Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Heart and Blood Diseases

Breast Neoplasms

Heart Failure

Heart Failure, Diastolic

Breast Diseases

Skin Diseases

Antihypertensive Agents

Natriuretic Agents

All Drugs and Chemicals

Eplerenone

Mineralocorticoid Receptor Antagonists

Mineralocorticoids

Hormones

Hormone Antagonists

Diuretics

Diuretics, Potassium Sparing

One tablet by mouth daily. If serum potassium level is \<5.0 mmol/L at four weeks, increase to two tablets by mouth daily.

If estimated glomerular filtration rate (eGFR) is between 30-49 ml per min per 1.73m2, initial dose is: one tablet by mouth every other day. If serum potassium level is \<5.0 mmol/L at four weeks, increase to one tablet by mouth daily.

Eplerenone 25 mg tablet by mouth daily. If serum potassium level is \<5.0 mmol/L at four weeks, increase to two 25 mg tablets by mouth daily.

If estimated glomerular filtration rate (eGFR) is between 30-49 ml per min per 1.73m2, initial dose is: eplerenone 25 mg tablet by mouth every other day. If serum potassium level is \<5.0 mmol/L at four weeks, increase to 25 mg tablet by mouth daily.

Placebo

Sean A Virani, MD, MSc, MPH

Margot Davis, MD

Doxorubicin and other anthracyclines are commonly used to treat breast cancer and other types of cancer. Unfortunately, they can cause heart muscle damage, resulting in scarring, abnormal contraction and relaxation, and heart failure symptoms. This side effect occurs more frequently at higher doses, and limits the total dose that can be given to cancer patients. Eplerenone is an oral medication that prevents or reverses heart damage in other disease states, and is commonly used to treat heart failure. This study will investigate the use of eplerenone to protect the heart from these harmful side effects of doxorubicin.

Few therapies have been shown to prevent heart damage in patients receiving anthracyclines. Small studies have suggested that other heart failure medications (ACE inhibitors, beta-blockers) may reduce the incidence of cardiac toxicity, but eplerenone and other drugs in its class (aldosterone antagonists) have not previously been studied. Eplerenone inhibits enzyme pathways that cause scarring of the heart, and animal studies suggest that anthracyclines cause damage through these same pathways.

This study aims to investigate whether eplerenone protects the heart from the harmful effects of doxorubicin chemotherapy. Specifically, it will measure the effect that eplerenone has on heart muscle relaxation. It will randomly assign women undergoing chemotherapy with doxorubicin to one of two groups: one group will receive eplerenone, and the other group will receive placebo (sugar) pills. The subjects will not know which type of pills they are taking. Heart muscle relaxation will be measured at baseline, after completion of chemotherapy (8-12 weeks), and after 6 months. There will also be various blood tests measured in the study subjects, to determine whether there might be certain blood tests that identify patients at particularly high risk of heart toxicity after doxorubicin therapy.

Study of the Effect of Eplerenone on Heart Function in Women Receiving Anthracycline Chemotherapy for Breast Cancer

A Prospective Randomized Placebo-controlled Study of the Effect of Eplerenone on Left Ventricular Diastolic Function in Women Receiving Anthracycline Therapy for Breast Cancer

Incidence of hyperkalemia defined as serum potassium \>5.5 mmol/L

Incidence of adverse events leading to discontinuation of study drug, including hypotension, dizziness, hyperkalemia, or renal failure

Change in late potentials measured on SAECG

Change in QT/RR interval slope, exercise capacity, peak heart rate, heart rate recovery, ventricular arrhythmias during exercise, ventricular arrhythmias during recovery, presence of ischemia

Genetic predictors of cardiotoxicity and of response to eplerenone

The average early diastolic tissue velocity of the mitral valve annulus measured by tissue Doppler echocardiography (averaged velocities of the mitral annulus measured at the lateral edge and the septal edge)

Development of worsening diastolic function, defined as a decline by at least one American Society of Echocardiography gradation of diastolic dysfunction

Development of worsening systolic function, defined as a decline in LVEF of ≥10% to ≤50%

Change in early diastolic tissue velocity of the septal mitral annulus (E', measured by tissue Doppler echocardiography)

Change in early diastolic tissue velocity of the lateral mitral annulus (E', measured by tissue Doppler echocardiography)

Change in the ratio of early diastolic mitral inflow velocity (E, measured by pulse wave Doppler echocardiography) to the average early diastolic tissue velocity of the mitral annulus (E', measured by tissue Doppler echocardiography)

Change in the ratio of peak early diastolic mitral inflow velocity (E) to peak mitral inflow velocity during atrial systole (A), both measured by pulse wave Doppler echocardiography

Change in the left atrial volume index, defined as the left atrial volume measured on the 2D echocardiogram indexed to body surface area

Change in LVEF, measured by echocardiogram using Simpson's method

Change in biomarkers of myocardial injury, inflammation, and collagen turnover as predictors of cardiotoxicity

Canadian Cancer Society (CCS)

Pfizer

University of British Columbia

Nutritional and Metabolic Diseases

Gland and Hormone Related Diseases

Behaviors and Mental Disorders

Nervous System Diseases

Symptoms and General Pathology

Musculoskeletal Diseases

Infections

Rare Diseases

Diabetes Mellitus

Depressive Disorder

Syncope

Syncope, Vasovagal

Acute Coronary Syndrome

Syndrome

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Coronary Disease

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Hypertension

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Ischemia

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Ischemic Attack, Transient

Tachycardia

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Tachycardia, Sinus

Panic Disorder

Arrhythmias, Cardiac

Necrosis

Vascular Diseases

Muscular Diseases

Rheumatic Diseases

Collagen Diseases

Neuromuscular Diseases

Cardiac Conduction System Disease

Unconsciousness

Consciousness Disorders

Neurobehavioral Manifestations

Neurologic Manifestations

Brain Ischemia

Brain Diseases

Central Nervous System Diseases

Encephalomyelitis

Neuroinflammatory Diseases

Chronic Disease

Disease Attributes

Orthostatic Intolerance

Anxiety Disorders

Mental Disorders

Psychotic Disorders

Tachycardia, Supraventricular

Chronic Graft Versus Host Disease

Acute Graft Versus Host Disease

Consecutive patients who consult a cardiologist - electrophysiologist since June 2006, regardless of the age or gender in the city of Medellin, Colombia. They could have consulted previously (considered as the enrollment date) if they had, at least, one measurement of their BP in supine position, and an immediate measurement of their BP in standing position that allows diagnosing their group of blood pressure. All patients have a record in paper and/or magnetic file and in OpenClinica.

No interventions.

Luis Eduardo Medina, MD.

Luis E Medina, MD

Jose F Florez, PhD

Jose M Cotes, PhD

The essential arterial hypotension and allostasis registry is a prospective, observational research that has the purpose of demonstrating that essential blood pressure (BP) disorders and the associated comorbidities are a result of the inappropriate allostatic response to daily life stress. This required a functioning brain orchestrating the evaluation of the threat and choosing the response, this is a mind-mediated phenomenon. If the response is excessive it contributes to high BP, if deficient to low BP, and the BP itself will identify the allostatic pattern, which in turn will play an important role in the development of the comorbidities.

To do so, consecutive patients of any age and gender that visit a cardiologist's office in Medellin, Colombia, are recruited. Individuals are classified according to their arterial BP and allostasis and follow them in time to see what kind of diseases develops the most (including BP) in the follow up according to the categorization of the characteristic chosen and after adjustment for confounder's variables. In addition, stress events with their date are registered.

HYPOTHESIS

The causes of the diseases are multifactorial.

Physical, biochemical, psychological, social, and cultural dimensions of development dynamically interact to shape the health development process.

A person´s health depends on their:

1. Biological and physiologic systems
2. External and internal environment (a) physical, b) internal behavioural and arousal state as registered by the brain.
3. Their interaction.

The allostatic mechanisms to the internal and external stressors (allostatic load) involves a network composed by:

1. Functional systems; mediated by:

   1. The Autonomic Nervous System
   2. The endocrine system
   3. The immune system
2. Structural changes: whenever the internal and/or external stressors are long lasting and/or strength enough, they may induce changes in:

   1. Epigenetic, endophenotypes, polyphenism.
   2. Plasticity
3. The interaction between a) and b).

The network response do not affect exclusively the BP, propitiating the development of comorbidities, which may prompt strategies for prevention, recognition and ultimately, treatment.

The allostatic model defines health as a state of responsiveness.

The concept of psycho-biotype: The allostasis is the result of both: biological (allostasis) and psychological (psychostasis) abilities. It is proposed that both components behave in similar direction and magnitude.

Immune disorders may be associated with the development of cancer. High BP population has a higher sympathetic and lower vagal tone, this has been associated with a decrease in the immune´s system function.

Resources and energy depletion: Terms like weathering have been used to describe how exposures to different allostatic loads gradually scrape away at the protective coating that keeps people healthy. It is postulated that High BP individuals have more resources and energy.

Essential Hypotension and Allostasis Registry

Essential Arterial Hypotension and Allostasis Registry

Clinical syncope characteristics (age of first syncope, number of syncope episodes, trauma, duration, clinical score, convulse, sphincter relaxation, etc.) Syncope cause Blood pressure group Adaptability group Prognosis

TTT protocol: describe the protocol, the time at positive response, nitroglycerine use, autonomic and hemodynamic variables.

TTT outcome for syncope: positive or negative TTT other outcomes: 1) Chronotropic incompetence, 2) arterial orthostatic hypotension, 3) carotid hypersensitivity, 4) POTS, 5) IST The relationship between TTT results and Clinical score for syncope in regard to: syncope behaviour and other orthostatic intolerance entities, symptoms and comorbidities.

The relationship between neurally mediated syncope response at the TTT and comorbidities.

EPS variables: AH, AV, CL, sino atrial conduction time (SACT), sinus node recovery time (SNRT), corrected sinus node recovery time (CSNRT), response to Isoproterenol, intrinsic heart rate Diagnosis: control, sick sinus syndrome, IST, chronotropic incompetence at the TTT HR at the ECG HR at the Holter monitoring HR at the TTT HRV at the Holter monitoring Syncope, cardiac or neurally mediated HR at the physical treadmill test Relationship with the blood pressure group Relationship with the adaptability group

Define how the blood pressure group and/or the adaptability group may add to the already known and include in this registry, in the diagnosis of cardiovascular complications as coronary artery disease, cerebrovascular disease, peripheral artery disease, nephropathy.

Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension.

Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable. Comorbidities: As describe in the protocol, as a summary: 1) cardiovascular, 2) metabolic, 3) Endocrine, 4) psychiatric disorders: depression and panic disorder, 5) orthostatic intolerance: neurally mediated syncope, vasovagal syncope, inappropriate sinus tachycardia, Postural orthostatic syndrome, carotid sinus hypersensitivity; 6) others: chronic fatigue syndrome, fibromyalgia, arthritis, autoimmune diseases, pulmonary thromboembolism, OSA (obstructive sleep apnea), Alzheimer disease, Parkinson disease, others dementias, epilepsia, nephropathies, COPD, and others.

Mortality

Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension.

Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable.

Psychiatric variables:

1. Big Five Questionary (BFQ) for personality.
2. Modify of the Coping Scale (Scale of modified coping strategies)
3. Zung questionary for depression and anxiety
4. MINI in those patients with moderate or severe depression and/or anxiety at the Zung questionary

High sodium intake in the diet is recognized as a risk factor for hypertension development.

Essential hypotension population is advised to increase the sodium (at least 10 grams a day) and water intake (at least 2 liters a day), or as much as possible, several have taken Fludrocortisone (is not a exclusion criteria). Normal blood pressure population are advised to have a normal or low sodium intake. Physical exercise is recommended in both groups.

This registry is a good opportunity to test how important sodium diet is to induce hypertension, or if by the contrary adaptability could prevail over high sodium intake in this registry.

Blood pressure groups: essential hypotension and normotension and those with new essential hypertension. Adaptability groups.

The results will be adjusted for age, gender and BMI.

Consistent bradycardia in the ECG at the office and normal HR in the holter monitoring or the contrary.

There are patients with complaints that may be attributed to bradycardia, low blood pressure, hypothyroidism, or other entities.

Some patients very often have bradycardia in the ECG taken in the office and normal HR in the 24 Holter monitoring, the opposite is also possible.

Patients with bradycardia (without medication or physiological condition as exersice affecting heart rate) in at least 2 ECG (less 60 bpm) and at least 2 Holter monitoring will be analyzed,

Other variables to consider are:

Age, gender, blood pressure group, adaptability group, maximum HR in the treadmill test, white coat or masked hypertension, Tilt-Table-test result or syncope cause, Electrophysiological study if available.

The acknowledge of this phenomenon could have clinical implications in the diagnosis of sick sinus syndrome and physiopathological ones.

Bradycardia is the classical presentation form for sinus node dysfunction, mainly when associated with symptoms. Chronotropic incompetence is also a manifestation. Absence of medications with effects on the heart rate (HR) must be ruled out.

Variables

1. HR at the ECG, Holter monitoring, stress text, and at the physical examination previous to pacemaker implantation,
2. Electrophysiological study (EPS): Basic cycle length, Sino-atrial conduction time, Sinus node recovery time, Corrected sinus node recovery time, Intrinsic HR when available 3. Pacemaker variables: HR at day and night or rest time Percentage of stimulation in A and V chambers 4. Syncope: Clinical characteriscs and clinical score Tilt table test results Trans Thoracic Echocardiogram in rest and or stress text Hypothesis: patients with ANSD will start to decrease the percentage atrial stimulation.

A non invasive, beat to beat BP monitoring, with the ability to measure BP, HR, Cardiac Output and Systemic Vascular Resistance (SVR) was started to use in the EHAR registry since May 2017. A description of this variables in the three BP groups will be collected in the data base (DB).

This will allow to characterize whether SVR and/or CO maintain BP. Until now BP levels are related with prognosis. In the prognosis model SVR and CO will be add them to know what matter the most: BP levels, SVR and/or CO? In the EHAR registry a collection of the variables recognized as a risk factor for several comorbidities are available to adjust in multivariable analysis.

Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension.

Comorbidities: As describe in the protocol, as a summary: 1) cardiovascular, 2) metabolic, 3) Endocrine, 4) psychiatric disorders: depression and panic disorder, 5) orthostatic intolerance: neurally mediated syncope, vasovagal syncope, inappropriate sinus tachycardia, Postural orthostatic syndrome, carotid sinus hypersensitivity; 6) others: chronic fatigue syndrome, fibromyalgia, arthritis, autoimmune diseases, pulmonary thromboembolism, OSA (obstructive sleep apnea), Alzheimer disease, Parkinson disease, others dementias, epilepsia, nephropathies, and others.

Cardiovascular mortality Total mortality

Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable. Comorbidities: As describe in the protocol, as a summary: 1) cardiovascular, 2) metabolic, 3) Endocrine, 4) psychiatric disorders: depression and panic disorder, 5) orthostatic intolerance: neurally mediated syncope, vasovagal syncope, inappropriate sinus tachycardia, Postural orthostatic syndrome, carotid sinus hypersensitivity; 6) others: chronic fatigue syndrome, fibromyalgia, arthritis, autoimmune diseases, pulmonary thromboembolism, OSA (obstructive sleep apnea), Alzheimer disease, Parkinson disease, others dementias, epilepsia, nephropathies, and others.

Cardiovascular mortality Total mortality

Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension.

Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable. Comorbidities: As describe in the protocol, as a summary: 1) cardiovascular, 2) metabolic, 3) Endocrine, 4) psychiatric disorders: depression and panic disorder, 5) orthostatic intolerance: neurally mediated syncope, vasovagal syncope, inappropriate sinus tachycardia, Postural orthostatic syndrome, carotid sinus hypersensitivity; 6) others: chronic fatigue syndrome, fibromyalgia, arthritis, autoimmune diseases, pulmonary thromboembolism, OSA (obstructive sleep apnea), Alzheimer disease, Parkinson disease, others dementias, epilepsia, nephropathies, and others.

Cardiovascular mortality Total mortality

Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension.

Habits: smoke and drink

Anthropometric variables: Body mass index, waist, hip

Metabolic variables: Fasting glucose, 2 hs postprandial plasma glucose, insulin plasma levels, homoeostasis model assessment (HOMA), total cholesterol, LDL, HDL, triglycerides.

Endocrine variables: plasma cortisol, free cortisol in 24 hs. urine, epinephrine, norepinephrine, metanephrines, vanilmandelic acid, ACTH, aldosterone, renin, thyrotropine, free thyroxine, triiodothyronine, testosterone

Electrocardiogram: HR; PR interval, QRS complex, cQT interval

Holter variables: HR, standard deviation of NN intervals (SDNN) and sympathovagal balance, at day, night and 24 hs.

ABPM: Systolic, diastolic, and heart rate, at day, night and 24 hs., BP matinal surge.

Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension.

Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable.

Habits: smoke and drink

Anthropometric variables: Body mass index, waist, hip

Metabolic variables: Fasting glucose, 2 hs postprandial plasma glucose, insulin plasma levels, HOMA, total cholesterol, LDL, HDL, triglycerides.

Endocrine variables: plasma cortisol, free cortisol in 24 hs. urine, epinephrine, norepinephrine, metanephrines, vanilmandelic acid, ACTH, aldosterone, renin, thyrotropine, free thyroxine, triiodothyronine, testosterone

Electrocardiogram: PR interval, QRS complex, Heart rate, cQT interval

Holter variables: HR, SDNN and sympathovagal balance, at day, night and 24 hs.

ABPM: Systolic, diastolic, and heart rate, at day, night and 24 hs., BP matinal surge.

Blood pressure group: 1) Essential arterial hypotension, 2) normotension and 3) Essential arterial hypertension.

Adaptability group: 1) Hyper adaptable, 2) normal adaptability and 3) hypo adaptable.

Habits: smoke and drink, exercise

Anthropometric variables: Body mass index, waist, hip

Metabolic and other variables: Fasting glucose, 2 hs postprandial plasma glucose, insulin plasma levels, HOMA, total cholesterol, LDL, HDL, triglycerides; thyrotropine,

Holter variables: HR, standard deviation of NN intervals (SDNN) and sympathovagal balance, at day, night and 24 hs.

ABPM: Systolic, diastolic, and heart rate, at day, night and 24 hs., BP matinal surge.

Adaptability group: Hyper adaptable, normal adaptability, hypo adaptable.

Habits: smoke and drink Anthropometric variables: Body mass index, waist, hip

Metabolic variables: Fasting glucose, 2 hs postprandial plasma glucose, insulin plasma levels, HOMA, total cholesterol, LDL, HDL, triglycerides.

Endocrine variables: plasma cortisol, free cortisol in 24 hs. urine, epinephrine, norepinephrine, metanephrines, vanilmandelic acid, ACTH, aldosterone, renin, thyrotropine, free thyroxine, triiodothyronine, testosterone

Electrocardiogram: PR interval, QRS complex, Heart rate, cQT interval

Holter variables: HR, SDNN and sympathovagal balance, at day, night and 24 hs.

ABPM: Systolic, diastolic, and heart rate, at day, night and 24 hs., BP matinal surge.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of the Effect of Eplerenone on Heart Function in Women Receiving Anthracycline Chemotherapy for Breast Cancer	NCT01708798	Breast Cancer	Eplerenone Placebo	18 Years -	University of British Columbia
Essential Hypotension and Allostasis Registry	NCT02018497	Blood Pressure Depression Panic Attack Fibromyalgia POTS Inappropriate S... Coronary Heart ... Acute Coronary ... Acute Myocardia... Cerebrovascular... Transient Ische... Atrial Fibrilla... Diabetes Mellit... Cancer Systolic Heart ... Diastolic Heart... Chronic Fatigue... Syncope Vasovagal Synco...		-	CES University

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