Factors determining the activity of ischemic heart disease

Factors Determining the Activity of lschemic Heart Disease

STEPHEN CAMPBELL, B.Sc., M.R.C.P. MICHAEL B. ROCCO, M.D. ELIZABETH G. NABEL, M.D. JOAN BARRY, B.A. GEORGE S. REBECCA, M.D. JOHN E. DEANFIELD, M.R.C.P. ANDREW P. SELWYN, M.D.

Boston, Massachusetts

From the Department of Medicine (Cardiovascular Division), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts. This work was done during the tenure of a British-American Research Fellowship of the American Heart Asso- ciation and the British Heart Foundation, with Dr. Stephen Campbell the recipient. Requests for re- prints should be addressed to Dr. Andrew P. Sel- wyn, Cardiovascular Division, Brigham and Wom- en’s Hospital, 75 Francis Street, Boston, Massa- chusetts 02115.

Transient regional myocardial ischemia appears to underlie symp toms such as angina pectoris and represents a key pathophysiologic step, since it is an objective marker of disease activity and is capable of causing disabling symptoms and damage to left ventricular myocardium. A study of the characteristics of transient ischemia in and out of the hospital has shown that symptoms are an inconsistent underestimation of these events. lschemia is generally prolonged, mostly asymptomatic, and usually accompanied by a regional decrease in myocardial perfusion. Studies out of the hospital have also shown that these episodes are frequently triggered by a wide range of ordinary everyday activities. These new features of transient ischemia are worth noting when searching for relevant causes that are present during everyday life and when trying to choose more rational therapy. More detailed studies of patient activity have shown that different levels of mental arousal are the most common triggering mechanism causing ischemia out of the hospital. In addition, the occurrence of transient ischemia during every day life displays a circadian rhythm, with an increase and peak occurrence between 6:00 A.M. and 12 noon each day. The day-to-day variability of ischemia is marked, indicating functional disturbances of coronary stenoses against a background of a severe reduction in cross-sectional area. The examination of proximal stenoses has shown that (1) the reduction in cross-sectional area is usually underestimated by conventional angiography; (2) pressure gradients across coronary stenoses are common and, with reduced poststenotic blood pressure, can jeopardize perfusion; (3) disturbances of vessel caliber and antegrade flow can accompany many of the ordinary everyday activities known to trigger ischemia detected in Hol- ter tapes studied out of the hospital; and (4) there is clear-cut evidence of endothelial dysfunction in these patients, with reversal of the normal dilator response to acetylcholine and paradoxical constriction of stenoses. This evidence of endothelial dysfunction in humans could be central to the problems of atheromatous narrowing, thrombus, and disturbed vasomotion.

Despite evidence of a recent decline [I ,2] in ischemic heart disease, it remains the major cause of mortality in the United States, accounting for 500,000 deaths annually [3], many of which are sudden and unexpected. This mortality rate is overwhelmingly due to coronary atherosclerosis that develops over two or three decades [4] with no clinical manifestations until plaque development is sufficient to cause significant reductions in the cross-sectional areas of epicardial coronary arteries [5]. Despite the

April 30, 1986 The American Journal of Medicine Volume 80 (suppl 4C) 9

SYMPOSIUM ON EXPLORING MYOCARDIAL ISCHEMIA-CAMPBELL ET AL

Afegofve F&back

1 Descefdhg 5 H-TNeuron

-I h Dorso/afero/

Funicu/us

- - Primary -

\tt- Sympafiefk _

Figure 7. Schematic diagram of pathways that are likely to participate in cardiac nociception. Free nerve endings of ventricular sympathetic afferents are ex- cited by a variety of chemical and mechanical stimuli that may be produced during ischemia. Modulation of the sen- sory input may then occur at a spinal segmental level by both local and descending inputs. The latter may involve a system that is proposed to descend from the periaqueductal gray (PAG) of the midbrain via the nucleus raphe magnus (NRM) of the medulla and involve enkephalin (E) and serotonergic (5H-T) neurons. This system would act to inhibit the primary nociceptive afferents and may be stimulated by secondary afferent fibers via the reticular formation and nucleus raphe magnus, thus forming a neg- ative feedback loop for modulation of pain sensation.

many therapeutic modalities currently available, the out- look for patients with coronary disease is quite different from that of a population with normal coronary arteries [6]. It is, therefore, reasonable to search for those factors that determine the onset of “activity” of ischemic heart disease-i.e., the point at which previously clinically silent coronary atherosclerosis becomes complicated by the occurrence of transient regional myocardial ischemia that may result in symptoms and damage to the ventricular myocardium [7].

The aims of this article are to reexamine the role of chest pain in the assessment of clinical ischemic heart disease activity; to consider the new information available concerning the nature and causes of transient ischemic activity that occurs out of the hospital and that underlies the symptoms of coronary artery disease; and to examine what is known about the changing pathology of coronary

atherosclerosis and how it may cause the exacerbations and remissions of ischemic heart disease activity observed in most patients.

PATHOPHYSIOLOGY OF CARDIAC PAIN

Cardiac nociception is believed to be subserved mainly by primary sympathetic afferents [8-111. These run in the cardiac nerves to the upper five thoracic sympathetic gan- glia and thence, primarily via white rami communicantes to the upper five thoracic dorsal roots of the spinal cord [8,9]. Within the cord, the sympathetic afferents synapse with secondary afferents of the spinothalamic tract that ascend to the thalamus, from which projections may pass to the cortex. Some contribution from vagal afferents may also play a role, especially in referred pain [9].

The precise nature of the nociceptors remains un- known, but they are probably free nerve endings that may

10 April 30, 1988 The American Journal of Medicine Volume 80 (suppl 4C)


Faiher Q

82 to S9 one minute b;e;fOrb

Ewv 0 d 0

ACW77-Y Driving a cai

Tgurc? 2. Ari example of 2 typical lo-minutb e&ode of painless ST-segment depression that occurred while a patient wit; angina and coronary attery disease was driving a car.

be responsive to both mechanical and local chemical stimuli [9]. These local chemical stimuli probably include bradykinin [9,12], potassium [13], and acids [9,14], all of which are produced during ischemia [15-171. These stimuli appear to exhibit threshold and interactive effects that may be important in niodujating bain at the level of the receptor. In addition, there is, now considerable exljeri- mental evidence that nociceptive stimuli may be extenz sively modulated within the central nervous system via both segmental [18] and higher mechanisms. [I g-211. Some of the mechanisms proposed would appear to involve endogenous opioid neurotransmitters [19:21], although nonopioid systems are probably also involved [2i]. Thus, the potential for modulation of cardiac pain exists at many levels, as illustrated schematically in Fig& 1; therefore, it should not be surprising that pain may be a very unpredictable symptom on the basis of these mechanisms alohe.

PAIN AS A MARKET 6~ ISCHEMIA

In clinical practice, chest pain is still used as a guide to disease “activity” in patients with ischemic heart disease, although the development of ischemia unaccompanied by pain has frequently been observed during various forms of stress testing [23-261. Numerous studies using ambulatory monitoring of the ST-T segment in symijtomatic patients tvith known or probable coronary artery disease [27- 33] have shown that the majority of ischemfc episodes (59

April 30, 1988 The American Journal of Medicine Volume 80 (suppl 4C)

to 87 percent) that occur during normal daily activities are, in fact, asymptomatic. Figure 2 illustrates this point. In addition, the 30-year follow-up of the Framingham Study [34] confirmed that more, than 25 percent of myocardial infarctions in a “general population” may occur unrecog- nizedi and about half of these may be silent.

Thus, although ischemia .may indeed result in chest pain, the relationship betwe,&, the two is unpredictable. Accordingly, chest pain must now be regarded as an un- reliable marker of the frequency, and perhaps the severity, of ischemic events in patients with coronary artery disease.

MYOCARdlAL ISCHEMIA Il’i CilNlCAL PRACTiCE

fvluch has been learned from.the experimental laboratory about the effects of transient regional ischemia on the myocardium [7,35] and its evolution to myocardial infarction [36]. However, beyond the useful principle of imbdl- ahce between’ supply and demand, it seems cieai that there is no satisfactory experimental model for the charac- ter or causes of ischemic heart disease activity in humans. The severity of angina pecioris [371 and the ability to elicit evidence of ischemia during stress testing, especially at low workloads [38] and even in the absence of symptoms [39,40], are now kho?n to be associated with an adverse prognosjs. This evidence of ischemjc heart disease activity can therefore be used to assess prognosis without ie- gard to coronary anatomy and left ventricular function.

11


CONTROL SMOKING

EXERCISE POST.

15 MINS POST.

-

Indeed, the traditional use of the assessment of coronary occlusive disease and the extent of damage to ventricular function takes into account only established and appar- ently fixed changes in epicardial coronary arteries and contractile function of the heart, whereas the study and understanding of transient ischemia addresses a poten- tially damaging, but reversible, aspect of the disease.

Transient ST-segment depression ,during ambulatory monitoring has been validated as a reasonable and quantitative marker of isctiemic heart disease activity in people with typical angina and proven, coronary disease [33]. It has been demonstrated that these patients commonly have asymptomatic myocardial ischemia that is surpris- ihgly prolonged and that js triggered by a variety of everyday activities [28,29,31,32]. This raises the issue in each patient of the “total ischemic activity,” which may need management apart from the traditional approach to the relief of chest pain.

Positron emission tomography has been used to mea- sure the regional myocaibial uptake of rubidium-82 as a marker of regional coronary blood flow [32,33,41]. Normal subjects show homogeneous increases in regional myocardial perfus/on with exposure to cold, mental arithmetic, and exercise, whereas patients with angina and coronary disease show inhomogeneous regional perfusion charac- terized by increased perfusion in remote areas and absolute decreases in perfusion in poststenotic segments of the myocardium [33]. As shown in the examples (hgbres 3 and 4), ischemic disturbances in regional myocardial perfusion may occur spontaneously or in response to a

Figure 3. Positron emission tomograms dembnstrating changes in regipnal myocardial uptake of rubidium-82 during smoking and exercise. Note thai the control scan shows uniform uptdke; with smoking and exercise, .defects appear in the anterior and free walls of the left ventricle (arrows) and resolve thereafter.

variety of stimuli (exercise, mental arithmetic, cold exposure, cigarette smoking), but neariy always include an absolute decrease in perfusion in the affected segment (Figure 5). This may occur because of a pathologic decrease in poststenotic perfusion pressure and a failure of endocardial perfusion, both caused by an increased myocardial oxygen demand and dilation of the resistance vessels in the presence of fixed critical stenoses; collapse of the distal stenosis and poststenotic epicardial coronary artery segment owing to a pathologic decrease in the poststenotic distending pressure; sympathetically mediated constriction of epicardial coronary arteries around a critical segmental narrowing due to atherosclerosis; or an inappropriate reaction of critically stenosed epicardial coronary arteries to neurohumoral and/or cellular factors because of vasomotor dysfunction resulting from the presence of atherosclerotic lesions (to be discussed later).

The examples shown in the figures demonstrate that different patterns of disturbed regional perfusion can develop in each patient. Stimuli such as exercise cause increased perfusion in remote areas of the myocardium, presumably in response to the increase in the double product and myocardial oxygen demand. At the same time, the affected segment shows-a decrease in perfusion [32,33], This type of response appears to be associated with both chest pain and electrocardiographic signs of ischemia [32,33]. Conversely, cold exposure and spontaneous ischemia are associated with a much smaller increase in the double product and, therefore, less of an increase in


SYMPOSIUM ON EXPLORING MYOCARDIAL ISCHEMIA-CAMPBELL E-f AL

Figure 4. Regional myocardial cfistribu- tion of rubidium-82 in positron emission tomograms during spontaneous episodes of ischemia and mental arithmetic stress in a patient with previous anterior infarction. Note the fixed anterior defect; during the spontaneous and stress- induced episodes, the defect enlarges (arrows) to include the septum. These changes are reversible, as seen after administration of isosorbide dinitrate (ISDN).

perfusion in remote areas of the myocardium; however, these types of ischemia still show a decrease in perfusion in the affected segment. This sequence of events is usually “silent” [32,33]. The rational approach to the treat: ment of these ischemic disturbances in regional coronary blood flow must consider the invariably occurring decreases in regional perfusion. Since the occurrence of pain and electrocardiographic signs of ischemia seem to depend on the affected segment’s being subjected to both decreased perfusion and increased demand [32], therapy should probably be directed toward both mechanisms.

THE “ACTIVE” CORONARY LESION

The vast majority of patients presenting with clinical signs of ischemic heart disease already have important atheromatous narrowing of at least one epicardial coronary artery [42]. The severity of these lesions is underestimated by conventional at-teriography [43-453. However, quantitative arteriography has shown that the minimum cross- sectional area appears to be the major static factor affecting flow [5], although determinants such as lesion length, eccentricity [46], and collaterals [47] are also important. Nevertheless, this simple understanding does not explain the fluctuating exacerbations and remissions in disease activity that typically affect these patients. Recent experimental, pathologic, and clinical research has elucidated a number of pathophysiologic features in the evolution of atheromatous lesions that might well explain the fluctuating clinical activity. These physical, humoral, and cellular factors may be central not only to the further development of atheroma but also to the functional disturbances that lead to the “active ischemic state,” with all its attendant symptoms, morbidity, and mortality.

DEVELOPMENT OF PLAQUE

The processes responsible for atherogenesis [4] result in disease progression that eventually may produce fixed stenosis that is sufficient to produce impairment of flow. This impairment initially occurs in the context of increased demand; eventually, it occurs even at rest. This process is usually gradual, but plaques can enlarge rapidly. Evi- dence of disease progression in vivo has been demonstrated in a series of patients restudied angiographically shortly after an episode of unstable angina [48]. Stenoses in unstable angina also have been noted to be more com- plex and associated with thrombus more often than stenoses occurring in patients with stable symptoms [49,50]. Plaque development changes the normal elastic proper- ties of a vessel wall, and fissuring, hemorrhage, and rup- ture can abruptly worsen the lesion [51].

THROMBOSIS

The role of platelets in classic stable angina related to increased myocardial oxygen demand is uncertain [52-- 541, but platelets have been implicated in unstable angina [55], myocardial infarction [SS], and sudden death [57]. Indeed, platelet deposition, with subsequent aggregation and release of thromboxane A2 and other vasoactive substances, including platelet-derived growth factor [58], may play a pivotal role in the development of acute ischemic syndromes [40]. These processes are normally inhibited by the presence of an intact endothelium; this may be due, in part, to the production of prostacyclin, but also may be attributable to an endothelial-dependent dilatation triggered by platelet products [40]. This tends to lead to increased flow and inhibition of further aggregation. When

April 30, 1986 The American Journal of Medicine Volume 60 (suppi 4C) 13


Control Exercise Control Spontaneous

I 1 SepWlTl Apex Free Wall Septum Apex Free Wall

Regions of Myocardium

Figure 5. Patient with three-vessel coronary artery disease had tomograms (scans) of the heart recorded before arid after exercise (left), and before and during spontaneous ST-segment depressidn (right). Arrows indicate the ischemic decrease in regional perfusion affecting the free wall of the left ventricle. The graphic scale below shows the perfusion in each segment of the scan and demori- strates decreased perfusion that occurs due to exercise and duritig unbroifoked events. However, perfusion in remote areas increases only with. exercise. This example demonstrates two different eat- tenis of disturbed coronary blood flow, both leading to ischemia in’ the same patient.

the endothelium is not intact, as may be the case in the vicinity of an atheromatous plaque, these protective pechanisms can break down; this !eads to platelet aggregation, vasoconstriction, and, possibly, generation of p!atelet mitiroemboli, resulting in physical ,and vasocon- strictive obstnictions in downstream vessels [40,59].

This hypothesis is supported by the fact that elevated throtnboxane B2 levels (the inactive metabolite of thromboxane AZ) have been found in the coronary sinus effluent of patients with unstable angina [bO]. iutthermore, Animal studies @I,621 have demonstrated cyclic reductions in flow resulting from platelet deposition at the site of severe exp&imehtaily produced coronary stenoses; these reductions can be abolished by aspirin and dazoxiben. Finally, daily administration of 324 rnd of aspirin h&s been shown to reduce the mortality rate aiid risk of myocardial infarc: tion after an episode of unstable angina [63].

Plaielets may also influetlce disease activity by their participation in the actual process of atherogenesis, as pqstulated in the “response t? injury” hypothesis [64].

Coagulation’is also undoubtedly important in the development of acute manifest&ohs of ischemic heart disease [65,66] and may be a major factor in disease progression [65]. The role of thrombosis in the pathophysiology of coronary artery disease has b&en recognized for many years and was classically described by Herrick [67] in 1912.

Occlusive coronary thrombus has been found in up to 90 percent df patients dying shortly after infarction [51]; based qn these fivdings, there have been many recent trials of early acute thrombolysis [68,69].

Thrombdsis, usually nonocclusive and possibly oc+- ring iri a layered fashion, has also been noted in unstable angina [5b]. Two interventibnal studies of the role of thrombosis in unstable angina demonstrated a therapeutic benefit qf fibrinol#ic ‘and apticoagulant therapy in pre- venting death an,d/or infarction [70,71].

VASOMOTION OF EPlCARi+L CORONARY ARTERIES

Epicardiai doronary arteries constrict and relax in response to a wide variety of humoral and neural factors [72], everl when they are severely diseased [73].Tfiis vasomotor activity is part’of their normal function and usually of little consequenke, but it may lead to severe ischemia, especially in the presence of critical atheromatljus narrowing [74-771. Many-of the external stimuli,known to trigger myocardial ischemia d,uring daily life produce sympathetically mediated constriction of these epicardial vessels [72]; this, in turn, causes a critical increase in resistance and a decrease in flow, even when modesi constriction occurs, in or around an atheromatous stenosis. The constriction of epicardial vessels may be mediated vi” alpha, sympathetic activity, alterations in vessel reactivity due to



incorporation of cholesterol into smooth muscle cells, a decrease in the number of affinity or inhibitory alpha2 re- ceptors, or platelet vessel wall interactions resulting in the release of various vasoactive substances [78].

ENDOTHELIAL-DEPENDENT DILATION OF EPICARDIAL ARTERIES

Even more exciting is the recent evidence that normal dilation of muscular arteries such as epicardial coronary arteries occurs in response to a varfety of physiologic stimuli but is dependent upon intact and functioning endothelium [78,79]. Endothelial dysfunction may inhibit this dilator response and even lead to paradoxical constriction. Furchgott [79] postulated the release of an endothelial- dependent relaxant factor, and this notion has been closely examined in a variety of experimental models [80]. More recently, Ludmer et al [81] demonstrated that this mechanism is active and important in patients with angina, positive exercise test results, and atheromatous lesions in epicardial coronary arteries. The release of this endothelial-dependent relaxant factor is stimulated by a variety of substances, such as acetylcholine, adenosine diphosphate, histamine, thrombin, and various physiologic peptides [80]. This relaxant factor has a very short half-life (six seconds) and appears to act by elevating levels of smooth muscle cell cyclic guanosine monophos- phate, an intracellular inhibitor of smooth muscle cell con- traction.

ENDOTHELIAL DYSFUNCTION AS A CENTRAL PATHOPHYSIOLOGIC PROBLEM

There is much evidence that endothelial dysfunction or disruption may be the necessary first step in the development of atherosclerosis [4,64]. Additionally, there is evidence that local endothelial injury promotes platelet deposition and thrombosis [40] and that a dysfunctional endo-

thelium also results in disturbed vasomotion, failure of normal dilation, and even paradoxical constriction. All this evidence suggests that endothelial dysfunction may be a central pathophysiologic event, determining the tendency for thrombosis and disturbed vasomotion, as well as atherogenesis. It is, therefore, particularly interesting that clinical research to date has identified the development of atheromatous lesions, the tendency for thrombosis, and disturbed vasomotion as the pathophysiologic mechanisms most important in and most likely to give rise to the activation of ischemic heart disease, producing symptoms, morbidity, and mortality.

COMMENTS

In conclusion, an important goal of the management of coronary artery disease is to understand and treat manifestations of ischemia before the atheromatous occlusion of vessels and damage to left ventricular myocardium occur. Observations in patients with angina have already shown frequent and prolonged ischemic activity that is predominantly silent and associated with ordinary activities that represent extrinsic trigger mechanisms.

The fluctuating activity of ischemic heart disease cannot be due only to these external stimuli; it also must be due to intrinsic pathophysiologic factors in the atherosclerotic epicardial vessels. There is evidence of endothelial dysfunction at the site of atheromatous lesions in the coronary arteries of patients with angina and active ischemic heart disease that may account for the challenging problems of worsening stenosis due to atheroma, the tendency for thrombosis, and disturbed vasomotion. Future research must determine the optimal treatment for this ischemic activity. It may be that understanding and treat- ing endothelial dysfunction, and thus promoting healing of active atheromatous lesions, are necessary to achieve control of ischemia.

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April 30, 1986 The American Journal of Medicine Volume 80 (suppl 4C) 17

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Factors determining the activity of ischemic heart disease