Transmural variation in microvascular remodelling following percutaneous revascularization of a chronic coronary stenosis in swine

Despite successful revascularization of patients with stable angina, recurrent angina post PCI occurs in 20-40% of the patients within 1 year of follow-up,1 suggesting a role for the microvasculature in these events. Microvascular dysfunction resulting in increased microvascular resistance after PCI has been associated with major adverse events up to 4 years after revascularization as it may prevent adequate perfusion in the revascularized area especially during high metabolic demand.2 However, although functional alterations in the microvasculature distal to a chronic coronary stenosis have been described earlier in animal models, the structural changes are still under debate.3-5 Animal studies indicate inward vascular remodelling distal to a chronic stenosis,3,5 while studies in CAD patients undergoing PCI indicated a normal minimal microvascular resistance immediately after PCI,6 although, when evaluated at 6 months, recurrent angina was associated with a high microvascular resistance and a lower CFR7.
To investigate the functional importance of microvascular remodelling distal to a chronic coronary stenosis and its reversibility upon revascularization in an integrative manner, Weil et al. performed an elegant study in a translationally relevant animal model. Thus, swine were instrumented with a chronic silastic stenosis on the left anterior descending coronary artery to produce hibernating myocardium. Three months later swine underwent PCI and were compared to animals with a persistent stenosis, as well as sham controls. Swine with a coronary stenosis demonstrated an increased subendocardial arteriolar wall thickness-to-lumen ratio and reduced lumen area per arteriole, which was accompanied by a compensatory increase in arteriolar density. As a result, adenosine-induced maximal subendocardial blood flow measured immediately after PCI was similar to maximal flow in remote normally perfused regions. Strikingly, one month after PCI, increases in wall thickness-to-lumen diameter and reductions in lumen area per arteriole persisted, whereas arteriolar density had returned to normal. Consequently, maximum subendocardial flow during adenosine markedly declined and was lower than in remote regions. In contrast, in the sub epicardium no microvascular remodelling occurred and maximum perfusion remained unaffected.
The study by Weil et al. is important for several reasons. First, it not only confirms previous animal observations of inward coronary arteriolar remodelling distal to a severe proximal coronary artery stenosis, but it also reveals the functional importance of this inward coronary arteriolar remodelling. Second, the increased arteriolar density that acts to maintain maximal perfusion capacity upon revascularization explains (possibly in conjunction with vasodilator drug therapy8) why in clinical studies a normal or even slightly lower minimal resistance was observed immediately following revascularization.6 Third, while arteriolar density had normalized at one month post-PCI, inward arteriolar remodelling persisted, resulting in an increased microvascular resistance and impaired maximal subendocardial blood flow. The latter may also explain the blunted myocardial functional response to dobutamine in swine observed by Kelly et al., at one month following coronary artery bypass grafting, and suggests that persistent inward microvascular remoding may contribute to recurrent angina observed after successful revascularization in the clinical setting.6
The mechanisms underlying the inward remodelling were not assessed in the study by Weil et al. However, previous studies have shown that subendocardial arterioles distal to a chronic coronary stenosis display increased vasoconstrictor responsiveness to ET-1, principally due to a loss of (NO-dependent) ETB-receptor mediated vasodilation.4 The resultant increase in vasomotor tone, together with a lower post-stenotic coronary pressure, can lead to inward remodelling.9 Importantly, these experimental studies were performed in normal swine with healthy blood vessels, whereas CAD patients usually present with multiple co-morbidities, including diabetes, hypercholesterolemia, chronic kidney disease. These co-morbidities are associated with a pro-inflammatory milieu and result in impaired endothelial function, oxidative stress and reduced NO availability as shown in humans10 and animal models.11,12,13 The resultant coronary microvascular dysfunction may lead to perturbations in myocardial oxygen balance even in the absence of of a coronary occlusion (INOCA).10,14 Additionally, it may also aggravate the microvascular response to the stenosis, especially in the vulnerable sub-endocardium, where arterio- and angiogenesis may be hampered by the presence of endothelial dysfunction. Such dynamic changes in microvascular function and structure may explain, at least in part, the recurrent angina episodes, thereby limiting functional recovery in patients after PCI. These questions should be addressed in future studies in patients and animal models with multiple risk factors.
In conclusion the paper by Weil et al provides important novel insight in the time-course of sub-endocardial microvascular remodelling following PCI, suggesting that novel therapeutic interventions directed at alleviating such structural modifications may benefit patients with chronically ischemic myocardium.