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Coronary heart disease: Overview
THE LANCET
OVERVIEW
Coronary heart disease: overview Andrew Henderson
No disease can have been so extensively studied. The work of recent years has yielded remarkable advances in our understanding, and in diagnostic and interventional cardiology, surgery, and pharmacology--effort well spent for a disease that carries such heavy social and economic costs. The clinical condition of coronary heart disease (CHD) presents as (i) angina, (ii) myocardial infarction, (iii) sudden death, and (iv) consequent chronic heart failure. It is responsible for about 50% of cardiovascular mortality, which itself accounts for 30-50% of all deaths in developed nations. It is the major cause of premature death, in women as in m e n - - w o m e n lagging behind men by some 10 years in this age-related disease. It was not always so. Despite uncertainties about its" diagnosis in earlier years, C H D appears to be an epidemic of our time and a disease of at least some aspects of affluence. Its prevalence varies ten-fold across different nations.' It is becoming more c o m m o n in nations previously impoverished by history or recent circumstance, as living standards "improve". C H D mortality has, however, already declined by up to 50% in some developed nations despite the ageing of their populations--a decline said to be attributable in equal measure to healthier lifestyle, better medical treatment, and factors yet unknown. There is growing evidence too that fetal malnutrition predisposes to C H D in later life. 2 The still high prevalence of C H D seems indeed not to be immutable. Clinically manifest CHD is truly end-stage disease, with its origins in longstanding subclinical atheroma. Trials of its prevention need to be designed and interpreted in knowledge of the different stages of its pathogenesis. It is, however, amenable to a remarkable range of effective therapeutic measures--at enormous cost but to the enormous relief of a high proportion of the adult and ageing p o p u l a t i o n - - w i t h o u t cure of the underlying condition once established. Management of C H D is longterm management, covering generally unpredictable acute episodes, relief of consequences, and slowing of progression.
The heart Myocardial ischaemia The underlying physiology is well known. Normally, increased energy consumption is met by dilation of arterioles (about 0-1 m m in diameter) mediated by still uncertain metabolic signals from the myocardium. This is amplified by flow-related release of locally acting nitric oxide (Nature's archetypal nitrovasodilator) from endothelium predominantly of slightly larger (0'2 mm) microvessels, while flow is stabilised (autoregulated) over a range of different pressures, and vasomotor tone is under the influence also of neurohumoral agents. It is a remarkably flexible, well-integrated, and stable system. Upstream atheromatous stenosis of >50% can, however,
Vol 348 • November 1996
pose a limit to coronary perfusion reserve. Myocardial ischaemia represents the state of metabolic imbalance when blood supply is inadequate to maintain energy levels for normal function--reversible if brief, irreversible if prolonged. Myocardial energy utilisation can be related to empirical measures of energy consumption--heart rate, systolic wall stress (pressure and, by the LaPlace relationship, cavity volume), and, to a smaller degree, contractility. Knowledge of these principles underlies the medical management of angina. Additional factors that come into play to protect against ischaemia are collaterals, the recently recognised phenomenon of preconditioning, and arterial pressure (especially during diastole, when most subendocardial coronary perfusion occurs) if this falls below the autoregulatory range. Collaterals
Perfusion reserve is augmented through microvascular as well as angiographically demonstrable collateral arteries from adjacent vascular beds, provided that pressure in these beds is not equally prejudiced by coronary artery disease; once collaterals have developed, the different vascular beds of the coronary tree are interdependent. The development of collaterals is encouraged by angiogenic agents released from ischaemic myocardium. This may account for the observation that the unheralded myocardial infarct in patients with no antecedent ischaemia can be the more catastrophic. It also offers possibilities for the development of gene therapy.
Preconditioning Preconditioning describes the protective effect of a brief (2-10 min) period of ischaemia in limiting for a few hours the adverse impact of subsequent ischaemia. 3 The mechanism seems to represent a process of pharmacological "priming" whereby ischaemia-induced adenosine (or other pharmacological agonists that activate protein kinase C) engineers a protective response to subsequent ischaemia via mechanisms as yet uncertain. Induced expression of protective proteins appears to mediate an additional period of preconditioning for 1-3 days after the priming event. This would suggest that angina--little and often--might be good for you once you have got coronary artery disease. Not only will ischaemia encourage the development of collaterals, but short-term it may also buffer the impact of subsequent ischaernic episodes by preconditioning. Preconditioning could help to explain the "warm up" relief of angina on repeated exercise, and how a recent episode of angina may reduce infarct severity. It offers potential pharmacological targets during controlled ischaemia, as in cardiac surgery.
Reperfusion, stunning, hibernation Contractile recovery from brief periods of ischaemia is
sl
OVERVIEW
normally rapid. Full recovery from more severe episodes can, however, take hours or even days--the phenomenon of myocardial stunning.4 Stunning represents delayed recovery from the combined insults of ischaemia and of the reperfusion, which induces a damaging burst of oxygen free radicals. Such reperfusion p h e n o m e n a underlie the ventricular fibrillation observed experimentally, and, less obviously, with clinical reperfusion, especially if this occurs early (as is desirable for optimal myocardial salvage). Repeated episodes of angina or of silent ischaemia, before full recovery, result in sustained impairment of cardiac function and thus lead to the compensatory responses which characterise heart failure. This has important practical implications. Prevention of recurrent ischaemia, as by revascularisation, will allow full recovery. Impaired ventricular function or heart failure, which once were relative contraindications to coronary artery surgery, may if due to stunning be indications for the procedures. Stunning must always therefore be considered when ventricular function deteriorates or heart failure develops in the context of coronary artery disease. Confirmation rests on the demonstration of impaired contraction (responsive to inotropic stimulation) in the presence of good perfusion. Hibernation, by contrast, refers to an unexpectedly stable state of "down-regulated" myocardial metabolism whereby contractile performance is reduced to match a sustained reduction in flow that would otherwise cause low intracellular levels of ATP and ischaemia. 5 The myocyte remains viable, albeit dysfunctional and even histologically damaged, and very vulnerable to further ischaemia. Restoration of flow can lead to full recovery, though this may be delayed. Ischaemia, reperfusion, stunning, and preconditioning are all quite likely to coexist clinically, with spatial and temporal heterogeneity. Much of what is thought to be hibernation may be the net result of a mixture of these conditions, leaving doubt about the existence of this clinically described p h e n o m e n o n . Experimental evidence that hibernation can be induced by the measured reduction of flow adds support to the reality of the phenomenon. In practice, hibernation is difficult to diagnose without positron emission tomography, to confirm metabolic viability despite regionally reduced function and perfusion. Hibernating (like stunned) myocardium may still respond to positive inotropic stimulation. Impaired ventricular function due to hibernation is an indication for revascularisation.
Myocardial infarction Infarction results when ischaemia is prolonged and cellular changes become irreversible. Beginning in the vulnerable subendocardium it extends to "full thickness" as a function of time. Resultant infarct size is a major determinant of subsequent heart failure and of life expectancy. The same considerations of "supply and demand" apply in determining infarct size as they do in angina. The major influences here are the severity and duration of the critical reduction in coronary flow, as modified by pre-existing collaterals and by spontaneous or therapeutic thrombolysis, and any pre-existing state of preconditioning that will buy time. The cause is usually an occluding thrombus that has formed over an "unstable" atheromatous plaque. Acute myocardial infarction is often preceded by brief periods of what in retrospect was unstable angina, attributable presumably to intermittent s2
THE LANCET
thrombus formation as part of the acute coronary syndrome--a dynamic process of thrombus formation, dislodgement, lysis, and further thrombosis that may lead to stuttering progression of the infarction. This variability and clinical uncertainty of timing would account for the bigger time-window for effective thrombolysis than would be predicted from "clean" experimental coronary artery occlusion. The complication of early ventricular fibrillation from still living b u t severely ischaemic myocardium remains a major issue in the management of acute infarction; some half of all patients die before reaching hospital. After infarction, remaining viable heart muscle undergoes compensatory regional hypertrophy with dilation, while the healing infarct flbroses into a scar, in the composite process known as remodelling. Spontaneous recanalisation can be shown to have occurred in some 50% of cases six months later--too late to salvage ischaemic myocardium, though there is some evidence that an open artery in the early phases of repair improves structural remodelling of the heart. Beta-blocker therapy following acute infarction, if not contraindicated, lengthens survival. Angiotensin converting enzyme (ACE) inhibitors, particularly if introduced when left ventricular function is impaired, also prolong survival--perhaps by modifying the adverse neuroendocrine consequences of heart failure, but also by reducing further acute coronary events.
The arteries A therogenesis The real villain of the piece is not the myocardium but coronary atheroma--clinically silent for many years and manifest only by its complications. In the chronic inflammatory condition of atheroma, endothelial function has a seminal role. Low density lipoproteins (LDL) oxidised in transit through the intimal layer of large arteries seem to be a common initiating cause, though almost certainly not the only one. Among the factors that may tilt the balance are circulating levels of LDL, its rate of transport through the artery, antioxidant status in the artery wall, and nitric oxide (NO) activity. NO, among other antiatherogenic actions, exerts an antioxidant effect by interacting with superoxide (02). 02, as well as oxidising LDL, promotes the proliferative processes of atheroma. The ratio of 02 to NO may indeed be important in the balance of pro and anti atherogenic influences. Hypercholesterolaemia, and raised tissue levels of ACE and thus of angiotensin II (AII), for example, induce m e m b r a n e oxidase systems to increase 02 productign; healthy endothelium produces NO, particularly at sites of high flow and shear stress. ACE inhibitors have antiatherogenic potential both by reducing AII levels and by increasing NO production, for NO production is stimulated by endogenous bradykinin whose breakdown is also slowed by ACE inhibitors. Plaque fissure and thrombosis Atheroma in its early stages is not angiographically visible: vascular remodelling ensures that it does not obtrude u p o n the lumen, though it is demonstrable by intravascular ultrasound and at necropsy. A plaque (whose lipid core is liquid at body temperature) may, however, crack at sites of mechanical stress. Platelet adhesion, activation, and aggregation occur, with
Vol 348 • November
1996
THE LANCET
OVERVIEW
thrombosis stimulated by exposed tissue factor, the outcome depending on physical factors of flow and on the balance of pro and anti thrombotic and fibrinolytic influences. Occlusive thrombus can thus develop on minor lesions as well as on critically stenotic lesions. Plaques rich in inflammatory cells--macrophages, T cells, and mast cells--are more prone to develop fissures or erosions than more strongly fibromuscular plaques, independent of the severity of underlying stenosis. 6 Most such episodes will be clinically silent but incorporation of the thrombus will contribute to intermittent growth of the now complex plaque. Indeed, these complications may account for most of the growth of atheromatous coronary stenosis, from the angiographically normal to the critically stenosed artery. Plaque fissure or erosion with thrombosis underlies also the unstable clinical coronary syndrome manifest as unstable angina, myocardial infarction, and sudden death.
Endothelium If endothelial dysfunction participates in sowing the seeds of atherogenesis, measures of endothelial dysfunction may provide a marker of susceptibility to atheroma. When present, endothelial dysfunction is usually widespread throughout the vascular tree and thus accessible to measurement--for example, non-invasive measurement of flow-induced vasodilation in large systemic arteries. 7 This aspect of endothelial function is likely to correlate with those that lead to atherogenesis, both because N O is antiatherogenic and because flow-mediated dilation is impaired (commonly because of increased O 2 production) with all known risk factors for atheroma, including ageing. Endothelial dysfunction can be shown experimentally also to impair microvascular dilator reserve and the homogeneous distribution of perfusion, thus prejudicing tissue perfusion and contributing potentially to ischaemia, s Since endothelial dysfunction underlies both atherogenesis and loss of integrated microvascular fine-tuning, the two will commonly coexist, though the consequences of declining microvascular efficiency will be less dramatic and are less easily investigated. Several conditions characterised overtly by "small vessel disease", such as diabetes, hypertension, and microvascular angina, are associated with endothelial dysfunction.
Microvascular angina Syndrome X, empirically defined as angina with positive exercise test and normal coronary arteriogram in the absence of other cardiac diseasefl is all too common. These practical but soft criteria embrace many with noncardiac chest pain but include some who undoubtedly have a reduced coronary perfusion reserve and inducible regional myocardial ischaemia, due by inference to microvascular d y s f u n c t i o n - - " m i c r o v a s c u l a r angina". Confusingly, another cardiovascular syndrome X (also known as Reaven's syndrome) describes the epidemiological clustering of atheroma, hypertension, insulin resistance, and dyslipidaemia.1° Both syndromes X (the cardiologists' term being restricted to those patients with microvascular angina) seem to be characterised by endothelial dysfunction u and by insulin resistanceY It is even possible that, by chance, they represent different ends of the same s p e c t r u m - - b o t h having coronary atheroma (albeit angiographically "silent" in the one) and microvascular dysfunction (albeit unrecognised in the other). Endothelial dysfunction is associated with insulin
Vol 348 • N o v e m b e r
1996
resistance across a wide range of conditions (including all risk factors for C H D ) and could contribute to ]t by limiting flow-dependent uptake of glucose, so further unifying our concept of this vascular disease complex.
Prevention Measures directed towards (i) preventing or slowing atherogenesis should be distinguished from those which address (ii) plaque instability and (iii) thrombosis/lysis. Clearly these operate at very different phases and over quite different time courses in the evolution of CHD. Experimental and circumstantial evidence suggests that interventions aimed at one phase may, however, affect other phases. Reducing hypercholesterolaemia, for example, is likely to affect both atherogenesis and its thrombotic complications; interventions affecting the cellular processes of atherogenesis are likely to influence also the vulnerabiity of the plaque to fissuring; smoking will favour (and aspirin inhibit) thrombosis, and thereby influence also the silent episodic growth of stenosis; improvement of endothelial function, by antioxidant influences including exercise, oestrogens, and reduction of lipid levels, may be expected to reduce the initiation of atherogenesis, its progression, and also its thrombotic complications. "Prevention" of C H D has predominantly (and by default) been the territory of non-cardiologists, whether based in epidemiology, lipid metabolism, hypertension, diabetes, or public health, while vascular medicine is a yet young specialty and vascular biology is only now beginning to take centre stage. The distinction between primary prevention (before clinical C H D is diagnosed) and secondary prevention (after it has presented clinically) is largely academic except that in secondary prevention the higher absolute risk (and recognition of it) increases both cost-effectiveness and the motivation of patients to comply. The impact of primary prevention has to many been disappointing, perhaps because expectations have been simplistically high, regimens too rigorous, and time-scales too short. Population measures, though small in individual impact, can have larger community effects than more individually effective measures for high-risk individuals. Such community-wide preventive strategies, involving social change and governmental policy (as in relation to tobacco), are likely to have far-reaching effects, but they seem to find less support than health education initiatives, to which the necessary individual responses tend in practice to relapse. T h e roots go deeper and the social subsoil cannot be ignored. Screening for risk helps to target delivery of preventive measures where the stakes are highest, but screening cannot be uncoupled from its consequences and costs. These must be evaluated just as critically as any therapeutic intervention. In secondary prevention, the screening is in effect already done for you.
The future Much has been learnt about environmental factors which increase the risk of CHD. Genetic stratification of risk is also fast becoming possible, generating further questions about the practical consequences of such screening. Targets will become more focused as underlying mechanisms are clarified. Provision of effective therapy for established symptomatic C H D is a costly but uncontested necessity. ~3
ATHEROMA
The principles are highly developed and well-established though still the subject of intensive refinement and evaluation. The issue here is to ensure that new developments and their implementation are guided by science and evidence, rather than by the seductions of technology and the interests of industry. The many people with unrecognised but treatable CHD are a further target for improving overall management of C H D in the community, and thus also its secondary prevention. Many with angina remain undiagnosed. Worse still, many with unstable coronary syndrome escape the benefits of urgent medical management. The net might also be cast more widely to identify patients with very early evidence of reversible disease, as manifest by endothelial dysfunction. This is now a practical possibility with non-invasive tests, albeit only as a research procedure to date. Endothelial dysfunction is amenable to improvement and could perhaps provide a surrogate target for therapy. Advances on many fronts, not least of communication between those active in the many aspects of C H D causation, prevention, and management, are combining to bring a sense of real and further imminent progress. This article has been a general view. T h e rest of the Supplement is taken up with specialist views of CHD, ending with the insights of a cardiologist-patient.
THE LANCET
References 1
2
3
4 5 6
7
8
9 10 11
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Tunstall-Pedoe H. Cardiovacular diseases. In: Detels R, Holland W, McEwen J, O m e n n GS, eds. Oxford textbook of public health. Oxford: Oxford Medical, 1996. Barker DJP, Osmond C, Golding J, K u h D, Wadsworth MEJ. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 1989; 298: 564-67. Murray CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal ceil injury in ischemic myocardium. Circulation 1986; 74: 1124-36. Braunwald E, IGoner RA. The stunned myocardium prolonged postischemic ventricular dysfunction. Circulation 1983; 6 6 : 1 1 4 6 - 4 9 . Rahimtoola SH. The hibernating myocardium. Am HeartJ 1989; 117: 21121. Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. BrHeartJ 1985; 53: 363-73. Ramsey MW, Goodfenow J, Jones CJH, Luddington LA, Lewis MJ, Henderson AH. Endothelial control of arterial distensibility is impaired in chronic heart failure. Circulation 1995; 92: 3212-19. Griffith T M , Edwards D H , Davies RLI, Harrison TJ, Evans KT. E D R F co-ordinates the behaviour of vascular resistance vessels. Nature 1987; 329: 442-45. Editorial. Syndrome X. Lancet 1987; ii: 1247-48. Reaven G M . Role of insulin resistance in h u m a n disease. Diabetes 1988; 37: 1595-1607. Egashira K, Inou T, Hirooka Y, Yamada A, Urabe Y, Takeshita A. Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. N EnglJ Med 1993; 3 2 8 : 1 6 5 9 - 6 4 . Goodfellow J, Owens D, Henderson A. Cardiovascular syndromes X, endothelial dysfunction and insulin resistance. Diabetes Res Clin Prac 1996; 31 (suppl 1): 163-71.
Atheroma: more than mush
Peter Libby Not long ago, most physicians envisaged atheroma as an inert collection of cholesterol, calcium, and fibrous tissue that grew steadily and ineluctably until it eventually obstructed an artery and impeded blood flow. Over the past few years the picture has evolved considerably, as clinical and pathological insights have pointed the way for rethinking atherogenesis at the level of cell and molecular biology. Rather than viewing atheroma as progressive clogging of the pipes with nondescript, amorphous sludge, we now appreciate the dynamic and vital aspects of atheroma. These lesions team with cells, particularly in their early phases. The cellular residents of the lesion include intrinsic vascular wall cells such as endothelium and smooth muscle (figure 1). In addition to these indigenous cells, the biological role of infiltrating leucocytes attracts ever-growing attention. These various cell types actively exchange messages that regulate functions critical to lesion initiation and progression and to clinical complications. An u n d e r s t a n d i n g of the clinical manifestations of coronary atherosclerosis requires knowledge of this cellular interplay, the theme of this article. We now recognise that the function of cells within lesions can influence the clinical manifestations of atherosclerosis more decisively than the mere anatomy. As pointed out by Valentin Fuster and his colleagues (p s7), lesions that do not critically stenose coronary arteries may nonetheless provoke coronary thromboses. 1 Such thrombi, if non-occlusive or evanescent, can precipitate episodes of unstable angina pectoris. If the intracoronary clot becomes s4
obstructive and persists, acute myocardial infarction may result. Likewise, dysfunction of morphologically intact endothelium, rather than frank denudation of these cells, can seriously disrupt coronary haemodynamics (see Andreas Zeiher's contribution, p sl0). For example, atherosclerotic coronary arteries, or even those exposed to humoral conditions associated with atherogenesis such as hypercholesterolaemia, may be unable to vasodilate normally in response to neurohumoral stimuli? Thus, altered behaviour of cells, often morphologically inapparent, may promote vasospastic components of the acute coronary syndromes in addition to the thrombotic aspects.
Cellular activation What regulates these cellular functions that determine such clinically important features of atherosclerosis? Work performed in the 1950s identified the early arrival of blood-borne monocytes in lesion formation. Poole and Florey stated: "in rabbits fed with cholesterol there appears to be some patchy alteration in aortic endothelium as . . . macrophages adhere"2 These workers stated that the problem could not be "profitably pursued" with the tools available to them in mid-century.
Adhesion molecules Today the technology exists; and we know of specific adhesion molecules on the surface of endothelial cells that
Vo1348 • November
1996
OVERVIEW
Coronary heart disease: overview Andrew Henderson
No disease can have been so extensively studied. The work of recent years has yielded remarkable advances in our understanding, and in diagnostic and interventional cardiology, surgery, and pharmacology--effort well spent for a disease that carries such heavy social and economic costs. The clinical condition of coronary heart disease (CHD) presents as (i) angina, (ii) myocardial infarction, (iii) sudden death, and (iv) consequent chronic heart failure. It is responsible for about 50% of cardiovascular mortality, which itself accounts for 30-50% of all deaths in developed nations. It is the major cause of premature death, in women as in m e n - - w o m e n lagging behind men by some 10 years in this age-related disease. It was not always so. Despite uncertainties about its" diagnosis in earlier years, C H D appears to be an epidemic of our time and a disease of at least some aspects of affluence. Its prevalence varies ten-fold across different nations.' It is becoming more c o m m o n in nations previously impoverished by history or recent circumstance, as living standards "improve". C H D mortality has, however, already declined by up to 50% in some developed nations despite the ageing of their populations--a decline said to be attributable in equal measure to healthier lifestyle, better medical treatment, and factors yet unknown. There is growing evidence too that fetal malnutrition predisposes to C H D in later life. 2 The still high prevalence of C H D seems indeed not to be immutable. Clinically manifest CHD is truly end-stage disease, with its origins in longstanding subclinical atheroma. Trials of its prevention need to be designed and interpreted in knowledge of the different stages of its pathogenesis. It is, however, amenable to a remarkable range of effective therapeutic measures--at enormous cost but to the enormous relief of a high proportion of the adult and ageing p o p u l a t i o n - - w i t h o u t cure of the underlying condition once established. Management of C H D is longterm management, covering generally unpredictable acute episodes, relief of consequences, and slowing of progression.
The heart Myocardial ischaemia The underlying physiology is well known. Normally, increased energy consumption is met by dilation of arterioles (about 0-1 m m in diameter) mediated by still uncertain metabolic signals from the myocardium. This is amplified by flow-related release of locally acting nitric oxide (Nature's archetypal nitrovasodilator) from endothelium predominantly of slightly larger (0'2 mm) microvessels, while flow is stabilised (autoregulated) over a range of different pressures, and vasomotor tone is under the influence also of neurohumoral agents. It is a remarkably flexible, well-integrated, and stable system. Upstream atheromatous stenosis of >50% can, however,
Vol 348 • November 1996
pose a limit to coronary perfusion reserve. Myocardial ischaemia represents the state of metabolic imbalance when blood supply is inadequate to maintain energy levels for normal function--reversible if brief, irreversible if prolonged. Myocardial energy utilisation can be related to empirical measures of energy consumption--heart rate, systolic wall stress (pressure and, by the LaPlace relationship, cavity volume), and, to a smaller degree, contractility. Knowledge of these principles underlies the medical management of angina. Additional factors that come into play to protect against ischaemia are collaterals, the recently recognised phenomenon of preconditioning, and arterial pressure (especially during diastole, when most subendocardial coronary perfusion occurs) if this falls below the autoregulatory range. Collaterals
Perfusion reserve is augmented through microvascular as well as angiographically demonstrable collateral arteries from adjacent vascular beds, provided that pressure in these beds is not equally prejudiced by coronary artery disease; once collaterals have developed, the different vascular beds of the coronary tree are interdependent. The development of collaterals is encouraged by angiogenic agents released from ischaemic myocardium. This may account for the observation that the unheralded myocardial infarct in patients with no antecedent ischaemia can be the more catastrophic. It also offers possibilities for the development of gene therapy.
Preconditioning Preconditioning describes the protective effect of a brief (2-10 min) period of ischaemia in limiting for a few hours the adverse impact of subsequent ischaemia. 3 The mechanism seems to represent a process of pharmacological "priming" whereby ischaemia-induced adenosine (or other pharmacological agonists that activate protein kinase C) engineers a protective response to subsequent ischaemia via mechanisms as yet uncertain. Induced expression of protective proteins appears to mediate an additional period of preconditioning for 1-3 days after the priming event. This would suggest that angina--little and often--might be good for you once you have got coronary artery disease. Not only will ischaemia encourage the development of collaterals, but short-term it may also buffer the impact of subsequent ischaernic episodes by preconditioning. Preconditioning could help to explain the "warm up" relief of angina on repeated exercise, and how a recent episode of angina may reduce infarct severity. It offers potential pharmacological targets during controlled ischaemia, as in cardiac surgery.
Reperfusion, stunning, hibernation Contractile recovery from brief periods of ischaemia is
sl
OVERVIEW
normally rapid. Full recovery from more severe episodes can, however, take hours or even days--the phenomenon of myocardial stunning.4 Stunning represents delayed recovery from the combined insults of ischaemia and of the reperfusion, which induces a damaging burst of oxygen free radicals. Such reperfusion p h e n o m e n a underlie the ventricular fibrillation observed experimentally, and, less obviously, with clinical reperfusion, especially if this occurs early (as is desirable for optimal myocardial salvage). Repeated episodes of angina or of silent ischaemia, before full recovery, result in sustained impairment of cardiac function and thus lead to the compensatory responses which characterise heart failure. This has important practical implications. Prevention of recurrent ischaemia, as by revascularisation, will allow full recovery. Impaired ventricular function or heart failure, which once were relative contraindications to coronary artery surgery, may if due to stunning be indications for the procedures. Stunning must always therefore be considered when ventricular function deteriorates or heart failure develops in the context of coronary artery disease. Confirmation rests on the demonstration of impaired contraction (responsive to inotropic stimulation) in the presence of good perfusion. Hibernation, by contrast, refers to an unexpectedly stable state of "down-regulated" myocardial metabolism whereby contractile performance is reduced to match a sustained reduction in flow that would otherwise cause low intracellular levels of ATP and ischaemia. 5 The myocyte remains viable, albeit dysfunctional and even histologically damaged, and very vulnerable to further ischaemia. Restoration of flow can lead to full recovery, though this may be delayed. Ischaemia, reperfusion, stunning, and preconditioning are all quite likely to coexist clinically, with spatial and temporal heterogeneity. Much of what is thought to be hibernation may be the net result of a mixture of these conditions, leaving doubt about the existence of this clinically described p h e n o m e n o n . Experimental evidence that hibernation can be induced by the measured reduction of flow adds support to the reality of the phenomenon. In practice, hibernation is difficult to diagnose without positron emission tomography, to confirm metabolic viability despite regionally reduced function and perfusion. Hibernating (like stunned) myocardium may still respond to positive inotropic stimulation. Impaired ventricular function due to hibernation is an indication for revascularisation.
Myocardial infarction Infarction results when ischaemia is prolonged and cellular changes become irreversible. Beginning in the vulnerable subendocardium it extends to "full thickness" as a function of time. Resultant infarct size is a major determinant of subsequent heart failure and of life expectancy. The same considerations of "supply and demand" apply in determining infarct size as they do in angina. The major influences here are the severity and duration of the critical reduction in coronary flow, as modified by pre-existing collaterals and by spontaneous or therapeutic thrombolysis, and any pre-existing state of preconditioning that will buy time. The cause is usually an occluding thrombus that has formed over an "unstable" atheromatous plaque. Acute myocardial infarction is often preceded by brief periods of what in retrospect was unstable angina, attributable presumably to intermittent s2
THE LANCET
thrombus formation as part of the acute coronary syndrome--a dynamic process of thrombus formation, dislodgement, lysis, and further thrombosis that may lead to stuttering progression of the infarction. This variability and clinical uncertainty of timing would account for the bigger time-window for effective thrombolysis than would be predicted from "clean" experimental coronary artery occlusion. The complication of early ventricular fibrillation from still living b u t severely ischaemic myocardium remains a major issue in the management of acute infarction; some half of all patients die before reaching hospital. After infarction, remaining viable heart muscle undergoes compensatory regional hypertrophy with dilation, while the healing infarct flbroses into a scar, in the composite process known as remodelling. Spontaneous recanalisation can be shown to have occurred in some 50% of cases six months later--too late to salvage ischaemic myocardium, though there is some evidence that an open artery in the early phases of repair improves structural remodelling of the heart. Beta-blocker therapy following acute infarction, if not contraindicated, lengthens survival. Angiotensin converting enzyme (ACE) inhibitors, particularly if introduced when left ventricular function is impaired, also prolong survival--perhaps by modifying the adverse neuroendocrine consequences of heart failure, but also by reducing further acute coronary events.
The arteries A therogenesis The real villain of the piece is not the myocardium but coronary atheroma--clinically silent for many years and manifest only by its complications. In the chronic inflammatory condition of atheroma, endothelial function has a seminal role. Low density lipoproteins (LDL) oxidised in transit through the intimal layer of large arteries seem to be a common initiating cause, though almost certainly not the only one. Among the factors that may tilt the balance are circulating levels of LDL, its rate of transport through the artery, antioxidant status in the artery wall, and nitric oxide (NO) activity. NO, among other antiatherogenic actions, exerts an antioxidant effect by interacting with superoxide (02). 02, as well as oxidising LDL, promotes the proliferative processes of atheroma. The ratio of 02 to NO may indeed be important in the balance of pro and anti atherogenic influences. Hypercholesterolaemia, and raised tissue levels of ACE and thus of angiotensin II (AII), for example, induce m e m b r a n e oxidase systems to increase 02 productign; healthy endothelium produces NO, particularly at sites of high flow and shear stress. ACE inhibitors have antiatherogenic potential both by reducing AII levels and by increasing NO production, for NO production is stimulated by endogenous bradykinin whose breakdown is also slowed by ACE inhibitors. Plaque fissure and thrombosis Atheroma in its early stages is not angiographically visible: vascular remodelling ensures that it does not obtrude u p o n the lumen, though it is demonstrable by intravascular ultrasound and at necropsy. A plaque (whose lipid core is liquid at body temperature) may, however, crack at sites of mechanical stress. Platelet adhesion, activation, and aggregation occur, with
Vol 348 • November
1996
THE LANCET
OVERVIEW
thrombosis stimulated by exposed tissue factor, the outcome depending on physical factors of flow and on the balance of pro and anti thrombotic and fibrinolytic influences. Occlusive thrombus can thus develop on minor lesions as well as on critically stenotic lesions. Plaques rich in inflammatory cells--macrophages, T cells, and mast cells--are more prone to develop fissures or erosions than more strongly fibromuscular plaques, independent of the severity of underlying stenosis. 6 Most such episodes will be clinically silent but incorporation of the thrombus will contribute to intermittent growth of the now complex plaque. Indeed, these complications may account for most of the growth of atheromatous coronary stenosis, from the angiographically normal to the critically stenosed artery. Plaque fissure or erosion with thrombosis underlies also the unstable clinical coronary syndrome manifest as unstable angina, myocardial infarction, and sudden death.
Endothelium If endothelial dysfunction participates in sowing the seeds of atherogenesis, measures of endothelial dysfunction may provide a marker of susceptibility to atheroma. When present, endothelial dysfunction is usually widespread throughout the vascular tree and thus accessible to measurement--for example, non-invasive measurement of flow-induced vasodilation in large systemic arteries. 7 This aspect of endothelial function is likely to correlate with those that lead to atherogenesis, both because N O is antiatherogenic and because flow-mediated dilation is impaired (commonly because of increased O 2 production) with all known risk factors for atheroma, including ageing. Endothelial dysfunction can be shown experimentally also to impair microvascular dilator reserve and the homogeneous distribution of perfusion, thus prejudicing tissue perfusion and contributing potentially to ischaemia, s Since endothelial dysfunction underlies both atherogenesis and loss of integrated microvascular fine-tuning, the two will commonly coexist, though the consequences of declining microvascular efficiency will be less dramatic and are less easily investigated. Several conditions characterised overtly by "small vessel disease", such as diabetes, hypertension, and microvascular angina, are associated with endothelial dysfunction.
Microvascular angina Syndrome X, empirically defined as angina with positive exercise test and normal coronary arteriogram in the absence of other cardiac diseasefl is all too common. These practical but soft criteria embrace many with noncardiac chest pain but include some who undoubtedly have a reduced coronary perfusion reserve and inducible regional myocardial ischaemia, due by inference to microvascular d y s f u n c t i o n - - " m i c r o v a s c u l a r angina". Confusingly, another cardiovascular syndrome X (also known as Reaven's syndrome) describes the epidemiological clustering of atheroma, hypertension, insulin resistance, and dyslipidaemia.1° Both syndromes X (the cardiologists' term being restricted to those patients with microvascular angina) seem to be characterised by endothelial dysfunction u and by insulin resistanceY It is even possible that, by chance, they represent different ends of the same s p e c t r u m - - b o t h having coronary atheroma (albeit angiographically "silent" in the one) and microvascular dysfunction (albeit unrecognised in the other). Endothelial dysfunction is associated with insulin
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resistance across a wide range of conditions (including all risk factors for C H D ) and could contribute to ]t by limiting flow-dependent uptake of glucose, so further unifying our concept of this vascular disease complex.
Prevention Measures directed towards (i) preventing or slowing atherogenesis should be distinguished from those which address (ii) plaque instability and (iii) thrombosis/lysis. Clearly these operate at very different phases and over quite different time courses in the evolution of CHD. Experimental and circumstantial evidence suggests that interventions aimed at one phase may, however, affect other phases. Reducing hypercholesterolaemia, for example, is likely to affect both atherogenesis and its thrombotic complications; interventions affecting the cellular processes of atherogenesis are likely to influence also the vulnerabiity of the plaque to fissuring; smoking will favour (and aspirin inhibit) thrombosis, and thereby influence also the silent episodic growth of stenosis; improvement of endothelial function, by antioxidant influences including exercise, oestrogens, and reduction of lipid levels, may be expected to reduce the initiation of atherogenesis, its progression, and also its thrombotic complications. "Prevention" of C H D has predominantly (and by default) been the territory of non-cardiologists, whether based in epidemiology, lipid metabolism, hypertension, diabetes, or public health, while vascular medicine is a yet young specialty and vascular biology is only now beginning to take centre stage. The distinction between primary prevention (before clinical C H D is diagnosed) and secondary prevention (after it has presented clinically) is largely academic except that in secondary prevention the higher absolute risk (and recognition of it) increases both cost-effectiveness and the motivation of patients to comply. The impact of primary prevention has to many been disappointing, perhaps because expectations have been simplistically high, regimens too rigorous, and time-scales too short. Population measures, though small in individual impact, can have larger community effects than more individually effective measures for high-risk individuals. Such community-wide preventive strategies, involving social change and governmental policy (as in relation to tobacco), are likely to have far-reaching effects, but they seem to find less support than health education initiatives, to which the necessary individual responses tend in practice to relapse. T h e roots go deeper and the social subsoil cannot be ignored. Screening for risk helps to target delivery of preventive measures where the stakes are highest, but screening cannot be uncoupled from its consequences and costs. These must be evaluated just as critically as any therapeutic intervention. In secondary prevention, the screening is in effect already done for you.
The future Much has been learnt about environmental factors which increase the risk of CHD. Genetic stratification of risk is also fast becoming possible, generating further questions about the practical consequences of such screening. Targets will become more focused as underlying mechanisms are clarified. Provision of effective therapy for established symptomatic C H D is a costly but uncontested necessity. ~3
ATHEROMA
The principles are highly developed and well-established though still the subject of intensive refinement and evaluation. The issue here is to ensure that new developments and their implementation are guided by science and evidence, rather than by the seductions of technology and the interests of industry. The many people with unrecognised but treatable CHD are a further target for improving overall management of C H D in the community, and thus also its secondary prevention. Many with angina remain undiagnosed. Worse still, many with unstable coronary syndrome escape the benefits of urgent medical management. The net might also be cast more widely to identify patients with very early evidence of reversible disease, as manifest by endothelial dysfunction. This is now a practical possibility with non-invasive tests, albeit only as a research procedure to date. Endothelial dysfunction is amenable to improvement and could perhaps provide a surrogate target for therapy. Advances on many fronts, not least of communication between those active in the many aspects of C H D causation, prevention, and management, are combining to bring a sense of real and further imminent progress. This article has been a general view. T h e rest of the Supplement is taken up with specialist views of CHD, ending with the insights of a cardiologist-patient.
THE LANCET
References 1
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Tunstall-Pedoe H. Cardiovacular diseases. In: Detels R, Holland W, McEwen J, O m e n n GS, eds. Oxford textbook of public health. Oxford: Oxford Medical, 1996. Barker DJP, Osmond C, Golding J, K u h D, Wadsworth MEJ. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 1989; 298: 564-67. Murray CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal ceil injury in ischemic myocardium. Circulation 1986; 74: 1124-36. Braunwald E, IGoner RA. The stunned myocardium prolonged postischemic ventricular dysfunction. Circulation 1983; 6 6 : 1 1 4 6 - 4 9 . Rahimtoola SH. The hibernating myocardium. Am HeartJ 1989; 117: 21121. Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. BrHeartJ 1985; 53: 363-73. Ramsey MW, Goodfenow J, Jones CJH, Luddington LA, Lewis MJ, Henderson AH. Endothelial control of arterial distensibility is impaired in chronic heart failure. Circulation 1995; 92: 3212-19. Griffith T M , Edwards D H , Davies RLI, Harrison TJ, Evans KT. E D R F co-ordinates the behaviour of vascular resistance vessels. Nature 1987; 329: 442-45. Editorial. Syndrome X. Lancet 1987; ii: 1247-48. Reaven G M . Role of insulin resistance in h u m a n disease. Diabetes 1988; 37: 1595-1607. Egashira K, Inou T, Hirooka Y, Yamada A, Urabe Y, Takeshita A. Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. N EnglJ Med 1993; 3 2 8 : 1 6 5 9 - 6 4 . Goodfellow J, Owens D, Henderson A. Cardiovascular syndromes X, endothelial dysfunction and insulin resistance. Diabetes Res Clin Prac 1996; 31 (suppl 1): 163-71.
Atheroma: more than mush
Peter Libby Not long ago, most physicians envisaged atheroma as an inert collection of cholesterol, calcium, and fibrous tissue that grew steadily and ineluctably until it eventually obstructed an artery and impeded blood flow. Over the past few years the picture has evolved considerably, as clinical and pathological insights have pointed the way for rethinking atherogenesis at the level of cell and molecular biology. Rather than viewing atheroma as progressive clogging of the pipes with nondescript, amorphous sludge, we now appreciate the dynamic and vital aspects of atheroma. These lesions team with cells, particularly in their early phases. The cellular residents of the lesion include intrinsic vascular wall cells such as endothelium and smooth muscle (figure 1). In addition to these indigenous cells, the biological role of infiltrating leucocytes attracts ever-growing attention. These various cell types actively exchange messages that regulate functions critical to lesion initiation and progression and to clinical complications. An u n d e r s t a n d i n g of the clinical manifestations of coronary atherosclerosis requires knowledge of this cellular interplay, the theme of this article. We now recognise that the function of cells within lesions can influence the clinical manifestations of atherosclerosis more decisively than the mere anatomy. As pointed out by Valentin Fuster and his colleagues (p s7), lesions that do not critically stenose coronary arteries may nonetheless provoke coronary thromboses. 1 Such thrombi, if non-occlusive or evanescent, can precipitate episodes of unstable angina pectoris. If the intracoronary clot becomes s4
obstructive and persists, acute myocardial infarction may result. Likewise, dysfunction of morphologically intact endothelium, rather than frank denudation of these cells, can seriously disrupt coronary haemodynamics (see Andreas Zeiher's contribution, p sl0). For example, atherosclerotic coronary arteries, or even those exposed to humoral conditions associated with atherogenesis such as hypercholesterolaemia, may be unable to vasodilate normally in response to neurohumoral stimuli? Thus, altered behaviour of cells, often morphologically inapparent, may promote vasospastic components of the acute coronary syndromes in addition to the thrombotic aspects.
Cellular activation What regulates these cellular functions that determine such clinically important features of atherosclerosis? Work performed in the 1950s identified the early arrival of blood-borne monocytes in lesion formation. Poole and Florey stated: "in rabbits fed with cholesterol there appears to be some patchy alteration in aortic endothelium as . . . macrophages adhere"2 These workers stated that the problem could not be "profitably pursued" with the tools available to them in mid-century.
Adhesion molecules Today the technology exists; and we know of specific adhesion molecules on the surface of endothelial cells that
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