Stress Response Study for Heart Issues

Recruiting at 3 trial locations

Overseen By Puja K Mehta, MD

Age: 18+

Sex: Female

Trial Phase: Academic

Sponsor: Emory University

Must not be taking: Cardiac medications

Disqualifiers: Hypertension, Diabetes, Hyperlipidemia, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

150 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Coronary Microvascular Dysfunction (CMD) occurs when there are problems in small blood vessels/arteries in the heart and symptoms of persistent chest pain that impact women. There are an estimated 3 million women in the US with CMD and about 100,000 new cases annually. This research will investigate whether the stress response physiology and autonomic function in response to mental stress are different in women with CMD compared to other groups. The autonomic nervous system (ANS) controls normally involuntary activities, such as heart rate, respiration (breathing), body temperature, blood pressure, and urinary function. This study will also examine how chronic and daily life mental stress affects the heart, blood vessels. Participants from this study will be recruited mainly from Emory Healthcare-associated hospitals, the Emory Heart Disease Center for Prevention, and Emory Healthcare outpatient cardiology clinics. Participants will have physical exams, blood tests, stress tests, exercise tests, surveys, questionnaires, and images taken of their hearts and blood vessels. They will be asked to take home devices to monitor their autonomic function, sleep and to track their mood, stress level, and symptoms for one week. Data and specimens will be saved for future research.

Will I have to stop taking my current medications?

The trial requires that participants be able to safely withdraw medications for mental stress testing. If you cannot safely stop your medications, you may not be eligible to participate.

Is ranolazine safe for humans?

Ranolazine is generally considered safe for treating chronic stable angina, with side effects like dizziness, constipation, nausea, and a potential for affecting heart rhythm. It does not significantly alter heart rate or blood pressure, making it a safe option in combination with other heart medications. ^{1 2 3 4 5}

How does this drug differ from other treatments for stress-related heart issues?

This drug may differ from other treatments by specifically targeting stress-induced changes in heart rate and blood pressure, potentially using a unique mechanism or combination of effects not seen in standard treatments. For example, some drugs like calcium antagonists can reduce blood pressure response to stress while preserving normal heart function, which might not be achieved by other medications. ^{6 7 8 9 10}

What evidence supports the effectiveness of the drugs used in the Stress Response Study for Heart Issues?

Research shows that ACE inhibitors, like ramipril, can reduce the risk of heart attacks and strokes in people with cardiovascular risks, even if they don't have heart failure. Angiotensin receptor blockers also help reduce heart-related problems, especially in those who can't tolerate ACE inhibitors. ^{11 12 13 14 15}

Who Is on the Research Team?

Puja K Mehta

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for women over 50 with menopause-related chest pain and Coronary Microvascular Dysfunction (CMD), who can consent to tests. They must be willing to undergo a cardiac scan, mental stress testing, and have no acute illnesses or diabetes. Excluded are those with severe heart issues, uncontrolled hypertension, recent heart attacks, certain blood conditions, or significant artery blockages.

Inclusion Criteria

Willing to sign the informed consent

I have never been diagnosed with heart disease.

I am healthy with no heart disease risk factors.

Exclusion Criteria

My blood pressure is not higher than 180/100.

I have a serious blood disorder or significant anemia.

LDL >120 mg/dL

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants undergo baseline assessments including physical exams, blood tests, and stress tests

1 week

1 visit (in-person)

Mental Stress Testing

Participants undergo mental stress tests including speech and math tasks, with monitoring of autonomic and vascular responses

1 week

Multiple visits (in-person)

Home Monitoring

Participants use home devices to monitor autonomic function, sleep, mood, and stress levels

1 week

Follow-up

Participants are monitored for changes in quality of life and anginal symptoms

12 months

Periodic follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Study Procedures

Trial Overview The study investigates how mental stress affects the autonomic function in postmenopausal women with CMD compared to others. It involves physical exams, blood tests, imaging of the heart and vessels, plus home monitoring of autonomic function and daily stress levels for one week.

How Is the Trial Designed?

Group I: Symptomatic women with no obstructive CAD who have CMD Experimental Treatment 1 Intervention

Symptomatic women with chest pain and no obstructive CAD who have an abnormal myocardial flow reserve (MFR \< 2.5)

Group II: Symptomatic women with chronic obstructive CAD (oCAD) Experimental Treatment 1 Intervention

This group will serve as one comparison group since these women represent the prevailing paradigm of ischemia from obstructive stenosis while sharing common cardiovascular risk factors with the CMD group.

Group III: Asymptomatic control women with no prior history of CAD or angina Active Control 1 Intervention

Asymptomatic control women with no prior history of CAD or angina, who are age-matched to the CMD women; not on any cardiac medications, who will also have to pass a maximal Bruce protocol exercise treadmill test.

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Published Research Related to This Trial

A systematic review of three major trials involving 29,805 patients showed that ACE inhibitors significantly reduce all-cause mortality and cardiovascular events in patients with atherosclerosis, even if they do not have heart failure or left ventricular systolic dysfunction.

ACE inhibitors were associated with lower rates of cardiovascular mortality, non-fatal myocardial infarction, and strokes, suggesting they are beneficial for a broader range of patients with atherosclerosis, not just those with existing heart conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Dagenais, GR., Pogue, J., Fox, K., et al.[2020]

The HOPE study demonstrated that the ACE inhibitor ramipril significantly reduces the risk of major cardiovascular events, such as heart attacks and strokes, in high-risk patients, with a relative risk reduction of 22% compared to placebo.

In diabetic patients, ramipril showed even greater efficacy, reducing the combined risk of cardiovascular death, non-fatal heart attacks, and strokes by 25%, suggesting benefits beyond just lowering blood pressure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The HOPE Study (Heart Outcomes Prevention Evaluation). Sleight, P.[2013]

ACE inhibitors, like ramipril, are effective not only in lowering blood pressure and treating heart failure but also in preventing ischemic events such as myocardial infarction (MI) in patients at risk, as shown in the large HOPE trial with a diverse group of participants.

The HOPE trial demonstrated that ramipril significantly reduces the risk of MI and other cardiovascular events in patients without heart failure or left ventricular dysfunction, suggesting its broader application in cardiovascular disease management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anti-ischemic potential of angiotensin-converting enzyme inhibition: insights from the heart outcomes prevention evaluation trial. Pitt, B.[2020]

Heart failure affects about 5 million adults in the U.S., and current treatments focus on regulating overactive systems in the body, specifically the renin-angiotensin-aldosterone and sympathetic autonomic systems.

The 2016 guidelines introduced two new medications, valsartan/sacubitril and ivabradine, which have shown additional benefits in reducing mortality and morbidity in heart failure patients with reduced ejection fraction, beyond the improvements already seen with standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heart failure guidelines: What's new? Papadimitriou, L., Hamo, CE., Butler, J.[2021]

Angiotensin II receptor blockers (ARBs) may offer additional benefits over ACE inhibitors in treating heart failure by more effectively blocking the harmful effects of angiotensin II, making them suitable for patients who cannot tolerate ACE inhibitors.

Clinical trials have shown that ARBs improve morbidity and mortality outcomes in heart failure patients, and when combined with spironolactone, they provide even greater benefits, leading to their recommendation in recent treatment guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on therapy for heart failure. DiBianco, R.[2019]

Ranolazine is a new medication approved for treating angina that works by preventing sodium-induced calcium overload in heart cells, which helps reduce ischemia without causing low blood pressure or slow heart rate, common side effects of other treatments.

This review evaluates ranolazine's pharmacology and clinical trial data, highlighting its safety and efficacy in treating chronic stable angina and acute coronary syndrome, marking it as the first new angina treatment approved in the USA in over a decade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ranolazine: a novel agent that improves dysfunctional sodium channels. Pham, DQ., Mehta, M.[2015]

Ranolazine is a newly approved antianginal medication that can be used as an add-on therapy for patients with stable angina who still experience symptoms despite optimal treatment with traditional medications like beta-blockers and nitrates.

This review emphasizes ranolazine's unique mechanism of action and its favorable tolerability profile, suggesting it may provide clinical benefits without the common side effects associated with other antianginal therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ranolazine in the treatment of chronic stable angina]. Gustapane, M., Cardillo, MT., Biasillo, G., et al.[2015]

Ranolazine is an innovative treatment for stable angina pectoris that uniquely does not affect heart rate or systemic blood pressure, making it a safer option for patients.

The drug works by inhibiting the late sodium current, which helps prevent calcium overload in heart cells, and it shows potential for treating other conditions like atrial fibrillation and diastolic heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ranolazine--an additional anti-anginal drug]. Michels, G., Kochanek, M., Hoppe, UC.[2015]

In a study of 107 elderly patients with stable angina, both trimetazidine and ranolazine combined with bisoprolol and ivabradine significantly improved exercise tolerance and quality of life after 6 months of treatment.

Trimetazidine was found to be more effective than ranolazine in reducing silent ST-segment depression, making it the preferred choice for treating silent myocardial ischemia in this patient population due to its higher efficacy and lower cost.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Triple antianginal combinations in the treatment of elderly and senile patients with stable angina]. Kanorskii, SG., Smolenskaya, NV.[2018]

Ranolazine is an effective treatment for chronic stable angina pectoris, as demonstrated in three randomized trials that showed it can increase exercise capacity and reduce anginal episodes.

While ranolazine is generally safe and can be used alongside traditional angina medications, it may cause side effects like dizziness and constipation, and it has the potential to prolong the QT(c) interval, which requires monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ranolazine for chronic stable angina. Nash, DT., Nash, SD.[2015]

A study involving 298 participants (ages 20 to 60) found that stress significantly affects cardiovascular responses, particularly through changes in stroke volume and total peripheral resistance, which are important for understanding stress-induced blood pressure increases.

In hypertensive patients treated with various antihypertensive medications, only beta-blockers (oxprenolol) and calcium antagonists (nitrendipine) showed significant changes in heart rate and peripheral resistance during stress, while other treatments did not alter the hemodynamic response to emotional stress.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemodynamic response patterns to mental stress: diagnostic and therapeutic implications. Rüddel, H., Langewitz, W., Schächinger, H., et al.[2019]

In a study of 30 healthy normotensive subjects, the beta-blocker bisoprolol significantly reduced cardiovascular reactivity to mental stress, with 6 out of 15 treated individuals becoming non-reactive compared to those on placebo.

The findings suggest that bisoprolol may help prevent future hypertension by mitigating hyperreactive blood pressure responses during stress, indicating its potential as a preventive treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cardiovascular response to mental and physical stress in hyper-reactive normotensive subjects. Beta blockade effect]. Przybylski, J., Resnik, M., Corsi, M., et al.[2013]

The hand grip test (HGT) elicited the highest cardiovascular reactivity (CVR) in a study of 82 young Indian adults, making it the most effective stressor for generating maximum CVR.

In contrast, the cold pressor task (CPT) revealed significant gender differences in CVR, while the video game stressor did not produce meaningful changes in heart rate or blood pressure, indicating it is not perceived as a stressor by this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular reactivity to stressors in Indian young adults with normotensive parents. Verma, A., Kumar, M., Saxena, I., et al.[2021]

In a 6-week study involving 52 men with mild-to-moderate hypertension, isradipine effectively reduced diastolic blood pressure responses to mental stress without significantly altering cardiac output or total peripheral resistance.

Metoprolol decreased cardiac output but increased total peripheral resistance, leading to a greater blood pressure response to stress, indicating that while it reduces heart responsiveness, it may not effectively lower blood pressure under stress due to compensatory vascular mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacological modulation of stress-induced cardiovascular hyperreactivity in essential hypertension. Schulte, W., Rüddel, H., Schmieder, R., et al.[2013]

In a study involving 36 participants (6 healthy volunteers and 30 hypertensive patients), both amlodipine and lacidipine did not change the body's blood pressure and heart rate responses to stress from cold exposure or isometric exercise.

While these calcium antagonists effectively lowered resting blood pressure in hypertensive patients, they did not influence the increased blood pressure and heart rate caused by stress, indicating that their efficacy may not extend to stress-induced cardiovascular reactivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of calcium antagonists on stress-induced rise in blood pressure and heart rate: a double-blind, placebo-controlled study. Malhotra, S., Kumari, S., Pandhi, P.[2019]

Citations

1. England pubmed.ncbi.nlm.nih.gov

Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. [2020]

2. England pubmed.ncbi.nlm.nih.gov

The HOPE Study (Heart Outcomes Prevention Evaluation). [2013]

3. United States pubmed.ncbi.nlm.nih.gov

The anti-ischemic potential of angiotensin-converting enzyme inhibition: insights from the heart outcomes prevention evaluation trial. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Heart failure guidelines: What's new? [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Update on therapy for heart failure. [2019]

6. India pubmed.ncbi.nlm.nih.gov

Ranolazine: a novel agent that improves dysfunctional sodium channels. [2015]

7. Italy pubmed.ncbi.nlm.nih.gov

[Ranolazine in the treatment of chronic stable angina]. [2015]

8. Germany pubmed.ncbi.nlm.nih.gov

[Ranolazine--an additional anti-anginal drug]. [2015]

9. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Triple antianginal combinations in the treatment of elderly and senile patients with stable angina]. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Ranolazine for chronic stable angina. [2015]

11. United States pubmed.ncbi.nlm.nih.gov

Hemodynamic response patterns to mental stress: diagnostic and therapeutic implications. [2019]

12. Argentina pubmed.ncbi.nlm.nih.gov

[Cardiovascular response to mental and physical stress in hyper-reactive normotensive subjects. Beta blockade effect]. [2013]

13. India pubmed.ncbi.nlm.nih.gov

Cardiovascular reactivity to stressors in Indian young adults with normotensive parents. [2021]

14. United States pubmed.ncbi.nlm.nih.gov

Pharmacological modulation of stress-induced cardiovascular hyperreactivity in essential hypertension. [2013]

15. Germany pubmed.ncbi.nlm.nih.gov

Effect of calcium antagonists on stress-induced rise in blood pressure and heart rate: a double-blind, placebo-controlled study. [2019]