Renin-angiotensin-aldosterone System Polymorphisms in Resistant Hypertension and Adverse Cardiovascular Events (GENHART)

Observational Study of the Polymorphisms of the Renin-angiotensin-aldosterone System and Their Relation to Resistant Systemic Arterial Hypertension and Adverse Cardiovascular Events

Renin-angiotensin-aldosterone system (RAAS) polymorphisms influence 24h arterial pressure fluctuation. Resistant systemic arterial hypertension (RSAH) has an increased risk of end organ damage and unfavourable prognosis, whereas pseudo-RSAH usually respond favourably to drug therapy.

To prospectively investigate, in subjects with RSAH in a tropical South American city: 1) Adverse cardiovascular events defined as fatal and non-fatal stroke or acute myocardial infarction (AMI); and 2) the association of RAAS polymorphisms and adverse cardiovascular events in this population.

Study population: 212 hypertensives recruited from primary care assistance (time since first diagnosis of hypertension: 16.5±8.1 years) and without appropriate pressure control, between 2001 and 2006, corresponding to 0.48% of all hypertensives under care (18 new cases/year), 57±10 years old, 66% females. Under drug treatment schedule: three or more drugs including a diuretic. Ninety two randomly selected hypertensives basis had renin-angiotensin-aldosterone system genetic profile determined. Genetic assessment was carried out using a polymerase chain reaction assay amplification technique. The following single nucleotide polymorphisms were analyzed: renin (G1051A), angiotensinogen (M235T), angiotensin converting enzyme-ACE (I/D), angiotensin II type 1 receptor (A1166C), aldosterone synthase (C344T) and mineralocorticoid receptor (G3514C).

Study Overview

• Status: Completed
• Conditions: Myocardial Infarction; Stroke; Hypertension Resistant to Conventional Therapy; Systemic Arterial Hypertension
• Intervention / Treatment: Drug: Anti-hypertensive drug treatment

• Study Type: Observational
• Enrollment (Actual): 92

Contacts and Locations

Study Locations

• Brazil
  • RH
    • Rio de Janeiro, RH, Brazil, 22240-006
      • Instituto Nacional de Cardiologia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Subjects of both genders in investigation for resistant systemic arterial hypertension at the Hypertension Unit, whose arterial pressure control was not achieved by primary care assistance despite regular use of three anti-hypertensive drugs, including one diuretic. All subjects received standard drug therapy, aiming at achieving outpatients clinics pressure <140/90mmHg and were re-evaluated up to four weeks later, including 24h ambulatory arterial pressure monitoring.

Description

Inclusion Criteria:

• Subjects with uncontrolled systemic arterial hypertension despite use of three anti-hypertensive drugs, including one diuretic

Exclusion Criteria:

• Secondary causes of systemic arterial hypertension

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Resistant Arterial Hypertension; Subjects with systemic arterial hypertension in whom arterial pressure control was not achieved (24hr ambulatory pressure monitoring: mean 24hr systolic pressure >/=130 mmHg or mean 24hr diastolic pressure >/=80mmHg) by non-investigation specialized hypertensive unit care, in spite of appropriate drug treatment regimen with three or more anti-hypertensive drugs including a diuretic. Anti-hypertensive drug treatment was non-investigational and was prescribed at discretion of the physician who performed primary evaluation.	Drug: Anti-hypertensive drug treatment; Anti-hypertensive drug treatment was non-investigational. Drug regimen, including which drug and the number of drugs prescribed, was left at discretion of the physician who carried primary assistance.; Other Names: Beta-blockers; ACE inhibitors; Calcium channel blockers; Thiazide Diuretics; Aldosterone receptor antagonist; Angiotensin receptor blockers
Pseudo-resistant Arterial Hypertension; Subjects with systemic arterial hypertension in whom arterial pressure control was achieved (24hr ambulatory pressure monitoring: mean 24hr systolic pressure <130 mmHg and mean 24hr diastolic pressure <80mmHg) by non-investigation specialized hypertensive unit care, with appropriate drug treatment regimen with three or more anti-hypertensive drugs including a diuretic. Anti-hypertensive drug treatment was non-investigational and was prescribed at discretion of the physician who performed primary evaluation.	Drug: Anti-hypertensive drug treatment; Anti-hypertensive drug treatment was non-investigational. Drug regimen, including which drug and the number of drugs prescribed, was left at discretion of the physician who carried primary assistance.; Other Names: Beta-blockers; ACE inhibitors; Calcium channel blockers; Thiazide Diuretics; Aldosterone receptor antagonist; Angiotensin receptor blockers

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Strokes, Either Fatal or Nonfatal	Evidence of clinically definite stroke (focal neurological deficits persisting for more than 24 hours) confirmed or not by non-investigational computerized tomography. Death was considered to be related to the event if occurring up to 30 days after the acute event. Assessment twice an year by active and direct contact to patients or relatives and review of medical records.	up to 10 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of Acute Myocardial Infarctions and/or Strokes Either Fatal or Nonfatal	Evidence of clinically definite stroke (focal neurological deficits persisting for more than 24 hours) confirmed or not by non-investigational computerized tomography. Evidence of clinically definite acute myocardial infarction (prolonged > 20min chest pain, not relieved by sublingual nitrate, ST-T segment deviation on 12-lead surface ECG, elevation of plasma troponin >0.2 ng/dL 6h following chest pain episode). Death was considered to be related to the event if occurring up to 30 days after the acute event. Assessment twice an year by active and direct contact to patients or relatives and review of medical records.	up to 10 years

Collaborators and Investigators

• Sponsor: Universidade Gama Filho
• Collaborators: Instituto Nacional de Cardiologia de Laranjeiras
• Investigators: Principal Investigator: Paulo R Benchimol-Barbosa, MD, DSc, Universidade Gama Filho; Principal Investigator: Priscilla Campos, Universidade Gama Filho; Study Chair: José Barbosa-Filho, MD, DSc, Universidade Gama Filho; Study Chair: Ivan Cordovil, MD, Instituto Nacional de Cardiologia, Rio de Janeiro

Publications and helpful links

General Publications

• Benchimol Barbosa PR, Silva PC, Cordovil I, Barbosa-Filho J. Renin-angiotensin-aldosterone system polymorphisms in resistant hypertension and adverse cardiovascular events: GENHART-RIO Study. Eur Heart J 2010;31(suppl 1):243-243.
• Benchimol-Barbosa PR, Silva PC, Cordovil I, Barbosa-Filho J. Renin-angiotensin-aldosterone system polymorphisms in resistant arterial hypertension: a genetic risk score for adverse cardiovascular events - GENHART-RIO study. Eur Heart J (2011) 32 (suppl 1): 103-103.
• Campos PS, Benchimol-Barbosa PR, Cordovil I, Gomes-Filho JB, Tura BR. Polimorfismos do sistema renina-angiotensina-aldosterona na hipertensão arterial resistente e desfechos cardiovasculares adversos: Estudo GENHART-RIO. Arq Bras Cardiol; 2010. 95(3 supl. 1): 59-59
• Campos FV, Benchimol-Barbosa PR, Vilela FD, Miranda CS, Gobbi GN, Barbosa-Filho J, Gondar AF, Barros MV, Lima AB, Cordovil I. Evaluation on the risk of target organ damage based on the genetic profile of AGT 235MT, mineralocorticoid receptor GCC5GG4C and ACE I/D in subjects with resistant hypertension. Circulation. 2008; 118:e223-e223.
• Vilela FD, Benchimol-Barbosa PR, Zeno CC, Lima AB, Barros M, Campos FV, Miranda CS, Gobbi GN, Barbosa-Filho J, Cordovil I. The resistant hypertension genotypes of the population resident in Rio de Janeiro. Circulation. 2008; 118:e356-e357.
• Benchimol-Barbosa PR, Varanda-Rosario AD, Rollin-Ornelas M, Vilela FD, Miranda CS, Gobbi GN, Barbosa-Filho J, Cordovil I. Aldosterone synthase C344T polymorphisms determine circadian arterial blood pressure variation in resistant systemic arterial hypertension. Circulation. 2008; 118:e398-e398.

Study record dates

Study Major Dates

• Study Start: June 1, 2001
• Primary Completion (ACTUAL): November 1, 2009
• Study Completion (ACTUAL): December 1, 2010

Study Registration Dates

• First Submitted: July 29, 2010
• First Submitted That Met QC Criteria: July 29, 2010
• First Posted (ESTIMATE): July 30, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): April 22, 2013
• Last Update Submitted That Met QC Criteria: April 13, 2013
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Keywords: Stroke; Acute myocardial infarction; Adverse events; Genetic polymorphisms; Hypertension Resistant to Conventional Therapy; Systemic arterial hypertension; Renin-angiotensin-aldosterone system genetic polymorphism; Risk markers
• Additional Relevant MeSH Terms: Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Coronary Disease; Myocardial Infarction; Infarction; Hypertension; Coronary Vasospasm; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Natriuretic Agents; Membrane Transport Modulators; Hormone Antagonists; Calcium-Regulating Hormones and Agents; Diuretics, Potassium Sparing; Antihypertensive Agents; Diuretics; Mineralocorticoid Receptor Antagonists; Calcium Channel Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Sodium Chloride Symporter Inhibitors
• Other Study ID Numbers: 0204/21.07.08