Microvascular Angina Clinical Trial
Official title:
Nebivolol for the Relief of Microvascular Angina in Women
Women have less significant blockages of coronary arteries, however have greater symptoms and worse outcomes compared to their age-matched male counterparts. This paradox has led to the recognition and importance of the microvasculature ( small vessels) as a contributor to symptoms and outcomes. Nebivolol has unique antioxidant properties and dilates blood vessels and it is therefore proposed that treatment with nebivolol will reduce angina (chest symptoms) in women with microvascular disease as well as improve exercise capacity, reduce resource utilization and improve other measures of artery function.
Though women have less obstructive coronary artery disease (CAD) they continue to have a
greater burden of symptoms, more myocardial ischemia, and a higher rate of adverse outcomes
than their age-matched male counterparts. This ostensible paradox has led to the recognition
of a distinct pathophysiology of ischemic heart disease, in part related to microvascular
dysfunction, and abnormal coronary reactivity. The term primary microvascular angina, (MVA)
is used to describe a syndrome among patients who have symptoms suggestive of cardiac
ischemia, evidence of electrocardiographic abnormalities, abnormalities on stress imaging or
a history of ACS, but no evidence of obstructive epicardial coronary disease. In this
population, microvascular angina causes significant morbidity and in some may contribute to
increased mortality.
The treatment of microvascular disease remains empirical due to lack of data regarding
symptom alleviation, as well as ultimate mortality reduction. Women with ischemic heart
disease and microvascular angina continue to report more frequent angina and worse quality
of life. They frequently seek medical attention for the evaluation of cardiovascular
symptoms including chest pain and shortness of breath. Consequently, these women incur
greater healthcare costs, with more office visits, hospitalizations, and myocardial
infarctions. In fact, more than one half of women without obstructive coronary disease
continue to have ischemic symptoms that lead to further consumption of CAD resources, most
often because of diagnostic uncertainty.
In the absence of robust outcomes data to drive the care of these women with microvascular
ischemia, various approaches are taken, in addition to the fundamental management of
baseline risk factors. Some physicians treat these women as they would treat patients with
known obstructive CAD, while some, in the setting of "open" coronary arteries and persistent
chest pain, opt for reassurance. Nevertheless, given that these women with microvascular
ischemia continue to have higher morbidity and mortality, as well as increased resource
consumption, there is a widely recognized need for effective therapeutic agents to reduce
symptoms, improve quality of life, decrease resource consumption, and ultimately reduce
mortality.
Nebivolol, due to its unique antioxidant and vasodilator properties, via its effect on NO
bioactivity, and subsequent effects on the endothelium may be a potentially ideal
therapeutic agent for the treatment of microvascular angina among women. For example, one
previous study showed that nebivolol improved exercise parameters, as well as endothelial
function, more effectively than other beta blockade with metoprolol, among patients with
persistent angina and non-obstructive coronary disease.
Cardiopulmonary exercise testing is an ideal diagnostic test in this study as it will
provide unique information on how microvascular ischemia influences functional capacity as
measured through sensitive gas exchange parameters. Because it is known that a distinct
pathophysiology contributes to microvascular angina among this subset of women, these
parameters provided by CPET may provide essential information regarding the mechanism of
symptom mitigation should nebivolol confer therapeutic value.
Furthermore, because exercise tolerance is often significantly impaired, objective measures
of gas exchange that reflect submaximum and maximum fitness among these women will be useful
both at baseline and on nebivolol.
Peripheral arterial tone and pulse wave analysis will also be performed. PAT signal
technology provides a widely validated measurement of endothelium-mediated changes in
vascular tone, using non-invasive bio-sensors on the fingertips that are elicited by
creating a down-stream hyperemic response. This parameter correlates well with endothelial
dysfunction in coronary arteries. We will perform endothelial function testing at baseline
and after 3 months.
Metabolomics is an emerging field that offers the possibility of using the body's
metabolites to both phenotype a disease as well as track its response to isolated
perturbations, such as administration of a drug. In this study we will utilize metabolomics
to define signatures of microvascular ischemia as well as nebivolol-mediated changes in
metabolic profiles. Baseline metabolic profiling, as well as metabolic profiling after 3
months of nebivolol treatment will be performed in this study.
This type of assessment is an ideal complement to the clinical parameters delineated above
as it combines targeted mass spectrometry to measures small molecules related to nitric
oxide metabolism (ie: arginine, arginosuccinate, citrulline, ornithine, cGMP, ADMA) as well
as more unbiased screening of metabolites that are not known to be associated with either
nebivolol exposure or microvascular angina.
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Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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