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| Name | Class |
|---|---|
| Instituto Nacional de Cardiologia de Laranjeiras | OTHER |
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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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
| |
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Anti-hypertensive drug treatment | Drug | 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. |
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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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.
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| Name | Affiliation | Role |
|---|---|---|
| Paulo R Benchimol-Barbosa, MD, DSc | Universidade Gama Filho | Principal Investigator |
| Priscilla Campos | Universidade Gama Filho | Principal Investigator |
| José Barbosa-Filho, MD, DSc | Universidade Gama Filho | Study Chair |
| Ivan Cordovil, MD | Instituto Nacional de Cardiologia, Rio de Janeiro | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Instituto Nacional de Cardiologia | Rio de Janeiro | RH | 22240-006 | Brazil |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| Result | 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. | ||
| Result | 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. | ||
| Result | 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 | ||
| Result | 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. | ||
| Result | 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. | ||
| Result |
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Participants who have been diagnosed as secondary hypertension were excluded from the trial before assignment to resistant and pseudo-resistant groups.
Recruitment was carried out in outpatient clinics at Instituto Nacional de Cardiologia.
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| ID | Title | Description |
|---|---|---|
| FG000 | Resistant Arterial Hypertension | Subjects with systemic arterial hypertension in whom arterial pressure control was not achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure >/=130 mmHg and mean 24h 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. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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|
| up to 10 years |
| 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. |
| FG001 | Pseudo-resistant Arterial Hypertension | Subjects with systemic arterial hypertension in whom arterial pressure control was achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure <130 mmHg and mean 24h 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. |
| COMPLETED |
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| NOT COMPLETED |
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Subjects referred from primary care with diagnosis of resistant arterial hypertension. Each one had a clinical visit scheduled in the center within one week of referral. All were taking two AH drugs plus diuretic.
ABP was measured in seated position, after 5 min of rest. If the highest average of two measures was >140/90mmHg, subject was admitted.
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| ID | Title | Description |
|---|---|---|
| BG000 | Resistant Arterial Hypertension | Subjects with systemic arterial hypertension in whom arterial pressure control was not achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure >/=130 mmHg and mean 24h 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. |
| BG001 | Pseudo-resistant Arterial Hypertension | Subjects with systemic arterial hypertension in whom arterial pressure control was achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure <130 mmHg and mean 24h 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. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||||
| Age Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Region of Enrollment | Number | participants |
| ||||||||||||||||||
| Renin-Angiotensin-Aldosterone System Polymorphism | Genetic assessment was carried out using polymerase chain reaction assay amplification. The following single nucleotide polymorphisms were analyzed: renin (G1051A), angiotensinogen (M235T), ACE (I/D), angiotensin II type 1 receptor (A1166C), aldosterone synthase (C344T) and mineralocorticoid receptor (G3514C) | Number | participants |
| |||||||||||||||||
| Renin-Angiotensin-Aldosterone System Polymorphism | Genetic assessment was carried out using polymerase chain reaction assay amplification. The following single nucleotide polymorphisms were analyzed: renin (G1051A), angiotensinogen (M235T), ACE (I/D), angiotensin II type 1 receptor (A1166C), aldosterone synthase (C344T) and mineralocorticoid receptor (G3514C) | Number | participants |
| |||||||||||||||||
| Renin-Angiotensin-Aldosterone System Polymorphism | Genetic assessment carried out using polymerase chain reaction assay amplification. The following single nucleotide polymorphisms were analyzed: renin (G1051A), angiotensinogen (M235T), ACE (I/D), angiotensin II type 1 receptor (A1166C), aldosterone synthase (C344T) and mineralocorticoid receptor (G3514C) | Number | participants |
| |||||||||||||||||
| Renin-Angiotensin-Aldosterone System Polymorphism | Genetic assessment was carried out using polymerase chain reaction assay amplification. The following single nucleotide polymorphisms were analyzed: renin (G1051A), angiotensinogen (M235T), ACE (I/D), angiotensin II type 1 receptor (A1166C), aldosterone synthase (C344T) and mineralocorticoid receptor (G3514C). | Number | participants |
| |||||||||||||||||
| Renin-Angiotensin-Aldosterone System Polymorphism | Genetic assessment was carried out using polymerase chain reaction assay amplification. The following single nucleotide polymorphisms were analyzed: renin (G1051A), angiotensinogen (M235T), ACE (I/D), angiotensin II type 1 receptor (A1166C), aldosterone synthase (C344T) and mineralocorticoid receptor (G3514C) | Number | participants |
| |||||||||||||||||
| Anti-hypertensive treatment | Anti-hypertensive treatment, including regimen, drug and the number of drugs prescribed, was left at discrtion of the physician who carried primary assiatnce. | Number | participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Number of participants was based on input demand at outpatient clinics. Those who provided provided consent for genetic testing were included. A post-hoc sampling procedure (power calculation) validated sample size. | Posted | Number | participants | up to 10 years |
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| Secondary | 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. | Number of participants was based on input demand at outpatient clinics. Those who provided provided consent for genetic testing were included. A post-hoc sampling procedure (power calculation) validated sample size. | Posted | Number | participants | up to 10 years |
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| Post-Hoc | Polygenic Risk Score | Among all analyzed, four renin-angiotensin-aldosterone polymorphisms had statistical significance relating to composite endpoint. They were: Angiotensinogen, renin, angiotensin II type 1 receptor and aldosterone synthase. Each polymorphism was arbitrarily weighted according to respective presentation in both alleles as follows: zero (low risk homozygosis), one (heterozygosis) and two (high risk homozygosis). In a following step, they were summed up for each subject, thus, creating a polygenic risk score. The weights of the polymorphisms were, thus, defined:
The polygenic risk score value ranges from zero (all low risk polymorphisms in homozygosis) to eight (all high risk polymorphisms in homozygosis). | Subjects in both resistant systemic arterial hypertension and pseudo-resistant systemic arterial hypertension groups had their respective genetic background scored according to present rule. | Posted | Number | composite enpoint events | up to 10 years |
|
Adverse events data were collected every 1 year. Study subjects were actively contacted either by telephone or by visit to their home places.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Resistant Arterial Hypertension | Subjects with systemic arterial hypertension in whom arterial pressure control was not achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure >/=130 mmHg and mean 24h 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. | 0 | 62 | 0 | 62 | ||
| EG001 | Pseudo-resistant Arterial Hypertension | Subjects with systemic arterial hypertension in whom arterial pressure control was achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure <130 mmHg and mean 24h 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. | 0 | 31 | 0 | 31 |
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Drugs prescribed were at the discretion of attending physician. The impact of anti-hypertensive drugs on the outcomes was not assessed.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Paulo Robeto Benchimol Barbosa | Universidade Gama Filho | +55-21-95320182 | ecgar@yahoo.com |
| ID | Term |
|---|---|
| D006973 | Hypertension |
| C563514 | Hypertension Resistant to Conventional Therapy |
| D009203 | Myocardial Infarction |
| D020521 | Stroke |
| ID | Term |
|---|---|
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D007238 | Infarction |
| D007511 | Ischemia |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009336 | Necrosis |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D049993 | Sodium Chloride Symporter Inhibitors |
| D000451 | Mineralocorticoid Receptor Antagonists |
| D000319 | Adrenergic beta-Antagonists |
| D000806 | Angiotensin-Converting Enzyme Inhibitors |
| D057911 | Angiotensin Receptor Antagonists |
| D002121 | Calcium Channel Blockers |
| ID | Term |
|---|---|
| D049990 | Membrane Transport Modulators |
| D045504 | Molecular Mechanisms of Pharmacological Action |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
| D004232 | Diuretics |
| D045283 | Natriuretic Agents |
| D045505 | Physiological Effects of Drugs |
| D006727 | Hormone Antagonists |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D062865 | Diuretics, Potassium Sparing |
| D018674 | Adrenergic Antagonists |
| D018663 | Adrenergic Agents |
| D018377 | Neurotransmitter Agents |
| D011480 | Protease Inhibitors |
| D004791 | Enzyme Inhibitors |
| D000077264 | Calcium-Regulating Hormones and Agents |
| D002317 | Cardiovascular Agents |
| D045506 | Therapeutic Uses |
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| >=65 years |
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| Male |
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| Renin (G1051A) GA |
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| Renin (G1051A) AA |
|
| ACE (I/D) ID |
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| ACE (I/D) DD |
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| Angiotensin II type 1 receptor (A1166C) AC |
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| Angiotensin II type 1 receptor (A1166C) CC |
|
| aldosterone synthase (C344T) TC |
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| aldosterone synthase (C344T) TT |
|
| Angiotensinogen (M235T) MT |
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| Angiotensinogen (M235T) MM |
|
Subjects with systemic arterial hypertension in whom arterial pressure control was achieved (24h ambulatory pressure monitoring: mean 24h systolic pressure <130 mmHg and mean 24h 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.
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| OG002 | Polygenic Score: Two | Sum of the weights for analyzing polymorphisms equal to two. |
| OG003 | Polygenic Score: Three | Sum of the weights for analyzing polymorphisms equal to three. |
| OG004 | Polygenic Score: Four | Sum of the weights for analyzing polymorphisms equal to four. |
| OG005 | Polygenic Score: Five | Sum of the weights for analyzing polymorphisms equal to five. |
| OG006 | Polygenic Score: Six | Sum of the weights for analyzing polymorphisms equal to six. |
| OG007 | Polygenic Score: Seven | Sum of the weights for analyzing polymorphisms equal to seven. |
| OG008 | Polygenic Score: Eight | Sum of the weights for analyzing polymorphisms equal to eight. |
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