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Coronary Microcirculation: Anatomy and
Pathophysiology; Implications to Contrast
Echo Perfusion Imaging

Eduardo M. Escudero, MD

Physiology and Biophysics and Magister of Ultrasound in Cardiology,
School of Medicine, Universidad Nacional de la Plata, La Plata, Argentina

    Although acute and chronic ischemic syndromes are commonly due to coronary flow limiting atherosclerotic plaques in epicardial coronary arteries, 10 to 20% of patients undergoing cardiac catheterization are found to have normal coronary angiograms (Figure 1).

Figure 1: 10 to 20% of patients with ischemic syndromes undergoing cardiac catheterization are found to have normal coronary angiograms.

   Thus many investigators since 1960s have speculated that disease or dysfunction of the coronary microcirculation may be responsible for angina-like chest pain symptoms or abnormal test results.

   In recent years our understanding of the coronary physiology and principally of the coronary microcirculation has advanced substantially, providing new ways to investigate abnormalities of myocardial perfusion, an area of inquiry that until recently has been limited to examination of coronary pressure-flow relationships.

   However the investigation of coronary microcirculatory function entails several difficulties that are not found in other microcirculatory beds.

   There are differents experimental, in-vitro and in- vivo, methodologies that has been used to study the coronary microcirculation.

   Radionuclear studies, angiography studies and more recently myocardial opacification by injection of an ultrasound contrast agent has been proposed to study human myocardial perfusion.

   The coronary circulation can be thought of as a system of interconnecting pathways with conduit arteries, distribution vessels (arterioles), exchanged vessels (capillaries) and reception vessels (venules and veins) with two anatomical compartment: conduit (epicardial arteries) and mixing chambers (microcirculation) (Figure 2 and 3).

Figure 2: Schematic of coronary flow system. Coronary circulation consisted of interconnecting pathways with conduit arteries, distribution vessels (arterioles), exchanged vessels (capillaries) and reception vessels (venules and veins).

Figure 3: Schematic representation of anatomical and physical analogues of coronary circulation. Top panels: anatomic system composed of the epicardial coronary arteries and the myocardial microcirculation. Bottom panels: physical analogues that simulate the flow and distribution volume behavior of the respective anatomic compartments- a rigid conduit and a well-stirred mixing chamber.

   Although cardiologists are very familiar with the morphology of conduit epicardial coronary vessels, they are not as conversant with the coronary microcirculation, formed by vessels with < 300 microns in diameter.

   Anatomically and functionally distinct categories of myocardial vessels segregated in discrete areas have called vascular microdomains because they are reminiscent of the protein microdomains that provide for specialization of functions.

   In the pig, with similar coronary morphology of humans without coronary artery disease, the entire coronary system (epicardial conduit arteries, arterioles, capillaries, venules and veins) contains 12 ml of blood · 100g LV mass -1 . This volume is distributed in the arterial, capillaries and venous compartments as 3.5,3.8 and 4.9 ml · 100g LV mass -1 respectively.

    The blood present in the LV myocardial vessels (myocardial blood volume) is 4.5 ml· 100g LV mass -1 and resides primarily (> 90%) in microvessels (principally capillaries) (Figure 4).

Figure 4: Blood volume distribution in pig's coronary circulation.

   Mechanoenergetic interaction between coronary vessels and myocardium is tightly coupled because the high oxygen consumption and flow rate of the myocardium.

   Such interaction is not uniform transmurally: the mechanical effect of cardiac contraction on the myocardial vessels is greater in deeper myocardial layers than in the superficial myocardial layers despite its greater metabolic demand in deeper myocardium.

   Therefore, in order to match the oxygen supply to myocardial metabolic requirement, locally and highly organized vascular regulations are required (Figure 5).

Figure 5: To match the oxygen supply to myocardial metabolic requirement, locally and highly organized vascular regulations are required.

   The coronary vessels are expected not only to connect the entrance of the coronary artery with the capillary vessels near each cardiac myocyte by increasing the number of vascular segments, but also to provide integrated regulatory systems so as to produce the required flow rate at each path in the vascular tree.

   This integrative mechanisms is founded in multiple signals (physical, nervous, humoral, molecular) that are involved linking between longitudinal and parallel vascular segments and also between coronary vessels and the myocytes.
(Figure 6)

Figure 6: Multiple signals that are involved to link between longitudinal and parallel vascular segments and also between coronary vessels and the myocytes.

   Traditionally, the close matching of coronary blood flow to myocardial oxygen consumption has been attributed to metabolic mechanisms, although the precise mediators have eluded discovery.

   Myocardial oxygen delivery occurs at the capillary level. When myocardial oxygen consumption increases, the coronary circulation compensates by increasing myocardial blood flow through dilatation of coronary microvessels.

   Recent studies indicate that myogenic and endothelial mechanisms strongly influence diameters of coronary microvessels through the transudation of intravascular pressure (stretch) and flow (shear stress) (Figure 7).

Figure 7: Schematic representation of myogenic and endothelial mechanisms influencing diameters of coronary microvessels.

   Myogenic dilatation and constriction are potentially autoregulatory and a fall in arteriolar pressure, during either coronary occlusion or metabolic vasodilatation would be expected to reduce coronary vascular resistance through this mechanisms.

   Longitudinal gradients for pressure - and flow - dependent responses can be integrated into a hypothetical system that could match coronary blood flow to myocardial metabolic demands:
   1: the smallest arterioles (< 30 microns), apparently the most sensitive to metabolic stimuli, dilate during increase metabolic demand, lowering microvascular resistance and increasing myocardial perfusion.
   2: as the upstream arteriolar pressure falls, myogenic dilatation of slightly larger arterioles (30 a 60 microns) as consequence of the decrease of tensile-stress, with a further decrease in resistance occur.
   3: increased flow in large arterioles (120 a 150 microns) upstream stimulates flow dependent dilatation and further reducing network resistance (Figure 8).

Figure 8: Longitudinal integration of regulation mechanisms into a hypothetical system that could match coronary blood flow to myocardial metabolic demands:

    Elucidating the contributions of these microvascular mechanisms to metabolic hyperemia is imperative for understanding coronary vascular physiology.

   Methodology and measurements in the coronary microcirculation

   The investigation of coronary microcirculation and consecutively the understanding of myocardial perfusion entails several difficulties as the notably gross movement attributed to cardiac contraction.

   In vitro methodologies has been used to avoid this limitation. Microvessels of interest can be dissected form any region of the heart and can be cannulated and perfused at varied pressure and flow. Isolated vessels have been used to measure many vasomotor response of coronary arterioles and muscular venules. The newest methods offer the promise of isolating endothelial cells derived from different segments of the microcirculation.

    Microvessels on the epicardial surface of the beating heart have been studied with a microscope-video system that freeze the movement of the vessels using stroboscopic epi-illumination synchronized with cardiac cycle. Recently a new method has been developed for directly viewing subendocardial and intramural vessels in beating heart (Figure 9 and 10).

Figure 9: Portable needle- probe CCD video-microscope approaching subendocardial vessels. The needle probe is enclosed in a silatic double-lumen sheath. A doughnut-shaped balloon on the tip of the sheath avoids direct compression of the vessels by the needle tip. To obtain a clear image of the blood between the tip of the needle-probe and endocardial surface, the inside of the doughnut was flushed away with buffer solution.

Figure 10: Phasic nature of subendocardial arteriole. Left: subendocardial blood-flow visualization using microspheres. Right: phasic blood-flow pattern (top) and diameter chane (bottom) of subendocardial arteriole.

   Using different tracers injected directly in the coronary artery, the aortic root, the left atrial or in a periferical vein could be used to evaluate several aspects of myocardial perfusion.

   The images of the myocardium can be obtained using radioactive microespheres (Figure 11 and 12), radiopaque dyes, radionucleids, bubbles, paramagnetic tracers and analyzing its myocardial distribution with Xray, gamma counter, magnetic resonator, ultrafast cine computed topography and ultrasound.

Figure 11: Diagram showing the experimental design to study myocardial flow distribution in a perfused, metabolically supported canine heart preparation with tracer microspheres. RV: right ventricle; LV: Left ventricle; A: aorta; RF reference flow; PT pressure transducer; P: pump; IM: injection of microspheres; DD: donor dog; CF: coronary blood flow.

Figure 12: Left: pattern followed in the processing of the hearts. Groups of rectangles represent the transmural samples and their divisions (subendocardial, midmyocardial and subepicardial). Right: average myocardial flow distribution in empty beating heart. Red bar: subendocardial blood flow. Blue bar: subepicardial blood flow.

   Myocardial contrast echocardiography (MCE) is a technique capable of providing information on the anatomy and function of the microcirculation in vivo. It employs an intravascular tracers with rheologic properties similar to red blood cells. This tracers freely flows into the coronary microcirculation, without ever leaving the vascular compartment, and it is detectable by ultrasound procedures during its passage into the microvessels.

   The spatial distribution of this effect within the ventricular walls and the change in the intensity of myocardial contrast over time constitute the basis for the study of myocardial perfusion by contrast echo (Figure 13).

Figure 13: Microbubbles distribution within the ventricular walls and the change in the intensity of myocardial contrast over time constitute the basis for the study of myocardial perfusion by contrast echo.

   The myocardial contrast echo effect appears to depend on several physical (properties of microbubbles, doses, bolus or continuous infusion, electronic signal processing) and biologic factors (coronary blood flow, intramyocardial blood volume and coronary blood pressure) some of which are not completely understood.

   Thus despite the useful information provided by MCE and the growing interest in the field, the meaning or regional contrast intensity remains elusive and potential clinical applications of this technique remain uncertain.

   Over the past few years several studies have been performed with the aim of quantifying coronary blood flow by contrast echo. These studies were performed in vitro and experimental models of the coronary circulation as well in humans. Although shedding light on specific aspects of myocardial contrast, such studies have not proved a comprehensive understanding of this phenomenon and the relative rol of coronary blood flow and intramyocardial blood volume or other factors in determing contrast effect.

   As ultrasound can cause microbubble destruction, if are administrated as continuous infusion, their destruction within the myocardium and measurement of their myocardial reappearance rate at steady state will provide a measure of mean myocardial microbbuble velocity. Conversely measurement of their myocardial concentration at steady state will provide an assessment of microvascular cross-sectional area. Myocardial blood flow can then calculated from the product of the two using contrast echo (Figure 14).

Figure 14: Quantification of myocardial perfusion in dogs. Right: relation between pulsing interval of echo-images captures and video intensity in an region of interest. Left: Relation between radiolabeled microsphere-derived myocardial blood-flow (x axis) and myocardial blood flow derived on contrast echo (y axis).

Despite the presence of coronary stenosis, resting myocardial blood flow is normal in the majority of stable patients with coronary artery disease (CAD) who have not had previous myocardial infarction. Blood flow is maintained distal to a stenosis by autoregulation.

   As the severity increase, arterioles in microcirculation (< 300 microns) distal to obstruction dilate in order to maintain resting blood flow as close to normal as possible. When autoregulation is exhausted (usually at > 85% luminal narrowing) resting flow decline, particularly if collateral flow is low or absent.

   For de majority of patient with coronary artery disease, with < 85% luminal diameter narrowing of the coronary arteries, resting perfusion is normal and the detection of CAD depends of unmasking abnormal myocardial blood flow reserve within region supplied by stenotic vessels. Since microvessels in these regions have already used some of their reserve, blood flow cannot increase during stress to the same extent as in other regions with greater microvascular reserve. The resulting perfusion mismatch can be detected on myocardial perfusion imaging which forms the physiological basis for many imaging modalities for the detection of CAD.

The Figure 15 shows an image from an contrast- echo study in a patient with total obstruction of Cx and a clear defect of perfusion at left ventricular apex and lateral wall.

Figure 15: Myocardial opacification in a patient with recen myocardial infarction and occluded Cx. Myocardial perfusion defects can be seen at the lateral apex and middle lateral wall..

   Although acute and chronic coronary syndrome are commonly due to coronary flow- limiting atherosclerotic plaque in epicardial coronary arteries, the participation of coronary microcirculation in the pathophysiology of myocardial ischemia is important.

   During the past decade, significant anatomical, functional and molecular biological observations have been made regarding coronary microcirculation. On the basis of these multidisciplinary investigations, integrated physiology of the coronary microcirculation has emerged as a new area.

   Future research needs to encompass both basic and clinical investigations. There is a great need for inquiry into basic mechanisms at a variety of scientific levels, from integrative techniques to decipher complexities of gene expression at all levels of the coronary vasculature. It cannot be emphasized strongly enough that many important fundamental mechanisms, such metabolic hyperemia, are still poor understood.

   Conversely clinically oriented investigations will be indispensable to understanding the role of microcirculation in human disease and determining whether is a link between coronary microvascular dysfunction and inducible myocardial ischemia.
There is an strong need for further refinement of non invasive methodologies, such as PET, MRI, contrast-echo. These techniques with higher resolution and greater sensitivity will be central to documenting clinical consequence of coronary microvascular pathology conditions and establishing the relationship between heterogeneity of flow and metabolism in humans.

   Finally it is necessary emphasize that investigations should incorporate the many technological advances of molecular biology in conjunction with physiological measurements to best elucidate the regulation or the coronary microcirculation in health and disease, in this scenario the echo-contrast is a very interesting tool and it is possible than in the future will become the leading for assessing myocardial perfusion in humans.


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