SYSTEMIC
HYPERTENSION
Significance of Ventricular Arrhythmias Systemic Hypertension with Left, Ventricular Hypertrophy
in
Stuart D. Pringle, MD, Francis G. Dunn, MB ChB, Peter W. Macfarlane, PhD, James H. McKillop, PhD, A. Ross Lorimer, MD, and Stuart M. Cobbe, MD
Hypertensive patients with the eleetrocardiographic (ECG) pattern of left ventricular (LV) hypertrophy and strain are at increased risk of sudden death. It has been suggested that ventricular arrhythmias may be responsible. The prevalence and significance of ventricular arrhythmias was therefore studied in 90 hypertensive patients with LV hypertrophy and strain by undertaking 46 hour ambulatory EGG monitoring, ECG dgnal-averaging and programmed ventricular stimulation. Complex ventricular ectopic activity (Lawn grade 23) was detected in 59 patients (66%). Eleven patients (12%) had episodes of nonsustained ventricular tachycardia. There were no sustained arrhythmias either on ambulatory ECG monitoring or induced by programmed ventricular stimulation. Only 1 patient had ventricular late potentials recorded by the signal-averaged electrocardiogram. Therefore, there was little to suggest an underlying arrhythmogenic substrate in these patients. In conclusion, whereas ventricular arrhythmias occur often in patients with LV hypertrophy associated with systemic hypertension, their significance, if any, remains to be established. (AmJ Cardiol 1992;69:913-917)
I
n the Framingham Study, hypertensivepatients with electrocardiographic (ECG) left ventricular (LV) hypertrophy were at increased risk of premature cardiovascular death.’ The fact that the majority of these deaths were sudden (i.e., within 1 hour from the onset of symptoms)2has led to the theory that ventricular arrhythmias may be responsible.Certainly, patients with LV hypertrophy have an increased frequency of complex ventricular ectopic beats3 and nonsustained ventricular tachycardia.4~5Although these studies have demonstrated an association between ventricular arrhythmias and hypertensiveLV hypertrophy, the pathologic significance of these arrhythmias has not been clarified. In particular, whether these arrhythmias are benign or are causally related to sudden death remains to be established.It is therefore important to determine whether hypertensive LV hypertrophy provides a genuine arrhythmogenic substrate. The aim of this study was (1) to determine the prevalence of ventricular arrhythmias in a large series of patients with hypertensive LV hypertrophy and, (2) to evaluate their significance by investigating the potential for a reentry substratethrough studying the signal-averaged electrocardiogram and undertaking invasive electrophysiologic studies. METHODS Patients: Patients with essential hypertension and
ECG LV hypertrophy and strain were identified from the blood pressureclinic databaseand invited to participate. Those who agreed were recruited consecutively. The study group consistedof 90 patients (68 men and 22 women, mean age 57 years [range 25 to 791) (Table I). Secondary hypertension was excluded by clinical evaluation, routine biochemical screening, chest x-ray and, in most cases,by previous intravenous pyelography. Electrocardiography: To ensure uniformity all the 12-lead electrocardiograms were recorded using computer-based methods developed locally.6 For the purposesof this study, LV hypertrophy and strain were delined as being present when there was ST depressionof From the University Departments of Medical Cardiology and Medi10.05 mV and T-wave inversion of 10.1 mV in leads I, cine, Glasgow Royal Infirmary, and Department of Cardiology, Stob hill General Hospital, Glasgow,Scotland,United Kingdom. Dr. Pringle aVL and VS or V6 in the presenceof voltage criteria was in receipt of British Heart FoundationJunior ResearchFellowship (SVl + RV5 >3.5 mV) for LV hypertrophy. These are F141. Manuscript receivedJuly 22, 1991;revised manuscript received not the criteria used by the computer program but were December 5,199 1, and acceptedDecember 7. Addressfor reprints: Stuart D. Pringle, MD, Department of Cardi- selected for comparative reasons with the knowledge ology, Royal Infirmary of Edinburgh, Lauriston Place,Edinburgh EH3 that the presenceof LV hypertrophy was confirmed by echocardiography. 9YW, Scotland, United Kingdom. VENTRICULAR ARRHYTHMIAS IN HYPERTENSION
913
1 TABLE
t
I Clinical
Characteristics
Age (yr) Men:women Angina pectoris Previous myocardlal infarction Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Hypertension duration (yr) Drug therapy Thiazides (no. [%I) p blockers (no. [%I) Ca antagonists (no. [%I) Angiotensin-converting enzyme inhibitors (no. [%I) Mean no. of drugs Potassium (mmol/liter) Magnesium (mmol/liter) LV mass index (g/m2)
TABLE II Prevalence
of Patients 57 (range 25-79) 68:22 9 5 155 (28) 89 (15) 7.4 (8.0) 34 38 40 23 2.51 4.16 0.81 196.4
120 beats/min. Signal-averaged electrocardiogram: The signalaveraged electrocardiograms were recorded with an Arrhythmia Research Technology 101 system with the patient supine. The normal range was defined by combining the most discriminatory features from several previous reports.“-l5 Normal values were a filtered QRS duration of 5 114 ms, a duration of low-amplitude signals 3 times the baseline noise. Eleetrophysiologii study: The desirability of performing electrophysiologic studies was considered for each patient bearing in mind their age, general health and co-existent medical problems. For logistic and ethical reasons,it was not possible for all patients to have an electrophysiologicstudy performed but it was considered important to include patients both with and without ventricular arrhythmias detected noninvasively. In practice, 62 patients were consideredto be suitable and THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
Arrhythmias
Ventricular Ectopic Beats Per Hour
Results are expressedas mean -c 1 SD unless otherwIse stated. Ca = calcium; LV = left ventricular.
914
of Ventricular
No. of pts.
70
Downgrade No. of pts.
0 3
10-30
1 28
>30 8
12
2 0
3 15
Couplets
Nonsustained Ventricular Tachycardia
25
11
4a 4
4b 4
5 36
24 agreed to undergo electrophysiologictesting. The remaining 38 patients declined mainly becauseof a reluctance to be admitted to the hospital rather than anxiety about the procedure. Programmed ventricular stimulation was performed with a quadripolar pacing catheter, introduced under local anaesthesia,using first single (S2) and then double extrastimuli (S2 + S3) at the right ventricular apex and outflow tract. The extrastimuli were introduced after every 8-paced beat (Sl), with cycle lengths of 600 and 450 ms. The extrastimuli were begun 400 ms after the last Sl and the interval then reduced in 10 ms stages until a sustainedventricular arrhythmia was induced or until the extrastimulus failed to capture (i.e., the effective refractory period was reached). If no arrhythmia was induced with single extrastimuli, the same procedure was repeated with double extrastimuli. The end point of the protocol was sustained monomorphic ventricular tachycardia lasting 30 secondsor requiring immediate termination, ventricular fibrillation, or completion of the protocol at both pacing sites and both cycle lengths. Statistical methods: When the 2 groups of data were compared, a 2-sample t test was used if the data were normally distributed, and when the distribution was skewed,the nonparametric Mann-Whitney U test was used.A 5% significance level was usedto determine differences.16 Ethical approval: The study was approved by the hospital ethical committee. The patients provided written informed consent for the invasive procedures and verbal consent for the noninvasive investigations. RESULTS
Results are expressedas the number of patients followed by the percentagein parentheses. Ambulatory
ektrocardiographic
monitoring:
ISO-
Twelve patients (13%) had >30 ventricular ectopic beats per hour, 8 (9%) had between 10 and 29 ventricular ectopic beats per hour, a further 67 patients (74%) had 3 beats. The longest run was 9 beats. In no patient were these episodesassociated with symptoms recorded on the diary cards. Three patients with nonsustained ventricular tachycardia also had >30 ectopic beats per hour. The mean number of ectopic beats tended to be greater in patients with nonsustained ventricular tachycardia than in those without (863 f 1,850 vs 345 f 890). However, becauseof the large standard deviations, this difference was not statistically significant. LOWN GRADING: The distribution of patients by their maximal Lown grade of ectopic beats was as follows (Table II): grade 0, 3 (3%); grade 1, 28 (31%); grade 2, 0; grade 3, 15 (17%); grade 4a, 4 (4%); grade 4b, 4 (4%); and grade 5, 36 (40%). Signal-averaged electrocardiogram: The signal-averagedelectrocardiogram was technically satisfactory in 88 patients: 23 (26%) patients had a prolonged QRS duration, 3 had a decreasedroot-mean-squarevoltage, and 1 patient had prolonged duration of low-amplitude signals. In terms of fulfilling the criteria for late potentials, 2 patients met 2 criteria and only 1 patient fulfilled all 3 criteria. This latter patient was the only one to have visible late potentials. Electrophysidogic testing: There were no inducible sustained ventricular arrhythmias. Seven patients had short episodesof nonsustained polymorphic ventricular tachycardia with a maximal duration of 13 beats.There was no apparent relation between nonsustainedventricular tachycardia detected on Holter monitoring and that induced by ventricular stimulation. Seven of the patients with Holter nonsustainedventricular tachycardia underwent electrophysiologic testing: 3 had inducible nonsustainedventricular tachycardia and 4 did not. Of the 17 who did not have nonsustained ventricular tachycardia on Holter, 4 had inducible nonsustained ventricular tachycardia and 13 did not. There were no differences in the effective refractory period or HV interval in those with or without induced nonsustained ventricular tachycardia. Comparison of patients with and without nonsustained ventricular tachycardia detected on Halter monitoring: There were no significant differences in age,
basal blood pressure,duration of hypertension, LV mass index, serum potassium, serum magnesium or drug therapy in patients with nonsustainedventricular tachycardia compared with those without nonsustainedventricular tachycardia detected on Holter monitoring (Table III). The electrocardiogram, signal-averaged electrocardiogram and electrophysiologicmeasurements were also’similar in the 2 groups. DISCUSSION Prevalence
of ventricular arrhythmias: The hypothesis that ventricular arrhythmias may be important in hypertensive heart diseasewas suggestedinitially by epidemiologic data showing that hypertensive patients with LV hypertrophy were at increased risk of sudden death compared with hypertensive patients without LV hypertrophy.‘,2,i7 Furthermore, patients with hyperten-
TABLE III
Comparison of Age, Blood Pressure, Potassium, Magnesium, Left Ventricular Mass and Drug Therapy in Patients With and Without Nonsustained Ventricular Tachycardia Nonsustained Ventricular Tachycardia
Present (n = 11)
Age (yr) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Hypertension duration (yr) LV mass index (g/m*) Potassrum (mmol/liter) Magnesrum (mmol/liter) Drug therapy Thiazrdes (no. [%I) p blockers (no. [%I) Ca antagonists (no. [%I) Angiotensrn-convertrng enzyme inhibitors (no. [%I) Mean no. of drugs
58 149 92 a.4 203 4.2 0.84 5 6 4 2
Absent (n = 79)
(11) (31) (17) (10.0) 142.6) (0.48) (0.06)
57 155 a9 7.2 196 4.2 0.81 29 32 36 21
(45) (55) (36) (la)
2.2 (1.3)
Results are expressed as mean ? 1 SD unless otherme sigmflcant differences. Abbrewations as in Table I
(11) (27) (14) (7.8) (52.0) (0.42) (0.10) (37) (41) (46) (27)
2.6 (1.4) stated.
There were no
sive LV hypertrophy have an increased frequency of complex ventricular ectopic beats3 and nonsustained ventricular tachycardia.4~5Although these studies have demonstrated an association between ventricular arrhythmias and hypertensive LV hypertrophy, whether these arrhythmias are benign or are causally related to sudden death remains to be established.Therefore, the aim of this study was to examine the pathologic significance of these arrhythmias. In the present study, simple and complex ventricular ectopic beats occurred often in patients with hypertensive LV hypertrophy. Their prevalence was similar to previous studiesof patients with hypertrophic cardiomyopathy,** aortic valve disease19 and hypertensiveLV hypertrophy.3,20,21 Nonsustained ventricular tachycardia occurred in 12%of the patients. This is also in keeping with the results of most other studies of hypertensive patients with reported prevalencesof 10% (6 of 61),22 15%(29 of 196),2317%(3 of 18)20and 28% (14 of 50).4 Thiazide diuretics may increaseand p blockers may decreaseventricular arrhythmias. Although there were no significant differences in treatment between the groups (Table III), we cannot exclude an effect from continuing drug therapy basedon the prevalenceof ventricular arrhythmias. Coronary arteriography was performed in 35 and thallium perfusion scintigraphy in 80 of these patients. There was no relation between silent or symptomatic ischemia and ventricular arrhythmias. Significance of ventricular arrhythmias: More important than simply the prevalenceof complex ventricular ectopic beats is their significance in terms of providing a genuine arrhythmogenic substrate. There are no reports of hypertensive LV hypertrophy causing sustained ventricular tachycardia; all reports are of triplets or runs of nonsustainedventricular tachycardia with a median duration of 7 beats.Nor have there beenstudies examining the relation between ventricular ectopic beats detected on ambulatory ECG monitoring and prognosisin hypertensivepatients with LV hypertrophy. VENTRICULAR
ARRHYTHMIAS
IN HYPERTENSION
915
Two studies, however, have examined the influence of ventricular ectopic beats detectedon short ECG recordings in general population samples that included patients with hypertension and LV hypertrophy.‘7,25Ventricular ectopic beats alone were associatedwith only a modestincreasein risk of suddendeath (2.2-fold).25Although ventricular ectopic beats on 1Zlead electrocardiograms in the Framingham Study were associated with an increasedrisk of sudden death,‘l they were not predictive independently of other ECG abnormalities.26 The published data concerning ventricular arrhythmias as independent predictors for suddendeath has recently been reviewed.27In patients without heart disease or with heart diseaseand normal LV function, there is little evidence to support the hypothesis that simple or complex arrhythmias including short runs of nonsustained ventricular tachycardia are associatedwith increasedrisk of sudden death. For these reasonsit was consideredimportant in the present study to assesswhether an arrhythmogenic substrate exists in patients with hypertensive LV hypertrophy. Evidence for an arrhythmogenic substrate? In contrast to the findings of increasedectopic activity in these patients, there was little evidence of an underlying arrhythmogenic substrate. There were no inducible arrhythmias on electrophysiologic testing in 24 patients and only 1 patient had ventricular late potentials on the signal-averaged electrocardiogram. The argument might be put forward that by performing electrophysiologic studies in only one fourth of the patients, it is not possibleto comment on the group as a whole. This was the reason for recording the signal-averagedelectrocardiogram in all patients. Evidence is accumulating that the signal-averagedelectrocardiogram is extremely useful in predicting the inducibility of ventricular tachycardia by electrophysiologic testing in patients with syncope of unknown origin,13 in patients with nonsustained ventricular tachycardia,i5 and in patients with sustained ventricular tachycardia or previous cardiac arrest.14The chief advantage of the signal-averaged electrocardiogram in the context of the present study is the excellent negative predictive accuracy of approximately 90%.15 Thus, the absenceof late potentials in most hypertensive patients in this study adds considerable weight to the negative findings of the electrophysiologic studies. There have been 2 other reports of programmedventricular stimulation in patients with hypertensive LV hypertrophy.27,28In thesestudiesthe patients underwent electrophysiologic testing as part of the routine investigation of suspectedheart diseaseor unexplained syncope, whereas the patients in the present report were selected purely for this study. Nonsustained ventricular tachycardia was induced in 25% (3 of 12)27and in 29% (4 of 14)28of patients in the previous reports and in 29% (7 of 24) of patients in the presentstudy. Sustained ventricular tachycardia was not inducible in 1 study,27 and in the other study was inducible in only 2 patients, both of whom had cardiac decompensation.28Unfortunately it was not stated whether this was a monomor-
916
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
phic or polymorphic tachycardia. It is questionable whether the induction of polymorphic ventricular tachycardia during electrophysiologic testing is a clinically relevant finding or a nonspecific responseto ventricular premature stimuli. 29Sustained monomorphic ventricular tachycardia, which is more likely to be a clinical rhythm, was not induced in either of these studies or in the presentstudy. Another considerationwas whether a more aggressive protocol using triple extrastimuli should have been used in this study. The increasedsensitivity of using triple extrastimuli would risk inducing nonclinical rhythms.29,30Furthermore, the signal-averaged ECG results in this study reinforce the negative electrophysiologic studies.
REFERENCES
1. Kannel WB, Gordon T, Castelli WP, Ma&is JR. Electrocardiographic left ventricular hvoertroohv and risk of coronarv heart disease: The Framineham Study. Ann %tern if& 1970;72:813-822. ’ 2. Kannel WB. Prevalence and natural history of electrocardiographic left ventricular hypertrophy. Am J Med 1983;75(suppl 3A):4-11. 3. Messerli FH. Ventura HO. Elizardi DJ. Dunn FG. Frohlich ED. Hvtxrtension .. and sudden death: increased ventricular ectopic activity in left ventricular hypxtrophy. Am J Med 1984;77:18-22. 4. McLenachan JM, Henderson E, Morris KI, Dargie HJ. Ventricular arrhythmias in patients with hypertensive left ventricular hypertrophy. N Engi J bed 1987;317:787-192, 5. Pringle SD, Macfarlane PW, McKillop JH, Lorimer AR, Dunn FG. Pathophysiologic assessment of left ventricular hypertrophy and strain in asymptomatic patients with essential hypertension. J Am Co/l Cardial 1989;13:1377-1381. 6. Macfarlane PW, Watts MP, Podolski M. Shoat D, Lawrie TDV. The new Glaseow svstem. In: Willems JL. van Bemmel JH. Zvweitz C. eds. Cornouter EC& Analysis: Towards Standar&ation. Amsterdam: Elsevie;, 19863 l-j,. 7. Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man: anatomic validation of the method. Circularion 1977;55:613-618. 6. Macfarlane PW, McLung JM, Irving A, Watts MP, Taylor TP, Lawrie TDV. Comouter assisted analvsis of dvnamic (24-hour) electrocardioerams. In: Macfarlane ‘PW, ed. Progress-in Ele&card&logy. L&don: Pitmany 1979:123-126. 9. Khurmi NS, Raftery EB. Reproducibility and validity of ambulatory ST segment monitoring in patients with chronic stable angina pxtoris. Am Hem J 1987;113:1091-10%. 10. Lown B, Wolf M. Approaches to sudden death from coronary heart disease. Circulation 1971;44:130-142. 11. Simson MB. Clinical application of signal averaging. Cardiol Clin 1983;l: 109-119. 12. Breithardt G. Boraerefe M. Pathoohvsioloeical mechanisms and clinical significance of ventricular late potentials. Eur b&t J 1986;7:364-385. 13. Winters SL, Stewart D, Games A. Signal averaging of the surface QRS complex predicts inducibility of ventricular tachycardia in patients with syncope of unknown origin: a prospective study. J Am Coil Cardiol 1987;10:775-781. 14. Nalos PC, Gang ES, Mandell WJ, Ladenheim ML, Lass Y, Peter T. The signal-averaged electrocardiogram as a screening test for inducibility of sustained ventricular tachycardia in high risk patients: a prospective study. J Am Coil Cardiol 1987;9:539-548. 15. Turitto G, Fontaine JM, Ursell SN, Caref EB, Henkin R, El-Sherif N. Value of signal-averaged electrocardiogram as a predictor of the results of programmed stimulation in nonsustained ventricular tachycardia. Am J Cardiol 1988;61: 1272-1278. 16. Swinscow TDV. Statistics at Square One. 8th ed. Plymouth: Latimer and Trend, 1987. 17. Kannel WB, Schatzkin A. Sudden death: lessons from subsets in population studies. J Am Coil Cardiol 1985;5:14lB-149B. 16. McKenna WJ, England D, Doli YL, Dean&Id JE, Oakley C, Goodwin JF. Arrhythmia in hypertrophic cardiomyopathy. I. Influence on prognosis. Br Heart J 1981;46:168-172. 19. Klein RC. Ventricular arrhythmias in aortic valve disease: analysis of 102 oatients. Am J Cardiol 1984:53:1079-1083. i0. Papademetriou V, Price M, Notargiacomo A, Gottdiener J, Fletcher RD, Freis ED. Effect of diuretic therapy on ventricular arrhythmias in hypertensive patients with or without left ventricular hypertrophy. Am Hearr J 1985;llO: 595-599. 21. Luque-Otero M, Perez-Casar F, Alcazar J, Simal J, Martell-Claros N, Fernandez-Cruz A, Fernandez-Pinilla. Increased ventricular arrhythmias in hy-
APRIL 1, 1992
pertensives with left ventricular hypertrophy. J Hyperfemion 1986;4(suppl 6):S66-S67. 22. Loaldi A, Pepi M, Agostoni PG. Fiorentini C, Grazi S, Bella PD, Guazzi MD. Cardiac rhythm in hypertension assessed through 24 hour ambulatory electrccardiographic monitoring. Effects of load manipulation with atenolol, verapamil and nifedipine. Br Heart J 1983;50:118-126. 23. Aronow WS, Epstein S, Schwartz KS, Koenigsberg M. Correlation of complex ventricular arrhythmias detected by ambulatory electrocardiographic monitoring with echocardiographic left ventricular hypertrophy in persons older than 62 years in a long-term health care facility. Am J Cm&/ 1987;60:730-732, 24. Le Heuzey JY, Guize L. Cardiac prognosis in hypertensive patients. Incidence of sudden death and ventricular arrhythmias. Am J Med 1988;84(suppl I B):65-68. 25. Kreger BE, Cupples A, Kannel WB. The electrocardiogram in prediction of sudden death: Framingham Study experience. Am Heorr J 1987;113:377~382.
26. Surawicz B. Prognosis of ventricular arrhythmias in relation to sudden cardiac death: therapeutic implications. J AWI Coil Cur&o1 1987;10:435-447. 27. Coste P, Clementy J, Besse P, Bricaud H. Left ventricular hypertrophy and ventricular dysrhythmic risk in hylwtensive patients: evaluation by programmed electrical stimulation. J Hyperkmion 1988;6(suppl 4):SI l6-SI 18. 26. Bethge C, Motz W, Hehn AV, Strauer BE. Ventricular arrhythmia in hypertensive heart disease with and without heart failure. J Cardicmasc ffiarmacol 1987;lO(suppl 6):SI l9-Sl28. 29. Bigger JT, Reiffel JA, Livelli FD, Wang PJ. Sensitivity, specificity, and reproducibility of programmed ventricular stimulation. Circulofion 1986;73 (suppl 11):11-73-11-78. 30. Brugada P, Green M, Abdollah H, Wellens HJJ. Significance of ventricular arrhythmias initiated by programmed ventricular stimulation: the importance of the type of ventricular arrhythmia induced and the number of premature stimuli required. Circulafion 1984;69:87-92.
VENTRICULAR ARRHYTHMIAS IN HYPERTENSION
917
HYPERTENSION
Significance of Ventricular Arrhythmias Systemic Hypertension with Left, Ventricular Hypertrophy
in
Stuart D. Pringle, MD, Francis G. Dunn, MB ChB, Peter W. Macfarlane, PhD, James H. McKillop, PhD, A. Ross Lorimer, MD, and Stuart M. Cobbe, MD
Hypertensive patients with the eleetrocardiographic (ECG) pattern of left ventricular (LV) hypertrophy and strain are at increased risk of sudden death. It has been suggested that ventricular arrhythmias may be responsible. The prevalence and significance of ventricular arrhythmias was therefore studied in 90 hypertensive patients with LV hypertrophy and strain by undertaking 46 hour ambulatory EGG monitoring, ECG dgnal-averaging and programmed ventricular stimulation. Complex ventricular ectopic activity (Lawn grade 23) was detected in 59 patients (66%). Eleven patients (12%) had episodes of nonsustained ventricular tachycardia. There were no sustained arrhythmias either on ambulatory ECG monitoring or induced by programmed ventricular stimulation. Only 1 patient had ventricular late potentials recorded by the signal-averaged electrocardiogram. Therefore, there was little to suggest an underlying arrhythmogenic substrate in these patients. In conclusion, whereas ventricular arrhythmias occur often in patients with LV hypertrophy associated with systemic hypertension, their significance, if any, remains to be established. (AmJ Cardiol 1992;69:913-917)
I
n the Framingham Study, hypertensivepatients with electrocardiographic (ECG) left ventricular (LV) hypertrophy were at increased risk of premature cardiovascular death.’ The fact that the majority of these deaths were sudden (i.e., within 1 hour from the onset of symptoms)2has led to the theory that ventricular arrhythmias may be responsible.Certainly, patients with LV hypertrophy have an increased frequency of complex ventricular ectopic beats3 and nonsustained ventricular tachycardia.4~5Although these studies have demonstrated an association between ventricular arrhythmias and hypertensiveLV hypertrophy, the pathologic significance of these arrhythmias has not been clarified. In particular, whether these arrhythmias are benign or are causally related to sudden death remains to be established.It is therefore important to determine whether hypertensive LV hypertrophy provides a genuine arrhythmogenic substrate. The aim of this study was (1) to determine the prevalence of ventricular arrhythmias in a large series of patients with hypertensive LV hypertrophy and, (2) to evaluate their significance by investigating the potential for a reentry substratethrough studying the signal-averaged electrocardiogram and undertaking invasive electrophysiologic studies. METHODS Patients: Patients with essential hypertension and
ECG LV hypertrophy and strain were identified from the blood pressureclinic databaseand invited to participate. Those who agreed were recruited consecutively. The study group consistedof 90 patients (68 men and 22 women, mean age 57 years [range 25 to 791) (Table I). Secondary hypertension was excluded by clinical evaluation, routine biochemical screening, chest x-ray and, in most cases,by previous intravenous pyelography. Electrocardiography: To ensure uniformity all the 12-lead electrocardiograms were recorded using computer-based methods developed locally.6 For the purposesof this study, LV hypertrophy and strain were delined as being present when there was ST depressionof From the University Departments of Medical Cardiology and Medi10.05 mV and T-wave inversion of 10.1 mV in leads I, cine, Glasgow Royal Infirmary, and Department of Cardiology, Stob hill General Hospital, Glasgow,Scotland,United Kingdom. Dr. Pringle aVL and VS or V6 in the presenceof voltage criteria was in receipt of British Heart FoundationJunior ResearchFellowship (SVl + RV5 >3.5 mV) for LV hypertrophy. These are F141. Manuscript receivedJuly 22, 1991;revised manuscript received not the criteria used by the computer program but were December 5,199 1, and acceptedDecember 7. Addressfor reprints: Stuart D. Pringle, MD, Department of Cardi- selected for comparative reasons with the knowledge ology, Royal Infirmary of Edinburgh, Lauriston Place,Edinburgh EH3 that the presenceof LV hypertrophy was confirmed by echocardiography. 9YW, Scotland, United Kingdom. VENTRICULAR ARRHYTHMIAS IN HYPERTENSION
913
1 TABLE
t
I Clinical
Characteristics
Age (yr) Men:women Angina pectoris Previous myocardlal infarction Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Hypertension duration (yr) Drug therapy Thiazides (no. [%I) p blockers (no. [%I) Ca antagonists (no. [%I) Angiotensin-converting enzyme inhibitors (no. [%I) Mean no. of drugs Potassium (mmol/liter) Magnesium (mmol/liter) LV mass index (g/m2)
TABLE II Prevalence
of Patients 57 (range 25-79) 68:22 9 5 155 (28) 89 (15) 7.4 (8.0) 34 38 40 23 2.51 4.16 0.81 196.4
120 beats/min. Signal-averaged electrocardiogram: The signalaveraged electrocardiograms were recorded with an Arrhythmia Research Technology 101 system with the patient supine. The normal range was defined by combining the most discriminatory features from several previous reports.“-l5 Normal values were a filtered QRS duration of 5 114 ms, a duration of low-amplitude signals 3 times the baseline noise. Eleetrophysiologii study: The desirability of performing electrophysiologic studies was considered for each patient bearing in mind their age, general health and co-existent medical problems. For logistic and ethical reasons,it was not possible for all patients to have an electrophysiologicstudy performed but it was considered important to include patients both with and without ventricular arrhythmias detected noninvasively. In practice, 62 patients were consideredto be suitable and THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
Arrhythmias
Ventricular Ectopic Beats Per Hour
Results are expressedas mean -c 1 SD unless otherwIse stated. Ca = calcium; LV = left ventricular.
914
of Ventricular
No. of pts.
70
Downgrade No. of pts.
0 3
10-30
1 28
>30 8
12
2 0
3 15
Couplets
Nonsustained Ventricular Tachycardia
25
11
4a 4
4b 4
5 36
24 agreed to undergo electrophysiologictesting. The remaining 38 patients declined mainly becauseof a reluctance to be admitted to the hospital rather than anxiety about the procedure. Programmed ventricular stimulation was performed with a quadripolar pacing catheter, introduced under local anaesthesia,using first single (S2) and then double extrastimuli (S2 + S3) at the right ventricular apex and outflow tract. The extrastimuli were introduced after every 8-paced beat (Sl), with cycle lengths of 600 and 450 ms. The extrastimuli were begun 400 ms after the last Sl and the interval then reduced in 10 ms stages until a sustainedventricular arrhythmia was induced or until the extrastimulus failed to capture (i.e., the effective refractory period was reached). If no arrhythmia was induced with single extrastimuli, the same procedure was repeated with double extrastimuli. The end point of the protocol was sustained monomorphic ventricular tachycardia lasting 30 secondsor requiring immediate termination, ventricular fibrillation, or completion of the protocol at both pacing sites and both cycle lengths. Statistical methods: When the 2 groups of data were compared, a 2-sample t test was used if the data were normally distributed, and when the distribution was skewed,the nonparametric Mann-Whitney U test was used.A 5% significance level was usedto determine differences.16 Ethical approval: The study was approved by the hospital ethical committee. The patients provided written informed consent for the invasive procedures and verbal consent for the noninvasive investigations. RESULTS
Results are expressedas the number of patients followed by the percentagein parentheses. Ambulatory
ektrocardiographic
monitoring:
ISO-
Twelve patients (13%) had >30 ventricular ectopic beats per hour, 8 (9%) had between 10 and 29 ventricular ectopic beats per hour, a further 67 patients (74%) had 3 beats. The longest run was 9 beats. In no patient were these episodesassociated with symptoms recorded on the diary cards. Three patients with nonsustained ventricular tachycardia also had >30 ectopic beats per hour. The mean number of ectopic beats tended to be greater in patients with nonsustained ventricular tachycardia than in those without (863 f 1,850 vs 345 f 890). However, becauseof the large standard deviations, this difference was not statistically significant. LOWN GRADING: The distribution of patients by their maximal Lown grade of ectopic beats was as follows (Table II): grade 0, 3 (3%); grade 1, 28 (31%); grade 2, 0; grade 3, 15 (17%); grade 4a, 4 (4%); grade 4b, 4 (4%); and grade 5, 36 (40%). Signal-averaged electrocardiogram: The signal-averagedelectrocardiogram was technically satisfactory in 88 patients: 23 (26%) patients had a prolonged QRS duration, 3 had a decreasedroot-mean-squarevoltage, and 1 patient had prolonged duration of low-amplitude signals. In terms of fulfilling the criteria for late potentials, 2 patients met 2 criteria and only 1 patient fulfilled all 3 criteria. This latter patient was the only one to have visible late potentials. Electrophysidogic testing: There were no inducible sustained ventricular arrhythmias. Seven patients had short episodesof nonsustained polymorphic ventricular tachycardia with a maximal duration of 13 beats.There was no apparent relation between nonsustainedventricular tachycardia detected on Holter monitoring and that induced by ventricular stimulation. Seven of the patients with Holter nonsustainedventricular tachycardia underwent electrophysiologic testing: 3 had inducible nonsustainedventricular tachycardia and 4 did not. Of the 17 who did not have nonsustained ventricular tachycardia on Holter, 4 had inducible nonsustained ventricular tachycardia and 13 did not. There were no differences in the effective refractory period or HV interval in those with or without induced nonsustained ventricular tachycardia. Comparison of patients with and without nonsustained ventricular tachycardia detected on Halter monitoring: There were no significant differences in age,
basal blood pressure,duration of hypertension, LV mass index, serum potassium, serum magnesium or drug therapy in patients with nonsustainedventricular tachycardia compared with those without nonsustainedventricular tachycardia detected on Holter monitoring (Table III). The electrocardiogram, signal-averaged electrocardiogram and electrophysiologicmeasurements were also’similar in the 2 groups. DISCUSSION Prevalence
of ventricular arrhythmias: The hypothesis that ventricular arrhythmias may be important in hypertensive heart diseasewas suggestedinitially by epidemiologic data showing that hypertensive patients with LV hypertrophy were at increased risk of sudden death compared with hypertensive patients without LV hypertrophy.‘,2,i7 Furthermore, patients with hyperten-
TABLE III
Comparison of Age, Blood Pressure, Potassium, Magnesium, Left Ventricular Mass and Drug Therapy in Patients With and Without Nonsustained Ventricular Tachycardia Nonsustained Ventricular Tachycardia
Present (n = 11)
Age (yr) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Hypertension duration (yr) LV mass index (g/m*) Potassrum (mmol/liter) Magnesrum (mmol/liter) Drug therapy Thiazrdes (no. [%I) p blockers (no. [%I) Ca antagonists (no. [%I) Angiotensrn-convertrng enzyme inhibitors (no. [%I) Mean no. of drugs
58 149 92 a.4 203 4.2 0.84 5 6 4 2
Absent (n = 79)
(11) (31) (17) (10.0) 142.6) (0.48) (0.06)
57 155 a9 7.2 196 4.2 0.81 29 32 36 21
(45) (55) (36) (la)
2.2 (1.3)
Results are expressed as mean ? 1 SD unless otherme sigmflcant differences. Abbrewations as in Table I
(11) (27) (14) (7.8) (52.0) (0.42) (0.10) (37) (41) (46) (27)
2.6 (1.4) stated.
There were no
sive LV hypertrophy have an increased frequency of complex ventricular ectopic beats3 and nonsustained ventricular tachycardia.4~5Although these studies have demonstrated an association between ventricular arrhythmias and hypertensive LV hypertrophy, whether these arrhythmias are benign or are causally related to sudden death remains to be established.Therefore, the aim of this study was to examine the pathologic significance of these arrhythmias. In the present study, simple and complex ventricular ectopic beats occurred often in patients with hypertensive LV hypertrophy. Their prevalence was similar to previous studiesof patients with hypertrophic cardiomyopathy,** aortic valve disease19 and hypertensiveLV hypertrophy.3,20,21 Nonsustained ventricular tachycardia occurred in 12%of the patients. This is also in keeping with the results of most other studies of hypertensive patients with reported prevalencesof 10% (6 of 61),22 15%(29 of 196),2317%(3 of 18)20and 28% (14 of 50).4 Thiazide diuretics may increaseand p blockers may decreaseventricular arrhythmias. Although there were no significant differences in treatment between the groups (Table III), we cannot exclude an effect from continuing drug therapy basedon the prevalenceof ventricular arrhythmias. Coronary arteriography was performed in 35 and thallium perfusion scintigraphy in 80 of these patients. There was no relation between silent or symptomatic ischemia and ventricular arrhythmias. Significance of ventricular arrhythmias: More important than simply the prevalenceof complex ventricular ectopic beats is their significance in terms of providing a genuine arrhythmogenic substrate. There are no reports of hypertensive LV hypertrophy causing sustained ventricular tachycardia; all reports are of triplets or runs of nonsustainedventricular tachycardia with a median duration of 7 beats.Nor have there beenstudies examining the relation between ventricular ectopic beats detected on ambulatory ECG monitoring and prognosisin hypertensivepatients with LV hypertrophy. VENTRICULAR
ARRHYTHMIAS
IN HYPERTENSION
915
Two studies, however, have examined the influence of ventricular ectopic beats detectedon short ECG recordings in general population samples that included patients with hypertension and LV hypertrophy.‘7,25Ventricular ectopic beats alone were associatedwith only a modestincreasein risk of suddendeath (2.2-fold).25Although ventricular ectopic beats on 1Zlead electrocardiograms in the Framingham Study were associated with an increasedrisk of sudden death,‘l they were not predictive independently of other ECG abnormalities.26 The published data concerning ventricular arrhythmias as independent predictors for suddendeath has recently been reviewed.27In patients without heart disease or with heart diseaseand normal LV function, there is little evidence to support the hypothesis that simple or complex arrhythmias including short runs of nonsustained ventricular tachycardia are associatedwith increasedrisk of sudden death. For these reasonsit was consideredimportant in the present study to assesswhether an arrhythmogenic substrate exists in patients with hypertensive LV hypertrophy. Evidence for an arrhythmogenic substrate? In contrast to the findings of increasedectopic activity in these patients, there was little evidence of an underlying arrhythmogenic substrate. There were no inducible arrhythmias on electrophysiologic testing in 24 patients and only 1 patient had ventricular late potentials on the signal-averaged electrocardiogram. The argument might be put forward that by performing electrophysiologic studies in only one fourth of the patients, it is not possibleto comment on the group as a whole. This was the reason for recording the signal-averagedelectrocardiogram in all patients. Evidence is accumulating that the signal-averagedelectrocardiogram is extremely useful in predicting the inducibility of ventricular tachycardia by electrophysiologic testing in patients with syncope of unknown origin,13 in patients with nonsustained ventricular tachycardia,i5 and in patients with sustained ventricular tachycardia or previous cardiac arrest.14The chief advantage of the signal-averaged electrocardiogram in the context of the present study is the excellent negative predictive accuracy of approximately 90%.15 Thus, the absenceof late potentials in most hypertensive patients in this study adds considerable weight to the negative findings of the electrophysiologic studies. There have been 2 other reports of programmedventricular stimulation in patients with hypertensive LV hypertrophy.27,28In thesestudiesthe patients underwent electrophysiologic testing as part of the routine investigation of suspectedheart diseaseor unexplained syncope, whereas the patients in the present report were selected purely for this study. Nonsustained ventricular tachycardia was induced in 25% (3 of 12)27and in 29% (4 of 14)28of patients in the previous reports and in 29% (7 of 24) of patients in the presentstudy. Sustained ventricular tachycardia was not inducible in 1 study,27 and in the other study was inducible in only 2 patients, both of whom had cardiac decompensation.28Unfortunately it was not stated whether this was a monomor-
916
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
phic or polymorphic tachycardia. It is questionable whether the induction of polymorphic ventricular tachycardia during electrophysiologic testing is a clinically relevant finding or a nonspecific responseto ventricular premature stimuli. 29Sustained monomorphic ventricular tachycardia, which is more likely to be a clinical rhythm, was not induced in either of these studies or in the presentstudy. Another considerationwas whether a more aggressive protocol using triple extrastimuli should have been used in this study. The increasedsensitivity of using triple extrastimuli would risk inducing nonclinical rhythms.29,30Furthermore, the signal-averaged ECG results in this study reinforce the negative electrophysiologic studies.
REFERENCES
1. Kannel WB, Gordon T, Castelli WP, Ma&is JR. Electrocardiographic left ventricular hvoertroohv and risk of coronarv heart disease: The Framineham Study. Ann %tern if& 1970;72:813-822. ’ 2. Kannel WB. Prevalence and natural history of electrocardiographic left ventricular hypertrophy. Am J Med 1983;75(suppl 3A):4-11. 3. Messerli FH. Ventura HO. Elizardi DJ. Dunn FG. Frohlich ED. Hvtxrtension .. and sudden death: increased ventricular ectopic activity in left ventricular hypxtrophy. Am J Med 1984;77:18-22. 4. McLenachan JM, Henderson E, Morris KI, Dargie HJ. Ventricular arrhythmias in patients with hypertensive left ventricular hypertrophy. N Engi J bed 1987;317:787-192, 5. Pringle SD, Macfarlane PW, McKillop JH, Lorimer AR, Dunn FG. Pathophysiologic assessment of left ventricular hypertrophy and strain in asymptomatic patients with essential hypertension. J Am Co/l Cardial 1989;13:1377-1381. 6. Macfarlane PW, Watts MP, Podolski M. Shoat D, Lawrie TDV. The new Glaseow svstem. In: Willems JL. van Bemmel JH. Zvweitz C. eds. Cornouter EC& Analysis: Towards Standar&ation. Amsterdam: Elsevie;, 19863 l-j,. 7. Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass in man: anatomic validation of the method. Circularion 1977;55:613-618. 6. Macfarlane PW, McLung JM, Irving A, Watts MP, Taylor TP, Lawrie TDV. Comouter assisted analvsis of dvnamic (24-hour) electrocardioerams. In: Macfarlane ‘PW, ed. Progress-in Ele&card&logy. L&don: Pitmany 1979:123-126. 9. Khurmi NS, Raftery EB. Reproducibility and validity of ambulatory ST segment monitoring in patients with chronic stable angina pxtoris. Am Hem J 1987;113:1091-10%. 10. Lown B, Wolf M. Approaches to sudden death from coronary heart disease. Circulation 1971;44:130-142. 11. Simson MB. Clinical application of signal averaging. Cardiol Clin 1983;l: 109-119. 12. Breithardt G. Boraerefe M. Pathoohvsioloeical mechanisms and clinical significance of ventricular late potentials. Eur b&t J 1986;7:364-385. 13. Winters SL, Stewart D, Games A. Signal averaging of the surface QRS complex predicts inducibility of ventricular tachycardia in patients with syncope of unknown origin: a prospective study. J Am Coil Cardiol 1987;10:775-781. 14. Nalos PC, Gang ES, Mandell WJ, Ladenheim ML, Lass Y, Peter T. The signal-averaged electrocardiogram as a screening test for inducibility of sustained ventricular tachycardia in high risk patients: a prospective study. J Am Coil Cardiol 1987;9:539-548. 15. Turitto G, Fontaine JM, Ursell SN, Caref EB, Henkin R, El-Sherif N. Value of signal-averaged electrocardiogram as a predictor of the results of programmed stimulation in nonsustained ventricular tachycardia. Am J Cardiol 1988;61: 1272-1278. 16. Swinscow TDV. Statistics at Square One. 8th ed. Plymouth: Latimer and Trend, 1987. 17. Kannel WB, Schatzkin A. Sudden death: lessons from subsets in population studies. J Am Coil Cardiol 1985;5:14lB-149B. 16. McKenna WJ, England D, Doli YL, Dean&Id JE, Oakley C, Goodwin JF. Arrhythmia in hypertrophic cardiomyopathy. I. Influence on prognosis. Br Heart J 1981;46:168-172. 19. Klein RC. Ventricular arrhythmias in aortic valve disease: analysis of 102 oatients. Am J Cardiol 1984:53:1079-1083. i0. Papademetriou V, Price M, Notargiacomo A, Gottdiener J, Fletcher RD, Freis ED. Effect of diuretic therapy on ventricular arrhythmias in hypertensive patients with or without left ventricular hypertrophy. Am Hearr J 1985;llO: 595-599. 21. Luque-Otero M, Perez-Casar F, Alcazar J, Simal J, Martell-Claros N, Fernandez-Cruz A, Fernandez-Pinilla. Increased ventricular arrhythmias in hy-
APRIL 1, 1992
pertensives with left ventricular hypertrophy. J Hyperfemion 1986;4(suppl 6):S66-S67. 22. Loaldi A, Pepi M, Agostoni PG. Fiorentini C, Grazi S, Bella PD, Guazzi MD. Cardiac rhythm in hypertension assessed through 24 hour ambulatory electrccardiographic monitoring. Effects of load manipulation with atenolol, verapamil and nifedipine. Br Heart J 1983;50:118-126. 23. Aronow WS, Epstein S, Schwartz KS, Koenigsberg M. Correlation of complex ventricular arrhythmias detected by ambulatory electrocardiographic monitoring with echocardiographic left ventricular hypertrophy in persons older than 62 years in a long-term health care facility. Am J Cm&/ 1987;60:730-732, 24. Le Heuzey JY, Guize L. Cardiac prognosis in hypertensive patients. Incidence of sudden death and ventricular arrhythmias. Am J Med 1988;84(suppl I B):65-68. 25. Kreger BE, Cupples A, Kannel WB. The electrocardiogram in prediction of sudden death: Framingham Study experience. Am Heorr J 1987;113:377~382.
26. Surawicz B. Prognosis of ventricular arrhythmias in relation to sudden cardiac death: therapeutic implications. J AWI Coil Cur&o1 1987;10:435-447. 27. Coste P, Clementy J, Besse P, Bricaud H. Left ventricular hypertrophy and ventricular dysrhythmic risk in hylwtensive patients: evaluation by programmed electrical stimulation. J Hyperkmion 1988;6(suppl 4):SI l6-SI 18. 26. Bethge C, Motz W, Hehn AV, Strauer BE. Ventricular arrhythmia in hypertensive heart disease with and without heart failure. J Cardicmasc ffiarmacol 1987;lO(suppl 6):SI l9-Sl28. 29. Bigger JT, Reiffel JA, Livelli FD, Wang PJ. Sensitivity, specificity, and reproducibility of programmed ventricular stimulation. Circulofion 1986;73 (suppl 11):11-73-11-78. 30. Brugada P, Green M, Abdollah H, Wellens HJJ. Significance of ventricular arrhythmias initiated by programmed ventricular stimulation: the importance of the type of ventricular arrhythmia induced and the number of premature stimuli required. Circulafion 1984;69:87-92.
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