Pilot Study of Supervised Exercise and Intensive Medical Therapy in Patients with INOCA and Coronary Microvascular Dysfunction

Symptoms of ischemia with no evidence of obstructive coronary artery disease (INOCA) has a high prevalence and rate of major adverse cardiac events. We have previously identified a high symptom burden, physical limitation, substantial levels of cardiac anxiety, and significant economic impact in this population (1). Between 50–65% of INOCA patients have coronary microvascular dysfunction (CMD) as identified by impaired myocardial perfusion reserve (MPR) on stress positron emission tomography (PET) or cardiac magnetic resonance (CMR) imaging (2). Limited data exists regarding effective treatments of symptoms and MPR in CMD and typical anti-anginal medical therapy have minimal proven benefit (3). Exercise may be a potential treatment as it improves functional capacity in patients with obstructive CAD and MPR among healthy volunteers (4). This pilot study aims to investigate whether supervised exercise, in addition to intensive medical therapy (IMT), could improve symptom burden, aerobic capacity, and MPR in patients with CMD.

We prospectively enrolled nineteen subjects aged 18 to 85 who presented with symptoms of ischemia, no obstructive CAD on coronary angiography, no known cardiomyopathy and CMD on stress CMR. Subjects underwent regadenoson stress CMR on a 1.5T Siemens Aera scanner with quantitative rest and stress spiral first-pass perfusion imaging and quantification of absolute myocardial blood flow and MPR using Fermi deconvolution (2). MPR <2.4 was used as a cut-off for CMD, a threshold established from prior literature and supported by comparison to 20 healthy controls with mean MPR 2.93 ± 0.44 (2). The University of Virginia Institutional Review Board approved this study, and all subjects provided informed written consent.

Study subjects completed 8-weeks of IMT consisting of the initiation and titration of carvedilol, lisinopril, atorvastatin, and amlodipine (for refractory angina or uncontrolled hypertension) with repeat CMR testing after completion. Ten subjects completed 12-weeks of supervised exercise thrice weekly and home exercise twice weekly (45 minutes of moderate intensity exercise) with repeat CMR to evaluate changes in MPR. Peak VO2 assessing aerobic capacity was measured by cardiopulmonary exercise testing (CPET) at baseline and with IMT and exercise. Subjects completed Seattle Angina (SAQ) and Cardiac Anxiety Questionnaires (CAQ) at baseline, after both the IMT and exercise programs, and at 1-year follow-up. SAQ scores were reported as the average of all five domains. Changes in MPR, peak VO2, SAQ scores, and CAQ results following interventions were compared using linear mixed modeling with p-values derived from paired comparisons with Tukey-Kramer correction for multiple comparisons including age.

The study population had a mean age of 60.3 ± 10.5 years, and 58% were female. The baseline mean MPR was 2.09 ± 0.19 and baseline peak VO2 was 22.5 ± 6.6 mL/kg*min. The results of linear mixed models comparing responses in MPR and average SAQ following IMT and exercise are shown in the Figure. There was a trend toward MPR improvement with IMT (p=0.067) and a significant improvement from baseline with supervised exercise. Average SAQ score was unchanged with IMT and increased significantly from baseline with supervised exercise, with changes persistent at one year. There were no changes in peak VO2 after IMT (− 0.56, 95% CI −1.90 to +0.79, p=0.70) or exercise (−0.14, 95% CI −1.72 to +1.43, p=0.98).

Figure:

Results of linear mixed models comparing (A.) changes in MPR and (B.) average SAQ score following IMT and supervised exercise. IMT= intensive medical therapy; MPR= myocardial perfusion reserve; SAQ= Seattle Angina Questionnaire. P-values derived from paired comparisons with the Tukey-Kramer multiple comparisons correction following analysis of variance.

Likewise, CAQ scores were unchanged following IMT (−0.07, 95% CI −0.27 to +0.12, p=0.95) and exercise (−0.14, 95% CI −0.34 to +0.06, p=0.64). There was no evidence of LVH on CMR testing and no late gadolinium enhancement before or after intervention.

Our results indicate that supervised exercise added to IMT improves MPR and reduces symptoms (average SAQ score). There was a smaller trend seen with medication that has been shown in CorMicA (5). We predict that a larger cohort or longer exercise regimen would have resulted in statistical significance. Likewise, a larger number of patients would have resulted in demonstrating a significant incremental improvement to exercise over IMT. There was no improvement in aerobic capacity, but as peak VO2 is known to decline with beta-blocker use, the maintenance of peak VO2 with exercise despite initiation/titration of carvedilol is notable. A substantial dropout rate highlights the challenge of incorporating exercise therapy. These results agreed with Larsen et al’s findings showing high-intensity interval training improved coronary flow velocity reserve and flow-mediated vasodilation. Similarly, our study did not confirm findings of the CorMicA trial, which randomized INOCA patients to invasive versus sham diagnostic procedure and demonstrated improvements in SAQ scores for the invasive diagnostic group once they optimized antianginal therapy. The CorMicA trial was also a heterogenous group (6). Our study has the comparative advantage of using a noninvasive and rigorous MPR assessment using CMR and while also including quality of life data demonstrating that both followed a similar trend. Our study also tested stabilizing patients on medical therapy to show incremental benefit albeit without statistical difference whereas Larsen et al’s study may have been limited by their small control group and variable medication regimens (5). The results of this pilot study demonstrate feasibility; however, further randomized studies with more subjects are needed to further identify the specific mechanisms of improvement and optimal exercise regimen that maximizes benefit and adherence.