the vicious circle ef ischemic left ventricular dysfunction

The vicious Circle of lschemic Wt Ventricular Dysfunction

Charles Knight, MA, MRCP, and Kim Fox, MD

Myocardial ischemia tends to be self-propagating, metabolic reserve of the myocyte, even short per+ and minor events such as plaque rupture can lead ods of ischemia can lead to left ventricular dysfunc- to the catastrophic sequelae of myocardial infarction and arrhythmias. This article examines the tion and death. The biology of the endothelium and clinical implications of the disordered biology of the the cardiac myocyte is crucial to the development of endothelial cell and the myocyte that is the basis for these vicious circles. The abnormal responses of the ischemic left ventricular dysfunction. endothelial cell in atherosclerosis tend to provoke (Am J Cardiol 1995;75: 1 OE-1 SE) and propagate &hernia, and because of the limited

T he simple statement that cardiac muscle contracts less forcefully when deprived of part of its blood flow belies the complex

series of vascular interactions that occur during episodes of ischemic left ventricular dysfunction. Just as in health the biologic characteristics of the endothelium and the myocardium determine cardiovascular physiology, the effect of atherosclerosis on these biologic parameters delineates the patho- physiology of ischemic heart disease. Our view of both of these important tissues has been changed radically over the last decade.

In the past, the coronary vasculature has been regarded as an inert transport system that, although able to contain and deliver blood, is not capable of interaction with blood or the surround- ing myocardium. The only implication of atherosclerotic obstruction to such a system was thought to be mechanical: a fixed limitation to the supply of blood generating ischemia under conditions of increased demand. It is now clear that the endothelium (whose total weight is some 4-5 times that of the heart) is not merely a passive vascular lining but an organ system whose central role is to sense, and respond to, changes in shear stress and blood flow. Disturbance of this function may induce pathologic vasomotor responses to even small alterations in the local vascular milieu, destroying the delicate homeostatic balance that usually operates to link blood flow to tissue demand. The disease process of atherosclerosis is not only a conse- quence of obstruction of flow, but also involves the absence or modification of normal endothelial function.

From the Royal Brompton National Heart and Lung Hospital, London, United Kingdom.

Address for reprints: Charles Knight, MRCP, Roy01 Brompton National Heart and Lung Hospital, Sydney Street, London SW3 6NP, United Kingdom.

In addition, the myocyte, previously regarded as operating only in a binary fashion, either contracting fully in the presence of an uninterrupted blood supply, or not contracting at all if its perfusion is suspended, is capable of a much wider set of responses to ischemia. It may be preconditioned to resist subsequent ischemic episodes by a brief alteration in coronary flow, it may be stunned by a longer period of ischemia, and it may hibernate in response to chronic partial deprivation of its blood supply. Despite this, it is still acutely sensitive to ischemia as a result of its limited metabolic reserve.

There is a great deal of evidence that ischemia, once generated, will tend to be propagated by inappropriate pathologic responses in the patient with coronary artery disease. The 2 key biologic parameters driving these vicious circles are the altered endothelial response and the sensitivity of myocardial function to ischemia. In this brief article, we examine the endothelial contribution to the development of ischemia, the myocardial reac- tions that result in ventricular dysfunction, and the protective mechanisms that may limit it.

THE ENDOTHELIUM AND THE GENERATION OF ISCHEMA

Vasomotor changes, while far from being the primary pathologic mechanism in coronary artery disease, are important determinants of symptom variation and possibly of progression to unstable coronary syndromes. The abnormal behavior of the diseased coronary vessel tends to propagate rather than mitigate ischemia. An altered endothelial response is probably the basis for the vicious circle in which ischemia may generate further ischemia.

The recent interest in the endothclium stems from the discovery that its presence is essential for acetylcholine-induced vasodilation. In vitro work showed that arterial segments changed their re-

10E THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 75 APRIL 27, 1995

sponse to acetylcholine from vasodilation to vasoconstriction when the endothelium was removed.’ Vascular smooth muscle was therefore shown to be under some endothelial control, probably as a result of a diffusible factor produced in the endothe- hum and acting on the smooth muscle to produce relaxation. This factor was named endothelium- derived relaxing factor (EDRF). There is considerable evidence that nitric oxide, a labile inorganic gas, is the biologically active component of EDRF.2 EDRF is only one of a large number of vasoactive factors secreted by endothelial cells. Other vasodi- later (e.g., endothelium-derived hyperpolarizing factor) and vasoconstrictor (e.g., endothelin) sub- stances have now been described. The resting basal tone of blood vessels is dependent on constant basal endothelial production of nitric oxide,’ and the endothelium can also alter vascular tone by changing the secretion of 2 1 of its vasoactive factors in response to changes in shear stress. The endothelium can therefore exert a profound effect on blood flow and pressure by transducing endothelial signals into cyclic guanosinc monophosphate- dependent relaxation of vascular smooth muscle.

The endothelium is probably involved from the outset in the development of atherosclerosis, and it is not surprising that the disease appears to disturb its function. At the simplest level, the atherosclerotic artery behaves in an analogous fashion to the isolated arterial strip denuded of endothelium, in that its response to acetylcholine is changed from vasodilation to vasoconstriction. The abnormal endothelium seems incapable of the correct secretion of its vasoactive messengers. Experiments in humans have shown that intracoronary acetylcholine causes endothelium-dependent vasodilation of normal coronary arteries, which is abolished by preadministration of the nitric oxide synthase in- hibitor, L-NG-monomethyl- I -arginine ( L-NMMA).J Ludmer et al5 showed that in patients with signifi- cantly stenosed coronary arteries the response to acetylcholine was changed to vasoconstriction. This did not seem to be the result of abnormal smooth muscle function, as there was a normal response to the endothelium-independent vasodilator nitroglycerin. The presence of an angiographic abnormality represents a late stage in the atherosclerotic process; there is now evidence that endothelial dysfunction, as manifested by an abnormal response to acetylcholine, may be detected in earlier stages of the disease. Acetylcholine causes constriction not only of stenotic, but also of angiographically smooth arterial segments in the patient with coronary artery disease,h and loss of endothelium-depen-

dent relaxation is also seen in patients with risk factors for ischemic heart disease but angiographi- tally normal coronary arteries. In one study, the more risk factors (male sex, elevated cholesterol concentration, positive family history, and age) that the patient had, the more likely the arteries were to constrict when acetylcholine was adminis- tered.’ Abnormalities of arterial vasomotion have also been shown to occur in patients with a single risk factor for atherosclerosis (hypertension)s and in patients with syndrome X.”

Although the endothelial response to intracoronary acetylcholine may provide a useful marker for endothelial dysfunction, it tells little about the physiologic responses of the artery in health and disease. Further work has shown that atherosclc- rotic coronary arteries also exhibit abnormalities of vasomotion in response to increased flow. Proximal segments of angiographically smooth coronary ar- tcries dilate in response to 3-fold increases in flow induced by the resistance vessel dilator papaverine, whereas stenotic arteries fail to dilate and in some cases constrict.“’ Other physiologic stimuli such as exercise,” stress,” and exposure to cold” have also been shown to provoke an abnormal response in coronary artery disease. The mechanism behind these changes may be an abnormal response to catecholamines, as coronary artery segments that exhibit endothelial dysfunction (a constrictor response to acetylcholine) constrict with a l(K)-fold lower concentration of phenylephrine than normal arteries.‘j

The cndothelium reacts not only with the smooth muscle, but also with its other neighbor, blood. EDRF can inhibit aggregation and adhesion of platelets,t5 and aggregating platelets cause endothe- hum-dependent relaxation in isolated segments of human coronary arterics,t6 possibly as the result of platelet products such as adenosine diphosphate and adenosine triphosphatc (ATP) and serotonin. However, with an absent or dysfunctional endothelium, thromboxane A2 and serotonin released from platelets produce vasoconstriction via a direct cf- feet on smooth muscle. In addition, thrombin causes the release of the vasoconstrictor endothelin from the intact endothelium and also causes direct smooth muscle contraction if the endothelium is absent. In the setting of a stimulus to thrombus formation, such as plaque rupture, normal endothelial function, acting as a negative feedback loop to limit vasoconstriction and further thrombus formation, will be absent in coronary artery disease and there will be a predisposition for further lumjnal reduction, initiating the vicious

A SYMPOSIUM: LEFT VENTRICULAR DYSFUNCTION 11E

circle that can lead to myocardial infarction. The situation will worsen as thrombus accumulates, because thrombus itself is one of the most power- fully thrombogenic surfaces,i7 and catecholamine levels rise, causing more platelet aggregation and thrombin generation. l8 The catecholamine release consequent on ischemia, in addition to promoting vasoconstriction and thrombosis, also causes an increase in heart rate and blood pressure, which will increase myocardial oxygen demand at the same time as shortening diastole and thus the time available for coronary perfusion. Once a brief period of ischemia is established, however, its effects go beyond the responses of the vasculature and involve the target tissue, the myocardium.

MYOCARDIAL RESPONSE TO ISCHEMA Metabolic consequences of ischemia on the

myocyte: The human myocyte is acutely sensitive to the effects of ischemia, and a cessation of blood flow to the myocardium causes a rapid arrest of contraction. Under usual circumstances, the myocyte is dependent on aerobic metabolism and contains large numbers of mitochondria. The metabolic and ionic consequences of ischemia are complex and beyond the scope of this article. In brief, ATP depletion following exhaustion of glycogen, which is consumed rapidly during a brief period of anerobic metabolism, causes activation of the ATP- sensitive potassium channel. This has 2 principal effects. First, it results in a shortening of the action potential, leading to a reduction in the trigger for sarcoplasmic reticular calcium release, hence reducing contraction. Second, it allows a rise in the extracellular potassium concentration, which induces membrane depolarization and may trigger arrhythmias. In addition, ATP depletion causes a rise in intracellular sodium as the activity of the Na+K+-ATPase is reduced. Ionic calcium concen- trations in the cell also rise as the sodium-calcium exchange reverses. ly The level of ionic calcium concentration achieved during an episode of ischemia seems to be a marker of the subsequent fate of the myocyte on reperfusion.20v21 After a short period of ischemia, reoxygenation of a previously anoxic single myocyte results in full morphologic and functional recovery, whereas an anoxic insult of 220 minutes results in hypercontracture and disruption of the already damaged cytoskeleton on reoxygenation. It is clear, however, even in single cell studies, that there is considerable variation in the response to hypoxia, both between different cells and between levels of oxygen deprivation.

There is evidence that abnormalities persist in

the myocyte for several days following a brief ischemic insult, despite adequate reperfusion. These abnormalities, such as ATP and glycogen depletion, mitochondrial edema, and clumping of nuclear chromatin, correlate with the impaired myocardial function following ischemia, known as myocardial stunning. The metabolic basis for stunning may be myofilament desensitization to calcium as a result of transient exposure to high levels of intracellular calcium during ischemia.22

Clinical sequelae of episodes of myocardial &hernia: The consequences of ischemia on the intact human heart have also been extensively studied. Percutaneous transluminal coronary angio- plasty (PTCA) has allowed the detailed study of the hemodynamic consequences of a period of coronary occlusion. Serruys et a123 studied a variety of parameters in 19 patients undergoing PTCA. The earliest manifestation of ischemia was impairment of early relaxation, which occurred between 1 and 15 seconds after the onset of ischemia. This was followed by further changes, such as a rise in left ventricular filling pressure. These periods of occlusion, lasting 51 2 12 seconds, were insuffi- cient to stun the myocardium, and full recovery of function returned rapidly after balloon deflation. Sigwart et al,24 in a similar study, noted a sequence of changes following balloon inflation that again began with relaxation failure. Next, there was contraction failure, then an increase in filling pressures, and then the onset of electrocardio- graphic changes at around 20 seconds. All these parameters were affected before the onset of angina1 pain at around 25 seconds (Figure 1).

Neither the observation of changes occurring in the single myocyte, nor the effect of a sudden balloon inflation in a single coronary artery, can completely mimic the effects of ischemia experi- enced during daily life in chronic, stable angina pectoris. In this much more heterogeneous situation, different areas of the myocardium may be exposed to different gradations of ischemia for varying periods of time. There is evidence, however, that left ventricular function is reduced during periods of ischemia, both silent and painful, in patients with stable angina. A reduction in ejection fraction has been shown during exercise radionu- elide ventriculography,25 and also during mental stress.% In a study of 19 patients with stable angina who underwent simultaneous ambulatory ST- segment and pulmonary artery pressure monitoring,27 the overwhelming majority of episodes of painless and painful ischemia were associated with a significant rise in the pulmonary artery pressure.


Despite cvidcnce that a small amount of blood flow to the ischemic region (as might be expected during episodes of ischemia in this setting) mark- edly cnhanccs the rate of recovery of contractile function following rcperfusion, it seems that even brief episodes of ischemia induced by cxcrcise can result in some degree of myocardial stunning.‘” Fragasso et al” studied the effect of symptom- limited exercise testing on left ventricular function in I5 patients. Ejection fraction became normal during the recovery phase, but peak filling rates were still reduced 2 days after exercise.

The effects of ischcmic myocardial dysfunction tend to propagate rather than diminish ischemia. Ischcmia promotes left ventricular dilation and a rise in left ventricular filling pressure, which causes a worsening of the demand/how balance by increasing myocardial oxygen demand and reducing coronary flow. Ischemia may also result in mitral regurgitation. Hypokinesia of the ventricular segment overlying the papillary muscle can cause retraction of the mitral leaflets, which then fail to coapt.“” There is also cvidcnce that the development of ischemia worsens the situation by affecting the endothelium and that damage to the endothelium may have direct cffccts on the myocardium.

In a study of the effect of a brief period of ischcmia (15 minutes), followed by reperfusion, isolated canine coronary artery rings showed impairment of the vasodilator response to acetylcholine for the first hour after reperfusion, with gradual recovery over 90 minutes.3’ These periods of ischemia were not sufficient to cause either structural endothelial damage, assessed by transmission elec- tron microscopy, or blunting of endothelium- independent smooth muscle response. This implies that in the case of repeated short episodes of ischcmia, such as might occur during unstable angina, there may be progressive impairment of

endothelial function, leading to the generation of further thrombosis and vasospasm.

Independent of ischemia induced by intraluminal occlusion, there is intriguing evidence that both vascular and endocardial endothelium can modify the contraction of adjacent myocardium.“’ Nitric oxide has a number of actions on the myocyte, increasing diastolic cell length and diminishing peak contractile performance. It has been sug- gcstcd that increased endothelial shear stress induces endothclial release of nitric oxide or other EDRFs, which act on the myocardium to produce an earlier onset of relaxation and greater diastolic distensibility, thus improving coronary and suben- docardial perfusion.“’ Whether this homeostatic system will prove to be of physiologic importance or whether its disruption is a factor in ischemic left ventricular dysfunction is at present unclear. A study in isolated rabbit papillary muscles showed that the induction of coronary endothelial dysfunction, by injecting Triton X-100 into the aorta, induced changes in the contraction of adjacent myocardium.3’ Studying such alterations at the level of cell-to-ccl1 communication between cndo- thclium and myocardium may improve our under- standing of the mechanisms of ventricular dysfunction in coronary disease.

The delicate homeostatic balances that are re- quired for local vascular control depend on the functioning of a healthy cndothelium. Increased myocardial oxygen demand on stress or exertion is matched, via cndothelial transduction, by an appro- priate increase in coronary blood flow. When the endothelium is damaged by atherosclerosis, these mechanisms preventing myocardial ischemia and intraluminal thrombosis are changed into pathologic responses that tend to propagate ischemia via catccholamine-induced vasoconstriction and thrombus generation. In addition, once ischemia is initi- ated, there is a rapid decline in left ventricular

FIGURE 1. Appeamnce of events during tmnsht coronary ocdu- sion. ECG = ektmcardioam&ic. (Reprinted with permissionfrkm Sigwart et aLz4)

Angina

ECG changes 1

Occlusion Time (set)

A SYMPOSIUM: LEFT VENTRICUWR DYSFUNCTION 13E

function, the structural consequences of which are a further reduction in coronary perfusion. Further ischemia may induce a period of stunning of both myocardium and endothelium, lowering the thresh- old for further ischemic insults, even if perfusion is returned in time to save the myocytc from irrevers- ible damage. The disturbances of homeostasis at cellular, tissue, and organ level within the myocardium and the endothelium in ischcmic heart disease limit the adaptability of the cardiovascular system and increase its fragility to relatively small insults. Thus, a relatively minor random event, such as plaque fissure, may initiate a complex series of inappropriate vascular responses that build on each other to produce the unstable coronary syndromes.

PROTECTIVE MECHANISMS It would be quite wrong to suggest that all

episodes of ischemia progress irreversibly toward myocardial infarction. Although local vascular homeostasis is impaired in coronary artery disease, a range of other protective mechanisms occur to terminate episodes of myocardial ischemia. The first, and probably most important of these, is the alerting signal of angina1 pain, prompting the patient to cease activity or use nitroglycerin, thus diminishing myocardial oxygen demand. However, much ischemia is silent, and other mechanisms apply: collateral blood vessels may both open acutely and develop over time to improve blood flow. In the presence of obstruction to flow in a coronary artery, flow across small preexisting collateral channels increases, leading to an increase in their size. This can occur rapidly, for example during episodes of coronary spasm, where collateral vessels can be seen to appear and disappear on angiography within minutcsJ4 Patients in whom collateral vessels supply flow to an occluded artery during the acute phase of myocardial infarction have been shown to maintain left ventricular ejection fraction better than patients without such flow,“” which suggests that collateral blood flow can make a significant contribution to myocardial pcr- fusion. The role of repeated episodes of ischemia and hypoxia in promoting collateral growth and development is not yet clear and there may well be a genetic predisposition toward collateral development.36 Manipulation of angiogenesis is a conceiv- able strategy for augmenting myocardial revascular- ization procedures in the future.

Independently of collateral opening, cpisodcs of ischemia can help to increase myocardial resistance to further ischemia by ischemic precondition-

ing. In animal experiments, myocardium that was pretreated with brief episodes of ischemia was better able to withstand the effect of sustained ischemia.“‘These findings have also been reported, independent of changes in collateral flow, in humans during intermittent cross-clamp fibrillation at coronary artery bypass grafting.jx It has been sug- gested that factors such as adenosine, nitric oxide, prostacyclin, and free radicals produced during the initial episodes can alter the response of the myocardium toward subsequent episodes of ischemia.

A variety of protective mechanisms therefore can operate to allow stable angina1 symptoms to remain static over many years. The basic alterations in local vascular homeostasis do, however, mean that even minor alterations in plaque struc- turc can upset these delicate protective feedback loops and, via thrombosis and vasospasm, initiate deterioration into unstable coronary syndromes.

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the vicious circle ef ischemic left ventricular dysfunction

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