Physiopathology of coronary microcirculation

Coronary microcirculatory is the main target of contrast echocardiography. Coronary flow is one of the parameters which influence the myocardial blood flow but not the only one. Therefore, the knowledge of microcirculatory physiopathology is required in order to analyze datas from contrast echo.     

Functional characteristics of the coronary microcirculation

For over 50 years, it has been recognized that coronary blood flow is precisely matched to cardiac metabolism. The interactions which govern this matching remain unknown. In the current review, 3 specific aspects of coronary flow regulation will be discussed: Specialization of function in different microvascular domains, influence of cardiac region on microvascular function and the interactions of vasoactive agents in control of coronary blood flow. Each level of the coronary microcirculation is affected by different physical and chemical forces within the heart. These forces place special demands on these vessels and are in turn met by specialized vasodilator responses, including metabolic and flow-mediated vasodilation. Perfusion of the heart is also profoundly affected by the region perfused. The endocardium is affected by forces, notably cardiac contraction, in a different manner than the epicardium. Thus, the microcirculation has specialized to meet these demands. Finally, the factors determining microvascular tone appear to be coordinated such that the loss of any individual dilator, such as nitric oxide, can be compensated for by the increased contribution of another, such as adenosine. This interplay may serve to protect the heart from ischemia during the early phases of coronary vascular disease when individual dilators may be impaired.     

Regulation of blood flow in the microcirculation

The regulation of blood flow has rich history of investigation and is exemplified in exercising skeletal muscle by a concerted interaction between striated muscle fibers and their microvascular supply. This review considers blood flow control in light of the regulation of capillary perfusion by and among terminal arterioles, the distribution of blood flow in arteriolar networks according to metabolic and hemodynamic feedback from active muscle fibers, and the balance between peak muscle blood flow and arterial blood pressure governed by sympathetic nerve activity. As metabolic demand increases,the locus of regulating oxygen delivery to muscle fibers "ascends" from terminal arterioles, through intermediate distributing arterioles, and into the proximal arterioles and feed arteries, which govern total flow into a muscle. At multiple levels, venules are positioned to provide feedback to nearby arterioles regarding the metabolic state of the tissue through the convection, production and diffusion of vasodilator stimuli. Electrical signals initiated on microvascular smooth muscle and endothelial cells can travel rapidly for millimeters through cell-to-cell conduction via gap junction channels, rapidly coordinating vasodilator responses that govern the distribution and magnitude of blood flow to active muscle fibers. Sympathetic constriction of proximal arterioles and feed arteries can restrict functional hyperemia while dilation prevails in distal arterioles to promote oxygen extraction. With vasomotor tone reflecting myogenic contraction of smooth muscle cells modulated by shear stress on the endothelium, the initiation of functional vasodilation and its modulation by sympathetic innervation dictate how and where blood flow is distributed in response to metabolic demand. A remarkable ensemble of signaling pathways underlies the integration of smooth muscle and endothelial cell function in microvascular networks. These pathways are being defined with refreshing new insight as novel approaches are applied to understanding the cellular and molecular mechanisms of blood flow control.     

Interaction of the coronary macro- and microcirculation

In the following the impact of epicardial vessels on flow regulation in downstream resistive arteries and, vice versa, the potential influence of coronary microvascular disease on upstream conduit arteries will be reviewed. There is ample evidence that coronary artery disease of epicardial vessels leads to microvascular dysfunction not only due to a flow limiting stenoses with an altered regulation of vessel tone in the intra- and poststenotic segments, but also via distal microembolization of atherosclerotic material derived from upstream plaques. On the other hand, patients with hypertensive microvascular disease frequently reveal a disturbed endothelium-dependent and -independent regulation of epicardial vessel tone, although angiographic appearance is regular. Most strikingly, it could be demonstrated that in these patients with microvascular disease the incidence of coronary artery disease of epicardial vessels is increased several-fold as compared to age-matched populations. These findings suggest that hypertensive microvascular disease independent from the direct effect of hypertension on epicardial vessel affects upstream conduit arteries. Therefore a thorough and careful follow up of hypertensive patients with initially normal coronary arteriograms but preexistent microvascular disease appears advisable.     

冠状动脉微循环的功能评价

冠状动脉(冠脉)微循环是指心脏微动脉和小静脉之间的血液循环,是心肌细胞与血液进行物质交换的重要场所.冠脉微循环的功能状态可以直接影响心脏功能和代谢,它对于心血管疾病的发生、发展、疗效及预后等具有重要影响,而心血管疾病本身也是造成或加重微循环结构和功能的障碍的因素[1].     

Extended-volume image-derived models of coronary microcirculation

Objective

Recent advances in tissue clearing and high-throughput imaging have enabled the acquisition of extended-volume microvasculature images at a submicron resolution. The objective of this study was to extract information from this type of images by integrating a sequence of 3D image processing steps on Terabyte scale datasets.

Methods

We acquired coronary microvasculature images throughout an entire short-axis slice of a 3-month-old Wistar–Kyoto rat heart. This dataset covered 13 × 10 × 0.6 mm at a resolution of 0.933 × 0.933 × 1.866 μm and occupied 700 Gigabytes of disk space. We used chunk-based image segmentation, combined with an efficient graph generation technique, to quantify the microvasculature in the large-scale images. Specifically, we focused on the microvasculature with a vessel diameter up to 15 μm.

Results

Morphological data for the complete short-axis ring were extracted within 16 h using this pipeline. From the analyses, we identified that microvessel lengths in the rat coronary microvasculature varied from 6 to 300 μm. However, their distribution was heavily skewed toward shorter lengths, with a mode of 16.5 μm. In contrast, vessel diameters ranged from 3 to 15 μm and had an approximately normal distribution of 6.5 ± 2 μm.

Conclusion

The tools and techniques from this study will serve other investigations into the microcirculation, and the wealth of data from this study will enable the analysis of biophysical mechanisms using computer models.     

冠状动脉微循环及评估方法简介

过去20年,研究者发现冠状动脉微循环功能障碍也是引起心肌缺血的原因之一,并且对于冠心病患者的远期预后存在影响。尽管无法直接通过影像学观察到冠状动脉微血管,但最新的有创及无创技术,可通过特定参数来反映冠状动脉微循环功能。这些技术包括通过导管检查获得的有创冠状动脉血流动力学参数,及无创的影像学检查,如磁共振、核素显像。尽管每项检查都有各自的优势及局限性,但通过这些检查让人们对冠状动脉微循环及整个冠状动脉体系的生理、病生理状态及调节有了更加深入的理解,并用于指导临床治疗。     

The effect of norepinephrine on the coronary microcirculation.

The role of the sympathetic nervous system in the regulation of large coronary artery tone has been well defined. Studies of adrenergic regulation of coronary-resistance vessels have largely been limited to indirect inferences based on flow measurement obtained in vivo. The purpose of the present study was to determine the effects of norepinephrine (NE) on the coronary microcirculation using direct in vitro approaches. Porcine coronary microvessels (80-200 microns in diameter) were pressurized in isolated organ chambers. Diameters were measured using a Halpern microvessel imaging apparatus. After preconstriction with leukotriene D4, NE caused complete relaxation. Relaxations to NE were inhibited by propranolol. Relaxations to NE were also inhibited by LY83583 (which depletes cGMP) and hemoglobin (which binds endothelium-derived relaxing factor, EDRF). NE caused minimal or no constriction in both preconstricted and nonpreconstricted microvessels even in the presence of hemoglobin and propranolol. In conclusion, NE predominantly dilates porcine coronary microvessels, both by beta-adrenoceptor activation and by stimulating release of EDRF. There is minimal alpha-adrenoceptor-mediated constriction of coronary microvessels.     

The functional morphology of the coronary microcirculation in the dog

Dog hearts were perfused in a Langendorff preparation with whole blood. When beating was established a silicone rubber injectate (Microfil) was added to the perfusion and allowed to flow until it appeared on the venous side of the system. Perfusion was stopped, Microfil allowed to harden, and the specimen cleared. The basic anatomy comprised subepicardial networks of anastomosing vessels maximum dimension between 70 and 120 μm from which arose superficial precapillary networks and many perforating vessels of varying length which supplied the subendocardial networks, the muscle mass of the ventricle and the papillary muscles. The venous drainage was by short venules leading through a system of short branches to the main veins. In general the larger veins were distributed in close association with the arteries. Evidence is presented to show the existence of routes of flow through the microcirculation of continuously fluctuating resistance. The evidence is compatible with “physiological shunting” taking place through low resistance channels and against the separate existence of arteriovenous anastomoses in the dog myocardium. Following acute ligation of the anterior descending coronary artery, arterioles and precapillaries up to 20 μm in diameter remained patent distal to the ligature and filled retrogradely from arteries unaffected by the ligature. However, Microfil entering these vessels retrogradely did not enter capillaries. Veins in the ischaemic area remained filled with blood and engorged. Injections of Trypan Blue, having a lower viscosity than Microfil, also demonstrated a patchy failure of capillaries to fill. The evidence indicates a large increase in resistance to blood flow at the level of precapillaries, which is, however, irregular so that in the infarct there are areas of normal irrigation and areas in which no capillary filling at all can be demonstrated. A possible active component in the infarction process is suggested.