Drugs 43 (Suppl. I): 1-8. 1992 00 12-6667/92/0 I00-000 1/$4.00/0 © Adis International Limited. All rights reserved. DRSUP3355
Therapeutic Targets in Ischaemic Heart Disease s.H.
University Department of Cardiovascular Studies, The General Infirmary, Leeds, West Yorkshire, England
The adequate treatment of a disease syndrome is dependent upon a clear definition of the symptomatic, pathological, physiological and prognostic targets against which therapy is to be deployed. The syndromes of ischaemic heart disease, including angina pectoris, are complex in origin, pathology, pathophysiology and natural history, and a complete clinical profile is difficult, if not impossible, to achieve in individual patients. The prime goals of pharmacotherapy in ischaemic heart disease are easy to define, but difficult to accomplish in practice. Relief of pain, breathlessness and fatigue are the prime clinical targets for pharmacotherapy. In view oftheir sinister significance, the electrophysiological indications of myocardial ischaemia, whether symptomatic or silent, are also crucial targets towards which therapy must be directed. Ischaemic heart disease is accompanied by a wide variety of regional and global abnormalities of myocardial contractile function associated with widespread reflex stimulation of the peripheral vascular system and neuroendocrine systems. Primarily, drug therapy must be directed at correction of these pathophysiological components of the syndrome. Longer term but no less essential goals in the treatment of ischaemic heart disease are the prevention of the clinical sequelae of the syndrome and its progression. A natural sequel of coronary artery obstructive disease is successive thrombotic events and loss of myocardium. Calcium antagonists, by preventing the increase in myocardial cytosolic calcium during acute ischaemic episodes, defer cell necrosis; in this respect, they are unique among currently available antianginal drugs. With regard to progression, the prime pathological cause of ischaemic heart disease is coronary atheroma. It has now been clearly demonstrated that while calcium antagonists may not reverse large established lesions, they are capable of preventing the development of new atheromatous plaques and may even retard the progression of minimal lesions. These basic benefits of the calcium antagonists are complemented by their proven ability to improve the coronary risk profile. The immediate and long term therapeutic targets in symptomatic and silent ischaemic heart disease are probably met more completely by the calcium antagonists than by any other currently available anti-ischaemic drug class.
The aims of treatment of ischaemic heart disease, including angina pectoris, are easier to define in theory than to accomplish in practice. Ischaemic heart disease is the most frequent cardiac disorder in Western society and its rate of increase far exceeds that of other cardiovascular disease syndromes. Thus, it poses a major problem in the community, despite the progress made in unrav-
elling the complexities ofthe syndrome in both the experimental laboratory situation and the field of clinical investigation. These advances, however, expose the gulf between such knowledge and its application to the treatment of individual patients. Fortunately, the gap has been narrowed by the development of potent anti anginal drugs that benefit the patient without it being clear exactly how such
Drugs 43 (Suppl. 1) 1992
Table I. Major pharmacotherapeutic goals in patients with ischaemic heart disease
Relief of symptoms Reduction of myocardial ischaemia during angina attacks Reduction of silent myocardial ischaemia Improvement in Pathophysiology Haemodynamic profile Neuroendocrine activity Striated muscle metabolism Prevention of progression Reduction of coronary atheroma Improvement in coronary risk profile Limitation of infarct size Extension of life span
benefit has been achieved. However, such pragmatic successes, among which the calcium antagonist group of drugs rates highly, should not be allowed to obscure the quite separate targets at which drug therapy should be aimed. Definition of these goals also facilitates evaluation of the overall therapeutic potential of anti-ischaemic drugs. This review is concerned with highlighting the major pharmacotherapeutic goals in patients with ischaemic heart disease (table I) and outlining the role of the calcium antagonists in achieving these goals.
1. Relief of Symptoms The relief of symptoms associated with ischaemic heart disease, particularly angina pectoris, must always remain the highest clinical priority. Since the time of Heberden (1772), therapeutic attention has been rightly concentrated on relieving this distressing symptom and, in this regard, calcium antagonists hold a major place among the drug classes currently available for first-line therapy. There are numerous reports ofthe positive benefits of calcium antagonists on formal measurements of exercise tolerance in patients with angina pectoris (Dargie et al. 1981; Frishman et al. 1988; Subramanian et al. 1982; Taylor et al. 1991). Of equal importance, this family of drugs has been shown
to be pre-eminent in the relief of anginal pain in everyday life. Furthermore, calcium antagonists completely suppress the circadian rhythm of anginal attacks (Taylor 1991). All calcium antagonists have been shown to be efficacious, and little or no tolerance to their symptomatic benefits has been demonstrated during long term administration. The reduction in anginal pain achieved by the calcium antagonists has a major additional benefit in many patients, i.e. a reduced requirement for sublingual nitroglycerin (glyceryl trinitrate) which is very effective in aborting anginal attacks but causes headache in many patients. It is natural for the physician to concentrate on the relief of anginal pain, but it is less frequently appreciated that, even in the absence of such pain, exercise tolerance is impaired in patients with ischaemic heart disease, because of breathlessness and fatigue. This is probably a result of2 factors. Firstly, angina pectoris and, to a lesser extent, silent myocardial ischaemia during exercise are associated with the syndrome of acute left heart insufficiency (Sharma & Taylor 1970), aggravated by abruptly reduced ventricular compliance (Sharma et al. 1976). Thus, left ventricular relaxation is impaired and filling rate retarded, resulting in a reduction in ejection fraction and cardiac output and an increase in pulmonary venous pressure. The resulting increase in stiffness of the lungs probably accounts for much of the breathlessness suffered during exercise in patients with ischaemic heart disease (Sharma & Taylor 1970). These primary changes in left ventricular function are accompanied by activation of a variety of neurohumoral systems, particularly the sympathoadrenal and renin-angiotensin systems. This explains the vasoconstriction that is an intrinsic component of the syndrome, but the contribution that this peripheral reflex activity, the reduced cardiac output response to exercise, and the increasing inactivity of patients with angina pectoris make to fatigue is open to question. It is also possible that the metabolic changes demonstrable in striated muscle of patients with heart failure are also present in patients with ischaemic heart disease. How far the calcium antagonists will alleviate the symptoms of breathless-
Therapeutic Targets in IHD
ness and fatigue, attenuate the heightened neurohumoral reflexes, and influence the disorder in striated muscle metabolism is unknown, but these are important questions for future research. In conclusion, the first priority of therapy in the patient with ischaemic heart disease is attenuation of pain, breathlessness and fatigue. Calcium antagonists are highly effective in ameliorating ischaemic pain and modulating the circadian rhythm of attacks in many patients with severe coronary heart disease. The mechanisms by which this is achieved are not entirely clear and, at present, it is impossible to predict which patients will benefit symptomatically from treatment with this group of drugs. This can only be determined by individual patient trial.
2. Electrocardiographic Evidence of Ischaemic Heart Disease It is possible that ischaemic heart disease may be present without clinical electrophysiological evidence but, as the electrocardiogram is the only instrument widely available to the practising physician, it remains the most convenient method of confirming the diagnosis. Because of its high degree of selectivity and sensitivity, it is also an essential tool for therapeutic monitoring although in routine clinical practice its utility is limited by the difficulties of carrying out such recordings during induced anginal attacks. In many patients with mild angina, the electrocardiogram recorded at rest often does not reflect the potential for the development of myocardial ischaemia; this can only be determined by stress investigations (usually dynamic exercise performed on a treadmill or bicycle). Am. bulatory 24-hour continuous electrocardiographic monitoring is an equally sensitive tool, particularly in determining the total ischaemic load on the heart due to both symptomatic and silent myocardial ischaemia (Fox & Mulcahy 1989) [fig. 1]. There is now a considerable body of evidence confirming that the precipitating factors, the pathophysiology and, presumably, the prognosis of silent ischaemic attacks are similar to those associated with symptomatic attacks (Dean field et al. 1983). The im-
portance of electrocardiographic evidence of myocardial ischaemia, with or without accompanying arrhythmias, makes amelioration of the associated symptoms a prime therapeutic target (Bayes et al. 1989). Fortunately, calcium antagonists are effective in reducing the extent of such electrocardiographic evidence of myocardial ischaemia (Frishman et al. 1988; Taylor et al. 1991; von Arnim 1987).
3. Haemodynamic Changes in Ischaemic Heart Disease While abolition of symptoms and electrocardiographic signs of myocardial ischaemia remain the prime goals of clinical therapy, improvement in the associated impaired haemodynamic profile remains an important, if more clinically obscure, objective. Ischaemic heart disease is associated with widespread disturbances in cardiac pumping and many related peripheral vascular and neuroendocrine functions. The advent of myocardial ischaemia, particularly when giving rise to angina pectoris, is associated with a complex pattern of changes in regional and global cardiac dysfunction (Sharma & Taylor 1970, 1975). Left ventricular compliance is decreased, left heart filling pressure is raised, ejection fraction and cardiac output are decreased, peripheral vasoconstriction is increased and a wide variety of neuroendocrine reflexes are activated. The increase in peripheral vascular resistance resulting from activation of the reninangiotensin system is augmented by direct sympathetic stimulation of (1'\ -adrenoceptors and leads to increased aortic impedance and pressure-work of the heart. The resulting increase in myocardial oxygen consumption is further augmented by direct sympathetic stimulation of the myocardium. These effects are most prominent in patients with symptomatic angina pectoris and are rapidly reversed when the patient stops exercising (Taylor 1975) [fig. 2]. The haemodynamic disorder is less severe but more frequent and of longer duration in silent myocardial ischaemia. These acute haemodynamic changes are the third prime target of therapy. Calcium antagonists, by
Drugs 43 (Suppl. 1) 1992
___ Total ischaemia --0-- Silent ischaemia 40
- -- -, "
12 13 14
15 16 17 18 19 20 21 22 23
Time of day (hours) Fig. 1. Circadian distribution of total and silent episodes of ischaemia (from Fox & Mulcahy 1989).
limiting calcium ion entry through calcium-selective voltage-sensitive channels in the cardiac myocytes and vascular smooth muscle cells, attenuate many of the haemodynamic features of ischaemic heart disease, despite their intrinsic negative inotropic activity. The reason for this apparent paradox is that the haemodynamic benefits of amelioration of myocardial ischaemia and the energysparing in normal myocardium, augmented in some instances by reflex sympathoadrenal activation, far outweigh the disadvantages of intrinsic negative inotropism (Silke et al. 1990). However, it is also reassuring that, even in the absence of such reflex sympathetic stimulation, the impact of negative inotropism is either absent or clinically insignificant. The theoretically possible clinical disadvantages of the negative inotropism exerted by calcium antagonists in patients with ischaemic heart disease who are not in heart failure have never materialised. The haemodynamic features of the angina episode, and presumably episodes of silent ischaemia, are not confined to the disordered contractile func-
tion of the myocardium. Changes in the coronary artery supply due to dynamic vasomotricity also contribute in varying degrees to the overall deficit in pumping activity of the ventricle. Despite the apparent limitations imposed by a rigid atheromatous obstruction, the coronary artery in the vicinity of such an obstruction frequently demonstrates excessive vasoconstriction (Epstein & Talbot 1981). Damage to the endothelium overlying atheromatous plaques also appears to render the vessel more susceptible to blood-borne vasoconstrictor elements (Ludmer et al. 1986). Although the distal vessels dilate progressively as the proximal coronary artery is narrowed at rest, the advent of sympathetic stimulation results in an increase in coronary vascular resistance in the more distal vessels (Heusch & Deussen 1983) and possibly the collateral arteries, leading to a reduction in blood flow in the ischaemic zone (Gallagher et al. 1984). The calcium antagonists attenuate or may even completely prevent these adverse constrictive activities in the coronary vascular tree.
Therapeutic Targets in !HD
4. Prevention 0/ Progression In individual patients it is impractical to attempt to determine, with any degree of precision, the rate of progression of ischaemic heart disease. However, from extensive investigative group studies, it is clear that the extent of the coronary lesions when first measured is directly related to the subsequent mortality risk (Griffith & AchutT 1977) [fig. 3]. Moreover, the same studies clearly demonstrate
that there is a continuous progression of these coronary obstructive lesions (table 11). In routine clinical practice, it is unrealistic to directly measure the rate of development of coronary atheroma and associated myocardial damage in individual patients. Information derived from group studies highlights the importance of the syndrome at presentation and its inexorable progression if it remains untreated. How can this progression be limited? It is likely
(> Mild (> Moderate •
"OS E .5.,
*~ '--.. .,m
10 Time (min)
Fig. 2. Relation of exercise-induced anginal pain to electrocardiographic and haemodynamic changes in 12 patients with angina pectoris (from Taylor 1975). LVEDP = left ventricular end-diastolic pressure; SBP = systolic blood pressure.
Drugs 43 (Suppl, 1) 1992
Time aiter coronary arteriogram (years)
Fig. 3. Survival of patients with single- (n = 359), double- (n = 405) and triple- (n relation to initial angiographic findings (from Griffith & Achuff 1977),
that the prognosis is dominated by the obstructive lesions in the coronary arteries and the degree of myocardial damage at presentation; these are the prime targets of preventive therapy. Calcium antagonists have been shown to retard the development of atherosclerosis in animal models (Parmley 1990; Parmley et al. 1985; Ram 1990) but in human subjects the results have been less encouraging as regards regression of established atheromatous lesions (Gottlieb et al. 1989; Lichtlen et al. 1990; Waters et al. 1990). However, pretreatment with calcium antagonists was associated with a significant reduction in the appearance of new lesions (Lichtlen et al. 1990) and retardation of the development of initially minimal atheromatous Table 11. Progression of coronary artery disease over 3 years in 184 patients
Artery status at baseline
Artery status at 3 years (% of patients)
Normal Narrowed < 50% Narrowed> 50%
> 50% narrowed (5) > 50% narrowed (10) Occluded (15)
vessel coronary artery disease in
plaques (Waters et al. 1990). Thus, their role in the treatment of advanced coronary atherogenesis is limited, but their prophylactic potential in earlier stages of the disease renders them unique among the first-line antianginal drugs in current use. While coronary artery atheromatous obstruction and associated myocardial damage remain the prime therapeutic targets for secondary preventive intervention, there are other factors to be considered if full therapeutic benefit is to be afforded to the patient with ischaemic heart disease. The coronary risk profile in ischaemic heart disease is similar to that of the patient with hypertension. Control of high blood pressure and reversal of left ventricular hypertrophy, both present in many patients with ischaemic heart disease, can be expected to be of positive long term benefit. Correction of blood lipid abnormalities and the control of glucose intolerance are also crucial, as is the reduction of obesity. Plasma fibrinogen concentration, increased platelet aggregability and white cell clumping also appear to be deleterious coronary risk factors and should be corrected. The presence of oxygen free-radicals in the ischaemic myocardium
Therapeutic Targets in rHD
also poses a potential arrhythmia threat. In many of these regards, the calcium antagonists possess some major advantages. They are capable of controlling systemic blood pressure and reversing left ventricular hypertrophy (Hachamovitch et al. 1988), without adverse effects on the blood lipid profile, glucose tolerance, or plasma fibrinogen and urate concentrations (Midtbo 1990; Trost & We idmann 1987). Blood viscosity and neutrophil clumping have also been shown to be reduced by calcium antagonists (Ernst & Matai 1989; Rauch et al. 1991). A further, often neglected, therapeutic target must be the nature of any further coronary event in the patient with coronary heart disease. In the patient with declared coronary artery obstructive disease, subsequent myocardial infarctions carry logarithmically increasing risk of both fatal arrhythmias and development of heart failure. Limitation of such further myocardial damage must therefore be considered a prime therapeutic aim of anti-ischaemic therapy. In this regard, calcium antagonists are foremost among antianginal drugs in limiting the excessive influx of calcium into the ischaemic myocardial cell, thus limiting the area of myocardial necrosis in an ischaemic zone (Naylor 1981) and preserving myocardial contractile function (Perez et al. 1980). Calcium antagonists are therefore capable of playing a vital role in reducing, or even preventing, the transition from myocardial injury to cell death. The experimental confirmation of such a potentially clinically important property may even explain the benefits of some calcium antagonists in prolonging survival in myocardial infarction patients (Danish Study Group on Verapamil in Myocardial Infarction 1990; Multicenter Diltiazem Postinfarction Trial Research Group 1988). These arguments emphasise the prognostic importance of determining a detailed clinical risk profile of patients with ischaemic heart disease before drug therapy is started, enabling the impact of treatment to be continually monitored.
5. Conclusion It is easier to define therapeutic objectives than it is to correct them in practice in patients with
ischaemic heart disease; the detailed diagnostic profile of these patients poses insuperable practical problems under routine clinical conditions. However, the immense fund of knowledge now available from both experimental and clinical studies greatly facilitates understanding of the syndrome and the practical utility of methods of treatment, including pharmacotherapy. Despite the absence of detailed diagnostic information in every patient with ischaemic heart disease, the drugs available to the physician now allow many therapeutic targets to be achieved. Drugs that reduce calcium entry into myocardial and vascular smooth muscle cells provide a rational treatment based not only on extensive experimental experience but also on results from numerous valid clinical trials. The symptomatic benefit of calcium antagonists in patients with angina pectoris is immediately apparent, both to the physician and the patient, and the clinical benefits are maintained during prolonged therapy. Fortunately, this group of drugs also allows the physician to be confident that, in the current state of knowledge, they are pre-eminent and, in certain instances, unique in the long term prophylactic benefit they can afford such patients. It is for this reason that calcium antagonists have a high profile as first-line drugs in the treatment of patients with ischaemic heart disease. The therapeutic targets defined in this review are probably more completely met by this family of drugs than by any other antianginal agent at the present time.
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Correspondence and reprints: Dr S.H. Tay/or, Emeritus Physician, University Department of Cardiovascular Studies, The General Infirmary, Leeds, West Yorkshire, England.