In patients with obstructive atherosclerosis of large epicardial arteries, the occurrence of myocardial ischemia during increased oxygen demand is usually attributed to the inadequate flow increase despite maximal vasodilatation of the coronary microvasculature [9]. According to this view, maximal coronary flow capacity and CFR have been proposed as accurate functional descriptors of stenosis severity to identify the need for revascularization [10]. Yet, the clinical correlation between stenosis severity and CFR is widely scattered [3, 4, 11–14]. These findings suggest that other factors might precipitate myocardial ischemia. For instance, the angiographic severity of coronary stenoses can increase during exercise or atrial pacing because of increased tone [15]. More importantly, in experimental studies, an increase in calculated total coronary resistance has been observed during tachycardia in regions supplied by severely stenotic coronary arteries [16]. Thus, it seems conceivable that in CAD, the response of the coronary microcirculation to increased oxygen demand might be more complex than a progressive arteriolar vasodilatation and that changes at the level of coronary stenosis may modulate flow response. To further clarify the possible role of the microcirculation, Sambuceti et al. assessed the resistance of both the stenotic arterial segment and the downstream microvasculature at rest and during pacing-induced ischemia in patients with stable angina. The authors found that tachycardia-induced ischemia was associated with an increase of the resistance of both the stenotic segment and the microvasculature. Interestingly, the infusion of adenosine during pacing reduced microvascular resistance (Fig. 6.2) [17]. This paradoxical behavior of vasomotor tone might reflect the intrinsic control mechanisms of the coronary circulation finalized to the maintenance of the driving pressure in a range of values high enough to perfuse vessels, but low enough to prevent capillary damage (see Chap.​ 1). Such a control could be as powerful as the metabolic control, although the two may go in opposite directions in this pathological condition. In this line, the response of coronary microcirculation to excessively low perfusion pressure could be a heterogeneous vasoconstriction, able to maintain pressure at the cost of excluding some vascular units. Although somewhat paradoxical and apparently not finalized to avoid or reduce ischemia, this hypothesis agrees with the evidence of both flow heterogeneity during hypoperfusion [18] and heterogeneous distribution of the metabolic fingerprints of ischemia in the subendocardial and subepicardial layers of the LV [19]. It is also worth mentioning that this complex microvascular response which is beneficial when microcirculation is intact, as it is the case in canine experimental models, might contribute to ischemia in atherosclerotic patients. Accordingly, in patients with severe epicardial coronary stenoses, adenosine administration during pacing resulted not only in reduction of microvascular resistance but also in reduction of myocardial ischemia, thus confirming that microvascular constriction contributes to negatively modulate the severity of ischemia [20].

The “plaque-centric” hypothesis can also be called into question when the impact of therapeutic strategies based on the removal of coronary atherosclerotic obstructions is considered. Most reports agree that, on a background of medical therapy, revascularization improves symptoms, but in many patients angina recurs after 2–3 years and myocardial infarction and death are not prevented. In the COURAGE trial, which evaluated PCI on top of optimal medical therapy, more than 30 % of patients were still symptomatic with angina 1 year after the percutaneous procedure. Interestingly, at 5-year follow-up, the incidence of angina was not significantly different from that in patients who did not undergo a revascularization procedure (Fig. 6.3) [21]. Moreover, no significant between-group differences were noted for the composite end-point (death, myocardial infarction, and stroke), all-cause mortality, hospitalization for acute coronary syndrome, or myocardial infarction. Similarly, in the RITA-2 trial patients randomized to myocardial revascularization exhibited an initial greater improvement of symptoms and quality of life as compared to patients randomized to medical treatment. Yet, at 3-year follow-up, these differences between the two groups were not significant (Fig. 6.4) [22]. The pathophysiological relevance of obstructive lesions in the genesis of ischemia was further elucidated in the FAME study, where patients with multivessel coronary artery disease were randomly assigned to undergo PCI with implantation of DES guided by angiography alone or guided by FFR measurements in addition to angiography [23]. Patients assigned to FFR-guided PCI underwent stenting of indicated lesions only if the FFR was ≤0.80, whereas those assigned to angiography-guided PCI underwent stenting of all angiographically significant lesions. The 1-year event rate was significantly higher in the angiography-guided group than in the FFR-guided group (18.3 % vs. 13.2 %), in spite of a smaller number of stents implanted in the former. Importantly, 21 % of patients in the angiography-guided group and 19 % of patients in the FFR-guided group still complained of angina at 1-year follow-up, a figure similar to that observed in the COURAGE trial. The FAME 2 study randomized patients in whom at least one stenosis was functionally significant (FFR ≤0.80) to FFR-guided PCI plus optimal medical therapy or optimal medical therapy alone. Again the incidence of death and myocardial infarction was similar in the two groups. In contrast, the rate of urgent revascularization was higher in patients randomized to optimal medical treatment only and for this reason the study was closed prematurely. However, as FAME 2 was an open label study, a soft end-point like “urgent revascularization” is difficult to interpret [24].

In addition, in the STICH study, in patients with obstructive atherosclerosis and heart failure, no significant difference in all-cause mortality was observed between patients randomized to the medical therapy and those randomized to CABG [25]. Other large clinical trials have consistently shown a lack of mortality and symptomatic benefit in patients with stable angina and low to intermediate risk randomized to stent implantation in addition to optimal medical treatment or to optimal medical treatment alone [26] (Fig. 6.5).

These disappointing results for symptom control in patients with stable angina after coronary revascularization have been attributed to a number of factors, including incomplete revascularization, in-stent restenosis, and patient-related factors. However, in a highly selected cohort of 220 patients in which all possible confounding factors had been excluded, one-third of patients were symptomatic with angina and presented with a positive exercise stress test 1 month after the index procedure [27].

These observations certainly do not deny the usefulness of revascularization in patients with ACS, when coronary revascularization is needed to prevent an impending catastrophe, but they do raise questions about whether revascularization should continue to be regarded as the ultimate treatment for obstructive atherosclerosis in stable patients. The unchanged prognosis and the high recurrence rate of angina clearly suggest that revascularization procedures remove the atherosclerotic obstructions but do not cure the underlying disease. Indeed, obstructive plaque is only one of the causes of stable angina, the other being represented by CMD.

As proof of concept, it is worth mentioning an elegant trial in which patients with stable angina and inducible myocardial ischemia were randomized to percutaneous coronary revascularization or a program of physical training. After 1-year follow-up, major cardiovascular event rate was lower and exercise capacity was better in the latter. This study highlights that physical training-related improvement of microvascular endothelial function and, perhaps, of collateral circulation function are more important than removal of epicardial coronary stenosis in improving symptoms and outcome in patients with stable angina [28].

Endothelial dysfunction has been shown to play an important role in the development of atherothrombosis through its regulation of vascular tone, platelet activity, leukocyte adhesion, and thrombosis [29]. Endothelial dysfunction is a predictor of cardiovascular events in patients with stable angina with or without obstructive atherosclerosis when assessed in the peripheral circulation, in large epicardial arteries and in coronary microcirculation [30, 31]. In keeping, coronary vasomotor response to acetylcholine has been shown to be an independent predictor of cardiovascular events in women with no, noncritical or critical epicardial stenosis, and suspected ischemia [32]. Accordingly, in a recent follow-up study of women with suspected myocardial ischemia, decreasing levels of CFR assessed by intracoronary adenosine (a nonendothelium dependent vasodilator stimulus) were significantly related to increasing risk of major adverse cardiovascular events (death or hospitalization for nonfatal AMI, congestive heart failure or stroke), with an adjusted hazards ratio of 1.14 per unit decrease in log-transformed CFR [33]. Inflammation is also a prominent part of the pathological process. Monocyte-derived macrophages and T-lymphocytes produce and secrete mediator molecules, such as cytokines, chemokines, growth-factors, proteolytic enzymes, and adhesion molecules, which activate endothelial cells, increase vasoreactivity, and cause smooth muscle cell proliferation. These events can enhance atherosclerotic plaque progression when occurring in large epicardial coronary arteries, while they cause dysfunction when occurring in coronary microcirculation by promoting both functional and structural alterations. In particular, plasma CRP, a prototypic marker of inflammation has been shown to be a risk factor for cardiovascular events in asymptomatic as well as in patients with known obstructive atherosclerosis [34, 35].

Women represent an interesting patient population in whom CMD is likely to play a key role in accounting for angina and myocardial ischemia in the presence of obstructive atherosclerosis [36]. In fact, while presenting with a lower coronary atherosclerotic burden, cardiovascular morbidity and mortality in women is similar to that in men [37]. The morbidity and mortality associated with the disease in this patient population have been a driving force in the exploration of other causes of myocardial ischemia including CMD. In line with these considerations, microvascular dysfunction in chronic angina can almost be considered as a “female gender disease.” According to experimental studies, sex plays a relevant role in a number of microvascular mechanisms which may affect microvascular function and disease. Sex-specific differences in microvascular blood flow and vasodilator capacity are observed very early in development.

In summary, a large body of evidence supports the notion that obstructive atherosclerosis is neither a sufficient nor a necessary cause for stable angina, but just one component of a complex pathophysiologic process. In patients with stable angina and obstructive atherosclerosis, the mechanisms responsible for angina are complex and related to both the presence of critical stenoses in large epicardial coronary arteries and the presence of microvascular dysfunction, which can also affect collateral circulation.