(Circulation. 1999;99:1600-1605.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Electrocardiographic Signs of Chronic Cor Pulmonale
A Negative Prognostic Finding in Chronic Obstructive Pulmonary Disease
From the Departments of Respiratory Physiopathology and Geriatrics (R.A.I.), Catholic University, Rome, Italy.
Correspondence to Leonello Fuso, MD, Fisiopatologia Respiratoria, Università Cattolica S. Cuore, Largo A. Gemelli 8, 00168 Roma, Italy.
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Abstract |
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Background—Chronic cor pulmonale (CCP) is a strong predictor of death in chronic obstructive pulmonary disease (COPD). The aims of this study were to assess the prognostic role of individual ECG signs of CCP and of the interaction between these signs and abnormal arterial blood gases.
Methods and Results—Two hundred sixty-three patients (217 men)
with COPD, mean age 67±9 years, were grouped according to whether they
had no ECG signs (group 1, n=100) or 
1 ECG signs (group 2, n=163) of
CCP and were followed up for 13 years after an exacerbation of
respiratory failure. The median survival was significantly shorter in
group 2 than in group 1 (2.58 versus 3.45 years, respectively;
Mantel-Cox test, 9.58; P=0.002). The Cox regression
analysis identified S1S2S3
pattern, right atrial overload (RAO), and alveolar-arterial
oxygen gradient
(PAO2-PaO2)
>48 mm Hg during oxygen therapy as the strongest predictors of
death, with hazard rate (HR)=1.81 (95% CI, 1.22 to 2.69), HR=1.58
(95% CI, 1.15 to 2.18), and HR=1.96 (95% CI, 1.19 to 3.25),
respectively. The median survivals of patients having both
S1S2S3 pattern and RAO (n=14) and
of patients having either S1S2S3
pattern or RAO (n=77) were 1.33 and 2.70 years, respectively
(P=0.022). Group 2 patients had a 3-year survival of
18% or 53%, depending on whether their
PAO2-PaO2 during
oxygen therapy was or was not >48 mm Hg.
Conclusions—Some ECG signs of CCP and PAO2-PaO2 >48 mm Hg during oxygen therapy qualified as a simple and inexpensive tool for targeting subsets of COPD patients with severe or very severe short-term prognosis.
Key Words: hypertension, pulmonary • pulmonary heart disease • electrocardiography • prognosis
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Introduction |
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Age, forced expiratory volume in 1 second (FEV1), and several respiratory function indices have been shown to be independent correlates of survival in chronic obstructive pulmonary disease (COPD).1 The prognostic role of variables reflecting the onset and progression of chronic cor pulmonale (CCP) has rarely been assessed.2 3 4 5 6 7 Kok-Jensen2 found that COPD patients with a QRS axis ranging between +90° and +180° and with a P-wave amplitude of
0.20 mV had a 4-year survival of 37% and 42%,
respectively, whereas the corresponding figure for patients with normal
ECG was 75%. Traver et al3 showed that the clinical
diagnosis of cor pulmonale is associated with higher mortality. In a
small series of COPD patients, ECG signs of CCP were found to be the
hallmark of pulmonary hypertension, but only 33% of patients
with high pulmonary vascular resistances had ECG signs of
CCP.4 In the same study, 7-year survival was inversely
related to pulmonary vascular resistances.4 In the
Nocturnal Oxygen Therapy Trial (NOTT), a decrease in pulmonary
hypertension after 6 months of oxygen therapy was associated with
improved survival.5 The important prognostic role of
pulmonary hypertension was further confirmed in COPD patients
on long-term oxygen therapy.6 7 Recently, we found that
ECG signs of CCP were the second strongest predictor of death in COPD
patients discharged after an acute exacerbation of their respiratory
failure.8 The aims of the present study were to clarify the prognostic role of individual ECG signs of CCP and to verify whether coexisting CCP signs have additive effects on the prognosis of COPD patients as well as whether hypoxemia and hypercapnia, which are the main determinants of pulmonary hypertension,9 may be independent predictors of death in a multivariate model including ECG signs of CCP.
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Methods |
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Study Population and Design
We studied the relationships between ECG signs of CCP and mortality in 263 patients affected by COPD (217 men; mean age, 67±9 years) hospitalized in the years 1980 to 1990 in the Pneumology Unit of the Catholic University in Rome because of an acute exacerbation of their disease. The study design has been reported in detail elsewhere.8 The diagnosis of COPD was made according to the standards provided by the American Thoracic Society,10 and the acute exacerbation was defined as an increase in dyspnea and a reduction of physical function severe enough to require hospitalization. All patients were admitted through the Emergency Department, and the admission procedures were reevaluated by 2 of us (L.F. and R.P.). Once in stabilized condition according to standardized criteria,11 patients underwent a multidimensional assessment exploring nutritional status, comorbidity, respiratory function indices, arterial blood gases measured both with and without oxygen supplementation, and ECG signs of CCP.8 Continuous oxygen therapy was performed with a Venturi mask (Baxter) at a concentration ranging from 24% to 40%, according to individual needs. All patients were followed up every 6 months by telephone calls from the date of discharge up to June 30, 1994. If neither the patient nor his/her relatives could be contacted, the municipal register office was consulted. In the event of death, the death certificate was obtained.
The following ECG signs reflecting CCP were collected: (1) a P-wave axis of +90° or more, a finding consistent with right atrial overload (RAO) and associated with lung overinflation12 ; (2) an S1S2S3 pattern, a relatively uncommon finding not highly specific for COPD13 that reflects an anomalous wave front rightward and superiorly oriented and opposed to the electrical forces of the ventricular free wall14 ; (3) an S1Q3 pattern, a well-known ECG sign associated with acute cor pulmonale15 but occasionally seen in RBBB CCP13 ; (4) right bundle-branch block, significantly associated with COPD16 but also present as a function of age in the healthy population17 ; (5) right ventricular hypertrophy (RVH), as defined by 1 of the following patterns: type A, characterized by a dominant R wave in V1-V2 and by an rS pattern in V5-V618 ; type B, characterized by an Rs pattern in V1 and by a R amplitude not at all or only slightly decreasing from V1 to V618 ; and type C, characterized by small R waves and deep S waves persistent throughout the precordial leads18 ; and (6) low-voltage QRS, a finding frequently associated with CCP from COPD but not with CCP from other pulmonary diseases.13
The diagnosis of coronary artery disease was made if ECG findings met the Minnesota criteria for previous acute myocardial infarction or for myocardial ischemia.19 To limit the confounding effect of RVH, criteria for myocardial ischemia were considered to lack validity if they coexisted with a pattern of RVH in precordial leads.
The ECGs were read by 2 independent observers unaware of the remaining clinical and laboratory information. In the event of disagreement, a third assessor was consulted, and his opinion prevailed.
The original design of the study aimed at assessing the prognostic implications of echocardiographic signs of pulmonary hypertension as well. However, a good-quality echocardiogram was obtained in only 61% of the patients. Furthermore, over an 11-year period, 4 operators performed the echocardiograms, and no measure of interrater reliability of measurements was available. Accordingly, we excluded echocardiograms from the analysis. We judged that even repeating the analysis on patients having a good-quality echocardiogram would have been misleading because of an important selection bias; indeed, the best echocardiograms were obtained in patients having a relatively shorter history of respiratory disease and a predominantly bronchitic rather than emphysematous type of COPD.
Data Analysis
The statistical analysis was performed by use of BMDP
Statistical Software. Interobserver reproducibility of diagnoses of
each ECG sign of CCP was assessed by the
K-test.20 Patients were grouped
according to whether they had no ECG signs (group 1) or 1 ECG signs
(group 2) of CCP. The Kaplan-Meier method was used to describe the
survival curves of the 2 groups. The differences between curves were
evaluated by the Mantel-Cox and Breslow tests, which explore mainly the
early and the late phases of survival curves,
respectively.21
The significance of the association between each ECG sign of CCP and
survival was assessed by the Cox regression analysis, adjusted
for age, sex, severity of the episode of exacerbation, and
comorbidity.8 Then, the prognostic importance of
coexisting ECG signs was evaluated by splitting group 2 into 3
subgroups, as follows: subgroup 2a, 72 patients without
S1S2S3
pattern and RAO but with 1 of the other ECG signs; subgroup 2b, 77
patients having either
S1S2S3
pattern or RAO; and subgroup 2c, 14 patients having both
S1S2S3
pattern and RAO. The survival curves of these subgroups and of group 1
were compared by the Mantel-Cox and Breslow tests.
An alternative partitioning of groups 1 and 2 into subgroups 1n, 1y, 2n, and 2y was also made according to whether the individual patients had (y, yes) or did not have (n, no) an alveolar-arterial oxygen gradient (PAO2-PaO2) measured during oxygen therapy >48 mm Hg, which corresponded to the 75th percentile of PAO2-PaO2 distribution. Survival curves of these subgroups were then compared. This procedure was made to test the prognostic relevance of the interaction between ECG signs of CCP and PAO2-PaO2, the latter being the only prognostically significant index derived from the arterial gas analysis.
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Results |
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We found a very high interobserver reproducibility in detecting the whole set of ECG signs of CCP with K-values always >0.80.
The survival curves of patients without any ECG signs of CCP (group 1)
and 1 ECG signs of CCP (group 2) are plotted in Figure 1
. The median survivals were 3.45 years
for group 1 and 2.58 years for group 2. The difference between the
survival curves was significant by both the Mantel-Cox test (9.58,
P=0.002) and the Breslow test (5.52, P=0.019). As
reported in Tables 1 and 2, many variables possibly associated
with the length of survival were significantly different between the 2
groups of patients. Group 2 subjects were younger and had a lower
prevalence of systemic hypertension; however, they had a longer length
of hospital stay, a higher prevalence of a coma status associated with
the respiratory exacerbation, a greater need for mechanical ventilation
during the hospital stay, a lower oxygen arterial tension
(PaO2), and a higher carbon
dioxide arterial tension
(PaCO2). In addition,
FEV1 was lower in group 2 patients, with a
P value close to statistical significance. Hypoxemia could
not be normalized in 35% of patients by oxygen supplementation because
of the frequently very severe impairment in pulmonary gas
exchanges, as reflected by the high values of
PAO2-PaO2.
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Table 3 summarizes the results of the Cox
regression analysis: 2 of the 6 ECG signs of CCP, ie,
S1S2S3
pattern and RAO, were significant independent predictors of mortality.
A
PAO2-PaO2
value >48 mm Hg measured during oxygen therapy was a strong
negative predictor of survival. On the contrary, none of the remaining
arterial gas data with or without oxygen supplementation,
tested separately to avoid collinearity and interaction between
variables, had an independent prognostic significance.
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In Figures 2 and 3, we plotted the survival curves of
groups 1, 2a, 2b, and 2c and of subgroups 1y, 1n, 2y, and 2n,
respectively. The median survivals of these groups and the results of
the Mantel-Cox and Breslow tests are reported in Table 4. Subgroup 2y, including patients with
at least 1 ECG sign of CCP and
PAO2-PaO2
>48 mm Hg during oxygen therapy, had the shortest median
survival (0.78 years). A very short survival was also observed in
subgroup 2c (1.33 years), which was characterized by a coexisting
S1S2S3
pattern and RAO.
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Three-year and 5-year survivals of patients are shown in Table 5. Both classifications adopted could
discriminate groups with very different prognoses. However, the
classification based on both ECG signs of CCP and
PAO2-PaO2
achieved a stronger discrimination, as reflected by the 8-fold
difference between 5-year survival of subgroups 1n (48%) and 2y (6%),
whereas group 1 and subgroup 2c had 5-year survivals of 39% and 7%,
respectively.
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Discussion |
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The present study demonstrates that 2 of the 6 collected ECG signs of CCP were significantly associated with a shorter survival in COPD patients and that a PAO2-PaO2 >48 mm Hg during oxygen therapy further worsened the prognosis. Among CCP signs, S1S2S3 pattern was the strongest predictor of death and preceded RAO. S1S2S3 has been found to be associated with acute pulmonary thromboembolism and has been reported to be among suggestive but not specific criteria of CCP.13 15 Most of our patients with S1S2S3 pattern had radiological evidence of severe lung hyperinflation. However, residual volume and total lung capacity were measured only in a minority of them, which prevented us from testing the association between S1S2S3 and lung hyperinflation.
The presence of both
S1S2S3
pattern and RAO was a strong predictor of mortality, but even patients
with only 1 of these signs and/or any other ECG sign of CCP survived
for shorter periods than patients without ECG evidence of CCP. The
analysis of survival curves shows that the impact of CCP on
survival became more evident 
1 year after discharge from the
hospital. Indeed, all our COPD patients had a very high risk of death
in the early period after the discharge whether ECG signs of CCP were
present or not. The progressively declining fraction of surviving
patients and the effect of age per se and of comorbidity on survival
are likely to decrease the strength of the association between CCP and
survival in the last phases of the study. Our findings agree with the
results of a large multicenter trial assessing survival of hypercapnic
COPD patients discharged from an acute-care hospital after an acute
exacerbation: 33% of them died within 6 months, and CCP was an
independent predictor of mortality.22 However, CCP was
diagnosed according to 6 alternative criteria, only 1 of which took ECG
findings into account.22 Indeed, our data focus on ECG
signs of CCP and provide a standardized diagnosis for each of them.
Collaterally, in our study, ECG signs of CCP were also strong positive correlates of the length of hospital stay and of the use of mechanical ventilation. This finding should be interpreted with some caution, but if confirmed by prospective studies taking into account ECG features on admission, it would allow us to identify COPD patients requiring a heavier burden of care.
A high PAO2-PaO2 value measured during oxygen therapy was the only index derived from the arterial gas analysis that was likely to improve the prognostic model on the basis of the ECG signs of CCP. This might be consistent with ECG signs of CCP reflecting pulmonary hypertension more closely than hypoxemia and hypercapnia or providing some additional information on the disease severity, eg, by reflecting the adaptation of the right heart to pulmonary hypertension. Indeed, in advanced COPD, structural changes in pulmonary vasculature, lung hyperinflation, and possibly thrombosis in the pulmonary arterial tree contribute to causing pulmonary hypertension, making pulmonary vascular resistances less dependent on hypoxemia and hypercapnia.23 Furthermore, whereas PaO2 and PaCO2 are differently affected by the relative proportions of high and low ventilation/perfusion units across the lungs, PAO2-PaO2 can be considered a cumulative index of efficiency of pulmonary gas exchanges.24 This might provide a clue to understanding the prognostic role of PAO2-PaO2. The relationship between CCP and respiratory function data deserves some additional comment: in the last stages of COPD, the range of spirometric values is very narrow, which limits the possibility of further decline paralleling the worsening of the gas exchange function.2 25 This probably explains both the lack of differences in spirometric values between patients with and without ECG signs of CCP and the lack of prognostic implications of the respiratory function data. Moreover, oxygen supplementation frequently cannot completely correct hypoxemia and hypercapnia.26 However, increasing the inspired fraction of oxygen results in higher PAO2-PaO2 values according to the alveolar gas equation.27 Given that the inspired fraction of oxygen ranged between 24% and 40%, the ensuing increased dispersion of PAO2-PaO2 values could have contributed to strengthening the prognostic role of PAO2-PaO2 measured during oxygen supplementation.
None of the methods for a noninvasive diagnosis of pulmonary hypertension can be considered fully satisfactory. Indeed, radiological measurements achieve poor sensitivity and specificity, whereas catheter-measured and echo Doppler–assessed pulmonary artery pressures are significantly correlated.28 29 However, a good-quality echocardiogram cannot be obtained in a large fraction of COPD patients, mainly because a Doppler-detected tricuspid regurgitation jet is lacking.30 This and the high standard error of the estimated pressure limit the usefulness of echocardiographic measurements in the diagnosis of pulmonary hypertension and prevented us from testing their prognostic implications. ECG compares favorably with radiological methods in diagnosing pulmonary hypertension. Furthermore, ECG achieves better specificity but lower sensitivity than the echocardiogram and is easily measurable in every CCP patient.28 Thus, despite its low sensitivity, ECG seems worthy of being used in the assessment of CCP complicating COPD. The prognostic importance of ECG signs of CCP in our study further supports this conclusion.
Limitations of this study are the following: first, lack of right heart
catheterization in most of our patients prevented us
from assessing the relationship between ECG signs of CCP and
pulmonary hypertension; second, 2 ECG signs of CCP coexisted
in a large fraction of patients, which is expected to weaken the
prognostic meaning of individual ECG signs; and third, the diagnosis of
coronary artery disease based on ECG criteria might be
unreliable in some CCP patients.31 Indeed, left
ventricular systolic dysfunction is relatively
uncommon in COPD, whereas left ventricular
diastolic dysfunction has been reported to occur in a
variable proportion of COPD patients and might to some extent
reflect the effects of hypoxemia or silent myocardial ischemia
as well as that of greater age itself on left ventricular
relaxation.11 The lack of a stress test assessing
coronary perfusion prevented us from making or excluding a
diagnosis of coronary artery disease with a high degree of
reliability.
Despite these limitations, the present study shows that ECG signs of CCP qualify as a simple and inexpensive tool for targeting COPD patients at risk of shorter survival and that a severely impaired gas exchange function has additional negative prognostic implications. Coexisting S1S2S3 pattern and RAO is a marker of a very high risk of death in the short term. Future studies should verify to what extent individual ECG signs of CCP reflect pulmonary hypertension. Collaterally, our findings confirm that hypoxemia with or without hypercapnia characterizes a consistent proportion of COPD patients despite continuous oxygen therapy. Any effort should be made to optimize arterial blood gases, whose derangement is the main determinant of increased pulmonary vascular resistances. Thus, properly defined programs aimed at improving oxygen delivery, mainly during physical exercise and sleep, and at realizing a comprehensive management of these patients could reverse the progression of pulmonary hypertension, although pulmonary artery pressure rarely normalizes.32 Finally, the present findings show that even in an era of rapidly developing and highly sophisticated cardiological technology, elementary diagnostic techniques maintain intrinsic validity provided that their meaning is carefully analyzed.
Received September 25, 1998; revision received December 1, 1998; accepted December 17, 1998.
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