Microvascular Disease Exercise Trial

Cardiac angina is a major source of morbidity, affecting more than 5% of the U.S. population.2 It leads to more than 1.5 million hospitalizations and $190 billion in costs yearly.3 Obstructive coronary artery disease (CAD) is the most common cause of angina. However, no obstructive CAD is found on elective coronary angiography in more than 50% of cases.4, 5 These patients with angina but no obstructive CAD are a heterogeneous group. Some have noncardiac explanations for their angina or nonobstructive epicardial abnormalities such as coronary spasm. However, many patients with angina and no obstructive CAD have microvascular dysfunction from endothelial dysfunction or microvascular obstructive disease as the cause. These patients have microvascular angina.

The coronary microvasculature is responsible for more than 70% of coronary resistance and thus plays a key role in regulating blood flow to match demand.6 Microvascular dysfunction can occur in the setting of dilated, hypertrophic, and restrictive cardiomyopathies. However, it is commonly seen in the setting of atherosclerotic risk factors or can be idiopathic.6, 7 Microvascular dysfunction is manifest as insufficient stress myocardial blood flow and/or reduced myocardial perfusion reserve (MPR), the ratio of stress flow to rest flow, in response to a stress such as vasodilator administration. Absolute myocardial blood flow and MPR can be assessed noninvasively with high precision and accuracy by cardiac magnetic resonance (CMR) imaging Reduced MPR in patients with angina is associated with significant morbidity, including a high risk of cardiac events, high medical costs, and a decreased quality of life.Despite the poor prognosis of this population, therapeutic options to reduce angina and improve MPR have not been well studied. Preliminary analysis shows that statins may improve endothelial function. ACE-inhibitors and beta-blockers improve symptoms in Syndrome X, a related disorder in which patients have angina, no obstructive CAD, and ischemic changes but a better prognosis. Therapeutic exercise has also been used in the Syndrome X population, improving exercise tolerance and endothelial function and reducing symptom severity.Improvements in MPR could be expected with exercise due to the reduced resting flow and increased MPR seen in healthy volunteers and improved endothelial function from increased nitric oxide bioactivity in patients with probable microvascular dysfunction. However, no studies have examined the effect of these medications or their synergism with exercise on MPR, aerobic capacity, anginal symptoms, or quality of life in patients with angina and reduced MPR. Identification of an effective therapy that improved symptoms and prognosis would have dramatic impact on this highly prevalent patient population.

The primary goal of this study is to characterize which patients with angina but no obstructive CAD have reduced MPR and test the effectiveness of intensive medical therapy plus a 12-week supervised exercise program versus intensive medical therapy alone to improve MPR, aerobic capacity, and the patient-centered outcomes of cardiac events, angina severity, and quality of life in this population with microvascular angina.

Inclusion criteria

• Age 18 - 85
• Anginal symptoms of chest pain, dyspnea on exertion, or other anginal equivalent suspected to be secondary to myocardial ischemia
• Coronary angiogram without obstructive epicardial coronary artery disease (≥50% epicardial stenosis or fractional flow reserve of <0.80) within 6 months prior to enrollment or date of CMR #1, whichever is later and without intervening signs or symptoms suggestive of new obstructive epicardial CAD.

Exclusion criteria

• Prior CABG (due to limitations of CMR quantitative perfusion in this population)
• Prior myocardial infarction (due to its effects on myocardial flow reserve)
• Hypertrophic or restrictive cardiomyopathy
• Coronary vasospasm
• Acute coronary syndrome unless concurrent coronary angiography reveals no epicardial stenoses of >50%
• Contraindications to CMR including - intracranial aneurysm clips, implantable pacemaker or defibrillator, metal cochlear/intraocular implants, any metallic implant not listed as magnetic resonance compatible, severe claustrophobia or other inability to tolerate a 30 minute CMR study
• GFR < 45 ml/min/1.73² (to avoid nephrogenic systemic fibrosis and iodinated contrast dye - mediated ATN) based on creatinine within 30 days of CMR #1
• Acute kidney injury, defined by the KDIGO Clinical Practice Guidelines as an increase in serum creatinine of ≥0.3 mg/dL within 48 hours, an increase in serum creatinine ≥1.5 times baseline thought to have occurred in the past 7 days, or a urine volume <0.5mL/kg/h for 6 hours
• Severe liver disease, paraproteinemia syndromes (such as multiple myeloma), hepatorenal syndrome, or planned liver transplantation (gadolinium contraindication)
• Pregnancy (assessed by serum beta- HCG prior to CMR) due to unclear gadolinium fetal effects
• Known hypersensitivity to regadenoson, or gadolinium
• Other contraindications to regadenoson (heart rate < 40 bpm, 2nd or 3rd degree heart block, sick sinus syndrome without a pacemaker, severe asthma or COPD with ongoing wheezing or hospitalization within the past 6 months, systolic blood pressure <90mmHg, recent use of dipyridamole, methylxanthine (such as aminophylline) or dipyridamole use within the past 48 hours, or caffeine within 12 hours)
• Atrial fibrillation with rapid ventricular response, frequent ectopy, or other contraindications to ECG gating
• Inability to provide informed consent
• Life expectancy of < 2 years

• List any restrictions on use of other drugs or treatments.
• Subject will be asked to refrain from use of caffeine for 12 hours and methylxanthines and dipyridamole for 48 hours prior to any administration of regadenoson. Subject may not participate if pregnant or breastfeeding.

Phase 2:

• List the criteria for inclusion

• Enrollment in phase #1.
• MPR <2.0 ml/g/min on CMR #1.
• List the criteria for exclusion

•Unable to exercise.

• List any restrictions on use of other drugs or treatments. Subject will be asked to refrain from use of caffeine for 12 hours and methylxanthines and dipyridamole for 48 hours prior to any administration of regadenoson. Subject may not participate if pregnant or breastfeeding.