Genetic influence on blood pressure and lipid parameters in a sample of Polish twins.

We studied 76 healthy monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs (mean age 35 +/- 8 years, body mass index, BMI, 23.6 +/- 3.9 kg/m2) to determine genetic and environmental contributions to systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR) and serum lipids [total cholesterol (TC), low-density lipoprotein cholesterol (LDL-chol), high-density lipoprotein cholesterol (HDL-chol) and triglycerides (TG)I. SBP, DBP and HR were measured clinically and by ambulatory blood pressure monitoring (ABPM). Parameters of the genetic models for age-, sex- and BMI-adjusted data were estimated by model fitting and path analysis technique using LISREL 8. We found significant genetic effect on SBP and DBP for both clinical and ABP measurements, ranging from 37% for night-time ambulatory DBP to 79% for daytime ambulatory SBP. Estimates of genetic effects were higher for daytime than night-time ABP values, and higher for ambulatory 24-h SBP than office SBP measurements, with the reverse true for DBP. Significant genetic effect on HR ranged from 59% for office measurements to 69% for 24-h mean values. In summary, we also found genetic effect on TC, LDL-chol and HDL-chol with estimates ranging from 36% to 64%, but not on TG. Furthermore, a shared environmental component for TG was found, estimated at 36%. We showed significant genetic effect on both office and ambulatory BP and HR, with stronger genetic effect on daytime than night-time BP. We also found genetic effect on TC and lipoprotein fractions, but no significant genetic effect on TG. Environmental factors influencing serum TG, such as alcohol consumption, may explain the apparent lack of genetic effect in this healthy, non-obese population.

Dopamine and dopa urinary excretion in patients with pheochromocytoma--diagnostic implications.

Pheochromocytoma, a potentially life-threatening disease, is a rare cause of hypertension. Most pheochromocytomas secrete excessive amounts of noradrenaline and adrenaline. It has been suggested by some authors that high circulating levels of dopamine and the catecholamine precursor dihydroxyphenylalanine (dopa) are more often associated with malignant rather than benign pheochromocytomas. Therefore the aim of this study was to evaluate urinary excretion of dopamine and dopa in patients with pheochromocytoma and to determine their role as a potential marker for malignancy of the tumour. We retrospectively analysed 120 consecutive patients (mean age 41 +/- 12 years) with histopathologically confirmed pheochromocytomas. All subjects were divided as follows: group 1 included patients with both elevated and normal dopamine urinary excretion; group 2 was characterized by increased and normal dopa urinary excretion. Dopamine urinary excretion was increased in all patients with malignant pheochromocytoma, but higher levels were also observed in some patients with a benign tumour included in group 1. Urinary excretion of dopa was in the normal range in all subjects with malignant pheochromocytoma. The results indicate that in some pheochromocytoma patients excessive dopamine excretion may point to malignant tumour, but is not a discriminating marker for malignancy in the whole studied group.

Immunomorphological studies and cytometric DNA ploidy in diagnostics of pheochromocytoma.

The aim of the study was to define features indicating malignancy in pheochromocytoma through analysis of clinical data, immunomorphological and nuclear DNA ploidy patterns with flow cytometry. The studied group consisted of 33 patients with hypertension and adrenal gland tumor. In all patients 24 hr measurements of adrenaline, noradrenaline, dopamine and their metabolites were taken and the content of these substances in the tumor tissue was measured. Morphologically most pheochromocytomas displayed alveolar pattern with polyhedral cells with clear cytoplasm. Nuclear pleomorphism was infrequent and mitotic figures were rare. In 5 tumors areas of ganglioneuromatous differentiation were present with neurofilament expression. Morphological features indicating malignancy were noted--vascular emboli of tumor cells, capsular infiltration and foci of necrosis. However, in the patient with metastases evident during operation, none of those features was found in the tumor sample. All pheochromocytomas expressed neuroendocrine markers (chromogranin A, synaptophysin and NSE) and most also vimentin. Reactivity of other markers was negligible. In DNA ploidy studies in 22/33 cases there was DNA diploid (normal) pattern. The patient with metastases belonged to this group. In 3 cases there were aneuploid tumor cells on histograms and in 8 increased number of tetraploid cells. The follow-up period of our patients was 1-43 months.

Incidence and clinical relevance of RET proto-oncogene germline mutations in pheochromocytoma patients.

BACKGROUND: Autosomal dominant cancer syndrome--multiple endocrine neoplasia type 2 (MEN 2), may exist more often than expected in patients with pheochromocytoma. Germline mutations identified recently in MEN 2 can be revealed by genetic screening. OBJECTIVE: To evaluate the frequency of RET (rearranged during transfection) mutations in patients with pheochromocytoma. DESIGN AND METHODS: We genetically screened germline mutations in the RET proto-oncogene and clinically re-evaluated patients with pheochromocytoma. A pentagastrin test and other biochemical studies were performed in all patients. SETTING: Department of Internal Medicine and Hypertension, The Medical University of Warsaw, Warsaw, Poland and the Department of Nephrology and Hypertension, Albert Ludwigs University, Freiburg, Germany. PARTICIPANTS: Seventy seven unselected patients with pheochromocytoma (19 men, 58 women, mean age: 51.55 +/- 1.5 years; pheochromocytoma confirmed histopathologically) out of 162 diagnosed and treated in the years 1957-1998 in the Department of Internal Medicine and Hypertension in Warsaw, Poland. The other 85 patients did not respond to the written invitation. MAIN OUTCOME MEASURES: The finding of RET mutations and diagnosis of MEN 2 in patients with pheochromocytoma. RESULTS: Genetic testing revealed germline mutations in the RET proto-oncogene in six patients (7.8%). All carriers had mutation of exon 11, codon 634: TGC to CGC. In four patients with this mutation, medullary thyroid carcinoma (MIC) was diagnosed and in three cases, surgically treated. Biochemical parameters: parathormone 31.88 +/- 2.87 pg/ml, calcitonin: 0 min 0.23 +/- 0.14 ng/ml; 2 min 0.49 +/- 0.21 ng/ml; 5 min 0.48 +/- 0.21 ng/ml, metoxycatecholamines: 601.62 +/- 42.71 microg/24h, epinephrine: 1.94 +/- 0.17 microg/24h, norepinephrine 13.96 +/- 1.3 microg/24h, carcinoembryonic antigen (CEA) 9.94 +/- 4.3 ng/ml. Ambulatory blood pressure monitoring (ABPM): systolic blood pressure (SBP): 116 +/- 1.9 mmHg, diastolic blood pressure (DBP): 73.7 +/- 0.9 mmHg. Clinical, biochemical and imaging procedures did not reveal any recurrence of pheochromocytoma in the 77 patients studied. CONCLUSIONS: Patients with pheochromocytoma should be genetically screened for mutations of the RET proto-oncogene. These patients should undergo clinical screening for MEN 2. In addition, genetic studies can be useful for the screening of the families of the carriers.

Blood pressure, plasma NPY and catecholamines during physical exercise in relation to menstrual cycle, ovariectomy, and estrogen replacement.

Some evidences indicate that the female sex hormones protect against the development of cardiovascular diseases. Modulation of sympathetic activity may be one of the possibilities. We investigated the influence of treadmill stress on blood pressure (BP) and plasma neuropeptide Y (NPY), norepinephrine (NE) and epinephrine (E) concentrations in 11 normotensive, menstruating women in the follicular (HWf) and luteal (HWl) phases and in eight ovariectomized women, before (OVX) and after estrogen supplementation (OVXe). Both at rest and during exercise there were no differences in BP between HWf and HWl and between OVX and OVXe. During stress BP was significantly lower in HWf and HWl than in OVX but not in OVXe. NPY did not differ significantly between the groups of women either at rest or during activity. We did not observe differences in resting and stimulated NE and E between HWf and HWl and between OVX and OVXe. Neither resting nor activated NE and E differed between the groups, except higher stimulated NE in OVX than in HWf. These results suggest that the female sex hormones may modulate the BP response to dynamic exercise. Our data support evidence that this influence may be exerted by circulating catecholamines and not by NPY.

Alterations in plasma neuropeptide Y immunoreactivity and catecholamine levels during surgical removal of pheochromocytoma.

BACKGROUND: Neuropeptide Y, an abundant neurohormone present with catecholamines in the adrenal medulla, is a potent non-adrenergic vasoconstrictor and a vascular growth factor. OBJECTIVE: To determine the mechanism of the release from, and possible role of neuropeptide Y in, pheochromocytomas, compared with those of catecholamines. METHODS: Plasma and tumour levels of neuropeptide Y-immunoreactivity (by, radioimmunoassay) and of noradrenaline and adrenaline (by a radioenzymatic method) in 29 patients (19 women and 10 men, aged 22-68 years) were measured during surgical removal of the tumour, during alpha-adrenergic and beta-adrenergic blockade. Arterial systemic blood samples were withdrawn before the ligation of the vessels supplying the tumour, during its surgical manipulations and after its removal, while haemodynamics was monitored. RESULTS: Plasma neuropeptide Y levels in 17 patients (58.6%, group I) significantly increased during manipulations of the pheochromocytoma and returned completely to normal after its removal. This response was independent of the plasma neuropeptide Y immunoreactivity manipulation and was correlated to increases in plasma noradrenaline (r = 0.638, P < 0.02) but not adrenaline levels. Manipulation-induced increases in plasma neuropeptide Y-immunoreactivity were associated with greater neuropeptide Y content in tumours (r = 0.508, P < 0.05) but neither plasma nor tumour levels of neuropeptide Y immunoreactivity were correlated to tumour mass. Plasma levels of neuropeptide Y immunoreactivity in the remaining 12 patients (41.4%, group II) remained unchanged throughout the experimental period, while levels of circulating catecholamine rose. In all, in spite of our attempt at complete adrenergic blockade, tumour manipulation elevated arterial blood pressure and these changes were significantly correlated to increases in levels of catecholamines in patients in both groups but also to plasma neuropeptide Y immunoreactivity in patients in group I. CONCLUSION: Pheochromocytomas exhibit different patterns of secretion. For about half of the patients either the secretion of neuropeptide Y is uncoupled from that of catecholamines or its secretion could be obscured by an increase in degradation of neuropeptide Y to inactive fragments undetectable by radioimmunoassay.

Hemorrheological indices, catecholamines, neuropeptide Y and serotonin in patients with essential hypertension.

Hemorrheological and humoral abnormalities and excessive platelet activity can predict the development of cardiovascular complications in patients with essential hypertension. A study was conducted to assess the influence of gender on these factors and the interrelations between changes in hemorrheology and the sympatho-adrenal system in 54 patients (18 women, 36 men) with essential hypertension (aged 39.6 +/- 9.7 years) and 25 healthy volunteers (10 women, 15 men; aged 36.0 +/- 7.2 years). A decrease in erythrocyte deformability (p < 0.01) was found in the hypertensive men compared with the hypertensive women. Hematocrit (p < 0.01), blood viscosity at the shear rates of 0.3 s-1 (p < 0.01) and 6 s-1 (p < 0.01), plasma viscosity (p < 0.01), erythrocyte aggregation (p < 0.01), and neuropeptide Y (p < 0.02) concentrations were higher in the hypertensive men than in the hypertensive women. A positive correlation between blood fibrinogen and serotonin was found in the pooled hypertensive group and in the hypertensive men (p < 0.01) and between blood viscosity (shear rate 6 s-1) and neuropeptide Y in the pooled hypertensive group (p < 0.01). Neuropeptide Y correlated with filtration time of 1 mL blood in the hypertensive men (p < 0.05) and in the pooled normotensive group (p < 0.01) and with beta-thromboglobulin in the hypertensive women (p < 0.001). A positive correlation was also found in the hypertensive men between erythrocyte and platelet aggregation (p < 0.01) and between beta-thromboglobulin and adrenaline (p < 0.01). Hemorrheological and humoral abnormalities are more pronounced in men than in women with essential hypertension and may contribute to the increased incidence of cardiovascular events in men.

[Pheochromocytoma in a 81 year old woman treated with surgery--case report]. / Guz chromochlonny u 81. letniej chorej leczony operacyjnie--opis przypadku.

A case of pheochromocytoma in 81 year old woman hospitalized due to choledocholithiasis is reported. During premedication pronounced blood pressure elevation was observed. Operation was discontinued and diagnostic of pheochromocytoma was carried out. USG and CT scanning revealed right sided adrenal tumor. Elevated urine catecholamines and methoxycatecholamines were found. The patient underwent adrenalectomy and cholecystectomy. Histological examination confirmed diagnosis of pheochromocytoma. The patients done uneventful recovery.

[Evaluation of the usefulness for measuring catecholamines and their principle metabolites in the diagnosis of pheochromocytoma]. / Ocena przydatnosci oznaczania katecholamin i ich glównych metabolitów w diagnostyce guzów chromochlonnych.

Objective of the study was assessment of the usefulness of determination of noradrenaline (NA) and adrenaline (A) in urine and blood as well as the total methoxycatecholamines (MNA +MA), vanillylmandelic acid (VMA), DOPA and dopamine (DA) urinary excretion in diagnosis of pheochromocytoma. The experience based on 155 patients with pheochromocytoma (105F, 50M, age 18-82 yrs) diagnosed in the Department of Hypertension and Angiology Academy of Medicine in Warsaw will be discussed. In all patients excluding 2 cases pheochromocytoma has been proven histopathologically. The most considerable diagnostic usefulness of MNA + MA indication was proven. MNA + MA was increased in 96.6 patients. In 89.6% patients an increased excretion of NA and A or one of this catecholamines was demonstrated. An increased excretion of VMA was demonstrated in 75%. The excretion of DOPA and dopamine was tested in 120 cases. An increased excretion of DA was shown in 31% and DOPA in 16%.

[Pheochromocytoma with hemorrhagic necrosis and rupture with symptoms of acute abdomen and shock]. / Pheochromocytoma--martwica krwotoczna i przerwanie guza z objawami ostrego brzucha i wstrzasem.

A case of a pheochromocytoma with haemorrhagic necrosis resulting in signs of acute abdomen with shock is reported. Diagnosis of a ruptured adrenal tumor was made by CT scanning. Elevated urine and plasma catecholamines as well as histological examination of the removed tumor confirmed the clinical suspicion of pheochromocytoma. The patient made uneventful recovery and is asymptomatic 2 years after surgery. Ruptured pheochromocytoma as a cause of abdominal emergency is discussed in view of the existing literature.

Circulating neuropeptide Y in humans: relation to changes in catecholamine levels and changes in hemodynamics.

Neuropeptide-Y (NPY) is a sympathetic cotransmitter, which causes vasoconstriction, decreases coronary blood flow and decreases cardiac output. Circulating immunoreactive NPY (ir-NPY) levels increase with exercise, in patients admitted to the coronary care unit, and during thoracic surgery, and may play a role in postoperative hemodynamics. We studied changes in ir-NPY, epinephrine (E) and norepinephrine (NE) arterial plasma levels, and their correlation to simultaneous hemodynamic measurements at 8 perioperative time points in 13 patients undergoing open heart surgery. Changes in circulating ir-NPY negatively correlated with changes in systemic vascular resistance index (SVRI), mean arterial pressure (MAP) and mean pulmonary arterial pressure (MPAP) (P < 0.05), suggesting that the hemodynamic changes were the cause of the changes in ir-NPY levels, inducing overflow of NPY into the circulation via sympathetic activation. Changes in NE and E levels positively correlated with changes in heart rate (HR), SVRI and MPAP. Changes in E levels also positively correlated with changes in stroke volume index (SVI), central venous pressure (CVP) and cardiac index (CI). NE levels correlated well with E levels, but catecholamine levels did not correlate with ir-NPY levels. These results suggest, that the elevation in circulating NPY levels previously noted in patients with heart failure and acute myocardial infarction may reflect changes in NPY overflow and/or clearance secondary to increased sympathetic activity and to hemodynamic changes.

[Evaluation of blood rheology indices in patients with pheochromocytoma]. / Ocena wskazników reologicznych krwi u chorych z pheochromocytoma.

Investigated group consisted of 28 patients (21 female and 7 male) with pheochromocytoma in mean age of 39.9 +/- 13 years, while control group comprised 25 healthy volunteers in mean age 36.0 +/- 7.2 years. Following parameters were determined: plasma and blood viscosity, erythrocyte and platelets aggregation, erythrocyte deformability, hematocrit, beta-thromboglobulin plasma concentration, plasma fibrinogen concentration, lipids concentration, noradrenaline, adrenaline, serotonin, neuropeptide Y plasma concentrations. Plasma fibrinogen and beta-thromboglobulin were increased in pheochromocytoma before surgery after pharmacological treatment and also after excision of the tumor. Whereas altered erythrocyte deformability before any treatment, only. Plasma neuropeptide Y concentration was higher in pheochromocytoma before surgery and after pharmacological treatment. There was no correlation between plasma catecholamines, plasma fibrinogen, beta-thromboglobulin, and erythrocyte deformability. Our results suggest that rheological abnormalities observed in patients with pheochromocytoma may contribute to vascular complications in this subjects. Sympathetic nervous system seems to influence indirectly observed rheological abnormalities.

[Effect of positive pressure respiration on diurnal catecholamine excretion by patients with obstructive sleep apnea]. / Wplyw oddychania pod dodatnim cisnieniem na dobowe wydalanie katecholamin przez chorych na obturacyjny bezdech senny.

The aim of the study was to investigate effects of CPAP treatment on diurnal catecholamine excretion in urine in patients with obstructive sleep apnea (OSA). 12 males with severe OSA (mean AHI = 63) were measured in 3 separate 8 hour samples by fluorimetric method. NA levels were higher in OSA patients in all urine samples than in obese, mildly hypertensive males (control group = C). In C group patients NA levels were significantly lower at night than during the day contrary to OSA patients in whom NA levels dropped insignificantly during sleep. In OSA patients NA levels during sleep correlated with severity of apneas (r = 0.42) and night hypoxaemia (r = -0.46). CPAP treatment resulted in significant fall in NA levels during sleep (p < 0.01). A levels did not change after CPAP treatment. We conclude that abnormally high NA level during sleep in OSA patients may be related to sleep fragmentation and hypoxia. CPAP treatment restores normal circadian rhythm of NA excretion.

Heart rate variability before sudden blood pressure elevations or complex cardiac arrhythmias in phaeochromocytoma.

In phaeochromocytoma, sudden hypertensive or arrhythmic episodes are believed to be associated with excessive free catecholamine excretion. However, lack of correlation between blood pressure (BP) and plasma catecholamine levels has been reported. Therefore an attempt was made to assess the sympathovagal balance before and during episodes of BP elevation or complex cardiac arrhythmias in this disease. Ten patients with phaeochromocytoma and 10 matched controls with essential hypertension underwent simultaneous 24 h Holter ECG and BP monitoring. BP elevation was diagnosed when the BP exceeded the mean 24 h values by 40 mm Hg systolic or 30 mm Hg diastolic, respectively. Heart rate variability (HRV) was measured for 5 min periods 1 h before, 15 min before and during 13 episodes of BP elevation in phaeochromocytoma and 13 episodes in the control group, as well as at 1 h, 15 min and immediately before five arrhythmic events in phaeochromocytoma. In phaeochromocytoma, vagal activity measured 1 h before BP elevation was markedly higher than in control hypertensives. However, in both groups at 15 min before and during the hypertensive events, the vagal tone decreased significantly. In contrast, just before the arrhythmic events HRV remained unaltered with a slight insignificant increase in sympathetic activity. We conclude that in phaeochromocytoma, pronounced BP elevations during daily activities are preceded by a parasympathetic withdrawal, similar to the findings in essential hypertension. Such a sequence does not seem to precede sudden complex arrhythmic events in phaeochromocytoma.

Heart rate variability in pheochromocytoma.

The results of our study show that parasympathetic tone was higher in patients with pheochromocytoma than in patients with primary hypertension. An unusual spectral form of vagal activity was seen during excessive beta-adrenergic stimulation, while persistent hypertension with an excessive alpha-adrenergic stimulation was responsible for low cardiac sympathetic tone, probably due to desensitization of beta-adrenergic receptors.

Influence of alpha-adrenergic blockade on ventricular arrhythmias, QTc interval and heart rate variability in phaeochromocytoma.

There are strong experimental evidences that alpha 1-adrenergic stimulation significantly influences cardiac arrhythmogenesis, especially during myocardial ischaemia and reperfusion. However, anti-arrhythmic effects of alpha-blockade in humans were scarcely utilised. Thus the purpose of our study was to assess these effects in patients with phaeochromocytoma. In 22 patients simultaneous 24 h ECG and blood pressure (BP) monitoring, as well as estimation of the urinary 24 h free catecholamine excretion, were performed twice: before and during the treatment with the non-selective alpha-blocker, phenoxybenzamine. The heart rate variability was measured during four 5 min periods, at 10.00, 16.00, 22.00 and 04.00. During alpha-blockade systolic blood pressure (SBP) decreased from 137.6 +/- 23.8 to 126.5 +/- 15.7 mm Hg (P < 0.01), heart rate increased from 83.0 +/- 9.9 to 88.5 +/- 10.0/min (P < 0.02) and duration of QTc interval unsignificantly increased. Incidence of frequent or repetitive ventricular arrhythmias was significantly higher before treatment (in 9 vs 3 of 22 patients, P < 0.05). Heart rate variability significantly decreased during the treatment, with regard to all parameters, representing both the sympathetic and parasympathetic activity. We conclude that non-selective alpha-blockade significantly decreases the incidence of frequent or repetitive ventricular arrhythmias in patients with phaeochromocytoma, although the lack of QTc interval shortening suggests that the effect of class I drugs may participate in the anti-arrhythmic effects of phenoxybenzamine. Moreover, non-selective alpha-blockade in phaeochromocytoma significantly diminishes vagal activity.

Endothelin-1 and neuropeptide Y plasma concentrations in renal venous blood of hypertensive patients with unilateral renal artery stenosis.

The aim of the study was to investigate endothelin-1 (ET-1) and neuropeptide Y (NPY) plasma concentrations in renal venous blood of hypertensive patients with unilateral renal artery stenosis (URAS). The study was performed in 22 patients with URAS and 18 patients diagnosed as essentially hypertensive. In each subject renal arteriography and renal vein catheterisation was performed. Blood samples for ET-1, NPY and plasma renin activity (PRA) were withdrawn from renal veins and vena cava inferior, and for ET-1 and NPY from the aorta. Patients with URAS were divided in two subgroups according to the renal vein renin ratio. Both in nine patients with URAS and ratio > 1.5 and in 13 patients with URAS and ratio < 1.5, ET-1 and NPY plasma concentrations evaluated in renal venous blood of the ischaemic kidney were not different from those assessed in the contralateral side, in vena cava inferior and in the aorta. In essential hypertension, the mean ET-1 and NPY plasma concentrations of both renal veins were not different from the ET-1 and NPY plasma values assessed in renal vein of stenosed and contralateral side, vena cava and aorta of patients with URAS with and without activation of the renin system. Our study indicates that chronic ischaemia does not affect ET-1 and NPY plasma concentrations in renal venous blood of hypertensive URAS patients both with and without activation of the renin system.