Worsening of heart failure in Becker muscular dystrophy after nonsteroidal anti-inflammatory drugs.

Abstract: A 40-year-old male with Becker muscular dystrophy and cardiac involvement was stable in New York Heart Association class II for 7 years. He then had arthralgia caused by bilateral gonarthrosis. He received diclofenac 100 mg/d and 500 mg/d mephenamine acid. Six weeks later, he was hospitalized because of heart failure (New York Heart Association class IV). Echocardiography revealed biatrial and biventricular dilation, a left ventricular end-diastolic diameter of 82 mm, an ejection fraction of 26%, a severe tricuspid regurgitation, and an elevated pulmonary artery pressure of 60 mm Hg. Nonsteroidal anti-inflammatory drugs were discontinued, and physiotherapy and equipment with a corset were initiated. He improved after treatment with parenteral diuretics, returning to class II. Nonsteroidal anti-inflammatory drugs should be given with caution in Becker muscular dystrophy with cardiac involvement.

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Muscular pain and pain from joints, insufficiently stabilized by weak muscles, is a frequent finding in patients with neuromuscular disorders (NMD). It is also well known that frequently, NMD show not only involvement of the skeletal muscle but also of the myocardium. (1) Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to have cardiovascular side effects, in particular worsening of heart failure, fluid retention, and increasing blood pressure. (2) Whether cardiovascular side effects in patients with NMD and cardiac involvement are more intense than in patients without NMD is unknown.

Case Report

The patient was a 40-year-old male in whom Becker muscular dystrophy (BMD) had been diagnosed clinically, bioptically, and genetically 11 years before. He had muscle weakness and wasting of the proximal upper and lower limb muscles since age 3 years. When he was 32 years old, exertional dyspnea was noted for the first time. One year later, he was hospitalized because of heart failure. Echocardiography at that time revealed biatrial and biventricular dilation (left ventricular end-diastolic diameter, 82 mm), reduced left ventricular systolic function (ejection fraction, 28%), concentric thickening of the left ventricular myocardium (18 mm), a moderate tricuspid regurgitation, a slightly elevated pulmonary artery pressure of 36 mm Hg, and, surprisingly, left ventricular hypertrabeculation/noncompaction. (3) Under therapy with furosemide, digoxin, angiotensin-converting enzyme inhibitors and [beta]-blockers, his condition improved and he remained stable, in New York Heart Association (NYHA) class II heart failure.

Seven years later, the patient was still able to walk unaided, but weakness and wasting had increased to such a degree that he was no longer able to lift himself into an upright position when lying on the floor. For the previous 2 months, the patient had had arthralgias in both knees. Magnetic resonance imaging of the knees revealed bilateral gonarthrosis. Because of worsening gonalgia, he received 100 mg/d diclofenac and 500 mg/d mephenamine acid. Six weeks later, he was rehospitalized because of NYHA class IV heart failure, manifesting as dyspnea at rest, leg edema, neck vein distension, and weight gain of 3 kg. Electrocardiography showed sinus rhythm, a left anterior hemiblock, signs of left ventricular hypertrophy, and repolarization abnormalities. Radiography revealed an enlarged cardiac silhouette and pulmonary congestion. Echocardiography revealed biatrial and biventricular dilation, a left ventricular end-diastolic diameter of 82 mm, an ejection fraction of 26%, a severe tricuspid regurgitation, and an elevated pulmonary artery pressure of 60 mm Hg. Coronary angiography showed normal coronary arteries. NSAIDs were discontinued, physical therapy was initiated, and the patient was equipped with a supporting corset. After treatment with parenteral diuretics, his condition improved to the level before worsening of heart failure. After 21 days, he was discharged in NYHA class II heart failure.

Discussion

Pain of a different type and origin is a frequent complaint of patients with NMD. Pain in these patients may originate from the skeletal muscles because of muscle cramps, myotonia, myalgia, or exercise-induced muscle pain. (4) Pain in these patients may also derive from secondary effects on the joints and tendons because of declining stabilization from the skeletal muscles. This secondary impact on the joints leads to degeneration manifesting as calcification, cartilage destruction, and tears of the articular capsule and the muscles. Frequently, these patients also have abdominal pain because of involvement of the smooth muscles of the gastrointestinal tract. Furthermore, pain in patients with NMD may be due to frequent falls because of muscle weakness.

Although NSAIDs are one of the most frequently prescribed drugs, they have side effects that increase with duration of medication. Their side effects concern the gastrointestinal, hematologic, cardiovascular, renal, optical, hepatic, muscular, dermatologic, and central nervous system, and, in addition, allergic reactions have been described. (2) The cardiovascular side effects of NSAIDs are most probably due to inhibition of the prostaglandin synthesis. Furthermore, NSAIDs interact with many drugs that are used in patients with cardiovascular disorders by attenuating the effects of diuretics, [beta]-blockers, angiotensin-converting enzyme inhibitors, and angiotensen-2 blockers, by increasing digoxin levels and potentiating the effect of oral anticoagulants.

Although we have no definitive proof, the most probable explanation for worsening of heart failure of the presented patient is the use of NSAIDs over a period of 6 weeks. We propose that NSAIDs are responsible for the deterioration of heart failure because the cardiac medication remained unchanged, no other cardiac event had occurred, and systolic function was echocardiographically only slightly deteriorated compared with previous investigations. Fluid retention, which is a common side effect of NSAIDs, may have led to mainly right heart failure and to the increase of the pulmonary artery pressure. Declining right heart function caused by the myopathic process, however, could be another explanation for the patient's right heart failure. However, the patient's heart failure could be easily recompensated, thus making a myopathic cause of his heart failure worsening rather unlikely. Also, the discontinuation of NSAIDs is no convincing argument for their causative role in the development of heart failure, since simultaneously he received intravenous diuretics.

Our suspicion that NSAIDs were causative for worsening of heart failure is supported by previous reports in which NSAID intake resulted in either worsening or precipitation of heart failure. In an epidemiologic study in patients with preexisting heart failure, current use of NSAIDs increased the risk of rehospitalization by 3.8 compared with heart failure patients, who did not use NSAIDs. (5) In a further study, NSAID use was associated with an increased risk of hospitalizations due to heart failure (relative risk, 1.08). (6) A further study in patients older than 55 years found that the risk of hospitalization for heart failure during periods of concomitant use of diuretics and NSAIDs was 2 times higher than when diuretics were given alone. (7) A case-control study in hospitalized patients found that the use of NSAIDs in the previous week was associated with a doubling of the odds of a hospital admission with heart failure. Use of NSAIDs by patients with a history of heart disease was associated with an odds ratio of 10.5, compared with 1.6 in those without such a history. (8) As in the presented case, in the clinical routine, the relevance of these drug side effects and interactions of NSAIDs seems to be frequently ignored.

Conclusion

This case shows that NSAIDs may cause deterioration of heart failure or at least contribute to deterioration in BMD with preexisting affection of the myocardium. Discontinuation of NSAIDs together with the usual therapy for advanced heart failure led to prompt recovery. NSAIDs should be given with caution in patients with BMD with cardiac involvement.

For, what other dungeon is so dark as one's own heart! What jailer so
inexorable as one's self!
--Nathaniel Hawthorne, The House of Seven Gables

Accepted June 21, 2004.

References

1. Finsterer J, Stollberger C. Cardiac involvement in primary myopathies. Cardiology 2000;94:1-11.

2. Stollberger C, Finsterer J. Nonsteroidal anti-inflammatory drugs in patients with cardio- or cerebrovascular disorders. Z Kardiol 2003;92:721-729.

3. Stollberger C, Finsterer J, Blazek G, et al. Left ventricular non-compaction in a patient with Becker's muscular dystrophy. Heart 1996;76:380.

4. Jerusalem F, Zierz S, Muskelerkrankungen. New York, Thieme, 1991.

5. Feenstra J, Heerdink ER, Grobbee DE, et al. Association of nonsteroidal anti-inflammatory drugs with first occurrence of heart failure and with relapsing heart failure: the Rotterdam Study. Arch Intern Med 2002;162:265-270.

6. Merlo J, Broms K, Lindblad U, et al. Association of outpatient utilisation of non-steroidal anti-inflammatory drugs and hospitalised heart failure in the entire Swedish population. Eur J Clin Pharmacol 2001;57:71-75.

7. Heerdink ER, Leufkens HG, Herings RMC, et al. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med 1998;158:1108-1112.

8. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients. Arch Intern Med 2000;160:777-784.

RELATED ARTICLE: Key Points

* Nonsteroidal anti-inflammatory drugs may lead to worsening of heart failure, fluid retention, and an increase in blood pressure.

* Nonsteroidal anti-inflammatory drugs attenuate the effects of diuretics, [beta]-blockers, angiotensin-converting enzyme inhibitors, and angiotensin-2 blockers.

* Nonsteroidal anti-inflammatory drugs should be given with caution to patients with cardiac involvement of Becker muscular dystrophy.

Claudia Stollberger, MD, and Josef Finsterer, MD

From the Second Medical Department and the Neurological Department, KA Rudolfstiftung, Wien, Osterreich-Europe.

Reprint requests to Dr. Claudia Stollberger, Steingasse 31/18, A-1030 Wien, Osterreich-Europe. E-mail: [e-mail]