DISCUSSION
Angioplasty, angina, obstructive coronary artery disease, ANOCA, ischemia, chest pain, obstructive CAD, CMD, gain, coronary vascular dysfunction
ISCHEMIA, VASODILATATION
In ChaMP-CMD, patients with ANOCA and an impaired CFR had an improvement in exercise time in response to anti-ischemic therapy, whereas those with a normal CFR did not. The gain in function with therapy was lost on cessation of therapy in patients with CMD, which suggests a causal link between the pathophysiological classification and response to therapy. We believe that this is the first robust demonstration of the association between CFR and an improvement in exercise capacity in response to anti-ischemic therapy. This, in turn, demonstrates the practical utility of measuring CFR in patients with ANOCA as a means of personalizing therapies. Among patients with CMD, functional CMD was the most prevalent endotype and these patients had an increment in exercise time in response to anti-ischemic therapy similar to patients with structural CMD.We had previously demonstrated that an impaired CFR reliably identifies those with an ischemic substrate and maladaptive physiology during exercise,We have previously shown that patients with an impaired CFR have an ischemic substrate regardless of whether they have elevated or normal minimal microvascular resistance (structural and functional CMD endotypes, respectively); these endotypes have a similar core phenotype but disparate underlying pathobiological mechanisms.When objectively assessing the efficacy of therapies on exercise capacity, the minimum clinically relevant increment in exercise time is often regarded to be 30 s. It is notable that patients with CMD had an increment in exercise time after anti-ischemic therapy that was, on average, greater than twice this minimum difference. This treatment effect is in keeping with those reported in seminal anti-ischemic trials of patients with obstructive coronary artery disease (CAD)The patients enrolled in ChaMP-CMD reported a degree of impairment in their quality of life, on account of angina, that was comparable to that reported by patients with obstructive CAD in ORBITA (Objective Randomized Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina)The discordance in treatment effect, as assessed by exercise time versus SAQ summary score, may be because the subjective assessment of quality of life is multifactorial (the coefficient of determination, There was some evidence of a training effect, with participants walking for 22 s longer, on average, during their fourth ETT compared with the first one. Although this may have led to slight overestimation of the treatment effects overall, there is no evidence that this has affected the comparison of treatment effect between groups or between drugs, given the randomized crossover design. Likewise, patients scored 5 points higher on their fourth SAQ than on the first one; however, this did not reach the minimum clinically relevant threshold of 8 points.There is currently marked heterogeneity in the diagnosis and management of patients with ANOCA for a variety of reasons, some of which we have addressed with the findings of our study. First, there is a widely held belief that empirical management of patients with ANOCA (without embarking on definitive diagnostic testing to confirm or refute the presence of CMD) is an acceptable alternative. We have demonstrated that patients with ANOCA, but no CMD, do not experience any improvement in objective exercise capacity or subjective quality of life with anti-ischemic therapies. To treat these patients empirically would not only potentially expose them to ineffective therapies but also delay the pursuit of alternative causes for their symptoms. The cause of chest pain in patients with ANOCA and normal CFR is unclear, but our findings suggest that inducible ischemia may not be an appropriate treatment target in this group.We chose to study ranolazine and amlodipine as the exemplar drugs in our study, because these were expected to address the pathobiological processes that are believed to underlie each CMD endotype. The hallmark of functional CMD is submaximal vasodilatation at rest, which could be due to heightened myocardial oxygen demand at rest (although other reasons have been postulated). Ranolazine has been shown to modulate myocyte metabolism (by switching fatty acid oxidation to glucose oxidationOur study has some limitations that should be considered when interpreting the findings. First, this was a single-center study with a relatively small sample size with inherent limitations of generalizability. Second, we did not include a placebo therapy arm, and, hence, this was not double blinded in the conventional sense. Knowledge of the medications patients were taking may have led to some treatment bias, but this would be expected to occur in both CMD and reference groups equally. Furthermore, patients and researchers were blinded to the physiological classification (phenotype-blinding) and had no means of knowing whether a given drug was expected to affect their exercise time or quality of life. Third, we did not repeat coronary physiology measurements, which may have provided an important mechanistic link. However, repeating these measurements 3 times within a course of 12 weeks would have been highly burdensome for our patients and beyond the study resources. Fourth, we have studied 2 specific anti-ischemic agents with different mechanistic profiles and therefore cannot be certain that the differential effect we observed (in CMD versus reference patients) would be replicated with other classes of drugs. Last, it is important to emphasize that this was a carefully selected patient cohort with a high symptom burden and pretest probability of coronary vascular dysfunction (Figure In summary, we have demonstrated that an invasive diagnosis of CMD, on the basis of CFR, distinguishes patients with ANOCA who derive objective benefit from anti-ischemic therapy. The CFR threshold that is commonly used to diagnose CMD was also the most accurate in identifying patients who respond to anti-ischemic therapy. These findings support measurement of CFR in patients with ANOCA and typical limiting symptoms to not only establish a diagnosis and predict prognosis, but also to guide medical therapy. Our findings should also inform future trials of anti-ischemic therapies for CMD, which should selectively enroll patients with diminished CFR or be designed to allow comparison of patients who have ANOCA with versus without evidence of CMD.