Headache response to glyceryl trinitrate in patients with and without obstructive coronary artery disease.

OBJECTIVES: To examine the hypothesis that glyceryl trinitrate (GTN) may cause headache in patients with normal coronary arteries more often than in patients with obstructive coronary artery disease (CAD). This simple assessment may aid clinicians in the initial evaluation of chest pain syndrome and possible CAD. PATIENTS AND METHODS: 118 patients (66 men and 52 women) with new onset of chest pain were enrolled in this study. Patients were excluded from the study if they had a history of chronic headache, long term nitrates use, or any coronary artery procedures. Mean age of the patients was 62.5 years. Coronary angiography was performed within one month of GTN administration with the usual clinical indications such as recurrent chest pain, abnormal ECG, or abnormal results of stress tests. Thirty patients had normal coronary arteries or minimal or non-obstructive CAD. Eighty eight patients had obstructive CAD defined as luminal narrowing greater than 50% in any one or more of the left or right coronary arteries or their major branches. All the patients had a varying degree of relief of chest pain with GTN administration within 10 minutes. 36% of patients reported significant headache after GTN administration. RESULTS: In patients with normal coronary arteries or minimal CAD, 73% had significant headache caused by sublingual GTN. In patients with obstructive CAD, only 23% had significant headache after GTN use (p < 0.001). There were no differences in patients' sex and vascular risk factors concerning the frequency of headache in patients with or without obstructive CAD. CONCLUSIONS: GTN causes significantly more frequent headache episodes in patients with normal coronary arteries or minimal CAD than in patients with obstructive CAD. This unique finding may provide clinicians with an additional tool for the differential diagnosis of patients with chest pain syndrome.

Coexpression of endothelin-converting enzyme-1 and endothelin-1 in different stages of human atherosclerosis.

BACKGROUND: Endothelin-converting enzyme (ECE)-1 activates endothelin-1 (ET-1) and may thus contribute to the regulation of vascular tone and cell growth during atherosclerosis. METHODS AND RESULTS: To evaluate ECE-1 immunoreactivity concerning big ET-1/ET-1, we performed qualitative and quantitative immunohistochemistry in normal internal mammary arteries (n=10), in coronary arteries with adaptive intimal fibrosis (n=10), in aortic fatty streaks (n=10), and in distinct regions of advanced carotid plaques (n=15). Furthermore, we determined ECE-1 activity in the control specimens and in the inflammatory intimal regions of carotid plaques. Double immunolabeling showed that ECE-1 was present in endothelial cells, vascular smooth muscle cells, and macrophages. All ET-1(+) cells were simultaneously ECE-1(+). Most importantly, there were significantly more ET-1(+) cells in the intima and media when atherosclerosis was in an inflammatory stage than when it was in a noninflammatory stage. Moreover, ECE-1 activity was upregulated in the intima of carotid plaques, although immunohistochemically, there were no significant differences between the number of ECE(+) cells in the different compartments of the arterial wall. CONCLUSION: Together with ET-1, ECE-1 is abundantly present in human arteries and at different stages of atherosclerotic plaque evolution. The upregulation of the ECE-1/ET-1 system is closely linked to the presence of chronic inflammation and is present in very early stages of plaque evolution. Therefore, enhanced production of active ET-1 may substantially contribute to cell growth and the regulation of vascular tone in advanced atherosclerotic lesions and in the very early stages of plaque evolution, when a plaque is still imperceptible clinically.

Inhibitor sensitivity of human serum and vascular semicarbazide-sensitive amine oxidases.

Recent data suggest that elevated serum semicarbazide-sensitive amine oxidase activity (SSAO) may cause endothelial injury. Formation of cytotoxic metabolites (especially formaldehyde) and increased oxidative stress might lead to initiation or progression of atherosclerosis. Effective and selective inhibitors of human SSAO might exert cytoprotective effect on endothelial cells. To compare the inhibitor sensitivity of human serum and vascular tissue SSAO enzyme, the inhibitory effect of semicarbazide and MDL 72974A was investigated. Serum and vascular SSAO activity has been determined using 14C-benzylamine as a substrate. The IC50 values of semicarbazide were estimated to be 5x10(-3) M and 5x10(-4) M for SSAO from human serum and saphenous vein, respectively. MDL 72974A amine oxidase inhibitor was more than thousand times more effective than semicarbazide. The IC50 values were 10(-7) M and 10(-8) M for SSAO from human serum and saphenous vein, respectively. This finding supports the hypothesis that soluble and membrane-bound vascular SSAO enzymes might have similar structure.

Angiotensin II type 1 receptor gene polymorphism and mitral valve prolapse syndrome.

BACKGROUND: Mitral valve prolapse syndrome (MVPS), a term applied to patients who have a variety of symptoms, has been associated with autonomic or neuroendocrine dysfunction. Recent evidence suggests that effects of angiotensin II mediated by the angiotensin II type 1 (AT(1)) receptor are involved in modulation of cardiovascular autonomic control in human beings. Association of a genetic polymorphism (A-C(1166)) of the AT(1) gene with abnormal vasomotion and low blood pressure related to autonomic control has been reported recently. Because the role of this genetic variant in MVPS has not been studied, we performed a case-control study of the A-C(1166) variant in a group of 76 white subjects with MVPS. METHODS AND RESULTS: All patients were genotyped by use of a mismatch polymerase chain reaction/Afl II restriction fragment length polymorphism analysis. Frequency of the C(1166) allele was 0.4 in patients with MVPS and 0.26 in control patients. The difference in genotype (chi square = 6.5; P <.05) and allele (chi square = 5.9; P =.02) frequencies between the groups was significant. The odds ratio in favor of carrying the C allele was 4 times greater for patients with MVP than for control patients (95% confidence interval 1.4 to 12.1). CONCLUSIONS: The current results indicate that the A-C(1166) polymorphism of the angiotensin II type 1 receptor gene is associated with MVPS in the white population.

Cystic medial degeneration of the aorta is associated with p53 accumulation, Bax upregulation, apoptotic cell death, and cell proliferation.

OBJECTIVE: To address a potential role for p53, Bcl2 associated protein X (Bax), and apoptosis in the processes associated with cell turnover during cystic medial degeneration (CMD) of the aorta. METHODS: Histochemical, immunohistochemical, biochemical, and morphometric methods were used to assess the presence and distribution of p53 immunoreactivity (p53-IR) and Bax immunoreactivity (Bax-IR), as well as the presence of apoptosis and tissue repair processes. RESULTS: Immunohistochemical staining disclosed evidence for p53-IR in all specimens in 26.1 (11.5)% of vascular smooth muscle cells (VSMCs) (controls 0.8 (1.3)%; p < 0. 001). Bax-IR was present in all specimens in 10 (5.4)% of medial cells (controls 0.3 (0.5)%; p < 0.001). Medial VSMCs (alpha-actin positive) with cytoplasmic staining for an apoptosis specific protein (c-jun/ASP) were present in 20/20 specimens (0.7 (0.6)% of VSMCs, controls 0%, p < 0.001), whereas terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL) positive VSMCs were present in 17/20 specimens (1 (1.5)% of VSMCs, controls 0%, p < 0.001). The presence of apoptosis was confirmed by electron microscopy and the demonstration of oligonucleosomal DNA fragments after agarose gel electrophoresis. As shown by double labeling and investigation of serial sections, p53-IR, Bax-IR, c-jun/ASP-IR, and positive TUNEL labeling localised to the same compartments of the aortic media, raising a possible role for p53 and Bax in the triggering of apoptosis of VSMC during CMD. MIB1/Ki-67 positive medial VSMCs (alpha-actin positive) and mesenchymal cells (vimentin positive) were present in all specimens (2.5 (2.8)% of medial cells; controls 0.3 (0.9)%, p < 0.001) mainly in the region around the vasa vasorum, indicating that cell regeneration during CMD may originate mainly from the mesenchyme surrounding the vasa vasorum. CONCLUSION: This study shows that the formal pathogenesis of CMD is characterised by p53 accumulation, Bax upregulation, cell death by apoptosis, and cell regeneration. Nevertheless, the precise stimuli of p53 activation and Bax upregulation as well as the role of p53 and apoptosis in the dissection process itself remain elusive.

Elevated serum semicarbazide-sensitive amine oxidase activity in non-insulin-dependent diabetes mellitus: correlation with body mass index and serum triglyceride.

Previous clinical studies reported elevated semicarbazide-sensitive amine oxidase (SSAO) activity in insulin-dependent diabetes mellitus (IDDM), but there are not sufficient data about SSAO in non-insulin-dependent diabetes mellitus (NIDDM). The present study was conducted to investigate serum SSAO activity in NIDDM patients compared with nondiabetic and IDDM patients. Serum SSAO activity in 61 patients with diabetes (n = 34 NIDDM and n = 27 IDDM) and 36 controls was determined using 14C-benzylamine as a substrate. NIDDM and IDDM patients exhibited higher SSAO activity compared with controls ([mean +/- SD] NIDDM, 164.60+/-69.43 pmol/mg protein/h, P<.0001; IDDM, 143.91+/-72.45 pmol/mg protein/h, P<.002; control, 91.46+/-28.11 pmol/mg protein/h). There was a significant positive correlation between serum SSAO activity and the body mass index (BMI), body weight, hemoglobin A1c (HbA1c), fasting plasma glucose, and triglycerides. Within the control group, SSAO correlated with total cholesterol levels. The progression and severity of diabetic complications such as angiopathy may be exacerbated by cytotoxic metabolites (e.g., formaldehyde and hydrogen peroxide) formed by SSAO. These results reveal the possibility that elevated serum SSAO activity in association with obesity and hyperlipidemia may be a cardiovascular risk factor in diabetes mellitus.

Determination of human serum semicarbazide-sensitive amine oxidase activity: a possible clinical marker of atherosclerosis.

Semicarbazide-sensitive amine oxidase (SSAO) is present in the plasma membrane of several human tissues, e.g. vascular smooth muscle cell adipocytes, and is also found in human serum. Some previous studies on cultured endothelial cells indicate that cytotoxic metabolites (e.g. hydrogen peroxide, formaldehyde, acrolein) formed by serum SSAO may cause endothelial injury and subsequently induce atherosclerosis. To investigate the role of this enzyme in the pathogenesis of macrovascular complications in diabetes, a simple and sensitive radiometric procedure was adapted for human serum measurements. Serum SSAO activity of 35 patients with non-insulin dependent diabetes mellitus (NIDDM) and that of 30 controls was determined using [14C]-benzylamine as substrate. The severity of atherosclerosis was assessed by carotid sonography. Diabetic patients with atherosclerosis exhibited a higher SSAO activity compared to diabetic patients without complications (212.91 +/- 90.54 pmol/mg protein/h versus 133.17 +/- 65.40 pmol/mg protein/h, P <0.04). In diabetic patients without complications, serum SSAO activity was elevated compared to control subjects (133.17 +/- 65.40 pmol/mg protein/h versus 91.79 +/- 31.70 pmol/mg protein/h, P <0.01). These results suggest that determination of human serum SSAO activity might be a useful marker in the prognostic evaluation of diabetic angiopathy and atherosclerosis.

Platelet MAO-B activity and serotonin content in patients with dementia: effect of age, medication, and disease.

This study aimed at determining the effect of drug therapy, age and type of dementia on biological markers. Both platelet monoamine oxidase type B (MAO-B) activity and serotonin content of 57 demented patients and 20 control subjects were determined. Platelet MAO-B activity was measured using [14C]tyramine as substrate. Serotonin content was determined by HPLC-EC method. Increased platelet serotonin content and platelet count was found in patients with dementia compared to controls. A positive correlation was experienced between platelet MAO-B activity, platelet serotonin content and age. Platelet MAO-B activity was higher in the haloperidol treated group, compared with patients treated with anxyolitics. The main original finding of the present study is that platelet serotonin content is increased in demented patients with delusions compared to dementia without complications (p = 0.006). It seems, that platelet MAO-B activity is influenced mainly by drug therapy, while serotonin content rather reflects clinical characteristics in dementia.

Association of angiotensin II type 1 receptor polymorphism with resistant essential hypertension.

Angiotensin II type 1 receptor (AT1) mediates the vasoconstrictive and growth-promoting effect of angiotensin II in humans. It has been reported that a polymorphism of the AT1 gene (an A/C transversion at position 1166: A-C1166) occurs more frequently in resistant hypertensives taking two or more antihypertensive drugs. On the contrary, a recent study of the influence of the A-C1166 polymorphism on aortic stiffness demonstrated that the distribution of the genotypes did not differ between normotensive and hypertensive subjects. In addition, a recent population-based survey of Caucasian hypertensives reported lower blood pressure values in CC homozygotes than in heterozygotes and AA homozygotes. Because of these controversial results and the lack of a sufficient amount of data the present study was designed to assess the contribution of the AT, gene A-C1166 polymorphism to resistant essential hypertension. Forty-eight subjects with resistant essential hypertension (HT) and 48 normotensive (NT), age and sex-adjusted controls (from a population of 300 healthy blood donors) were selected. All subjects were genotyped for the A-C1166 polymorphism in the 3'-UTR of the AT1 gene using PCR-based techniques. The influence of genotype on blood pressure (BP) was investigated using ANOVA Randomized Complete Block (ANOVA RCB) design according to sex, age and BMI. There were no significant differences in allele or genotype frequencies between HT and NT subjects (X2 = 0.61; P = NS). In HT subjects higher values of systolic blood pressure were associated with the C allele of the AT1 gene only in older and overweight patients (P < 0.001 and P < 0.001, respectively). Also in HT patients an association between the presence of the C allele of the AT1 gene and higher values of diastolic blood pressure was present in overweight patients (P = 0.001). These results suggest that in resistant hypertensive subjects the AT1 A-C1166 polymorphism is potentially involved in the regulation of blood pressure. As the effects of genotypes on blood pressure are pronounced in older and overweight subjects this polymorphism may amplify the effects of age and BMI on resistant essential hypertension.

[Relapsing polychondritis associated with myelodysplasia and acute eosinophilic leukemia]. / Polychondritis recidivanshoz társuló myelodysplasiás syndroma és akut eosinophilsejtes leukaemia esete.

Authors report a case in which relapsing polychondritis had been diagnosed two years before myelodysplastic syndrome developed and terminated in eosinophilic leukemia. The observation that relapsing polychondritis may precede myelodysplasia is not in concordance with some of the previous reports regarding relapsing polychondritis as a paraneoplastic phenomenon of myelodysplastic syndrome. The terminally developed eosinophilic leukemia is not supposed to be a blastic phase of the underlying myelodysplasia, much rather a second malignant process. This opinion may be confirmed by the early presence of blast cells in the myelodysplastic process without eosinophilia. It seems interesting to note that both our patient and his daughter suffered from diseases of autoimmune origin: acquired vitiligo and subacute cutan lupus erythematodes, respectively.