False positive exercise ECG: a misnomer?

263

References 1 Hammermeister KE. Myocardial infarction during coronary artery bypass surgery - not a benign event. Int J Cardiol 1983;2:516-518. 2 Codd JE, Wiens RD. Kaiser GC, et al. Late sequelae of perioperative myocardial infarction. Ann Thorac Surg 1978;26:208-214. KE, Zia MS. DeRouen TA, Dodge HT, Namay K. The effect of 3 Namay DL, Hammermeister perioperative myocardial infarction on late survival in patients undergoing coronary bypass surgery. Circulation 1982;65:1066-1071. 4 Gray RJ, Matloff JM, Conklin CM, et al. Perioperative myocardial infarction: late clinical course after coronary artery bypass surgery. Circulation 1982;66:1185-1189. 5 Chaitman BR, Alderman EL, Sheffield LT. et al. Use of survival analysis to determine the clinical significance of new Q waves after coronary bypass surgery. Circulation 1983;67:302-309. 6 Brindis RG, Brundage BH, Ullyot DJ. McKay CW, Lipton MJ, Turley K. Graft patency in patients with coronary artery bypass operation complicated by perioperative myocardial infarction. J Am Co11 Cardiol 1984;3:55-62. 7 Gray RJ, Harris WS. Shah PK, Miyamoto ATM, Matloff JM, Swan HJC. Coronary sinus blood flow and sampling for detection of unrecognized myocardial ischemia and injury. Circulation 3977:56(suppl 2):58-61. 8 Gray R, Maddahi J, Berman D, et al. Scintigraphic and hemodynamic demonstration of transient left ventricular dysfunction immediately after uncomplicated coronary artery bypass grafting. J Thorac Cardiovasc Surg 1979;77:504-510. 9 Maddahi J. Gray R, Berman D. Hemodynamic and scintigraphic demonstration of transient right ventricular dysfunction immediately after uncomplicated coronary artery bypass graft surgery (abstract). Am J Cardiol 1979;43:423. 10 Bateman T. Conklin C. Weiss M, et al. Determinants of early mortality after perioperative myocardial infarction (abstract). Clin Res 1984;32:2A. 11 Gray RJ, Matloff JM. Effect of intraoperative MI on late survival after CABG. Circulation 1983;67:249-250.

IJC 0169C

False positive exercise ECG: a misnomer? * (Key words:

exercise ECG;

coronary

Exercise ECG is widely used in coronary artery disease (CAD) and However, experts in the field differ of exercise ECG-testing. The main especially false positive tests.

* From the Medical

International 0 Elsevier

Department

artery disease;

cardiomyopathy)

the study of patients with known and suspected as a screening procedure in healthy populations. considerably in their attitude about the reliability concern is the high number of false negative and

B, Rikshospitalet,

Journal of Cardiology, 6 (1984) 263-268 Science Publishers B.V.

University

Hospital,

Oslo, Norway.

264

TABLE Diseases/conditions

known

to be associated

with a high frequency

of false positive exercise ECGs.

Left ventricular hypertrophy (including physiologic hypertrophy in athletes) Various drugs (e.g. digitalis, diuretics. psychotropic drugs) Hypopotassemia from any cause Non-fasting state Hyperventilation Vasoregulatory asthenia Unspecific ST depression from any cause in resting ECG Grave anemia Left bundle branch block Mitral prolapse syndrome Severe hypertension Wolff-Parkinson-White syndrome Other pre-excitation types (Acute) cerebral (damage) disease Excessive double product “Too strenuous” starting load in diseased or poorly trained subjects Remember:

Inadequate

frequency-response

of ECG-recorder

and unsuitable

leads (e.g. Y-lead).

Basic Definitions Whereas there exists a great number of exercise protocols, criteria for terminating the tests and criteria for describing the ECG-recordings, the discussion below refers to the following protocol/definitions: a positive exercise ECG is an ECG presenting ST depression of 2 1.0 mm 2 0.08 set from the J-point during and/or post exercise, using a symptom-limiting graded exercise test protocol [1,2]. Although noninvasive tests such as thallium-201 scanning, echocardiography, electrokymography and apexcardiography can be used to assess whether or not a positive exercise ECG is related to localized myocardial ischemia, coronary angiography is commonly used as the “gold standard”. Thus an exercise ECG is labelled false positive in the absence of at least one luminal obstruction of ~75% of a major coronary artery. Since positive exercise ECGs often are found in several well-defined conditions or disorders independent of the presence of CAD (some of which are summarized in the Table), a “true” false positive exercise ECG is said to be present when no such obvious cause can be found for a positive exercise ECG in the presence of normal coronary angiograms. This discussion mainly deals with such exercise ECGs, and the prerequisite is also that a meticulous search has been made to exclude the above-mentioned confounding conditions. Main Reasons for Differences in Opinion by Different Authors Most differences in opinion expressed by various authors on the usefulness of exercise ECGs are related to their use of different techniques for conducting the exercise ECG tests, their different criteria for labelling a test positive and to differences in target populations [2]. The following should, however, be kept in mind.

265

Attempts at making tests more sensitive or more specific by applying less or more strict criteria invariably show the inherent inverse relation between sensitivity and specificity. The more sensitive the test is made, the more it loses specificity and vice versa. Like all other diagnostic tests exercise ECG testing “obeys” the statistical theorem of Bayes, which expresses that, given a particular test-sensitivity and specificity the diagnostic value is critically dependent on the prevalence of the disease searched for within the population studied. This rule, therefore, readily explains why exercise ECG testing is of poorer value in women than in men because of their lower prevalence of CAD and also why the diagnostic yield is higher in symptomatic than in asymptomatic populations of similar age. True false positive exercise ECG Symptomatic patients. As mentioned above, a positive exercise ECG in the presence of normal coronary arteries has been labelled false positive. In the presence of angina, however, small-vessel disease, aberrations in the hemoglobin dissociation curve, coronary spasm, microembolism, subclinical myocarditis or cardiomyopathy are among the explanations given for the angina in such patients [3]. Recently the maximal dilatory capacity of the coronary vessels has been found subnormal in a group of such patients as judged from a maximal dilatory stimulus given by the coronary vasodilator persantin [4]. Using a variety of techniques, other authors have found evidence of reduced blood flow per unit muscle mass in such cases [3]. Still other groups have found metabolic changes such as myocardial lactate production in some patients with angina and normal coronary arteries, and structural changes in the mitochondria have also been postulated [5]. These data, however, only refer to symptomatic patients. Thus, only rarely have asymptomatic patients with a pathologic exercise ECG had a coronary angiogram. Asymptomatic Subjects. In a recent study we followed 36 men with normal coronary angiograms, 30 of whom had an abnormal exercise and 6 had angina but normal exercise ECG [l]. They were derived from a group of 2014 males participating in a cardiovascular survey aimed at searching for asymptomatic CAD in an apparently healthy, middle-aged male population [6]. In none of these angionegative men could any of the conditions noted in the Table be found and they therefore were said to have false positive exercise ECGs. At a 7-year follow-up examination a number of more or less subtle aberrations in cardiac function had developed in some, whereas 3 had died from a cardiac cause and 5 had signs of definite cardiomyopathy not detected during the baseline study. Moreover, as a group the men still alive also presented a more rapid decline in physical work performance and maximal heart rate during exercise than could be accounted for by the 7 years increase in age. This work throws some doubt on the validity of the term “false positive” exercise ECG in a substantial number of apparently healthy middle aged males when such ECG findings are observed in relation to a symptom-limited exercise ECG test. It rather seems probable that subtle cardiac physiological aberrations were present at

266

the time of the baseline study. It should be emphasized that none were studied less than 14 days after a febrile illness and that all but 3 also have a positive exercise ECG at follow-up. We therefore have suggested that a “false” positive exercise ECG might be an early sign of cardiomyopathy [l]. However, none of the patients alive fulfilled the criteria for a diagnosis of dilated or restrictive cardiomyopathy [7], although 4 had a myocardial biopsy compatible with this diagnosis. It is, however, conceivable that the spectrum of cardiac aberrations during the early course of cardiomyopathies is wider than hitherto appreciated and that at least some of our cases represent a more slowly progressing type with a far better prognosis than reported in clinically detected cases of dilated cardiomyopathy [7]. Little attention has been paid to the early, possible subclinical stage of dilated and restrictive cardiomyopathy, which through oxygen-wasting mechanisms may explain the presence of a pathologic exercise ECG. Recent Research Data with Possible Relevance to Triggering of Cardiomyopathy False Positive exercise ECG

and

In some recent review articles very little attention has been paid to preclinical stages of cardiomyopathies [7,8]. Excess use of alcohol and subclinical myocarditis are mentioned as possible underlying causes, the latter possibly leading to a self-perpetuating progressive immunologic disease in patients with genetic aberrations of the supressor T lymphocytes [9]. It might therefore be of interest to study asymptomatic men with a positive stress test with immunologic techniques if other tests render CAD unlikely. Other authors have suggested that microembolism may trigger a degenerative reaction in the heart as judged from animal experiments [lo]. Although the implications are uncertain, it might be mentioned that previously our group has reported aberrations in thrombocytes among patients with angina pectoris, including patients with angina and normal coronary arteries [ll]. Previously we have also noted that the transit time of X-ray contrast through the coronary circulation was significantly longer in the present group of 36 angionegative men compared with the 69 with pathologic angiograms from the same angiographic study [12]. Although rheologic this particular finding may represent the factors might deserve consideration. angiographic counterpart of Opherk et al.‘s finding of an increased vascular resistance in some patients with angina and normal coronary arteries [4]. In a recent study free radicals liberated through the oxidation of cathecholamines have been said to play a possible role in the development of cardiomyopathy by destroying cell membranes in the myocardium [13]. At least this mechanism may play a role in the well-known cathecholamine-induced cardiomyopathy. However, the implications for this experimental finding in other types of cardiomyopathy is obscure, although a Swedish group has suggested that hypersensitivity to cathecholamines/adrenergic stimuli play an important role in the development and progression of dilated cardiomyopathy [14]. The above-mentioned theory might possibly be modified by postulating a link between a detrimental effect of free

261

radicals from cathecholamine metabolism effect via adrenergic stimulation.

and cardiomyopathy

rather

than a direct

Practical and Theoretical Implications Analysis of the ST-segment response to exercise and its relation to various aberrations in cardiac function has shown that coronary angiography and exercise ECG response represent two distinct sides of “the truth”. The first represents a pathoanatomic, and the latter a physiologic side of the coin. As mentioned above an ST depression without obvious cause should not be considered innocuous but should rather serve as an impetus for further research. In view of our almost complete ignorance about etiologic and pathogenetic mechanisms, the therapeutic implications of the above-mentioned considerations are at best uncertain. In the presence of symptoms and/or in the presence of definite albeit subtle signs of cardiac dysfunction, trial with beta-adrenergic blocking drugs might be used. No harm should be done by using antioxidants such as vitamin E and zinc to prevent the postulated membrane damage by free radicals [13]. Otherwise usual precautions such as alcohol restriction should be considered [7]. Further Research The ultimate outcome in cases with false positive exercise tests should be studied. In addition, more basic research is needed. Fields of interest are studies of immune mechanisms, aberrations in cathecholamine metabolism rheology and platelet functions. When feasible invasive studies might elucidate cardiac mechanisms involved, e.g. by use of histochemical methods and biochemical studies. As mentioned above the present cardiac derangement represents a “no man’s land”, and the link towards known clinical entities is obscure. Medical Department Rikshospitalet Oslo 1, Norway

B

Jan Erikssen Erik Myhre References

1 Erikssen J, Dale J, Rootwelt K, Myhre E. False suspicion of coronary heart disease: a 7 year follow-up study of 36 apparently healthy middle-aged men. Circulation 1983;68:490-497. 2 Johnson RL, Bungo MW. The diagnostic accuracy of exercise electrocardiography - a review. Aviat Space Environ Med 1983;54:150-157. 3 Pasternac A, Bourassa MG. Pathogenesis of chest pain in patients with cardiomyopathies and normal coronary arteries. Int J Cardiol 1983;3:273-280. 4 Opherk D, Scwartz F, Mall G, Manthey J, Ballen D, Kubler W. Coronary dilatory capacity in idiopathic dilated cardiomyopathy. Analysis of 16 patients. Am J Cardiol 1983;51:1657-1662. 5 Boudoulas H, Cobb TC, Leighton RF, Wiet SM. Myocardial lactate production in patients with angina like chest pain and angiographically normal coronary arteries and left ventricle. Am J Cardiol 1974;34:501-505. 6 Erikssen J, Enge 1. Forfang K, Storstein 0. False positive diagnostic tests and coronary angiographic findings in 105 presumably healthy males. Circulation 1976;54:371-376.

268

7 Shabetai

8 9 10 11 12 13 14

R. Cardiomyopathy How far have we come in 25 years. how far yet to go? J Am Coil Cardiol 1983;1:252-263. Goodwin JF. The frontiers of cardiomyopathy. Br Heart J 1982;48:1-18. Eckstein R, Mempel W, Bolte H-D. Reduced supressor cell activity in congestive cardiomyopathy and myocarditis. Circulation 1982:65:1224-1229. Smiseth OA, Linda1 S, Mjes OD, Vik-Mo H. Jorgensen L. Progression of myocardial damage following microemolization in dogs. Acta Pathol Microbial Immunol Stand (sect A) 1983;91:115-124. Thaulow E, Etikssen J, Myhre E, Stormorken H, Hellem A. Platelet function related to the development and presenting symptoms in coronary artery disease. Stand J HaematoI1982;28:281-288. Erikssen J, Enge I. Left coronary artery contrast transit time. Acta Radio1 1977;18:385-391, Singal PK. Kapur N. Dhillon KS, Beamish RE, DhaIIa NS. Role of free radicals in cathecholamine-induced cardiomyopathy. Can J Physiol Pharmacol 1982;60:1390-1397. Waagstein F, Hjalmarson A. Varnauskas E, Wallentin 1. I. Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J 1975;37:1022-1036.

IJC 0169D

The nature of the relationship between obesity and cardiovascular disease * (Key words: obesity;

body mass; cardiovascular

disease;

coronary

heart disease)

It is well established that obesity is associated with elevated blood pressure, blood lipids, lipoproteins, and blood glucose and that changes in body weight are accompanied by changes in these risk factors for cardiovascular disease [l-6]. The existing data, both clinical and epidemiological, suggest that obesity even in mild form may lie at the beginning of the chain of events leading to disease causation, and that preventive strategies which include successful weight control need to be encouraged. It is unfortunate that the fundamental role of obesity in the development of cardiovascular disease has been diminished by studies that suggest that the increased risk observed among heavier individuals is due primarily to the influence of the associated risk factor profile and not to the degree of obesity per se [7,8]. In turn, such data also have been interpreted to suggest that obesity is benign when it exists without other major risk factors for disease. However, these latter notions have been challenged by results from Framingham and other long-term, prospective studies concerned with the “independent” role of obesity in cardiovascular risk [9-131. The Framingham Heart Study Recent observations of cardiovascular disease occurrence over 26 years in Framingham suggest that the degree of obesity is a significant and independent * From the National

International

Journal

Elsevier Science

Heart,

Lung and Blood Institute,

of Cardiologv.

Publishers

B.V.

6 (1984)

268-274

Bethesda,

Maryland.