Aleksander Prejbisz

Effects of Renal Sympathetic Denervation on Blood Pressure, Sleep Apnea Course, and Glycemic Control in Patients With Resistant Hypertension and Sleep Apnea

Percutaneous renal sympathetic denervation by radiofrequency energy has been reported to reduce blood pressure (BP) by the reduction of renal sympathetic efferent and afferent signaling. We evaluated the effects of this procedure on BP and sleep apnea severity in patients with resistant hypertension and sleep apnea. We studied 10 patients with refractory hypertension and sleep apnea (7 men and 3 women; median age: 49.5 years) who underwent renal denervation and completed 3-month and 6-month follow-up evaluations, including polysomnography and selected blood chemistries, and BP measurements. Antihypertensive regimens were not changed during the 6 months of follow-up. Three and 6 months after the denervation, decreases in office systolic and diastolic BPs were observed (median: −34/−13 mm Hg for systolic and diastolic BPs at 6 months; both P<0.01). Significant decreases were also observed in plasma glucose concentration 2 hours after glucose administration (median: 7.0 versus 6.4 mmol/L; P=0.05) and in hemoglobin A1C level (median: 6.1% versus 5.6%; P<0.05) at 6 months, as well as a decrease in apnea-hypopnea index at 6 months after renal denervation (median: 16.3 versus 4.5 events per hour; P=0.059). In conclusion, catheter-based renal sympathetic denervation lowered BP in patients with refractory hypertension and obstructive sleep apnea, which was accompanied by improvement of sleep apnea severity. Interestingly, there are also accompanying improvements in glucose tolerance. Renal sympathetic denervation may conceivably be a potentially useful option for patients with comorbid refractory hypertension, glucose intolerance, and obstructive sleep apnea, although further studies are needed to confirm these proof-of-concept data.

Cardiovascular manifestations of phaeochromocytoma

Clinical expression of phaeochromocytoma may involve numerous cardiovascular manifestations, but usually presents as sustained or paroxysmal hypertension associated with other signs and symptoms of catecholamine excess. Most of the life-threatening cardiovascular manifestations of phaeochromocytoma, such as hypertensive emergencies, result from a rapid and massive release of catecholamines from the tumour. More rarely, patients with phaeochromocytoma present with low blood pressure or even shock that may then precede multisystem crisis. Sinus tachycardia, with palpitations as the presenting symptom, is the most prevalent abnormality of cardiac rhythm in phaeochromocytoma, but tumours can also be associated with more serious ventricular arrhythmias or conduction disturbances. Reversible dilated or hypertrophic cardiomyopathy are well established cardiac manifestations of phaeochromocytoma, with more recent attention to an increasing number of cases with Takotsubo cardiomyopathy. This review provides an update on the cause, clinical presentation and treatment of the cardiovascular manifestations of phaeochromocytoma. As the cardiovascular complications of phaeochromocytoma can be life-threatening, all patients who present with manifestations that even remotely suggest excessive catecholamine secretion should be screened for the disease.

Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort

BACKGROUND Although unilateral primary aldosteronism is the most common surgically correctable cause of hypertension, no standard criteria exist to classify surgical outcomes. We aimed to create consensus criteria for clinical and biochemical outcomes and follow-up of adrenalectomy for unilateral primary aldosteronism and apply these criteria to an international cohort to analyse the frequency of remission and identify preoperative determinants of successful outcome. METHODS The Primary Aldosteronism Surgical Outcome (PASO) study was an international project to develop consensus criteria for outcomes and follow-up of adrenalectomy for unilateral primary aldosteronism. An international panel of 31 experts from 28 centres, including six endocrine surgeons, used the Delphi method to reach consensus. We then retrospectively analysed follow-up data from prospective cohorts for outcome assessment of patients diagnosed with unilateral primary aldosteronism by adrenal venous sampling who had undergone a total adrenalectomy, consecutively included from 12 referral centres in nine countries. On the basis of standardised criteria, we determined the proportions of patients achieving complete, partial, or absent clinical and biochemical success in accordance with the consensus. We then used logistic regression analyses to identify preoperative factors associated with clinical and biochemical outcomes. FINDINGS Consensus was reached for criteria for six outcomes (complete, partial, and absent success of clinical and biochemical outcomes) based on blood pressure, use of antihypertensive drugs, plasma potassium and aldosterone concentrations, and plasma renin concentrations or activities. Consensus was also reached for two recommendations for the timing of follow-up assessment. For the international cohort analysis, we analysed clinical data from 705 patients recruited between 1994 and 2015, of whom 699 also had biochemical data. Complete clinical success was achieved in 259 (37%) of 705 patients, with a wide variance (range 17-62), and partial clinical success in an additional 334 (47%, range 35-66); complete biochemical success was seen in 656 (94%, 83-100) of 699 patients. Female patients had a higher likelihood of complete clinical success (odds ratio [OR] 2·25, 95% CI 1·40-3·62; p=0·001) and clinical benefit (complete plus partial clinical success; OR 2·89, 1·49-5·59; p=0·002) than male patients. Younger patients had a higher likelihood of complete clinical success (OR 0·95 per extra year, 0·93-0·98; p<0·001) and clinical benefit (OR 0·95 per extra year, 0·92-0·98; p=0·004). Higher levels of preoperative medication were associated with lower levels of complete clinical success (OR 0·80 per unit increase, 0·70-0·90; p<0·001). INTERPRETATION These standardised outcome criteria are relevant for the assessment of the success of surgical treatment in individual patients and will allow the comparison of outcome data in future studies. The variable baseline clinical characteristics of our international cohort contributed to wide variation in clinical outcomes. Most patients derive clinical benefit from adrenalectomy, with younger patients and female patients more likely to have a favourable surgical outcome. Screening for primary aldosteronism should nonetheless be done in every individual fulfilling US Endocrine Society guideline criteria because biochemical success without clinical success is by itself clinically important and older women and men can also derive post-operative clinical benefit. FUNDING European Research Council; European Unions Horizon 2020; Else Kröner-Fresenius Stiftung; Netherlands Organisation for Health Research and Development-Medical Sciences; Japanese Ministry of Health, Labour and Welfare; Ministry of Health, Slovenia; US National Institutes of Health; and CONICYT-FONDECYT (Chile).

Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial

BACKGROUND The distinction between unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia as causes of primary aldosteronism is usually made by adrenal CT or by adrenal vein sampling (AVS). Whether CT or AVS represents the best test for diagnosis remains unknown. We aimed to compare the outcome of CT-based management with AVS-based management for patients with primary aldosteronism. METHODS In a randomised controlled trial, we randomly assigned patients with aldosteronism to undergo either adrenal CT or AVS to determine the presence of aldosterone-producing adenoma (with subsequent treatment consisting of adrenalectomy) or bilateral adrenal hyperplasia (subsequent treatment with mineralocorticoid receptor antagonists). The primary endpoint was the intensity of drug treatment for obtaining target blood pressure after 1 year of follow-up, in the intention-to-diagnose population. Intensity of drug treatment was expressed as daily defined doses. Key secondary endpoints included biochemical outcome in patients who received adrenalectomy, health-related quality of life, cost-effectiveness, and adverse events. This trial is registered with ClinicalTrials.gov, number NCT01096654. FINDINGS We recruited 200 patients between July 6, 2010, and May 30, 2013. Of the 184 patients that completed follow-up, 92 received CT-based treatment (46 adrenalectomy and 46 mineralocorticoid receptor antagonist) and 92 received AVS-based treatment (46 adrenalectomy and 46 mineralocorticoid receptor antagonist). We found no differences in the intensity of antihypertensive medication required to control blood pressure between patients with CT-based treatment and those with AVS-based treatment (median daily defined doses 3·0 [IQR 1·0-5·0] vs 3·0 [1·1-5·9], p=0·52; median number of drugs 2 [IQR 1-3] vs 2 [1-3], p=0·87). Target blood pressure was reached in 39 (42%) patients and 41 (45%) patients, respectively (p=0·82). On secondary endpoints we found no differences in health-related quality of life (median RAND-36 physical scores 52·7 [IQR 43·9-56·8] vs 53·2 [44·0-56·8], p=0·83; RAND-36 mental scores 49·8 [43·1-54·6] vs 52·7 [44·9-55·5], p=0·17) for CT-based and AVS-based treatment. Biochemically, 37 (80%) of patients with CT-based adrenalectomy and 41 (89%) of those with AVS-based adrenalectomy had resolved hyperaldosteronism (p=0·25). A non-significant mean difference of 0·05 (95% CI -0·04 to 0·13) in quality-adjusted life-years (QALYs) was found to the advantage of the AVS group, associated with a significant increase in mean health-care costs of €2285 per patient (95% CI 1323-3248). At a willingness-to-pay value of €30 000 per QALY, the probability that AVS compared with CT constitutes an efficient use of health-care resources in the diagnostic work-up of patients with primary aldosteronism is less than 0·2. There was no difference in adverse events between groups (159 events of which nine were serious vs 187 events of which 12 were serious) for CT-based and AVS-based treatment. INTERPRETATION Treatment of primary aldosteronism based on CT or AVS did not show significant differences in intensity of antihypertensive medication or clinical benefits for patients after 1 year of follow-up. This finding challenges the current recommendation to perform AVS in all patients with primary aldosteronism. FUNDING Netherlands Organisation for Health Research and Development-Medical Sciences, Institute of Cardiology, Warsaw.

Clinical characteristics of patients with resistant hypertension: the RESIST-POL study.

Recent studies indicate that resistant hypertension (RHTN) is present in about 12% of the treated hypertensive population. However, patients with true RHTN (confirmed out of the office) have not been widely studied. We prospectively studied 204 patients (123 male, 81female, mean age 48.4 years, range 19–65 years) with truly RHTN (ambulatory daytime mean blood pressure >135/85 mm Hg). We evaluated the frequency of obstructive sleep apnea (OSA), renal artery stenosis (RAS), primary aldosteronism (PA) and other secondary forms of hypertension (HTN) and conditions. Mild, moderate and severe OSA were present in 55 (27.0%), 38 (18.6%) and 54 (26.5%) patients, respectively. Secondary forms of HTN were diagnosed in 49 patients (24.0%), the most frequent being PA (15.7%) and RAS (5.4%). Metabolic syndrome (MS) was present in 65.7% of patients. Excessive sodium excretion was evident in 33.3% of patients and depression in 36.8% patients. In patients with RHTN, OSA and MS were the most frequent conditions, frequently overlapping with each other and also with PA. Our data indicate that in the vast majority of patients with truly RHTN, at least one of three co-morbidities—OSA, MS and PA—is present. Other conditions, even though less frequent, should also be taken into the consideration.

Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans

Emerging evidence supports an important role for T cells in the genesis of hypertension. Because this work has predominantly been performed in experimental animals, we sought to determine whether human T cells are activated in hypertension. We used a humanized mouse model in which the murine immune system is replaced by the human immune system. Angiotensin II increased systolic pressure to 162 versus 116 mm Hg for sham-treated animals. Flow cytometry of thoracic lymph nodes, thoracic aorta, and kidney revealed increased infiltration of human leukocytes (CD45+) and T lymphocytes (CD3+ and CD4+) in response to angiotensin II infusion. Interestingly, there was also an increase in the memory T cells (CD3+/CD45RO+) in the aortas and lymph nodes. Prevention of hypertension using hydralazine and hydrochlorothiazide prevented the accumulation of T cells in these tissues. Studies of isolated human T cells and monocytes indicated that angiotensin II had no direct effect on cytokine production by T cells or the ability of dendritic cells to drive T-cell proliferation. We also observed an increase in circulating interleukin-17A producing CD4+ T cells and both CD4+ and CD8+ T cells that produce interferon-&ggr; in hypertensive compared with normotensive humans. Thus, human T cells become activated and invade critical end-organ tissues in response to hypertension in a humanized mouse model. This response likely reflects the hypertensive milieu encountered in vivo and is not a direct effect of the hormone angiotensin II.Emerging evidence supports an important role for T cells in the genesis of hypertension. Because this work has predominantly been performed in experimental animals, we sought to determine whether human T cells are activated in hypertension. We used a humanized mouse model in which the murine immune system is replaced by the human immune system. Angiotensin II increased systolic pressure to 162 versus 116 mm Hg for sham-treated animals. Flow cytometry of thoracic lymph nodes, thoracic aorta, and kidney revealed increased infiltration of human leukocytes (CD45+) and T lymphocytes (CD3+ and CD4+) in response to angiotensin II infusion. Interestingly, there was also an increase in the memory T cells (CD3+/CD45RO+) in the aortas and lymph nodes. Prevention of hypertension using hydralazine and hydrochlorothiazide prevented the accumulation of T cells in these tissues. Studies of isolated human T cells and monocytes indicated that angiotensin II had no direct effect on cytokine production by T cells or the ability of dendritic cells to drive T-cell proliferation. We also observed an increase in circulating interleukin-17A producing CD4+ T cells and both CD4+ and CD8+ T cells that produce interferon-γ in hypertensive compared with normotensive humans. Thus, human T cells become activated and invade critical end-organ tissues in response to hypertension in a humanized mouse model. This response likely reflects the hypertensive milieu encountered in vivo and is not a direct effect of the hormone angiotensin II. # Novelty and Significance {#article-title-34}

Biochemical diagnosis of phaeochromocytoma using plasma-free normetanephrine, metanephrine and methoxytyramine: importance of supine sampling under fasting conditions.

To document the influences of blood sampling under supine fasting versus seated nonfasting conditions on diagnosis of phaeochromocytomas and paragangliomas (PPGL) using plasma concentrations of normetanephrine, metanephrine and methoxytyramine.

Analysis of plasma 3-methoxytyramine, normetanephrine and metanephrine by ultraperformance liquid chromatography–tandem mass spectrometry: utility for diagnosis of dopamine-producing metastatic phaeochromocytoma

Background Measurements of plasma normetanephrine (NMN) and metanephrine (MN) provide a sensitive test for diagnosis of phaeochromocytomas and paragangliomas (PPGLs), but do not allow detection of dopamine-producing tumours. Here we introduce a novel mass spectrometric based method coupled to ultraperformance liquid chromatography (LC-MS/MS) for measuring NMN, MN and 3-methoxytyramine (MTY), the O-methylated metabolite of dopamine. Methods Specific collision-induced fragment ions assessed by multireaction monitoring transitions were used for identification, with quantification according to signal intensities of analytes relative to stable isotope labelled internal standards. Results for solid-phase extracted samples from 196 subjects analysed by LC-MS/MS were compared with those analysed by liquid chromatography with electrochemical detection (LC-ECD). Concentration ranges in 125 volunteers were compared with those from 63 patients with PPGLs, including 14 with metastatic disease. Results The LC-MS/MS method showed linearity over four orders of magnitude with analytical sensitivity sufficient to measure to 0.02 nmol/L. Intra- and inter-assay coefficients of variation ranged from 2.8% to 13.5%. NMN and MN were respectively measured 17% and 10% higher and MTY 26% lower by LC-MS/MS than by LC-ECD. Medians and ranges for 3-methoxytramine, NMN and MN were respectively 0.08 (0.03-0.13), 0.35 (0.13-0.95) and 0.15 (0.07-0.33) nmol/L in volunteers. Among patients with PPGLs, plasma methoxytyramine was six-fold higher in patients with than without metastastases (1.09 versus 0.19 nmol/L) and in three patients was the only metabolite increased. Conclusions The LC-MS/MS method enables accurate, selective and sensitive measurements of catecholamine O-methylated metabolites that should be particularly useful for screening and management of dopamine-producing metastatic PPGLs.

Simultaneous liquid chromatography tandem mass spectrometric determination of urinary free metanephrines and catecholamines, with comparisons of free and deconjugated metabolites

OBJECTIVE We introduce a novel liquid chromatographic tandem-mass spectrometric method for simultaneous measurements of urinary catecholamines and their free O-methylated metabolites, which we compare to the deconjugated metabolites. METHODS Method performance was validated for recovery, linearity, precision and accuracy, analyte stability, ion suppression and carry over. Results from 53 patients with and 138 volunteers without pheochromocytoma were compared. RESULTS Analyte recoveries ranged from 60 to 96% and intra- and inter-assay coefficients of variation from 2.7 to 13.2%. The method showed excellent linearity over 3 orders of magnitude with analytical sensitivity sufficient to measure to 1.2 nmol/L. Free O-methylated metabolites were excreted at less than 20% the rates of the deconjugated metabolites, but were easily measureable. Increases in urinary normetanephrine in pheochromocytoma patients relative to volunteers were higher for free than deconjugated metabolites and higher for both than for norepinephrine (10 vs 5.5 vs 3.7 fold increases). In contrast, relative increases in urinary free versus deconjugated metanephrine (2.7 and 3.2) and methoxytyramine (2.1 and 1.9) did not differ, but for methoxytyramine were larger than for dopamine (1.2). CONCLUSION Measurements of urinary catecholamines and their free O-methylated metabolites by our method provide potential advantages over urinary deconjugated metanephrines for diagnosis of pheochromocytoma.

Reference intervals for plasma free metanephrines with an age adjustment for normetanephrine for optimized laboratory testing of phaeochromocytoma

Background Measurements of plasma normetanephrine and metanephrine provide a useful diagnostic test for phaeochro-mocytoma, but this depends on appropriate reference intervals. Upper cut-offs set too high compromise diagnostic sensitivity, whereas set too low, false-positives are a problem. This study aimed to establish optimal reference intervals for plasma normetanephrine and metanephrine. Methods Blood samples were collected in the supine position from 1226 subjects, aged 5-84 y, including 116 children, 575 normotensive and hypertensive adults and 535 patients in whom phaeochromocytoma was ruled out. Reference intervals were examined according to age and gender. Various models were examined to optimize upper cut-offs according to estimates of diagnostic sensitivity and specificity in a separate validation group of 3888 patients tested for phaeochromocytoma, including 558 with confirmed disease. Results Plasma metanephrine, but not normetanephrine, was higher (P < 0.001) in men than in women, but reference intervals did not differ. Age showed a positive relationship (P < 0.0001) with plasma normetanephrine and a weaker relationship (P = 0.021) with metanephrine. Upper cut-offs of reference intervals for normetanephrine increased from 0.47 nmol/L in children to 1.05 nmol/L in subjects over 60 y. A curvilinear model for age-adjusted compared with fixed upper cut-offs for normetanephrine, together with a higher cut-off for metanephrine (0.45 versus 0.32 nmol/L), resulted in a substantial gain in diagnostic specificity from 88.3% to 96.0% with minimal loss in diagnostic sensitivity from 93.9% to 93.6%. Conclusions These data establish age-adjusted cut-offs of reference intervals for plasma normetanephrine and optimized cut-offs for metanephrine useful for minimizing false-positive results.