J Mol Cell Cardiol 30, 2529–2530 (1998)Article No. mc980846

The Microcirculation as a Foundation of Cardiovascular Disease

Introduction to the Focused Issue: TheMicrocirculation as a Foundation ofCardiovascular DiseaseGuest Editors: John Gavin and Stig Haunso

The XVI World Congress of the International Society perfusion the normal feedback mechanisms may beoverridden by local inflammatory responses in-for Heart Research was held in Rhodes, Greece, in

May 1998 and included over 50 symposia. These volving cytokines, polymorphonuclear leukocytesand reactive oxygen species. The papers in thissymposia reviewed advances in understanding of

the cardiovascular system, and of the heart in issue cover many of the topics which are becomingimportant to our understanding of the micro-particular. The six papers published in full in this

issue were presented at the symposium which was circulation in health and disease.The essential functions of the cardiovascular sys-focused on the microcirculation. They include new

knowledge which has clinical relevance and may tem are performed at the level of the micro-circulation which is defined as the passage of bloodlead to new approaches to the treatment of cardio-

vascular disease. through the microvasculature (vessels less than300 microns in diameter), i.e. arterioles, capillariesAlthough cardiologists are very familiar with the

morphology of conduit epicardial vessels, they are and venules. This is where oxygen, nutrients andhormones are delivered and catabolites removed,not as conversant with the coronary micro-

circulation in which two thirds of the coronary and where, in inflammation, antibodies, fibrinogen,elements of the complement system and leukocytesblood volume resides. Experimental findings con-

tinue to stimulate great clinical interest, particularly enter injured tissues.The heart continually circulates the blood toas research highlights the relevance of saving myo-

cardial tissue following coronary occulsion, and the microvasculature. The myocardium thereforerequires a generous blood supply of about 300 ml/demonstrates the consequences of myocardial isch-

aemia and reperfusion injury on myocardial re- min at rest and indeed 35% of its volume is madeup by its vasculature. Capillaries are the mostmodelling and function. Furthermore, it is now

increasingly accepted that it is not sufficient simply numerous vessels, some 2500–3000/mm2 in cross-section, where exchange between plasma and inter-to correct structural epicardial lesions by throm-

bolysis, coronary artery angioplasty or coronary stitial fluid occurs.Throughout the body, the response of tissues toby-pass without considering whether this therapy

also corrects the underlying microvascular de- various forms of cell injury is by inflammation inwhich the microvasculature is centrally involved.rangement.

A variety of humoral and cellular mediators Microvascular changes are responsible for three ofthe four classical signs of acute inflammation. Theseinteract in regulating the microcirculation of the

heart. The importance of nitric oxide is increasingly are redness (vasodilation, hyperaemia), swelling(increased microvascular permeability) and heatrecognized. However, during ischaemia and re-

0022–2828/98/122529+02 $30.00/0 1998 Academic Press

J. Gavin and S. Haunso2530

(increased capillary blood flow). The proliferation in many types of cardiac disease. Riis Hansen re-views the inflammatory mechanisms and discussesof new microvessels (angiogenesis) is an essential

feature of the healing which follows. their relationship to microvascular endothelial dys-function. This can arise from reduced bioactivity ofThe symposium considered the dynamics of

microvascular permeability (Michel) and control of NO or be due to inflammatory mediators whichmay serve not only as molecular markers of cardiacblood flow to capillary beds (DeFily), surveyed the

various types of cardiac pathology to define the disease but also be targets for anti-inflammatoryintervention.extent to which the microvasculature may be in-

volved in the pathogenesis of these diseases (Gavin Leukocyte activation, adhesion and emigrationoccurs in the microvasculature as an integral partet al.), considered ischaemic and reperfusion injury

in greater detail (DeFily, Lefer et al.) and then the of the inflammatory response to cell injury. How-ever, in the heart these processes paradoxicallyeffects of inflammation on microvascular function

(Riis Hansen). It concluded with a detailed con- often appear to contribute to microvascular andmyocardial injury. Lefer et al. have demonstratedsideration of cytokines in the mediation of both the

acute inflammatory response to injury and also in experimentally how on reperfusion the neutrophilleukocytes entering temporarily ischaemic tissuethe repair which follows (Frangogiannis et al.).

Despite rapid advances in understanding the promote significant contractile dysfunction, and,further, that this phenomenon can be virtuallyamazingly diverse biology of endothelial cells, we

are still some way from fully understanding the eliminated by a metalloproteinase mocarhaginwhich inhibits P-selectin mediated leukocyte ad-molecular events which alter the permeability of

the walls of microvessels. Michel concludes that hesion.The mediation of the inflammatory response fromcyclic guanosine monophosphate may play a key

role in the physiological modulation of permeability, its initial reactive phase through to healing byrepair involves a sequence of cellular events. Thewhereas increases in endothelial intracellular Ca2+

and flow dependent effects of nitrous oxide (NO) paper by Frangogiannis et al. provides a com-prehensive overview of the complex interplay ofare involved in the substantial increases in micro-

vascular permeability which occur in acute in- cytokines which orchestrate the events which leadfrom the initial acute microvascular response toflammation.

The responsiveness of small arteries, large ar- densely collagenous scar. This provides a molecularbiological conclusion to a symposium which re-terioles and small arterioles to the regulatory in-

fluences of metabolic, myogenic, a-adrenergic and viewed new insights into normal microvascularfunction and control, and demonstrated that struc-endothelial cell mediated regulatory influences is

not uniform. DeFily reviews these mechanisms and tural and functional abnormalities of the micro-circulation are primarily involved in thethe alterations which occur in them in a variety of

pathophysiological conditions, including re- pathogenesis of some types of heart disease. Thera-peutic improvement should now be focused onperfusion injury in which the endothelium is a

primary target. He suggests that manipulation of mechanisms affecting the microvasculature in theseconditions.the levels of tetrahydrobiopterin within endothelial

cells may prevent or delay the pathophysiological All of the manuscripts have undergone a fullpeer review and we thank Dr Norman R. Alpert,sequelae of post-ischaemic reperfusion.

Alterations in the structure and function of the Editor-in-Chief, and Dr Ellen J Zeman, AssociateEditor of Journal of Molecular and Cellular Car-microvasculature occur in most forms of heart

disease and, in some, these abnormalities are cent- diology for their help and cooperation in developingthis special issue on the involvement of the micro-rally involved in their pathogenesis. Gavin et al.

conclude that stimulation of angiogenesis prior to circulation in cardiovascular disease. We are grate-ful to the Servier Research Group for the educationalmyocyte necrosis in myocardial hypertrophy, and

prevention of post-ischaemic microvascular in- grant which made this symposium possible. Wehope you will enjoy reading these papers as much ascompetence are potential theraupeutic targets.

Ischaemic necrosis and the inflammatory reponse we enjoyed organizing the symposium and bringingthis issue to you.this initiates appear to be a final common pathway