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(Circulation. 2001;103:2153.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Respiratory Muscle Dysfunction in Congestive Heart Failure

Clinical Correlation and Prognostic Significance

F. Joachim Meyer, MD; Mathias M. Borst, MD; Christian Zugck, MD; Andreas Kirschke; Dieter Schellberg, PhD; Wolfgang Kübler, MD, FRCP; Markus Haass, MD

From the Department of Cardiology, Angiology, and Respiratory Medicine, Medical Center of the University Heidelberg, Heidelberg, Germany.

Correspondence to Dr med F. Joachim Meyer, Abteilung Innere Medizin III, Bergheimer Strasse 58, D-69115 Heidelberg, Germany. E-mail Joachim_Meyer{at}med.uni-heidelberg.de

	Abstract

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Background—In congestive heart failure (CHF), the prognostic significance of impaired respiratory muscle strength has not been established.

Methods and Results—Maximal inspiratory pressure (Pi_max) 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%). Pi_max 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 Pi_max (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 Pi_max (P=0.014). Pi_max 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 O₂), and norepinephrine plasma concentration. The areas under the receiver-operating characteristic curves for prediction of 1-year survival were comparable for Pi_max and peak O₂ (area under the curve [AUC], 0.68 versus 0.73; P=0.28), and they improved with the triple combination of Pi_max, peak O₂, and LVEF (AUC, 0.82; P=0.004 compared with AUC of Pi_max).

Conclusions—In patients with CHF, inspiratory muscle strength is reduced and emerges as a novel, independent predictor of prognosis. Because testing for Pi_max is simple in clinical practice, it might serve as an additional factor to improve risk stratification and patient selection for cardiac transplantation.

Key Words: heart failure • muscles • exercise • prognosis

	Introduction

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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 O₂) has been widely recommended for risk stratification.^{1 2} However, the existence of an optimal peak O₂ cut-off value for the prediction of survival in CHF remains a matter of debate.² The continuous parameter peak O₂ 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 (Pi_max) was prospectively assessed in CHF patients with a wide range of exercise limitations, and the impact of Pi_max for prognosis was determined during long-term follow-up. This study sought to clarify whether Pi_max predicts survival independently of established predictors of prognosis (left ventricular ejection fraction [LVEF], peak O_2,, and norepinephrine) and whether the combination of Pi_max with other noninvasive prognostic parameters improves risk stratification in patients with CHF.

	Methods

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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 ß-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

Pi_max 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 (Pe_max) 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 (P_0.1) was assessed 0.1 s after the onset of inspiration during spontaneous breathing at rest.²⁰ Pi_max and P_0.1 are expressed as positive values, although they are negative pressures with respect to atmosphere. Because published reference values for Pi_max, Pe_max, and P_0.1 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).

View this table: [in this window] [in a new window]   Table 1. Baseline Clinical and Functional Characteristics of Patients With CHF and Control Subjects

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).

Follow-Up
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.

Statistics
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.

	Results

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Clinical Correlation
The duration of CHF before inclusion into the study was 59±62 months (range, 1 to 300 months). Compared with control subjects, Pi_max was reduced by 23% in CHF, whereas Pe_max (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 Pi_max (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). Pi_max correlated weakly with peak O₂ (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, Pi_max (7.7±3.4 versus 7.6±3.3 kPa; P=NS) and Pe_max (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 O₂ (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).

Survival Analysis
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 O₂), 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 P_0.1, an index of respiratory center output, did not differ in survivors and nonsurvivors (Tables 1 and 2), Pi_max was reduced by 22% in nonsurvivors compared with survivors (Table 2).

View this table: [in this window] [in a new window]   Table 2. Clinical and Functional Characteristics of Patients With CHF: Survivors Versus Nonsurvivors

Kaplan-Meier survival curves for patients subdivided in quartiles according to Pi_max allowed accurate prognostic stratification (Figure 1). A high Pi_max (>9.8 kPa) indicated the best prognosis at 12, 24, and 36 months of follow-up compared with lower Pi_max quartiles. Survival in this highest Pi_max quartile group was 3-fold higher than in patients in the lowest Pi_max quartile (<5.3 kPa; Figure 1). When patients with an intermediate peak O₂ of 10 to 20 mL · min^–1 · kg^–1 were analyzed separately, a low Pi_max (<5.3 kPa) indicated a 20% and 40% reduction in survival rate at 12 and 36 months, respectively, compared with a high Pi_max (>9.8 kPa; Figure 2).

View larger version (13K): [in this window] [in a new window]   Figure 1. Kaplan-Meier survival curves of the total study population subdivided into quartiles (n=61 each) according to Pimax: quartile 1 (Q1), 5.3 kPa; quartile 2 (Q2), >5.3 to 7.5 kPa; quartile 3 (Q3), >7.5 to 9.8 kPa; and quartile 4 (Q4), >9.8 kPa. Significant differences in survival are shown (log-rank 2=11; df=3; P=0.014). There were 183, 168, and 127 individuals at risk at 12, 24, and 36 months follow-up, respectively.

View larger version (15K): [in this window] [in a new window]   Figure 2. Risk stratification among patients with an intermediate peak O2 of 10 to 20 mL · min–1 · kg–1 is significantly improved by combination with Pimax (log-rank 2=8; df=2; P=0.018).

Sensitivity and specificity of Pi_max for predicting survival at 12 and 36 months was assessed for different arbitrary thresholds (Table 3). Of all nonsurvivors, 64% and 59% had a Pi_max 7 kPa (sensitivity) at 12 and 36 months follow-up, respectively. In 58% and 60% of survivors, Pi_max was >7 kPa (specificity) after 12 and 36 months, respectively. Lower thresholds provided a higher sensitivity but a lower specificity and vice versa.

View this table: [in this window] [in a new window]   Table 3. Sensitivity and Specificity of Thresholds in Pimax for Predicting Survival at 12 and 36 Months

Univariate and Multivariate Analysis
In the univariate Cox regression analysis, Pi_max, LVEF, peak O₂ (Table 4), norepinephrine (²=8.92; hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.05 to 1.24; P=0.003), and NYHA functional class (²=4.56; HR, 1.55, 95% CI, 1.04 to 2.32; P=0.03) were all significant prognostic indicators with descending statistical significance; Pe_max was not a significant prognostic indicator (²=0.62; HR, 0.97, 95% CI, 0.90 to 1.04; P=0.43).

View this table: [in this window] [in a new window]   Table 4. Univariate and Multivariate Cox Regression Analysis of Study Variables and Survival

Multivariate analysis using 3 variables indicated that Pi_max provided independent prognostic information that was comparable to peak O₂ (Table 4).

With 4 variables, including LVEF, peak O₂, NYHA class, and Pi_max, only LVEF (²=9.04; HR, 0.95, 95% CI, 0.87 to 1.04; P=0.003), peak O₂ (²=5.23; HR, 0.92, 95% CI, 0.84 to 1.01; P=0.02), and Pi_max (²=4.97; HR, 0.90; 95% CI, 0.82 to 0.99; P=0.03), but not NYHA class (²=0.18; HR, 0.91; 95% CI, 0.83 to 0.99; P=0.67), were significant independent prognostic indicators. Norepinephrine (²=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 (²=7.06; HR, 0.95, 95% CI, 0.92 to 0.98; P=0.008), peak O₂ (²=4.43; HR, 0.93, 95% CI, 0.88 to 0.99; P=0.04), and Pi_max (²=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 O₂ (area under the curve [AUC], 0.73) and Pi_max (AUC, 0.68; P=0.28) were comparable. However, prediction of survival was weakly improved by combining Pi_max and peak O₂ (AUC, 0.75). By using a triple combination of Pi_max, peak O₂, and LVEF, risk stratification was most accurate (Figure 3). Addition of plasma norepinephrine did not further improve risk prediction.

View larger version (19K): [in this window] [in a new window]   Figure 3. Receiver-operating characteristic curves for Pimax for prediction of survival at 12 months (AUC, 0.68). The triple combination of Pimax, peak O2, and LVEF yields significantly increased prognostic information (AUC, 0.82).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The major findings of this prospective study in 244 CHF patients are as follows. (1) Pi_max, but not Pe_max, decreases with NYHA functional class, and it correlates weakly with peak O₂ and plasma norepinephrine but not with LVEF. (2) Pi_max and Pe_max are not different between subgroups with ischemic and dilated cardiomyopathy. (3) During follow-up, nonsurvivors are characterized by a lower Pi_max. (4) Pi_max predicts prognosis independently from the established predictors peak O₂, LVEF, plasma norepinephrine, and NYHA functional class. (5) Pi_max improves risk stratification in candidates for cardiac transplantation, especially when combined with other prognostic parameters such as peak O₂ and LVEF.

Respiratory Muscle Dysfunction is Related to Severity of CHF
As shown previously, the reduction in respiratory muscle strength as determined by Pi_max is related to the severity of CHF.^{8 9 14 15 16} This is confirmed by the decline in Pi_max with increasing NYHA functional class and the correlation between Pi_max and peak O₂ in the present and previous reports.^{8 9 21}

In the CHF patients, Pi_max was related to IVC. However, a restrictive ventilatory pattern does not seem to be responsible for changes in Pi_max, because the decline of Pi_max with increasing severity of CHF was still observed when Pi_max was corrected for IVC (data not shown).

Increased respiratory muscle strain did not play a major role in the observed reduction in Pi_max in CHF, because P_0.1 (an index of respiratory center output²⁰ ) was not augmented. This finding is consistent with previous observations.^{8 10} When P_0.1 was corrected for individual respiratory muscle strength (P_0.1/Pi_max), again no difference between groups was found (data not shown).

Respiratory Muscle Strength and Survival
Because Pi_max 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 Pi_max quartile of the cohort, mortality was increased 3-fold compared with patients who had CHF but preserved respiratory muscle strength (Pi_max >9.8 kPa; Figure 1). Approximately 50% of patients with Pi_max 5 kPa died during follow-up, but only 15% of those with Pi_max >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 O₂ of 10 to 20 mL · min^–1 · kg^–1 risk stratification solely based on peak O₂ is often inaccurate,²² the use of Pi_max 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 Pi_max 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 O₂, Pi_max allowed significantly better risk stratification than peak O₂ alone.

Because peak O₂ is dependent on patients’ motivation to endure an incremental exercise test, it frequently underestimates exercise capacity in candidates for cardiac transplantation.²² Moreover, peak O₂ 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 O₂.²³

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 O₂ 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 O₂ alone predicted 1-year survival with an AUC of 0.73. When Pi_max was added, AUC increased to 0.75. With the combination of the significant predictors identified by multivariate Cox regression analysis (Pi_max, peak O₂, 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 Pi_max is noninvasive and independent of the patients’ ability to walk or cycle. The determination of Pi_max is easily performed during routine pulmonary function testing.¹⁹ Although Pi_max depends on patients’ cooperation, repeated measurements revealed good reproducibility after 3 days¹⁹ and after 3 months.²⁵ Although Pi_max values in the present control group are comparable to data published elsewhere,^{19 20} substantial variation in Pi_max between different laboratories, depending on equipment and technique, may occur. Thus, risk stratification using the Pi_max 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 P_0.1 and PaCO₂ at rest are not increased.⁸ Alternatively, the reduction in Pi_max may be due to a generalized skeletal muscle disorder in CHF.^{4 5 9} However, the unchanged Pe_max 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 Pi_max, however, maximal voluntary ventilation is influenced by reduced static lung volumes, thus reflecting respiratory muscle capacity less accurately than Pi_max.

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 Pi_max might thus serve as a new parameter to further improve risk stratification in patients with CHF.

	Acknowledgments

 
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.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Constanzo M, Augustine S, Bourge R, et al. Selection and treatment of candidates for heart transplantation. Circulation. 1995;92:3593–3612.[Abstract/Free Full Text]
   
2. Myers JL, Gullestad L, Vagelos R, et al. Clinical, hemodynamic, and cardiopulmonary exercise test determinants of survival in patients referred for evaluation of heart failure. Ann Intern Med. 1998;129:286–293.[Abstract/Free Full Text]
   
3. Jones NL. Clinical Exercise Testing. 4th ed. Philadelphia: Saunders; 1997.
   
4. Anker SD, Ponikowski P, Varney S, et al. Wasting as independent risk factor for mortality in chronic heart failure. Lancet. 1997;349:1050–1053.[Medline] [Order article via Infotrieve]
   
5. Coats AJS. The "muscle hypothesis" of chronic heart failure. J Mol Cell Cardiol. 1996;28:2255–2262.[Medline] [Order article via Infotrieve]
   
6. Lindsay DC, Lovegrove CA, Dunn MJ, et al. Histological abnormalities of muscle from limb, thorax and diaphragm in chronic heart failure. Eur Heart J. 1996;17:1239–1250.[Abstract/Free Full Text]
   
7. Stassijns GA, Gayan-Ramirez G, DeLeyn P, et al. Effects of dilated cardiomyopathy on the diaphragm in the Syrian hamster. Eur Respir J. 1999;13:391–397.[Abstract]
   
8. Meyer FJ, Zugck C, Haass M, et al. Inefficient ventilation and reduced respiratory muscle capacity in congestive heart failure. Basic Res Cardiol. 2000;95:333–342.[Medline] [Order article via Infotrieve]
   
9. Opasich C, Ambrosino N, Felicetti G, et al. Heart failure-related myopathy. Eur Heart J. 1999;20:1191–1200.[Abstract/Free Full Text]
   
10. Witt C, Borges AC, Haake H, et al. Respiratory muscle weakness and normal ventilatory drive in dilative cardiomyopathy. Eur Heart J. 1997;18:1322–1328.[Abstract/Free Full Text]
    
11. McParland C, Krishan B, Wang Y, et al. Inspiratory muscle weakness and dyspnoea in chronic heart failure. Am Rev Respir Dis. 1992;146:467–472.[Medline] [Order article via Infotrieve]
    
12. Mancini DM, Henson D, LaManca J, et al. Respiratory muscle function and dyspnea in patients with chronic congestive heart failure. Circulation. 1992;86:909–918.[Abstract/Free Full Text]
    
13. Ambrosino N, Opasich C, Crotti P, et al. Breathing pattern, ventilatory drive and respiratory muscle strength in patients with chronic heart failure. Eur Respir J. 1994;7:17–22.[Abstract]
    
14. Chua TP, Anker SD, Harrington D, et al. Inspiratory muscle strength is a determinant of maximum oxygen consumption in chronic heart failure. Br Heart J. 1995;74:381–385.[Abstract/Free Full Text]
    
15. Nishimura Y, Maeda H, Tanaka K, et al. Respiratory muscle strength and hemodynamics in chronic heart failure. Chest. 1994;105:355–359.[Abstract/Free Full Text]
    
16. Hammond MD, Bauer KA, Sharp JT, et al. Respiratory muscle function in congestive heart failure. Chest. 1990;98:1091–1094.[Abstract/Free Full Text]
    
17. Zugck C, Krüger C, Dürr S, et al. Is the six minutes walk test a reliable substitute for peak oxygen uptake in patients with dilated cardiomyopathy? Eur Heart J. 2000;21:540–549.[Abstract/Free Full Text]
    
18. Quanjer PH, Tammeling GJ, Cotes JE, et al. Lung volumes and forced ventilatory flows: European Community for Steel and Coal. Eur Respir J. 1993;6:5–10.[Medline] [Order article via Infotrieve]
    
19. Black LF, Hyatt RE. Maximal respiratory pressures: normal values and relationship to age and sex. Am Rev Respir Dis. 1969;99:696–702.[Medline] [Order article via Infotrieve]
    
20. Milic-Emili J, Whitelaw WA, Derenne JP. New tests to assess lung function: occlusion pressure-a simple measure of the respiratory center’s output. N Engl J Med. 1975;293:1029–1030.[Medline] [Order article via Infotrieve]
    
21. Nanas SN, Nanas J, Kassiotis Ch et al. Respiratory muscles performance is related to oxygen kinetics during maximal exercise and early recovery in patients with congestive heart failure. Circulation. 1999;100:503–508.[Abstract/Free Full Text]
    
22. Ramos-Barbon D, Fitchett D, Gibbons WJ, et al. Maximal exercise testing for the selection of heart transplantation candidates: limitation of peak oxygen consumption. Chest. 1999;115:410–417.[Abstract/Free Full Text]
    
23. Robbins MR, Francis G, Pashkow FJ, et al. Ventilatory and heart rate response to exercise. Circulation. 1999;100:2411–2417.[Abstract/Free Full Text]
    
24. Aaronson K, Schwartz JS, Chen T, et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation. 1997;95:2660–2667.[Abstract/Free Full Text]
    
25. Mancini DM, Henson D, La MJ, et al. Benefit of selective respiratory muscle training on exercise capacity in patients with chronic congestive heart failure. Circulation. 1995;91:320–329.[Abstract/Free Full Text]
    
26. Mancini DM, Henson D, LaManca J, et al. Evidence of reduced respiratory muscle endurance in patients with heart failure. J Am Coll Cardiol. 1994;24:972–981.[Abstract]
    
27. Walsh JT, Andrews R, Johnson P, et al. Inspiratory muscle endurance in patients with chronic heart failure. Heart. 1996;76:332–336.[Abstract/Free Full Text]
    
28. Granton JT, Naughton MT, Benard DC, et al. CPAP improves inspiratory muscle strength in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med. 1996;153:277–282.[Abstract]
    
29. Naughton MT, Rahman A, Hara K, et al. Effect of continuous positive airway pressure on intrathoracic and left ventricular transmural pressures in patients with congestive heart failure. Circulation. 1995;91:1725–1731.[Abstract/Free Full Text]
    

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				R. Torchio, C. Gulotta, P. Greco-Lucchina, A. Perboni, L. Avonto, H. Ghezzo, and J. Milic-Emili Orthopnea and tidal expiratory flow limitation in chronic heart failure. Chest, August 1, 2006; 130(2): 472 - 479. [Abstract] [Full Text] [PDF]

				R. Torchio, C. Gulotta, P. Greco-Lucchina, A. Perboni, L. Montagna, M. Guglielmo, and J. Milic-Emili Closing Capacity and Gas Exchange in Chronic Heart Failure Chest, May 1, 2006; 129(5): 1330 - 1336. [Abstract] [Full Text] [PDF]

				P. Dall'Ago, G. R.S. Chiappa, H. Guths, R. Stein, and J. P. Ribeiro Inspiratory Muscle Training in Patients With Heart Failure and Inspiratory Muscle Weakness: A Randomized Trial J. Am. Coll. Cardiol., February 21, 2006; 47(4): 757 - 763. [Abstract] [Full Text] [PDF]

				R. Naeije Breathing more with weaker respiratory muscles in pulmonary arterial hypertension Eur. Respir. J., January 1, 2005; 25(1): 6 - 8. [Full Text] [PDF]

				F. J. Meyer, D. Lossnitzer, A. V. Kristen, A. M. Schoene, W. Kubler, H. A. Katus, and M. M. Borst Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension Eur. Respir. J., January 1, 2005; 25(1): 125 - 130. [Abstract] [Full Text] [PDF]

				J van der Palen, T D Rea, T A Manolio, T Lumley, A B Newman, R P Tracy, P L Enright, and B M Psaty Respiratory muscle strength and the risk of incident cardiovascular events Thorax, December 1, 2004; 59(12): 1063 - 1067. [Abstract] [Full Text] [PDF]

				F J Meyer, R Ewert, M M Hoeper, H Olschewski, J Behr, J Winkler, H Wilkens, C Breuer, W Kubler, and M M Borst Peripheral airway obstruction in primary pulmonary hypertension Thorax, June 1, 2002; 57(6): 473 - 476. [Abstract] [Full Text] [PDF]

				C. Zugck, A. Haunstetter, C. Kruger, R. Kell, D. Schellberg, W. Kubler, and M. Haass Impact of beta-blocker treatment on the prognostic value of currently used risk predictors in congestive heart failure J. Am. Coll. Cardiol., May 15, 2002; 39(10): 1615 - 1622. [Abstract] [Full Text] [PDF]

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