PHYS THER
Vol. 89, No. 3, March 2009, pp. 257-266
DOI: 10.2522/ptj.20080155
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Case Reports

Suspected Statin-Induced Respiratory Muscle Myopathy During Long-Term Inspiratory Muscle Training in a Patient With Diaphragmatic Paralysis

Ken Chatham, Colin M Gelder, Thomas A Lines and Lawrence P Cahalin

K Chatham, Grad Dip Phys, is Clinical Specialist Physiotherapist, Physiotherapy Department, Llandough Hospital, Cardiff, United Kingdom.
CM Gelder, MB, PhD, FRCP, is Chest Physician, Section of Respiratory Medicine, Llandough Hospital.
TA Lines, BsCHonsPhys, is Senior Physiotherapist, Physiotherapy Department, Llandough Hospital.
LP Cahalin, PT, PhD, is Clinical Professor, Department of Physical Therapy, Northeastern University, 6 Robinson Hall, Boston, MA 02115 (USA).

Address correspondence to Dr Cahalin at: L.Cahalin{at}neu.edu


Submitted May 23, 2008; Accepted November 19, 2008


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Abstract
 
Background and Purpose: Abnormal lipids are associated with the development of coronary heart disease; for this reason, lipid-lowering agents have become a standard of care. The purposes of this case report are: (1) to highlight the association of impaired inspiratory muscle performance (IMP) with statin therapy and (2) to describe potentially useful methods of examining and treating people with known or suspected statin-induced skeletal myopathies (SISMs).

Case Description: The patient had breathlessness on exertion and a restrictive lung disorder from a right hemidiaphragmatic paralysis, for which he was prescribed high-intensity inspiratory muscle training (IMT). He had a secondary diagnosis of hyperlipidemia, which was treated with 40 mg of simvastatin after 51/2 months of IMT.

Outcomes: The improvements in IMP, symptoms, and functional status obtained from almost 6 months of high-intensity IMT were lost after the commencement of simvastatin. However, 3 weeks after termination of simvastatin combined with high-intensity IMT, the patient's IMP, symptoms, and functional status exceeded pre-statin levels.

Discussion: This case report suggests that high-intensity IMT can be used effectively in a patient with impaired diaphragmatic function and during recovery from a respiratory SISM. The marked reduction in IMP and inability to perform IMT resolved with the cessation of statin therapy. The case report also highlights the potential effects of SISMs in all skeletal muscle groups. The clinical implications of this case report include the potential role of physical therapy in monitoring and possibly facilitating the spontaneous recovery of an SISM, as well as the need to investigate the IMP of a person with dyspnea and fatigue who is taking a statin.


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Introduction
 
Abnormal lipids have long been associated with coronary heart disease.1 The lipid abnormalities found to be associated with coronary heart disease include: (1) elevated total cholesterol, low-density lipoprotein-cholesterol, and triglycerides and (2) depressed levels of high-density lipoprotein-cholesterol.1,2 Because of the favorable effects of statins (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) on these lipid abnormalities, they have become a standard of care for people with abnormal lipids.3 The use of statin drugs such as atorvastatin (Lipitor*), simvastatin (Zocor{dagger}), and lovastatin (Mevacor{dagger}) to lower cholesterol is extremely common.3 More than 76 million prescriptions for statin drugs were filled in 2000.4 Additionally, the number of US prescriptions for statins increased 50% between 2002 and 2006, and the number of Canadian prescriptions for statins increased 69% during the same 4-year period.5 As these data indicate, the use of statin drugs to improve abnormal lipid levels has increased considerably. Furthermore, it is possible that the use of statin drugs will increase even more due to questionable cardioprotective results from the drugs ezetimibe (Zetia{ddagger}) and ezetimibe + simvastatin (Vytorin{dagger},{ddagger}).6 In view of these findings, the use of statins to lower cholesterol is very likely to continue to rise.

The mechanism of action of statin drugs is blocking the rate-limiting step in de novo cholesterol biosynthesis.7,8 Blocking HMG-CoA reductase inhibits the formation of mevalonate (Fig. 1). Mevalonate is a precursor to cholesterol, farnesylated proteins, and ubiquinone. The statin-induced effect upon cholesterol production has a similar effect upon ubiquinone (coenzyme Q10) by inhibition of the same biosynthetic pathway, which has the potential to decrease mitochondrial adenosine diphosphate production and antioxidant activity.8 Thus, decreases in ubiquinone can lead to decreased energy availability, insufficient DNA repair, and muscle fatigue. The consequence of blocking the HMG-CoA channel, therefore, may explain the potential muscle abnormalities associated with statin administration.7,8


Figure 1
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  		Figure 1. Mechanism of action of statins on lipids, proteins, and ubiquinones. Blocking 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibits the formation of mevalonate and every subsequent product below the entry point of statins, including cholesterol, isoprenylated proteins, and coenzyme Q10.

Although statin drugs are commonly used to improve abnormal lipid levels, they have been observed to have numerous adverse effects on skeletal muscle and tendons. Skeletal muscle pain, weakness, rhabdomyolysis, and myopathies have been observed with the administration of statins.3 Tendon damage, including tendinitis and tendon rupture, has been reported.9 Factors associated with the occurrence of these adverse effects include a high dosage of statins (>60 mg per day), concomitant use of glucocorticoids and other myotoxic medications, older age (>80 years), female sex, frailty, small body frame, multisystem disease, and perioperative periods.3 The mechanism of action of statin-induced skeletal myopathies (SISMs) has been hypothesized to be due to a variety of factors (Appendix).3,10 The major factor appears to be the inhibited synthesis of compounds arising from cholesterol synthesis, such as ubiquinone or other essential intracellular compounds (eg, guanosine triphosphate binding proteins). The interaction of statins with the cytochrome P-450 hepatic enzyme system also has been implicated as a potential mechanism for SISMs.3,10–12 In addition, altered gene expression and apoptosis have been hypothesized as factors responsible for SISMs.10–12

Several case reports have described the development of an SISM, and the majority have reported marked dyspnea and fatigue.13–16 In these case reports, it is difficult to determine whether the dyspnea and fatigue were due to a general peripheral SISM, respiratory SISM, or combined peripheral and respiratory SISM. Only one case report16 mentioned the potential effects of statins on respiratory muscles, but it did not examine measures of respiratory performance in the recipient of a heart transplant who required mechanical ventilation. We are unaware of any literature that has investigated the specific effects of exercise training with and without statin drugs. Our case report appears to be the first describing the effects of a statin drug on respiratory muscle performance and the subsequent changes after the drug was discontinued and the patient underwent extensive training of the respiratory muscles.

A recent update by Tomlinson and Mangione17 on the potential adverse effects of statins on muscle posed several important questions related to statin use and the role of physical therapy, including: (1) Can physical therapists provide interventions that facilitate the spontaneous recovery that occurs after discontinuation of the statin? (2) Is exercise contraindicated in people who have SISMs? and (3) Does high-intensity exercise exacerbate complaints of muscle weakness or pain in patients taking statins? The authors concluded that patients with unexplained muscle pain or weakness who are taking statins should be referred to a physician and that intense exercise should be discontinued until the cause of the muscle problem is determined.17

In this case report, we will begin to address the questions that were posed by Tomlinson and Mangione in 2005.17 We will examine and describe the effects of high-intensity inspiratory muscle training (IMT) in a patient with hemidiaphragmatic paralysis. We also will report on the association of commencement and cessation of statin therapy on inspiratory muscle performance (IMP) during IMT. This may have bearing on the suggestion posed by Tomlinson and Mangione that physical therapy may facilitate recovery from SISMs.17 Finally, due to the methods of testing that we used with out patient, we will identify the metabolic abnormalities that appear to be associated with statins and the tests and measures that a physical therapist may consider using when an SISM is suspected in such a patient.


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Patient History and Review of Systems
 
The patient was a 57-year-old man who was referred for physical therapy for examination and IMT after a variety of medical tests performed over the previous year led to a diagnosis of hemidiaphragmatic paralysis and brachial plexus neuritis. It was unclear whether the diaphragmatic impairment was related to an extension of the neuritis or previous trauma to the neck during his sporting history as a first-class rugby player. A computed tomography scan of the cervical spine revealed a cervical spondylosis, with severe degenerative changes and narrowing of the foramen of C5, C6, and C7. Electromyographic testing revealed denervation of both the deltoid and infraspinatus muscles, bilaterally. The symptoms reported included dyspnea on exertion (DOE), particularly if swimming or bending forward, and bilateral shoulder weakness. His occupation was a computer programmer. He took no medications. His height was 185.4 cm (6 ft 1 in), and his weight was 86.2 kg (190 lb).

Prior to commencing IMT, the patient demonstrated a mild to moderate restrictive impairment of lung function with a forced expiratory volume in the first second of expiration (FEV1) and a forced vital capacity (FVC) of 58% and 59%, respectively, of predicted values and an FEV1/FVC of 82%. Chest radiography revealed an elevated right hemidiaphragm and paradoxical abdominal movement during inspiration. Arterial blood gas (ABG) analysis revealed a pH of 7.44, a partial pressure of oxygen (PO2) of 74 mm Hg, a partial pressure of carbon dioxide (PCO2) of 37 mm Hg, and a bicarbonate level (HCO3) of 25 mEq/L. Functionally, the patient was unable to fully participate in his hobby of gardening due to DOE with bending and gardening tasks.

Clinical Impression

The clinical decision-making process used to select the below-mentioned tests and measures for the patient was based on progressive DOE; pulmonary function test (PFT) results revealing a mild to moderate restrictive lung disorder based on the FEV1, FVC, and FEV1/FVC; chest radiograph consistent with right hemidiaphragmatic paralysis; a paradoxical breathing pattern; ABG analysis identifying mild hypoxia18; and limited gardening due to DOE during gardening tasks and bending. The DOE, right hemidiaphragmatic paralysis, and mild hypoxia warranted the examination of the strength (force-generating capacity) and endurance of the inspiratory muscles. Thus, the clinical impression of the patients problems was one of impaired ventilation and respiration/gas exchange associated with ventilatory pump dysfunction.19


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Examination
 
The IMP of the patient was measured using the Test of Incremental Respiratory Endurance (TIRE) incorporated within the RT2 device.§ A video showing a person performing high-intensity inspiratory muscle training via the TIRE within the RT2 device is available. Inspiratory muscle strength was measured as peak inspiratory pressure (PImax) at residual volume (RV). Inspiratory work capacity was measured as sustained peak inspiratory pressure (SPImax) measured from RV to total lung capacity (TLC), and inspiratory muscle work/endurance was measured as accumulated 80% SPImax or {Sigma}SPImax. We have previously described the conversion of pressure generation through the 2-mm leak of the manometer to SI units of power and work.20,21

The TIRE is characterized by the serial presentation of submaximal isokinetic profiles based on maximum voluntary contraction (MVC) of the respiratory muscles. These efforts are presented at an on-screen target of 80% of MVC or SPImax within a progressive work-to-rest ratio, with rest periods decreasing from 60 seconds at level A to 45, 30, 15, 10, and 5 seconds at levels B through F, respectively (Fig. 2). Each level has 6 resisted breaths through the manometer's 2-mm leak but is fixed at 80% of SPImax at each examination. Thus, the examination session continues until task failure, as indicated by an inability to match the on-screen target, or until a maximum of 36 resisted breaths have been performed (Fig. 2). Measurement of IMP via the TIRE has been shown to be valid and reliable as an examination and training method in a variety of patient populations.20–26


Figure 2
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  		Figure 2. Training with the Test of Incremental Respiratory Endurance (TIRE). (A) A subject matches the on-screen training template within the TIRE protocol. (B) A sample computer screen showing the ongoing inspiratory effort (line B) exceeding the 80% training template (line A, the longer diagonal line). Numerical data are presented in the middle of the computer screen (identified within brackets) listing: (1) initial test data, including the peak inspiratory pressure (PImax) (T1: MIP=191 cm H2O, and PAve1=185; PAve1 is PImax measured over 1 second) and sustained peak inspiratory pressure (SPImax) (area=1,467.50 pressure-time units [PTUs], representing the area under the curve) from which the 80% training template (line A) was automatically developed via TIRE software, and (2) first inspiratory effort during the first TIRE level (A1: MIP=165 cm H2O, PAve1=158, area=1,225.38 PTUs, % of the target area=104) with the inspiratory effort ending at 7 seconds, but passing the template requirements because both the PImax (MIP=165/191=86%) and SPImax (1,225.38/1,467.50=83.5%, which represents an SPImax that achieves 104% of the submaximal target area; 104%=83.5%/80%) have achieved 80% of the training template. The calculations of power and work at several different time points also are shown for lines A and B. For line A, PImax=158 cm H2O (yielding a power of 6.22 W) at 1 second, PImax=88 cm H2O (yielding a power of 2.587 W) at 8 seconds, and PImax=10 cm H2O (yielding a power of 0.99 W) at 16 seconds, with total amount of work for line A=40.3 J. For line B, PImax=170 H2O (yielding a power of 6.947 W) at 1 second and PImax=100 cm H2O (yielding a power of 3.13 W) at 7 seconds, with total amount of work for line B=33.5 J. The amount of work described above is ongoing because the line is obtained during mid-effort. A1=the first level of high-intensity inspiratory muscle training via the TIRE, T1=test 1, MIP=maximal inspiratory pressure.

Baseline IMP included a PImax of 80 cm H2O (2.16 W), a SPImax of 404 pressure-time units (PTUs; 10.7 J), and work/endurance of 7,800 PTUs (162 J) at level D2 (Fig. 3). These measures of IMP were reduced, with PImax being 76% of the predicted value27 and other values being lower than expected.20–26,28–30


Figure 3
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  		Figure 3. Several measures of inspiratory muscle performance. Each data point for each week is the best result of the 3 Test of Incremental Respiratory Endurance (TIRE) sessions performed that week. Visual examination of the data for (A) peak inspiratory pressure (PImax), (B) sustained peak inspiratory pressure (SPImax), and (C) inspiratory work performed at test completion (totalized sustained peak inspiratory pressure [totalized SPImax]) reveals that the level and trend of data were most dramatic at the commencement and cessation of the statin. The slopes of the trend lines during the inspiratory muscle training (IMT) and statin+IMT phases in Figure 3C are steeper than the same phases in Figures 3A and 3B. FEV1=forced expiratory volume in the first second of expiration, FVC=functional vital capacity, PaO2=arterial partial pressure of oxygen, PTU=pressure-time unit.

Clinical Impression

These examination findings supported the initial clinical impression of impaired ventilation and respiration/gas exchange associated with ventilatory pump dysfunction,19 as the PFT results revealed a restrictive lung disorder combined with decreased IMP that resulted in pronounced dyspnea and fatigue. The lower-than-expected PImax, SPImax, and inspiratory work/endurance identified the ventilatory pump dysfunction and provided a baseline measure from which to develop the plan of care, which included high-intensity IMT via the TIRE and patient education about IMT. All baseline measurements of IMP were reduced, but the measure of inspiratory work/endurance identified the patients inability to complete the TIRE protocol due to very poor inspiratory muscle endurance (Fig. 3). The RT2 TIRE system was used to perform high-intensity IMT because it provided the serial presentation of submaximal isokinetic profiles at 80% of MVC within a progressive work-to-rest ratio, with rest periods decreasing from 60 seconds to 5 seconds. Currently, the RT2 TIRE system used with this patient has limited availability. However, standard examination of inspiratory muscle strength (eg, PImax) and endurance (eg, duration of repeated inspirations at a particular percentage of PImax until task failure) would provide potentially useful information regarding IMP and the possibility of a respiratory muscle SISM.


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Intervention
 
The patient attended the clinic 3 times weekly and performed the TIRE protocol described earlier. After 51/2 months of successful IMT, the patient began treatment for abnormal lipids, commencing with 40 mg of simvastatin. Approximately 10 years earlier, the patient was diagnosed with type V hyperlipidemia, which had been controlled with dietary and lifestyle adjustments. Due to increasing dyspnea and fatigue, inability to perform IMT, and decreased IMP, simvastatin was terminated after 3 weeks of use, with subsequent improvement in symptoms, ability to perform IMT 1 week after the cessation of the statin, and an increase in IMP (Fig. 3).


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Outcome
 
After 51/2 months of TIRE training, the PImax had risen from 80 cm H2O to 100 cm H2O (3.13 W), the SPImax had increased from 404 PTUs to 605 PTUs (17.3 J, with a contraction time of 16 seconds), and work/endurance had increased from 7,800 PTUs to 20,120 PTUs (492 J) at level F6. These increases were associated with the patient's reported improvements in activities of daily living (ADLs), with reduced breathlessness and self-reported improved quality of life resulting primarily from greater gardening abilities.

During the sixth month of IMT, all measurements of IMF began to fall (Fig. 3). This trend continued for a period of 3 weeks such that the TIRE data were reduced to levels below starting values: PImax=67 cm H2O (1.72 W), SPImax=378 PTUs (8.9 J), and {Sigma}SPImax=1,340 PTUs (28.4 J; the patient failed at the A2 level). The fall in work/endurance indicated that the patient was unable to effectively perform IMT, completing only 2 resisted breaths.

Visual analysis of the TIRE results shown in Figure 3 demonstrates the favorable changes in IMP before commencement and after cessation of statin therapy, which were accompanied by substantial improvements in pulmonary function and PO2 (Fig. 3A). The observed improvements in pulmonary function consisted of the FEV1 and FVC increasing from 58% and 59%, respectively, to 73% and 74%, respectively, of predicted values. The PO2 level increased from 74 mm Hg to 93 mm Hg. These changes led to an improved ability to garden, with less dyspnea.


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Discussion
 
The clinical intervention of fixed-load, high-intensity IMT was associated with increases in IMP. These increases were manifested by the patient's reports of improved quality of life and ADLs similar to several studies of IMT.23–31 The substantial improvement in IMP during the first several weeks of IMT may represent a learned response and neural adaptation, with slower yet steady improvements thereafter, possibly representing a morphological response to IMT.22–31 The prescription of simvastatin to treat hyperlipidemia was associated with a dramatic fall in IMP and an inability to undertake the serial resisted breaths required for effective and progressive IMT. The decrease in IMP was progressive and more profound through the 3 weeks of statin treatment. After withdrawal of simvastatin and initiation of high-intensity IMT, IMP exceeded previous levels of strength, power output, single-breath work capacity, and work/endurance within a 3-week period of IMT. The patient reported feeling better, and his ADLs returned to levels he had attained following the initial 51/2 months of IMT.

We are unaware of any previous reports or studies identifying the decrement in IMP associated with commencement of a statin. However, a recent case report of a recipient of a heart transplant who had been administered simvastatin and a variety of immunosuppressive agents, including prednisone, described the need for mechanical ventilation due to a fatal toxic myopathy.16 Some studies32,33 have identified the effect of glucocorticoids on IMP, finding that patients without underlying pulmonary disease who received high-dose corticosteroids (range=40–90 mg per day) developed inspiratory muscle weakness. Furthermore, IMT performed at 60% of PImax over an 8-week period prevented the decrement in IMP.33 These findings and those of our case report highlight several important issues, including: (1) the potential effect of statins, glucocorticoids, and other myotoxic medications on IMP; (2) the frequent chronic or intermittent use of glucocorticoids in the management of many pulmonary diseases and the possibility that many patients with pulmonary disorders may be prescribed glucocorticoids and statins concomitantly; and (3) the possible preventative role of IMT on a respiratory SISM or myopathy due to myotoxic agents.16,32,33 Worsening dyspnea or nonresponse to physical therapy after administration of a statin, glucocorticoid, or a combined regimen should warrant the examination of IMP. Furthermore, IMT may be used as a preventative measure if measurements of IMP are known or suspected to be reduced and statin or glucocorticoid therapy is being considered.

Our patient complained of a general malaise at the same time his IMP deteriorated. The breathlessness associated with reduced IMP may have contributed to this, but there also may have been a generalized SISM affecting all muscle groups. Furthermore, this patient was not at increased risk for SISMs, because he was young, took no other myotoxic medications, had no multisystem disease, and had no other recognized risk factors for SISMs.3 These issues have profound implications for individuals undergoing rehabilitation. Due to the underlying pathology of patients in both pulmonary and cardiac rehabilitation, there is a high likelihood that statins will be prescribed. Future investigation of the occurrence of SISMs in such patients appears to be warranted.

The examination and management of IMP was the focus of our patient care due to the diagnosis of impaired ventilation and respiration/gas exchange associated with ventilatory pump dysfunction.19 We were able to identify and address task failure during the TIRE sessions as an indicator of fatigue in the measures of power and single- and multiple-breath work capacity. The limitation of our case report is that peripheral skeletal muscle function was not addressed, because this was not the focus of our intervention. A comprehensive assessment of the peripheral skeletal muscles would have provided additional information that may have facilitated the physical therapy intervention provided to this patient. This speculation is particularly relevant to this case report because IMP has been observed to fall with a loss of lean body mass, progression of chronic lung disease, or during infective exacerbations.20,22,24

Between weeks 26 and 27, the patient vacationed in Australia, and the decrease in IMP initially was thought to be associated with some degree of detraining effect, jet lag, and possibly a viral infection. The patient did not demonstrate signs suggestive of a viral infection (eg, elevated body temperature or auscultation findings associated with an upper respiratory tract infection) or a change in lean body mass (determined via appearance and no change in body weight).20,22,24 Additionally, the decrease in IMP was progressive and more pronounced as statin treatment continued; jet lag, detraining, and infection are unlikely to demonstrate such a response. Furthermore, the patient was provided with the handheld mouthpiece resistor from the TIRE device to perform IMT on his vacation, which he did but without the fixation of through-range resistance or the measure of IMT adherence provided by the complete RT2 TIRE system.

Although PImax was reduced in the patient prior to IMT and after statin prescription, the SPImax and {Sigma}SPImax (reflecting power output and work capacity of single and multiple resisted breaths, respectively) were particularly affected. Although several clinical trial databases have observed the incidence of severe SISMs to be 0.08%, the incidence of lesssevere myopathy has not been reported.3 Furthermore, it does not appear that the power output or work capacity of SISMs has been investigated previously, which, based on our results, may be better markers for myopathy than muscle strength. If future studies demonstrate results similar to ours, power output and work capacity of people with known or suspected SISMs may be helpful to identify and manage the SISMs.

It has been hypothesized that the presence of a severe or less-severe SISM is likely due to the disruption of muscle energy production by reduction of ubiquinone and coenzyme Q10 production.3,7–12 The PImax can be described as a maximal inspiratory muscle power effort at RV, the SPImax can be described as the accumulated power output (reflecting single-breath work capacity from RV to TLC), and the {Sigma}SPImax can be described as the work/endurance achieved at 80% of MVC or SPImax throughout the entire TIRE training session. These latter measures are likely to more sensitively reflect impaired muscle energetics than the one on-off power effort of PImax (particularly work/endurance). This has been alluded to in corticosteroid-induced respiratory myopathies.33 In addition, SPImax, used as a measure of single-breath capacity, has been described as a more-sensitive indicator than PImax of readiness to wean from mechanical ventilation.26

The data provided by the measures of power, work capacity, and work/endurance of the inspiratory muscles have provided unique insights into this case report and the possible examination and management of SISMs. These measures enable us to speculate upon the possible pathophysiological mechanisms that may have taken place during and after statin administration. Fatigue, muscle weakness, and pain have been described previously as side effects of statin use.3,9,17

However, despite not being addressed previously, the loss of work capacity and, most importantly, work/endurance (SPImax and {Sigma}SPImax, respectively) could be explained by a reduction of ubiquinone levels and subsequent ATP synthesis due to inhibition of the HMG-CoA channel. This explanation would suggest that measures of work and work/endurance are of particular value when statin therapy is instigated and an SISM is suspected. The addition of measures of isokinetic performance of the limb girdle muscles to SPImax and {Sigma}SPImax measures of the respiratory muscles would be of particular interest in better understanding these speculations. Furthermore, our observation of a 15% improvement in lung function during high-intensity IMT makes the measurement of pulmonary function a potentially valuable tool when statin therapy is known or suspected to produce an SISM. Due to the clinical impact of dramatically reduced IMP, no pulmonary function tests were performed at the cessation of simvastatin. However, PFTs combined with measures of IMP may help to detect and quantify the potential effects of an SISM on respiratory performance and the effects of physical therapy intervention.


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Implications for Physical Therapy
 
The implications of this case report for physical therapy include the need to be aware of the occurrence of respiratory and peripheral SISMs as well as potential examinations when an SISM is suspected and the possible role of physical therapy intervention when an SISM is discovered. The questions posed by Tomlinson and Mangione17 that we would like to address include: (1) Can physical therapists provide interventions that facilitate the spontaneous recovery that occurs after discontinuation of the statin? (2) Is exercise contraindicated in people who have an SISM? and (3) Does high-intensity exercise exacerbate complaints of muscle weakness or pain in patients taking statins?

The information provided by this case report makes it difficult to determine whether the decrement in IMP during statin administration was worsened by high-intensity IMT. Conversely, it also is difficult to determine whether IMP would have decreased more if high-intensity IMT were not performed, as observed when IMT was not performed during glucocorticoid administration.33 It also is difficult to know whether high-intensity IMT facilitated the improvement in IMP after cessation of the statin. It has been suggested that an SISM resolves spontaneously upon cessation of a statin.3 However, no previous case reports or studies have investigated the manner by which skeletal muscle recovers after an SISM. The findings of this case report indicate that combined statin administration and high-intensity IMT worsened IMP, which improved once the statin was terminated, suggesting that the statin was the primary offender of poor IMP. High-intensity IMT performed for 3 weeks after statin withdrawal produced results that were greater than those obtained before statin commencement, which took almost 6 months to achieve.

We believe that the early improvements in IMP due to learning and neural adaptation that we observed in this case and that were observed by numerous investigators22–31 contributed less to the improvements in IMP after the statin was terminated and more to an improved morphological and physiological response. In view of this, it appears that the spontaneous recovery of the respiratory SISM after cessation of the statin in our patient was facilitated by physical therapy intervention.

Surprisingly, the short-term administration of a statin in this patient appeared, paradoxically, to stimulate improvements in IMP after 3 weeks of high-intensity IMT, resulting in greater IMP and a steeper trend line than before commencement of the statin. However, further investigation is needed to determine the manner and magnitude of recovery associated with an SISM alone and combined with different levels of exercise. Perhaps low-intensity IMT rather than high-intensity IMT would produce changes during and after statin administration that are different from those that we observed. Moreover, perhaps the muscles of patients after long-term statin therapy recover differently than those of patients who receive short-term statin administration. Based on our case report and the slope of the post-statin trend line, short-term statin administration may have facilitated exercise training adaptations after the cessation of the statin by favorably altering DNA transcription and synthesis, regulating cytotoxic activity, and improving vasomotor tone (relaxation and constriction of the vasculature) via activation of endothelium-derived relaxing factor.34 In addition, a unique set of operational conditions under which the respiratory muscles function, such as the metaboreflex,35 may have allowed an earlier return to high-intensity exercise than that which might occur in the peripheral musculature. These speculations should be examined in prospective controlled studies.

Given the widespread prescription of statins, their potential effects on all muscle groups are of some concern. The findings of this case report suggest an association between the commencement of simvastatin and the impairment of both IMP and the ability to effectively perform IMT. We believe that in individuals with compromised cardiorespiratory systems, such as those undergoing cardiac or pulmonary rehabilitation, further investigation of IMP and skeletal muscle function is needed. It is likely that many individuals undergoing cardiac or pulmonary rehabilitation may have been prescribed statins and that nonresponse to rehabilitation or breathlessness secondary to impaired IMP could be due to statin administration. Furthermore, patients with pre-existing muscle disorders (such as the right hemidiaphragm paralysis in our patient) or those who are receiving glucocorticoids or other myotoxic medications appear to be more susceptible to an SISM.3,13–17,32,33

In summary, this case report is the first published description of an intervention aimed at facilitating the recovery of an SISM. Our case report and the report by Francis et al16 show that the respiratory muscles can be affected by statin use, with our case report being the first to identify the progressive decrements in IMP. Furthermore, it appears to be the first report examining the endurance and work capacity associated with an SISM. The clinical implications of this case report are substantial and include the potential role of physical therapy intervention in monitoring and possibly facilitating the spontaneous recovery of an SISM as well as the need to investigate the performance of the respiratory muscles in people with unexplained dyspnea and fatigue who are prescribed statin drugs.


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Appendix.
 


Figure 1
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  		Appendix. Mechanisms Hypothesized to be Responsible for Statin-Induced Skeletal Myopathy

a Atrogin-1 is a key gene involved in skeletal muscle atrophy.

b COQ2 gene disturbances are common in severe, inherited skeletal muscle myopathies.


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Footnotes
 
All authors provided concept/idea/project design, writing, and consultation (including review of manuscript before submission). Mr Chatham, Dr Gelder, and Mr Lines provided data collection. Mr Chatham and Dr Cahalin provided data analysis. Mr Chatham, Dr Gelder, and Dr Cahalin provided project management. Mr Chatham and Mr Lines provided the patient. Mr Chatham and Dr Gelder provided facilities/equipment. Mr Chatham provided institutional liaisons.

* Parke-Davis, Div of Warner-Lambert Co LLC (a Pfizer company), 235 E 42nd St, New York, NY 10017-5755. Back

{dagger} Merck & Co Inc, PO Box 4 WP39-206, West Point, PA 19496-0004. Back

{ddagger} Schering-Plough Corp, Galloping Hill Rd, Kenilworth, NJ 07033-0530. Back

§ DeVilbiss Healthcare, High Street, Wollaston, West Midlands, DY8 4PS United Kingdom. Back


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References
 
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