Skeletal muscle dysfunction in patients with idiopathic pulmonary arterial hypertension

Open ArchivePublished:August 07, 2007DOI:https://doi.org/10.1016/j.rmed.2007.06.014

      Summary

      Dyspnea and exercise limitation are common in patients with idiopathic pulmonary arterial hypertension (IPAH). Recently, a reduction in inspiratory and expiratory muscle strength has been observed in IPAH. However, it has not been investigated whether this respiratory muscle weakness might be part of a general muscle dysfunction as observed in congestive left heart failure.
      Therefore, in 24 consecutive IPAH patients (16 female; age 58.7±16.2; WHO class II–III; systolic pulmonary artery pressure during echocardiography at rest (sPAP) 65.0±20.6mmHg, and 6-min-walk test (6-MWT) 473.6±127.7m), the maximal isometric forearm muscle strength (best of three hand grip manoeuvres), maximal inspiratory and expiratory mouth occlusion pressures (Pimax, Pemax) were prospectively evaluated.
      The isometric forearm muscle strength was significantly lower in IPAH patients (281.7±102.6N) than in matched 24 healthy controls (397.1±116.8N; p=0.03). In IPAH patients, there was a correlation between maximal isometric forearm muscle strength and 6-MWT (r=0.67; p=0.0007) and both, Pimax (r=0.69; p=0.0003) and Pemax (r=0.63; p=0.01), respectively. There was no correlation between forearm muscle strength and sPAP (r=0.30; p=0.16). The present skeletal muscle dysfunction is a novel finding in patients with IPAH. The correlation with respiratory muscle dysfunction and severity of disease might indicate a generalised “myopathy” in IPAH.

      Keywords

      Introduction

      Idiopathic pulmonary arterial hypertension (IPAH) is defined as a pulmonary vasculopathy of unknown aetiology.
      • Simmeneau G.
      • Galie N.
      • Rubin L.J.
      • et al.
      Clinical classification of pulmonary hypertension.
      It is characterised by dyspnoea and exercise limitation eventually resulting in progressive right ventricular failure.
      • Rubin L.J.
      Primary pulmonary hypertension.
      • Sun X.G.
      • Hansen E.J.
      • Oudiz R.
      • Wassermann K.
      Exercise pathophysiology in patients with primary pulmonary hypertension.
      Recently, weakness of the in- and expiratory musculature has been described in patients with IPAH.
      • Meyer F.J.
      • Lossnitzer D.
      • Kristen A.V.
      • et al.
      Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension.
      In the accompanying editorial, Naeije called attention to pulmonary hypertension as a “systemic disease”, where a general myopathy might occur, in analogy to observations in congestive left heart failure heart.
      • Naeije R.
      Breathing more with weaker respiratory muscles in pulmonary arterial hypertension.
      • Meyer F.J.
      • Borst M.M.
      • Zugck C.
      • et al.
      Respiratory muscle dysfunction in congestive heart failure: clinical correlation and prognostic significance.
      • Meyer F.J.
      • Zugck C.
      • Haas M.
      • et al.
      Inefficient ventilation and reduced respiratory muscle capacity in congestive heart failure.
      • Clark A.L.
      • Poole-Wilson P.A.
      • Coats A.J.S.
      Exercise limitation in chronic heart failure: central role of the periphery.
      • Hambrecht R.
      • Niebauer J.
      • Fiehn E.
      • et al.
      Physical training in patients with stable chronic heart failure: effects on cardiorespiratory fitness and ultrastructural anbnormalities of leg muscles.
      • Drexler H.
      • Riede U.
      • Munzel T.
      • Konig H.
      • Funke E.
      • Hust H.
      Alterations of skeletal muscle in chronic heart failure.
      • Anker S.D.
      • Ponikowski P.
      • Varney S.
      • et al.
      Wasting as independent risk factor for mortality in chronic heart failure.
      However, the function of the peripheral skeletal musculature has not been investigated in patients with IPAH so far.
      Therefore, the present study evaluates the strength of the forearm musculature, in relation to respiratory muscle function and to severity of disease in patients with IPAH.

      Material and methods

       Patients

      This prospective study included 24 patients (Table 1) with the diagnosis of IPAH made according to present guidelines,
      • Galie N.
      • Torbicki A.
      • Barst R.
      • et al.
      Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The task force on diagnosis and treatment of pulmonary arterial hypertension of the European society of cardiology.
      including right heart catheterization: the systolic pulmonary artery pressure (sPAP) was 78.1±23.7mmHg, the mean pulmonary artery pressure was 47.9±13.5mmHg; the pulmonary vascular resistance was 867.6±476.1dynscm−5, and the cardiac output was 4.2±1.3Lmin−1. Eight patients were in WHO functional class II, 16 patients in class III.
      Table 1Characteristics of patients with idiopathic pulmonary hypertension and in controls.
      IPAH n=24Controls n=24p-Value
      Male88ns
      Female1616ns
      Age (years)58.7±16.257.6±14.2ns
      Height (cm)165.9±8.3171.2±16.0ns
      Body mass index (kgm−2)27.7±6.524.5±2.6ns
      Fore arm strength (N)281.7±102.6397.1±116.80.03
      Systolic PAP echo (mmHg)65.0±20.6
      PAP=pulmonary artery pressure; ns=not significant.
      Patients included in the study showed no clinical or radiological signs of cardiopulmonary decompensation. By definition, concomitant left heart disease or other pulmonary disease was excluded.
      Approval from the local ethics committee was obtained. Patients gave written informed consent.

       Forearm muscle function testing

      The maximal isometric forearm muscle strength of the dominant arm was assessed in standing position by a hand grip dynamometer. The hand grip dynamometer was held along the axis of the arm in a comfortable position. Maximum forearm muscle strength was assessed according to the assessment of the one-repetition-maximum.
      • Kraemer W.J.
      • Gordon S.E.
      • Fleck S.J.
      • et al.
      Endogenous anabolic hormonal and growth factor responses to heavy resistance exercise in males and females.
      Briefly, after familiarisation with the measurement device and procedure, subjects performed at least three attempts of maximal voluntary “hand grip” contraction against the dynamometer separated by a resting period of at least 3min. If muscle strength was still increasing after the third attempt, they had additional attempts until muscle strength decreased. The maximum number in the present study was five attempts. The best of all hand grip manoeuvres was analysed as maximal forearm muscle strength in Newton (N=1kgms−2).
      Since reference values for forearm muscle strength are lacking, 24 matched controls were included in the study. Age, height, weight, body mass index, gender proportion did not differ between the patient group and the controls.

       Respiratory muscle function testing

      Mouth pressures were determined as described previously
      • Meyer F.J.
      • Lossnitzer D.
      • Kristen A.V.
      • et al.
      Respiratory muscle dysfunction in idiopathic pulmonary arterial hypertension.
      • Naeije R.
      Breathing more with weaker respiratory muscles in pulmonary arterial hypertension.
      • Polkey M.I.
      • Green M.
      • Moxham J.
      Measurement of respiratory muscle strength.
      with the patients sitting upright and breathing through a flanged mouthpiece inside the lips (Jaeger-Viasys Healthcare; MasterLabPro 4.2; Wuerzburg; Germany).
      • Black L.F.
      • Hyatt R.E.
      Maximal respiratory pressures: normal values and relationship to age and sex.
      American Thoracic SocietyEuropean Respiratory Society
      ATS/ERS statement on respiratory muscle testing.
      In brief, maximal inspiratory pressure (Pimax) was determined during a deep inspiration from functional residual capacity against a shutter with a minor air leak preventing undesirable glottis closure. Pimax is a negative pressure, but is expressed as a positive value. Maximal expiratory pressure (Pemax) was measured during maximal expiratory effort at total lung capacity. Pimax and Pemax were determined from the best of five consecutive manoeuvres (varying <20%).

       Six-min-walk test (6-MWT)

      The 6-MWT was performed according to American Thoracic Society guidelines.
      American Thoracic Society
      ATS statement: guidelines for the six-minute walk test.

       Echocardiography

      Patients underwent routine transthoracic echocardiography using commercially available equipment (Vivid 7, GE Vingmed Ultrasound, Horten, Norway) with a 3.5MHz transducer. The tricuspid inflow velocity was measured in the apical four-chamber view using continuous-wave Doppler. The sample volume was positioned at the tips of tricuspid leaflets. sPAP was estimated as a sum of the pressure difference across the tricuspid valve calculated using the Bernoulli equation and RAP, since there was no evidence of pulmonary valve stenosis. Sweep speed used in all Doppler recordings was 100mm/s. Five consecutive beats were recorded and averaged for each measurement. The investigator was unaware of the results in the 6-MWT or muscle testing.

       Data analysis

      All results are expressed as means±standard deviation. Unpaired Student's t-test and linear regression analysis were used as appropriate.
      • Altmann D.G.
      • Gore S.M.
      • Gardner M.J.
      • Pocock S.J.
      Statistical guidelines for contributors to medical journals.
      A level of p<0.05 was accepted as statistically significant.

      Results

       Function of the skeletal and respiratory musculature

      In patients with IPAH, the maximal isometric forearm muscle strength (hand grip) was significantly lower than in healthy controls (281.7±102.6 vs. 397.1±116.8N, respectively; p=0.03). This finding indicates peripheral skeletal muscle dysfunction in patients with IPAH.
      Moreover in IPAH patients, there was a linear correlation between hand grip strength and both maximal mouth occlusion pressures: Pimax (Fig. 1) and Pemax (r=0.63; p=0.01), respectively.
      Figure thumbnail gr1
      Figure 1Significant correlation between maximal static lower arm musculature strength (“hand grip”) and the maximal inspiratory mouth occlusion pressure in 24 patients with IPAH.

       Muscle function and severity of disease

      There was a significant correlation between the maximal isometric forearm muscle strength and the functional severity of disease, assessed by the 6-MWT (Fig. 2).
      Figure thumbnail gr2
      Figure 2Dependence of maximal static lower arm musculature strength (“hand grip”) and 6-min-walk test in 24 IPAH patients.
      The changes in hand grip strength were not significantly related to sPAP (r=0.30; p=0.16).

      Discussion

      The present study provides first evidence of skeletal muscle dysfunction in IPAH:
      (1) the maximal isometric forearm muscle strength (“hand grip”) in patients with IPAH is significantly reduced as compared with respective controls; (2) the reduction in skeletal muscle strength is paralleled by an inspiratory and expiratory muscle dysfunction; (3) skeletal muscle weakness is closely related to clinical severity of disease, as assessed by the 6-MWT.
      The maximal isometric forearm muscle strength depends on age, gender and body mass index.
      • Mathiowetz V.
      • Kashman N.
      • Volland G.
      • Weber K.
      • Dowe M.
      • Rogers S.
      Grip and pinch strength: normative data for adults.
      • Bassey E.J.
      Measurement of muscle strength and power.
      • Bassey E.J.
      • Harries U.J.
      Normal values in hand grip strength in 920 men and women aged over 65 years, and longitudinal changes over 4 years in 620 survivors.
      Since reference values are scarce, matched healthy controls were included in the present study.
      The parallel reduction in both, the peripheral skeletal and the respiratory muscle strength in the present IPAH patients might indicate a generalised systemic muscle weakness syndrome, in analogy to observations in patients with congestive left heart failure.
      • Clark A.L.
      • Poole-Wilson P.A.
      • Coats A.J.S.
      Exercise limitation in chronic heart failure: central role of the periphery.
      • Hambrecht R.
      • Niebauer J.
      • Fiehn E.
      • et al.
      Physical training in patients with stable chronic heart failure: effects on cardiorespiratory fitness and ultrastructural anbnormalities of leg muscles.
      • Drexler H.
      • Riede U.
      • Munzel T.
      • Konig H.
      • Funke E.
      • Hust H.
      Alterations of skeletal muscle in chronic heart failure.
      Consequently one might speculate, that the cardiac output limitation in IPAH could lead to continuously activated sympathetic nervous system, together with reflexes of metabaro- and ergo-receptors, as seen in congestive heart failure, and recently in pulmonary hypertension.
      • Clark A.L.
      • Poole-Wilson P.A.
      • Coats A.J.S.
      Exercise limitation in chronic heart failure: central role of the periphery.
      • Velez-Roa S.
      • Ciarka A.
      • Najem B.
      • Vachiery J.L.
      • Naeije R.
      • van de Borne P.
      Increased sympathetic nerve activity in pulmonary arterial hypertension.
      Moreover in congestive left heart failure and in chronic obstructive airway disease (COPD), skeletal and respiratory muscle weakness has been attributed to the impaired muscle perfusion and reduced peripheral oxygen delivery. As a consequence, deconditioning, changes in muscle fibre composition towards type IIb-fibres, abnormal intracellular calcium profiles, muscle bulk atrophy and the clinical state of wasting or cachexia have been described in experimental and clinical studies in congestive left heart failure.
      • Hambrecht R.
      • Niebauer J.
      • Fiehn E.
      • et al.
      Physical training in patients with stable chronic heart failure: effects on cardiorespiratory fitness and ultrastructural anbnormalities of leg muscles.
      • Drexler H.
      • Riede U.
      • Munzel T.
      • Konig H.
      • Funke E.
      • Hust H.
      Alterations of skeletal muscle in chronic heart failure.
      • Anker S.D.
      • Ponikowski P.
      • Varney S.
      • et al.
      Wasting as independent risk factor for mortality in chronic heart failure.
      • Lindsay D.C.
      • Lovegrove C.A.
      • et al.
      Histological abnormalities of muscle from limb, thorax and diaphragm in chronic heart failure.
      The present findings indicate that the peripheral skeletal muscle weakness might contribute to the exercise limitation, i.e. 6-MWT. However, hand grip strength was independent from haemodynamics. This is in accordance with previous findings in pulmonary hypertension, where the patients’ functional status and prognosis were more significantly correlated to walk distances than to haemodynamics.
      • Miyamoto S.
      • Nagaya N.
      • Satoh T.
      • et al.
      Clinical correlates and prognostic significane of 6-minute walk test in patients with pulmonary hypertension. Comparison with cardiopulmonary exercise testing.
      Moreover, the close relation between peripheral muscle function and 6-MWT is paralleled by recent findings in COPD patients.
      • Dourado V.Z.
      • Antunes L.C.
      • Tanni S.E.
      • de Paiva S.A.
      • Padovani C.R.
      • Godoy I.
      Relationship of upper-limb and thoracic muscle strength to 6-min walk distance in COPD patients.
      Since pronounced exercise limitation is a major disabling symptom in IPAH patients, and it is closely correlated to peripheral skeletal muscle weakness in the present study, future investigations should aim to identify therapeutic interventions capable to improve the skeletal muscle dysfunction.
      So far in congestive left heart failure, exercise training has been shown to improve exercise tolerance.
      • Hambrecht R.
      • Niebauer J.
      • Fiehn E.
      • et al.
      Physical training in patients with stable chronic heart failure: effects on cardiorespiratory fitness and ultrastructural anbnormalities of leg muscles.
      A recent interventional study in patients with IPAH, demonstrated a significant improvement in exercise tolerance.
      • Mereles D.
      • Ehlken N.
      • Kreuscher S.
      • et al.
      Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension.
      However, the study by Mereles et al. did not measure skeletal und respiratory muscle function explicitly.
      The assessment of peripheral skeletal and respiratory muscle dysfunction is relatively simple and also feasible during routine out-patient evaluation. Therefore, “hand grip strength” and maximal mouth occlusion pressures should be evaluated for their potential role as non-invasive therapy monitoring tool or for risk stratification, since two studies in patents with congestive left heart failure, have characterized Pimax as a significant and independent prognostic marker.
      • Meyer F.J.
      • Borst M.M.
      • Zugck C.
      • et al.
      Respiratory muscle dysfunction in congestive heart failure: clinical correlation and prognostic significance.
      • Meyer F.J.
      • Zugck C.
      • Haas M.
      • et al.
      Inefficient ventilation and reduced respiratory muscle capacity in congestive heart failure.

      Clinical implication and conclusion

      The present skeletal muscle dysfunction is a novel finding in IPAH. It is related to respiratory muscle weakness and to clinical severity of disease, suggesting the presence of a “generalised myopathy” in patients with IPAH. The underlying pathomechanisms and the therapeutic options to improve this generalised muscle weakness should be further investigated.

      Conflict of interest statement

      Disclosure of any financial support for the work and other financial or personal connections to the work: None.

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