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

Abstract

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.

Keywords: collateral circulation; coronary artery disease; stable angina.

Figure 1.

Study design and experimental model for the placebo-controlled balloon occlusion protocol. A guiding catheter was placed into the coronary ostium. A pressure and Doppler sensor–tipped Combowire was placed beyond the stenosis. A pigtail catheter was placed into the right atrium. The collateral flow index was calculated during low-pressure balloon occlusion episodes from simultaneous measures of aortic pressure (Pa) from the guiding catheter, distal coronary wedge pressure (P(occl)) from the Combowire distal to the occluding balloon, and central venous pressure (CVP) from the pigtail catheter in the right atrium. After each episode, balloon occlusion or placebo inflation, patients reported the intensity of any pain experienced on a 10-point ordinal scale, on which 0 is no perceived sensation and 10 is the worst pain imaginable. CCS indicates Canadian Cardiovascular Society; CFR, coronary flow reserve; FFR, fractional flow reserve; iFR, instantaneous wave-free ratio; PCI, percutaneous coronary intervention; and SAQ, Seattle Angina Questionnaire.

Figure 2.

Example pressure waveforms displaying simultaneous aortic pressure and distal coronary wedge pressure during a 60-s balloon occlusion episode. The distal coronary pressure (green line) can be seen to fall to a steady pulsatile nadir as the occluding balloon is inflated (distal coronary wedge pressure). This pressure is a surrogate of collateral blood flow. As the occluding balloon is deflated, the distal coronary pressure returns to baseline. Pa indicates aortic pressure and P(occl), distal coronary wedge pressure.

Figure 3.

Association between daily angina frequency reported via the smartphone app and physiological stenosis severity as assessed by FFR (A) and iFR (B). Each patient is depicted as an individual row. Each colored panel is an individual day of the trial in which darker colors indicate greater angina frequency. The patients have been sorted with the most ischemic (lowest fractional flow reserve [FFR] and instantaneous wave-free ratio [iFR]) stenoses toward the top and the least ischemic (highest FFR and iFR) stenoses toward the bottom. To the right of each row is the absolute FFR or iFR value for each patient (blank where not measured). There was no detectable relationship between physiological stenosis severity and daily angina frequency.

Figure 4.

Association between the collateral flow index (CFI) and fractional flow reserve (FFR; A), the instantaneous wave-free ratio (iFR; B), and stress echocardiography score (where higher scores indicate a greater burden of ischemia; C).

Figure 5.

Greater collateralization, as indicated by higher collateral flow index (CFI), was associated with significantly reduced (milder) placebo-controlled pain intensity scores (Pr>0=0.999). Participants with less collateral blood flow were more likely to have severe pain with balloon occlusion.