Study to Evaluate Effect of Nebivolol on Angina in Women With Microvascular Disease
Condition: Microvascular Angina
MeSH terms: Angina Pectoris; Microvascular Angina
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Nebivolol
Intervention type(s): Drug
Intervention description(s): Patient to start nebivolol and have repeat testing in 3 months
Other intervention name(s): Bystolic
Intervention MeSH terms: Nebivolol
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: angina; cardiopulmonary testing; metabolomics; nebivolol