|Year : 2016 | Volume
| Issue : 1 | Page : 18-24
Management options for coronary microvascular dysfunction: Present status and future perspectives
Sita Ram Mittal MD, DM
Department of Cardiology, Mittal Hospital and Research Centre, Ajmer, Rajasthan, India
|Date of Web Publication||14-Jun-2016|
Sita Ram Mittal
11/101, Brahmpuri, Kutchery Road, Ajmer - 305 001, Rajasthan
Source of Support: None, Conflict of Interest: None
Coronary micro vessels are not visible on coronary angiography. These include prearterioles, arterioles, and capillaries. Significant number of patients of angina have coronary microvascular dysfunction alone or in combination with stenosis and/or spasm of epicardial coronary arteries. Its management is challenging. Several different therapeutic options have been tried with variable success. The present review provides overview of the available evidence with various therapeutic modalities for the treatment of microvascular angina.
Keywords: Angina, coronary, coronary artery disease, ischemic heart disease, microcirculation
|How to cite this article:|
Mittal SR. Management options for coronary microvascular dysfunction: Present status and future perspectives. J Clin Prev Cardiol 2016;5:18-24
|How to cite this URL:|
Mittal SR. Management options for coronary microvascular dysfunction: Present status and future perspectives. J Clin Prev Cardiol [serial online] 2016 [cited 2021 Aug 2];5:18-24. Available from: https://www.jcpconline.org/text.asp?2016/5/1/18/184011
| Introduction|| |
Initially, the terms "Syndrome X" and "microvascular angina" were used interchangingly. Now, it is clear that "Syndrome X" includes all patients of angina with normal coronaries on angiography. "Microvascular angina" is a specific subset of patients where coronary microvascular dysfunction is demonstrated. Coronary micro vessels include prearterioles, arterioles, and capillaries. These vessels are not directly visible on coronary angiography or on other modes of scanning. Diagnosis is based on the combination of classical angina, evidence of myocardial ischemia on electrocardiogram or stress test, normal coronary angiogram, exclusion of spasm of epicardial coronary arteries, and coronary flow reserve 2.5 or less. Because of interchanging use of these terms, there is a significant overlap in literature regarding management. It is not clear if management options found useful in "Syndrome X" will be equally effective in "microvascular angina." Present review provides an overview of literature. We have specifically used the term used by various authors.
| Life Style Modification|| |
These are beneficial because of the following:
- Many of the known risk factors associated with coronary microvascular dysfunction are similar to the risk factors for obstructive epicardial coronary artery disease.
- Coronary microvascular dysfunction is associated with impaired flow mediated vasodilation of peripheral vessels, progressive involvement of epicardial coronaries, and higher incidence of stroke on follow-up.
| Heart Rate Reducing Drugs|| |
Betablockers reduce heart rate, cardiac contractility, and blood pressure, thus reducing myocardial oxygen demand. These drugs are, therefore, also effective in coronary microvascular dysfunction. Betablockers are more effective in patients with increased adrenergic drive as manifested by resting tachycardia, disproportionate tachycardia at low work load, coexisting anxiety, and hypersensitive heart.
It reduces the rate of sinoatrial node by selectively inhibiting if current. It is useful in patients where beta blockers are contraindicated or not tolerated. Skalidis et al.  observed significant improvement in hyperemic coronary flow velocity and coronary flow reserve in nonculprit vessels in patients with stable coronary artery disease indicating improved microvascular function. Villano et al.  observed that ivabradine improved the quality of life when given in addition to standard anti-ischemic therapy to patients of microvascular angina. However, there was no significant effect on time to 1 mm ST segment depression, exercise duration, coronary microvascular function, and flow mediated vasodilation.
| Drugs that Reduce Coronary Microvascular Tone|| |
These agents prevent microvascular spasm and are the first choice in microvascular spastic angina. They also reduce resting tone of microvasculature and therefore, may benefit some patients of stable microvascular angina, especially those with additional rest angina or variable threshold effort angina.
Calcium channel blockers
In coronary microvasculature, they act at the level of prearterioles. Verapamil and diltiazem also reduce heart rate and can be used in patients intolerant to beta blockers. Results of previous trials are controversial probably due to differences in patient selection, drug evaluated, and method of evaluation. ,
Sublingual nitrates are effective in relieving angina only in 40-50% of patients of syndrome X. It is attributed to the lack of any significant effect of nitric oxide on coronary microcirculation except at the level of prearterioles. Long acting nitrates have not been found to be effective in reducing episodes of angina in patients of syndrome X.  Sublingual nitrates do not have any significant effect on exercise stress test in patients of microvascular angina.  On the contrary, there may be a significant worsening in exercise duration and time to 1 mm ST segment depression. This is likely to happen in patients with fixed (rather than dynamic) narrowing of coronary microcirculation. Failure of dilation of diseased coronary microvessels with dilation of normal vessels resulting in 'steal' phenomenon could contribute to deterioration.
It opens ATP sensitive potassium channels thereby dilating peripheral and coronary resistance arterioles (part of microcirculation), unlike nitrates which dilate only epicardial coronaries. It also possesses a nitrate moiety and therefore also dilates systemic veins and epicardial coronary arteries. In one small short-term study, 5 mg given 3 times a day for 2 weeks moderately improved exercise induced ischemia in nine out of thirteen patients with microvascular angina (coronary flow reserve <3).  Nicorandil treatment has been shown to significantly decrease incidence of angiographical "no reflow" after reperfusion in patients with acute myocardial infarction and incidence of "slow flow" phenomenon following percutaneous coronary intervention.  "Slow flow" and "no reflow" are angiographic signs of coronary microvascular dysfunction. Sulfonylurea's eliminate the effect of nicorandil by inhibiting the opening of K-ATP channels and should not be co-administered.
Phosphodiesterase - five inhibitors
About 100 mg of sildenafil has been shown to significantly increase coronary flow reserve in women with coronary microvascular dysfunction.  Co-administration with nitrates can produce significant hypotension.
Blocking of alpha receptors causes vasodilation and fall in systemic arterial pressure. It was expected that these drugs will reduce the tone of coronary microvasculature. Results of studies in patients of syndrome X have been disappointing. 
Niacin has direct effects on vessel wall at the level of endothelium and vascular smooth muscle. Prolonged release niacin (up titrated to a maximum dose of 1500 mg/day given for 12 weeks) improved peripheral small artery vasodilatory function and compliance in statin treated type 2 diabetic patients with endothelial dysfunction.  It has not been evaluated in coronary microvascular dysfunction.
It is a precursor of nitric oxide. In one study, 2 mg given thrice daily for 4 weeks improved endothelial function and angina symptoms in patients without obstructive coronary artery disease. 
It is a rhokinase inhibitor. It inhibits calcium influx in vascular smooth muscle cells thereby reducing myosin light chain cross linking. Intracoronary fasudil has been shown to prevent acetylcholine-induced microvascular spasm.  It is not clear if oral therapy will be effective in angina due to coronary microvascular spasm.
It is a direct donor of nitric oxide. It strongly dilates the resistance arterioles and plays a significant role in blood flow through coronary microvasculature. It is effective in the management of coronary microvascular dysfunction following percutaneous coronary intervention. 
| Drugs with Positive Effect on Vascular Remodeling|| |
Angiotensin converting enzyme inhibitors
Long-term therapy with perindopril has been shown to cause structural repair of coronary arterioles as shown by transvenous endomyocardial biopsies. 
Angiotensin receptor blockers
Losartan and telmesartan have been shown to have protective effect against vascular remodeling in stroke prone spontaneously hypertensive rats. Losartan has been shown to increase microvascular recruitment in muscles in rat model.  There are no studies on coronary microcirculation in humans.
Mineralocorticoid receptor blockers
Eplerinone has been shown to reduce resistance artery stiffness by decreasing the collagen to elastin ratio. Bavry et al.  did not find any improvement in coronary endothelial microvascular function among women with signs and symptoms of ischemia in the setting of nonobstructive coronary artery disease. In another study, addition of 25 mg of spironolactone to 20 mg/day of enalapril improved coronary microvascular function in individuals with type 2 diabetes. 
Edothelin receptor antagonists
Reriani et al.  evaluated effect of endothelin A-receptor antagonist - alrasentan on coronary endothelial function in patients with early atherosclerosis. Coronary blood flow response to acetylcholine significantly increased after 6 months.
Phosphodiesterase - five-inhibitors
Tadalafil has been shown to improve peripheral microcirculation in Raynaud's phenomenon. It has also been shown to modulate microvascular recruitment in diabetic postmenopausal females.  It may be beneficial in coronary microvascular dysfunction.
| Drugs Improving Hemorheology|| |
It is a selective phosphodiesterase-3 (PDE-3) inhibitor. By inhibiting PDE-3, it inhibits the breakdown of intracellular cyclic adenosine monophosphate (cAMP). Increased concentration of cAMP in vascular smooth muscle promotes vasodilation. It also inhibits vascular smooth muscle spasm. About 100 mg BD has been shown to be effective in vasospastic angina not controlled by calcium channel blockers and/or nitrates.  It has not been evaluated in patients with coronary microvascular dysfunction. It is expected to be beneficial in coronary microvascular spasm.
It lowers blood viscosity and improves erythrocyte flexibility. It is expected to improve microcirculation in patients with fixed narrowing of micro vessels.
Oral anticoagulants, low molecular weight heparins, factor Xa inhibitors (e.g., fondaparinux) can improve flow through narrowed micro vessels.
Clopidogrel has antiatherosclerotic potential via its antioxidant and anti-inflammatory properties. It has been shown to improve microvascular endothelial function in subjects with stable coronary disease.  This effect is independent of effect on adenosine diphosphate-induced platelet reactivity. These drugs may be beneficial in patients of coronary microvascular dysfunction presenting with acute coronary syndrome.
| Drugs Acting at the Level of Myocytes|| |
It inhibits late sodium current associated with ischemia thereby inhibiting consequent calcium overload and resultant diastolic stiffness. Decreased diastolic stiffness decreases diastolic compression of intramural vessels resulting in increased late diastolic coronary flow. About 500-1000 mg BD improved angina in women with evidence of ischemia but no obstructive coronary artery disease.  Villano et al.  observed improvement in the quality of life, time to 1 mm ST segment depression, and exercise stress test duration by ranolazine (375 mg BD) in patients with microvascular angina. However, there was no effect on coronary microvascular function (response to adenosine and to cold pressor test) and on peripheral endothelial function (assessed by flow mediated dilatation). Tagliamonte et al.,  however, observed significant increase in coronary flow reserve following 8 weeks treatment with 500 mg BD of ranolazine. It is useful in patients of coronary microvascular dysfunction refractory to conventional antianginals.
It shifts the cardiac metabolism form fatty acid oxidation to glucose oxidation during ischemia. It is likely to provide symptomatic relief in coronary microvascular dysfunction. A small, placebo controlled, trial has shown improvement in time to 1 mm ST segment depression and total exercise time.  However, there was no significant reduction in exercise-induced ST segment depression.
| Method to Increase Diastolic Coronary Flow|| |
Enhanced external counter pulsation
Pneumatic stockings are placed on the patient's lower extremities. These are deflated during systole and inflated during diastole. The aim is to increase diastolic blood pressure and thus promote diastolic coronary flow. It has been found to be effective in treatment of syndrome X. 
| Modulation of Pain Perception|| |
Tricyclic antidepressants - e.g., imipramine, amitryptiline
These drugs inhibit visceral pain probably by inhibiting reuptake of serotonin and norepinephrine. Imipramine (50 mg/day for 5 weeks) reduced the episodes of chest pain in patients of syndrome X.  This dose was, however, associated with high incidence of side effects with the result that there was no improvement in overall quality of life.
Transcutaneous electric nerve stimulation
It is based on the concept that activity in touch fibers in the periphery can inhibit ongoing transmission of pain at the level of spinal cord. Low voltage electrical painless impulses are delivered through electrodes on the skin overlying area of angina. de Vries et al.  have observed reduction in pain and nitroglycerine consumption and increased exercise capacity and walking distance in patients with refractory chest pain and normal coronary arteries.
Spinal cord stimulation
Epidural space is punctured at the level of T6 and a quadripolar electrode is introduced and positioned at a level where neurostimulation produces paresthesia covering the area of radiation of angina. Stimulation of inhibitory neurones in the posterior horns of spinal cord is probably responsible for relief. Prospective follow-up of small number of patients of cardiac syndrome X showed significant sustained benefit in anginal status, exercise tolerance, and exercise-induced ST segment changes. 
| Impact of Management of Comorbidities on Microcirculation|| |
Lowering blood pressure to a normal level is necessary to improve coronary microvascular dysfunction. Keeping diastolic blood pressure to a higher level within normal range has the most beneficial effect. 
Angiotensin-converting enzyme inhibitors
These drugs have been shown to improve endothelial nitric oxide bioavailability, microvascular function, total exercise capacity, and exercise duration in patients with coronary microvascular dysfunction. 
Angiotensin II receptor blockers
Telmesartan and olmesartan have been shown to improve microcirculation among hypertensives.  Olmesartan is more potent in controlling hypertension and reducing inflammatory markers.
From microcirculation perspective, dual blockade is no more beneficial than a monotheraphy approach with either class of agents, especially given the increased risk of renal insufficiency, hyperkalemia, and hypotension.
Combination of aldosterone antagonists and angiotensin converting enzyme inhibitors has been shown to improve coronary endothelial function among women with coronary microvascular dysfunction. 
Proper control of diabetes reduces rate of cardiovascular events in patients with epicardial coronary artery disease. This should be equally true for coronary microvascular dysfunction.
Exerts anti-inflammatory effect, restores endothelial function, improves vasodilation, and improves fibrinolytic profile. It is not clear if these effects are independent of glucose lowering effect.
It has several intrinsic effects on microcirculation which are independent of the glucose lowering effect and are observed at doses below the doses used for management of hyperglycemia. Jadhav et al.  evaluated the effect of 8 weeks therapy with metformin (500 mg BD) in nondiabetic women with a prior history of normal coronary angiography. Maximal ST segment depression and chest pain incidence improved as compared to placebo recipients. Coronary microvascular functions were not evaluated.
Dyslipidemia/atherosclerosis/raised inflammatory markers
These improve endothelial function. They have been shown to increase exercise duration and time to >1 mm ST segment depression during stress test in patients of cardiac syndrome X. Combination of fluvastatin (40 mg/day) and diltiazem (90 mg/day) has been shown to have more pronounced effect than either drug alone.  Statins have been shown to increase coronary flow reserve in patients with slow coronary flow. Statins also have anti-inflammatory and antioxidant property and may be beneficial in patients with elevated C-reactive protein and other markers of inflammation.
It has been shown to improve endothelial function in statin treated type 2 diabetic patients. It may be beneficial in coronary microvascular dysfunction in diabetics with hypertriglyceridemia.
Chronic obstructive airway disease
Adenosine receptor blockers
Adenosine is a major mediator of cardiac pain. Its enhanced release from ischemic areas could contribute to increased pain sensation in microvascular angina. Xanthine derivatives; e.g., aminophylline, block adenosine-receptors. Acute (6 mg/kg given intravenously over 15 min) as well as chronic oral (325-350 mg BD) administration of aminophylline have been shown to improve angina and exercise capacity in patients of syndrome X.  However, there was no effect on peak exercise ST depression and frequency and duration of ST segment depression during Holter monitoring. Exact status in isolated coronary microvascular dysfunction without chronic obstructive airway disease is not clear.
| Other Therapies|| |
Estrogen replacement therapy in perimenopausal women
Various trials have revealed conflicting results. Most of these studies have used the combination of conjugated equine estrogen and medroxyprogesterone acetate, which is suspected to abolish the beneficial effects of estrogen on microcirculation. Knuuti et al.  observed that combination of estradiol (1 mg) and drospirenone (2 mg) for 6 weeks significantly increased myocardial perfusion reserve in postmenopausal women with angina pectoris.
N-3 polyunsaturated fatty acids
Four months treatment with long chain n-3 polyunsaturated fatty acid has been shown to improve ST segment depression on stress testing in patients with chest pain, ST segment depression on stress testing, and angiographically normal coronary arteries. 
| Therapies Expected to Promote Angiogenesis|| |
Stem cell therapy
It has significant potential  and needs evaluation in documented coronary microvascular dysfunction.
Extracorporeal shock wave myocardial revascularization
Low intensity special acoustic waves are given to the border of ischemic area under echocardiographic guidance. It is expected to trigger angiogenesis in viable myocardium. It has been shown to be safe and effective in management of refractory angina.  Randomized double blind, sham controlled trials are required to find role of this procedure in coronary microvascular dysfunction.
Proposed plan of management is shown in [Table 1].
|Table 1: Proposed scheme for selection of therapeutic options for management of coronary microvascular dysfunction |
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| Conclusion|| |
Management of coronary microvascular dysfunction is challenging. Several therapeutic options have been tried with variable success. Life style modification and management of risk factors and comorbidities is essential. Drugs can be selected depending on clinical presentation and expected etiopathogenesis [Table 1]. Stem cell therapy, gene therapy, and extracorporeal shock wave myocardial revascularization are under evaluation. Well designed, long-term trials enrolling adequate number of documented cases, and properly selected control group are likely to give more precise information.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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