Sympathetic Activity and Cardiometabolic Complications

Overview

Recent studies on catecholamine physiology have shown a direct correlation with arterial hypertension, overcoming the exclusive role in the diagnosis and follow-up of chromaffin tumors.

Nevertheless, in literature, few studies explore and reveal the utility of testing metanephrines for the evaluation of sympathetic activity and its associated cardiometabolic complications in patients with essential hypertension.

Full Title of Study: “Association Between Enhanced Sympathetic Activity and Cardiometabolic Complications: a Cross-sectional Study on Predictive Power of 24-hour Urinary Metanephrines (SYMPACT)”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Cross-Sectional
  • Study Primary Completion Date: July 1, 2015

Detailed Description

Catecholamines (noradrenaline, adrenaline and dopamine) are adaptive and maladaptive stress hormones.

In the classic "fight or flight" mechanism, they activate behavioral and physiological processes that facilitate the overcoming of stress; for instance, challenged by a physical stressor, an organism responds to the threat either fighting and prevailing or accepting defeat and fleeing in avoidance.

In the pathological context, an excessive catecholamine secretion is typical of the chromaffin tissue tumors, determining a clinical picture characterized by blood pressure elevation, tachycardia, anxiety, pallor, sweating and headache.

COMT enzyme catalyzes the O-methylation of the 3-hydroxyl group of catecholamines. The O-methylated derivatives of noradrenaline, adrenaline and dopamine are normetanephrine, metanephrine and 3-methoxytyramine, respectively. The term "metanephrines" is generally used to collectively refer to the first two compounds.

Compared to catecholamines, metanephrines are characterized by longer half-life and more stable levels over time. Their superior accuracy for the diagnosis and follow-up of pheochromocytoma and paraganglioma (PPGL) has been widely proved.

Excluding patients with PPGL, however, metanephrines can be more broadly considered as reliable markers of the whole sympathetic system activity; therefore, their levels may be hypothesized to be associated to a higher rate of concurrent cardiometabolic complications and, if so, could be useful for the stratification of cardiovascular risk.

Clinical Trial Outcome Measures

Primary Measures

  • Presence of left ventricular hypertrophy
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of the presence of left ventricular hypertrophy
  • Presence of chronic kidney disease
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of the presence of chronic kidney disease
  • Presence of type 2 diabetes mellitus
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of the presence of type 2 diabetes mellitus
  • Presence of metabolic syndrome
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of the presence of metabolic syndrome

Secondary Measures

  • Systolic blood pressure (SBP)
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of systolic blood pressure values (mmHg)
  • Diastolic blood pressure (DBP)
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of diastolic blood pressure values (mmHg)
  • Resting heart rate
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of resting heart rate (bpm)
  • eGFR
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of eGFR values (ml/min, as estimated by CKD-EPI formula)
  • Urinary albumin/creatinine ratio
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of albumin/creatinine ratio values (mg/mmol)
  • Fasting glucose
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of fasting glucose values (mg/dl)
  • Total cholesterol
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of total cholesterol values (mg/dl)
  • HDL cholesterol
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of HDL cholesterol values (mg/dl)
  • LDL cholesterol
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of LDL cholesterol values (mg/dl, as estimated by Friedewald formula)
  • Triglycerides
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of triglycerides values (mg/dl)
  • Body Mass Index (BMI)
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of BMI values (kg/m2)
  • Cardiovascular risk as estimated by Framingham Risk Score (FRS)
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of cardiovascular risk as estimated by FRS; FRS is expressed as a percentage, with higher values indicating higher risk; patients in which the risk estimation is not applicable will be excluded from the analysis
  • Cardiovascular risk as estimated by Systematic COronary Risk Evaluation (SCORE)
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of cardiovascular risk as estimated by SCORE; SCORE is expressed as a percentage, with higher values indicating higher risk; patients in which the risk estimation is not applicable will be excluded from the analysis
  • Cardiovascular risk as estimated by Progetto Cuore Score (english translation: “Heart Project Score”)
    • Time Frame: At baseline
    • The value of urinary metanephrines will be evaluated as a possible predictor of cardiovascular risk as estimated by Progetto Cuore Score; Progetto Cuore Score is expressed as a percentage, with higher values indicating higher risk; patients in which the risk estimation is not applicable will be excluded from the analysis

Participating in This Clinical Trial

Inclusion Criteria

  • Measurement of 24h urinary metanephrines at the laboratory of "City of Health and Science" hospital in Turin between 2007 and 2015
  • Availability of contextual clinical patient data as collected in prospective registries of Piedmont region

Exclusion Criteria

  • Diagnosis of pheochromocytoma or paraganglioma (at the time of urinary metanephrines collection or within the following 5 years)
  • Diagnosis of other forms of secondary hypertension
  • Previous cardiovascular or cerebrovascular event
  • Chronic heart failure
  • eGFR < 50 ml/min (according to CKD-EPI)
  • Liver cirrhosis
  • Acute conditions and/or hospitalization in ICU (at the time of urinary metanephrines collection)
  • Assumption of acetaminophen during the day before the 24-hour urine collection
  • Therapy with labetalol
  • Therapy with sotalol
  • Therapy with alpha-methyldopa
  • Therapy with MAO inhibitors
  • Therapy with tricyclic antidepressants
  • Therapy with buspirone
  • Therapy with phenoxybenzamine
  • Therapy with sulfasalazine
  • Therapy with L-Dopa
  • Therapy with sympathomimetic drugs or other vasopressors
  • Alcohol abuse
  • Cocaine abuse

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Turin, Italy
  • Provider of Information About this Clinical Study
    • Principal Investigator: Mauro Maccario, Medical Doctor, Professor – University of Turin, Italy
  • Overall Official(s)
    • Mauro Maccario, MD, Principal Investigator, Endocrinology, Diabetology and Metabolism; University of Turin
    • Ezio Ghigo, MD, Study Chair, Endocrinology, Diabetology and Metabolism; University of Turin

References

Ton QV, Hammes SR. Recent insights on circulating catecholamines in hypertension. Curr Hypertens Rep. 2014 Dec;16(12):498. doi: 10.1007/s11906-014-0498-9. Review.

Esler M. The sympathetic nervous system in hypertension: back to the future? Curr Hypertens Rep. 2015 Feb;17(2):11. doi: 10.1007/s11906-014-0519-8. Review.

Coulson JM. The relationship between blood pressure variability and catecholamine metabolites: a pilot study. J Hum Hypertens. 2015 Jan;29(1):50-2. doi: 10.1038/jhh.2014.23. Epub 2014 Apr 3.

Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr; Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014 Jun;99(6):1915-42. doi: 10.1210/jc.2014-1498.

Okuyama Y, Sakata Y. [Device treatment approaches targeting the sympathetic nervous system in patients with resistant hypertension]. Nihon Rinsho. 2015 Nov;73(11):1857-63. Japanese.

Grassi G, Mark A, Esler M. The sympathetic nervous system alterations in human hypertension. Circ Res. 2015 Mar 13;116(6):976-90. doi: 10.1161/CIRCRESAHA.116.303604. Review.

Rothwell PM, Howard SC, Dolan E, O'Brien E, Dobson JE, Dahlöf B, Sever PS, Poulter NR. Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010 Mar 13;375(9718):895-905. doi: 10.1016/S0140-6736(10)60308-X.

Esler M, Lambert G, Jennings G. Increased regional sympathetic nervous activity in human hypertension: causes and consequences. J Hypertens Suppl. 1990 Dec;8(7):S53-7. Review.

Eisenhofer G, Kopin IJ, Goldstein DS. Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev. 2004 Sep;56(3):331-49. Review.

Tank AW, Lee Wong D. Peripheral and central effects of circulating catecholamines. Compr Physiol. 2015 Jan;5(1):1-15. doi: 10.1002/cphy.c140007. Review.

Goldstein DS, Eisenhofer G, Kopin IJ. Sources and significance of plasma levels of catechols and their metabolites in humans. J Pharmacol Exp Ther. 2003 Jun;305(3):800-11. Epub 2003 Mar 20. Review.

Eisenhofer G, Friberg P, Pacak K, Goldstein DS, Murphy DL, Tsigos C, Quyyumi AA, Brunner HG, Lenders JW. Plasma metadrenalines: do they provide useful information about sympatho-adrenal function and catecholamine metabolism? Clin Sci (Lond). 1995 May;88(5):533-42.

Masuo K, Kawaguchi H, Mikami H, Ogihara T, Tuck ML. Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension. 2003 Oct;42(4):474-80. Epub 2003 Sep 2.

Dudenbostel T, Acelajado MC, Pisoni R, Li P, Oparil S, Calhoun DA. Refractory Hypertension: Evidence of Heightened Sympathetic Activity as a Cause of Antihypertensive Treatment Failure. Hypertension. 2015 Jul;66(1):126-33. doi: 10.1161/HYPERTENSIONAHA.115.05449. Epub 2015 May 18.

Flaa A, Aksnes TA, Kjeldsen SE, Eide I, Rostrup M. Increased sympathetic reactivity may predict insulin resistance: an 18-year follow-up study. Metabolism. 2008 Oct;57(10):1422-7. doi: 10.1016/j.metabol.2008.05.012.

Masuo K, Mikami H, Ogihara T, Tuck ML. Sympathetic nerve hyperactivity precedes hyperinsulinemia and blood pressure elevation in a young, nonobese Japanese population. Am J Hypertens. 1997 Jan;10(1):77-83.

Quarti Trevano F, Dell'Oro R, Biffi A, Seravalle G, Corrao G, Mancia G, Grassi G. Sympathetic overdrive in the metabolic syndrome: meta-analysis of published studies. J Hypertens. 2020 Apr;38(4):565-572. doi: 10.1097/HJH.0000000000002288.

Mancia G, Bousquet P, Elghozi JL, Esler M, Grassi G, Julius S, Reid J, Van Zwieten PA. The sympathetic nervous system and the metabolic syndrome. J Hypertens. 2007 May;25(5):909-20. Review.

Straznicky NE, Grima MT, Sari CI, Karapanagiotidis S, Wong C, Eikelis N, Richards KL, Lee G, Nestel PJ, Dixon JB, Lambert GW, Schlaich MP, Lambert EA. The relation of glucose metabolism to left ventricular mass and function and sympathetic nervous system activity in obese subjects with metabolic syndrome. J Clin Endocrinol Metab. 2013 Feb;98(2):E227-37. doi: 10.1210/jc.2012-3277. Epub 2012 Dec 27.

Schlaich MP, Kaye DM, Lambert E, Sommerville M, Socratous F, Esler MD. Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. Circulation. 2003 Aug 5;108(5):560-5. Epub 2003 Jul 7.

Wang W, Mu L, Su T, Ye L, Jiang Y, Jiang L, Zhou W. Plasma Metanephrines Are Associated With Glucose Metabolism in Patients With Essential Hypertension. Medicine (Baltimore). 2015 Sep;94(37):e1496. doi: 10.1097/MD.0000000000001496.

Brown MJ, Causon RC, Barnes VF, Brennan P, Barnes G, Greenberg G. Urinary catecholamines in essential hypertension: results of 24-hour urine catecholamine analyses from patients in the Medical Research Council trial for mild hypertension and from matched controls. Q J Med. 1985 Oct;57(222):637-51.

Zhou Y, Yuan J, Wang Y, Qiao S. Plasma metanephrins are associated with myocardial hypertrophy and cardiac diastolic function in patients with essential hypertension. Clin Invest Med. 2020 Apr 5;43(1):E22-E29. doi: 10.25011/cim.v43i1.33581.

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