Stable primary microvascular angina

"Microvascular angina" was first used by Cannon and Epstein in 1988 to describe 1) normal epicardial coronary arteries despite 2) typical anginal symptoms and 3) evidence of myocardal ischemia: up to 30% of patients undergoing invasive coronary angiography due to their symptoms and/or abnormal exercise test results have normal coronary arteries (1-3). 
Microvascular angina is considered "primary" when patients have no specific concomitant diseases. It is further defined as stable if anginal episodes are frequently related to exercise.
Primary microvascular angina is unstable if anginal attacks worsen at rest or in response to mild exercise and sometimes lead to acute coronary syndromes (4).
Stable Primary MVA
Prognosis of primary stable MVA was initially presented as "cardiac syndrome X", and was thought similar to that of the general population, however long-term results of the WISE study have demonstrated that prognosis is worse in patients with reduced coronary flow reserve. Furthermore, a significant proportion of these patients have progressive anginal symptoms which significantly impair quality of life, and increase the need for healthcare services and spendings (5).
As the underlying cause in the majority of these patients the following have been suggested:

• Coronary microvascular dysfunction - both the risk factors and pathophysiological mechanisms leading to functional abnormalities of coronary resistive vessels are not yet established (6). 
• Abnormal pain processing
• Insulin resistance, estrogen deficiency in women, oxidative stress and subclinical inflammation - they have been shown to contribute to CMVD in patients with stable primary in addition to conventional cardiovascular risk factors - diabetes mellitus, hypertension, hyperlipidemia, smoking.

Several therapeutic options have been explored but the complicated underlying pathogenetic mechanisms are the reasons for which they were deemed insufficient (7). We review the current treatment options for stable primary MVA.

I - Therapeutic lifestyle changes

Therapeutic lifestyle changes should be encouraged. These are:

1. Smoking cessation and weight loss to improve endothelial function (8,9).
2. The mediterranean diet combined with regular moderate exercise training  to improve microcirculatory endothelial function (10). 
3. Physical training ameliorates exercise capacity and decreases chest pain, as a result of adrenergic modulation (11). 

II -  Drugs targeting microvascular function

With increasing understanding of the pathophysiological mechanisms underlying coronary microvascular dysfunction, new therapeutic strategies that target these processes have been proposed. ACE inhibitors, statins, biguanides, xanthine oxidase inhibitors and oestrogen replacement therapy improve coronary microvascular function (12).

ACE inhibitors

Beneficial effects of ACE inhibitors on endothelial function in hypertensive patients have been shown repeatedly.
Enalapril and clazapril reduce the magnitude of ST-segment depression and increased total exercise duration in these patients: Eight week treatment with enalapril when compared to placebo increased coronary flow reserve and endothelial nitric oxide. These studies point to a beneficial effect of ACE inhibitors through improving microvascular function.

Statins

Statins improve endothelial function independently from their cholesterol lowering effect, possibly through their anti-inflammatory and anti-oxidative actions. Treatment with pravastatin and simvastatin improved exercise duration, time to 1mm ST-segment depression and endothelial functions (assessed by brachial artery flow mediated dilatation) (12). Atorvastatin combined with ramipril improved quality of life and endohelial function in these patients through reduction of oxidative stress in the arterial wall (13). 

Metformin

Insulin resistance has been considered a pathophysiological mechanism underlying microvascular dysfunction and metformin seems to have a potential for treating this condition. Metformin was shown to improve endothelial function in patients with type 2 diabetes (14). Also, an eight week treatment with metformin significantly improved microvascular endothelial function and reduced ishemic burden in non-diabetic stable primary MVA patients (15).  

III - Antianginal therapy

Since exercise-related anginal symptoms significantly impair quality of life in these patients, antianginal drugs have been the mainstay of therapy. Conventional anti-ishemic drugs are always the first step of medical treatment and newer antianginal drugs have been used for patients with resistant symptoms.

Beta blocking agents

Beta-blocker therapy seems a rational approach, and particularly in those with exercise related symptoms and evidence of increased adrenergic activity.
Atenolol and propranolol was shown to reduce anginal episodes and ischemic burden. In these studies, atenolol was also found to be more effective than nitrates and calcium channel blockers (16,17).
Nebivolol, a third generation beta blocker, was shown to increase nitric oxide release from vascular endothelium and significantly improve coronary flow reserve (18). However, response to beta blockers has been variable and ranged from 19 to 60%, necessitating a search for further therapeutic options (19). 

Calcium channel blockers 

Calcium channel blockers have shown conflicting results in clinical trials.
Nisoldipine and sublingual nifedipine reduced ischemic burden and improved anginal symptoms while diltazem and verapamil failed to show any beneficial effects.
Therefore, calcium antagonists are more helpful in addition to a beta blocker when symptoms are inadequately controlled and rarely used as first-line therapy.

Nitrates   

Despite their beneficial effects in patients with coronary artery disease, nitrates have disappointing efficacy. While no benefit was shown with oral isosorbide mononitrate, sublingual nitrates was found to be effective only in 42% of patients. Some studies also showed that sublingual nitrate therapy fails to improve their exercise tolerance (20). Thus, there is a controversy about the role of nitrate therapy.   

Newer antianginal drugs

Nicorandil is a potassium channel activator which has arterial vasodilator properties. Intravenous nicorandil administration during thallium myocardial perfusion scan was shown to lead to a significant improvement in both the extent and severity of the perfusion score in patients with angina and nearly normal coronary angiogram (21). In another randomised controlled study, 2-week therapy of nicorandil in patients with microvascular angina caused a significant improvement in exercise-induced myocardial ischemia when compared to the placebo arm (22). Thus, there is a potential effect of nicorandil for the treatment of patients with primary stable MVA, but the data on its efficacy on this syndrome is limited and warrant further studies.

Trimetazidine is a 3-ketoacyl coenzyme A thiolase inhibitor which was shown to inhibit oxidative phosphorylation, decreases FFA oxidation and increases glucose utilisation and ATP production, thereby limiting generation and extracellular release of adenosine (23). Two small-sized studies investigating the effects of trimetazidine in patients with exercise induced ischemia and normal coronary arteries have shown that treatment with trimetazidine increased exercise capacity and decreased anginal episodes (24,25). Although, trimetazidine may have favorable effects in patients with primary stable MVA, further studies are needed.

Ivabradine is a specific If channel inhibitor which acts through direct inhibition of sinoatrial node activity. In a recent study, a four week treatment with ivabradine in addition to the usual antianginal therapy improved symptoms in patient with microvascular angina without affecting coronary flow reserve and endothelial function (26). These results suggest a clinical benefit of ivabradine independently of any beneficial effect on coronary microvascular function.  

Ranolazine is a relatively new molecule for treatment of angina which inhibits late sodium current and in this way, improves left ventricular diastolic function. In one study, a four week treatment with ranolazine was shown to improve anginal symptoms and myocardial ishemia in women with microvascular angina (27). In another study, a four week treatment with ranolazine in addition to usual antianginal therapy improved symptoms in patients with microvascular angina without effecting coronary flow reserve and endothelial function. Although the mechanism is not clear, ranolazine seems to have beneficial effects in patients with primary stable MVA. 

IV - Drugs and procedures related to pain perception

Abnormal pain processing and increased pain perception has been proposed as a pathogenic mechanism underlying refractory MVA. Therefore, drugs interfering with mechanisms related to pain processing and perception have been another option for the treatment of primary stable MVA.

Xanthine derivatives

Adenosine is one of the major mediators of cardiac pain and its increased release has been suggested to be involved in enhanced pain perception of patients with MVA. Xanthine derivatives (aminophylline) have antialgogenic effects related to adenosine receptor blockade. A three week treatment with oral aminophylline was shown to have favourable effect on exercise-induced chest pain thresholds. Aminphylline was also shown to have beneficial effects in MVA patients related to its capacity to favor coronary blood flow redistribution through ischemic areas (28).    

Imipramine

Imipramine is one of the most widely used antidepressants and its antidepressant effect is based on serotonin and noradrenaline uptake inhibition. It is also a pure visceral pain inhibitor and therefore can be used to treat refractory cases of MVA. Studies have shown that imipramine improved the symptoms of patients with chest pain and normal coronary angiograms, possibly through a visceral analgesic effect (29). Thus, low dose imipramine may be a choice in refractory MVA patients, but its significant side effects should be considered. 

Spinal cord stimulation

Spinal cord stimulation has been used in patients with refractory MVA. Spinal cord stimulation led to a significant reduction in chest pain and improved quality of life in patients resistant to all other treatment. Electrical neuromodulation devices, such as the transcutaneous electrical nerve stimulation machine, have found to be moderately successful in the treatment of CSX. The exact mechanismis of effect is not clear but suggested hypothesis includes direct effect of spinal cord stimulation on coronary microvasculature tone leading to increased coronary blood flow and normalisation of abnormal cortical pain processing (30,31). Complications related to the procedure include epidural abscess formation, bleeding, and neurological damage. It is significantly more expensive than conventional therapies, but can be considered to control symptoms and reduce hospitalisations multidrug resistant patients.

V - Current ESC guidelines

Current ESC guidelines (stable coronary artery disease) recommends beta blockers in addition to secondary prevention medication including aspirin and statins as first line therapy. Calcium channel blockers are recommended if beta blockers are insufficient or untolerated in these patients (32). 

Conclusions

Primary stable MVA defines a group of patients with stable angina pectoris, positive stress test results and angiographically normal coronary arteries.
This is a heterogeneous entity and multiple pathophysiological mechanisms are proposed.
Patients usually suffer from debilitating symptoms that are always resistant to conventional drug therapy. Prognosis of these patients is not as benign as previously thought.
Even though drugs can help alleviate symptoms, many patients still have refractory symptoms and treatment of these patients remains challenging.