Cardiovascular Complications in Pheochromocytoma and Paraganglioma: Does Phenotype Matter?

BACKGROUND: Adrenaline-producing tumors are mostly characterized by a sudden release of catecholamines with episodic symptoms. Noradrenergic ones are usually less symptomatic and characterized by a continuous overproduction of catecholamines that are released into the bloodstream. Their effects on the cardiovascular system can thus be different. The aim of this study was to determine the prevalence of cardiovascular complications by catecholamine phenotype. METHODS: We retrospectively analyzed data on the prevalence of cardiovascular events in 341 consecutive patients with pheochromocytoma and paraganglioma treated from 1995 to 2023. Biochemical catecholamine phenotype was determined based on plasma or urinary catecholamines and metanephrines. RESULTS: According to the phenotype, 153 patients had noradrenergic pheochromocytoma and paraganglioma and 188 had adrenergic pheochromocytoma and paraganglioma. In the whole sample, the incidence of serious cardiovascular complications was 28% (95 patients), with no difference between the phenotypes or sexes. The noradrenergic phenotype had significantly more atherosclerotic complications (composite end point of type 1 myocardial infarction and symptomatic peripheral artery disease; odds ratio, 3.58 [95% CI, 1.59-8.83]; P=0.003), while the adrenergic phenotype more often had type 2 myocardial infarction and takotsubo-like cardiomyopathy (OR, 0.24 [95% CI, 0.09-0.57]; P=0.002). These changes remained even after adjustment for conventional risk factors of atherosclerosis. CONCLUSIONS: We found a 28% incidence of cardiovascular complications in a consecutive group of patients with pheochromocytoma and paraganglioma. Patients presenting with a noradrenergic phenotype have a higher incidence of atherosclerotic complications, while the adrenergic phenotype is associated with a higher incidence of acute myocardial damage due to takotsubo-like cardiomyopathy.

Validation of Existing Clinical Prediction Tools for Primary Aldosteronism Subtyping.

The new clinical prediction score (SCORE) has been recently proposed for primary aldosteronism (PA) subtyping prior to adrenal vein sampling (AVS). This study aimed to compare that SCORE with previously published scores and their validation using a cohort of patients at our center who had had positive SIT confirming PA and had been diagnosed with either bilateral PA according to AVS or unilateral PA if biochemically cured after an adrenalectomy. Final diagnoses were used to evaluate the diagnostic performance of the proposed clinical prediction tools. Only Kamemura's model (with a maximum score of 4 points) and Kobayashi's score (with a maximum score of 12 points) reached 100% reliability for prediction of bilateral PA; however, with sensitivity of only 3%. On the other hand, the values of SCORE = 3 (with sensitivity of 48%), the SPACE score ≥18 (with sensitivity of 35%), the Kobayashi's score ≤2 (with sensitivity of 28%), and the Kocjan's score = 3 (with sensitivity of 28%) were able to predict unilateral PA with 100% probability. Furthermore, Umakoshi's and Young's models both reached 100% reliability for a unilateral PA with score = 4 and both predictive factors together respectively; however, the sensitivity was lower compared with previous models; 4% and 14%, respectively. None of the clinical prediction tools applied to our cohort predicted unilateral and bilateral subtypes together with the expected high diagnostic performance, and therefore can only be used for precisely defined cases.

Hypermetabolism and Substrate Utilization Rates in Pheochromocytoma and Functional Paraganglioma.

The overproduction of catecholamines in pheochromocytoma/paraganglioma (PPGL) induces a hypermetabolic state. The aim of this study was to evaluate the incidence of a hypermetabolic state and differences in substrate metabolism in consecutive PPGL patients divided by catecholamine phenotype. Resting energy expenditure (REE) and respiratory quotient (RQ) were measured in 108 consecutive PPGL patients and 70 controls by indirect calorimetry. Hypermetabolic state was defined according to the Mifflin St. Jeor Equation as a ratio above 110%. Hypermetabolic state was confirmed in 70% of PPGL patients, regardless of phenotype. Older age, prevalence of diabetes mellitus and arterial hypertension were correlated with hypermetabolic PPGL as compared to normometabolic form. Analysis according to overproduced catecholamine showed differences in VCO2 (p < 0.05) and RQ (p < 0.01) and thus different substate metabolism between phenotypes in hypermetabolic form of PPGL. Lipid utilization was higher in the adrenergic phenotype (p = 0.001) and positively associated with the percentage of REE ratio (R = 0.48, p < 0.001), whereas the noradrenergic phenotype preferentially oxidizes carbohydrates (P = 0.001) and is correlated with the percentage of REE ratio (R = 0.60, p < 0.001). Hypermetabolic state in PPGL is a common finding in both catecholamine phenotypes. Hypermetabolic PPGL patients are older and suffer more from diabetes mellitus and arterial hypertension. Under basal conditions, the noradrenergic type preferentially metabolizes carbohydrates, whereas the adrenergic phenotype preferentially metabolizes lipids.

Adrenal Venous Sampling Could Be Omitted before Surgery in Patients with Conn's Adenoma Confirmed by Computed Tomography and Higher Normal Aldosterone Concentration after Saline Infusion Test.

PURPOSE: Adrenal venous sampling (AVS) performed to distinguish unilateral and bilateral primary aldosteronism (PA) is invasive and poorly standardized. This study aimed to identify non-invasive characteristics that can select the patients with unilateral PA who could bypass AVS before surgery. METHODS: A single-center study collected a total of 450 patients with PA. Development and validation cohorts included 242 and 208 patients. The AVS was successful in 150 and 138 patients from the cohorts, and the unilateral PA was found in 96 and 94 patients, respectively. Clinical factors independently associated with lateralized AVS in multivariable logistic regression were used to construct a unilateral PA prediction score (SCORE). RESULTS: The proposed SCORE was calculated as a sum of the prevalence of adrenal nodule on computed tomography (2 points) and plasma/serum aldosterone concentration ≥ 165 ng/L after the saline infusion test (SIT) (1 point). Importantly, the SCORE = 3 points identified 48% of unilateral PA patients with a specificity of 100% in the development cohort. The zero rate of false-positive classifications was preserved with the same cut-off value in the validation cohort. CONCLUSIONS: AVS could be omitted before surgery in patients with typical Conn´s adenoma provided the aldosterone concentration ≥ 165 ng/L after the SIT.

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.

Gene Profile of Adipose Tissue of Patients with Pheochromocytoma/Paraganglioma.

Background: Brown adipose tissue (BAT) is a therapeutic target to combat obesity and related disorders. Pheochromocytoma and functional paraganglioma (PPGL) are associated with activated BAT due to catecholamine excess. Our aim was to evaluate BAT activity by gene profile and assess its relation to clinical characteristics and overproduced catecholamine. Methods: mRNA expression of 15 genes in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) was measured via RT-PCR in 25 patients with PPGL and 14 controls undergoing cholecystectomy. Results: We found in VAT of PPGL higher expression of UCP1 (p < 0.001), CEBPB, PPARGC1A (both p < 0.001), PRDM16 (p = 0.069) and DIO2 (p = 0.005). UCP1 expression correlated only with norepinephrine levels and its metabolite. UCP1 expression, among others, correlated negatively with BMI, age and positively with HDLc levels. Dominance of BAT or BeAT markers was not assessed in PPGL. In SAT of PPGL, we found higher expression of ADRB3, CIDEA (both p < 0.05), and PPARGC1A (p = 0.001), but not UCP1. Conclusion: We demonstrate signs of UCP1-dependent norepinephrine-induced thermogenesis connected with higher expression of DIO2, PPARGC1A, CEBPB and PRDM16 in retroperitoneal VAT of PPGL and its relations to circulating HDLc and triglycerides levels. However, no direct relationship with increased basal energy metabolism measured by calorimetry was found.

Postoperative adrenal insufficiency in Conn's syndrome-does it occur frequently?

Primary aldosteronism (PA) is the most frequent form of endocrine hypertension. Recently, frequent clinically significant adrenal insufficiency after adrenalectomy in subjects with PA has been reported, which may make the early postsurgical management difficult. We retrospectively searched for possible adrenal insufficiency in subjects who underwent adrenalectomy for PA and have measured cortisol in the early postoperative course. We included subjects with confirmed diagnosis of PA who underwent either posture testing (blood draw at 06:00 and 08:00) and/or adrenal venous sampling (AVS) (blood draw between 08:00 and 09:00) and have also measured cortisol after surgery (cortisol measured approximately at 07:00). Cortisol was measured by immunoassay. In this study, we identified 150 subjects (age 48.5 ± 10.3 years) with available cortisol values in the early postoperative course (median [25th percentile, 75th percentile]) 6 [5,6] days. Postoperative cortisol values (551 ± 148 nmol/l) were normal and significantly higher, compared to preoperative standing cortisol values (404 ± 150 nmol/l; (P < 0.001) and AVS cortisol values (493 ± 198 nmol/l; P = 0.009), and did not significantly differ from preoperative supine cortisol values. Postsurgical cortisol values were not different among subjects with or without abnormal dexamethasone suppression test or elevated urinary free cortisol pre-surgery, and were significantly higher in subjects with abnormal diurnal cortisol variability compared with subjects with normal diurnal variability. No patient presented with adrenocortical crisis in the later follow-up. In conclusion, postoperative cortisol values did not indicate any suspicion of possible adrenal insufficiency. To exclude possible adrenal insufficiency, it may be sufficient to measure morning cortisol in the early postoperative course.

Effect of adrenalectomy on remission of subclinical left ventricular dysfunction in patients with pheochromocytoma: a speckle-tracking echocardiography study.

BACKGROUND: Pheochromocytomas (PHEO) are tumours with the ability to produce, metabolize and secrete catecholamines. Catecholamines overproduction leads to the decrease of longitudinal function of the left ventricle (LV) measured by speckle-tracking echocardiography. Patients with PHEO have a lower magnitude of global longitudinal strain (GLS) than patients with essential hypertension. GLS normalization is expected after resolution of catecholamine overproduction. METHODS: Twenty-four patients (14 females and 10 males) with a recent diagnosis of PHEO have been examined before and 1 year after adrenalectomy. An echocardiographic examination including speckle-tracking analysis with the evaluation of GLS and regional longitudinal strain (LS) in defined groups of LV segments (basal, mid-ventricular and apical) was performed. RESULTS: One year after adrenalectomy, the magnitude of GLS increased (-14.3 ± 1.8 to -17.7 ± 1.6%; P < 0.001). When evaluating the regional LS, the most significant increase in the differences was evident in the apical segment compared to mid-ventricular and basal segments of LV (-5.4 ± 5.0 vs -1.9 ± 2.7 vs -1.6 ± 3.8; P < 0.01). CONCLUSIONS: In patients with PHEO, adrenalectomy leads to an improvement of subclinical LV dysfunction represented by the increasing magnitude of GLS, which is the most noticeable in apical segments of LV.

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.

Pheochromocytoma With Adrenergic Biochemical Phenotype Shows Decreased GLP-1 Secretion and Impaired Glucose Tolerance.

CONTEXT: Impaired glucose homeostasis is a common finding in pheochromocytoma (PHEO), especially with adrenergic phenotype. The possible contribution of incretin dysfunction to dysglycemia in PHEO patients has not been studied. OBJECTIVE: To compare changes in pancreatic endocrine function and gut hormones' production during a liquid meal test before and 1 year after adrenalectomy. METHODS: In a prospective study, we included 18 patients with PHEO (13 females) with adrenergic biochemical phenotype. A liquid meal test with predefined isocaloric enteral nutrition was performed to evaluate dynamic changes in pancreatic hormones and incretins. RESULTS: During the meal test, insulin levels were significantly lower before adrenalectomy only in the early phase of insulin secretion, but changes in area under the curve (AUC) did not reach statistical significance (AUC = 0.07). Plasma glucagon (AUC < 0.01) and pancreatic polypeptide levels (AUC < 0.01) were suppressed in comparison with the postoperative state. Impaired response to the meal was found preoperatively for glucagon-like peptide-1 (GLP-1; AUC P < 0.05), but not glucose-dependent insulinotropic polypepide (GIP; AUC P = 0.21). No significant changes in insulin resistance indices were found, except for the homeostatic model assessment-beta index, an indicator of the function of islet ß cells, which negatively correlated with plasma metanephrine (R = -0.66, P < 0.01). CONCLUSIONS: Our study shows suppression of pancreatic α and ß cell function and impaired GLP-1 secretion during a dynamic meal test in patients with PHEO, which is improved after its surgical treatment. These data demonstrate a novel and potentially significant interconnection between excessive catecholamine production and the secretion of glucoregulatory hormones.

Vascular age.

Age can be evaluated according to many criteria. Of course the objective measure is the calendar age which may differ from the biological age. The biological age more or less correlates with the vascular age. The concept of vascular age is based on the statement that “An individual is as old as his blood vessels”. The process of vascular aging already starts in childhood. Arterial aging may essentially be viewed from two standpoints. First, it involves stiffening of arteries and loss of their elasticity; second, degenerative changes and formation of atherosclerotic plaques occur, being the cause of ischemia, especially in case of the development of atherothrombosis. Both these processes can be monitored: The change of elasticity (arteriosclerosis) mainly by examination of pulse wave velocity (PWV), atherosclerosis then primarily with non-invasive methods, ultrasound or CT angiography examination. From the clinical point of view it is particularly important whether we can influence vascular age in some way. Evidence is available now that atherosclerosis can be affected by hypolipidemic treatment, arteriosclerosis then in particular by ACE inhibitors. The aforementioned possibility of influencing vascular age brings us to another problem, which is compliance of patients. With regard to that it is good that in a situation where we have two drugs affecting vascular age, we can use their fixed combination. It is available as a combination of atorvastatin and perindopril.

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.

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.

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.

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.

Meta-analysis of randomized controlled trials of renal denervation in treatment-resistant hypertension.

OBJECTIVE: The blood pressure (BP)-lowering effect of renal sympathetic nervous denervation (RDN) in resistant hypertension (rHT) shows large variation among studies. METHODS: We meta-analyzed summary statistics of randomized clinical trials on RDN in rHT. For continuous outcomes, we assessed heterogeneity by Cochran's Q test and used random-effect models weighted for the inverse of the variance. We assessed safety by assessing the risk of major adverse events from stratified contingency tables. RESULTS: Of 5652 patients screened in seven trials, 985 (17.4%) qualified and were randomized to control (n = 397) or RDN with SYMPLICITY(™) catheters (n = 588). Follow-up was 6 months. In both control and RDN patients, antihypertensive treatment was continued or optimized. At enrolment, age averaged 58.1 years, systolic/diastolic office and 24 h BP 168.5/93.3 mmHg and 151.8/86.1 mmHg, respectively, and estimated glomerular filtration rate (eGFR) 79.3 ml/min/1.73 m². For BP outcomes, there was heterogeneity among trials. Pooled effects (control minus RDN) were -4.9/-3.5 mmHg (95% confidence interval, -20.9 to 11.1/-8.9 to 1.9) for office BP, -2.8/-1.5 mmHg (-6.5 to 0.8/-3.3 to 0.4) for 24 h BP and 0.81 ml/min/1.73 m² (-1.69 to 3.30) for eGFR. Removing one trial at a time produced confirmatory results. Adverse events occurred in 7.4% and 9.9% of control and RDN patients, respectively (p = 0.24). CONCLUSION: In selected rHT patients maintained on antihypertensive drugs, RDN with the SYMPLICITY systems does not significantly decrease BP but is safe. Future trials with next-generation catheters should aim at identifying responders in patients with evidence of sympathetic nervous overactivity.