Physiology and pathology of coronary microcirculation

The heart is a unique organ in many respects since its activity is mandatory to sustain life. The heart’s circulatory system and coronary flow regulation are highly adapted to the vital role of the heart in sustaining life and to everyday physiological challenges.

Understanding coronary physiology is key for treating patients with ischemic heart disease in general, and patients with acute ST elevation myocardial infarction (STEMI) specifically. Coronary flow is regulated by myocardial oxygen consumption and can be increased by four-fold in healthy individuals. The ability to increase coronary flow is referred to as coronary flow reserve. Increased coronary flow is required for increased oxygen supply to the myocardium, as each molecule of hemoglobin that enters the coronary circulation delivers all the carried oxygen during its pass through the myocardium. Thus, only increased flow can provide more oxygen to the heart muscle. Blood flow in the coronary circulation is determined by intramyocardial resistance arteries. Vasodilation of these arteries increases coronary flow, which leads to some degree of vasodilation of the epicardial coronary arteries. In STEMI, all these physiological mechanisms are disrupted. For more details regarding physiology of the coronary system see references^1-5.

The last five decades have witnessed the advent of coronary angiography and physiological measurements of coronary flow in catheterization and experimental laboratories. These have contributed substantial knowledge regarding how myocytes are nourished by the coronary system without disrupting myocardial contraction. While the epicardial coronary arteries, which are demonstrated during coronary angiography, can be regarded as conductance vessels, the resistance vessels that determine blood distribution and flow rate cannot be demonstrated using contrast media. The diameter of these arteries is in the range of 30-500 microns. The endothelial cells that cover the luminal surface of all blood vessels, and the smooth muscle cells that constitute the media layer of blood vessels must operate in synchrony to provide the physiological challenges of normal heart function. Resistance arteries that penetrate the left and right ventricular wall are squeezed during systole; hence, most myocardial blood flow occurs during diastole. The driving force for coronary flow is the gradient of pressures during diastole, between the aorta and the right atrium, which drains most of the coronary flow. Nutrients and gas are exchanged between coronary blood and heart tissue, in the capillaries that connect the arterial and venous system^1,2. Each myocyte is in direct contact with several capillaries, thus securing continuous and sufficient supply of oxygen and nutrients^1,2.

While atherosclerotic plaques are the hallmark of atherosclerosis in the epicardial coronary arteries, dysfunction of microcirculation in the heart, namely malfunctioning resistance arteries and capillaries, plays a major role in chronic syndromes of atherosclerotic heart disease, and even more so in acute coronary syndrome.  Measurement of microvascular resistance is based on thermodilution^6-8. Temperature measurements are taken from the ostium of the coronary artery and the distal coronary artery. These are performed after pharmacological vasodilation is induced by intra-coronary injection of adenosine or papaverine. Pressure and temperature are measured simultaneously in the proximal and distal coronary artery using a pressure wire; the procedure requires only a few minutes. Microcirculatory resistance is calculated using Ohm’s law V=IR, in which V equals the pressure gradient between the distal coronary artery and the pressure in the venous system that drains the coronary flow. Coronary flow is measured using thermodilution and is denoted as I in the equation, and R is the resistance. The index of microcirculatory resistance (IMR) can be calculated after measuring the index distal coronary pressure and index coronary artery flow (the venous pressure is relatively low and considered to be zero), using the equation IMR=index distal coronary artery pressure/index coronary artery flow. Several technical issues must be considered in measuring IMR, but these issues are beyond the scope of this document. More details on measuring IMR can be found in references (6-12). Normal IMR is defined as IMR<20 units. IMR>25 units is considered abnormally high and an indication of disturbances to coronary flow. Continuous coronary resistance is also possible and normal values are defined as <450 woods units^12-14.

A second major method to measure coronary microcirculation function is by cardiac magnetic resonance. Contrast echocardiography, Doppler echo, CT, and PET are also currently used to assess microcirculation in the heart¹⁵.

For many years, the driver-regulator of arterial vasodilation in the myocardium was unknown. An oxygen sensor element was recently identified in smooth muscle cells of coronary resistance arteries¹⁶. When oxygen consumption exceeds oxygen supply, reduced myocardial oxygen tension leads to vascular dilation and increased coronary flow. Endothelial cells in the microcirculation and epicardial coronary have flow sensing elements¹⁷. With increased flow following dilation of resistance arteries, these cells secrete nitric oxide, which enhances vasodilation and increases coronary flow.

The importance of coronary microcirculation in STEMI cannot be understated. Ample evidence indicates that the return to normal of microvascular flow after myocardial infarction is an excellent predictor of short- and long-term prognosis and of left ventricular recovery. Patients with STEMI who have disturbed microcirculation (increased resistance) after angioplasty develop late complications, mostly heart failure, at higher rates than do patients with STEMI with functioning microcirculation (normal resistance) after angioplasty^18-22.

There is a clear relationship between the time between onset pf symptoms and revascularization to the short- and long-term outcome of STEMI and many patients who arrive late to the catheterization laboratory after the onset of STEMI symptoms develop massive myocardial loss. A minority of patients who arrive early may also suffer from massive myocardial loss. These two groups of patients usually present with TIMI flow grade 0 or 1 and in many instances, flow after stent implantation is TIMI 2 or lower^23,24. Several explanations are possible for this phenomenon, which is related to the pathophysiology of STEMI^25-27. First, embolization of downstream microcirculation with micro thrombi and microscopic debris from the ruptured plaque is integral to the STEMI syndrome. Notably, embolization can occur several hours or days before onset of STEMI symptoms. Second, the microcirculation responds to vasospastic materials that are released by the thrombus; the prolonged spasm results in very high resistance to flow and possibly damages both endothelial and smooth muscle cells. Third, myocardial edema compresses microcirculation and prevents flow through microcirculation. In addition to the three mechanisms delineated above, the role of reperfusion injury in irreversible myocardial damage has been investigated over many years, and optimal clinical practice is yet to be determined.

Multiple pharmacological interventions are advocated to alleviate microcirculatory dysfunction in patients with STEMI²⁸, among them, intracoronary adenosine and nitroglycerine injection; however, their effects are usually short term. Heparin, anti-platelet aggregation drugs, and thrombolytic therapy also contribute to normalization of microcirculation in patients with STEMI, but these cannot be effective in blood vessels with no sustained flow, as in the event of STEMI^28-29.

Devices to treat patients with STEMI are directed to unload the left ventricle and reduce afterload, and hence reduce myocardial oxygen consumption, to aspirate epicardial coronary thrombus^30,31. However, in large scale studies, these devices were not shown so far to have a beneficial effect on prognosis.

Currently, the only device directed at microcirculatory perfusion is the Pressure-controlled intermittent Coronary Sinus Occlusion (PiCSO) system, developed by Miracor, a company based in Belgium^32-36. This device explores the novel concept espoused by Prof. Mohl from the University of Vienna, Austria. Accordingly, a balloon catheter is placed in the coronary sinus of patients with anterior STEMI; the balloon is periodically inflated and the coronary sinus thereby intermittently occluded. Prof. Mohl showed that this system can improve coronary microcirculatory perfusion and achieve myocardial salvage.

The PiCSO therapy has been explored in multiple animal models and in several human trials and received CE mark for its use in patients with anterior STEMI. PiCSO therapy is started after restoration of flow in the epicardial artery and during stenting. The PiCSO procedure therefore does not interfere with the intervention in the epicardial coronary artery^31-33. The mechanism of action involves three basic consequences of intermittently occluding the coronary sinus:

1. The pressure in the coronary microcirculation is increased and the size of the small arteries and capillaries is enlarged. Larger size enables clearance of occluding thrombi and debris, and results in better flow during PiCSO balloon deflation.
2. The increased coronary sinus pressure leads to redistribution of coronary flow, with recruitment of collaterals and improved myocardial perfusion. In anterior STEMI, the protocol requires a 20-60-minutes of PiCSO.
3. In addition to the mechanistic effects, recent studies showed that the PiCSO treatment leads to the release of several cytokines and small RNAs that are associated with myocardial regeneration.

Currently, a large-scale, multicenter, multination, randomized study of the use of PiCSO in patients with anterior STEMI presenting with TIMI 0-1 flow is ongoing. The primary endpoint is infarct size measured by cardiac MRI at 5 days after reperfusion.