SYSTEMIC HYPERTENSION
Risk of Ventricular Arrhythmias in Hypertensive Men with Left Ventricular Hypertrophy David Siegel, MD, MPH, Melvin D. Cheitlin, MD, Dennis M. Black, PhD, Dana Seeley, MS, Norman Hearst, MD, MPH, and Stephen B. l-lulley, MD, MPH
The echocardiographic predictors of ventricular arrhythmias are reported for the Hypertension Arrhythmia Reduction Trial. Men with mild hypertension were withdrawn from their diuretic therapy and repleted with 40 mEq/day of oral potassium and 20 mEq/day of oral magnesium for 1 month. M-mode echocardiography and 24-hour continuous ambulatory eledrocardiography were performed on 123 men, mean age 62 years. Forty-eight men (39%) had echocardiiaphic evidence of left ventricular (LV) hypertrophy defined as an LV mass index >134 g/m* and this ffnding was not related to the presence of LV hypertrophy on dectrocardiogram or to age. Men who had echocardiiaphic LV hypertrophy were more likely than men without echocardiographic LV hypertrophy to have 130 ventricular premature complexes (VPCs)/hr (odds ratio = 2.7; 95% confidence interval = 0.9,&O), multiform extrasystoles (odds ratio = 1.7; confidence interval = 0.8,3.7), episodes of ventricular tachycardia (odds ratio = 2.3; confidence interval = 0.7,7.1) and the combination of frequent (130 VPCs/hr) or complex (ventricular couplets, multiform extrasystoles or episodes of ventricular tachycardia) ventricular arrhythmia (odds ratio = 1.7; confidence interval = 0.8,3.5). Similar associations between echocardiographic LV hypertrophy and ventricular arrhythmias were observed on 24-hour tracings obtained on entry to the study (before ele&olyte repletion) in the 96 men who were taking diuretics at this time. The combination of a frequent or complex arrhythmia was also more common in men aged 60 to 70 compared to men aged 35 to 59 (odds ratio = 3.4; confidence interval = 1.4,8.2). These findings suggest that ventricular arrhythmias occur more commonly in older hypertensive men and in hypertensive men with echocardiographic LV hypertrophy. (Am J Cardid l-,65:742-747)
From the Departments of Epidemiology and Biostatistics, Medicine, and Family and Community Medicine, University of California, San Francisco, California. This study was supported in part by grant HL 36821 from the National Institutes of Health, Bethesda, Maryland. Manuscript received September 25, 1989; revised manuscript received November 10,1989, and accepted November 15. Address for reprints: David Siegel, MD, MPH, Prevention Sciences Group, 74 New Montgomery, San Francisco, California 94105.
742
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOCUME
65
L
eft ventricular (LV) hypertrophy, whether defined by electrocardiographic criteria, chest x-rays or echocardiography, is associated with an increased risk of heart attack and sudden death.’ Hypertensive patients with LV hypertrophy by electrocardiographic criteria who are not receiving treatment have been shown to have significantly more ventricular ectopy than either hypertensive patients without electrocardiographic evidence of LV hypertrophy or normotensive patients.* It is not known whether this effect is also found in hypertensive patients with LV hypertrophy diagnosed by echocardiography. One recent study found that patients with LV hypertrophy by electrocardiographic criteria had significantly more premature ventricular contractions and more complex (higher Lown’s class) ventricular ectopy than hypertensive subjects without LV hypertrophy or with LV hypertrophy diagnosed only by echocardiographic criteria.3,4 However, tlie investigators used measurements of posterior wall thickness, septal wall thickness and relative wall thickness to define echocardiographic LV hypertrophy. This definition has not been found to correlate as well with clinical and necropsy LV hypertrophy as that calculated by LV mass index.5 Thus, many of the individuals included in the LV hypertrophy group in this study did not meet LV mass criteria of LV hypertrophy. A recent Framingham study found that the presence of echocardiographic LV hypertrophy was associated with an increased risk for ventricular arrhythmias on lhour ambulatory electrocardiographic readings.6 This study evaluated all surviving members of the Framingham cohort and did not control for the diagnosis of hypertension, the use of antihypertensive medicines or serum electrolyte values. Thus, the results may have been confounded by the use of antihypertensive medicines, especially hydrochlorothiazide, in the echocardiographic LV hypertrophy group who had higher systolic and diastolic blood pressures than those without echocardiographic LV hypertrophy. We compared the presence of ventricular arrhythmias on 24-hour ambulatory electrocardiographic readings in hypertensive men with and without echocardiographic LV hypertrophy who had been withdrawn from diuretic therapy and repleted with oral potassium and magnesium for 1 month. MFTHOD5 BackgrouM The Hypertension Arrhythmia Reduction Trial is a clinical trial designed to assess the frequency and severity of ventricular arrhythmias asso-
TABLE
I Characteristics
of Study
Sample
According
to Echocardiographic
Left
Present (n=48)
Ventricular Absent (n = 75)
62 f 8
Black Hispanic Indian White Other Systolic BP (mm Hg) Diastolic BP (mm Hg) Pulse BSA (m2) Potassium Magnesium Cigarette smoker (%) Current Past Never Antihypertensive other
6 13 8 2 69 2 144 86 68 1.91 4.29 1.99
than
diuretic
Status Total (n = 123)
62 f 6 7 24 5 0 64 0 147 88 76 1.91 4.34 2.01
f 17.2 f 9.7 f 9.6 f 0.20 f 0.32 f0.18
19 67 15 33
(%)
Hypertrophy
62 f 7 7 20 7
f f f f f f
62, 1 146 87 73 1.91 4.32 2.00
18.4 10.9 11.6 0.17 0.43 0.16
19 59 23 35
f f f f f f
17.9 10.4 11.5 0.18 0.40 0.17
19 62 20 34
All * data are mean i standard deviation. BP = blood pressure: BSA = body surface area
TABLE
II
Echocardiographic
Characteristics
of the
Study
Population
Echocardiographic LV Hypertrophy
Septal wall thickness (cm) Posterior wall thickness (cm) Left ventricle in diastole (cm) LV mass (9) LV mass index (g/m?) Data are mea” f standard LV = left ventricular
Present (n=48)
Absent (n = 75)
Total (n = 123)
1.20+0.16 1.11*0.14 5.44 f 0.53 302 f 52 159f24
1.07 1.03 4.90 221 116f
1.12 f 0.14 1.06f0.11 5.11 f0.50 253 f 57 133 f 28
fO.ll f 0.07 f 0.35 f 32 14
dewatmn.
ciated with different diuretic combinations in hypertensive men. The study group represents a target population of hypertensive men between the ages of 35 and 70 with abnormal electrocardiograms. Subjects were included in the study if they had been taking diuretics for at least 6 months and their diastolic blood pressure was 2.0 mg/dl) or other serious illness including psychiatric disabilities, or inability or unwillingness to give informed consent. Design oveniew: All patients were withdrawn from diuretic treatment for 1 month with a determination of their blood pressure 2 weeks after stopping the diuretic. After 1 month of oral therapy with both 40 mEq of potassium chloride and 20 mEq of magnesium oxide daily, serum potassium and magnesium were determined. Continuous 24-hour electrocardiographic monitoring was performed at the beginning and end of the electrolyte repletion month. Echocardiographii measurements: M-mode echocardiograms were performed on all patients at entry into the study using either an ATL 851-B or General Electric class C model. Measurements were made acTHE AMERICAN
JOURNAL
OF CARDIOLOGY
MARCH
15. 1990
743
TABLE III Echocardiographic Status Status
by Electrocardiographic
Left Ventricular Left Ventricular
Hypertrophy Hypertrophy
Echocardiographic LV Hypertrophy Electrocardiographic LV Hypertrophy
Present
Absent
Total
Present Absent Total
4 44 43
12 63 75
16 107 123
3 cording to the recommendations of the American Society of Echocardiography using a leading edge to leading edge convention.7 Two-dimensional echocardiography was used in the parasternal long-axis view to select the place where the M-mode echocardiographic measurements would be taken. Measurements were made at the tips of the mitral valve leaflets posterior to the tips of the papillary muscles. Measurements of the LV internal dimension, posterior wall thickness and ventricular septal thickness were used to calculate LV mass according to the formula: 1.04 [(LV internal dimension + posterior wall thickness + ventricular septal thickness)3 - (LV internal dimension)3] - 14 g.5 LV mass index was calculated by dividing the LV mass by the bcdy surface area. LV hypertrophy was defined as a calculated echocardiographic LV mass index of >134 g/m2. Ekctrocardiiraphic measurementr: Standard 12lead electrocardiograms were performed on all subjects and interpretation was performed by one of the investigators (MC) who was blinded to the echocardiographic and continuous 24-hour electrocardiographic monitoring results. Participants were judged as meeting criteria for electrocardiographic LV hypertrophy if they met either E&es, Sokolow-Lyons or frontal plane criteria.8-10 Continueus electrocardiiraphii monitoring: Continuous 24-hour electrocardiographic monitoring was performed using the Cardiotechorder III dual lead system. The electrocardiogram was recorded continuously on tape using a cassette system. Whole tapes were printed at high speed on recording paper using the Cardio Data Corp. Mark IV. Specific areas of interest, identified by irregularity on the QRS pattern, were printed at real time and analyzed by a cardiologist who was blinded to the blood pressure and echocardiographic status of the participant. Ventricular arrhythmias were classified in a manner similar to that of Lown et a1,3according to the presence of the following arrhythmia types: ventricular premature complexes (VPCs), multiform extrasystales, ventricular couplets, ventricular tachycardia and R-on-T ventricular premature complexes. A summary category of the presence of a frequent (230 VPCs/hr) or a complex (presence in 24 hours of any of the following: multiform extrasystoles, ventricular couplets, ventricular tachycardia or R-on-T VPC) ventricular arrhythmia was also created. Serum electrolytes: Peripheral venous blood was drawn from the antecubital fossa in lo-ml Vacutainers (Be&on-Dickinson) using the standard tourniquet 744
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
method. The subjects were seated and the arm firmly supported on a flat surface at about waist level. Care was taken to apply the tourniquet for no longer than 2 minutes. The vacutainer tube was centrifuged at 200 rpm at room temperature for 10 minutes to separate serum from clotted erythrocytes. Serum was then removed from the tube and centrifuged a second time to remove any remaining cells. For serum magnesium determinations, the serum was diluted 1:lOO in 0.5% lanthanum chloride and magnesium content of samples was measured in flame mode with a Perk&Elmer (model 2380) atomic absorption spectrophotometer using a 3-slot head. For serum potassium determinations, the serum was diluted 1:lOO in 0.5% lanthanum chloride and potassium content of samples was measured directly on a flame photometer. Statistical analysis: Statistical analysis was performed using Statistical Analysis System software on an IBM 4341 mainframe computer.” Odds ratios and 95% confidence intervals were calculated to evaluate the relation between age (35 to 59 vs 60 to 70) and arrhythmia outcomes (230 VPCs/hr, presence in 24 hours of any of the following: multiform extrasystoles, ventricular couplets, ventricular tachycardia or R on T VPC or complex or frequent arrhythmia). Odds ratios and 95% confidence intervals were also computed for the association between the presence of echocardiographic LV hypertrophy and the various arrhythmia outcomes. A similar analysis was performed to evaluate the association between LV hypertrophy by electrocardiographic and arrhythmia outcomes. RESULTS Study population: Clinical characteristics of the echocardiographic LV hypertrophy positive compared to the echocardiographic LV hypertrophy negative men are listed in Table I. There was little difference between the 48 echocardiographic LV hypertrophy positive and 75 echocardiographic LV hypertrophy negative men in terms of age, race, systolic and diastolic blood pressures, body surface area, serum electrolyes and smoking history. Electrocardiographic LV hypertrophy positive men tended to differ from electrocardiographic LV hypertrophy negative men: they were younger (mean age 56 vs 63 years), more commonly black (44 vs 16%), had higher systolic (152 vs 145 mm Hg) and diastolic (93 vs 87 mm Hg) blood pressures and body surface areas (1.99 vs 1.90 m2), and were less frequently a current smoker (0 vs 22%). However, there were only 16 men in the electrocardiographic LV hypertrophy positive group and the differences were not statistically significant. Echocardiiraphic characteristiis: Echocardiographic LV hypertrophy positive men had greater septal wall thickness, posterior wall thickness and greater LV internal dimension in diastole than echocardiographic LV hypertrophy negative men (p
Risk of Ventricular Arrhythmias in Hypertensive Men with Left Ventricular Hypertrophy David Siegel, MD, MPH, Melvin D. Cheitlin, MD, Dennis M. Black, PhD, Dana Seeley, MS, Norman Hearst, MD, MPH, and Stephen B. l-lulley, MD, MPH
The echocardiographic predictors of ventricular arrhythmias are reported for the Hypertension Arrhythmia Reduction Trial. Men with mild hypertension were withdrawn from their diuretic therapy and repleted with 40 mEq/day of oral potassium and 20 mEq/day of oral magnesium for 1 month. M-mode echocardiography and 24-hour continuous ambulatory eledrocardiography were performed on 123 men, mean age 62 years. Forty-eight men (39%) had echocardiiaphic evidence of left ventricular (LV) hypertrophy defined as an LV mass index >134 g/m* and this ffnding was not related to the presence of LV hypertrophy on dectrocardiogram or to age. Men who had echocardiiaphic LV hypertrophy were more likely than men without echocardiographic LV hypertrophy to have 130 ventricular premature complexes (VPCs)/hr (odds ratio = 2.7; 95% confidence interval = 0.9,&O), multiform extrasystoles (odds ratio = 1.7; confidence interval = 0.8,3.7), episodes of ventricular tachycardia (odds ratio = 2.3; confidence interval = 0.7,7.1) and the combination of frequent (130 VPCs/hr) or complex (ventricular couplets, multiform extrasystoles or episodes of ventricular tachycardia) ventricular arrhythmia (odds ratio = 1.7; confidence interval = 0.8,3.5). Similar associations between echocardiographic LV hypertrophy and ventricular arrhythmias were observed on 24-hour tracings obtained on entry to the study (before ele&olyte repletion) in the 96 men who were taking diuretics at this time. The combination of a frequent or complex arrhythmia was also more common in men aged 60 to 70 compared to men aged 35 to 59 (odds ratio = 3.4; confidence interval = 1.4,8.2). These findings suggest that ventricular arrhythmias occur more commonly in older hypertensive men and in hypertensive men with echocardiographic LV hypertrophy. (Am J Cardid l-,65:742-747)
From the Departments of Epidemiology and Biostatistics, Medicine, and Family and Community Medicine, University of California, San Francisco, California. This study was supported in part by grant HL 36821 from the National Institutes of Health, Bethesda, Maryland. Manuscript received September 25, 1989; revised manuscript received November 10,1989, and accepted November 15. Address for reprints: David Siegel, MD, MPH, Prevention Sciences Group, 74 New Montgomery, San Francisco, California 94105.
742
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOCUME
65
L
eft ventricular (LV) hypertrophy, whether defined by electrocardiographic criteria, chest x-rays or echocardiography, is associated with an increased risk of heart attack and sudden death.’ Hypertensive patients with LV hypertrophy by electrocardiographic criteria who are not receiving treatment have been shown to have significantly more ventricular ectopy than either hypertensive patients without electrocardiographic evidence of LV hypertrophy or normotensive patients.* It is not known whether this effect is also found in hypertensive patients with LV hypertrophy diagnosed by echocardiography. One recent study found that patients with LV hypertrophy by electrocardiographic criteria had significantly more premature ventricular contractions and more complex (higher Lown’s class) ventricular ectopy than hypertensive subjects without LV hypertrophy or with LV hypertrophy diagnosed only by echocardiographic criteria.3,4 However, tlie investigators used measurements of posterior wall thickness, septal wall thickness and relative wall thickness to define echocardiographic LV hypertrophy. This definition has not been found to correlate as well with clinical and necropsy LV hypertrophy as that calculated by LV mass index.5 Thus, many of the individuals included in the LV hypertrophy group in this study did not meet LV mass criteria of LV hypertrophy. A recent Framingham study found that the presence of echocardiographic LV hypertrophy was associated with an increased risk for ventricular arrhythmias on lhour ambulatory electrocardiographic readings.6 This study evaluated all surviving members of the Framingham cohort and did not control for the diagnosis of hypertension, the use of antihypertensive medicines or serum electrolyte values. Thus, the results may have been confounded by the use of antihypertensive medicines, especially hydrochlorothiazide, in the echocardiographic LV hypertrophy group who had higher systolic and diastolic blood pressures than those without echocardiographic LV hypertrophy. We compared the presence of ventricular arrhythmias on 24-hour ambulatory electrocardiographic readings in hypertensive men with and without echocardiographic LV hypertrophy who had been withdrawn from diuretic therapy and repleted with oral potassium and magnesium for 1 month. MFTHOD5 BackgrouM The Hypertension Arrhythmia Reduction Trial is a clinical trial designed to assess the frequency and severity of ventricular arrhythmias asso-
TABLE
I Characteristics
of Study
Sample
According
to Echocardiographic
Left
Present (n=48)
Ventricular Absent (n = 75)
62 f 8
Black Hispanic Indian White Other Systolic BP (mm Hg) Diastolic BP (mm Hg) Pulse BSA (m2) Potassium Magnesium Cigarette smoker (%) Current Past Never Antihypertensive other
6 13 8 2 69 2 144 86 68 1.91 4.29 1.99
than
diuretic
Status Total (n = 123)
62 f 6 7 24 5 0 64 0 147 88 76 1.91 4.34 2.01
f 17.2 f 9.7 f 9.6 f 0.20 f 0.32 f0.18
19 67 15 33
(%)
Hypertrophy
62 f 7 7 20 7
f f f f f f
62, 1 146 87 73 1.91 4.32 2.00
18.4 10.9 11.6 0.17 0.43 0.16
19 59 23 35
f f f f f f
17.9 10.4 11.5 0.18 0.40 0.17
19 62 20 34
All * data are mean i standard deviation. BP = blood pressure: BSA = body surface area
TABLE
II
Echocardiographic
Characteristics
of the
Study
Population
Echocardiographic LV Hypertrophy
Septal wall thickness (cm) Posterior wall thickness (cm) Left ventricle in diastole (cm) LV mass (9) LV mass index (g/m?) Data are mea” f standard LV = left ventricular
Present (n=48)
Absent (n = 75)
Total (n = 123)
1.20+0.16 1.11*0.14 5.44 f 0.53 302 f 52 159f24
1.07 1.03 4.90 221 116f
1.12 f 0.14 1.06f0.11 5.11 f0.50 253 f 57 133 f 28
fO.ll f 0.07 f 0.35 f 32 14
dewatmn.
ciated with different diuretic combinations in hypertensive men. The study group represents a target population of hypertensive men between the ages of 35 and 70 with abnormal electrocardiograms. Subjects were included in the study if they had been taking diuretics for at least 6 months and their diastolic blood pressure was 2.0 mg/dl) or other serious illness including psychiatric disabilities, or inability or unwillingness to give informed consent. Design oveniew: All patients were withdrawn from diuretic treatment for 1 month with a determination of their blood pressure 2 weeks after stopping the diuretic. After 1 month of oral therapy with both 40 mEq of potassium chloride and 20 mEq of magnesium oxide daily, serum potassium and magnesium were determined. Continuous 24-hour electrocardiographic monitoring was performed at the beginning and end of the electrolyte repletion month. Echocardiographii measurements: M-mode echocardiograms were performed on all patients at entry into the study using either an ATL 851-B or General Electric class C model. Measurements were made acTHE AMERICAN
JOURNAL
OF CARDIOLOGY
MARCH
15. 1990
743
TABLE III Echocardiographic Status Status
by Electrocardiographic
Left Ventricular Left Ventricular
Hypertrophy Hypertrophy
Echocardiographic LV Hypertrophy Electrocardiographic LV Hypertrophy
Present
Absent
Total
Present Absent Total
4 44 43
12 63 75
16 107 123
3 cording to the recommendations of the American Society of Echocardiography using a leading edge to leading edge convention.7 Two-dimensional echocardiography was used in the parasternal long-axis view to select the place where the M-mode echocardiographic measurements would be taken. Measurements were made at the tips of the mitral valve leaflets posterior to the tips of the papillary muscles. Measurements of the LV internal dimension, posterior wall thickness and ventricular septal thickness were used to calculate LV mass according to the formula: 1.04 [(LV internal dimension + posterior wall thickness + ventricular septal thickness)3 - (LV internal dimension)3] - 14 g.5 LV mass index was calculated by dividing the LV mass by the bcdy surface area. LV hypertrophy was defined as a calculated echocardiographic LV mass index of >134 g/m2. Ekctrocardiiraphic measurementr: Standard 12lead electrocardiograms were performed on all subjects and interpretation was performed by one of the investigators (MC) who was blinded to the echocardiographic and continuous 24-hour electrocardiographic monitoring results. Participants were judged as meeting criteria for electrocardiographic LV hypertrophy if they met either E&es, Sokolow-Lyons or frontal plane criteria.8-10 Continueus electrocardiiraphii monitoring: Continuous 24-hour electrocardiographic monitoring was performed using the Cardiotechorder III dual lead system. The electrocardiogram was recorded continuously on tape using a cassette system. Whole tapes were printed at high speed on recording paper using the Cardio Data Corp. Mark IV. Specific areas of interest, identified by irregularity on the QRS pattern, were printed at real time and analyzed by a cardiologist who was blinded to the blood pressure and echocardiographic status of the participant. Ventricular arrhythmias were classified in a manner similar to that of Lown et a1,3according to the presence of the following arrhythmia types: ventricular premature complexes (VPCs), multiform extrasystales, ventricular couplets, ventricular tachycardia and R-on-T ventricular premature complexes. A summary category of the presence of a frequent (230 VPCs/hr) or a complex (presence in 24 hours of any of the following: multiform extrasystoles, ventricular couplets, ventricular tachycardia or R-on-T VPC) ventricular arrhythmia was also created. Serum electrolytes: Peripheral venous blood was drawn from the antecubital fossa in lo-ml Vacutainers (Be&on-Dickinson) using the standard tourniquet 744
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
65
method. The subjects were seated and the arm firmly supported on a flat surface at about waist level. Care was taken to apply the tourniquet for no longer than 2 minutes. The vacutainer tube was centrifuged at 200 rpm at room temperature for 10 minutes to separate serum from clotted erythrocytes. Serum was then removed from the tube and centrifuged a second time to remove any remaining cells. For serum magnesium determinations, the serum was diluted 1:lOO in 0.5% lanthanum chloride and magnesium content of samples was measured in flame mode with a Perk&Elmer (model 2380) atomic absorption spectrophotometer using a 3-slot head. For serum potassium determinations, the serum was diluted 1:lOO in 0.5% lanthanum chloride and potassium content of samples was measured directly on a flame photometer. Statistical analysis: Statistical analysis was performed using Statistical Analysis System software on an IBM 4341 mainframe computer.” Odds ratios and 95% confidence intervals were calculated to evaluate the relation between age (35 to 59 vs 60 to 70) and arrhythmia outcomes (230 VPCs/hr, presence in 24 hours of any of the following: multiform extrasystoles, ventricular couplets, ventricular tachycardia or R on T VPC or complex or frequent arrhythmia). Odds ratios and 95% confidence intervals were also computed for the association between the presence of echocardiographic LV hypertrophy and the various arrhythmia outcomes. A similar analysis was performed to evaluate the association between LV hypertrophy by electrocardiographic and arrhythmia outcomes. RESULTS Study population: Clinical characteristics of the echocardiographic LV hypertrophy positive compared to the echocardiographic LV hypertrophy negative men are listed in Table I. There was little difference between the 48 echocardiographic LV hypertrophy positive and 75 echocardiographic LV hypertrophy negative men in terms of age, race, systolic and diastolic blood pressures, body surface area, serum electrolyes and smoking history. Electrocardiographic LV hypertrophy positive men tended to differ from electrocardiographic LV hypertrophy negative men: they were younger (mean age 56 vs 63 years), more commonly black (44 vs 16%), had higher systolic (152 vs 145 mm Hg) and diastolic (93 vs 87 mm Hg) blood pressures and body surface areas (1.99 vs 1.90 m2), and were less frequently a current smoker (0 vs 22%). However, there were only 16 men in the electrocardiographic LV hypertrophy positive group and the differences were not statistically significant. Echocardiiraphic characteristiis: Echocardiographic LV hypertrophy positive men had greater septal wall thickness, posterior wall thickness and greater LV internal dimension in diastole than echocardiographic LV hypertrophy negative men (p
