Jiří Widimský

Randomized Comparison of Renal Denervation Versus Intensified Pharmacotherapy Including Spironolactone in True-Resistant Hypertension Six-Month Results From the Prague-15 Study

This prospective, randomized, open-label multicenter trial evaluated the efficacy of catheter-based renal denervation (Symplicity, Medtronic) versus intensified pharmacological treatment including spironolactone (if tolerated) in patients with true-resistant hypertension. This was confirmed by 24-hour ambulatory blood pressure monitoring after excluding secondary hypertension and confirmation of adherence to therapy by measurement of plasma antihypertensive drug levels before enrollment. One-hundred six patients were randomized to renal denervation (n=52), or intensified pharmacological treatment (n=54) with baseline systolic blood pressure of 159±17 and 155±17 mm Hg and average number of drugs 5.1 and 5.4, respectively. A significant reduction in 24-hour average systolic blood pressure after 6 months (−8.6 [95% cofidence interval: −11.8, −5.3] mm Hg; P<0.001 in renal denervation versus −8.1 [95% cofidence interval: −12.7, −3.4] mm Hg; P=0.001 in pharmacological group) was observed, which was comparable in both groups. Similarly, a significant reduction in systolic office blood pressure (−12.4 [95% cofidence interval: −17.0, −7.8] mm Hg; P<0.001 in renal denervation versus −14.3 [95% cofidence interval: −19.7, −8.9] mm Hg; P<0.001 in pharmacological group) was present. Between-group differences in change were not significant. The average number of antihypertensive drugs used after 6 months was significantly higher in the pharmacological group (+0.3 drugs; P<0.001). A significant increase in serum creatinine and a parallel decrease of creatinine clearance were observed in the pharmacological group; between-group difference were borderline significant. The 6-month results of this study confirmed the safety of renal denervation. In conclusion, renal denervation achieved reduction of blood pressure comparable with intensified pharmacotherapy.

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.

Increased blood pressure variability in pheochromocytoma compared to essential hypertension patients

Objective Catecholamines are responsible for short and long-lasting blood pressure (BP) elevations in pheochromocytoma. We investigated whether in patients with pheochromocytoma this catecholamine excess would result in higher BP variability in comparison with patients suffering from essential hypertension (EH). Design We examined retrospectively 54 (26 treated with α1-blockers) patients with pheochromocytoma (30 patients also investigated after tumour removal) and 108 (42 treated with α1-blockers) patients with EH. They all underwent 24-h ambulatory BP monitoring. To assess the BP variability, coefficient of BP variability (SD of average BP/average BP) was used. Results In subjects with pheochromocytoma, a higher coefficient of BP variability was shown compared with EH during the 24-h period (0.12 ± 0.03 versus 0.10 ± 0.02, P = 0.003 for systolic BP in the treated group) and mainly during the daytime (0.11/0.13 ± 0.04/0.03 versus 0.09/0.11 ± 0.03/0.04, P = 0.007/0.06 for systolic/diastolic BP in the untreated group and 0.12/0.13 ± 0.04/0.04 versus 0.09/0.12 ± 0.04/0.02, P < 0.001/0.01 in the treated group). Tumour removal resulted in a decrease of the previously increased 24-h (0.11 ± 0.03 versus 0.10 ± 0.03, P = 0.04) and daytime (0.11 ± 0.03 versus 0.09 ± 0.03, P = 0.03) coefficient of systolic BP variation. Twenty-seven subjects with pheochromocytoma and inverted circadian BP rhythm (night-time BP > daytime BP) had a significantly higher 24-h (0.13 ± 0.03 versus 0.10 ± 0.03, P < 0.001 for systolic BP) and daytime coefficient of BP variation (0.13/0.15 ± 0.04/0.03 versus 0.09/0.12 ± 0.02/0.02, P < 0.001/<0.001) and also a higher occurrence of the isolated excretion of norepinephrine (14 versus seven subjects, P = 0.05) compared with the 27 subjects with pheochromocytoma without inverted circadian BP rhythm. Conclusion The excess of catecholamines in patients with pheochromocytoma is associated with higher long-term BP variability in comparison with patients suffering from EH especially in subjects with inverted circadian BP rhythm. Tumour removal resulted in the amelioration of the previously increased BP variability.

Risk Factors for Nonadherence to Antihypertensive Treatment

Nonadherence to antihypertensive treatment is a critical contributor to suboptimal blood pressure control. There are limited and heterogeneous data on the risk factors for nonadherence because few studies used objective-direct diagnostic methods. We used high-performance liquid chromatography-tandem mass spectrometry of urine and serum to detect nonadherence and explored its association with the main demographic- and therapy-related factors in 1348 patients with hypertension from 2 European countries. The rates of nonadherence to antihypertensive treatment were 41.6% and 31.5% in the UK and Czech populations, respectively. Nonadherence was inversely related to age and male sex. Each increase in the number of antihypertensive medications led to 85% and 77% increase in nonadherence (P<0.001) in the UK and Czech populations, respectively. The odds of nonadherence to diuretics were the highest among 5 classes of antihypertensive medications (P⩽0.005 in both populations). The predictive model for nonadherence, including age, sex, diuretics, and the number of prescribed antihypertensives, showed area under the curves of 0.758 and 0.710 in the UK and Czech populations, respectively. The area under the curves for the UK model tested on the Czech data and for the Czech model tested on UK data were calculated at 0.708 and 0.756, respectively. We demonstrate that the number and class of prescribed antihypertensives are modifiable risk factors for biochemically confirmed nonadherence to blood pressure–lowering therapy. Further development of discriminatory models incorporating these parameters might prove clinically useful in assessment of nonadherence in countries where biochemical analysis is unavailable.

Determination of doxazosin and verapamil in human serum by fast LC-MS/MS: application to document non-compliance of patients.

A rapid and sensitive method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for simultaneous determination of doxazosin and verapamil in human serum has been developed. Trimipramine-d₃ as an isotopic labelled internal standard was used for quantification. Serum samples were prepared by simple liquid-liquid extraction with mixture of tert butyl methyl ether and ethyl acetate (1:1, v:v). The analytes and internal standard were separated on C18 column using an isocratic elution with 5 mM ammonium formate with 0.02% formic acid and 0.02% formic acid in acetonitrile (55:45, v:v) at a flow rate of 1.1 mL/min. Positive TurboIonSpray mass spectrometry was used with multiple reaction monitoring of the transitions at: m/z 455.3→165.2 and 150.2 for verapamil, m/z 452.2→344.4 and 247.4 for doxazosin, m/z 298.2→103.1 for trimipramine-d₃. Linearity was achieved between 1 and 500 ng/mL (R² ≥ 0.997) for both analytes. An extensive pre-study method validation was carried out in accordance with FDA guidelines. This assay was successfully applied to determine the serum concentrations of doxazosin and verapamil in suspect non-compliance patients.

Elevated Inflammation Markers in Pheochromocytoma Compared to Other Forms of Hypertension

Objective: To investigate the effect of long-term catecholamine excess in pheochromocytoma on leukocyte and platelet count and on proteins of acute-phase response. Methods: Fifteen subjects with pheochromocytoma, 16 with primary aldosteronism, 18 with essential hypertension and 17 healthy controls were studied. Sixteen subjects with pheochromocytoma were investigated after tumor removal. Leukocyte, neutrophil and platelet count, as well as C-reactive protein were measured in all subjects, while fibrinogen, α1-antitrypsin, α2-macroglobulin, orosomucoid, transferrin and prealbumin were only measured in subjects with pheochromocytoma, primary aldosteronism and essential hypertension. Results: Subjects with pheochromocytoma showed significantly higher leukocyte [7.5 ± 0.9 109/l, p < 0.001 vs. primary aldosteronism (5.4 ± 0.9 109/l) and healthy controls (5 ± 0.9 109/l), p = 0.04 vs. essential hypertension (6.3 ± 1.6 109/l)], neutrophil (p < 0.001 vs. primary aldosteronism and healthy subjects) and platelet counts (p < 0.001 vs. primary aldosteronism; p = 0.01 vs. essential hypertension) compared to the other groups of subjects. Similar results were obtained for positive proteins of acute-phase response in subjects with pheochromocytoma [C-reactive protein: 0.62 ± 0.52 mg/dl, p < 0.001 vs. healthy subjects (0.08 ± 0.08 mg/dl), p = 0.001 vs. primary aldosteronism (0.17 ± 0.19 mg/dl), p = 0.04 vs. essential hypertension (0.31 ± 0.26 mg/dl); fibrinogen: p = 0.02 vs. primary aldosteronism; orosomucoid: p = 0.005 vs. primary aldosteronism; α2-macroglobulin: p = 0.009 vs. primary aldosteronism]. No significant differences were found in plasma levels of α1-antitrypsin, transferrin and prealbumin. Tumor removal led to a significant decrease in leukocyte (p = 0.004), neutrophil (p = 0.007) and platelet count (p = 0.003) and also to a significant decrease in acute-phase proteins (C-reactive protein: p = 0.03, fibrinogen: p = 0.008, α1-antitrypsin: p = 0.003, orosomucoid: p = 0.04). Conclusions: Chronic catecholamine excess in pheochromocytoma is accompanied by an increase in inflammation markers which was reversed by the tumor removal.

Metastatic pheochromocytoma: does the size and age matter?

Eur J Clin Invest 2011; 41 (10): 1121–1128

Long-term effect of specific treatment of primary aldosteronism on carotid intima-media thickness.

Background: Aldosterone has been shown to substantially contribute to the accumulation of different types of collagen fibres and growth factors in the arterial wall, thus increasing wall thickness. A previous study showed reduction of increased common carotid intima–media thickness (IMT) in patients with primary aldosteronism 1 year after adrenalectomy. Our study in patients with primary aldosteronism was aimed at comparing the long-term effect of adrenalectomy vs. spironolactone therapy on common carotid IMT regression. Method: Forty-two patients with confirmed primary aldosteronism (21 with aldosterone-producing adenoma treated by unilateral laparoscopic adrenalectomy, 21 treated with spironolactone) were investigated by carotid ultrasound at baseline and 1 and 6 years after the specific treatment. Results: There was a decrease in common carotid IMT from 0.956 ± 0.140 to 0.900 ± 0.127 mm (−5.9%; P < 0.05) at 1 year and to 0.866 ± 0.130 mm (−9.4%; P < 0.01) at 6 years after adrenalectomy; in the spironolactone group, common carotid IMT decreased from 0.917 ± 0.151 to 0.900 ± 0.165 mm (−1.8%; NS) at 1 year and to 0.854 ± 0.176 mm (−6.8%; P < 0.01) at 6 years of treatment. The magnitude of improvement at 1 year was significantly higher (by 70%; P < 0.05) in the adrenalectomy group; however, the difference (by 27%) became nonsignificant at 6 years. Comparing the adrenalectomy and spironolactone groups, there was no significant difference in blood pressure decrease after treatment. Conclusion: In the long term, spironolactone therapy in patients with primary aldosteronism had significant effect on regression of IMT, which was comparable to surgical treatment in patients with unilateral forms of primary aldosteronism.

Factors influencing arterial stiffness in pheochromocytoma and effect of adrenalectomy

The aim of the study was to evaluate arterial stiffness and its modulating factors measured by carotid-femoral pulse wave velocity (PWV) and central augmentation index (AI) in patients with pheochromocytoma (PHEO) before and after surgery. Forty-five patients with PHEO and 45 healthy controls were investigated using an applanation tonometer (SphygmoCor, AtCor Medical). The gender, age, BMI and lipid profiles were comparable among both groups. The main difference in basic characteristic was as expected for fasting plasma glucose (P<0.001) and all blood pressure modalities. PWV in PHEO was significantly higher than in controls (7.2±1.4 vs. 5.8±0.5 ms−1; P<0.001). Between-group difference in PWV remained significant even after the adjustment for age, heart rate, fasting plasma glucose and each of brachial (P<0.001) and 24 h blood pressure parameters (P<0.01). The difference in AI between groups did not reach the statistical significance (19±14 vs. 16±13%; NS). In multiple regression analysis, age (P<0.001), mean blood pressure (P=0.002), high-sensitive C-reactive protein (hs-CRP) (P=0.007) and 24 h urine norepinephrine (P=0.007) were independently associated with PWV in PHEO. In addition, 27 patients with PHEO were studied 1 year after tumor removal. Successful tumor removal led to a significant decrease in PWV (7.0±1.2 vs. 6.0±1.1 ms−1; P<0.001). In conclusion, patients with PHEO have an increase in PWV, which is reversed by the successful tumor removal. Age, mean blood pressure, hs-CRP and norepinephrine levels are independent predictors of PWV.

Discrepant Results of Adrenal Venous Sampling in Seven Patients with Primary Aldosteronism

Background: Adrenal venous sampling serves as a discrimination between uni- and bilateral forms of primary aldosteronism (PA). Even correctly performed adrenal venous sampling may lead to non-diagnostic results in some cases. Results: We describe 7 subjects with PA in whom correct cannulation of adrenal veins (high selectivity index defined as cortisol(adrenal)/cortisol(periphery) ratio) was associated with aldosterone (ALDO) suppression (ALDO/cortisol(adrenal)/ALDO/cortisol(periphery) ratio <1) in the left adrenal gland and in whom all subjects underwent a successful adrenalectomy on the right side. In 3 subjects, samples from the right side with lower selectivity indexes (1.11–1.7) compared to those samples with a higher index of selectivity (10.4–44.9) pointed to lateralization. Next, 2 subjects were operated because of relatively large adrenal masses in the right adrenal gland on CT despite ALDO suppression on this side. One subject presented with high selectivity indexes from the right side (19.5 and 37.6), but only one sample showed ALDO secretion. Patient 7 was treated with right-sided adrenalectomy despite a low lateralization index (ALDO/cortisol(right)/ALDO/cortisol(left) 1.78). Conclusions: Our results document some uncertainties in interpreting results of adrenal venous sampling in subjects with PA which may result from deep catheter insertion, anomalous venous drainage, or fluctuations in ALDO secretion.