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International Journal of Cardiology 97 (2004) 3 – 6 www.elsevier.com/locate/ijcard Pulmonary resistance in cardiovascular context Philip J. Kilner Cardiovascular Magnetic Resonance Unit, Royal Brompton and Harefield NHS Trust, Sydney Street, London SW3 6NP, United Kingdom Available online 22 September 2004 Abstract Comparison of the human cardiovascular system with arrangements of circulatory systems found in lower vertebrates and invertebrates allows appreciation of the functional elegance of our double circulation with systemic and pulmonary vascular trees served by a single looped and septated heart. In the pulmonary part of the circulation, consideration of the nature of alveolar microvessels in relation to the system as a whole may throw light on the pathophysiology of pulmonary regurgitation and pulmonary hypertension. Pulmonary microvessels impose remarkably little resistance to flow compared with the systemic. This may be attributed to their delicate, compliant structure, with tissue support on one side only, their respiratory walls remaining relatively free to expand in alveolar air. Low resistance may also depend on the branch pattern of alveolar capillaries, with almost immediate proximity between bifurcations and confluences in a uniquely dense, interconnected network. In the presence of free pulmonary regurgitation, pulmonary microvessels probably play a valve-like role, representing a low-resistance boundary or watershed between pulmonary arteries and veins. This microvascular watershed imposes little resistance to systolic forward flow, but in diastole, with venous pressures being kept low by function of the left heart, there is presumably little or no reversal of gradient to move blood back through the capillaries. The delicacy and potential vulnerability of alveolar capillaries to elevation of flow and pressure is likely, however, to go with a protective feedback circuit which, in abnormal circumstances, could contribute to development of arteriolar medial hypertrophy and pulmonary arterial hypertension. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Cardiovascular morphology; Pulmonary hypertension; Pulmonary regurgitation 1. Overall cardiovascular arrangements Among various phyla and classes of the animal kingdom, the higher vertebrates, including humans, have a unique arrangement of the heart and circulatory system, with systemic and pulmonary vascular trees supplied by separate but adjacent left and right sides of a single heart [1,2]. This is of course well known and perhaps taken for granted, but comparison with alternative cardiovascular arrangements found among the invertebrates gives perspective for appreciation of the functional significance of the layout of our own system. No organ that can be called a dlungT occurs among animals other than the air-breathing vertebrates. In contrast, insects have multiple small tracheal tubes that convey air directly into metabolising tissues of the body, but no lungs. Among living invertebrates, aquatic cephalopod molluscs E-mail address: [email protected]. 0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2004.08.002 (octopus and squid) attain the largest sizes and probably the greatest degree of organic complexity. They have rudimentary sub-respiratory dheartT cavities known as gill hearts, upstream of the vessels perfusing the gills. The gill hearts develop from bilateral vessel segments separate from the systemic heart and not by septation of the main heart tube into left and right sides. Snails that have taken to the land which are also molluscs, have incorporated an air-space adjacent to a modified gill structure known as the cnetidium, located under the front part of the shell. These snails have a heart structure remarkably similar in plan to the basic vertebrate heart found in fish, namely a single atrium and single ventricle, with inflow and outflow valves, contained by a pericardium. But in spite of its similarity of plan, this dorsal heart seems to have evolved quite separately from its ventral counterpart in the fish. Unlike the vertebrate heart, the snail heart shows no looping. Its output is to systemic followed by respiratory vessels, which is the reverse of the order found in fish. 4 P.J. Kilner / International Journal of Cardiology 97 (2004) 3–6 2. Vertebrate heart forms Vertebrates include fish, amphibia, reptiles, birds and mammals. All of these have their main, systemic heart located ventrally in the organism. Other valved and contractile vessel segments may exist, for example, the caudal and hepatic hearts of hagfish and lymphatic dheartsT of amphibia, but there is always one principal systemic heart, surrounded by pericardium, and located ventrally in the thorax that generates most of the pressure and flow for the circulatory system. In fish, blood from the ventricle perfuses microvessels of the gills before passing on to those of the systemic organs and muscles. This sequence, which contrasts with that found in the molluscs, does not seem ideal for maintenance of low pressure in respiratory microvessels, especially during exercise. This potential problem may have given impetus for evolution of an alternative arrangement in higher vertebrates. Separation of pulmonary from systemic circulations by gradual septation of the heart coincides with the emergence of vertebrates from water to land and with the development of lungs. The hearts of higher, air-breathing vertebrates—reptiles, birds and mammals—combine three characteristic features that are not found among invertebrates: Firstly, there is progressive looping, which may be defined as sinuous direction changes of flow, at atrial, ventricular and at great arterial level. Looping of the heart is not only retained from lower to higher vertebrate classes, but becomes increasingly marked, with acute changes of direction through the hearts of reptiles, birds and mammals. Arguably the asymmetries and direction changes of flow associated with looped curvature facilitate efficient, sling-like heart action as velocities and rates of change of momentum increase with exertion [3,4]. Secondly, there is gradual septation and separation of right from left atrial, and right from left ventricular cavities. While atrial septation is complete in amphibians, reptiles, birds and mammals, ventricular septation remains partial in amphibians and most reptiles, becoming complete in birds and mammals. Complete atrio-ventricular septation allows effective separation of low-pressure pulmonary from highpressure systemic arterial flows, which remain in continuity with one another in the whole circuit via the peripheral microvascular connections. The third morphological feature, which goes with ventricular septation, is spiral septation of the outflow tracts. The outflow tracts of right and left ventricles curve helically around one another. The functional importance of spiral division is apparent from the consequences of its absence in congenital heart disease. In transposition of the great arteries (ventriculo-arterial discordance), the left and right ventricular outflow tracts run parallel to one another, the outflows apparently having been divided by dstraightT rather spiral septation. This implies that, given concordant atrio-ventricular connections, spiral septation of outflows has evolved to achieve appropriate delivery of deoxygenated (systemic venous) blood to pulmonary arteries, and oxygenated (pulmonary venous) blood to systemic arteries. Fig. 1. Drawing, based on magnetic resonance flow studies, of principal paths of flow through left and right sides of the human heart in diastole (left) and systole (right). It shows relations of the two sides of the one heart, with direction changes of flow at atrial, ventricular and arterial levels, and spiral division of outflow tracts. P.J. Kilner / International Journal of Cardiology 97 (2004) 3–6 5 So all three features of heart form—looping, septation and helical division of outflows—are functionally significant. The looped and helically septated heart of higher vertebrates appears to be an elegant design for simultaneous and efficient function of low-pressure pulmonary and highpressure systemic circulatory systems over a range of physiological conditions from rest to strenuous exercise (Fig. 1). 3. Pulmonary and systemic microvascular resistance The diameters of capillary microvessels throughout the body are less than 10 Am, which is about 1/10 of a hair’s breadth. Blood cells pass in single file and have to deform through these delicate, microscopically small vessels, where they are brought into proximity with air of the alveoli and metabolising cells throughout the body. It is remarkable that the whole cardiac output, about 5 l/min in an adult, can pass through such minute vessels. It is also remarkable that output of the right heart to the lungs alone requires only about one fifth of the arterial pressure required to propel the same output through microvessels of the whole of the rest of the body. This means that total pulmonary resistance is only about one fifth of total systemic resistance. As the total volume of the lungs (about 6 l) is so much less than that of the rest of the body (about 65 l), pulmonary vascular resistance per unit volume of lung is less than one fiftieth of systemic vascular resistance per unit volume of tissue. The difference per unit weight of tissue would be even more extreme. The overall perfusion of body and lungs depends, of course, on there being many billions of capillaries, all linked to and from the heart by the branches of arterial and venous trees. The numbers of capillary branches are such that, in spite of their microscopically small diameters, the cumulated cross-sectional areas of capillaries summate to many times the cross-sectional area of the great vessels, which is reflected in marked deceleration of flow during passage from large central to small peripheral vessels via the repeated branching of arteries [5]. Blood seeps rather than flows through intricate capillary webs. The low-resistance capillary beds of the alveoli of the lungs have a unique pattern of branching and reconnection. Alveolar capillaries are distributed in a densely interconnected net with extremely short distances between branches and confluences (Fig. 2). Alveolar blood seeps through these capillary nets almost as a sheet or film, split only by the columns of epithelium that form the holes of the net [6]. These networks of alveolar microvessels must be particularly delicate and compliant, being supported by tissue on one side only, the other side being exposed alveolar air. This is necessary for respiratory gas exchange, but it may also imply extra vulnerability to any elevation of intra-capillary pressure. Fig. 2. Scanning electron micrograph showing human alveolar capillaries from a child who had been born with a ventricular septal defect. The interconnected web of capillaries, when filled as here, bulges into the air spaces of the alveoli. In contrast, systemic capillaries are generally embedded in surrounding tissues and have greater lengths between junctions. Scale bar = 20 Am (from reference [6]). On the systemic side, the spatial arrangements of microvessels vary considerably between organs, but the systemic capillaries, unlike those of the alveoli, are predominantly linearly arrayed, with many diameter-lengths between points of branching or confluence. While muscular arterioles with pre-capillary sphincters are known to modify local perfusion, the lengths and branch patterns of systemic capillaries, as well as their diameters, must contribute to the resistance, or lack of resistance, to microvascular flow. 4. Pulmonary regurgitation Free pulmonary regurgitation, as found after repair of Tetralogy of Fallot or in absent pulmonary valve syndrome, is generally well-tolerated for decades. Interestingly, free pulmonary regurgitation is typically associated with a regurgitant fraction of only about 40% [7]. This contrasts with aortic regurgitation. Free aortic regurgitation is not compatible with life, and an increasing aortic regurgitant orifice can be associated with as much as 60% regurgitant fraction, beyond which cardiac and circulatory failure are likely to follow. How can free pulmonary regurgitation be so relatively well tolerated? Part of the answer lies in the secondary role of the right heart with respect to the left. It is possible for left heart 6 P.J. Kilner / International Journal of Cardiology 97 (2004) 3–6 function alone to support both the systemic and pulmonary flows in series, as illustrated by the Fontan circulation. To some degree, this happens in the presence of free pulmonary regurgitation where, with a so-called drestrictiveT right ventricle, rising systemic venous and right heart pressures during diastole result in forward flow in the pulmonary artery at the time of atrial systole [8]. This occurrence will boost the proportion of forward pulmonary flow relative to regurgitant flow. However, there is probably another factor that limits the severity of free pulmonary regurgitation. This is valve-like function of the pulmonary microvessels. Right ventricular systole results in forward flow in the pulmonary arteries, a proportion of which must pass forward through the low-resistance microvessels to pulmonary veins. This blood is unlikely to return in diastole, having descapedT to a lower-pressure region, maintained by function of the left heart. The delicate, compliant pulmonary capillaries represent a low-resistance boundary or watershed between pulmonary arteries and veins, not too far removed in distance from the right ventricle. So the combination of Fontan-like function of the circulation as a whole and a valve-like function of pulmonary microvessels in this context may combine to limit the adverse impact of free pulmonary regurgitation. 5. Pulmonary hypertension A characteristic histological feature of pulmonary hypertension, whether primary or secondary, is thickening and proliferation of medial smooth muscle of pulmonary arteries and arterioles [9–11]. There is also thickening of the interna, eventually leading to obliteration of the lumen and development of plexiform vascular lesions. Various biochemical pathways are being investigated in the search for understanding of the pathogenesis of pulmonary hypertension. It could be that there is a physiological feedback mechanism built in to protect the delicate capillary nets of the alveoli from excessive flow and pressure through the range of physiological states from rest to exercise. This protective mechanism is likely to include activation of arteriolar smooth muscle. So it may be an exaggeration of a physiological response that underlies the changes seen in pulmonary hypertension, particularly when it is secondary to shunting and excessive pulmonary flow. 6. Summary The double systemic-pulmonary circulation, served by a looped and spirally septated heart, is unique to humans and other higher vertebrates. My aim has been to consider pulmonary resistance in the context of the cardiovascular system as a whole. In this context, the delicacy, compliance and location of pulmonary microvessels give them a potentially beneficial, valve-like role when there is free pulmonary regurgitation, although it leaves them vulnerable to elevation of flow and pressure. Natural protective feedback mechanisms may, in slightly altered forms, underlie the pulmonary arterial and arteriolar changes characteristic of pulmonary hypertension. References [1] Bourne GH. Hearts and heart like organs. Comparative Anatomy and Development, vol. 1. New York7 Academic Press; 1980. [2] Nielsen C. Animal evolution—interrelationships of the living phyla. Oxford7 Oxford University Press; 1995. [3] Kilner PJ, Yang GZ, Wilkes AJ, Mohiaddin RH, Firmin DN, Yacoub M. Asymmetric redirection of flow through the heart. Nature 2000;404:7759 – 61. [4] Kilner PJ, Henein M, Gibson DG. Our tortuous heart in dynamic mode—an echocardiographic study of mitral flow and movement in exercising subjects. Heart Vessels 1997;12:103 – 10. 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