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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

Prolongation of the corrected QT interval (QTc) has been described in obese subjects. This study assesses the relation of left ventricular (LV) mass to QTc in normotensive severely obese subjects. Fifty normotensive patients whose BMI was ≥40 kg/m2 (mean age: 38 ± 7 years) were studied. QTc was derived using Bazett's formula. LV mass was calculated using the formula of Devereux et al. and was indexed to height2.7. Mean QTc was 428.8 ± 19.0 ms and was significantly longer in those with than in those without LV hypertrophy (P < 0.01) QTc correlated positively and significantly with BMI (r = 0.392, P < 0.025), LV mass/height2.7 (r = 0.793, P < 0.0005), systolic blood pressure (r = 0.742, P < 0.001), LV end — systolic wall stress (r = 0.746, P < 0.001) and LV internal dimension in diastole (r = 0.788, P < 0.0005). Among five variables tested, LV mass/height2.7 was identified as the sole predictor of QTc by multivariate analysis. In conclusion, LV mass and loading conditions that may affect LV mass are important determinants of QTc in normotensive severely obese subjects.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

Ventricular repolarization is most commonly assessed electrocardiographically by measuring the corrected QT interval (QTc) and either QT or QTc dispersion (1,2,3,4). Known causes of QTc prolongation include the congenital long QT syndromes, the Brugada syndrome, electrolyte disturbances (hypokalemia, hypomagnesemia, hypocalcemia), selected drugs (e.g., certain anti-arrhythmic drugs, phenothiazines, tricyclic antidepressants, erythromycin in combination with certain antihistamines, pentamidine, and certain anti-malarials), liquid protein and starvation diets, hypothyroidism, central nervous system lesions, severe bradycardia, mitral valve prolapse, acute myocardial infarction, and possibly obstructive sleep apnea (3,4,5). Multiple studies of obese subjects have reported prolongation of QTc and/or increased QT or QTc dispersion, suggesting an association between obesity and delayed ventricular repolarization (5,6,7,8,9,10,11,12,13). Patient populations in these studies were heterogeneous. They included subjects with different degrees of severity of obesity and patients with and without systemic hypertension. Several studies have reported QTc prolongation and increased QTc dispersion in patients with left ventricular (LV) hypertrophy, particularly in association with hypertension (14,15,16,17,18,19). LV hypertrophy occurs commonly in severely obese persons, even in those who are normotensive (20). Thus, it remains uncertain whether obesity per se produces delay of ventricular repolarization or whether this phenomenon results from other factors associated with obesity. We hypothesized that LV mass is a key determinant of QTc in normotensive severely obese patients. This study assesses the relation of LV mass to QTc in normotensive severely obesity patients.

Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

Patient selection

This was a prospective cohort study conducted between 1989 and 1995. Patients whose actual body weight was greater than twice the upper limit of normal based on Metropolitan Life Insurance tables and whose blood pressure was <140/90 mm Hg on three consecutive clinical encounters separated by at least one week were considered for entry into the study. All patients were initially referred to a bariatric surgery clinic by their primary care physicians to determine their eligibility for bariatric surgery. Patients were subsequently referred to one of the investigators (M.A.A.) for cardiac evaluation. All patient evaluations were conducted in the outpatient setting. Patients with current, prior or treated hypertension were excluded from the study. Patients with clinical, electrocardiographic, radiographic, or echocardiographic evidence of coronary heart disease, idiopathic or secondary cardiomyopathies, valvular stenosis or moderate to severe valvular regurgitation, pericardial disease or congenital heart disease were excluded from the study. No patient in the study had clinical or radiographic evidence of heart failure (Framingham criteria). Also excluded from the study were patients with primary pulmonary disease based on clinical and radiographic assessment and pulmonary function tests and patients with cardiac arrhythmias on a standard 12 lead electrocardiogram. Patients with disorders of potassium, magnesium, and calcium, those with hyper- or hypothyroidism, patients with acute myocardial infarction or mitral valve prolapse, those on liquid protein or starvation diets and patients receiving drugs that might affect ventricular repolarization were also excluded.

Clinical and anthropometric assessment

A complete history and physical examination was performed by a single investigator (M.A.A.). Blood pressure was measured with a cuff sphygmomanometer in accordance with the recommendations of Russel et al. (21). Body weight was obtained following a 12-hour fast using wheelchair accessible scales with a weight limit of 800 pounds (361 kg). Weight was measured in the upright position with the patient wearing a thin lightweight gown. BMI was calculated from these data. Relative body weight was obtained by dividing actual body weight by ideal body weight (upper limit of normal) based on Metropolitan Life Insurance tables and then multiplying the quotient by 100. Duration of severe obesity was estimated from patient report.

Electrocardiographic measurements

A standard 12 lead electrocardiogram was obtained on all patients in the supine position using a standard technique with a Hewlett-Packard 1D: electrocardiograph (Andover, MA) with a filter setting of 100 Hz at a paper speed of 25 mm per s. All electrocardiograms were obtained in the fasting state between 1:00–5:00 pm in a quiet room at room temperature of 20–22° C. QT intervals were measured manually using the threshold method by a single investigator (M.A.A.) who was blinded to patient identity and to clinical, radiographic and echocardiographic data. QTc was calculated using Bazett's formula (1,2,3). The R-R interval used to calculate QTc was derived from the cycle containing the QRST complex from which the QT interval was measured. The upper limit of normal for QTc is 420 ms (1,2,3,4).

Echocardiographic measurements

M-mode and two-dimensional transthoracic echocardiograms were obtained in the left lateral and supine positions using a Hewlett-Packard Sonos 1000 echocardiograph with a 2.25 MHz transducer (Palo Alto, CA) and echocardiographic measurements were performed in accordance with American Society of Echocardiography guidelines (22). LV mass was calculated using the formula of Devereux et al. (23) and was indexed to height2.7 (24). The upper limits of normal for LV mass/height2.7 are 47 g/m2.7 in women and 50 g/m2.7 in men (25). LV hypertrophy was defined as LV mass/height2.7 that exceeded these thresholds. Echocardiograms were interpreted by a single investigator (M.A.A.) who was blinded to patient identity, and to clinical, radiographic and electrocardiographic data.

Other studies

Serum potassium, magnesium and calcium levels were obtained in the fasting state on the same day that the electrocardiograms and echocardiograms were performed. A posteroanterior and lateral chest x-ray was performed within two weeks of clinical, electrocardiographic and echocardiographic assessment.

Statistical analysis

SPSS 11 and R software were used for statistical analysis. Mean values are expressed ± 1 s.d. Mean values for continuous variables in patients with and without LV hypertrophy were compared using Student's “t” test for unpaired data. The proportions of categorical variables in patients with and without LV hypertrophy were compared using the χ2 test. Simple linear regression analysis with Pearson correlation coefficients was performed to assess the relation of QTc to selected clinical and echocardiographic variables. Multivariate analysis was performed using stepwise linear regression analysis. A P value < 0.05 was required for statistical significance for comparisons using Student's “t” test, the χ2-test and simple linear regression analysis.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

Patient characteristics

A total of 68 patients were referred from the bariatric surgery clinic for consideration of entry into the study. Fifty patients qualified for inclusion. Reasons for exclusion were: current, prior or treated hypertension in ten, heart failure in three, moderate to severe mitral regurgitation in three, and atrial fibrillation in two. Table 1 summarizes selected clinical, electrocardiographic and echocardiographic characteristics for the group as a whole (n = 50) and for subgroups with and without LV hypertrophy. There were no significant differences in the proportion of females, males, diabetics, and cigarette smokers between subgroups of patients with and without LV hypertrophy. BMI was ≥40 kg/m2 in all patients. QTc ranged from 391–469 ms. QTc exceeded 420 ms in 34 patients, 440 ms in 18 patients and 460 ms in only one patient.

Table 1.  Patient characteristics
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Relation of QTc to selected clinical and echocardiographic variables

Table 2 summarizes the relation between QTc and selected clinical and echocardiographic variables. There were significant positive correlations between QTc and % overweight, body mass index, duration of morbid obesity, LV mass/height2.7, systolic blood pressure, LV end-systolic wall stress, and LV internal dimension in diastole and transmitral E wave deceleration time. There were significant negative correlations between QTc and both LV fractional shortening and transmitral E/A ratio. Figure 1 shows the correlation between QTc and LV mass/height2.7.

Table 2.  Relation of QTc to selected clinical and echocardiographic variables
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Figure 1. Relation of QTc to LV mass/height2.7. There was a positive and significant correlation between QTc and LV mass/height2.7. LV, left ventricular; QTc, corrected QT interval.

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Multivariate analysis

Multivariate analysis was conducted using stepwise linear regression analysis. The strong correlations noted in Table 2 indicated the possibility of multicolinearity. The variable influence factors suggested serious multicolinearity and therefore the need to select a smaller number of predictors. The five predictors selected were LV mass/height2.7, BMI, systolic blood pressure, LV end-systolic wall stress, and LV internal dimension in diastole. Regression analysis was performed using these predictors. Analysis was conducted using QTc as the response variable. Among the five variables analyzed only LV mass/ height2.7 predicted QTc (mean square: 12532.2, F value: 115.05).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

Sudden cardiac death occurs with disproportionately high frequency in severely obese persons (26). Although the mechanism of sudden cardiac death in this population is unknown, ventricular tachyarrhythmias are suspected to play a role (27,28). For this reason ventricular repolarization has been the subject of investigative interest in severely obese subjects as well as in those with less severe obesity (6,7,8,9,10,11,12,13,29,30,31,32).

Ventricular repolarization in obese patients has been assessed most commonly by measuring the QT and QTc intervals and QT or QTc dispersion (6,7,8,9,10,11,12,13,29,30,31,32). Many of these studies compared QT or QTc intervals and/or dispersion in obese and lean subjects. Some have explored the relation of BMI to these electrocardiographic variables. Still others have studied ventricular repolarization in specific populations (females, males, children).

Seyfeli et al. reported that mean QTc and QTc dispersion values were significantly longer/greater in 42 obese than in 25 lean women (6). Park and colleagues found that QTc lengthened progressively from rest to 50% VO2 to VO2 max in 11 women with upper body obesity, but not in 11 women with lower body obesity or lean controls (7). Mizia-Stec and co-workers reported significantly higher mean QT dispersion values in 62 obese than in 15 lean women (9). Mean QTc dispersion, JTc dispersion, and transmural dispersion of repolarization were all significantly greater in 100 severely obese patients than in 50 lean controls in a study performed by Russo et al. (10). Mshui et al. reported significantly greater mean QTc dispersion in 38 obese subjects than in six lean controls (12). Mean QTc and mean QTc dispersion values were significantly longer/greater in 30 overweight or obese children than in 30 lean controls in a study reported by Olivares-Lopez and colleagues (13). In contrast, three studies found no relation between overweight or obesity and delayed ventricular repolarization. These include a study of 35 overweight, 54 obese, and 57 lean patients by Girola and co-workers (29), a study of 56 obese and 59 lean men by Bilora et al. (30) and 4,655 children by Fukushige and colleagues (31).

Our study showed a significant, but weak positive correlation between BMI and QTc in 50 normotensive severely obese subjects. BMI correlated positively and significantly with QTc and QTc dispersion in Seyfeli's study and independently predicted QTc (6). In a study of 122 men including 59 with uncomplicated obesity and 63 lean controls QTc correlated positively and significantly with BMI and waist circumference (8).

Our study population consisted of 80% women. Analysis by gender showed similar correlation of BMI with QTc in women and men. Three prior studies focused exclusively on women. In all three ventricular repolarization, variables were significantly longer/greater in obese than in lean women (6,7,9). In one study BMI correlated positively and significantly with QTc and QTc dispersion (6). In two studies exclusively involving men one showed a significant positive correlation of BMI with QTc and one showed no correlation of BMI with QTc (8,29).

Limitations of previous studies assessing ventricular repolarization in obesity include the fact that patients with various degrees of severity of obesity were studied and that patients with systemic hypertension were not excluded or analyzed separately in most investigations. The latter limitation is particularly important for two reasons. The first is that multiple studies have shown that systemic hypertension serves as a risk factor for QTc prolongation, particularly when LV hypertrophy is present (14,15,16,17,18,19). The second is that three studies reporting a greater delay in ventricular repolarization in obese than in lean subjects also reported increased LV mass in obese subgroups (9,13,32).

Our results demonstrate that LV mass is an important determinant of QTc in severely obese patients, even in the absence of systemic hypertension. QTc values were longest in those with LV hypertrophy; however, our analysis suggests that the relation between LV mass and the indices of repolarization is linear. We believe that the positive correlations of systolic blood pressure, LV end-systolic wall stress, and LV internal dimension with QTc exist due to their role as surrogate markers of afterload and preload, thus contributing to LV mass.

In prior studies of obese patients, QTc and QTc dispersion values frequently exceeded those of controls and were often >440 ms and >60 ms respectively (6,7,8,9,10,11,12,13). In this study of normotensive severely obese patients, 18 patients had a QTc value >440 ms and only one had a QTc value >460 ms Most QTc values observed in this study were normal. Those that were prolonged, were only mildly so, and thus were unlikely to serve as a substrate for ventricular arrhythmias. We believe that the lack of marked prolongation of QTc in our study is attributable to the absence of systemic hypertension, possibly signifying lower levels of LV mass than were present in prior studies.

Our results showed that longer QTc intervals were associated with greater impairment of LV diastolic filling and lower LV systolic function. It is likely that greater impairment of LV diastolic filling in those with longer QTc intervals was attributable to increased LV mass and the adverse loading conditions that predispose to increased LV mass. The adverse loading conditions in subjects with longer QTc intervals may also have contributed to the observed lower LV fractional shortening in these subjects.

There are multiple limitations to this study. These include the small sample size, the lack of a control group, and the absence of data derived from newer measures of ventricular repolarization such as transmural dispersion of repolarization. Polysomnography was not performed in most patients; thus, we were unable to assess the role of obstructive sleep apnea on ventricular repolarization in normotensive severely obese patients. Several metabolic factors that might influence ventricular repolarization were not measured. These include plasma insulin levels, free fatty acids, and catecholamines (33,34,35). Demonstrating that LV mass plays an important role in determining QTc does not exclude the possibility that these and other factors not assessed in this study might influence QTc in normotensive severely obese patients. Most studies assessing ventricular repolarization in obesity have used QTc as a diagnostic marker. We chose to focus on QTc rather than the QT interval to better compare our results with those reported in previous studies. Finally, the use of an electrocardiograph with 100 Hz signal acquisition rather than an electrocardiograph with a higher filter setting represents a limitation. At the time when patients entered the study, 100 Hz signal acquisition was considered acceptable.

In conclusion, LV mass and loading conditions that may affect LV mass are important determinants of QTc in normotensive severely obese subjects.

REFERENCES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES