antihypertensive drug therapy and arrhythmia risk

>75%. The left main coronary artery was narrowed >75% in 2 patients (nos. 2 and 13). Additionally, 8 patients had an occluding thrombus in the “infarct-related” coronary artery. The amounts of cross-sectional area narrowing in the 575 five-mm long coronary segments in 13 patients are shown in Figure 1. The infarct- related coronary artery was narrowed >7.5% in cross- sectional area by plaque in all 13 patients. The noninfarct-related coronary artery (left anterior descending coronary artery for posterior wall AMI, dominant left circumflex or dominant right coronary artery for anteri- or wall AMI) was narrowed >75% in 12 of the I3 patients. The percentage of segments narrowed >75% in cross-sectional area for each artery was greater in the infarct-related artery than in the noninfarct-related artery in 9 of the 13 patients. Thrombus was present in a saphenous vein conduit in 3 (20%) of 15 patients or in 4 (11%) of 37 conduits.

Findings in these 15 patients who had AM1 before entering the cardiac catheterization laboratory and oper- ating room (for CABG) and who survived <60 days postoperatively were compared with those in 121 previously reported3 necropsy patients who did not have an AM1 (angina pectoris only) before CABG and who survived <60 days (Table II). Comparison between these 2 groups showed 1 important significant difference: the mean heart weight in the AM1 group was significantly larger than that of the angina group (517 vs 444 g). Of the 15 patients, 14 (93%) in the AM1 group had hearts of increased weight compared with 84 of 121 patients (69%) in the angina group (p <0.05).

Table III summarizes previously published reports of results of CABG during AMI.4m11 None of these 14 reports described cardiac morphologic findings in the fatal cases. The present study attempts to fill that void.

1. Spray TL, Roberts WC. Changes in sophenous ueins used as aorta-coronary bypass grafts. Am Heart J 1977:94:500-516.

2. Roscher AA, Kern WH. Aortocoronory bypass surgeryfrom thepathologist’s point of view. A clinicopathologic study of240 cases with twenty-six autopsies. Inr Surg 1977.62:282-293. 3. Kalan JM, Roberts WC. Significance of cardiac weight in patients haoing coronary artery bypass grafting for angina pectoris. Am J Cardiol 1988,62:36- 40. 4. Favaloro RG. Effler DB, Cheanvechai C, Quint RA, Sones FM, Jr. Acute coronary insufficiency (impending myocardial infarction and myocardial infarction). Surgical treatment by the saphenous win graft technique. Am J Cardiol 1971;28:598-607. 5. Pifarre R, Spinazzola A, Nemickas R, Scanlon PJ, Tobin JR. Emergency aortocoronary bypass for acute myocardial infarction. Arch Surg 1971;103:525~ 528. 6. Sustaita H, Chatterjee K, Matloff JM, Marty AT, Swan HJC, Fields J. Emergency bypass surgery in impending and complicated acute myocardial infarction. Arch Surg 1972:105:30-35. 7. Dawson JT, Hall RJ, Hallman GL, Co&y DA. Mortality inpatients undergo- ing coronary artery bypass surgery after myocardial infarction. Am J Cardiol 1974;33:483-486. 6. Levine FH, Gold HK, Leinbach RC, Daggett WM. Austen WG, Buckley MJ. Management of acute myocardial ischemia with intraaortic balloon pumping and coronary bypass surgery. Circulation 1978;58(suppl 1):1-69-I-72. 9. Jones EL, Waitea TF, Craver JM, Bradford JM, Douglas JS, King SB, Bone DK, Dorney ER, Clements SD, Thompkins T, Hatcher CR, Jr. Coronary bypass

for relief of persistent pain following acute myocardial infarction. Ann Thorac Surg 1981:32:33-43. 10. Hines CL, Mohtashemi M. Delayed operatiue intervention in cardiogenic shock after myocardial infarction. Ann Thorac Surg 1982;33:132-138. 11. Roberts AJ, Sanders JH, Jr, Moran JH, Spies SM, Lcsch ML, Michaelis LL. The efficacy of medical stabilization prior to myocardial reuascularization in early refractory postinfarction angina. Ann Surg 1983;197:9/-98. 12.Nunley DL, Grunkemeier GL, Teply JF, Abbruzzese PA, Davis JS, Khonsari S, Starr A. Coronary bypass operation following acute complicated myocardial infarction. J Thorac Cardiooasc Surg 1983:85:485-491. 13. DeWood MA, Spores J, Berg R, Jr, Kendall RW, Grunwald RP, Selinger SL, Hensley GR, Sutherland KI, Sheilds JP. Acute myocardial infarction: a decade of experience with surgical reperfusion in 701 patients. Circulation 1983,68(suppl II):lI-8-11-16. 14. Phillips SJ, Kongtahworn C, Skinner JR, Zcff RH. Emergency coronary artery reperfusioc a choice therapy for evoluing myocardial infarction. Results in 339 patients. J Thorac Cardiovasc Surg 1983:86:679-688. 15. Baumgartner WA, Borkon AM, Zibulewsky J, Watkins L, Jr, Gardner TJ, Bulkley BH, Achuff SC, Baughman KL, Trail1 TA, Gott VL, Reitz BA. Opera- tive intervention for postinfarction angina. Ann Thorac Surg 1984;38:265-267. 16. Hochberg MS, Parsonnet V, Gielchinsky I, Hussain SM. Fisch DA, Norman JC. Timing of coronary revascularizntion after acute myocardial infarction. Early and late resulrs in patients reoascuiarized within seuen weeks. J Thorac Cardiooasc Surg 1984;88:914-921, 17. Katz NM, Kubanick TE, Ahmed SW, Green CE, Pearle DL, S&r LF. Rackley CE, Wallace RB. Determinants of cardiacfailure after coronary bypass surgery within 30 days of acute myocardial infarction. Ann Thorac Surg 1986;42:658-663.

Antihypertensive Drug Therapy and Arrhythmia Risk Daniel Levy, MD, Keaven M. Anderson, PhD, Jane C. Christiansen, MPH, Giovanni Campanile, MD, and Joseph Stokes Ill, MD

T he possibility of adverse coronary outcomes in hypertensive patients treated with potassium-depleting

diuretics has received recent attention. Subgroup analysis from the Multiple Risk Factor Intervention Trial (MRFIT)’ suggested that hypertensive subjects who had

From the Framingham Heart Study, Framingham, Massachusetts; the National Heart, Lung, and Blood Institute, Bethesda, Maryland; the Section of Epidemiology and Preventive Medicine and the Evans De- partment of Clinical Research of Boston University School of Medicine and University Hospital, Boston; and Framingham Union Hospital, Framingham, Massachusetts. Manuscript received November 30, 1987; revised manuscript received and accepted March 17, 1988.

abnormal resting electrocardiograms and who received special intervention, which included diuretic-based stepped care, had higher coronary mortality than control subjects receiving usual care. Similarly, early results in the Medical Research Council (MRC) trial suggested an excess of fatal cardiac events in diuretic-treated subjects2 that prompted an investigation of arrhythmias. In that study, subjects who were treated chronically with diuretics had an increased frequency of ventricular premature complexes (VPCs), compared with recipients of place- bo~.~ These studies have led to speculation about proarrhythmic effects of potassium-depleting diuretics. In con-

THE AMERICAN JOURNAL OF CARDIOLOGY JULY 1,1988 147

BRIEF REPORTS

TABLE I Mean Age and Age-Adjusted Characteristics of Subjects According to Hypertension Treatment Group

B Blocker Druretic Untreated

Men Age Ws)

Systolic BP (mm Hg)

Diastolic BP (mm Hg)

LV mass (g)

LV mass/ht (g/m)

LV hypertrophy (%)

FRSH (%)

HR (beats/min)

Women

Age Cm)

Systolic BP (mm Hg)

Diastolic BP (mm Hg)

LV mass (g)

LV mass/ht (g/m)

LV hypertrophy (%)

FRSH (%)

HR (beats/min)

57 61” (n = 47) (n = 251) 138” 14O* (n = 47) (n = 251) 84+ 86+ (n = 47) (n = 251) 252 246 (n = 34) (n = 165) 145 142 (n = 34) (n = 165) 21 22 (n = 34) (n = 165) 36 37’ (n = 34) (n = 165) 59*5 70 (n = 47) (n = 250)

59f§ (n = 53) 1410 (n = 53) 78’ (n = 53) 175 (n=44) 109 (n=44) 33 (n=44) 39 (n = 45) 65’5 (n = 57)

67” (n = 436) 141’ (n = 436) 80’ (n = 436) 182 (n = 260) 116 (n = 260) 36 (n = 260) 39 (n = 261) 73 (n = 436)

56 (n = 560) 149 (n = 560) 88 (n = 560) 242 (n = 442) 140 (n = 442) 20 (n = 442) 36 (n = 443) 70 (n = 560)

63 (n = 471) 154 (n = 471) 84 (n = 471) 180 (n = 358) 114 (n = 358) 33 (n = 358) 39 (n = 358) 74 (n = 471)

* p <O.oOl YS untreated group; t p <O.Ol YS untreated group; t p <0 05 vs untreated group. 5 p <O.oOl YS diuretac group.

BP = blood pressure: FRSH = echocardlographlc fracttonal shortening, HR = heart rate: Ht = height in meters: LV Mass = echocardlographlc left ventrwlar mass.

trast to diuretics, the antiarrhythmic properties of p blockers might, in part, be responsible for improved sur- vival among myocardial infarction survivors who received these drugs in several secondary prevention trials.4-6 In this study, we compared the prevalance of ventricular arrhythmias in Framingham Heart Study subjects who were receiving either diuretics or p blockers for the treatment of hypertension with those with hypertension who were not receiving antihypertensive medicines.

In 1948, a sample of the residents of Framingham, Massachusetts, ages 28 to 62, was selected to undergo biennial examinations in a prospective epidemiologic study. Offspring (and their spouses) of the original cohort were entered into a second prospective study in 1971. Selection criteria and study design have been previously describede7J

One-hour ambulatory electrocardiographic monitor- ing was routinely obtained during the sixteenth biennial examination of the original cohort and the second examination of the offspring. Ambulatory electrocardiogram methods used in this study have been previously reported.9 Ventricular arrhythmias were classified according to the presence or absence of the following arrhythmia

types: I/PCs, multiform VPCs, ventricular couplets, ventricular tachycardia, R-on-T VPCs. A summary of arrhythmia forms termed complex or frequent VPCs (>30/hour, multiform VPCs, couplets, ventricular tachycardia or R-on-T VPCs) was also considered.

M-mode echocardiographic images of the left ventri- cle were also routinely obtained at the sixteenth biennial examination of the original cohort and the second examination of the offspring. Left ventricular mass and frac- tional shortening were calculated. Left ventricular hypertrophy was defined on the basis of left ventricuyb mass/height 1163 g/m in men and 121 g/m in women.

Hypertensive subjects who were receiving either diuretics or /3 blockers (but not both) and a control group of untreated hypertensives (blood pressure 1140 systolic or 190 diastolic) were eligible for inclusion in this study. Subjects with a history or clinical evidence of coronary heart disease, congestive heart failure or valvular disease were excluded. The subjects selected for this study were stratified by sex and age group (<40,40 to 49, SO to 59,60 to 69, 70 to 79 and 180). The Mantel-Haenszel test was used to derive age- and sex-adjusted rates for the various arrhythmia grades in each treatment group. A 1 -sided Mantel-Haenszel test was used to test the hypothesis that arrhythmia rates are greater in diuretic- treated and lower in /3 blocker-treated hypertensive subjects compared with untreated hypertensives.

In all, 6,218 subjects underwent routine evaluation, including 2,805 men (mean age 53 f 15) and 3,413 women (mean age 5.5 f 16). Of these, 1,818 were hypertensive and eligible for inclusion in this study. The study group included 100 subjects treated with fi blockers (but not diuretics), 687 treated with diuretics (but not p blockers) and 1,031 hypertensive subjects not receiving antihypertensive drugs. Age-adjusted characteristics of the subjects in these 3 groups are listed in Table I. Diuretic-treated subjects tended to be older than untreated hypertensives and /3 blocker recipients, under- scoring the need for age-adjustment. Drug-treated hypertensive subjects had higher age-adjusted levels of systolic and diastolic blood pressure than untreated subjects. Beta blocker-treated subjects had lower age-adjusted heart rates. There were no differences between groups in age-adjusted left ventricular mass, left ven-

TABLE II Age- and Sex-Adjusted Prevalence (per 100) of Ventricular Arrhythmias in Hypertensive Subjects According to Treatment Group

6 Blocker Diuretic Untreated

VPCs > 1 /hour 40 40 39 VPCs >lO/hour 13 19* 15 VPCs 11OO/hour 1 5 4 VPCs (multiform) 9 13 13 VPC (pairs) 4 5 4 Ventricular tachycardia 0 1.2 0.7 VPCs with R-on-T 0 1.1 0.5 VPCs (complex or frequent) lo*+ 17 17

* p CO.05 vs untreated group; + p = 0 05 vs diuretic group. VPC = ventricular premature complex.

148 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 62

tricular mass/height or prevalence of left ventricular hypertrophy.

Age-adjusted prevalence of the various ventricular arrhythmias in drug-treated compared with untreated subjects are listed in Table II. Compared with untreated hypertensive subjects, the rates of arrhythmia tended to be higher (statistically significant only for 210 VPCs/ hour) in diuretic-treated subjects and lower (statistically significant only for complex or frequent VPCs) in subjects treated with fi blockers. The age- and sex-adjusted rate of complex or frequent ventricular arrhythmias was 17% among recipients of diuretics, 10% among hypertensives treated with p blockers and 17% in hypertensive subjects not receiving drug treatment. The overall significance of these findings (p = 0.05 p blocker US diuretic; p CO.05 /3 blocker us untreated; not significant for diuretic us untreated) suggests that arrhythmia rates differ between groups.

This study demonstrates trends toward an increased risk for complex or frequent ventricular arrhythmias in diuretic-treated hypertensive subjects and a reduced risk in hypertensive subjects treated with p blockers. This finding may reflect the proarrhythmic effects of diuretics, the antiarrhythmic effects of p blockers or a combination of these 2 factors.

One explanation for the excess of arrhythmias among diuretic-treated hypertensives is the hypokalemia which often results from the administration of diuretics. Al- though some investigators have failed to demonstrate arrhythmia provocation in diuretic-induced hypokalemia,’ 1,12 there is growing evidence to implicate potassium depletion as a mechanism that can promote arrhythmias.3J3-15 Additionally, hypomagnesemia, which also frequently results from diuretic administration, is another mechanism that has been reported to promote ventricular arrhythmias.16J7 The possibility of a direct proarrhythmic effect of diuretics must also be considered.

Beta blockers possess antiarrhythmic membrane-sta- bilizing and sympatholytic properties.18 The antiarrhythmic and antifibrillatory properties of p blockers have been identified as important mechanisms by which coronary mortality was decreased in several secondary prevention trials.4Jg,20 Additionally, it has been noted that diuretic-induced hypokalemia can be attenuated by /3 blockade.

These results may help to explain those findings from MRFIT study analysis’ that identified a subgroup of diuretic-treated hypertensives at increased risk for mortality. Those observations led to speculation about proarrhythmic properties of potassium-depleting diuretics and increased risk of sudden cardiac death in susceptible individuals.

Representing potential confounding conditions, subjects with evidence of coronary heart disease, congestive heart failure and valvular heart disease who were at increased risk for arrhythmias were excluded from analysis. Individuals with a history of congestive heart failure and

hypertension would be more likely to be treated with diuretics, whereas fi blockers would be the preferred treatment for hypertensive subjects with a history of pal- pitations, angina or myocardial infarction. Although the population included in this study was free of clinically overt cardiac end-organ disease, subclinical conditions may have led to preferential use of 1 treatment regimen over another. Despite efforts to eliminate confounding variables, the present study was not randomized and may therefore reflect selection bias. The demonstration in this study that hypertensive subjects treated with different drug regimens differed in risk for ventricular arrhythmias warrants further investigation.

1. Multiple Risk Factor Intervention Trial Research Group. Multiple Risk Fac- tor Intervention Trial: risk factor changes and mortality results. JAMA 1982;248:1465-1477. 2. Medical Research Council Working Party. MRC trial of treatment of mild hypertensiotr principal results. Br Med J 1985;291:97-104. 3. The Medical Research Council Working Party on Mild to Moderate Hyperten- sion. Ventricular extrasystoles during thiazide treatment: sub-study of MRC mild hypertension trial. Br Med J 1983:287:1249-l 253. 4. Koppes GM, Beckmann CH, Jones FG. Propranolol therapy for ventricular arrhythmias 2 months after acute myocardial infarction. Am J Cardiol 1980;46:322-328. 5. Lichstein E, Morganroth J. Harrist R, Hubble E, for the BHAT study group. Effect of propranolol on ventricular arrhythmia. The Beta-Blocker Heart Attack Trial experience. Circulation 1983,67(suppl 1):5-10. 6. Olsson G, Rehnquist N. Ventricular arrhythmias during the@ year after acute myocardial infarctiorr in/luence of long-term treatment with metoprolol. Circulation 1984.69:1129-l 134. 7. Dauber TR, Kannel WB, Lyell LP. An approach to longitudinal studies in a community: the Framingham Study. Ann NY Acad Sci 1963;107:539-556. 8. Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families. The Framingham Offspring Study. Am J Epidemiol 1979;110:281-290, 9. Levy D, Anderson KM, Savage DD, Balkus SA, Kannel WB, Castelli WP. Risk of ventricular arrhythmias in left ventricular hypertrophy: The Framing- ham Heart Study. Am J Cordiol 1987,60:560-565. 10. Levy D, Savage DD, Garrison RJ, Anderson KM, Kannel WB, Castelli WP. Echocardiographic criteria for left uentricular hypertrophy: The Framingham Heart Study. Am J Cardiol 1987:59:956-960. 11. Madias JE, Madias NE, Gavras HP. Nonurrhythmogenicity of diuretic- induced hypokalemia. Its evidence in patients with uncomplicated hypertension. Arch Intern Med 1984:144:2171-2176. 12. Papademetriou V, Price M, Notargiacomo A, Gottdeiner J, Fletcher RD. Freis ED. Effect of diuretic therapy on uentricular arrhythmias in hypertensive patients with or without left ventricular hypertrophy. Am Heart J 1985;110:595- 599. 13. Holland OB, Nixon JV, Kubnert L. Diuretic-induced ventricular ectopic activity. Am J Med 1981;70:762-768, 14. Duke M. Thiazide-induced hypokalemia. Association with acute myocardial infarction and ventricular fibrillation. JAMA 1978;239:43-45. 15. Kaplan NM. Our appropriate concern about hypokalemia. Am J Med 1984;77:1-4. 16. Wester PO, Dyckner T. Diuretic treatment and magnesium losses. Acta Med Stand 1981;209(suppl647):145-152. 17. Kuller L, Farrier N, Caggiula A, Borhani N, Dunkle S. Relationship of diuretic therapy andserum magnesium levels amongparticipants in the Multiple Risk Factor Intervention Trial. Am J Epidemiol 1985;122:1045-1059. 16. Anderson JL, Rodier HE, Green LS. Comparative effects of beta-adrenergic blocking drugs on experimental ventricular fibrillation threshold. Am J Cardiol 1983:51:1196-l 202. 19. Koch-Weser J, Frishman WH, Furbcrg CD, Friedewald WT. B-adrenergic blockade for suruioors of acute myocardial infarction. N Engl J Med 1984; 310:830-837. 20. Ryden L, Ariniego R, Amman K, Herlitz J, Hjalmarson A, Holmberg S, Reyes C, Smedgdrd P, Svcdberg K, Vedin A, Waagstein F, Waldenstiim A, Wilbelmsson C, Wedel H, Yamamoto M. A double-blind trial of metoprolol in acute myocardiol infarction. Effects on ventricular tachyarrhythmias. N Engl J Med 1983:308:614-618.

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antihypertensive drug therapy and arrhythmia risk

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