Severity of arrhythmias and extent of hypertrophy in hypertrophic cardiomyopathy

Severity of arrhythmias and extent of hypertrophy in hypertrophic cardiomyopathy To evaluate the relationship between the extent of left ventricular hypertrophy and ventricular or atrial arrhythmias, 77 patients with hypertrophic cardiomyopathy underwent two-dimensional echocardiography and 24-hour Holter monitoring. Antiarrhythmic treatment was discontinued before the study. Hypertrophy was septal in 33 patients, “extensive” (Le., involving the septum and free wall) in 38 patients, and predominantly apical in six patients. Lown grade I and II ventricular arrhythmias were detected in 37% of patients, grade Ill in 21%, and grade IV in 29%. Atrial extrasystoles were seen in 52% of patients and chronic atrial fibrillation in 13%. More serious ventricular arrhythmias (Lown grades Ill and IV) occurred significantly more frequently in patients with extensive than in those with only septal hypertrophy (22/38 vs 1 l/33; p < 0.001); similarly, chronic atrial fibrillation occurred more commonly in those with extensive hypertrophy (g/38 vs l/33; p < 0.01). During a mean follow-up period of 2.6 years, three patients died. All had a pattern of extensive hypertrophy. Two of them had ventricular tachycardia and the third had chronic atrial fibrillation. Results of this study suggest that an echocardiographic finding of extensive hypertrophy represents a useful marker for detecting patients at increased risk for serious ventricular and atrial arrhythmias. (AM HEART J 1989;118:734.)

Ettore Lazzeroni, MD, Stefano Domenicucci, MD, Angelo Finardi, MD, Antonello Zoni, MD, Claudio Dodi, MD, Paolo Francescon, PhD, and Giuseppe Botti, MD. Parma and Genoua, Italy

Arrhythmias represent one of the most significant problems in the management of patients with hypertrophic cardiomyopathy. The prognostic meaningre3 and the prevalence of arrhythmias2-5 have been defined sufficiently, whereas the mechanisms responsible for their genesis have not been totally clarified. Potentially useful information may come from results of morphologic studies of the distribution of hypertrophy, which have already proved useful in the evaluation of clinical, hemodynamic,6* 7 and ECG feature& g of this disease. In particular this method may help clarify the still uncertain relationship between the extent of hypertrophy and arrhythmias. It has been hypothesized that a greater degree of hypertrophy may predispose to atria1 fibrillation and ventricular arrhythmias. This has been suggested on the basis of results of limited M-mode5 and more extensive two-dimensional echocardiography,1° but the findings have not been confirmed. The aim of the From t,he Divisione di Cardiologia, di Cardiologia, Ospedale Galliera. Received

for publication

Jan.

Ospedale

5, 1989;

accepted

Regionale, June

Reprint requests: Ettore Lazzeroni, MD, Divisione ale Regionale, Via Gramsci 14, 43100 Parma. Italy. 4/l/14610

734

and

the Divisione

13. 1989. di Cardiologia,

Osped-

present study was to assess the possible relationship between the extent of left ventricular hypertrophy, assessed by two-dimensional echocardiography, and the prevalence and severity of arrhythmias, evaluated with ambulatory ECG monitoring. METHODS Selection and characterization of patients. On the basis of the satisfactory quality of two-dimensional echocardiograms and 24-hour ambulatory ECGs, we selected 77 patients with hypertrophic cardiomyopathy. The diagnosis was based on M-mode and two-dimensional echocardiographic demonstrations of a hypertrophied and nondilated left ventricle in the absence of another cardiac or systemic disease that could produce left ventricular hypertr0phy.l’ The clinical characteristics of the patients are shown in Table I. Fifty-one patients (66% ) were male and 26 (34% ) were female; their ages ranged from 15 to 75 years (mean 45). Thirty patients were in New York Heart Association class I, 28 were in class II, and only 18 were in classes III and IV. Forty-seven patients had palpitations, 33 had dyspnea, 28 had chest pain, and eight had at least one episode of syncope. Results of cardiac catheterization performed on 49 patients showed the presence of rest or provokable gradient in 30 of them (61%). Ambulatory ECG monitoring. Twenty-four-hour ambulatory ECG monitoring was performed with a model 660B

Volume Number

118 4

LV mass-arrhythmia

I. Clinical characteristics in 77 patients with hypertrophic cardiomyopathy Table

Sex (% males) Obstructive forms* New York Heart Association class I II III IV Symptoms Palpitations Dyspnea Chest pain Syncope

Holter monitoring Arrhythmia

45.5 (range 15 to 75) 66% 53%

39% 37% 22% 1% 61% 43% 36% 10%

*Outflow obstruction was detected by cardiac catheterization in 30 of 49 patients and by M-mode echocardiography in 11 of 28 patients.

Del Mar Avionics Dynamic Electrocardioscanner(Del Mar Avionics, Irvine, Calif.). In patients receiving antiarrhythmic therapy, treatment wasdiscontinued 2 to 7 daysbefore they were examined. The tapes were analyzed by an experienced cardiologist: when arrhythmic sequenceswere found, that portion of tape wasrerun at normal speedand

printed. At the end of the analysis procedure, the computer tabulated the frequency of single ectopic beats, couplets, and runs of a given wave shape. Ventricular arrhythmias were classifiedaccordingto the grading systemproposedby Ryan and Lown.i2 Atria1 ectopic activity wasclassifiedas occasional(< 30/hr) or frequent (3 30/hr premature beats) and atria1 fibrillation. Echocardiography.Two-dimensionalechocardiography wasperformed with a mechanicalsectorscanner(ATL MK 600 with a 3 MHz transducer). Imageswere obtained in parasternal long- and short-axis viewsat multiple levels,in apical four-chamber and long-axis views; standard Mmode echocardiogramswere also recorded from two-dimensionalimagesfor accurate measurementsof wall thickness.The twa-dimensional echocardiograms,videotaped on a Sony Betamax video recorder, were reviewed independently by two observerswho knew nothing about the identity of the patients. Hypertrophy wastaken into account if the diastolic wall thickness, measuredin the short-axis view, was at least 15 mm (or 17 mm for the anterolateral free wa11).6 The distribution of hypertrophy wasevaluated after the regional tomographic analysis proposed by Edwards et a1.13For the purposeof this study we have adopted a morphologic classification of the distribution of left ventricular hypertrophy simplified in comparisonto that of Maron et al.‘j; thus we have found three fundamental tomographic patterns. (1) Septal hypertrophy: localized at the anterior and/or posterior segmentof the septum in one or more regions; this pattern correspondsto types I, II, and part of IV of the classification of Maron et al.6 (2) Extensive hypertrophy: involving both the septum and free wall in one or more re-

735

Table II. Ventricular arrhythmias detected during 24-hour

Characteristics

Age (yrs)

relations in hypertrophic cardiomyopathy

grade*

0

NO.

%

9

12 27 10 21 10 19

21 8 16 8 15

I (< 30 VES/hr) II (3 30 VES/hr) III (multiform VES) IVa (couplets) IVb (VT)

VES, ventricular extrasystoles;VT, ventricular tachycardia. *Classification of Ryan and Lown.12 Ill. Supraventricular arrhythmias detected during 24-hour Holter monitoring

Table

Atrial

extrasystoles

None < 30/hr Z= 30/hr Atria1 fibrillation

No.

%

27 32 8 10

35 42 10 13

gions (corresponding to Maron’s type III). (3) Apical hypertrophy: predominantly localized at the apical region of the ventricle. This pattern wasincluded in Maron’s type IV. Statistical analyses. Appropriate chi-square test, Student’s t test, or Fisher’s test wasused to assessstatistical significance. RESULTS Ambulatory

Ventricular

ECG monitoring

arrhythmias. Table II summarizes the

ventricular arrhythmias detected during 24 hours of ambulatory ECG monitoring. Sixty-eight of 77 patients (88%) had ventricular arrhythmias: 27 % had Lown class I extrasystoles, 10% had class II, 21% had multiform, and 10% had paired extrasystoles. Fifteen patients (19 % ) had ventricular tachycardia. Supruventriculur

arrhythmias.

rizes the supraventricular

Table III summa-

arrhythmias

detected.

Atrial arrhythmias were seen in 50 patients (65 % ) 40

had atria1 extrasystoles (32 had fewer than 30/hr and eight had more than 30/hr); 10 patients had continuous atrial fibrillation. Extent of hypertrophy. Left ventricular hypertrophy, assessed by two-dimensional echocardiography, was localized to one or more septal segments in 33 patients (43%) (septal hypertrophy); in 38 (49%) it involved both the septum and free wall (extensive hypertrophy), and in six (8%) it was limited to the apical area. Relationship between the severity of ventricular arrhythmias and distribution of left ventricular hypertrophy. Table IV shows the severity of ventricular

October

736

Lazzeroni

et al.

American

Table IV. Relationship between severity of ventricular rhythmias and distribution of hypertrophy Septal LVH (n = 33)

Ex tensiue L VH (n = 38)

Arrhythmia grade

NO.

f’;‘l

NO.

(‘G)

O-I-II III-IVa-IVb

22 11

(67) (33)

10 28

(26) (73)

LVH, left ventricular see Table 11.

hypertrophy;

for classification

of arrhyt,hmia

ar-

Table VI. Relationship mias and distribution

P

Arrhythmias

< 0.001

Atria1 extrasystoles Atria1 fibrillation

< 0.001 grades

LVH,

Table V. Relationship between arrhythmias and clinical features Clinical

features

Age (yr) Sex (“v male) New York Heart Association class I-II

severity

Low2
Lown III-IV

15°C 24°C’ 21

arrhythmias in two different types of distribution of hypertrophy: septal and extensive. The presence of less serious arrhythmias (Lown classes I and II) was significantly more common in patients with septal (22 of 33,67%) than in those with extensive hypertrophy (10 of 38,26 % ; p < 0.001). On the other hand, the occurrence of more serious arrhythmias (Lown classes III to IVb) was significantly more frequent in patients with extensive hypertrophy (28 of 38,73 % ) than in those with hypertrophy localized to the septum (11 of 33,33% ; p < 0.001). No relationship was observed between the severity of ventricular arrhythmias and other variables such as age, sex, obstructive form, functional class, and septal thickness assessed by M-mode echocardiography (Table V). Relationship between the severity mias and the extent of LV hypertrophy.

ventricular

between supraventricular of hypertrophy

Septal L 1% (n = 33) No. I “c /

Extensive L VH (n = 38)

1989 Journal

arrhyth-

-

No.

(‘;I

P

15

1451

19

(50)

NS

1

c:iI

9

(“4)

< 0.01

hypertrophy;

NS. not significant

of ventricular

45 (range 15-70) 46 (range 17-75) 31°C. 35C,S 38”,J 37 (‘(,

Obstructive forms 30 CC’ M:r’Iptal thickness (mm) l:I’

left

Heart

of atrial

arrhyth-

Table VI shows the relationship between atrial arrhythmias and the two main morphologic types of hypertrophy. No relationship was observed between these patterns of left ventricular hypertrophy and the occurrence of sporadic or frequent extrasystoles. Atria1 fibrillation, by contrast, was significantly more common in patients with extensive (9 of 38,24 % ) than in those with septal hypertrophy (1 of 33, 3% ; p < 0.01). Arrhythmias related to mortality. During a mean follow-up period of 2.6 years (range 1 to 4) three patients

died. All had extensive hypertrophy. Two had one or more episodes of ventricular tachycardia and died suddenly. The third, in chronic atria1 fibrillation, died of heart failure. DISCUSSION

Results of our study of 77 patients with hypertrophic cardiomyopathy showed a 65% prevalence rate of supraventricular arrhythmias and an 88% rate of ventricular premature beats: 50 % of these extrasystoles were “complex” and 19% were sustained or nonsustained ventricular tachycardia. These data are in agreement with those of previous studies with 24-hour Holter monitoring12 ‘7 5, 14-16(Table VII). The most interesting result of this research is the prevalence of high-grade ventricular arrhythmias (Lown grades III and IV) in patients with widespread hypertrophy involving both the septum and free wall; thus a relationship seems to exist between the extent of myocardial hypertrophy and most serious, potentially lethal, ventricular arrhythmias. Recently, Spirit0 et al. lo demonstrated such a relationship between the extent of hypertrophy and ventricular tachycardia. Although in our investigation a different method was used to assess the amount of left ventricular hypertrophy, we found a correlation not only with ventricular tachycardia but also with multiform ventricular extrasystoles and couplets. Our data support the concept that a more extensive hypertrophic process, involving both the septum and free wall, enhances the development of arrhythmias. The explanation for this finding is only speculative. It seems reasonable to hypothesize that the electrophysiologic substrates of arrhythmias may be the histologic or functional alterations connected to hypertrophy, that is, myocardial disarray, ischemia, and fibrosis. Thus it would seem that diverse grades of these disorders could be related to a different grade of severity for arrhythmias.

Volume

118

Number

4

Table

LV mass-arrhythmia

VII. Prevalence

of arrhythmias

No. of patients

Reference Savage et a1.5 (1979) McKenna et a1.2 (1981) Bijarnoson et al.l* (1982) Shapiro and Zezvlka’” (1983) Frank et a1.15(1984) Mean frequency Lazzeroni et al. (1989) VT, ventricular

tachycardia;

in hypertrophic

PSVT,

paroxysmal

cardiomyopathy

Mean we

relations

(Holter

Ventricular

in hypertrophic

(% j

Suprauentricular

Total

z= III

VT

100 86 22 26 50

38 39 50 55 49

83 79 90 74 82

65 38 64 23 54 49

77

45

88

50

19 28 14 5 32 20 19

tachycardia;

Considering atria1 arrhythmias, it is well known that atria1 fibrillation is an adverse event in the evolution of this disease.4 It causes a sudden decrease in the atria1 contribution to the filling of a noncompliant left ventricle. l8 This arrhythmia usually produces a clinical worsening, so as to be considered as “potentially life-threatening” by some investigators. l8 In the present study we found a relationship between continuous atria1 fibrillation and the extent of left ventricular hypertrophy. Considering the adverse consequences of this arrhythmia in hypertrophic cardiomyopathy, the association with more extensive hypertrophy suggests potential prognostic significance of such hypertrophy. The prevalence of arrhythmias has been shown to increase progressively with time,15 and a progression of left ventricular hypertrophy has also been demonstrated in a percentage of patients with this disease.lgl 2o Results of the present study raise the possibility that increases in the occurrence of hypertrophy and arrhythmias may be related, representing two different expressions of a common phenomenon, that is, the progressive pathologic change involving the myocardium. This hypothesis is an attractive one but needs to be confirmed prospectively. In conclusion, identification of serious arrhythmias is an important goal in the management of patients with hypertrophic cardiomyopathy, as some studies have reported the efficacy of medical treatment in reducing the occurrence of arrhythmias and risk of sudden death.i5-18 Because of the poor positive predictive accuracy of symptoms for indicating the presence of serious arrhythmias,15-l* we think that an echocardiographic finding of extensive hypertrophy represents a useful marker for detecting patients at increased risk for potentially life-threatening arrhythmias. In these cases more frequent Halter monitoring and a more aggressive therapeutic strat-

AF, atria1

737

monitoring)

(Yr)

supraventricular

cardiomyopathy

Total 54

(%)

PSVT + AF

74

15 27 32 15 12 20

65

13

100

68

fibrillation.

egy than in patients with less extensive left ventricular hypertrophy may be appropriate. These possibilities should be explored. REFERENCES

1. Maron BJ, Savage DD, Wolfson JK, Epstein SE. Prognostic significance of 24-hour ambulatory electrocardiographic monitoring in patients with hypertrophic cardiomyopathy: a prospective study. Am J Cardiol 1981;48:252. 2. McKenna WJ, England D, Doi YL, Deanfield JE, Oakley CM, Goodwin JF. Arrhythmia in hypertrophic cardiomyopathy. I. Influence on prognosis. Br Heart J 1981;46:168. 3. McKenna WJ, Franklin RCG. Nihovannopoulos P, Robinson K, Deanfield JE. Arrhythmia and prognosis in infants, children and adolescents with hypertrophic cardiomyopathy. J Am Co11 Cardiol 1988;11:147. 4. Glancy DL, O’Brien KP, Gold HK, Epstein SE. Atria1 fibrillation in patients with idiopathic hypertrophic subaortic stenosis. Br Heart J 1970;32:652. 5. Savage DD, Seides SF, Maron BJ, Meyers DJ, Epstein SE. Prevalence of arrhythmias during 24-hour electrocardiographic monitoring and exercise testing in patients with obstructive and nonobstructive hypertrophic cardiomyopathy. Circulation 1979.59866. 6. Maron BJ, Gottdiener JS, Epstein SE. Patterns and significance of the distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy: a wide-angle, two-dimensional echocardiographic study of 125 patients. Am J Cardiol 1981;48:418. 7. Spirit0 P, Maron BJ. Significance of left ventricular out-flow tract cross-sectional area in hypertrophic cardiomyopathy: a two-dimensional echocardiographic study. Circulation 1983; 67:llOO. 8. Maron BJ, Wolfson JK, Cir6 E, Spirit0 P. Relation of electrocardiographic abnormalities and patterns of left ventricular hypertrophy identified by two-dimensional echocardiography in patients with hypertrophic cardiomyopathy. Am J Cardiol 1983;51:189. 9. Lazzeroni E, Domenicucci S, Ten Cate F, et al. Electrocardiographic abnormalities in hypertrophic cardiomyopathy: its relation to the extent of myocardial hypertrophy. Am J Noninvas Cardiol 1988;2:199. 10. Spirit0 P, Watson RM, Maron BJ. Relations between extent of left ventricular hypertrophy and occurrence of ventricular tachycardia in hypertrophic cardiomyopathy. Am J Cardiol 1987;60:1137. 11. Maron BJ, Epstein SE. Hypertrophic cardiomyopathy: a discussion of nomenclature. Am J Cardiol 1977;43:1242.

October

Lazzeroni et al.

American

12. Ryan M, Lown B, Horn H. Ventricular ectopic activity in patients with coronary heart disease. N Engl J Med 1975;292:224. 13. Edwards W, Tajik A, Seward J. Standardized nomenclature and anatomic basis for regional tomographic analysis of the heart. Mavo Clin Proc 1981:56:479. Herdarsen T,~ Jbnsson S. Cardiac arrhythmias in 14. Bjarnoson”1, hypertrophic cardiomvonathv. Br Heart J 1982:48:198. 15. F%k M>, Watkins Lb,*Pris&t ML, et al. Pote&ially lethal arrhythmias and their management in hypertrophic cardiomyopathy. Am J Cardiol 1984;53:1608. LM, Zezvlka A. Hypertrophic cardiomyopathy: a 16. Shapiro common disease with a good prognosis. Br Heart J 1983;50:530. 17. McKenna WJ, Chetty S, Oakley CM, Goodwin JF. Arrhythmia in hypertrophic cardiomyopathy: exercise and 48.hour

Heart

1989 Journal

ambulatory electrocardiographic assessment with and without beta adrenergic blocking therapy. Am J Cardiol 1980;45:1. 18. Canedo MI, Frank MJ, Abdulla AM. Rhythm disturbances in hypertrophic cardiomyopathy: prevalence, relation to symptoms and management. Am J Cardiol 1980;45:848. 19. Domenicucci S, Lazzeroni E, Roelandt J, Ten Cate FJ, Vletter W. Arntzenius AC, Das SK. Progression of hypertrophic cardiomyopathy: a cross-sectional echocardiographic study. Br Heart J 1985;53:405. 20. McKenna W.J, Borggrefe M, England D, Deanfield J, Oakley CM, Goodwin .JF. The natural history of left ventricular hypertrophy in hypertrophic cardiomyopathy: an electrocardiographic study. Circulation 1982;66:1233.

Diltiazem attenuates the inotropic and peripheral vascular effects of cardiac glycosides The influence of diltiazem on the hemodynamic effects of ouabain in 19 preinstrumented awake dogs was studied. Mean aortic pressure increased from 102 to 119 mm Hg with ouabain (p < O-05), an effect that was attenuated by pretreatment with diltiazem. The increase in systemic vascular resistance of 30% with ouabain was ablated by prior diltiazem. Heart rate did not significantly change with ouabain or with diltiarem plus ouabain, but intravenous diltiazem alone produced a reflex increase in heart rate of 26%. Left ventricular (LV) end-diastolic dimension was significantly greater with ouabain alone, but not with ouabain after pretreatment with diltiazem. LV dP/dt max increased by 40% with ouabain alone, but by only 23% (p < 0.001) after pretreatment with diltiazem plus ouabain. When observed at matched preload and heart rate, diltiarem markedly attenuates the positive iqotropic and peripheral arterial constrictive effects of acute ouabain administration in the conscious animal with normal LV function. (AM HEART J 1989;118:738.)

W. Hansford

Watford,

San Antonio,

Texas

MD, Richard

A. Walsh, MD, and Robert A. O’Rourke,

The cardiac glycosides are the only currently available positive inotropic agents administered orally for the long-term treatment of congestive heart failure. The mechanism by which digitalis enhances myocardial contractility is likely an increase in intracellular calcium through inhibition of sarcolemmal Na+-K+ATPase (adenosinetriphosphatase).lm3 Since many

From the Division

of Cardiology,

University

of Texas

Health

Science

Cen-

grants

TZHLO73.50,

ter at San Antonio. Supported HL33579, Received

in part by National and by the Veterans for publication

Apr.

Institutes Administration. 5, 1989;

Reprint requests: Robert A. O’Rourke, versity of Texas Health Science Center San Antonio, TX 78284.7877. 4/l/14515

738

of Health

accepted

May

MD, Division at San Antonio,

22, 1989. of Cardiology, Uni7703 Floyd Curl Dr.,

MD.

patients with heart failure also have ischemic heart disease and/or systemic hypertension, the concomitant use of digitalis and calcium entry blocking drugs is frequent. Currently available calcium entry blocking agents include diltiazem, nifedipine, nicardipine, and verapamil. While digitalis and calcium entry blockers appear to have directionally opposite effects upon trans-sarcolemmal calcium flux, there is no published in vivo data concerning the net effects of combining these agents. In vitro data suggest that the action of cardiac glycosides may be more complex than previously thought. There is controversial evidence that cardiac glycosides, through a feedback mechanism, may increase the amount of calcium that enters the cell through the slow channel.4 This inward calcium current through the slow channel is essential to the