Adherence and blood pressure control in patients with primary aldosteronism.

PURPOSE: The aim of our study was to evaluate the adherence to mineralocorticoid receptor (MR) antagonists and other antihypertensive therapy and blood pressure control in conservatively treated patients with primary aldosteronism (PA). MATERIALS AND METHODS: Conservatively treated subjects with previously confirmed PA (n-50, 64.5 ± 9 years of age, 24% women) were investigated via our outpatient hypertension clinic. All subjects underwent regular examinations in our clinic. In addition to basic laboratory and clinical parameters, 24 h ambulatory blood pressure monitoring (ABPM) (Spacelabs) was evaluated. Unplanned blood sampling for assessment of serum antihypertensive drug concentrations by the means of liquid chromatography-mass spectrometry was performed in all patients. In case of spironolactone, its active metabolite canrenone was also evaluated. Total non-compliance was then defined as the absence of all measured antihypertensive drugs. Partial non-compliance was calculated as the absence of serum levels of at least one, but not all antihypertensive drugs prescribed. RESULTS: Good blood pressure control was detected (mean 24 h systolic/diastolic BP 130 ± 12/77 ± 9 mmHg). The average number of antihypertensive drugs was 3.9 ± 1.5. All subjects were treated by MR antagonists. 44% of patients received spironolactone (average daily dose 45 ± 20 mg) and in the remaining 56% of subjects eplerenone was administered (average daily dose 80 ± 30 mg) due to spironolactone side effects. Assessment of antihypertensive drug concentrations revealed full adherence in 80% of all subjects, partial nonadherence was noted in the remaining 20% of subjects. MR antagonist levels were detected in almost all subjects (49 out of 50). CONCLUSIONS: Good blood pressure control and adherence to therapy were detected in conservatively treated patients with PA. Eplerenone had to be used quite often as male subjects did not tolerate dose escalation due to spironolactone side effects.

Primary Aldosteronism and Pregnancy.

OBJECTIVE: Primary aldosteronism (PA) may present at younger age and may thus complicate pregnancy. Our aim was to identify female patients in whom PA was diagnosed after pregnancy complicated with hypertension and to analyze possible hypertension-related complications during pregnancy. METHODS: We performed retrospective analysis of female patients with PA diagnosed and treated at our Department who were pregnant before the diagnosis of PA. RESULTS: We found 14 patients with PA (age at diagnosis 32.2 ± 4.2 years, hypertension duration 5.4 ± 3.6 years) suffering from hypertension 3 (IQR 0, 4) years before pregnancy (6 patients had hypertension diagnosed during pregnancy). Three subjects were pregnant twice, and 1 patient had been pregnant three times before the final diagnosis of PA was made. Ten subjects delivered by Caesarean section (in 3 cases due to early-onset preeclampsia and 2 subjects due to significantly increased blood pressure), and 9 cases spontaneously (1 subject complicated twice due to late-onset preeclampsia). Preterm delivery occurred in 5 cases - the earliest one in the sixth month of gestation. Subsequent diagnosis of PA (sometimes with a long delay up to a maximum of 12 years) was made on the basis of significantly low potassium values (2.7 ± 0.4 mmol/L; 2 subjects even suffered from muscle cramps) and hypertension (mostly moderate), elevated plasma/serum aldosterone (54.1 ± 20.2 ng/dL) and suppressed plasma renin activity (0.4 ± 0.2 ng/mL/h) or plasma renin (1.9 ± 1.6 ng/L). Thirteen subjects underwent laparoscopic adrenalectomy (in all but 2 cases, diagnosis of a large cortical adenoma [16 ± 5.9 mm] was made), and 1 subject was classified with bilateral hyperplasia according to adrenal venous sampling. Operation normalized BP in 10 subjects and improved BP control in the remaining 3 subjects. Two patients became pregnant after adrenalectomy, and their pregnancies were uneventful. CONCLUSION: PA is associated with a high rate of pregnancy-related complications. The most frequent complication is preeclampsia, in some cases leading to preterm delivery. The optimal prevention of these complications is early diagnosis of PA, and in these particular hypertensive cases, the awareness of hypokalemia.

FGF21 Levels in Pheochromocytoma/Functional Paraganglioma.

Fibroblast growth factor 21 (FGF21) is a hepatokine with beneficial effects on metabolism. Our aim was to evaluate the relationship between the serum FGF21, and energy and glucose metabolism in 40 patients with pheochromocytoma/functional paraganglioma (PPGL), in comparison with 21 obese patients and 26 lean healthy controls. 27 patients with PPGL were examined one year after tumor removal. Basic anthropometric and biochemical measurements were done. Energy metabolism was measured by indirect calorimetry (Vmax-Encore 29N). FGF21 was measured by ELISA. FGF21 was higher in PPGL than in controls (174.2 (283) pg/mL vs. 107.9 (116) pg/mL; p < 0.001) and comparable with obese (174.2 (283) pg/mL vs. 160.4 (180); p = NS). After tumor removal, FGF21 decreased (176.4 (284) pg/mL vs. 131.3 (225) pg/mL; p < 0.001). Higher levels of FGF21 were expressed, particularly in patients with diabetes. FGF21 positively correlated in PPGL with age (p = 0.005), BMI (p = 0.028), glycemia (p = 0.002), and glycated hemoglobin (p = 0.014). In conclusion, long-term catecholamine overproduction in PPGL leads to the elevation in serum FGF21, especially in patients with secondary diabetes. FGF21 levels were comparable between obese and PPGL patients, despite different anthropometric indices. We did not find a relationship between FGF21 and hypermetabolism in PPGL. Tumor removal led to the normalization of FGF21 and the other metabolic abnormalities.

Blood Pressure Profile, Catecholamine Phenotype, and Target Organ Damage in Pheochromocytoma/Paraganglioma.

CONTEXT: Impaired diurnal blood pressure (BP) variability is related to higher cardiovascular risk. OBJECTIVE: To assess diurnal variability of BP and its relation to target organ damage (TOD) and catecholamine phenotype in a consecutive sample of pheochromocytoma/paraganglioma (PPGL). DESIGN: We included 179 patients with PPGL All patients underwent 24 hours of ambulatory BP monitoring to determine dipping status. Differences in plasma metanephrine or urine adrenaline were used to distinguish catecholamine biochemical phenotype. To evaluate TOD, renal functions, presence of left ventricle hypertrophy (LVH), and the subgroup (n = 111) carotid-femoral pulse wave velocity (PWV) were assessed. Structural equation modeling was used to find the relationship among nocturnal dipping, catecholamine phenotype, and TOD parameters. RESULTS: According to the nocturnal dipping, patients were divided into the three groups: dippers (28%), nondippers (40%), and reverse dippers (32%). Reverse dippers were older (P < 0.05), with a higher proportion of noradrenergic (NA) phenotype (P < 0.05), a higher prevalence of diabetes mellitus (P < 0.05), and sustained arterial hypertension (P < 0.01) and its duration (P < 0.05), as opposed to the other groups. All parameters of TOD were more pronounced only in reverse dippers compared with nondippers and dippers. The presence of NA phenotype (=absence of adrenaline production) was associated with reverse dipping and TOD (LVH and PWV). CONCLUSIONS: Patients with reverse dipping had more substantial TOD compared with other groups. The NA phenotype plays an important role, not only in impaired diurnal BP variability but also independently from dipping status in more pronounced TOD of heart and vessels.

Catecholamines Induce Left Ventricular Subclinical Systolic Dysfunction: A Speckle-Tracking Echocardiography Study.

Background: Pheochromocytomas (PHEO) are tumors arising from chromaffin cells from the adrenal medulla, having the ability to produce, metabolize and secrete catecholamines. The overproduction of catecholamines leads by many mechanisms to the impairment in the left ventricle (LV) function, however, endocardial measurement of systolic function did not find any differences between patients with PHEO and essential hypertension (EH). The aim of the study was to investigate whether global longitudinal strain (GLS) derived from speckle-tracking echocardiography can detect catecholamine-induced subclinical impairments in systolic function. Methods: We analyzed 17 patients (10 females and seven males) with PHEO and 18 patients (nine females and nine males) with EH. The groups did not differ in age or in 24-h blood pressure values. Results: The patients with PHEO did not differ in echocardiographic parameters including LV ejection fraction compared to the EH patients (0.69 ± 0.04 vs. 0.71 ± 0.05; NS), nevertheless, in spackle-tracking analysis, the patients with PHEO displayed significantly lower GLS than the EH patients (-14.8 ± 1.5 vs. -17.8 ± 1.7; p < 0.001). Conclusions: Patients with PHEO have a lower magnitude of GLS than the patients with EH, suggesting that catecholamines induce a subclinical decline in LV systolic function.

Biochemical Screening for Nonadherence Is Associated With Blood Pressure Reduction and Improvement in Adherence.

We hypothesized that screening for nonadherence to antihypertensive treatment using liquid chromatography-tandem mass spectrometry-based biochemical analysis of urine/serum has therapeutic applications in nonadherent hypertensive patients. A retrospective analysis of hypertensive patients attending specialist tertiary care centers was conducted in 2 European countries (United Kingdom and Czech Republic). Nonadherence to antihypertensive treatment was diagnosed using biochemical analysis of urine (United Kingdom) or serum (Czech Republic). These results were subsequently discussed with each patient, and data on follow-up clinic blood pressure (BP) measurements were collected from clinical files. Of 238 UK patients who underwent biochemical urine analysis, 73 were nonadherent to antihypertensive treatment. Their initial urinary adherence ratio (the ratio of detected to prescribed antihypertensive medications) increased from 0.33 (0-0.67) to 1 (0.67-1) between the first and the last clinic appointments. The observed increase in the urinary adherence ratio in initially nonadherent UK patients was associated with the improved BP control; by the last clinic appointment, systolic and diastolic BPs were ≈19.5 and 7.5 mm Hg lower than at baseline (P=0.001 and 0.009, respectively). These findings were further corroborated in 93 nonadherent hypertensive patients from Czech Republic-their average systolic and diastolic BPs dropped by ≈32.6 and 17.4 mm Hg, respectively (P<0.001), on appointments after the biochemical analysis. Our data show that nonadherent hypertensive patients respond to liquid chromatography-tandem mass spectrometry-based biochemical analysis with improved adherence and significant BP drop. Such repeated biochemical analyses should be considered as a therapeutic approach in nonadherent hypertensive patients.

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.

Renal denervation in comparison with intensified pharmacotherapy in true resistant hypertension: 2-year outcomes of randomized PRAGUE-15 study.

OBJECTIVES: The randomized, multicentre study compared the efficacy of renal denervation (RDN) versus spironolactone addition in patients with true resistant hypertension. We present the 24-month data. METHODS: 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 SBP of 159 ±â€Š17 and 155 ±â€Š17 mmHg and average number of drugs 5.1 and 5.4, respectively. Two-year data are available in 86 patients. Spironolactone addition, as crossover after 1 year, was performed in 23 patients after RDN, and spironolactone addition followed by RDN was performed in five patients. RESULTS: Similar and comparable reduction of 24-h SBP after RDN or spironolactone addition after randomization was observed, 9.1 mmHg (P = 0.001) and 10.9 mmHg (P = 0.001), respectively. Similar decrease of office blood pressure (BP) was observed, 17.7 mmHg (P < 0.001) versus 14.1 mmHg (P < 0.001), whereas the number of antihypertensive drugs did not differ significantly between groups. Crossover analysis showed nonsignificantly better efficacy of spironolactone addition in 24-h SBP and office SBP reduction than RDN (3.7 mmHg, P = 0.27 and 4.6 mmHg, P = 0.28 in favour of spironolactone addition, respectively). Meanwhile, the number of antihypertensive drugs was significantly increased after spironolactone addition (+0.7, P = 0.001). CONCLUSION: In the settings of true resistant hypertension, spironolactone addition (if tolerated) seems to be of better efficacy than RDN in BP reduction over a period of 24 months. However, by contrast to the 12-month results, BP changes were not significantly greater.

Long-Term Effect of Adrenalectomy on Cardiovascular Remodeling in Patients With Pheochromocytoma.

Context: Catecholamines may contribute to the accumulation of collagen fibers and extracellular matrix in the arterial and myocardial wall due to various mechanisms. Reversibility of this process has not been studied on both structures simultaneously. Objective: To clarify the long-term effect of excess normalization of catecholamines on carotid and myocardial wall changes in patients with pheochromocytoma or functional paraganglioma (PHEO) after tumor removal. Design, Settings, and Patients: Carotid intima-media thickness (IMT) and the left ventricular (LV) mass index were studied in 50 patients with PHEO before tumor removal and 5 years after tumor removal, and in 50 blood pressure- and age-matched essential hypertensive patients before follow-up and after 5 years of follow-up. Main Outcome Measures: Common carotid artery (CCA)-IMT and LV mass indexed to lean body mass (LBM). Results: Elimination of catecholamine excess in the PHEO group resulted in a significant decrease in CCA-IMT and LV mass index from 0.86 ± 0.17 to 0.83 ± 0.18 mm (P < 0.05) and from 3.2 ± 0.9 to 2.9 ± 0.9 g/LBM (P < 0.001), respectively. In contrast, CCA-IMT and LV mass index increased significantly from 0.78 ± 0.14 to 0.81 ± 0.15 mm (P < 0.05) and from 3.1 ± 0.7 to 3.2 ± 0.6 g/LBM (P < 0.05), respectively, in patients with essential hypertension. Conclusion: In patients with PHEO, carotid IMT and LV mass index can significantly regress after tumor removal, in contrast to the impairment of these parameters in essential hypertensive patients during the same long-term period.

Should All Patients with Resistant Hypertension Receive Spironolactone?

PURPOSE OF REVIEW: Resistant hypertension is a common clinical situation. Identification of true resistant hypertension (using 24-h ambulatory blood pressure monitoring to exclude white coat phenomenon, excluding secondary causes and non-adherence to treatment) is important mostly because of the application of a proper therapeutic approach and the higher cardiovascular risk of these patients. This review surveys recent studies, with a focus on mineralocorticoid receptor antagonists, including spironolactone, in the treatment of resistant hypertension. RECENT FINDINGS: A range of randomized and non-randomized studies have proved the efficacy of mineralocorticoid receptor antagonists, including spironolactone. However, long-term mortality studies are still missing for the hypertensive population. In the case of spironolactone side effects, higher doses of amiloride or eplerenone might be used. Based on available data and our own experience, spironolactone (mineralocorticoid receptor antagonists) should be involved, if tolerated, in combination therapy in true resistant hypertensive patients. Spironolactone still represents primary therapeutic modality under specific conditions of primary aldosteronism.

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.

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.

Long-term effects of adrenalectomy or spironolactone on blood pressure control and regression of left ventricle hypertrophy in patients with primary aldosteronism.

INTRODUCTION: Primary aldosteronism (PA) represents the most common cause of secondary hypertension. Beyond increased blood pressure, additional harmful effects of aldosterone excess including inappropriate left ventricle (LV) hypertrophy were found. We evaluated the effect of adrenalectomy and spironolactone on blood pressure and myocardial remodelling in a long-term follow-up study. METHODS: Thirty-one patients with PA were recruited. Fifteen patients with confirmed aldosterone-producing adenoma underwent adrenalectomy; in the remaining 16 patients, treatment with spironolactone was initiated. Laboratory data, 24-hour ambulatory blood pressure monitoring (ABPM) and echocardiography parameters were evaluated at baseline and at a median follow-up of 64 months. RESULTS: Both approaches reduced blood pressure (p = 0.001 vs. baseline). In both groups we observed a decrease in end-diastolic (p = 0.04, p = 0.01) and end-systolic LV cavity diameters (p = 0.03, p = 0.01). Interventricular septum and posterior wall thickness reduction was significant only after adrenalectomy (p = 0.01, p = 0.03) as was reduction of LV mass index (p = 0.004). A trend to lower LV mass on spironolactone was caused predominantly by diminution of the LV cavity, which was reflected in increased relative wall thickness (p = 0.05). CONCLUSIONS: Although both surgical and conservative treatment can induce a long-term decrease of blood pressure, adrenalectomy seems to be more effective in reduction of LV mass, as it reverses both wall thickening and enlargement of the LV cavity.

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 ±â€Š0.140 to 0.900 ±â€Š0.127 mm (-5.9%; P < 0.05) at 1 year and to 0.866 ±â€Š0.130 mm (-9.4%; P < 0.01) at 6 years after adrenalectomy; in the spironolactone group, common carotid IMT decreased from 0.917 ±â€Š0.151 to 0.900 ±â€Š0.165 mm (-1.8%; NS) at 1 year and to 0.854 ±â€Š0.176 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.

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.

Left ventricle remodeling in men with moderate to severe volume-dependent hypertension.

We evaluated the influence of increased intravascular volume on the heart anatomy in salt-sensitive types of hypertension, represented by primary aldosteronism (PA) and low-renin essential hypertension (LREH). Echocardiography was performed in 128 males with moderate to severe or resistant hypertension: 44 patients had PA, 40 patients had LREH and 44 patients had normal-renin essential hypertension (NREH). Groups were comparable in demographic characteristics, blood pressure, duration of hypertension and previous antihypertensive treatment. Patients with PA and LREH, in comparison with NREH patients, showed both greater end-systolic (37.6±5.4 and 35.6±4.5 vs 32.6±4.4 mm, p<0.001 and p<0.05) and end-diastolic (56.1±4.5 and 54.0±4.8 vs 50.4±5.1 mm; p<0.001 and p<0.01) left ventricle (LV) diameter. There were no significant differences either in LV wall thicknesses or LV mass, although a higher percentage of patients with PA and LREH met the criteria of eccentric hypertrophy (p<0.001 and p<0.05 respectively). Aldosterone concentration was positively related to LV cavity dimensions, whether wall thicknesses were rather associated with blood pressure levels. In conclusion, plasma volume overload was identified as an important factor influencing LV remodeling in PA and LREH, whether due to excessive aldosterone levels in PA or other pathophysiological mechanisms.

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.

Pulse wave velocity in primary hyperparathyroidism and effect of surgical therapy.

The study was aimed at investigating the arterial stiffness assessed by aortic pulse wave velocity (PWV) in the presence of primary hyperparathyroidism (PH), with and without concomitant hypertension. Subsequently, we examined the effect of parathyroidectomy (PTX) on arterial stiffness. A total of 28 patients with PH and concomitant hypertension, and 16 with PH without hypertension were investigated in comparison with 28 essential hypertensive patients and 18 healthy controls, respectively. Patients were matched for age, blood pressure (BP), body mass index, lipid profile and fasting glucose. Six months after PTX, 15 patients were examined again (hypertensive as well as normotensive). PWV was obtained using the SphygmoCor applanation tonometer (AtCor Medical, West Ryde, Australia). PWV was significantly higher in patients with PH and hypertension when compared with patients with essential hypertension (10.1 vs. 8.5 ms(-1), P=0.013). PWV remained significant even after adjustment for age and BP (P=0.02). Similarly, PWV was significantly higher in PH patients without hypertension in comparison with healthy controls (7.6 vs. 5.8 ms(-1), P<0.001). Six months after surgery, in addition to a normalization of calcium metabolism, a significant decrease in systolic BP (131 vs. 123 mmHg, P=0.004) and PWV (9.1 vs. 8.5 ms(-1), P=0.024) was observed. After adjusting for BP reduction, the decrease in PWV appeared non-significant. Our data indicate that PH increases PWV as a marker of arterial stiffness, in both hypertensive and non-hypertensive patients. However, neither the calcium serum level nor the parathyroid hormone level has been associated with PWV. Specific treatment by PTX significantly decreases PWV, which may be determined primarily by improved BP control after surgery.

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.

Development of a fast LC-MS/MS method for quantification of rilmenidine in human serum: elucidation of fragmentation pathways by HRMS.

Rilmenidine is an alpha 2 adrenoreceptor agonist used in the treatment of mild and moderate hypertension. In this study, a fast and accurate liquid chromatographic method with tandem mass spectrometric detection has been validated in order to assure quantification of rilmenidine in human serum. The fragmentation pathway of protonated rilmenidine was studied using high-resolution mass spectrometry (HRMS). This study compared selectivity, linearity, accuracy, precision, extraction efficiency, matrix effect and sensitivity using common liquid-liquid extraction (LLE) and solid-phase extraction (SPE) procedures. The limit of quantitation for both extraction techniques was 0.1 ng/ml. Several differences between the LLE and SPE have been observed in terms of linearity, accuracy, precision and matrix effect. Additionally, the advantages of SPE included less manual work load and increased recovery of rilmenidine in human serum to approximately 80% (LLE, 57%). The developed method involving SPE was found to be accurate (relative error (RE) < 5%), reproducible (relative standard deviation, RSD < 7%), robust and suitable for quantitative analysis of rilmenidine in serum samples obtained from patients under antihypertensive treatment.