[Show abstract][Hide abstract] ABSTRACT: Background
Insulin resistance (IR) and endothelial dysfunction are frequently associated in cardiac disease. The T−786→C variant in the promoter region of the endothelial nitric oxide synthase (eNOS) gene has been associated with IR in both non-diabetic and diabetic subjects. Aim of the study was to assess the reciprocal relationships between T−786→C eNOS polymorphism and IR in ischemic and non-ischemic cardiomyopathy.
A group of 132 patients (108 males, median age 65 years) with global left ventricular (LV) dysfunction secondary to ischemic or non-ischemic heart disease was enrolled. Genotyping of T−786→C eNOS gene promoter, fasting glucose, insulin, and insulin resistance (defined as HOMA-IR index > 2.5) were determined in all patients.
Genotyping analysis yielded 37 patients homozygous for the T allele (TT), 70 heterozygotes (TC) and 25 homozygous for C (CC). Patients with CC genotype had significantly higher systemic arterial pressure, blood glucose, plasma insulin and HOMA index levels than TT. At multivariate logistic analysis, the history of hypertension and the genotype were the only predictors of IR. In particular, CC genotype increased the risk of IR (CI% 1.4-15.0, p < 0.01) 4.5-fold. The only parameter independently associated with the extent of LV dysfunction and the presence of heart failure (HF) was the HOMA index (2.4 CI% 1.1-5.6, p < 0.04).
T−786→C eNOS polymorphism was the major independent determinant of IR in a population of patients with ischemic and non-ischemic cardiomyopathy. The results suggest that a condition of primitive eNOS lower expression can predispose to an impairment of glucose homeostasis, which in turn is able to affect the severity of heart disease.
BMC Medical Genetics 10/2012; 13(1):92. DOI:10.1186/1471-2350-13-92 · 2.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endothelial dysfunction and carotid intima-media thickeness (IMT) are currently considered key early events in atherogenesis and markers of arterial damage. We investigated whether endothelial nitric oxide synthase (eNOS) glutamate (Glu)298-aspartate (Asp) polymorphism may influence the vascular response to weight, as measured by BMI, in young, healthy individuals.
One hundred young (30.6 ± 5.9 years) healthy individuals, without concomitant traditional cardiovascular risk factors took part in the study. Brachial artery endothelial function was assessed by vascular response to reactive hyperemia [flow-mediated dilation (FMD) and sublingual nitroglycerin (GTN)-mediated dilation] using high-resolution ultrasound. Carotid IMT was also measured.
Participants were grouped as Glu-homozygotes (n = 38) and Asp-carriers (n = 62). On univariate analysis, a higher response to GTN was associated with lower brachial baseline diameter (P < 0.001) and increasing value of high-density lipoprotein cholesterol (P = 0.04) in Asp-carriers, but not in Glu-homozygotes. Higher FMD correlated with lower brachial baseline diameter (P < 0.001), BMI (P = 0.03) and SBP (P = 0.03) in the Asp-carriers, but not in Glu-homozygotes. Higher IMT showed a similar Asp-genotype-dependent association with higher BMI (P = 0.001), SBP (P = 0.006) and DBP (P = 0.001). In individuals with Asp-alleles, the multivariate analysis showed that BMI was the only independent predictor of IMT.
Weight is independently associated with impaired arterial structure in healthy and genetically predisposed young individuals. The allelic variation (Asp298) of the eNOS gene polymorphism makes individuals vulnerable to the impact of weight on the development of atherosclerosis.
Journal of Cardiovascular Medicine 03/2012; 13(5):307-12. DOI:10.2459/JCM.0b013e3283536a0a · 1.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We describe a case of a patient with idiopathic dilated cardiomyopathy and cardiac conduction abnormalities who presented a strong family history of sudden cardiac death. Genetic screening of lamin A/C gene revealed in proband the presence of a novel missense mutation (R189W), near the most prevalent lamin A/C mutation (R190W), suggesting a "hot spot" region at exon 3.
[Show abstract][Hide abstract] ABSTRACT: Genetic testing has become an increasingly important part of medical practice for heritable form of cardiomyopathies. Hypertrophic cardiomyopathy and about 50% of idiopathic dilatative cardiomyopathy are familial diseases, with an autosomal dominant pattern of inheritance.
Some genotype-phenotype correlations can provide important information to target DNA analyses in specific genes. Genetic testing may clarify diagnosis and help the optimal treatment strategies for more malignant phenotypes. In addition, genetic screening of first-degree relatives can help early identification and diagnosis of individuals at greatest risk for developing cardiomyopathy, allowing to focus clinical resources on high-risk family members.
This paper provides a concise overview of the genetic etiology as well as the clinical utilities and limitations of genetic testing for the heritable cardiomyopathies.
[Show abstract][Hide abstract] ABSTRACT: The endothelin (ET) system plays a central role in the control of myocardial function and its pathophysiology. The aim of the present study was to explore whether genetic variations of ET-1 (G/T substitution that predicts an Lys/Asn change at codon 198) and its receptor ET(A) (T/C in exon 6, H323H) could predispose carriers to heart failure (HF).
Genotyping at these two loci was done in 122 patients with HF [echocardiographic left ventricular ejection fraction (LVEF) < or =40%] and 216 age-matched subjects without HF. Causes of HF included ischemic (n = 96) and idiopathic cardiomyopathies (n = 26).
The ET-1 Lys198Asn was significantly associated with the occurrence of HF (p = 0.005). The risk of HF was independently increased among Asn/Asn in comparison to Lys carriers (OR = 3.2, p = 0.03). Moreover, homozygous carriers of both ET-1 and ET(A) variants showed a marked increase in the risk of HF (adjusted OR = 8.6, p = 0.005), displayed significantly lower LVEF (p = 0.002) and higher left ventricular end-diastolic (p = 0.03) and end-systolic diameters (p = 0.04; for Asn/Asn and TT vs. Lys and C carriers of the ET-1 and ET(A )polymorphisms, respectively). Furthermore, the extent of coronary artery disease (r = -0.62, p < 0.0001) and the Asn/Asn and TT double genotype (r = -0.30, p = 0.0001) were the only significant and independent predictors of LVEF by multivariate analysis.
The ET-1 Lys198Asn and ET(A) receptor H323H polymorphisms seem to act synergistically to increase the risk of HF.
[Show abstract][Hide abstract] ABSTRACT: To assess the role of the endothelial nitric oxide synthase (eNOS) gene variants as risk factors for early atherosclerosis, we sought to investigate whether two polymorphisms located in the exon 7 (Glu298-->Asp) and in the promoter region (T-786-->C) of the eNOS gene were associated with functional changes in the endothelium and carotid intima-media thickness (IMT).
Endothelium-dependent flow-mediated brachial artery dilation (FMD), endothelium-independent dilation response to glyceryl trinitrate (GTN), and carotid IMT were assessed by high-resolution ultrasound in 118 healthy young nonsmoker subjects (30.1+/-0.5 years) genotyped for the eNOS Glu298-->Asp and T-786-->C polymorphisms.
Carotid IMT was inversely related to FMD by univariate analysis (r=-0.28, P=0.002) and after adjustment for possible confounders in all the subjects (P<0.01). Asp homozygotes had a significantly lower FMD than Glu carriers (Glu/Glu: 15.0%+/-1.0%, Glu/Asp: 13.3%+/-0.7%, Asp/Asp: 9.6%+/-1.6%; P=0.005), whereas FMD was unaffected by the T-786-->C variant. Neither the Glu298-->Asp nor the T-786-->C polymorphisms influenced the GTN-mediated dilation. With respect to Glu carriers, Asp/Asp genotype displayed a significantly greater carotid IMT (Glu/Glu: 0.37+/-0.01 mm, Glu/Asp: 0.35+/-0.01 mm, Asp/Asp: 0.45+/-0.03 mm; P=0.0002) and significant correlations between carotid IMT and FMD (r=-0.48, P=0.04) and between carotid IMT and resting brachial artery diameter (r=0.70, P=0.001). No difference in IMT was found across the T-786-->C genotypes. By multivariate regression analysis, Asp/Asp genotype was the only significant and independent predictor of flow-mediated brachial artery dilation (FMD) (P=0.04) and carotid intima-media thickness (IMT) (P=0.006).
The eNOS Glu298-->Asp polymorphism may be related to early atherogenesis.
[Show abstract][Hide abstract] ABSTRACT: Epidemiological studies indicated a role for polymorphisms in genes of folate and homocysteine (Hcy) metabolism in the etiology of neurodegenerative disease, congenital defects and coronary artery disease (CAD). This study investigated the effect of several polymorphisms [C677 T, A1298C of methylenetetrahydrofolate reductase (MTHFR) and A66G of methionine synthase reductase (MTRR) genes] on Hcy levels and DNA damage in 68 patients who underwent coronary angiography. Plasma Hcy concentrations were higher in patients with multivessel disease with respect to monovessel disease and no-CAD patients (19.4+/-2.6 vs 11.6+/-1.2 and 13.7+/-1.4 micromol/l, respectively; P=0.03). 677TT patients had higher Hcy levels than those with 677CC or 677CT genotypes (26.2+/-4.3 vs 13.1+/-1.4 and 13.0+/-1.4 micromol/l, respectively; P=0.0006). No significant associations were found between A1298C and A66G polymorphisms and plasma Hcy levels. Among patients with 677CC genotype, 66GG individuals tended to have higher levels of Hcy than 66AA homozygotes (14.5+/-1.9 vs 8.9+/-0.7 micromol/l, P=0.06). Multivessel disease patients showed an increased frequency of DNA damage, measured by the micronucleus (MN) frequency, as compared to monovessel disease and no-CAD subjects (12.5+/-1.1 vs 8.5+/-0.8 and 8.2+/-0.9, respectively; P=0.006). The MN were positively correlated with Hcy levels (r=0.33, P=0.006) and were significantly higher in subjects with the 677TT genotype compared with the 677CC or 677CT genotypes (14.4+/-2.0 vs 8.8+/-1.2 and 9.5+/-0.7, respectively; P=0.006). A1298C and A66G polymorphisms had no effect on MN frequency. However, among 677TT patients, 66GG subjects tended to have higher levels of MN than those 66AG and 66AA (18.2+/-3.6 vs 13.8+/-4.0 and 10.3+/-1.7, respectively; P=NS). Our results indicate that genetic instability may be associated with increased risk for multiple Hcy-related diseases.
European Journal of HumanGenetics 10/2003; 11(9):671-8. DOI:10.1038/sj.ejhg.5201024 · 4.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cardiovascular diseases and cancer are the main causes of death in developed countries. Mortality trends for these diseases suggest that they share common pathogenetic mechanisms. Glutathione S-transferase (GST) is a family of enzymes that detoxify reactive electrophiles, particularly present in tobacco smoke. Glutathione S-transferase null M1 and T1 (GSTM1 and GSTT1) genotypes have often been associated with increased risk of developing cancer. Our hypothesis was that the polymorphic GSTM1 and GSTT1 genes modulate the risk of smoking-coronary artery disease (CAD). We evaluated the distribution of GST genotypes in 430 angiographically defined patients (308 CAD and 122 non-CAD). The frequencies of GST null genotypes did not differ significantly between patients with CAD and without CAD. However, smokers with GSTM1 and GSTT1 null genotypes had a significantly higher risk of CAD than never-smokers with these genotypes present (OR 2.2 and 3.4 for smokers with null GSTM1 and GSTT1 genes, respectively). There was also evidence of multiple interaction between GSTM1 and GSTT1 deleted genotypes and smoking. In nonsmokers carrying both null genotypes the risk of CAD was 0.66. In smokers with both present genotypes the OR was 1.5 and was significantly increased in smokers with concurrent lack for GSTM1 and GSTT1 genes (OR=4.0). Moreover, smokers lacking GST genes had both more stenosed vessels and a higher Duke score than smokers expressing the genes. We also examined the levels of DNA damage in 66 men patients using the micronucleus test, a sensitive assay for evaluating chromosome damage. Micronucleus levels were higher in smokers with null genes than in smokers with present genes. These observations suggest that GST-null genotypes strengthen the effect of smoking on CAD risk by modulating the detoxification of genotoxic atherogens.
Journal of Molecular Medicine 09/2003; 81(8):488-94. DOI:10.1007/s00109-003-0448-5 · 5.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endothelial nitric oxide synthase (eNOS) could be a candidate gene for coronary artery disease (CAD). This study investigated the relationship of the eNOS Glu(298)-->Asp and T(786)-->C polymorphisms with the presence and severity of CAD in the Italian population.
We enrolled 415 unrelated individuals who underwent coronary angiography. The severity of CAD was expressed by means of the Duke score. The eNOS Glu(298)-->Asp and T(786)-->C variants were analyzed by PCR.
There was significant linkage disequilibrium between the two eNOS polymorphisms (P <0.0001). Both variants were significantly associated with the occurrence and severity of CAD (P = 0.01 and 0.004 for Glu(298)-->Asp and T(786)-->C, respectively). The risk of CAD was increased among individuals homozygous for the C allele of the T(786)-->C polymorphism compared with individuals homozygous for the T allele (odds ratio = 2.5; P <0.01) and was independent of the other common risk factors (P = 0.04). Moreover, individuals with both the Asp/Asp genotype of the Glu(298)-->Asp polymorphism and at least one C allele of the T(786)-->C variant in the promoter region of the eNOS gene had an increased risk of CAD (odds ratio = 4.0; P <0.001) and a significantly higher mean Duke score (26.2 +/- 2.9 vs 45.2 +/- 3.7; P = 0.002) compared with individuals with the TT genotype and the Glu allele.
The present study provides evidence that the Glu(298)-->Asp and T(786)-->C polymorphisms of the eNOS gene are associated with the presence and severity of angiographically defined CAD in the Italian population and that those individuals carrying both eNOS variants simultaneously might have a higher risk of developing CAD.
[Show abstract][Hide abstract] ABSTRACT: Elevated levels of plasma homocysteine (Hcy), a risk factor for coronary artery disease (CAD), can result from genetic errors, e.g., the methylenetetrahydrofolate reductase (MTHFR) polymorphism, or nutritional deficiencies, e.g., in vitamin B12 and folate. The mechanism by which Hcy induces atherosclerosis is not fully understood. Recently, Hcy has also been observed to induce DNA damage. In this study, we have investigated whether DNA damage is related to the C677T variant in the MTHFR gene and to plasma levels of Hcy, B12, and folate in patients with CAD. Patients ( n=46) with angiographically proven CAD were studied by using the micronucleus (MN) test, an accepted method for evaluating genetic instability. TT patients had plasma Hcy levels higher than those with the CT or CC genotypes (27.8+/-5.2 vs 13.7+/-2.2 and 12.9+/-1.9 micro mol/l, respectively; P=0.02). Patients with multi-vessel disease had higher plasma Hcy levels (11.6+/-1.2, 22.0+/-4.7, 19.3+/-3.9 micromol/l for one-, two- and three-vessel disease, respectively; P=0.05). The MN index increased with the number of affected vessels (8.4+/-0.7, 11.1+/-2.0, 14.2+/-1.7 for one-, two-, and three-vessels disease, respectively; P=0.02) and was significantly higher in subjects with the TT genotype compared with the CC or CT genotypes (15.7+/-2.4 vs 8.9+/-1.7 and 9.9+/-0.8; P=0.02). The MN index was also correlated negatively with plasma B12 concentration ( r=-0.343; P=0.019) and positively with plasma Hcy ( r=0.429, P=0.005). These data indicate that the MN index is associated with the severity of CAD and is related to the MTHFR polymorphism, suggesting an interesting link between coronary atherosclerosis and genetic instability in humans.
Human Genetics 03/2003; 112(2):171-7. DOI:10.1007/s00439-002-0859-3 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES; We investigated the presence of oxidative deoxyribonucleic acid (DNA) damage in the peripheral lymphocytes of patients undergoing percutaneous transluminal coronary angioplasty (PTCA) by using the micronucleus test and comet assay, which are sensitive biomarkers of DNA damage. BACKGROUND; Although it has recognized that ischemia-reperfusion can induce oxidative DNA damage, its occurrence in patients undergoing PTCA has not yet been demonstrated.
Three groups of patients were enrolled: 30 patients with documented coronary heart disease who underwent elective PTCA (group I); 25 patients who underwent elective coronary angiography for diagnostic purpose (group II); and 27 healthy, age- and gender-matched subjects (group III). For each subject, the frequency of micronucleated binucleated (MNBN) cells, DNA single-strand breaks (SSBs), endonuclease III-sensitive sites, and sites sensitive to formamidopyrimidine glycosylase (FPG) were analyzed before and after diagnostic procedures.
The mean basal values of MNBN cells (p = 0.04), DNA-SSBs (p = 0.001), endonuclease III-sensitive sites (p = 0.002), and FPG sites (p < 0.0001) were significantly higher in groups I and II than in group III. A high significant increase of MNBN cell frequency was observed in group I after the PTCA procedure (11.0 +/- 1.3 vs. 19.8 +/- 1.6, p < 0.0001), whereas no significant difference was observed in group II (10.2 +/- 1.3 vs. 12.9 +/- 1.4, p = 0.18). A significant positive correlation was observed between the increase in the MNBN cell rate and total inflation time during PTCA (R = 0.549, p = 0.0017). The levels of DNA-SSBs (11.7 +/- 1.4 vs. 26.5 +/- 3.0, p = 0.0003) and FPG sites (13.8 +/- 1.8 vs. 22.5 +/- 2.4, p = 0.01) were also higher after PTCA.
Our results provide evidence for oxidative DNA damage after PTCA, likely related to ischemia-reperfusion injury.
Journal of the American College of Cardiology 09/2002; 40(5):862-8. DOI:10.1016/S0735-1097(02)02042-9 · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A common polymorphism at codon 72 (Arg72Pro) of the p53 gene, a gene which codes for a tumor-suppressor protein with both antiproliferative and pro-apoptotic actions, has recently been reported to be a risk factor for coronary luminal narrowing after angioplasty. However, the association of the polymorphism with coronary artery disease (CAD) risk has not been studied. We evaluated the distribution of the Arg72Pro genotype in 250 patients, 180 with angiographically documented CAD and 70 with normal coronary angiography, by using polymerase chain reaction amplification of patient DNA followed by restriction enzyme digestion. We also examined the association between the Arg72Pro genotype and chromosome damage in 82 male patients (60 CAD and 22 no-CAD) by the micronucleus (MN) test in human lymphocytes, a sensitive assay for chromosome breakage and aneuploidy. The frequencies of Pro/Pro, Pro/Arg, and Arg/Arg genotypes in CAD patients were not significantly different from those who were CAD-free (chi(2) = 0.20, P = 0.90) and not significantly associated with the extent and severity of CAD. A significant increase in MN frequency was observed in relation to smoking status (8.4 +/- 0.6, 11.9 +/- 1 and 12.0 +/- 1.6, for non smokers, ex-smokers and smokers, respectively; P = 0.02). Moreover, diabetic patients showed higher levels of MN than normal patients (13.5 +/- 1.4 vs. 9.6 +/- 0.5, P = 0.0025). Also, MN frequency was significantly higher in CAD patients than in no-CAD patients (11.2 +/- 0.7 vs. 8.0 +/- 0.9, P = 0.02) and increased with the number of affected vessels (9.3 +/- 0.1, 12.2 +/- 1.5 and 12.5 +/- 1.3 for one-, two-, and three-vessel disease, respectively; P = 0.02). However, there were no associations between MN frequency and the Arg72Pro polymorphism. Although there appears to be an association between CAD and MN frequency, our results indicate that the Arg72Pro polymorphism does not have a significant impact on CAD or MN frequencies.
[Show abstract][Hide abstract] ABSTRACT: Functionally important variants of endothelial Nitric Oxide Synthase (eNOS) could influence individual susceptibility to atherosclerosis. Recent reports have suggested that the Glu298→Asp variant of eNOS is associated with coronary spasm and acute myocardial infarction. This finding is potentially important but requires further confirmation in other populations.In this study, we investigated the relationship between the Glu298→Asp polymorphism and atherosclerotic coronary artery disease (CAD) in an Italian population; moreover, we evaluated if this variant may affect endothelial function, which is not yet known.We studied 57 consecutive patients aged 50% stenosis affecting at least 1 vessel) and 65 normal controls. We performed PCR/restriction fragment length polymorphism analysis to detect the missense Glu298→Asp variant in exon 7 of the eNOS gene. For the evaluation of the endothelial function, in 11 healthy, non smokers and genotyped young subjects (28.7±2.4 years), the percentage change of the brachial artery diameter (FMD) after forearm cuff occlusion and glyceryl trinitrate (GTN) was assessed.The frequencies of the eNOS Glu/Glu, Glu/Asp and Asp/Asp genotypes in the CAD group were significantly different from those of controls (49.1%, 36.8% and 14.0% vs 38.5%, 55.4% and 6.1%, respectively, Chi Square=8.108, p=0.017). In comparison to Glu298 homozygotes, homozygosity for Asp298 was associated with an odds ratio of 1.8 (95% CI, 0.48 to 6.66). Moreover, homozigous carriers of the eNOS Asp298 displayed a significantly lower FMD compared to heterozygotes and individuals without the Asp298 allele (Asp/Asp: 7.35%±5.06% vs Glu/Glu: 18.1%±4.85%, Mean±SD, p=0.04). On the contrary, the endothelium-indipendent vasodilation did not change significantly in neither group.In conclusion, the eNOSGlu298→Asp polymorphism is associated with the occurence of CAD in an Italian population probably by altering the activity of the vascular NO system at endothelial level.
[Show abstract][Hide abstract] ABSTRACT: Several studies suggest that cancer, hypertension and atherosclerosis may share common biological mechanisms. Although an increase in the mutation rate may be involved in the pathogenesis of some cardiovascular disease, its presence in patients (pts) with coronary artery disease (CAD) has not yet studied.Aim of this study was to investigate the presence of chromosomal damage in peripheral blood lymphocytes in pts with CAD by using micronucleus (MN) test, a reliable biomarker in genetic and cancer risk assessment.In the present study were included 53 pts with angiographically documented CAD (Group I) were included; 10 pts with valvular heart disease in absence of atherosclerotic lesions of the coronary arteries (Group II); furthermore 16 healthy subjects, age and sex-matched (Group III) were included as controls. For each subject, two separate cultures of whole blood were incubated for 72 hours and harvested after a treatment with cytochalasin B (6 μg/ml) to block the cytokinesis of the lymphocytes. 1000 binucleated cells were scored for the evaluation of MN frequency. Means (±SEM) of MN frequency were 11.9±1.7, 5.9±1.2 and 3.6±0.7 in group I, II, and III respectively. The MN frequency of group I was significantly higher than that of the group III (p=0.02). Moreover, MN frequency increases with affected vessel number (6.3±0.7, 13.9±1.6, 14.9±5.3 for one-, two-, and three-vessel disease, respectively). ANOVA analysis showed that the MN frequency was significantly higher in two-vessel compared with one-vessel disease (p=0.0077).Multiple regression analysis also showed that the Duke score, which indicates the severity of CAD, and systolic blood pressure appeared to be the two determinant factors in determining MN frequency (R=0.310, p=0.01; R=0.267, p=0.03, respectively). These results suggest that CAD in humans is a condition characterized by an increase of DNA damage, which positively correlates with the increased systolic blood pressure and the severity of the atherosclerotic disease.
[Show abstract][Hide abstract] ABSTRACT: Endothelin (ET)-1 peripheral levels are high in children with respect to values of adults, but its pathophysiological significance remains to be established. In these conditions the interaction of ET-1 with its receptors may constitute a clue to the understanding of ET-1 function. Because a direct determination of ET binding sites in the heart of children is lacking, in this study we have attempted an assessment of the ET receptor status in cardiac tissue of infants (<1 year; 0.39 +/- 0.26 (SD) years, n=6) and children (1-14 years; 6.3 +/- 4.9 years, n=7) as well as an evaluation of the receptor modulation as a function of age, associated to the observed decrease of plasma ET levels between infants and children. ET-1 binding sites have also been evaluated in atrium and ventricle membranes of adult subjects recipient of cardiac transplantation (CHF) and of post-mortem cardiac specimens (autopsy) of non cardiac patients. Considering all the pediatric patients (infants +/- children) studied, an affinity constant (Kd) value of 38.2 +/- 6.1 (SEM) pM and a density (Bmax) value of 166.2 +/- 11.6 fmol/mg protein has been obtained for atrium. Similar values have been found in the ventricle. These values are significantly higher with respect to those obtained in adults: for atrial membranes, Kd = 22.2 +/- 9.7 and 11.6 +/- 1.8 pM; Bmax = 58.4 +/- 22.8 and 42.1 +/- 8.9 fmol/mg protein, respectively in explanted hearts and in post mortem specimens. No significant differences have been found in the binding parameters between infants and children, while, considering our results as a whole, a significant inverse correlation between Bmax and subject age (p<0.001) is suggested. The ET-A/ET-B ratio, evaluated by competition experiments with the specific ET-A antagonist BQ-123, was about 70:30 in pediatric patients, in both atrium and ventricle, without any difference between infants and children. Similar values for ET-A/ET-B ratio in adult CHF patients, in contrast to a reduction (significant only in ventricle) of the percent of ET-A subtype in autopsy, has been found. This is the first study concerning a direct evaluation of ET receptor status in children's hearts; the higher density of binding sites, associated to the elevation of plasma levels, could suggest a enhanced biological function of ET in children.
Life Sciences 01/1999; 64(8):697-705. DOI:10.1016/S0024-3205(98)00611-0 · 2.70 Impact Factor