the Framingham Heart Study (R.D., M.J.P., T.J.W., B.N., E.J.B., D.L., M.G.L., W.B.K., R.B.D., R.S.V.), National Heart, Lung, and Blood Institute, Framingham, Mass
Massachusetts Veterans Epidemiology Research and Information Center (R.D.), VA Boston Healthcare System and the Division of Aging, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass
Division of Cardiology (T.J.W.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass
National Heart, Lung, and Blood Institute (D.L.), Bethesda, Md
Department of Mathematics and Statistics (M.J.P., B.N., M.G.L., R.B.D.), Boston University, Boston, Mass
Cardiology Section (R.S.V., E.J.B.) and Department of Preventive Medicine and Epidemiology (E.J.B., D.L., M.G.L., W.B.K., R.S.V.), Boston University School of Medicine, Boston, Mass.
Abstract
Prolonged electrocardiographic QRS duration is frequently observed in congestive heart failure (CHF) patients. We hypothesized that CHF risk increases with longer QRS interval in individuals free of CHF. We evaluated 1759 Framingham Study participants (mean age, 69 years; 63% women) without prior myocardial infarction or CHF who attended a routine examination. QRS duration was analyzed as a continuous (log-transformed) and a categorical variable [referent, <100 ms; incomplete bundle branch block (BBB), 100 to 119 ms; complete BBB, 120 ms]. During follow-up (mean, 12.7 years), 324 participants (205 women) developed CHF. CHF incidence increased across the 3 baseline QRS duration categories in both sexes. Each SD increment in log-QRS duration was associated with a multivariable-adjusted 23% increase in CHF risk [95% confidence interval [CI] 8% to 38%; P<0.001]. In time- dependent models with QRS category and risk factors updated every 2 years, incomplete BBB was associated with a 1.4-fold (95% CI, 1.05 to 1.96; P=0.03) and complete BBB with a 1.7-fold (95% CI, 1.28 to 2.35; P<0.001) risk of CHF. These associations were maintained on adjustment for baseline left ventricular mass. In our community-based sample, longer electrocardiographic QRS was associated with increased CHF risk, consistent with the hypothesis that depolarization delay may increase CHF risk.
Key Words: electrocardiography epidemiology heart failure
Introduction
Approximately one fourth of congestive heart failure (CHF) patients have a prolonged QRS interval (120 ms) on the surface ECG.1 On a parallel note, men with a complete bundle branch block (BBB) experience a higher incidence of CHF prospectively.2 In addition, prolonged electrocardiographic QRS interval is associated with increased echocardiographic left ventricular (LV) mass cross-sectionally in individuals without prior history of CHF or myocardial infarction (MI).3 These observations raise the possibility that prolongation of the QRS duration may be a marker of adverse ventricular remodeling. Indeed, QRS prolongation has been the focus of intense research, because cardiac resynchronization therapy has emerged as a therapeutic option in CHF patients who have a QRS duration 130 ms.4 Cardiac resynchronization therapy has been reported to reduce morbidity4 and mortality5 and to reverse LV remodeling in CHF patients.6
It is unclear, however, whether the association of complete BBB with elevated CHF risk2,7 is because of a greater burden of risk factors,2,8 the consequence of associated higher LV mass3,9,10 or systolic dysfunction,11 or if it is attributable to dyssynchronous contraction.2,11,12 It is also uncertain whether lesser degrees of QRS prolongation (<120 ms) portend future risk of CHF.
We hypothesized that a gradient of increasing CHF risk exists with increasing electrocardiographic QRS interval and that the association of QRS interval with CHF risk may be mediated by increased LV mass and/or asymptomatic LV systolic dysfunction.3,9–11 Accordingly, we examined the relations of QRS duration on a routine ECG to CHF incidence on follow-up in a large, community-based sample.
Methods
The design and selection criteria of Framingham Heart Study have been described previously.13 Individuals from the original cohort who attended the 16th (1979–1981) or the 17th (1982–1984) biennial examination cycles and had computerized ECG recordings available at these examinations were eligible (n=2081). ECG recordings were obtained on attendees over 2 consecutive cycles (from the middle of examination 16 to the initial part of examination 17). At each examination, participants underwent medical history, physical examination including measurement of blood pressure, anthropometry, and laboratory assessment of risk factors. Attendees also underwent transthoracic 2D guided M-mode echocardiography at examination cycle 16.
We excluded individuals at the baseline examinations for the following reasons: prevalent CHF (by the Framingham criteria, see below; Reference 14) or MI [presence of 2 of 3 criteria (suggestive clinical symptoms, diagnostic ECG changes, and diagnostic serum enzymes); n=135] or use of antiarrhythmic medications or prior permanent pacemaker implantation (n=187). After exclusions, 1759 participants (1113 women) remained eligible. Informed consent was obtained from all of the participants, and the study was approved by the Institutional Review Board at the Boston Medical Center.
Ascertainment of CHF
All of the Framingham Study participants are under continuous surveillance for the development of cardiovascular disease events, including CHF. A panel of 3 experienced investigators reviews all of the medical records for adjudication of suspected cardiovascular disease events. The diagnosis of a first episode of CHF is based on the Framingham Heart Study criteria,14 which have a high specificity for the detection of CHF.15 The presence of 2 major or of 1 major and 2 minor criteria was used to define an episode of CHF. Criteria were attributed to CHF only in the absence of an alternative explanation for the symptoms and signs by other medical conditions (eg, cirrhosis, renal failure, or chronic pulmonary disease).
Electrocardiographic Measurements
At the baseline examinations, computerized ECGs were obtained on a 3-channel simultaneous system (Marquette Electronics). Standard 12-lead configuration and XYZ orthogonal leads were recorded in analog form and digitized and read by the IBM Bonner (V2) program.16 The program analyzed all 12 of the leads and measured the maximum QRS duration to the nearest 2 ms.
At each subsequent biennial examination, a standard 12-lead computerized resting ECG was obtained. ECGs at these visits were interpreted by a Heart Study physician, and the maximum QRS duration was recorded to the nearest 10 ms, based on assessment of all 12 of the leads.
The following criteria advocated by a World Health Organization working group17 were used to categorize BBB: left BBB (LBBB) was defined as a QRS 120 ms, absence of Q waves, and presence of wide-notched R waves in V5 and V6; presence of monophasic QS in V1 and V2; and absence of secondary R waves in V1.17 Criteria used for right BBB (RBBB) were QRS duration 120 ms; broad, notched R waves (rsr', rsR', or rSR' patterns) in V1 and V2; and wide, deep, and notched S waves in V5 and V6.17 All of the ECGs with QRS 120 ms that did not meet the criteria for LBBB or RBBB were categorized as "indeterminate."17
Echocardiographic Measurements
All of the attendees underwent routine transthoracic 2D guided M-mode echocardiography at the 16th examination cycle. For participants with computerized electrocardiographic measurements at examination 17, we used echocardiographic data from examination 16 (2 years prior). All of the echocardiographic measurements were obtained by using a "leading edge" technique.18 LV mass was calculated by using the standardized formula.19 LV fractional shortening (FS) was used as an indicator of LV systolic function, with a value of <0.29 indicating systolic dysfunction.20
Statistical Analyses
The primary outcome of interest was the incidence of a first episode of CHF on follow-up through December 2003.
QRS Duration as a Categorical Variable
We defined 3 QRS interval categories17: <100 ms (referent), 100 to 119 ms (incomplete BBB), and 120 ms (complete BBB). CHF event rates were calculated per 1000 person-years for each QRS category and also by type of BBB. Kaplan-Meier curves were estimated to illustrate the relations of baseline QRS categories to survival free of CHF. We verified that the assumption of proportionality of hazards was met.
Multivariable Cox proportional hazard regression21 was used to compare CHF incidence in participants with an incomplete BBB and complete BBB with that in individuals with a normal QRS duration (referent group). We also tested for a trend for increasing CHF across the 3 QRS categories. Two sets of regression models were evaluated, adjusting for: (1) age and sex; and (2) age, sex, body mass index (BMI), smoking status, diabetes mellitus, systolic blood pressure, use of antihypertensive treatment, valve disease (grade 3/6 systolic murmur or any diastolic murmur on physical examination), and MI on follow-up. All of the covariates, including the QRS duration category, were modeled as time-dependent variables; values were updated every 2 years based on observations obtained at routine Heart Study examinations.
We examined whether the potential associations of QRS interval with CHF incidence was mediated by increased LV mass3,9,10 or by LV systolic dysfunction11,22 by performing additional analyses. Initially, we repeated all of the analyses after excluding individuals with a FS <0.29 (Table 3, model 2). Next, we repeated analyses in the subgroup noted previously adjusting for baseline LV mass (as a continuous variable) in addition to all of the other covariates (all covariates modeled as time-dependent variables other than LV mass; Table 3, model 3). Lastly, we repeated the analyses noted above but with additional adjustment for baseline FS as a continuous variable (Table 3, model 4).
Baseline QRS Duration as a Continuous Variable
We evaluated Cox models with baseline QRS duration modeled as a continuous variable (logarithmically transformed to normalize the distribution). Two sets of models were evaluated adjusting for the following: (1) age and sex; and (2) all of the other covariates at baseline (as listed above). In contrast to QRS categories, we did not update continuous QRS duration values every 2 years, because the follow-up examinations did not use the same IBM program for QRS measurements; as noted previously, measurements at subsequent examinations were made to the nearest 10 ms, whereas measurements at the baseline examinations were made to the nearest 2 ms.
To gain insights into potential nonlinearity of associations between QRS duration and CHF risk, we examined generalized additive Cox models using penalized splines.23 The spline analysis permits the dose-response relation between QRS duration and CHF risk to be examined more accurately than by standard analyses using QRS categories, which may not adequately describe the trends in the data and do not make efficient use of within-category information.24
Additional Analyses
Effect Modification
We evaluated for effect modification by age (< versus 70 years), sex, BMI (< versus 30 kg/m2), and hypertension by incorporating appropriate interaction terms in multivariable models testing for increasing trend across the QRS duration categories.
QRS Duration Within the Normal Range and CHF Incidence
Whereas primary analyses focused on the entire range of QRS values, we performed supplementary analyses to investigate whether a gradient of increasing CHF risk was present for QRS duration within the normal range (<100 ms). For this purpose, we used time-dependent analyses in which individuals with QRS <100 ms were categorized at each biennial examination into 2 groups: QRS 80 ms (referent) and QRS >80 ms.
Type of BBB at Baseline and CHF Incidence
We also investigated whether CHF incidence varied according to the type of baseline BBB in Cox models (adjusting for baseline clinical covariates and MI on follow-up) that compared individuals with left, right, and indeterminate BBB (as defined above) with the referent group (QRS interval <100 ms).
Type of Heart Failure Associated With Baseline QRS Duration Category
To obtain insights into the type of heart failure (systolic versus diastolic) associated with the QRS categories, we reviewed echocardiographic reports in a subgroup of participants who had evaluation of LV systolic function within 30 days of their first hospitalization for CHF in a contemporary time period (1989–1998). CHF was presumed to be because of systolic dysfunction if the estimated LV ejection fraction (LVEF) obtained from hospitalization records was <0.50, whereas an ejection fraction of 0.50 was considered consistent with diastolic CHF.25
All of the analyses were performed using SAS.26 The display of the multivariable-adjusted hazards ratio on a logarithmic scale against the QRS duration was generated using S-Plus. A 2-sided P value <0.05 was considered statistically significant.
Results
Baseline characteristics of our sample are displayed in Table 1. The prevalence of hypertension rose across the QRS duration categories.
CHF Incidence on Follow-Up
During follow-up (mean, 12.7 years; range, 0.4 to 22.3 years), 324 participants (205 women) developed CHF, including 231 (17.3%) of 1339 individuals in the normal QRS group, 62 (20.2%) of 307 people with incomplete BBB, and 31 (27.4%) of 113 participants with complete BBB. The survival free of CHF decreased with increasing baseline QRS duration category (Figure 1; log-rank P<0.0001). Incidence rates of CHF increased across the QRS duration categories in a graded manner in both sexes (Table 2). A history of antecedent MI within 1 week of CHF onset was present in 57 (24.7%) of 231 CHF events in the normal QRS group, in 10 (16.1%) of 62 CHF events in the incomplete BBB group, and in only 4 (12.9%) of 31 CHF events in the complete BBB group.
Multivariable Models With QRS Duration Categories
In multivariable time-dependent Cox models (covariates and QRS duration categories updated every 2 years), incomplete BBB was associated with a 1.43-fold CHF risk (P=0.03), whereas individuals with complete BBB experienced a 1.74-fold risk of CHF (P<0.001) compared with the referent group (Table 3, model 1). The graded increase in CHF risk across QRS categories was confirmed in trend models.
At baseline, 1091 individuals (62%) had data on echocardiographic FS. We compared the group of individuals with adequate echocardiograms with those with inadequate echocardiograms and observed similar rates of CHF incidence overall and in the 3 QRS categories (data not shown). In the analyses of 1070 individuals with FS 0.29 (after excluding 21 individuals with diminished FS), the results of our primary analyses remained robust (Table 3, Model 2). On additional adjustment for baseline LV mass and FS sequentially (Table 3, models 3 and 4), the association of complete BBB with CHF risk was maintained, but the relations of incomplete BBB to CHF risk were rendered borderline statistically significant. In these models, the graded increase in CHF risk across QRS categories remained robust (trend across categories, Table 3, models 3 and 4).
Multivariable Models With Baseline QRS Duration as a Continuous Variable
In multivariable models with baseline log-QRS duration modeled as a continuous variable, CHF incidence rose with longer QRS interval in age- and sex-adjusted models [hazard ratio (HR) per SD increment, 1.27; 95% CI, 1.14 to 1.41; P<0.001] and in multivariable models (HR per SD, 1.23; 95% CI, 1.08 to 1.38; P<0.001). A 1-SD (0.15) increase in log-QRS corresponds to a 1.2-fold increase in QRS duration in original units, or approximately a 20-ms increment; thus, it may represent an increase from 80 to 100 ms or from 100 to 120 ms. Examination of regression splines demonstrated an increase in CHF hazard with increasing baseline QRS duration that became steeper for QRS values 100 ms (Figure 2).
Additional Analyses
Effect Modification
There was no effect modification by sex, BMI, or hypertension status. On stratification of our sample into 2 age groups (<70 versus 70 years), the association of QRS duration with CHF incidence remained statistically significant for individuals aged 70 years (HR per SD increment in log QRS, 1.26; 95% CI, 1.07 to 1.48; P=0.005) but was attenuated in those <70 years (HR per SD increment in log QRS, 1.13; 95% CI, 0.96 to 1.34; P=0.13).
QRS Duration Within the Normal Range (<100 ms) and CHF Incidence
In analyses restricted to individuals with a QRS <100 ms (n=1339), 66 (14.6%) of 453 individuals with a QRS 80 ms developed CHF compared with 165 (18.6%) of 886 persons with QRS >80 ms (but <100 ms). In time-dependent analyses, a QRS >80 ms was associated with a borderline significant 1.34-fold risk of CHF (95% CI, 0.95 to 1.91; P=0.09) in age- and sex-adjusted models and a 1.41-fold risk (95% CI, 0.92 to 2.17; P=0.11) in multivariable models compared with the group with QRS 80 ms.
Type of BBB at Baseline and CHF Incidence
Among individuals with complete BBB at baseline, those with LBBB experienced the highest CHF rates, those with RBBB had the lowest rates, and those with indeterminate BBB had intermediate CHF rates (Table I, available in an online supplement at http://www.hypertensionaha.org). In multivariable analyses, LBBB and indeterminate BBB were associated with a higher incidence of CHF (adjusted HR, 4.45; 95% CI, 2.33 to 8.51 for LBBB; P=0.0001; adjusted HR, 2.18; 95% CI, 1.13 to 4.20 for indeterminate BBB; P=0.02), whereas individuals with RBBB did not have a statistically significant increased risk of CHF (adjusted HR, 1.73; 95% CI, 0.93 to 3.21; P=0.08) when compared with those with a QRS duration <100 ms.
Type of Heart Failure Associated With Baseline QRS Duration Category
In exploratory analyses, we evaluated 82 participants (25% of CHF cases) who underwent echocardiographic evaluation within 30 days of their first hospitalization for CHF (using estimates of LVEF from hospitalization records). Of these CHF cases, 64% (37 of 58) in the normal QRS duration group, 50% (7 of 14) in the incomplete BBB group, and 50% (5 of 10) in the complete BBB category had an LVEF <0.50.
Discussion
Principal Findings
Our principal findings are 3-fold. First, we observed a significant association of longer QRS duration with rising CHF risk. Incomplete and complete BBB were associated with a 1.5- and 2-fold risk of CHF, respectively. On adjustment for baseline LV mass and FS, the association of complete BBB with CHF risk remained robust. However, the association of incomplete BBB with CHF risk became borderline significant, suggesting that a greater LV mass and lower systolic function may mediate, in part, the greater CHF risk in this group. In secondary analyses restricted to individuals with a QRS <100 ms, we observed a trend for increasing CHF within this range that did not achieve statistical significance, consistent with the steeper hazard for CHF beyond this threshold in regression splines. Second, baseline incomplete and complete BBB accounted for a modest proportion (30%) of CHF events on follow-up. We had limited statistical power to analyze the variation in CHF risk according to the type of BBB. A majority of CHF events occurred in individuals with a normal baseline QRS duration. Third, in secondary analyses of a subgroup of individuals who underwent echocardiographic evaluation within 30 days after their first hospitalization for CHF, incomplete and complete BBB were associated with both systolic and diastolic CHF.
Possible Mechanisms for the Association of Longer QRS Duration With CHF Risk
There are several mechanisms that may explain the observed association of longer QRS duration with CHF risk. First, it is possible that the association of electrocardiographic QRS with CHF is confounded by the greater burden of risk factors, such as hypertension,8 diabetes2 or ischemic heart disease,27 in individuals with BBB. To reduce potential confounding, we excluded participants with prevalent CHF and MI at baseline and adjusted for hypertension and other risk factors (including MI).
Second, it is conceivable that longer QRS duration may be associated with alterations in LV structure and function.3,9–11,22,28 We performed additional analyses excluding participants with a reduced FS and adjusted for LV mass and FS. In these analyses, the association of complete BBB with greater CHF risk remained robust, but the relations of incomplete BBB to CHF risk were attenuated. These results suggest that association of longer QRS duration with structural and functional LV changes3,9–11,22 may partly explain the increased CHF risk observed with incomplete BBB.
A third mechanism may be the greater prevalence of ventricular dyssynchrony in individuals with longer QRS, which may promote CHF risk. Because the baseline examination anteceded use of 2D and Doppler echocardiography, we could not explore this possibility. Overall, it is conceivable that all 3 of the pathophysiological mechanisms contribute to the increased risk of CHF in individuals with longer QRS duration.
Limitations
It is difficult to conclude on the basis of our epidemiological study that the association of longer QRS duration with greater CHF risk is a causal one. Even if QRS duration were simply a marker (and a not a cause) of CHF risk, the ease of measurement and routine availability would render it a potentially useful indicator of risk. It is noteworthy, though, that QRS duration satisfies several of Hill’s criteria29 for causality of associations, including prolongation of QRS duration antedated CHF (temporal relations), observed dose-response relation, consistent findings in multiple models, and a biologically plausible causal association is (as detailed in the section above). The measurement of QRS duration is known to be operator dependent, and measurement reproducibility is reduced by the presence of conduction abnormalities.30 For some of our analyses that used QRS categories, we combined assessment of QRS categories at baseline (that were computerized) with that at follow-up examinations (that were manually determined by physicians); we submit that ascertainment of QRS category status will not be biased in a major way by this strategy. However, we used only baseline QRS measurements when QRS duration was modeled as a continuous variable. Our sample of individuals with available echocardiograms was modest in size; hence, results of our subgroup analyses warrant confirmation by large studies. The use of FS by M-mode echocardiography as an indicator of LV systolic function is an additional limitation, because such assessment reflects systolic function of the basal LV segments. In addition, although we adjusted for LV mass, we did not account for LV diastolic function, because such measures were not available at the baseline examinations. It is important to emphasize the limited generalizability of our results to other ethnicities given the overwhelmingly white Framingham sample.
Conclusions
In our large, community-based sample of middle-aged and elderly individuals free of prior CHF and MI, longer electrocardiographic QRS duration was associated with elevated risk of CHF. The association was most striking in individuals with complete BBB, who experienced a 2-fold risk of CHF compared with people with a normal QRS duration (<100 ms). Additional prospective studies of larger multiethnic samples size are warranted to confirm our findings and to elucidate the mechanisms underlying the observed association.
Acknowledgments
This work was supported through National Institutes of Health/National Heart, Lung, and Blood Institute contracts N01-HC-25195, 1R01HL67288, and 2K24HL04334 (to R.S.V.) and K23HL74077 (to T.J.W.). The National Heart, Lung, and Blood Institute had no role in the study design, analyses, or drafting of the article. The National Heart, Lung, and Blood Institute reviews all articles submitted for publication but it was not involved in the decision to publish.
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Monique Van Vliet, Martijn A. Spruit, Geert Verleden, Ahmad Kasran, Erik Van Herck, Fabio Pitta, Roger Bouillon and Marc Decramer
Respiratory Rehabilitation and Respiratory Division, University Hospital Gasthuisberg; Department of Rehabilitation Sciences, Faculty of Kinesiology and Rehabilitation Sciences; and Laboratories of Pneumology, Experimental Immunology, and Experimental Medicine and Endocrinology (LEGENDO), Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium
ABSTRACT
Rationale: Circulating levels of testosterone and gonadotrophins of patients with chronic obstructive pulmonary disease (COPD) have never been compared with those of elderly men with normal pulmonary function. Moreover, the relationship of hypogonadism with quadriceps muscle weakness and exercise intolerance has been studied scarcely in men with COPD.
Objectives: To compare circulating levels of hormones of the pituitary–gonadotrophic axis of men with COPD with those of age-matched control subjects. Moreover, to study the relationship of hypogonadism with quadriceps muscle force, 6-min walking distance, and systemic markers of inflammation in the patients.
Methods and Measurements: Circulating levels of follicle-stimulating hormone, luteinizing hormone, testosterone, and sex homone–binding globulin were determined, and free testosterone was calculated in 78 patients (FEV1: 44 ± 17% of the predicted values) and 21 control subjects. Moreover, quadriceps muscle force, 6-min walking distance, number of pack-yr, and systemic inflammation were determined.
Main Results: Follicle-stimulating hormone and luteinizing hormone were higher in the patients, whereas testosterone was lower (p 0.05). The latter finding was also present in 48 non–steroid-using patients with normal blood gases. Low androgen status was significantly related to quadriceps muscle weakness (r = 0.48) and C-reactive protein (r = –0.39) in the patients, but not to exercise intolerance, the number of pack-yr, or increased circulating levels of interleukin 8 or soluble receptors of tumor necrosis factor .
Conclusions: In contrast to exercise intolerance, quadriceps muscle weakness is related to low circulating levels of testosterone in men with COPD.
Key Words: follicle-stimulating hormone luteinizing hormone quadriceps muscle strength sex hormone–binding globulin testosterone
The role of physical inactivity in the development and/or maintenance of quadriceps muscle weakness in patients with advanced chronic obstructive pulmonary disease (COPD) is well established. A reduction in weight-bearing activities has been observed in these patients (1), and quadriceps muscle weakness is closely related to upper leg muscle atrophy (2). Moreover, resistance training and transcutaneous neuromuscular electrical stimulation have been able to improve quadriceps muscle force and to facilitate ambulation in patients with COPD (3–9). Unfortunately, the recovery of quadriceps muscle force is incomplete even after 6 mo of exercise training (7). Therefore, besides physical inactivity, other factors may contribute to the development and/or presence of quadriceps muscle weakness in patients with COPD (10, 11).
In healthy elderly men, age-related decline in quadriceps muscle force has been related to the reduced circulating levels of testosterone (12), which is able to stimulate muscle protein anabolism and motor neuron size (13). Nevertheless, the relationship between testosterone and quadriceps muscle force does not appear to be straightforward. For example, a 20-wk suppression of the endogenous testosterone production in eugonadal, healthy elderly men resulted in reduced circulating testosterone concentrations (mean, 176 ng/dl) without changes in leg-press strength (14).
Uncertainty on the role of testosterone in the development and/or maintenance of quadriceps muscle weakness also remains in male patients with COPD. Laghi and colleagues (15) did not find a significant difference in quadriceps muscle force between 10 eugonadal and 10 hypogonadal male patients with COPD. By way of contrast, Casaburi and colleagues (16) reported significant improvements in quadriceps muscle force after 10 wk of testosterone injections in male patients with COPD who were selected as a result of low baseline circulating levels of testosterone (mean, 320 ng/dl). Moreover, 10 wk of testosterone injections combined with resistance training resulted in greater improvements in quadriceps muscle force than resistance training alone (16). Therefore, it is still reasonable to hypothesize that quadriceps muscle weakness is, at least in part, related to low circulating testosterone concentrations in male patients with advanced COPD.
In the past, increased systemic inflammation (17), a higher dose of oral corticosteroids (18), and hypoxemia have been related to low circulating testosterone concentrations in male patients with COPD (19, 20). The latter two observations, however, could not be substantiated by three recent studies and remain a matter of debate (16, 17, 21).
A dysfunctioning hypothalamic–pituitary–gonadal axis has been found in COPD (15, 16, 20, 21). For example, hypogonadotrophic hypogonadism has been reported in male patients with COPD (16, 20). Others have shown that hypogonadal patients with COPD may have significantly higher serum gonadotrophins than eugonadal patients (15). Moreover, a decreased response to administered gonadotrophin-releasing hormone has been found in hypoxemic patients with chronic airway diseases (20). Nonetheless, there has never been a direct comparison of circulating gonadotrophin concentrations in male patients with COPD and elderly control subjects with normal pulmonary function.
A cross-sectional study was designed to answer the following questions:
Are the systemic markers of the pituitary–gonadotrophic axis in men with COPD significantly different from those of elderly men with normal pulmonary function
What is the relationship between a low androgen status, clinical outcomes, and systemic markers of inflammation in men with COPD
Some of the results of this study have been previously reported in the form of two abstracts (22, 23).
METHODS
Additional details on the methods for making the measurements as described below are provided in an online supplement.
Patients
A total of 259 consecutive patients who attended the COPD outpatient clinic were asked to participate. Of these, 157 patients were reluctant to participate or were excluded (Figure E1 in the online supplement). Consenting patients with COPD had similar clinical characteristics as those who were not included, except for age (Table E1).
The remaining 102 patients with clinically stable COPD (78 men) voluntarily consented to partake in the present study. For obvious reasons, only the results of the male patients were taken into account to answer the aforementioned questions.
The results of the 78 men with COPD were compared with those of 21 men with normal pulmonary function and similar age distribution (Table 1), except for the results of circulating levels of the inflammatory markers, which were only determined in the male patients with COPD to answer the aforementioned second question.
All participants had to come for one morning to the outpatient clinic to perform the tests as described below and in the online supplement. The Medical Ethical Board of the University Hospitals Leuven approved this cross-sectional comparative study. All participants were white and gave informed consent. Seventeen control subjects were part of a previous publication about physical activity level in patients with COPD (1).
Blood Analyses
Venous blood samples were analyzed for C-reactive protein, soluble TNF receptors (sTNFR) p55 and p75 (24), interleukin 8 (IL-8) (11), follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and sex hormone–binding globulin (SHBG). Moreover, circulating levels of free testosterone were calculated.
Functional Measurements
Pulmonary function, quadriceps peak torque, and the distance walked in 6 min (6MWD) were assessed as described previously (6, 25).
Comorbidities
Comorbid conditions have been classified using the Charlson index, which is a simple weighted index that takes into account the number and the seriousness of comorbid disease (26). In addition, the scores on the age–comorbidity index (Charlson index II) were calculated (27).
Statistical Analyses
See the online supplement.
RESULTS
Cross-sectional Comparisons
Characteristics.
Patients with COPD had significantly worse pulmonary function, quadriceps muscle force, 6MWD, and scores on the Charlson comorbidity and age–comorbidity indexes than the control group (Table 1 and Table E2).
Hormones of the pituitary–gonadotrophic axis.
Patients with COPD had significantly higher circulating levels of FSH and LH and significantly lower circulating levels of testosterone and free testosterone than the control group. Moreover, circulating levels of SHBG tended to be higher in the patients with COPD (Table 1 and Figure 1).
The prevalence of low circulating testosterone concentrations in patients with COPD was significantly higher than in the control group, whereas the prevalence of low circulating free testosterone concentrations tended to be higher in the patients (Table 1 and Figure E2). Hypogonadal patients had circulating FSH and LH concentrations above the lower limit of normal or even above the upper limit of normal (Figure E3).
Stratification for current use of corticosteroids and PaO2 in COPD.
No significant differences were found between median circulating levels of FSH, LH, testosterone, free testosterone, and SHBG in the patients who had been stratified according to the current use of oral corticosteroids ("yes" or "no") and for the PaO2 (< or 70 mm Hg; Figure E4).
Systemic inflammatory markers in COPD.
Median (interquartile range) circulating levels of C-reactive protein (4.2 mg/L [1.8–9.1]), IL-8 (2.8 pg/ml [2.2–3.8]), sTNFR-p55 (2.4 ng/ml [2.0–2.8]), and sTNFR-p75 (5.1 ng/ml [4.2–6.2]) of the patients with COPD were comparable to previous findings in patients with clinically stable COPD (28) and higher than values obtained in healthy middle-aged adults (24) and elderly individuals (29).
Correlations
For correlations between hormones of the pituitary–gonadotrophic axis in COPD, see the online supplement.
Correlations between hormones of the pituitary–gonadotrophic axis and clinical outcomes in COPD.
In the patients with COPD, the impaired FEV1 did not correlate with the observed changes in the pituitary–gonadotrophic axis (Figure E5). Body mass index was inversely related to the circulating levels of testosterone (rs = –0.44, p = 0.0001), free testosterone (rs = –0.24, p = 0.037), and SHBG (rs = –0.48, p = 0.0001).
In contrast to the 6MWD (rs = 0.18, p = 0.12; Figure 2), quadriceps muscle force was positively related to circulating testosterone concentrations (rs = 0.48, p = 0.0001; Figure 3) and circulating free testosterone concentrations (rs = 0.37, p = 0.0012). Only circulating free testosterone concentrations tended to be inversely related to the number of pack-yr (rs = –0.22, p = 0.052), whereas circulating testosterone concentrations tended to be inversely related to the mean daily dose of oral corticosteroids (rs = –0.22, p = 0.058).
Correlations between hormones of the pituitary–gonadotrophic axis and systemic inflammation in COPD.
Circulating levels of IL-8 and the sTNFR-p55 were positively related to the circulating levels of FSH (rs = 0.27, p = 0.021, and rs = 0.23, p = 0.045, respectively) and LH (rs = 0.29, p = 0.012, and rs = 0.22, p = 0.054, respectively). Moreover, circulating C-reactive protein concentrations showed inverse relationships with the circulating levels of testosterone (rs = –0.39, p = 0.0004), free testosterone (rs = –0.28, p = 0.014), and SHBG (rs = –0.22, p = 0.057). Other systemic markers of the pituitary–gonadotrophic axis did not relate to the circulating levels of systemic inflammation in the patients with COPD (p 0.17).
DISCUSSION
The present study has found significant differences in circulating levels of hormones of the pituitary–gonadotrophic axis between male patients with COPD and elderly men with normal pulmonary function. In addition, low circulating levels of testosterone were positively related to quadriceps muscle weakness, but not to reduced functional exercise capacity in patients with COPD. Hypogonadism occurred also in non–steroid-using male patients with COPD who had normal arterial blood gases. Low-grade systemic inflammation and smoking did not appear to be the main determinants of hypogonadism in male patients with COPD. In fact, hypogonadism appeared, at least in part, to be caused by a primary testicular dysfunction and/or a hypofunctioning of the hypothalamic–pituitary–gonadal axis.
Prevalence of Hypogonadism
Although results were borderline, male patients with COPD had a higher prevalence of hypogonadism than control subjects (Table 1). Interestingly, the prevalence of hypogonadism was 13% higher than the values reported by Laghi and colleagues (21), even though the patients had similar age, FEV1, and PaO2, and a similar prevalence of oral corticosteroid use in the hypogonadal patients. The difference in prevalence may therefore be explained by the absence of comorbidities (30) or the presence of ethnic differences (31). Unfortunately, Laghi and colleagues (21) did not give details on these variables.
Hypogonadism was also present in about one-third of the control group. The present observation, although somewhat surprising, is in line with previous unrelated data in healthy, elderly Belgian men (32, 33).
Possible Causes of Hypogonadism in COPD
Hypothalamic–pituitary–testicular axis.
The present authors reasoned a priori that low circulating levels of FSH and LH may be responsible for low circulating testosterone concentrations in male patients with COPD, as seen previously (16, 20). In the present study, however, all hypogonadal patients with COPD (e.g., circulating levels of testosterone 300 ng/dl) showed circulating FSH and LH concentrations above the lower limit of normal (Figure E3). Some hypogonadal patients even had circulating FSH and LH concentrations above the upper limit of normal. Considering the role of FSH and LH in the biosynthesis of testosterone, hypergonadotrophism represents a compensatory mechanism of the hypothalamic–pituitary axis to correct for the low circulating testosterone concentrations in patients with COPD. In fact, a decrease in circulating testosterone concentrations and a compensatory increase in the circulating gonadotrophin concentrations have been reported in healthy elderly men (32, 34, 35) and in patients with COPD (15). These findings suggest that hypogonadism can be due to a primary testiscular dysfunction in COPD.
The remaining hypogonadal patients showed no increase in the circulating levels of LH and FSH on low circulating testosterone concentrations. In addition, a decreased response to administered gonadotrophin-releasing hormone has been found in hypoxemic patients with chronic airway diseases (20). Whether this is due to an impaired periodic release of gonadotrophin-releasing hormone, an impaired function of the gonadotropes, an impaired feedback action of the testes exerted through secretion of steroids or peptides, or a combination thereof remains to be determined (36–38). These findings, however, suggest that hypogonadism can also due to a hypofunctioning of the hypothalamic–pituitary–gonadal axis in COPD.
SHBG.
A somewhat unexpected increase of approximately 30% in the circulating levels of SHBG has been found in subjects with COPD as compared with control subjects, which obviously has affected the circulating free testosterone concentrations (Figure 1). Although aging has been shown to be responsible for increased circulating SHBG concentrations ( 1.1%/yr) (39), the present patients and control subjects were of similar age (Table 1). The biosynthesis of SHBG by the liver has been shown to be regulated by triiodothyronine (40), which, in turn, has been shown to be significantly higher in patients with COPD as compared with healthy control subjects (41). It can therefore be reasoned that hyperthyroidism may, at least in part, be responsible for the observed differences in SHBG and indirectly for a low androgen status in male patients with COPD. Unfortunately, thyroid function was not assessed in the present study. Moreover, the increased circulating SHBG concentrations may be a response to the increased circulating levels of FSH and LH (as shown by the positive relationships), which in turn may be a result of low circulating testosterone concentrations.
Current corticosteroid use, hypoxemia, and smoking.
Median circulating levels of testosterone and free testosterone of 48 non–steroid-using patients with COPD with normal arterial oxygen tension were low: 275 and 4.94 ng/dl, respectively (Figure E4). Moreover, Laghi and colleagues (21) found similar PaO2 and the same prevalence of oral corticosteroid users in hypogonadal and eugonadal patients with COPD. Therefore, the role of oral corticosteroid use and hypoxemia in the development of hypogonadism in COPD appears to be less prominent as suggested previously (18–20).
Smoking has been shown to cause hypogonadism (42, 43). In fact, fewer Leydig cells and degeneration of the remaining cells were found in the testes of men with longstanding chronic bronchitis and emphysema without changes in the circulating gonadotrophin concentrations (44). Nevertheless, the number of pack-yr was only weakly related to the circulating levels of free testosterone in the present patients with COPD. On the other hand, in 48 non–steroid-using patients with COPD with normal PaO2 ( 70 mm Hg), an a posteriori analysis revealed stronger relationships between the number of pack-yr and the circulating levels of free testosterone (r = –0.40, p = 0.0043) and testosterone (r = –0.30, p = 0.0418).
Systemic inflammation.
Systemic inflammation has been suggested as a possible cause of low circulating testosterone concentrations in male patients with COPD (45). To date, only a weak but significant inverse relationship between the circulating levels of IL-6 and bioavailable testosterone has been found in men with COPD (r = –0.33) (17). In the present study, circulating levels of IL-8, sTNFR-p55, and sTNFR-p75 did not correlate with the low circulating levels of testosterone in the male patients with COPD. This is in line with data from Debigare and colleagues (17). Nevertheless, weak inverse relationships were found between circulating levels of testosterone and free testosterone with acute-phase C-reactive protein. It would therefore be interesting to study the possible consequences of transiently increased systemic inflammation (11), together with an increased dose of systemic corticosteroids (46), on the low androgen status in men with COPD during an acute exacerbation.
Some markers of systemic inflammation showed positive relationships with FSH and LH. This may indicate an indirect compensatory reaction of the endocrine system against the presence of a chronic catabolic environment in men with COPD (e.g., low-grade systemic inflammation).
Hypogonadism and Quadriceps Muscle Weakness in COPD
Quadriceps muscle weakness has been related to physical disuse (1, 2), the insertion allele of the angiotensin-converting enzyme gene polymorphism (47), and low systemic levels of insulin-like growth factor I, and to chronic low-grade systemic inflammation in men with COPD (11, 17, 48). The present study is the first to find a weak but significant positive relationship between low androgen status and quadriceps muscle weakness in male patients with clinically stable but advanced COPD.
Recently, no significant differences were found between the mean maximal voluntary quadriceps muscle contraction of 10 eugonadal and 10 hypogondal men with COPD (15). Nevertheless, by using the same cut-off value as Laghi and colleagues (circulating free testosterone concentrations > or 5 ng/dl) (15), the present authors did find a significant difference in isometric quadriceps peak torque between 38 eugonadal (median [interquartile range] circulating free testosterone concentrations: 6.0 ng/dl [5.5–8.3]; mean ± SD quadriceps peak torque: 81 ± 19% predicted) and 40 hypogonadal men with COPD (free testosterone: 3.9 ng/dl [2.8–4.4], p = 0.0001; quadriceps peak torque: 68 ± 19% predicted, p = 0.0057) without a significantly different median score on the Charlson comorbidity index (p = 0.24). Currently, a clear explanation for these discrepant results is lacking. In fact, the present patients had comparable characteristics as those studied by Laghi and colleagues (15). Nevertheless, the number of patients studied by these authors was most probably too low to exclude a type II error. Moreover, the present results are in line with previous findings in healthy elderly individuals (49, 50) and the present control subjects had comparable results (see online supplement). Then again, circulating levels of bioavailable testosterone were similar between a group of patients with COPD with and without upper leg muscle atrophy (17). The mean circulating testosterone concentrations of the patients with COPD, however, were equal to those obtained in healthy elderly control subjects (17). Moreover, circulating testosterone concentrations have shown to be independent of daily physical activity level in healthy subjects and in patients with chronic pulmonary or cardiac disease (16, 21, 32). Therefore, the most straightforward suggestion is that patients with COPD with the lowest midthigh cross-sectional area probably had the lowest levels of daily physical activities (17). Unfortunately, the present study and others (15, 17) did not explicitly study the levels of daily physical activity using a validated activity monitor (51, 52).
Testosterone replacement therapy has not always been effective to improve quadriceps muscle strength in healthy elderly men (53). Moreover, improvements in skeletal muscle mass and leg-press strength in healthy elderly men receiving a combination of 600 mg testosterone enanthate injections (once every wk for 20 wk) together with 7.5 mg Lupron depot (a long-acting gonadotrophin agonist, once monthly for 20 wk) were not significantly different from those who received 125 or 300 mg testosterone enanthate injections together with 7.5 mg Lupron depot (14). Nevertheless, the relationship of quadriceps muscle weakness with physical disuse (2) and hypogonadism may provide a rationale to combine structured exercise programs with testosterone replacement therapy in highly selected hypogonadal patients with COPD. Actually, weekly injections of testosterone enanthate have shown to result in significant increases in bodyweight, lean body mass, and quadriceps muscle function, but not in respiratory muscle function or exercise capacity in male patients with COPD with low baseline circulating levels of testosterone (16). This dose (100 mg/wk) for this duration (10 wk) did not result in adverse effects in male patients with COPD who had low baseline androgen status (16). Nevertheless, additional safety and feasibility studies are necessary before testosterone supplements may be added to the management of highly selected patients with severe COPD (54).
Hypogonadism and Exercise Intolerance in COPD
Exercise capacity was not affected by the gonadal status in patients with COPD (Figure 2), corroborating previous findings (15, 16, 21). In fact, quadriceps muscle endurance was similar between eugonadal and hypogonadal patients with COPD (15). This seems reasonable considering the fact that quadriceps muscle endurance has shown to be related to the proportion of type I muscle fibers, citrate synthase activity (55), physical inactivity (56), and exercise-induced muscle oxidative stress (57).
Methodologic and Statistical Considerations
The present study has been performed in a tertiary care setting, and may therefore have led to a bias in the selection of males with only advanced COPD. Hence, external validity of the current findings is limited to this subgroup. Nevertheless, patients with Global Initiative for Chronic Obstructive Lung Disease stage II disease (58) also had low median circulating levels of testosterone and free testosterone (336 and 4.6 ng/dl, respectively), and this finding can therefore also be expected in male patients with COPD in primary and secondary care settings.
A relatively high number of the present patients used oral corticosteroids (29%), which may have biased the results. Nonetheless, previous studies reported a similar prevalence (15, 21).
Patients had a significantly higher score on the Charlson comorbidity index than control subjects (Table 1), which may have affected the circulating free testosterone concentrations. Nevertheless, circulating testosterone concentrations did not change significantly in elderly patients (mean age, 70 yr) directly or 3 mo after an acute myocardial infarction (32). In the present study, the circulating free testosterone concentrations remained significantly different between 52 patients (5.22 ng/dl [4.12–6.11]) and 20 control subjects (6.57 ng/dl [5.14–9.03], p = 0.03) after excluding 26 patients with COPD and one control subject with comorbidities. Moreover, hypogonadal patients with COPD had a similar median score on the Charlson comorbidity index as eugonadal patients.
At the time of the study, the present authors did not have access to a magnetic stimulator, which has been shown to be a painless, supramaximal method of assessing quadriceps force independent of the maximality of the effort made during the test by the participants (59). Nevertheless, the variability of maximal voluntary quadriceps femoris muscle contraction was found to be similar to measurements by magnetic stimulation (59), and a supramaximal twitch during a maximal voluntary contraction did not result in a significantly higher peak force (60). The present authors therefore believe that a maximal voluntary contraction is a valid technique to measure peak force of the femoral quadriceps muscles of patients with COPD.
Currently, a minimal clinically important difference for quadriceps peak torque has not been determined in COPD. Nonetheless, a mean difference of 13% of the predicted value for quadriceps peak torque between hypo- and eugonadal patients appears to be clinically relevant, in particular because quadriceps muscle force increased significantly with a mean of 7% of the predicted values after 3 mo of high-intensity progressive resistance and endurance training in 65 patients with advanced COPD (6).
Significant correlations do not necessarily imply causal relationships. Moreover, statistically significant differences between groups need to be interpreted in the light of the number of comparisons that were made in the present study. Nonetheless, the current statistical procedures have been used to test predefined hypotheses. Moreover, according to Perneger (61), "Bonferoni adjustments are at best, unnecessary and, at worst, deleterious to sound statistical inference."
Future Research
Although reduced quality of life was not related to the gonadal status of patients with COPD (21), endocrinological changes (i.e., hyposomatotrophism [11], hypogonadism [15, 21], hyperthyroidism [41], and elevated plasma ghrelin levels [62]) may still be of clinical importance for patients with advanced COPD. In the present study, the clinically relevant quadriceps muscle weakness (25, 63–66) was positively related to reduced circulating levels of testosterone. Other clinically important complaints of patients with COPD may also be, at least in part, due to low testosterone levels. For example, reduced libido and erectile dysfunction have been reported in approximately 67% of the male patients with COPD with chronic respiratory failure on long-term oxygen therapy (67). Sex hormone replacement therapy has already shown to result in an improved erectile function and overall sexual quality of life in male patients with COPD (68).
The possible role of the increased circulating levels of SHBG (Figure 1) in the loss of bone mineral density (69) may also be worthy of study. Indeed, in middle-aged men with idiopathic or secondary osteoporosis, the increased circulating levels of SHBG were related to the bone mineral density of the hip and spine (70).
Conclusions
About 50% of the male outpatients with clinically stable COPD have a low androgen status, which can be caused by a combination of factors. In the present study, a primary testicular dysfunction and/or a hypofunctioning of the hypothalamic–pituitary–gonadal axis appeared to be the main underlying mechanisms of hypogonadism in male patients with COPD. Moreover, low circulating levels of testosterone were positively related to quadriceps muscle weakness but not to exercise intolerance in these patients.
Acknowledgments
The authors thank physiotherapists Veronica Barbier, Iris Coosemans, and Vanessa Probst for assessing the functional outcomes in the present study.
FOOTNOTES
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Conflict of Interest Statement: M.V.V. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. M.A.S. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. G.V. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. A.K. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. E.V.H. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. F.P. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. R.B. does not have a relationship with a commercial entity that has an interest in the subject of this manuscript. M.D. has received an unrestricted grant from AstraZeneca to pay the salary of M.V.V. and has received $40,000 from AstraZeneca Belgium between 9/1/2003 and 8/31/2004.
These authors contributed equally to this study.
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