Tomas Zelinka

Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region.

Recently published studies from different parts of the world report significantly higher prevalence of primary hyperaldosteronism (PH) in hypertensives (ranging from 5 to 25%) than the previously accepted figures. There have been no data so far about the prevalence of PH in Central Europe. Therefore, we have undertaken this study to evaluate the prevalence of PH in patients with moderate to severe hypertension referred to a hypertension unit in the Czech Republic, together with the determination of the percentage of different subtypes of PH including familial forms. In addition to that, we have evaluated the prevalence of other types of secondary forms of hypertension.A total of 402 consecutive patients (230 females and 172 males) with hypertension, referred to our hypertension unit, were studied. Positive aldosterone/renin ratio (ARR, (ng/100 ml)/(ng/ml/h)) ⩾50 as a more strict marker of PH was found in 87 patients (21.6%), 30% of them were normokalaemic. The diagnosis of PH was later confirmed in 77 cases (89%); the total prevalence of PH was thus 19%. PH consisted of the following forms: idiopathic hyperaldosteronism 42%, unilateral aldosterone-producing adenoma 36%, unilateral hyperplasia 7%, nonclassifiable PH (refused operation/adrenal venous sampling) 13%, familial hyperaldosteronism type 1.2%. The prevalence of other types of secondary hypertension was as follows: pheochromocytoma 5%, renovascular 4.5%, hypercortisolism 2%, renal 0.75%.In conclusion, we have noted that PH in the Central Europe region (Czech Republic) is the most frequent form of endocrine hypertension with a considerably high prevalence in moderate to severe hypertension. Application of more strict criteria raises the probability of correct diagnosis of PH including the early normokalaemic stages of PH.

Precise assessment of noncompliance with the antihypertensive therapy in patients with resistant hypertension using toxicological serum analysis

Background: The aim of our study was to assess the prevalence of pseudo-resistance caused by noncompliance with treatment among patients with severe resistant hypertension and to analyze the contributing factors. Method: Three hundred and thirty-nine patients (195 men) with resistant essential hypertension were studied. The first group consisted of 176 patients admitted for hospitalization for exclusion of a secondary cause to our hypertension centre (103 men); the second one consisted of 163 out-patients (92 men) investigated for the first time in an out-patient hypertension clinic. Unplanned blood sampling for assessment of serum antihypertensive drug concentrations by means of liquid chromatography–mass spectrometry was performed in all patients. Results: Our main finding is a surprisingly low compliance with drug treatment in out-patients with resistant hypertension (23% partially noncompliant and 24% totally noncompliant – in total, 47% prevalence of noncompliance). Eighty-one percent of hospitalized patients were positive, in 10% the results were partially positive and in 9% of the patients, the drugs were all negative. The compliance among hospitalized patients was probably better due to lower numbers of prescribed drugs and expected thorough investigation. More frequently, noncompliance was found in nonworking (potential purpose-built behaviour), younger and less well educated patients. The most frequent noncompliance was to doxazosine, spironolactone and hydrochlorothiazide. We have observed a surprisingly low compliance with treatment among out-patients with severe hypertension. Conclusion: We conclude that the evaluation of antihypertensive drugs concentrations is a useful and precise method for assessment of noncompliance in patients with resistant hypertension. This evaluation is useful before starting the diagnostic work-up of secondary forms of hypertension and before assignment patients into protocols with new therapy modalities such as renal denervation.

High incidence of cardiovascular complications in pheochromocytoma.

Excess of catecholamines in pheochromocytoma is usually accompanied with classical symptoms and signs. In some cases, severe cardiovascular complications (e. g., heart failure, myocardial infarction) may occur. We performed a retrospective analysis focused on the incidence of cardiovascular complications (classified as follows: arrhythmias, myocardial involvement or ischemia and atherosclerosis, cerebrovascular impairment) before the establishment of diagnosis of pheochromocytoma among 145 subjects treated in our hospital. Cardiovascular complications occurred in 28 subjects, but these subjects did not differ significantly from subjects without complications in age, gender, body mass index, paroxysmal symptoms, symptom duration, tumor dimension, catecholamine secretory phenotype, and incidence of hypertension or diabetes mellitus. Arrhythmias occurred in 15 subjects (2 arrhythmia types in 2 subjects): atrial fibrillation in 9 subjects, supraventricular tachycardia in 3 cases, and ventricular tachycardia in 2 patients. Significant bradycardia was noted in 3 cases. Five subjects presented with heart failure with decreased systolic function (takotsubo-like cardiomyopathy found in 2 cases). One subject suffered from hypertrophic obstructive cardiomyopathy. Seven subjects presented with non-ST-segment elevation myocardial infarction, 2 patients with ST-segment myocardial infarction, and 1 subject underwent coronary artery bypass grafting. Two subjects suffered from significant peripheral atherosclerosis. Among cerebrovascular complications, transient ischemic attack was found in 3 cases, 2 subjects suffered from stroke, and subarachnoidal bleeding occurred in 1 patient. One subject suffered from diffuse neurological impairment due to multiple ischemic white matter lesions. These data show relatively high incidence of cardiovascular complications (19.3%) in subjects with pheochromocytoma. Early diagnosis is mandatory to prevent severe complications in pheochromocytoma.

Adrenalectomy Improves Arterial Stiffness in Primary Aldosteronism

BackgroundAldosterone has been shown to substantially contribute to the accumulation of different types of collagen fibers and growth factors in the arterial wall, which increase wall stiffness. We previously showed that arterial wall stiffness is increased in primary aldosteronism (PA) independently of concomitant hypertension. This study was aimed at assessing the effects of specific treatment of PA on the arterial stiffness.MethodsTwenty-nine patients with confirmed PA (15 with aldosterone-producing adenoma treated by unilateral laparoscopic adrenalectomy, 14 treated with spironolactone (mainly idiopathic aldosteronism) were investigated by Sphygmocor applanation tonometer (using measurement of carotid-femoral pulse wave velocity (PWV) and augmentation index (AI)) at the time of the diagnosis and then approximately 1 year after the specific treatment.ResultsThe office blood pressure (BP) decreased from 167 +/- 18/96 +/- 9 to 136 +/- 12/80 +/- 7 mm Hg after adrenalectomy (P = 0.001), and from 165 +/- 21/91 +/- 13 to 151 +/- 22/88 +/- 8 mm Hg (not significant (n.s.)) on spironolactone. The mean 24-h BP decreased from 150 +/- 18/93 +/- 11 mm Hg to 126 +/- 17/80 +/- 10 mm Hg after adrenalectomy (P < 0.01), and from 155 +/- 16/94 +/- 12 to 139 +/- 18/88 +/- 8 mm Hg (n.s.) on spironolactone. The PWV significantly decreased after surgery from 9.5 +/- 2.7 m/s to 7.6 +/- 2 m/s (P = 0.001), and the AI (recalculated for heart rate 75/min) decreased significantly from 27 +/- 10 to 19 +/- 9% (P < 0.01). On the other hand, we did not find significant change of arterial stiffness indices in patients treated with spironolactone (PWV: 9.3 +/- 1.6 m/s vs. 8.8 +/- 1.3 m/s (n.s.); AI: 25 +/- 9% vs. 25 +/- 8% (n.s.)).ConclusionsSurgical but not conservative treatment of PA led to a significant decrease of BP and arterial stiffness parameters.American Journal of Hypertension (2008). doi:10.1038/ajh.2008.243American Journal of Hypertension (2008); 21, 10, 1086-1092. doi 10.1038/ajh.2008.243.

Diurnal blood pressure variation in pheochromocytoma, primary aldosteronism and Cushing's syndrome

We examined circadian blood pressure (BP) variation (expressed as a relative night-time BP decline) in subjects with primary aldosteronism (78 patients), pheochromocytoma (n=45) and Cushings syndrome (n=18). Subjects with aldosterone-producing adenoma (n=21) and pheochromocytoma (n=27) were also investigated after the tumour removal. In all, 65 patients with essential hypertension served as a control group. The night-time BP decline was significantly attenuated in all three forms of endocrine hypertension compared to the control group (primary aldosteronism P<0.0001, pheochromocytoma P<0.0001 for systolic and diastolic BP and Cushings syndrome P<0.0001/<0.001 vs essential hypertension). In the case of pheochromocytoma, the absence of the night-time BP decrease was more prominent compared to the primary aldosteronism group (P=0.003/0.001) and for the diastolic BP also in comparison with the Cushings syndrome group (P=0.03). Tumour removal led in both groups to the restoration of the previously altered circadian rhythm (aldosterone-producing adenoma: P=0.0005/0.0009; pheochromocytoma: P=0.001/0.0007). Our study demonstrates a blunted circadian BP variation in all forms of adrenal hypertension in comparison with essential hypertension. This reduction of the night-time BP decrease was more prominent in pheochromocytoma than in primary aldosteronism or Cushings syndrome.

Role of Adding Spironolactone and Renal Denervation in True Resistant Hypertension: One-Year Outcomes of Randomized PRAGUE-15 Study.

This randomized, multicenter study compared the relative efficacy of renal denervation (RDN) versus pharmacotherapy alone in patients with true resistant hypertension and assessed the effect of spironolactone addition. We present here the 12-month data. A total of 106 patients with true resistant hypertension were enrolled in this study: 52 patients were randomized to RDN and 54 patients to the spironolactone addition, with baseline systolic blood pressure of 159±17 and 155±17 mm Hg and average number of drugs 5.1 and 5.4, respectively. Twelve-month results are available in 101 patients. The intention-to-treat analysis found a comparable mean 24-hour systolic blood pressure decline of 6.4 mm Hg, P=0.001 in RDN versus 8.2 mm Hg, P=0.002 in the pharmacotherapy group. Per-protocol analysis revealed a significant difference of 24-hour systolic blood pressure decline between complete RDN (6.3 mm Hg, P=0.004) and the subgroup where spironolactone was added, and this continued within the 12 months (15 mm Hg, P= 0.003). Renal artery computed tomography angiograms before and after 1 year post-RDN did not reveal any relevant changes. This study shows that over a period of 12 months, RDN is safe, with no serious side effects and no major changes in the renal arteries. RDN in the settings of true resistant hypertension with confirmed compliance is not superior to intensified pharmacological treatment. Spironolactone addition (if tolerated) seems to be more effective in blood pressure reduction.

Importance of thorough investigation of resistant hypertension before renal denervation: should compliance to treatment be evaluated systematically?

Catheter-based renal denervation (RD) has been introduced recently as a potentially effective invasive treatment of refractory hypertension. The proportion of patients with severe hypertension suitable for RD is not clear. The aim of this study was to identify what percentage of patients has truly resistant essential hypertension and are thus potentially eligible for RD. We investigated 205 consecutive patients referred to a university hypertension center for severe hypertension within 12 months. Ambulatory 24-h blood pressure (BP) monitoring (24 h ABPM), secondary hypertension screening and compliance to treatment testing (by use of plasma drug level measurements) were performed in all patients. Fifty-seven patients (27.8%) did not have truly resistant hypertension (RH) based on clinical BP. Among the remaining 122 patients (59.5%) with RH confirmed by 24 h ABPM, 50 patients (24.4% of the original cohort) had a secondary cause of hypertension and in 27 (13.2%) non-compliance to treatment was confirmed. Thus, only 45 patients (22%) had truly resistant essential hypertension and were considered for RD. Only one-third (n=15, 7.3% of the original cohort) was, however, finally referred for RD (14 were excluded due to contraindications for RD and 16 refused the invasive treatment). In conclusion, thorough examination of severe hypertension including 24 h ABPM, secondary hypertension exclusion and drug compliance testing before considering RD reveals that majority of these patients are not suitable for RD. Specifically, compliance to treatment testing should be mandatory in order to identify eligible candidates for RD.

RET mutation Tyr791Phe the genetic cause of different diseases derived from neural crest

Activating germline RET mutations are presented in patients with familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia (MEN) types 2A and 2B, whereas inactivating germline mutations in patients with Hirschsprung’s disease (HSCR). The aim of this study was to evaluate genotype–phenotype correlations of the frequently discussed Tyr791Phe mutation in exon 13 of the RET proto-oncogene. Screening of three groups of patients was performed (276 families with medullary thyroid carcinoma (MTC), 122 families with HSCR, and 29 patients with pheochromocytoma). We found this mutation in 3 families with apparently sporadic MTC, 3 families with FMTC/MEN2, 1 patient with pheochromocytoma, and 3 families with HSCR. All gene mutation carriers have a silent polymorphism Leu769Leu in exon 13. In three families second germline mutations were detected: Cys620Phe (exon 10) in MEN2A family, Met918Thr (exon 16) in MEN2B family, and Ser649Leu (exon 11) in HSCR patient. Detection of the Tyr791Phe mutation in MEN2/MTC and also in HSCR families leads to the question whether this mutation has a dual character (gain-of-function as well as loss-of-function). A rare case of malignant pheochromocytoma in a patient with the Tyr791Phe mutation is presented. This study shows various clinical characteristics of the frequently discussed Tyr791Phe mutation.

Changes in Energy Metabolism in Pheochromocytoma

CONTEXT Catecholamine overproduction in pheochromocytoma affects basal metabolism, resulting in weight loss despite normal food intake. OBJECTIVE The objective of the study was to evaluate changes in energy metabolism expressed as resting energy expenditure (REE) in patients with pheochromocytoma before and after adrenalectomy and the possible relationship with circulating inflammatory markers. DESIGN We measured REE in 17 patients (8 women) with pheochromocytoma by indirect calorimetry (Vmax-Encore 29N system) before and 1 year after adrenalectomy. Body fat percentage was measured with a Bodystat device. Inflammatory markers (leukocytes count and C-reactive protein) and cytokines (TNF-α, IL-6, and IL-8) were analyzed with a Luminex 200. RESULTS REE measured in the pheochromocytoma group was 10.4% higher than the predicted value (1731 ± 314 vs 1581 ± 271 kcal/d; P = .004). Adrenalectomy significantly increased body mass index (P =0.004) and the percentage of body fat (P = .01), with a proportional increase in fat distribution (waist circumference, P = .045; hip circumference, P = .001). REE significantly decreased after adrenalectomy (1731 ± 314 vs 1539 ± 215 kcal/d; P = .002), even after adjustments in body surface and body weight (P < .001). After adrenalectomy, we found a significant decrease in leukocyte counts (P = .014) and in the levels of TNF-α (P < .001), IL-6 (P = .048), and IL-8 (P = .007) but not C-reactive protein (P = .09). No significant correlations among calorimetry parameters, hormones, and proinflammatory markers were detected. CONCLUSIONS Chronic catecholamine overproduction in pheochromocytoma may lead to a proinflammatory and hypermetabolic state characterized by increased REE. Adrenalectomy leads to the normalization of energy metabolism followed by an increase in body mass index and body fat content and decreases in inflammatory markers and cytokines.

Impact of essential hypertension and primary aldosteronism on plasma brain natriuretic peptide concentration

Introduction. Brain natriuretic peptide (BNP) has important role in the diagnosis and management of heart failure. Data on the impact of blood pressure (BP) on BNP are controversial. In primary aldosteronism (PA), BNP production can be affected by both hypertension and specific endocrine mechanisms. This study was aimed at investigating the impact of hypertension and hyperaldosteronism on plasma BNP levels. Methods. Plasma BNP concentration, casual and 24‐h BP and echocardiographic indices were assessed in 40 patients with moderate to severe essential hypertension (EH), 40 BP‐matched patients with PA, and 40 age‐ and sex‐matched healthy controls. Results. BNP levels in PA and EH groups did not differ significantly and were higher compared with those in controls [median and interquartile range 26 (13–48) pg/ml, p = 0.01, and 23 (9–32) pg/ml, n.s., vs 14 (6–26) pg/ml in controls]. Remarkably elevated BNP was observed only in three PA and two EH patients, all having significant left ventricular (LV) hypertrophy. BNP levels in PA and EH groups correlated weakly with casual and 24‐h BP, interventricular septal thickness and LV mass index (LVMI). Diastolic BP and LVMI were identified as the strongest independent determinants of BNP (p = 0.002 and p = 0.01, respectively). Conclusions. Both PA and EH patients had modest and mutually comparable elevation of BNP, which was independently determined by diastolic BP and LVMI. Both subtypes of PA (aldosterone‐producing adenoma and bilateral adrenal hyperplasia) had similar effect on BNP production. Specific impact of hyperaldosteronism on BNP was not confirmed.