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Unstable with : Clinical and therapeutic implications

We prospectively evaluated 19 patients with prolonged chest not evolving to myocardiai infarction and accompanied with reversible ST-T changes and tachycardia ( rate >lOO beats/min) in order to correlate reduction with ischemic electrocardiographic (ECG) changes. Fourteen patients (74%) received previous long-term combined treatment with and nitrates. Continuous ECG monitoring was carried out until heart rate reduction and at least one of the following occurred: (1) relief of pain or (2) resolution of ischemic ECG changes. The study protocol consisted of carotid massage in three patients (IS%), intravenous in seven patients (37%), slow intravenous infusion in two patients (lo%), and intravenous in four patients (21%) with atrial . In three patients (16%) we observed a spontaneous heart rate reduction on admission. Patients responded with heart rate reduction from a mean of 126 + 10.4 beats/min to 64 k 7.5 beats/min (p < 0.005) and an ST segment shift of 4.3 k 2.13 mm to 0.89 k 0.74 mm (p < 0.005) within a mean interval of 13.2 + 12.7 minutes. Fifteen (79%) had complete response and the other four (21%) had partial relief of pain. A significant direct correlation was observed for heart rate reduction and ST segment deviation (depression or elevation) (f = 0.7527 and 0.8739, respectively). These patients represent a unique subgroup of , in which the mechanism responsible for is excessive increase in heart rate. Conventional vasodilator therapy may be deleterious, and heart rate reduction Is mandatory. (AM HEART J 1988;116:1188.)

Samuel Sclarovsky, MD, Roni Bassevich, MD, Boris Strasberg, MD, Eliezer Klainman, MD, Eldad Rechavia, MD, Alex Sagie, MD, and Jacob Agmon, MD. Petah Tikva and Tel Aviv, Israel

Unstable angina is a syndrome encompassing a patients with unstable angina and tachycardia. The variety of clinical and pathophysiologic entities.’ purpose of the present study was to characterize this Features of instability are largely determined by group clinically and electrocardiographically and to dynamic obstructions superimposed on a widely correlate heart rate reduction with clinical presenta- variable fixed obstruction.2-6 Continuous hemody- tion and ischemic ECG changes. namic and electrocardiographic (ECG) monitoring METHODS indicate that most episodes of ischemia in patients with unstable angina are not triggered by increases Nineteen consecutive patients (14 men and 5 women) with unstable angina and tachycardia were selected for in the major determinants of myocardial oxygen study provided they fulfilled the following criteria: (1) consumption. 7,g We recently discussedlo the prog- prolonged typical lasting longer than 15 nostic implications of the various patterns of ische- minutes accompanied by reversible ST- changes mic ECG changes in patients with unstable angina and (2) heart rate above 100 beats/min not related to without evidence of increased myocardial oxygen effort with careful clinical evaluation to assurethat it was demand. not secondary to underlying physiologic abnormalities Because heart rate is the best single index for (, , , overt ). Patients myocardial oxygen consumption,‘* we used this with complete left or with subse- parameter to evaluate prospectively a subgroup of quent development of a new Q wave or with diagnostic elevation in cardiac isoenzymes were excluded. ST seg- ment deviation was defined as a shift >l mm from the PR segment 80 msec after the J point. A 12-lead ECG was From the Israel and Ione Massada Center for Heart , Beilinson recorded on admission. All patients entered a protocol in Medical Center; and the Tel Aviv University Sackler School of Medi- CIIIC. -zhi& they r;xkrwsnt continuol;s ECG monitoring in the Received for publication Dec. 11, 1987; accepted June 15, 1988. lead presenting the maximal ST segment deviation until Reprint requests: S. Sclarovsky, MD, Massada Center for Heart Diseases, heart rate reduction to 100 beatslmin or less and at least Beilinson Medical Center, Petah Tikva 49100, Israel. one of the following: (1) relief of pain or (2) restoration of

1188 Volume 116 Number 5, Part 1 Unstable angina with tachycardia 1189

7.1.87 & Ln Lm AVR AVL AVF vt v2 v3 v4 cc-

Fig. 1. Example of unstable angina with tachycardia and ST segment elevation (case No. 1). A, (130 beats/min) with evidence of recent anteroseptal . ST segment elevation and positive T wave in leads V, to V,. B, Ten minutes after administration of propranolol. Note heart rate reduction to 94 beats/min, isoelectric ST segment, and T wave inversion.

Lr Ln Lrn AVR AVL AVF V, v2 v3 v4 v5 V6 I :

Fig. 2. Example of unstable angina with tachycardia and ST segmentdepression (case No. 13). A, Atria1 fibrillation (130 beats/min) with ST segment depression (9 mm in lead V,). B, Ten minutes after administration of verapamil. Conversion to at a rate of 77 beats/min with only 1 mm ST segmentdepression.

ECG changes.In order to assessthe net effect of heart rate tes, and three had both and . reduction on clinical features (pain) and ischemic ECG Fourteen patients (74 % ) received previous long- changes, no nitrates or treatment was given term treatment with nifedipine and nitrates in a throughout the study protocol. This protocol was as dose up to 60 mg and 160 mg, respectively; only one follows: (1) gentle carotid massagefor 3 minutes; (2) when of these patients received concomitant treatment carotid massage was ineffective or contraindicated (cervi- with beta blockers. One patient (No. 17) was admit- cal murmurs, previous TIA), intravenous propranolol up ted 24 hours after abrupt withdrawal of long-term t,o 0.1 mg/kg at the rate of 1 mg/min was administered; (3) when propranolol was contraindicated (bronchial , therapy. Eight patients received sublin- heart failure), amiodarone, 300 mg, was given in 30 gual nitrates for a short term (average dose 10 mg; minutes as a slow intravenous infusion; (4) in patients range, 5 to 20 mg) without clinical subjective with supraventricular tachycardia or atria1 fibrillation, improvement. verapamil was given intravenously up to 10 mg. Four patients (21% ) had ST segment elevation. Statistical analysis. All data are presented as the All had a recent myocardial infarction and the mean t standard deviation. Comparisonswere done by a maximal ECG changes occurred in the same lead paired t test. A p value <0.05 was considered signifi- demonstrating the previous infarction: two (50 % 1 cant. were in lead V, and the other two were in lead III (Fig. 1). Fifteen patients had ST segment depres- RESULTS sion. In 13 (87%) the maximal changes were The study group (Table I) consisted of 19 patients observed in leads V, and V, (Fig. 2). All patients had (14 or 74% were men) with a mean age of 65 -+ 9.8 typical chest pain lasting at least 15 minutes and years. Five patients had an old myocardial infarc- ranging from 15 to 420 minutes (mean 153 +- 130). tion, four had a recent (within 2 weeks) myocardial Three patients (16%) responded to carotid mas- infarction, seven had hypertension, five had diabe- sage. Seven patients (37%) were treated with beta November We8 1190 Sclarovsky et al. American Heart Journal

Table I. Clinical data and therapeutic modalities in patients with unstable angina and tachycardia

Interval Heart rate Pa- Type Lead with Duration till beatslmin tient Previous of tachy- ST segment max ST of pain effect No. Age Sex medical therapy cardia deviation changes min) Therapy (min) Pre Post

1 59 F N, NT ST Elevation V3 15 BB 10 130 94 2 50 M - ST Depression V, 90 BB 13 120 92 3 63 M N, NT, NTSL ST Elevation V3 120 CM 3 130 80 4 74 M N, NT, NTSL AF Depression V4 180 Verapamil 6 140 80 5 84 F N, NTSL ST Depression V4 360 CM 2 116 78 6 63 M N, NT ST Elevation L 180 BB 10 120 75 7 73 M N, NT, NTSL AF Depression V4 180 Verapamil 26 150 92 8 65 F NTIV ST Depression V5 15 BB 10 120 92 9 74 M AF Depression V5 420 Verapamil 20 140 75 10 58 F NTIV, N, NSL ST Depression V3 20 BB 10 120 90 11 49 M N, NT, I? ST Depression V, 90 CM 5 120 78 12 75 F - ST Elevation d 360 BB 15 135 96 13 71 M N, NT AF Depression V, 120 Verapamil 10 130 77 14 71 M N, NTSL ST Depression V, 180 Amiodarone 30 125 87 15 64 M N, NT ST Depression V4 120 Amiodarone 55 115 78 16 60 M N, NT, NTSL ST Depression V4 30 Spontaneous - 112 75 17 57 M BB withdrawal ST Depression VS 360 BB 12 120 90 18 63 M AF Depression V4 30 Spontaneous - 110 80 19 51 M N, NT, NTSL ST Depression V3 90 Spontaneous - 125 90

AF, atria1 fibrillation; BB, beta blockers; CM, carotid massage; IE, isoelectric; IV, intravenous; N, nifedipine; NT, nitrates; P, propranolol; SL, sublingual; ST, sinus tachycardia. *T wave inversion.

blockers, four (21%) were treated with verapamil, patients can be classified into more homogeneous and two (10%) were treated with amiodarone. In groups by the use of more precise anatomic and three (16 % ) we observed spontaneous heart rate functional criteriaal We believe that such criteria reduction on arrival. Patients responded with heart must include the different patterns of ischemic ECG rate reduction from a mean of 125 +- 10.4 to 84 +- changes, and we recentlylO correlated those patterns 7.5 beats/min (p <0.005) and an ST segment shift of with prognosis and coronary anatomy. 4.3 + 2.13 mm to 0.89 + 0.74 mm (p < 0.005). With- Continuous hemodynamic and ECG monitoring in a mean interval of 13.2 + 12.7 minutes. 15 indicate that most episodes of ischemia in patients patients (79%) had complete relief of pain and the with unstable angina are not preceded by increased other four (21% ) had partial relief of pain. The cardiac activity.7-g Because heart rate is the best correlation between heart rate and ST segment single index for myocardial oxygen consumption,” deviation (depression or elevation) is shown in Figs. we used this parameter to characterize a subgroup of 3 and 4. A significant direct correlation was observed patients with unstable angina and tachycardia not for both groups (r = 0.7527 and 0.8739, respective- related to effort, according to the following clinical ly). features. Duration of pain. The definition of unstable angina DISCUSSION used by the Veterans Administration cooperative Although it is widely recognized that unstable StudyI on the protective effect of against angina is a syndrome accompanying a variety of infarction and death included duration of pain clinical and pathophysiologic entities,” clinical trials longer than 15 minutes. The Coronary Sur- and guidelines for management still consider gery Study (CASS) investigators17 classified patients patients with this syndrome as a single homoge- with unstable angina into four subgroups and neous group.12 The current most widely used clinical defined coronary insufficiency as chest pain lasting classifications for unstable myin? are ba.scd oii longer than 80 minutes. In the present study, we aescriptive features of the patient’s symptoms and evaluated patients with prolonged chest pain rang- the number of angiographically detected diseased ing from 15 to 420 minutes without development of a vessels.13,14 It seems reasonable to assume that pre- new Q wave or diagnostic elevation of cardiac isoen- dictions of greater accuracy are achievable if zymes. This is most remarkable in the face of the Volume 116 Number 5, Part 1 Unstable angina with tachycardia 1191

ST segment shift (mm) Pain

Pre Post Pre Post

3 1* + - 4 0.5 + - 4 IE* + I 1 + - 5 1.5 + - 2 1* + 6 2.5 + 2 1 + I 2 IE + - 3 1 + 1 0.5 + + 3 IE* + 9 1 + I 2 + k Fig. 3. ST segment depression as a function of heart rate 5 2 + * reduction. The regression line is y = 0.083x - 5.8 5 1 + (r = 0.7527, p (r)

(mHR) CmnZ i Y=R= 0.054x-0.8739 4 107, I known correlation between duration of pain and P(R)< 0.005 I probability of evolution to infarction. A Pre I lschemic ECG changes. ST segment depression 5 0 Post I / reflects a diffuse subendocardial ischemic process and therefore does not suggest the artery causes the ischemia. The nonspecificity of the site of ST seg- ment depression during testing for localizing the likely region of myocardial ischemia is well known.18s20 Irrespective of the artery involved, leads I I ,MdIO,I, ) , ( , w 60 70 60 90 1001X) 120130140 160 HR(bpm) V, and L, are the leads with the higher prevalance of positivity.21 It is noteworthy that in the present Fig. 4. ST segment elevation as a function of heart rate study, in 87% of our patients the maximal magni- reduction. The regression line is y = 0.054x - 4 tude of ST depression was observed in these leads. (r = 0.8739, p (r) <0.005). The combination of this pattern of ischemic ECG changes and tachycardia found in this study resem- bles the findings of a positive stress test, besides its tension may cause an abrupt drop in coronary lack of relation to effort. ST elevation, on the pressure and may sufficiently attenuate contrary, reflects the site of ischemia and localizes subendocardial perfusion, producing myocardial the region perfused by the vessel involved. Most ischemia”“; (2) pharmacologic agents with pro- studies have indicated that ST segment elevation nounced vasodilator properties (especially nifedi- during stress testing is uncommon. The prevalence pine) may induce a “coronary steal” by diverting of such a finding is up to 30%) and it is not related perfusion away from an ischemic coronary vascular exclusively to the presence of prior infarction.2’~2~ bed to a normal nonischemic area of the heart27z28; The present study has shown ST segment elevation (3) a reflex increase in heart rate to the extent that it in 21% of patients-all with recent myocardial shortens the duration of diastole and increases infarction in the same anatomic region. oxygen demands may worsen or provoke myocardial Previous medical therapy. There are several ischemia.20 In our study, 14 patients (74% ) received reports23*24*26 that nifedipine and other vasodilators combined treatment with nifedipine and nitrates in could worsen or provoke angina pectoris. Several a dose up to 60 mg and 160 mg, respectively. Only mechanisms have been proposed to explain this one of these 14 received concomitant treatment with paradoxic response: (1) vasodilator-induced hypo- beta blockers. Eight patients received nitrates sub- November l@Se 1192 Sclarovsky et al. American Heart Jiwnsl lingually before hospital admission (average dose 10 sented here may be deleterious and may worsen the mg; range, 5 to 20 mg). One patient was admitted 24 ischemia further by creating a vicious circle in which hours after abrupt withdrawal of long-term therapy more pain leads to more vasodilators, more tachy- with propanolol in a dose of 120 mg. Because none of cardia, and more ischemia. Therapeutic intervention our patients were hypotensive on arrival and all had aimed at heart rate reduction may abort this hazard- heart rates above 100 beatsjmin (mean 125 & 10.4) ous cycle and terminate the ischemic event. not related to fever, anemia, or overt heart failure, Although our data were not obtained in a random- we speculate that a paradoxic increase in oxygen ized comparative study, the results observed were of demand due to reflex-mediated tachycardia may be high statistical significance. The marked effect of the underlying mechanism for myocardial ischemia heart rate reduction on ischemic ECG changes and in our patients. The tachycardia observed in our clinical features may have very significant conse- patients may be related to previous medical therapy quences upon our therapeutic approach to this and may provoke myocardial ischemia by increasing subgroup of patients with unstable angina. oxygen demand. 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