Heart Disease of the Small Arteries in Women

Women suffer disproportionately than men from coronary heart disease in the small vessels (arterioles) compared to the large vessels (arteries). This results in delays in diagnosis, missed opportunities for treatment, and likely contributes to the increased death rate from coronary heart disease in women compared to men. Current testing for small vessel disease is invasive in the cardiac catheterization laboratory and is not performed routinely. Accordingly, women with this condition are routinely either falsely reassured, or misdiagnosed as another non-cardiac condition.

New imaging and noninvasive technology exists that may improve this situation. Measurement of endothelial function, using non-invasive tonometry testing can detect the abnormality most associated with coronary heart disease, endothelial dysfunction. Imaging techniques such as cardiac magnetic resonance imaging can now show the subendocardial layer of the heart, where the small vessel abnormality exists. These techniques have not been tested to determine if they can be used to diagnose and treat the small vessel coronary heart disease condition.

40 women undergoing coronary angiography with non-obstructive coronary artery disease will be enrolled. They will receive invasive provocative acetylcholine testing in the cardiac catheterization laboratory, followed by noninvasive Peripheral Artery Tonometry (PAT)testing, and cardiac magnetic resonance testing. Correlation analyses will be analyzed with regard to the predictive value of the noninvasive testing for the outcome of small vessel disease by the invasive acetylcholine testing. The data from this study will be pilot data for a larger prospective study. These studies an important step toward better understanding, and safer diagnosis of the coronary heart disease that is prevalent in over 9 million American women today.

Assessment and treatment for the challenging group of patients with the Cardiac Syndrome X, e.g. signs and symptoms of myocardial ischemia with non-obstructive coronary arteries (<50% luminal obstruction in one or more coronary arteries on angiography). A conservative estimate suggests that approximately 20% of women undergoing coronary angiography for signs and symptoms of myocardial ischemia suffer from this condition. There are currently over 200,000 coronary angiograms performed in women in the US annually, suggesting as many as 40,000 new cases annually, and as many as 1 million existent patients.

Women suffer disproportionately than men from this disorder of the small vessels (arterioles) compared to the large vessels (arteries). This results in delays in diagnosis, missed opportunities for treatment, and likely contributes to the increased death rate from coronary heart disease in women compared to men. Current testing for small vessel disease is invasive in the cardiac catheterization laboratory and is not performed routinely. Accordingly, women with this condition are routinely either falsely reassured, or misdiagnosed as another non-cardiac condition. Unnecessary healthcare costs related to re-hospitalization and repeat angiography are incurred, while women are often not initiated on appropriate lifesaving treatment. We and others have demonstrated in randomized controlled trials that therapies that target the endothelium, e.g. statins, ACE inhibitors, and exercise are effective in this condition.

New imaging and noninvasive technology exists that may improve this situation. Measurement of endothelial function, using coronary angiography, ultrasound, and/or tonometry can detect the abnormality most associated with coronary heart disease and endothelial dysfunction. Imaging techniques such as cardiac magnetic resonance imaging can now show the subendocardial layer of the heart, where the small vessel abnormality and myocardial ischemia exists. Non-imaging techniques such as Peripheral Artery Tonometry (PAT) can help assess peripheral endothelial function. These techniques, while promising, have not been tested to determine if they can be used to diagnose and treat the small vessel coronary heart disease condition.

We have demonstrated in the NHLBI-sponsored WISE study that women with this condition have more diffuse atherosclerosis yet and equal amount of adverse endothelial dysfunction and microvascular disease. Treatment in randomized controlled trials suggests that therapies that target the endothelium, statins, ACE inhibitors, and exercise are effective in this condition.

Study Aims:

1. To establish prevalence of microvascular disease in women with Cardiac Syndrome X
2. To study the predictive value and utility of noninvasive tests like Peripheral Artery Tonometry (PAT) and Cardiac Magnetic Resonance (CMR) in diagnosing Cardiac Syndrome X.
3. To establish prognosis in women with Cardiac Syndrome X.

The women will be consented and enrolled. They will: 1) fill out baseline demographic and health history questionnaires. 2) undergo clinically indicated coronary angiography with adenosine coronary flow reserve measurement and acetylcholine provocative testing in the cardiac catheterization laboratory; 3) undergo noninvasive Peripheral Artery Tonometry (PAT) testing; 4) undergo Cardiac Magnetic Resonance (CMR) imaging to detect subendocardial ischemia (if indicated and referred by the treating physician). They will also be followed prospectively annually for clinical status, including symptoms, functional capacity measured by the Duke Activity Status questionnaire, and adverse events such as mortality, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for acute coronary syndromes or heart failure. All subjects will be evaluated regarding participation in all aspects of testing; however specific components and tests can be declined or not performed if not clinically appropriate or indicated.

The data from this study will be an important step toward better understanding, and improved diagnosis of the coronary heart disease that is prevalent in over 9 million American women today. This study will provide feasibility recruitment data as well as pilot efficacy data for a larger NIH application.

Inclusion Criteria:

• Women with signs and symptoms of myocardial ischemia (chest pain, abnormal stress testing, abnormal noninvasive testing) in the absence of obstructive coronary artery disease (<50% luminal obstruction in one or more coronary arteries on angiography).

Exclusion Criteria:

• Contraindications to angiography and invasive coronary function testing with acetylcholine.
• Contraindications to withholding nitrates, calcium channel agents, ACE/ARB agents for 48 hours prior to testing.
• Life expectancy less than 6 months