Respiratory Muscle Dysfunction in Congestive Heart Failure
Clinical Correlation and Prognostic Significance
Background—In congestive heart failure (CHF), the prognostic significance of impaired respiratory muscle strength has not been established.
Methods and Results—Maximal inspiratory pressure (Pimax) was prospectively determined in 244 consecutive patients (207 men) with CHF (ischemic, n=75; idiopathic dilated cardiomyopathy, n=169; age, 54±11 years; left ventricular ejection fraction [LVEF], 22±10%). Pimax was lower in the 244 patients with CHF than in 25 control subjects (7.6±3.3 versus 10.5±3.7 kPa; P=0.001). The 57 patients (23%) who died during follow-up (23±16 months; range, 1 to 48 months) had an even more reduced Pimax (6.3±3.2 versus 8.1±3.2 kPa in survivors; P=0.001). Kaplan-Meier survival curves differentiated between patients subdivided according to quartiles for Pimax (P=0.014). Pimax was a strong risk predictor in both univariate (P=0.001) and multivariate Cox proportional hazard analyses (P=0.03); multivariate analyses also included NYHA functional class, LVEF, peak oxygen consumption (peak V̇o2), and norepinephrine plasma concentration. The areas under the receiver-operating characteristic curves for prediction of 1-year survival were comparable for Pimax and peak V̇o2 (area under the curve [AUC], 0.68 versus 0.73; P=0.28), and they improved with the triple combination of Pimax, peak V̇o2, and LVEF (AUC, 0.82; P=0.004 compared with AUC of Pimax).
Conclusions—In patients with CHF, inspiratory muscle strength is reduced and emerges as a novel, independent predictor of prognosis. Because testing for Pimax is simple in clinical practice, it might serve as an additional factor to improve risk stratification and patient selection for cardiac transplantation.
In congestive heart failure (CHF), accurate assessment of disease severity and risk stratification are crucial for the optimal selection of candidates and the timing of cardiac transplantation. Currently, judgment of prognosis is primarily based on hemodynamic parameters and the impairment of functional capacity. In particular, peak oxygen consumption during cardiopulmonary exercise testing (peak V̇o2) has been widely recommended for risk stratification.1 2 However, the existence of an optimal peak V̇o2 cut-off value for the prediction of survival in CHF remains a matter of debate.2 The continuous parameter peak V̇o2 is determined by cardiac output and by pulmonary and skeletal muscle function.3 In severe CHF, a general atrophic loss of skeletal muscle bulk in patients has been reported.4 Moreover, even in early stages of CHF, peripheral muscle function is impaired due to structural and metabolic abnormalities of skeletal musculature.5 Biopsies of respiratory muscles showed a variety of histological abnormalities in CHF,6 including fiber type I atrophy of the diaphragm in experimental CHF in rats.7 Both a generalized skeletal muscle dysfunction and a chronically increased workload may result in decreased strength and endurance of respiratory muscles in CHF.8 9 10 11 12 13 14 15 16
Thus far, respiratory muscle strength has not been evaluated as an indicator of prognosis in various degrees of CHF. Earlier data from our laboratory indicated that respiratory muscle strength might be reduced in CHF patients who have an unfavorable outcome.8 Thus, it was hypothesized that respiratory muscle function might be a predictor of survival in patients with CHF. Therefore, maximal inspiratory pressure (Pimax) was prospectively assessed in CHF patients with a wide range of exercise limitations, and the impact of Pimax for prognosis was determined during long-term follow-up. This study sought to clarify whether Pimax predicts survival independently of established predictors of prognosis (left ventricular ejection fraction [LVEF], peak V̇o2,, and norepinephrine) and whether the combination of Pimax with other noninvasive prognostic parameters improves risk stratification in patients with CHF.
A total of 244 consecutive patients (207 men, 85%) with stable CHF (NYHA functional class I, n=31 [13%]; class II, n=100 [41%]; class III, n=113 [46%]) were prospectively enrolled after they gave written, informed consent. The study was approved by the Ethical Committee for human research of the University of Heidelberg.
The cardiac diagnosis was based on left heart catheterization and coronary angiograms taken before study inclusion. LVEF at rest was <40%, as determined by radionuclide ventriculography.17 Standard medical treatment was optimized for the individual patient before inclusion into the study and included angiotensin-converting enzyme inhibitors (97% of patients), diuretics (87%), digitalis (72%), and β-blockers (34%). Patients were studied while on stable doses of their medications. Blood samples were taken to exclude conditions that could possibly affect respiratory muscle function (eg, thyroid dysfunction, electrolyte disturbance) and to determine blood gases and plasma concentrations of norepinephrine, as described elsewhere.17
Patients with valvular defects, a history of pulmonary disease, or an episode of deterioration requiring intravenous inotropic support within 4 weeks before enrollment were excluded. Patients meeting the recently described criteria for cachexia or wasting4 or with symptoms at rest (NYHA functional class IV) were excluded, because particularly poor prognosis has been well established for these CHF subgroups.
Pulmonary and Respiratory Muscle Function Testing
A technician who was unaware of other variables in the study and who was blinded to the status of the patient determined inspiratory vital capacity (IVC) and forced expiratory volume in 1 s using a pneumotachograph (Erich Jaeger, MasterLabPro 4.2). Predicted values corrected for sex, age, and height were used.18
Pimax was determined through a flanged mouthpiece in deep inspiration from functional residual capacity against a shutter with a minor air leak preventing undesirable glottis closure (Erich Jaeger, MasterLabPro 4.2).19 Maximal expiratory pressure (Pemax) was measured at total lung capacity during a maximal expiratory effort. Of 3 measurements with <5% variability, the highest pressure was used for analysis. Two minutes of rest were allowed between the 2 maneuvers when necessary. Mouth occlusion pressure (P0.1) was assessed 0.1 s after the onset of inspiration during spontaneous breathing at rest.20 Pimax and P0.1 are expressed as positive values, although they are negative pressures with respect to atmosphere. Because published reference values for Pimax, Pemax, and P0.1 vary considerably,19 20 they were determined in 25 control subjects who were not on medication and who had normal left ventricular function, as determined by echocardiography (Table 1⇓).
Cardiopulmonary Exercise Testing
Patients underwent symptom-limited exercise testing in a semisupine position on a bicycle ergometer until exhaustion, according to a modified Bruce protocol.8 17 Briefly, after 5 minutes of sample collection at rest, exercise started with 2 minutes at 0 W. Workload was increased in steps of 15 W every 2 minutes. Airflow and expiratory O2 concentrations were continuously analyzed and averaged online from 8 consecutive breaths (OxyconAlpha, Jaeger; face mask by Hans Rudolph, Wyandotte).
Patients were included and followed from March 1996 until January 2000 at regular outpatient visits or by telephone calls to the patients’ home or family physician.
The predefined end point was all-cause mortality. Aortocoronary bypass grafts and left ventricular assist devices were not inserted in the studied patients. Those patients who underwent orthotopic heart transplantation were followed until the surgical procedure. Regardless of the postoperative outcome, these patients were classified as survivors.
Statistical analysis was performed with standard software (SAS version 6.09 and Microsoft Excel version 1997). The Spearman rank correlation coefficient was used as a measure of association. To test for differences between groups, a 2-sample-Wilcoxon-test was used.
Survival curves were calculated using the Kaplan-Meier method. Cox proportional hazard linear regression analysis was used to determine the prognostic value for a given independent continuous variable on time to death. Receiver-operating characteristic curves were constructed by means of plotting true-positive rates (sensitivity) against false-positive rates (1/specificity). P<0.05 was considered significant. Values are expressed as mean±SD.
The duration of CHF before inclusion into the study was 59±62 months (range, 1 to 300 months). Compared with control subjects, Pimax was reduced by 23% in CHF, whereas Pemax (Table 1⇑) and arterial carbon dioxide pressure (PaCO2; 37±4 versus 38±3 mm Hg; P=NS) did not differ. In CHF patients, IVC and forced expiratory volume in 1 s were correlated (r=0.9; P=0.0001) and were significantly lower than in controls, indicating a mild restrictive pattern in CHF (Table 1⇑). NYHA functional class III patients had a lower Pimax (6.9±3.1 kPa) than NYHA class I (8.4±3.2 kPa; P=0.02) and II patients (8.1±3.4; P=0.01). Pimax correlated weakly with peak V̇o2 (r=0.32; P=0.005), plasma norepinephrine (r=−0.14; P=0.05), and age (r=−0.23; P=0.001); it correlated moderately with IVC (r=0.37; P=0.0001) and not at all with LVEF (r=0.01; P=NS) or PaCO2 (r=0.04; P=NS).
When subgroups with different causes of CHF (ischemic, n=75 [31%]; dilated cardiomyopathy, n=169 [69%]) were compared, no differences in age, height, weight, NYHA functional class, lung volumes, PaCO2, or plasma norepinephrine concentration were found (data not shown). Moreover, Pimax (7.7±3.4 versus 7.6±3.3 kPa; P=NS) and Pemax (9.9±3.5 versus 9.2±3.4 kPa, P=NS) did not differ between patients in either group. Compared with patients with dilated cardiomyopathy, patients with ischemic heart disease were characterized by a slightly higher NYHA functional class (2.5±0.6 versus 2.3±0.8; P<0.05) but a lower peak V̇o2 (13.2±4.3 versus 15.2±5.5 mL · min–1 · kg–1; P<0.004), despite a comparable LVEF (23±9% versus 21±10%, NS).
During follow-up (23±16 months; range, 1 to 46 months) 57 patients died (mean time to death, 16±12 months; range, 1 to 44 months), all from cardiovascular causes. The 1-, 2-, and 3-year mortality was 12%, 23%, and 30%, respectively. Thirty-eight patients underwent cardiac transplantation after 13±9 months (range, 1 to 37 months).
Nonsurvivors and survivors did not differ in age, height, weight, NYHA functional class, or PaCO2 (37±4 versus 37±4 mm Hg; P=NS). However, nonsurvivors were characterized by a reduced LVEF, a decreased exercise capacity (as reflected by a reduction in maximal workload and peak V̇o2), and increased plasma concentrations of norepinephrine (Table 2⇓). Furthermore, nonsurvivors had significantly smaller lung volumes than survivors, but no signs of airflow obstruction (Table 2⇓). Although P0.1, an index of respiratory center output, did not differ in survivors and nonsurvivors (Tables 1⇑ and 2⇓), Pimax was reduced by 22% in nonsurvivors compared with survivors (Table 2⇓).
Kaplan-Meier survival curves for patients subdivided in quartiles according to Pimax allowed accurate prognostic stratification (Figure 1⇓). A high Pimax (>9.8 kPa) indicated the best prognosis at 12, 24, and 36 months of follow-up compared with lower Pimax quartiles. Survival in this highest Pimax quartile group was 3-fold higher than in patients in the lowest Pimax quartile (<5.3 kPa; Figure 1⇓). When patients with an intermediate peak V̇o2 of 10 to 20 mL · min–1 · kg–1 were analyzed separately, a low Pimax (<5.3 kPa) indicated a 20% and 40% reduction in survival rate at 12 and 36 months, respectively, compared with a high Pimax (>9.8 kPa; Figure 2⇓).
Sensitivity and specificity of Pimax for predicting survival at 12 and 36 months was assessed for different arbitrary thresholds (Table 3⇓). Of all nonsurvivors, 64% and 59% had a Pimax ≤7 kPa (sensitivity) at 12 and 36 months follow-up, respectively. In 58% and 60% of survivors, Pimax was >7 kPa (specificity) after 12 and 36 months, respectively. Lower thresholds provided a higher sensitivity but a lower specificity and vice versa.
Univariate and Multivariate Analysis
In the univariate Cox regression analysis, Pimax, LVEF, peak V̇o2 (Table 4⇓), norepinephrine (χ2=8.92; hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.05 to 1.24; P=0.003), and NYHA functional class (χ2=4.56; HR, 1.55, 95% CI, 1.04 to 2.32; P=0.03) were all significant prognostic indicators with descending statistical significance; Pemax was not a significant prognostic indicator (χ2=0.62; HR, 0.97, 95% CI, 0.90 to 1.04; P=0.43).
Multivariate analysis using 3 variables indicated that Pimax provided independent prognostic information that was comparable to peak V̇o2 (Table 4⇑).
With 4 variables, including LVEF, peak V̇o2, NYHA class, and Pimax, only LVEF (χ2=9.04; HR, 0.95, 95% CI, 0.87 to 1.04; P=0.003), peak V̇o2 (χ2=5.23; HR, 0.92, 95% CI, 0.84 to 1.01; P=0.02), and Pimax (χ2=4.97; HR, 0.90; 95% CI, 0.82 to 0.99; P=0.03), but not NYHA class (χ2=0.18; HR, 0.91; 95% CI, 0.83 to 0.99; P=0.67), were significant independent prognostic indicators. Norepinephrine (χ2=1.84; HR, 1.07; 95% CI, 0.97 to 1.19; P=0.17) was not a significant prognostic predictor in a multivariate analysis including LVEF (χ2=7.06; HR, 0.95, 95% CI, 0.92 to 0.98; P=0.008), peak V̇o2 (χ2=4.43; HR, 0.93, 95% CI, 0.88 to 0.99; P=0.04), and Pimax (χ2=4.68; HR, 0.90; 95% CI, 0.82 to 0.99; P=0.03).
Receiver-Operating Characteristic Curves for Survival at 12 Months
Parameters identified as independent predictors by multivariate Cox regression analysis were entered into receiver-operating characteristic analysis: peak V̇o2 (area under the curve [AUC], 0.73) and Pimax (AUC, 0.68; P=0.28) were comparable. However, prediction of survival was weakly improved by combining Pimax and peak V̇o2 (AUC, 0.75). By using a triple combination of Pimax, peak V̇o2, and LVEF, risk stratification was most accurate (Figure 3⇓). Addition of plasma norepinephrine did not further improve risk prediction.
The major findings of this prospective study in 244 CHF patients are as follows. (1) Pimax, but not Pemax, decreases with NYHA functional class, and it correlates weakly with peak V̇o2 and plasma norepinephrine but not with LVEF. (2) Pimax and Pemax are not different between subgroups with ischemic and dilated cardiomyopathy. (3) During follow-up, nonsurvivors are characterized by a lower Pimax. (4) Pimax predicts prognosis independently from the established predictors peak V̇o2, LVEF, plasma norepinephrine, and NYHA functional class. (5) Pimax improves risk stratification in candidates for cardiac transplantation, especially when combined with other prognostic parameters such as peak V̇o2 and LVEF.
Respiratory Muscle Dysfunction is Related to Severity of CHF
As shown previously, the reduction in respiratory muscle strength as determined by Pimax is related to the severity of CHF.8 9 14 15 16 This is confirmed by the decline in Pimax with increasing NYHA functional class and the correlation between Pimax and peak V̇o2 in the present and previous reports.8 9 21
In the CHF patients, Pimax was related to IVC. However, a restrictive ventilatory pattern does not seem to be responsible for changes in Pimax, because the decline of Pimax with increasing severity of CHF was still observed when Pimax was corrected for IVC (data not shown).
Increased respiratory muscle strain did not play a major role in the observed reduction in Pimax in CHF, because P0.1 (an index of respiratory center output20 ) was not augmented. This finding is consistent with previous observations.8 10 When P0.1 was corrected for individual respiratory muscle strength (P0.1/Pimax), again no difference between groups was found (data not shown).
Respiratory Muscle Strength and Survival
Because Pimax is a continuous parameter, values obtained in the present cohort were divided into 4 quartiles corresponding to 4 risk strata (Figure 1⇑). For the lowest Pimax quartile of the cohort, mortality was increased 3-fold compared with patients who had CHF but preserved respiratory muscle strength (Pimax >9.8 kPa; Figure 1⇑). Approximately 50% of patients with Pimax ≤5 kPa died during follow-up, but only 15% of those with Pimax >10 kPa died (Figure 1⇑ and Table 3⇑). These data provide the first evidence that respiratory muscle strength may be a powerful indicator of prognosis in CHF. Because in CHF patients with an intermediate peak V̇o2 of 10 to 20 mL · min–1 · kg–1 risk stratification solely based on peak V̇o2 is often inaccurate,22 the use of Pimax as an additional factor for risk stratification is particularly important. Of the 244 patients in this study, 160 belonged to that group. Those belonging to the highest Pimax quartile (n=37) had a 1-year survival rate of 100%, whereas 22% of those in the lowest quartile (n=45) died within the first year. Therefore, in the majority of the patients with an intermediate peak V̇o2, Pimax allowed significantly better risk stratification than peak V̇o2 alone.
Because peak V̇o2 is dependent on patients’ motivation to endure an incremental exercise test, it frequently underestimates exercise capacity in candidates for cardiac transplantation.22 Moreover, peak V̇o2 globally assesses cardiac, respiratory, and peripheral muscle function during exercise,3 which may all contribute to exercise limitation. Therefore, selected parameters derived from exercise testing, such as ventilatory and heart rate response, have recently been suggested as better predictors of CHF mortality than peak V̇o2.23
In a different approach to improve risk stratification in CHF, a heart failure survival score (HFSS) was recently proposed. The HFSS would combine multiple, independent, noninvasive variables.24 Peak V̇o2 alone predicted freedom of an outcome event (death, urgent transplantation, or implantation of ventricular assist device within 12 months) with an AUC of 0.62, whereas the HFSS noninvasive multivariate model provided an AUC of 0.76.24 The patients analyzed by HFSS and the present cohort are comparable in size and baseline clinical parameters. In the present study, peak V̇o2 alone predicted 1-year survival with an AUC of 0.73. When Pimax was added, AUC increased to 0.75. With the combination of the significant predictors identified by multivariate Cox regression analysis (Pimax, peak V̇o2, and LVEF), the AUC increased to 0.82 (Figure 3⇑). These findings underline the fact that a multivariable model is preferable to risk stratification relying on a single parameter only. Moreover, the present data suggest including respiratory muscle function in comprehensive prognostic models as an independent predictor.
Clinical Implications and Further Investigation
The present findings are of major clinical importance because the measurement of Pimax is noninvasive and independent of the patients’ ability to walk or cycle. The determination of Pimax is easily performed during routine pulmonary function testing.19 Although Pimax depends on patients’ cooperation, repeated measurements revealed good reproducibility after 3 days19 and after 3 months.25 Although Pimax values in the present control group are comparable to data published elsewhere,19 20 substantial variation in Pimax between different laboratories, depending on equipment and technique, may occur. Thus, risk stratification using the Pimax strata observed in the present study depends on reference values of individual laboratories.
The reduction in respiratory muscle strength may reflect increased work of breathing in CHF.12 As shown previously, restrictive ventilatory pattern, ventilatory inefficiency, and increased dead space ventilation may occur in CHF and partially contribute to the overload of the respiratory musculature in CHF, although respiratory drive as assessed by P0.1 and PaCO2 at rest are not increased.8 Alternatively, the reduction in Pimax may be due to a generalized skeletal muscle disorder in CHF.4 5 9 However, the unchanged Pemax is a strong argument against this hypothesis.
It has been shown that the reduction in inspiratory muscle strength in CHF is associated with a significant decline in respiratory muscle endurance, as measured by various techniques.21 26 27 Therefore, the assessment of respiratory muscle endurance, eg, by measuring maximal voluntary ventilation, might be another valuable parameter for risk stratification in CHF. As opposed to Pimax, however, maximal voluntary ventilation is influenced by reduced static lung volumes, thus reflecting respiratory muscle capacity less accurately than Pimax.
Respiratory muscle function can be improved by selective respiratory muscle training25 or by unloading respiratory muscles with noninvasive continuous positive airway pressure ventilation during acute training and long-term disease in selected patients.28 29
In conclusion, CHF is characterized by respiratory muscle dysfunction. For the first time, respiratory muscle strength has been characterized as an independent predictor of prognosis in CHF. The easily obtainable Pimax might thus serve as a new parameter to further improve risk stratification in patients with CHF.
The authors thank Professor Neil B. Pride, FRCP, of the National Heart and Lung Institute, Hammersmith Hospital/Royal Brompton Hospital, London, Great Britain, for most valuable discussions.
- Received October 16, 2000.
- Revision received January 29, 2001.
- Accepted February 5, 2001.
- Copyright © 2001 by American Heart Association
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