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J Genest

Publications and source records attributed to J Genest.

At least 19 recordsLinked to original sources
PubMed1992

Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease.

The prevalence of abnormalities of lipoprotein cholesterol and apolipoproteins A-I and B and lipoprotein (a) [Lp(a)] was determined in 321 men (mean age 50 +/- 7 years) with angiographically documented coronary artery disease and compared with that in 901 control subjects from the Framingham Offspring Study (mean age 49 +/- 6 years) who were clinically free of coronary artery disease. After correction for sampling in hospital, beta-adrenergic medication use and effects of diet, patients had significantly higher cholesterol levels (224 +/- 53 vs. 214 +/- 36 mg/dl), triglycerides (189 +/- 95 vs. 141 +/- 104 mg/dl), low density lipoprotein (LDL) cholesterol (156 +/- 51 vs. 138 +/- 33 mg/dl), apolipoprotein B (131 +/- 37 vs. 108 +/- 33 mg/dl) and Lp(a) levels (19.9 +/- 19 vs. 14.9 +/- 17.5 mg/dl). They also had significantly lower high density lipoprotein (HDL) cholesterol (36 +/- 11 vs. 45 +/- 12 mg/dl) and apolipoprotein A-I levels (114 +/- 26 vs. 136 +/- 32 mg/dl) (all p less than 0.005). On the basis of Lipid Research Clinic 90th percentile values for triglycerides and LDL cholesterol and 10th percentile values for HDL cholesterol, the most frequent dyslipidemias were low HDL cholesterol alone (19.3% vs. 4.4%), elevated LDL cholesterol (12.1% vs. 9%), hypertriglyceridemia with low HDL cholesterol (9.7% vs. 4.2%), hypertriglyceridemia and elevated LDL cholesterol with low HDL cholesterol (3.4% vs. 0.2%) and Lp(a) excess (15.8% vs. 10%) in patients versus control subjects, respectively (p less than 0.05). Stepwise discriminant analysis indicates that smoking, hypertension, decreased apolipoprotein A-I, increased apolipoprotein B, increased Lp(a) and diabetes are all significant (p less than 0.05) factors in descending order of importance in distinguishing patients with coronary artery disease from normal control subjects. Not applying a correction for beta-adrenergic blocking agents, sampling bias and diet effects leads to a serious underestimation of the prevalence of LDL abnormalities and an overestimation of HDL abnormalities in patients with coronary artery disease. However, 35% of patients had a total cholesterol level less than 200 mg/dl after correction; of those patients, 73% had an HDL cholesterol level less than 35 mg/dl.

Apolipoproteins↗
PubMed1992

The MspI restriction fragment length polymorphism 3' to the apolipoprotein A-II gene: relationships with lipids, apolipoproteins, and premature coronary artery disease.

In previous studies, a restriction fragment length polymorphism (RFLP) has been identified using MspI restriction endonuclease in the 3' region of the apo A-II gene. The rare variant site for this MspI (M2) has been reported to be associated with higher levels of HDL cholesterol and apo A-II. We have studied the frequency and lipid associations of this RFLP in a population of 168 coronary artery disease (CAD) male and female patients, who had more than 50% narrowing of one or more arteries prior to age 60 years, as well as 255 aged-matched males and females from the Framingham Offspring Study. We also studied 31 kindreds in which the proband had premature CAD. The frequency of the M2 allele was higher in CAD cases (0.20) than in the controls (0.13) (P less than 0.05). In general, those subjects carrying the M2 allele had lower HDL cholesterol and apo A-I plasma levels; however, this difference was only significant (P less than 0.02 and 0.002, respectively) in females with CAD. No cosegregation of the M2 allele with hypoalphalipoproteinemia was found in 31 kindreds studied. However, in both generations there was a trend for those subjects carrying the M2 allele to have lower HDL cholesterol levels than those carrying the M1 allele. Sequence analysis of the apo A-II gene of subjects homozygous for either the M1 (n = 1) or the M2 allele (n = 2) revealed that this RFLP is due to a T----C single base mutation 528 bp 3' to the apo A-II gene. In the subjects homozygous for the M2 allele no other mutations were found within the coding region of the apo A-II gene that could result in changes in the primary sequence of the protein. These data indicate that the MspI RFLP 3' to the apo A-II gene is somewhat more frequent in the CAD group. However, there was no significant association between this RFLP and any of the parameters examined. In conclusion, this DNA marker lacks the specificity to be clinically useful for CAD risk assessment in the population studied.

Adult↗
PubMed1991

Lipoprotein (a) blood levels in unstable angina pectoris, acute myocardial infarction, and after thrombolytic therapy.

Lipoprotein (a) [Lp(a)] appears to be involved in atherogenesis and in vitro studies have suggested that it may interfere with thrombolysis. In this study, Lp(a) serum levels were determined by radioimmunoassay in 124 patients with ischemic heart disease. Of these, 47 had acute myocardial infarction, 13 had unstable angina, and 64 were age-matched patients with stable angina. Of the 60 patients with acute coronary artery disease, 34 received thrombolysis and 26 did not. In addition to Lp(a), serum plasminogen, alpha 2 antiplasmin, fibrinogen, and D-dimer (cross-linked fibrin degradation products) levels were measured. These tests were repeated after 6 hours in patients with myocardial infarction and unstable angina. No significant difference was found for admission Lp(a) levels among patients with myocardial infarction (0.324 +/- 0.047 g/liter), unstable angina (0.435 +/- 0.123 g/liter) and stable angina (0.431 +/- 0.023 g/liter), between patients with myocardial infarction with or without thrombolytic treatment, nor between late and early measurements in patients with unstable angina and acute myocardial infarction. Plasminogen, alpha 2 antiplasmin and fibrinogen values decreased significantly after thrombolytic treatment. The size of this decrease correlated positively with higher Lp(a) blood levels (p less than 0.05). Patients with Lp(a) greater than 0.25 g/liter had a 66% decrease in fibrinogen and a 53% decrease in anti-plasmin, compared with 35 and 32%, respectively, in patients with Lp(a) level less than or equal to 0.25 g/liter (p less than 0.05). Plasminogen levels revealed a similar trend, with a 61% decrease for the higher values and a 45% decrease for the lower values.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina, Unstable↗
PubMed1991

Prevalence of lipoprotein (a) [Lp(a)] excess in coronary artery disease.

Lipoprotein (a) [Lp(a)] is composed of 1 low-density lipoprotein (LDL) particle, to which 1 molecule of apolipoprotein (a) is covalently linked. Elevated levels of Lp(a) have been associated with coronary artery disease (CAD) and Lp(a) has been shown to be highly heritable. Our purpose was to determine the prevalence of familial Lp(a) excess in patients with CAD. We determined plasma levels of Lp(a) in 180 patients (150 men and 30 women) with angiographically documented CAD before age 60 years, and in 459 control subjects (276 men and 183 women) clinically free of cardiovascular disease. In addition, Lp(a) levels were determined in families of 102 of the CAD probands (87 men and 15 women). No gender differences in Lp(a) levels were observed between men and women (patients or control subjects). Patients with CAD had higher Lp(a) levels than did control subjects (19 +/- 21 vs 13 +/- 15 mg/dl, p less than 0.001). The prevalence of Lp(a) excess (defined as greater than 90th percentile of controls) was 17% in patients with CAD (p less than 0.05). Lp(a) levels were not correlated with cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol or apolipoproteins A-I or B. There was a weak correlation between Lp(a) and triglycerides (r = 0.166, p less than 0.05) in patients and control subjects. Stepwise discriminant analysis revealed that Lp(a) was a risk factor for the presence of CAD in men, independent of smoking, hypertension, diabetes, LDL and HDL cholesterol, or apolipoprotein A-I and B levels. Family studies revealed that Lp(a) levels are strongly genetically determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoproteins↗
PubMed1991

Restriction fragment length polymorphisms of the apolipoprotein A-I, C-III, A-IV gene locus. Relationships with lipids, apolipoproteins, and premature coronary artery disease.

Data from various laboratories have indicated associations of various alleles determined by RFLPs within or adjacent to several apolipoprotein genes with abnormalities in plasma lipids and/or premature coronary artery disease (CAD). In order to assess such relationships we have examined allele frequencies of 8 different RFLPs within or adjacent to the apo A-I, C-III and A-IV gene complex on the long arm of chromosome 11 (MspI, 5' to the apo A-I gene; MspI, within the apo A-I gene; PstI, 3' to the apo A-I gene; SstI, 3' to the apo C-III gene; PvuII, within the apo C-III gene; PvuII, 5' to the apo C-III gene; XbaI, within the apo A-IV gene; and XbaI, 3' to the apo A-IV gene) in 202 patients with CAD (50% narrowing of one or more coronary arteries) prior to age 60 and 145 normal controls. None of the allele frequencies of these RFLPs were significantly different in cases as compared to controls. With regard to associations with plasma lipids and apolipoprotein levels, the rare allele determined by the absence of the PstI site was associated with elevated triglyceride levels (P less than 0.05) in cases, but not in controls. In contrast, the rate MspI allele 5' to the apo A-I gene was associated with elevated triglyceride levels (P less than 0.05) in controls but not in cases. In both cases and controls, subjects with the uncommon SstI allele had triglyceride levels that were 9 and 38% higher than in those without this allele. These differences were significant (P less than 0.05) only in controls. Our data indicate that the rare allele determined by the SstI site within this gene complex deserves further study in order to understand its association with elevated triglycerides in Caucasian populations. However, at the present time all these DNA markers lack sufficient specificity to be clinically useful for CAD risk assessment.

Age Factors↗
PubMed1990

Clinical research.

Explore the source record for details and available documents.

Clinical Protocols↗
PubMed1990

Immuno-electron microscopy of atrial natriuretic factor secretory pathways in atria and ventricles of control and cardiomyopathic hamsters with heart failure.

The secretory pathways of atrial natriuretic factor have been investigated in atrial and ventricular cardiocytes of control and cardiomyopathic Syrian hamsters in severe congestive heart failure with four antibodies: a monoclonal antibody (2H2) against rat synthetic atrial natriuretic factor (101-126), which is directed against region 101-103 of rat atrial natriuretic factor (99-126), and polyclonal, affinity-purified antibodies produced in rabbits against synthetic C-terminal atrial natriuretic factor (101-126), synthetic N-terminal atrial natriuretic factor (11-37) or the putative cleavage site of atrial natriuretic factor (98-99): atrial natriuretic factor (94-103). Application of the immunogold technique on thin frozen sections (immunocryoultramicrotomy) revealed an identical picture with the four antibodies. In atria of both control and cardiomyopathic hamsters where atrial natriuretic factor secretion is regulated, the atrial natriuretic factor propeptide travels, uncleaved, from the Golgi complex to immature and mature secretory granules. In ventricles of control hamsters, where secretion is constitutive, the atrial natriuretic factor propeptide travels from the Golgi complex to secretory vesicles. In the ventricles of hamsters with severe congestive heart failure, the Golgi complex is larger, secretory vesicles more abundant and a few secretory granules are present in approximately 20% of cardiocytes. Here again, the peptide travels uncleaved in all these pathways. These results reveal the pathways of secretion of atrial natriuretic factor in atrial and ventricular cardiocytes and indicate that the propeptide is not cleaved intracellularly.

Animals↗
PubMed1990

Brain natriuretic peptide binding sites in rats: in vitro autoradiographic study.

Brain natriuretic peptide (BNP) is a recently discovered family of natriuretic peptides highly homologous to atrial natriuretic factor (ANF). Quantitative in vitro autoradiography with a computerized microdensitometer demonstrated that the distribution of BNP binding sites is similar to the known distribution pattern of ANF binding sites in rat tissues. Analysis of saturation and competition curves disclosed that the maximal binding capacity for BNP-(Asp-81--Tyr-106) and ANF-(Ser-99--Tyr-126) is similar within the plexiform layer of the olfactory bulb, the choroid plexus, and the adrenal zona glomerulosa. Examination of the competition curves of BNP-(Asp-81--Tyr-106), ANF-(Ser-99--Tyr-126), and des-(Gln-116--Gly-120)ANF-(Asp-102--Cys-121)NH2 (C-ANF, a ligand highly specific for ANF-R2 receptors) for 125I-labeled BNP-(Asp-81--Tyr-106) and 125I-labeled ANF-(Ser-99--Tyr-126) binding revealed that ANF fully displaced 125I-BNP binding and, conversely, BNP completely displaced 125I-ANF binding in these tissues, whereas C-ANF partially displaced 125-BNP and 125-ANF binding. Angiotensin II, insulin, glucagon, and substance P had no influence on 125I-BNP binding in the above tissues. These results support the view that BNP and ANF share the same binding sites in rats.

Animals↗
PubMed1990

Localization and characterization of binding sites for circulating and cerebroventricular atrial natriuretic factor in rat choroid plexus.

In vitro autoradiographic studies showed that high-affinity atrial natriuretic factor (ANF) binding sites are present on rat choroid plexus (Kd = 83.8 pM, Bmax = 22.9 fmol/mg protein). Guanylate cyclase-coupled receptors (ANF-R1) represent 30% and non-guanylate cyclase-coupled ANF receptors (ANF-R2) represent 70% of the total ANF receptors present in this tissue. To provide detailed cellular localization of the binding sites, the technique of electron-microscopic autoradiography was applied using 125I-ANF (Ser 99-Tyr 126) as an in vivo ligand. In order to identify possible binding sites at the basolateral and the apical aspects of the choroid plexus, the ligand was injected into the carotid artery or into the lateral cerebral ventricles, respectively. Light-microscopic autoradiography demonstrated that ANF binds specifically to choroid plexus regardless of its route of administration. Electron-microscopic autoradiography showed that silver grains were localized primarily on epithelial cells of the choroid plexus (96-99%) and marginally on endothelial and pial cells. In choroidal epithelial cells, ultrastructural analysis of silver grain distribution revealed that, at 2 min after intracarotid or intracerebroventricular 125I-ANF injection, lysosomes were the most distinctly labeled organelle (highest relative specific radioactivity). HPLC Chromatographic analysis disclosed that 96-99% of choroid plexus-bound ANF was already degraded 2 min after injection and that at least 63-66% of the degradation took place at the plasma membrane. These results indicate that ANF binding sites are present on both aspects of choroidal epithelium, and suggest that ANF is very quickly degraded in choroid plexus by membrane-associated as well as lysosome-associated processes.

Animals↗
PubMed1989

Atrial natriuretic factor binding sites in the jejunum.

We have studied the localization and the characterization of atrial natriuretic factor (ANF) binding sites by radioautographic techniques. Quantitative in vitro radioautography with a computerized microdensitometer demonstrated the presence of high-affinity, low-capacity 125I-ANF-(99-126) binding sites (Kd, 48 pM; Bmax, 63 fmol/mg protein) mainly in the villi of 20-microns slide-mounted transverse sections of the rat jejunum. Competition curves showed 50% inhibitory concentrations of 55 and 1,560 pM for ANF-(99-126) and ANF-(103-123), respectively. In vivo electron microscope radioautography showed that 80% of the silver grains were localized on the lamina propria fibroblast-like cells, 18% on mature enterocytes, and 2% on capillaries. Bradykinin and adrenocorticotropin did not compete with ANF binding. These results demonstrate that ANF binding sites in the rat jejunum possess the pharmacological characteristics of functional ANF receptors encountered in other rat tissues, and ultrastructural radioautographs show their cellular distribution. Taken together, these results demonstrate the presence and the localization of specific binding sites for ANF in the jejunal villi of the rat small intestine.

Animals↗
PubMed1989

Atrial natriuretic factor binding sites in experimental congestive heart failure.

A quantitative in vitro autoradiographic study was performed on the aorta, renal glomeruli, and adrenal cortex of cardiomyopathic hamsters in various stages of heart failure and correlated, in some instances, with in vivo autoradiography. The results indicate virtually no correlation between the degree of congestive heart failure and the density of 125I-labeled atrial natriuretic factor [(Ser99, Tyr126)ANF] binding sites (Bmax) in the tissues examined. Whereas the Bmax was increased in the thoracic aorta in moderate and severe heart failure, there were no significant changes in the zona glomerulosa. The renal glomeruli Bmax was lower in mild and moderate heart failure compared with control and severe heart failure. The proportion of ANF B- and C-receptors was also evaluated in sections of the aorta, adrenal, and kidney of control and cardiomyopathic hamsters with severe heart failure. (Arg102, Cys121)ANF [des-(Gln113, Ser114, Gly115, Leu116, Gly117) NH2] (C-ANF) at 10(-6) M displaced approximately 505 of (Ser99, Tyr126)125I-ANF bound in the aorta and renal glomeruli and approximately 20% in the adrenal zona glomerulosa in both series of animals. These results suggest that ANF may exert a buffering effect on the vasoconstriction of heart failure and to a certain extent may inhibit aldosterone secretion. The impairment of renal sodium excretion does not appear to be related to glomerular ANF binding sites at any stage of the disease.

Adrenal Glands↗
PubMed1989

Atrial natriuretic factor in Purkinje fibers of rabbit heart.

The Purkinje fibers of the rabbit false tendons (chordae tendineae spuriae) are endocrine cells containing immunoreactive atrial natriuretic factor (ANF) and ANF messenger RNA (mRNA). These cells, as visualized by immunocryoultramicrotomy, contain immunoreactive ANF in their secretory granules and their Golgi complex and exhibit ANF mRNA, as visualized by in situ hybridization with an ANF complementary RNA probe. The content of immunoreactive ANF and ANF mRNA of the Purkinje fibers is midway between that of atrial and ventricular working cardiocytes. High-pressure liquid chromatography analysis of immunoreactive ANF using antibodies against the C-terminal and N-terminal moieties of the molecule indicates that part of immunoreactive ANF contained in Purkinje fibers is the propeptide [Asn1,Tyr126]ANF whereas part was nonspecifically cleaved into C-terminal and N-terminal ANF. The chordae tendineae spuriae exhibit binding sites for ANF (Kd:approximately 1.0 nM; Bmax:approximately 2.3 fmol/mg). ANF profoundly decreases basal and stimulated (epinephrine, dopamine, isoproterenol, and forskolin) adenylate cyclase activity and cyclic adenosine monophosphate (AMP) levels. ANF has little effect on norepinephrine-stimulated adenylate cyclase activity or on norepinephrine-stimulated cyclic AMP levels. ANF produces only a slight increase in guanylate cyclase activity and cyclic guanosine monophosphate levels at high (10(7)-10(6) M) concentrations. These results suggest an autocrine function for ANF in the modulation of the impulse in the peripheral conduction cells (Purkinje fibers) of the rabbit through changes in second messenger levels.

Animals↗
PubMed1989

Ventricles as a major site of atrial natriuretic factor synthesis and release in cardiomyopathic hamsters with heart failure.

The aim of the present study was to correlate in cardiomyopathic hamsters with congestive heart failure the levels of atrial and ventricular atrial natriuretic factor (ANF) messenger RNA (mRNA) with immunoreactive ANF (IR-ANF) plasma levels and the relative amount of IR-ANF released by the whole heart versus isolated ventricles in the Langendorff preparation. High-performance liquid chromatography analysis of the forms of ANF present in plasma and in the Langendorff effluent of whole heart versus isolated ventricles was also performed. As previously found for cardiac IR-ANF, the levels of ANF mRNA decreased gradually in atria and increased in an analogous fashion in ventricles with the severity of congestive heart failure. Plasma IR-ANF levels (C-terminal) were more elevated in moderate than in severe congestive heart failure, as were the IR-ANF levels in the Langendorff effluent of the whole heart. On the contrary, the effluent of isolated ventricles from animals in severe heart failure yielded more IR-ANF than that from hamsters in moderate heart failure. Thus, while the isolated ventricles from controls contributed 35.8% of IR-ANF released by the whole heart, ventricles from hamsters in moderate heart failure contributed 17.5%, and those from hamsters in severe heart failure contributed 73.9%. These results indicate that atrial cardiocytes contribute more IR-ANF than their ventricular counterpart in moderate heart failure and that ventricles are a major source of plasma IR-ANF in severe heart failure. Analysis of IR-ANF from plasma and the Langendorff effluent from whole hearts and isolated ventricles revealed that the ventricles are the major source of the propeptide (and of its cleaved products) found in the circulation of cardiomyopathic hamsters. These results suggest that ANF synthesis and secretion do not increase conjointly in atria but do increase in ventricles during congestive heart failure.

Animals↗
PubMed1989

Processing of the atrial natriuretic factor propeptide by atrial cardiocytes as revealed by immunocryoultramicrotomy.

Antibodies were raised against three fragments of the rat ANF molecule: C-terminal atrial natriuretic factor (ANF)-(101-126), N-terminal ANF-(11-37), and the putative cleavage site of the ANF propeptide, ANF-(94-103). These antibodies were purified by affinity chromatography and revealed a major band (17K) corresponding to the propeptide by Western blot analysis. Antibodies against ANF-(94-103) were used in a RIA. All of the peptides that possess this region (98-99) were able to displace iodinated pro-ANF from the antibody. However, peptides that have only one part of the fragment, such as ANF-(99-126) or ANF-(1-98), failed to displace pro-ANF; human ANF-(79-98) (100 pmol) demonstrated about 0.01% cross-reactivity. Immunohistochemical studies revealed that all atrial cardiocytes are reactive with the three antibodies. Immunocryoultramicrotomy revealed that the propeptide travels, uncleaved, from the Golgi complex to immature granules and mature secretory granules. These results indicate that cleavage of the ANF propeptide does not occur at these sites.

Animals↗