The Role of the Collateral Circulation in Stable Angina: An Invasive Placebo-Controlled Study

BACKGROUND: Little correlation exists between the burden of ischemia and severity of angina in patients with stable coronary artery disease. This placebo-controlled, n-of-1 study investigated the relationship between ischemia, the collateral circulation, and symptoms in stable coronary artery disease. Additionally, it explored the association between progressive collateral recruitment and ischemic preconditioning. METHODS: Fifty-one participants with severe single-vessel coronary artery disease and angina were recruited. Antianginal medications were stopped, and daily angina symptoms were documented using a dedicated smartphone application (ORBITA [Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina] app) for 14 days before undergoing invasive pressure wire studies and coronary flow reserve assessment. Each participant then underwent four 60-s episodes of low-pressure balloon occlusion across their coronary stenosis. Each episode was paired with an audiovisually identical placebo inflation in a randomized order. After each episode, participants scored pain intensity on a 10-point scale, and a placebo-controlled pain intensity score was calculated. Collateral flow index was calculated from simultaneous measures of aortic, right atrial, and distal coronary wedge pressure during balloon occlusion. Higher Pr values from Bayesian models indicate a greater likelihood of association. RESULTS: The mean (±SD) age of participants was 63±9 years, and 78% were men. The median (interquartile range) fractional flow reserve was 0.68 (0.57–0.79), the median instantaneous wave-free ratio was 0.80 (0.48–0.89), and the median coronary flow reserve was 1.42 (1.08–1.85). Daily angina frequency showed little correlation with severity of ischemia, as assessed by fractional flow reserve (Somers’ D 0.124, Pr =0.057) or instantaneous wave-free ratio (Somers’ D 0.056, Pr =0.150). However, there was strong evidence of an association between lower fractional flow reserve and instantaneous wave-free ratio values and greater collateral flow (Somers’ D 0.302, Pr =0.998 and Somers’ D 0.316, Pr =0.999, respectively). There was also strong evidence of an association between more collateralization (higher collateral flow index) and lower pain intensity scores (Somers’ D 0.341, Pr =0.999). Finally, pain intensity scores and collateral flow index remained stable between sequential balloon occlusion episodes within individual patients, indicating little evidence of ischemic preconditioning. CONCLUSIONS: Coronary collateralization is associated with ischemic burden and may reduce the intensity of ischemic chest pain. This may explain the nonlinear relationship between stenosis, ischemia, and angina. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04280575.