ß-blockers may have several beneficial effects in patients with stable MVA. They reduce myocardial oxygen consumption, in particular during exercise and stress conditions, but may also improve coronary perfusion by prolonging diastolic time and improving left ventricular dynamics. On the whole, ß-blockers are particularly useful in patients who show evidence for increased adrenergic activity, including those with increased heart rate at rest, a rapid increase of heart rate and/or blood pressure during exercise, abnormal heart rate circadian rhythm, and sympathovagal imbalance as assessed by heart rate variability [23].

The few studies that assessed the effects of ß-blockers on symptoms in MVA patients have all used atenolol and have all concordantly reported significant beneficial effects, as compared to placebo or other drugs [24–26]. Data are less consistent when exercise test endpoints are considered; indeed, an improvement of ischemic and angina threshold was reported in some studies [24, 26], but not in others [27, 28]. In a study, however, propranolol, but not verapamil, reduced the number of episodes of ST-segment depression during 24-h ECG Holter monitoring [29].

Calcium antagonists are powerful vasodilator drugs and are therefore used in the attempt to improve the reduced vasodilatory capacity of coronary microcirculation; furthermore, they also reduce cardiac afterload. In addition, nondihydropyridine calcium-antagonists reduce myocardial oxygen consumption due to negative chronotropic and inotropic effects. However, calcium-antagonists, in particular dihydropyridine drugs, may rapidly reduce blood pressure, and this effect causes a reflex increase in adrenergic activity, which may antagonise their favorable vasodilatatory effects.

Beneficial effects on chest pain symptoms in MVA have been reported in several studies [27, 30–32]. Furthermore, favorable effects of calcium-antagonists have also been reported on exercise-induced angina and ST-segment depression, as well as on exercise tolerance [28, 30, 32] (Fig. 8.4).

However, no significant improvement of angina symptoms were observed with amlodipine in a study [25], and verapamil failed to reduce spontaneous episodes of ST-segment depression during daily life as assessed by ambulatory ECG Holter monitoring in another study [29]. Disappointing results have also reported in the assessment of the effects of calcium antagonists on CBF. No effects of diltiazem on CBF response to dipyridamole were shown in a study [33]; in another study sublingual nifedipine improved myocardial perfusion, but was associated with a worsening of exercise-induced angina and ECG changes in a few patients [34].

In summary, nondihydropyridine calcium antagonists constitute a valid therapeutic first-line option, alternative to ß-blockers, particularly in patients in whom the prevailing mechanism of angina appears to be an increased microvascular constriction, as in patients who also report angina at rest.

The anti-ischemic effects of nitrates are mainly related to their capacity to reduce cardiac work through a reduction of preload, although they also have coronary dilator effects. However, the effects of nitrates on the coronary microcirculation seem to be variable and rather limited [35].

As in patients with obstructive CAD and in those with epicardial spam, sublingual short-acting nitrates are the first-choice drugs to treat angina attacks also in patients with MVA. However, the efficacy of sublingual nitrates seems less consistent in these patients, as a complete effect seems to be achieved in only about a half of patients [20, 36].

This is in agreement with the poor, or even negative, effects of short-acting nitrates on ischemic threshold assessed at exercise stress test [37, 38]. Of note, a significant relationship was recently found in MVA patients between the coronary microvascular dilator effect of sublingual nitroglycerin and time to ischemic threshold during exercise test performed after nitrate administration, thus suggesting that it may be beneficial in a subset of patients responsive to its vasodilator effect (Fig. 8.5) [39]. The reasons for the unsatisfactory effects of acute nitrates in MVA patients, in addition to a limited effect on CMD, are not fully known, but may include myocardial hypoperfusion caused by hypotension and reflex adrenergic activation, with an increase in heart rate and, possibly, coronary vasoconstriction. Paradoxical reduction of CBF was indeed observed after intravenous and/or intracoronary short-acting nitrate administration in a study [40].

There are no data concerning the effects of chronic oral nitrate therapy in CSX patients, with the exception of a small study in which the administration of isosorbide-5-mononitrate (40 mg) failed to improve symptoms and quality of life over a period of 4 weeks [25].

The beneficial effects of xanthines in MVA can be related to two different mechanisms [41]. First, xanthines inhibit the arteriolar dilator effects of adenosine, through antagonism on vascular A₂ receptors on smooth muscle cells. This effect in nondysfunctional coronary microvessels may favor CBF redistribution toward myocardial areas with CMD, where the release of adenosine is increased. Second, xanthines stimulate presynaptic α-1 sympathetic receptors; this results in enhanced noradrenaline concentrations in the synaptic space, which, again, causes a more significant microvascular constriction in nondysfunctional areas, thus favoring CBF toward dysfunctional microvessels. Furthermore, xanthines may also have, in addition, an “analgesic” effect, as they antagonize the stimulation of cardiac nerve pain fibers by adenosine, which is a major mediator of ischemic pain [41]. This effect can be particularly important in patients with a reduced pain threshold [42].

A reduction of exercise-induced angina symptoms and/or ischemic ECG changes by acute intravenous administration of aminophylline, a nonspecific A₁/A₂ adenosine receptor antagonist, in MVA patients was reported in two small controlled trials [43, 44]. A single oral dose of aminophylline (400 mg) [38] was also reported to significantly improve ischemic ST-segment depression and angina pain induced by exercise stress test in a study.

In an uncontrolled trial, however, intravenous aminophylline failed to improve exercise induced angina and ST-segment changes [45], and, in a small randomized placebo-controlled trial, intravenous administration of bamiphylline (300 mg) [46], a specific adenosine A₁-receptor antagonist, had no effect on exercise-induced ST segment changes, although reduced the severity of exercise-induced chest pain.

Only one study assessed the effects of chronic oral xanthine therapy on spontaneous angina attacks [47]. In this randomized crossover study 13 MVA patients received either aminophylline (225–350 mg twice daily) or placebo for 3 weeks. In the 10 patients who completed the trial, aminophylline failed to significantly improve angina episodes; furthermore, the drug was found to improve exercise induced angina, but not exercise induced ST-segment change nor episodes of ST-segment depression on ECG Holter monitoring (Fig. 8.6).

Thus, although data suggest that xanthines may improve exercise-induced angina in MVA patients and pharmacodynamics suggests their utility in case of increased pain sensitivity, their effects on spontaneous angina episodes during continuous therapy need further assessment.

ACE-inhibitors have been proposed as therapeutic agents in MVA due to their lowering effects of serum and tissue angiotensin II. Although there is no evidence of a major role of angiotensin II in the CMD of these patients, local tissue angiotensin II, in particular, is involved in the regulation of coronary microvascular structure and function, exerting, when increased, several potentially deleterious effects, including vasoconstriction, increased oxidative stress, and degradation of nitric oxide [48]. Furthermore, angiotensin II enhances the effects of sympathetic nervous system on coronary microvascular tone and may also favor structural microvascular changes by stimulating cell growth [48]. Accordingly, enalapril has been found to improve CMD through increase of NO availability and reduction of oxidative stress in MVA patients [49].

The favorable clinical effects of ACE inhibitors in stable MVA were suggested by a small randomized placebo-controlled trial [50], in which enalapril prolonged time to ischemic threshold. Similar results have subsequently been obtained with the use of cilazapril [51]. Moreover, an improvement of angina symptoms, as well as of exercise capacity, has been reported with the use of ramipril [31, 52, 53].