJ-BIO/0313042C).

Detection of myocardial injury during transvenous implantation of automatic cardioverter-defibrillators.

OBJECTIVES The present study was designed to assess the extent of myocardial injury in patients undergoing transvenous implantation of an automatic implantable cardioverter-defibrillator (ICD) using cardiac troponin I (cTNI), which is a highly specific marker of structural cardiac injury. BACKGROUND During ICD implantation, repetitive induction and termination of ventricular fibrillation (VF) via endocardial direct current shocks is required to demonstrate the correct function of the device. Transthoracic electrical shocks can cause myocardial cell injury. METHODS Measurements of total creatine kinase (CK), CK-MB, myoglobin, cardiac troponin T (cTNT) and cTNI were obtained before and after ICD implantation in 49 consecutive patients. Blood samples were drawn before and 2, 4, 8, and 24 h after implantation. RESULTS Elevations of CK, CK-MB, myoglobin, cTNT and cTNI above cut-off level were found in 25%, 6%, 76%, 37% and 14% of patients, respectively, with peak cTNI concentrations ranging from 1.7 to 5.5 ng/ml. Cumulative defibrillation energy (DFE), mean DFE, cumulative VF time, number of shocks as well as prior myocardial infarction (MI) were found to be significantly related to a rise of cTNI. Mean DFE > or = 18 J and a recent MI were identified as strong risk factors for cTNI rise. CONCLUSIONS During transvenous ICD implantation myocardial injury as assessed by cTNI rise occurs in about 14% of the patients. Peak cTNI concentrations are only minimally elevated reflecting subtle myocardial cell damage. Patients with a recent MI and a mean DFE > or = 18 J seem to be prone to cTNI rise.

The p22 phox A640G gene polymorphism but not the C242T gene variation is associated with coronary heart disease in younger individuals.

BACKGROUND Most recently, evidence has been presented that the NADH/NADPH oxidase p22 phox C242T, but not the A640G gene polymorphism is associated with a reduced risk of coronary artery disease (CAD). METHODS AND RESULTS We analysed the relationships of both p22 phox gene polymorphisms to CAD in 2205 male Caucasians whose coronary anatomy was defined by means of coronary angiography. In the total population and in high and low risk groups the relative frequencies of the C242T alleles were essentially the same in patients without or with CAD and in individuals without or with myocardial infarction. In contrast, the G allele of the A640G polymorphism was significantly more frequent in subjects without CAD than in patients with CAD (Odds ratio (OR) 0.74 (0.57-0.98); P = 0.038 in multiple logistic regression (MLR)). Correspondingly, the AA genotype of A640G was preferentially found in patients with CAD. These associations did not disappear when the analyses were corrected for multiple comparisons for other gene polymorphisms (ACE I/D gene variation, angiotensinogen T174M and M235T gene polymorphisms, AT1 receptor gene variation, phox C242T gene polymorphism, paraoxonase PON54 and PON191 gene variations) (2p = 0.01 in MLR for the presence of CAD; 2p = 0.039 in multiple regression for the extent of CAD). The association of the A640G gene variation with the presence and extent of CAD was not only identified in the total sample, but was even stronger in various high risk subpopulations of younger individuals (e.g. with hypertension with or without increased apolipoprotein B plasma levels). CONCLUSIONS Our observations allow the assumption that the p22 phox A640G gene polymorphism is independently associated with the presence and extent of coronary artery disease.

Gene Polymorphism but not Catalytic Activity of Angiotensin I–Converting Enzyme Is Associated With Coronary Artery Disease and Myocardial Infarction in Low-Risk Patients

BACKGROUND An insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene has been postulated to be associated with an increased risk of coronary artery disease (CAD) and myocardial infarction (MI). METHODS AND RESULTS In the present study, the effects of I/D gene polymorphism and of ACE activity on CAD and MI were investigated in 920 individuals who underwent coronary angiography for diagnostic purposes. In the total population and in all CAD and MI groups, a strong association was observed between the gene polymorphism and ACE activities; DD genotypes had approximately twofold higher ACE activities than II genotypes. Although classic risk and protective factors of CAD and MI were identified, associations of ACE genotype and of ACE activity to CAD and MI were not detected in the total population. Among subjects defined to be at lower risk of MI by low body mass index and low cigarette consumption, however, an association of the DD genotype with MI was found. Exclusion of individuals with triglyceride levels > 140 mg/dL and cholesterol levels > 180 mg/dL revealed an association of the DD genotype with CAD. An association of the ACE activity with CAD or MI could not be demonstrated in any of the low-risk populations. CONCLUSIONS Increased ACE activity obviously is not a risk factor of CAD or MI. The importance of the deletion polymorphism for the development of CAD and MI may be restricted to individuals without classic risk factors.

Metabolic Heterogeneity of Hepatocytes across the Liver Acinus

Periportal hepatocytes around the afferent vessels and perivenous hepatocytes around the efferent vessels of the liver acinus exhibit different metabolic capacities and subcellular structures. This observation led to the concept of the metabolic zonation of the liver acinus. Oxidative energy metabolism, gluconeogenesis, urea synthesis, bile formation and protective metabolism are catalyzed mainly in the periportal zone; glycolysis linked to liponeogenesis, glutamine synthesis and xenobiotic metabolism are predominant in the perivenous zone. This zonation is dynamic rather than static. Zonation develops gradually, depending on perinatal changes of the hepatic circulation and on postnatal alterations of the supply with energy substrates. Zonation also is modulated during puberty. Moreover, adaptation to longer-lasting physiological and pathological alterations occurs as observed during starvation and refeeding, diabetes and regeneration after partial hepatectomy or zonal necrosis. Periportal to perivenous gradients of oxygen, hormones and metabolites, as well as zonal differences in the hepatic innervation, seem to be responsible for the heterogeneous gene expression within the liver acinus.

The T allele of the missense Glu298Asp endothelial nitric oxide synthase gene polymorphism is associated with coronary heart disease in younger individuals with high atherosclerotic risk profile

AIMS Nitric oxide (NO) plays a protective role during atherogenesis. In the endothelium, NO is synthesised by the constitutive NO synthase (ecNOS). We analysed the relation of the ecNOS Glu(298)Asp and 4a/b gene polymorphisms to coronary artery disease (CAD) and myocardial infarction (MI) in a population of 3250 German subjects (533 healthy controls and 2717 individuals who underwent coronary angiography). RESULTS Although in the total sample, the ecNOS T allele was not associated with the risk of CAD (P=0.054) and the extent of this disease (P=0.078), a restriction to younger individuals (age</=61, mean age) revealed an association of the ecNOS T allele with an increased risk of CAD (1.43, 1.05-1.96; P=0.025) and with the severity of this disease (P=0.037). Similar observations were made in various high-risk populations. These associations were even more pronounced when the high-risk subgroups were restricted to younger individuals. For example, an odds ratio of 7.66 for CAD (95% CI, 2.0-29; P=0.003) was detected in diabetic individuals who were younger than 61 years. Also with respect to MI, the most pronounced associations of the ecNOS T allele with the risk of this disease were detected in younger individuals with at least one other cardiovascular risk factor. For example, in diabetics younger than 61 years, the relative risk for ecNOS T allele carriers was 9.73 (95% CI, 1.8-53; P=0.008). In contrast, the allele frequencies of the ecNOS 4a/b gene variation were essentially the same in controls and in CAD and MI patients. CONCLUSION The present data extends earlier observations by the findings that predominantly younger T allele carriers of the ecNOS Glu(298)Asp gene polymorphism with various coronary high-risk profiles had an increased risk to suffer CAD and/or MI. In contrast, no evidence was found for an association of the ecNOS 4a/b gene polymorphism with coronary heart disease.

The paraoxonase Leu–Met54 and Gln–Arg191 gene polymorphisms are not associated with the risk of coronary heart disease

BACKGROUND Evidence has been presented that gene polymorphisms (PON54 L/M, PON191 Q/R) of paraoxonase are risk factors of coronary heart disease. RESULTS We determined both PON genotypes in 535 male individuals who were free of vascular disease and in 2249 male subjects who underwent coronary angiography, and analysed the relation of both gene variations to CAD and MI. Both gene polymorphisms were in linkage disequilibrium (P<0.0001). Coronary artery disease: the PON54 gene polymorphism was not associated with an increased risk of CAD. In the total sample and also in younger subjects, an association of the PON191 gene variation with the risk of CAD was not detected when the control group of individuals without coronary heart disease was compared with patients with at least one diseased vessel (verified by coronary angiography). In individuals younger than 62 years, a moderate increase in the relative risk of CAD associated with the PON191 R allele (1.45 (1. 08-1.95); P=0.015) were found, when subjects without vessel disease (verified by coronary angiography) were compared with CAD patients. Myocardial infarction: an association of the PON54 gene variation with MI was not detected when the control group of individuals without coronary heart disease were compared with patients with at least one MI. A marginal increase in the risk of MI associated with the PON54 LL genotype (OR 1.27 (1.05-1.51); P=0.011) were detected when patients without MI but with coronary angiography were compared with MI positive patients. Subgroup analyses of low- and high-risk populations did not reveal any association of both PON gene polymorphisms with CAD or MI. CONCLUSION The present findings do not strengthen the hypothesis that the paraoxonase gene polymorphisms are independently associated with coronary heart disease indicating that these gene variations are of little usefulness as genetic markers of cardiovascular disease.

ACE I:D gene polymorphism: presence of the ACE D allele increases the risk of coronary artery disease in younger individuals

BACKGROUND Presence of the D allele or homozygosity for the deletion (D) allele of the ACE insertion/deletion (I/D) polymorphism has been discussed as potent risk factor for coronary artery disease (CAD) and myocardial infarction (MI). METHODS AND RESULTS In 2267 male Caucasians the relation of the ACE I/D gene polymorphism to CAD and MI were investigated. An association of the D allele to CAD was detected in younger subjects (e.g. < 61.7 years, mean value), but not in older patients (e.g. > or = 61.7 years). Additional exclusion of individuals with other cardiovascular risk factors (e.g. high BMI) produced an even stronger association of the D allele to CAD. In contrast, a relation of this polymorphism to non-fatal MI was only observed in older subjects; additional limitation to individuals without cardiovascular risk factors (e.g. BMI and/or diabetes) yielded a further enhancement of this association to MI. In younger subjects (e.g. < 61.7 years) the gene polymorphism was not related to non-fatal MI even after exclusion of additional risk factors. CONCLUSIONS The present large case-control study strengthens the assumption of an association of the ACE D allele with the risk of ischemic heart disease.

Angiotensinogen T174M and M235T gene polymorphisms are associated with the extent of coronary atherosclerosis

BACKGROUND The relations of the angiotensinogen (AGT) T174M and M235T gene polymorphisms to the risk of coronary heart disease (CHD) have been investigated in only a few studies with conflicting results. RESULTS Therefore, we analysed the relationship of the AGT gene polymorphisms to the presence and extent of CHD in 2250 male Caucasians whose coronary anatomy was defined by means of coronary angiography. The relative frequencies of the T and M alleles of the T174M and of the M235T gene variation did not significantly differ between patients without or with single-, double- or triple-vessel disease and between subjects without or with myocardial infarction (MI). In contrast the mean CHD score--defined by Gensini--was higher within MM homozygotes of the T174M gene variation than within TT genotypes; TM subjects had intermediate values. In M235T genotypes, mean CHD scores were similar in the total sample and in older individuals (> or = 62 years), whereas in younger individuals (< 62 years) a higher CHD score was found within AGT 235 T allele carriers than within MM homozygotes. In younger individuals with high apoAI plasma levels, the mean CHD score was clearly higher within TT homozygotes of the M235T gene variation than within MM genotypes; MT subjects had intermediate values. An interaction between both angiotensinogen gene polymorphisms on the extent of CHD or on the risk of non-fatal MI were not observed when the M allele of AGT T174M was combined either with the T allele or the TT genotype of M235T. CONCLUSIONS The present study strengthens the hypothesis of an association of both angiotensinogen gene polymorphisms with the extent of coronary heart disease.

Increased expression of disintegrin-metalloproteinases ADAM-15 and ADAM-9 following upregulation of integrins α5β1 and αvβ3 in atherosclerosis

Regulation of αvβ3 and α5β1 integrin function plays a crucial role in atherosclerosis. Possible regulators of integrin–matrix interactions are integrin‐binding ADAMs (proteins with a disintegrin‐ and metalloproteinase‐domain), like ADAM‐15 and ADAM‐9. Molecular interactions between ADAM‐15, α5β1, and αvβ3 have been demonstrated. ADAM‐9 and ADAM‐15 were found to be interdependently regulated. This study, therefore, investigated whether the upregulation of integrins α5β1 and αvβ3 was correlated with the expression of integrin‐binding ADAMs in atherosclerotic processes. Human arterial and venous vascular smooth muscle cells (VSMCs) were incubated with PDGF over different time intervals up to a 3‐day culture period. mRNA concentrations, quantified by real‐time RT‐PCR and normalized to PBGD, of integrins αvβ3 and α5β1 were strongly increased after a 12‐h PDGF‐incubation in arterial and venous VSMC. ADAM‐15 and ADAM‐9 mRNA production showed a corresponding increase following integrin upregulation after a 24‐h incubation period. Western blot anaylsis revealed an increased protein expression of integrins and ADAMs in PDGF‐stimulated VSMC. Additionally, mRNA concentrations of atherosclerotic and normal human specimens were quantified by real‐time RT‐PCR. mRNA of ADAMs and integrins was significantly increased in atherosclerotic arteries compared to normal arteries. Immunohistochemistry of these specimens showed an increased expression and codistribution of both ADAMs and integrins in atherosclerosis. In conclusion, upregulation of ADAM‐15 and ADAM‐9 in atherosclerosis appears to follow an increase in α5β1 and αvβ3 integrins. Since α5β1 and αvβ3 are known to promote smooth muscle cell migration and proliferation, upregulation of ADAM‐15 and ADAM‐9 could balance integrin–matrix interactions and cell migration, thus modulating neointima progression. J. Cell. Biochem. 89: 808–823, 2003.