Correspondence

Left Ventricular Assist Devices and Drug Therapy in Heart Failure

N Engl J Med 2007; 356:869-872February 22, 2007

Article

To the Editor:

The article by Birks et al. (Nov. 2 issue)1 is an important contribution to further development of a therapeutic approach to idiopathic dilated cardiomyopathy that remains controversial despite being repeatedly proved.2-4 The high recovery rate reported by the authors is encouraging, although it might have been facilitated by patient selection. Thus, Patient 11, with a small left ventricle and normal cardiac index value, underwent implantation of a left ventricular assist device with the diagnosis of idiopathic dilated cardiomyopathy. The survival rate after explantation in the study cohort (81.8% at 4 years) is similar to that among our 35 patients with idiopathic dilated cardiomyopathy who were weaned from left ventricular assist devices since 1995 (78.1% at 6 years). Freedom from recurrence of heart failure was higher among the patients in the study by Birks et al. than among our patients (88.9% vs. 69.3% at 4 years), but not significantly so. The mean (±SD) postexplantation left ventricular ejection fraction of 64±12% (higher than in professional cyclists),5 despite expected apical hypokinesia at the cannulation site, needs explanation. The short observation period (5 to 6 years of follow-up reached for only four patients) limits conclusions about long-term stability after weaning. However, our experience with 18 patients with postweaning cardiac stability for more than 5 years (for 3 patients, >11 years) suggests that recovery can be long-lasting.

Roland Hetzer, M.D., Ph.D.
Michael Dandel, M.D., Ph.D.
Christoph Knosalla, M.D., Ph.D.
Deutsches Herzzentrum Berlin, 13353 Berlin, Germany
hetzer@dhzb.de

5 References

1. 1

   Birks EJ, Tansley PD, Hardy J, et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med 2006;355:1873-1884
   Full Text | Web of Science | Medline

2. 2

   Muller J, Wallukat G, Weng YG, et al. Weaning from mechanical cardiac support in patients with dilated cardiomyopathy. Circulation 1997;96:542-549
   Web of Science | Medline

3. 3

   Frazier OH, Delgado RM III, Scroggins N, Odegaard P, Kar B. Mechanical bridging to improvement in severe acute “nonischemic, nonmyocarditis” heart failure. Congest Heart Fail 2004;10:109-113
   CrossRef | Medline

4. 4

   Dandel M, Weng Y, Siniawski H, Potapov E, Lehmkuhl HB, Hetzer R. Long term results in patients with idiopathic dilated cardiomyopathy after weaning from left ventricular assist devices. Circulation 2005;112:Suppl I:I-37
   

5. 5

   Abergel E, Chatellier G, Hagege AA, et al. Serial left ventricular adaptation in world-class professional cyclists: implications for disease screening and follow-up. J Am Coll Cardiol 2004;44:144-149
   CrossRef | Web of Science | Medline

To the Editor:

Birks et al. showed the therapeutic benefits of combining clenbuterol with myocardial unloading, but it may be prudent to clarify the wider anabolic and myotoxic effects of clenbuterol. Cardiotoxic effects of clenbuterol are mediated by β₁-adrenergic receptors,1 whereas therapeutic effects of the drug are mediated by β₂-adrenergic receptors. Hence, coadministration with a β₁-adrenergic–receptor antagonist is crucial to the successful use of clenbuterol as an adjunct to unloading of the myocardium. In contrast, in skeletal muscle, both the anabolic and toxic effects of clenbuterol are mediated by β₂-adrenergic receptors and cannot be separated by using β₁-adrenergic–receptor antagonism.1 In rats, clenbuterol increases muscle growth at doses lower than those required to induce myofiber death,2 but the translation of doses to humans is difficult. Notably, clenbuterol induces myofiber death in rat muscle at doses causing submaximal increases in heart rate,3 suggesting that this myotoxicity is apparent at physiologic doses possibly equivalent to those used by Birks et al. in humans. These findings argue against the arbitrary use of large doses of clenbuterol and highlight the need to reconcile its anabolic and myotoxic effects when considering its therapeutic potential.

Jatin G. Burniston, Ph.D.
Liverpool John Moores University, Liverpool L3 2ET, United Kingdom
j.burniston@ljmu.ac.uk

3 References

1. 1

   Burniston JG, Tan L-B, Goldspink DF. Beta2-adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle. J Appl Physiol 2005;98:1379-1386
   CrossRef | Web of Science | Medline

2. 2

   Burniston JG, Clark WA, Tan L-B, Goldspink DF. Dose-dependent separation of the hypertrophic and myotoxic effects of the beta2-adrenergic receptor agonist clenbuterol in rat striated muscles. Muscle Nerve 2006;33:655-663
   CrossRef | Web of Science | Medline

3. 3

   Burniston JG, Tan LB, Goldspink DF. Relative myotoxic and haemodynamic effects of the beta-agonists fenoterol and clenbuterol measured in conscious unrestrained rats. Exp Physiol 2006;91:1041-1049
   CrossRef | Web of Science | Medline

To the Editor:

The study by Birks et al. raises important questions about the mechanisms of reversibility of ventricular remodeling, which represents a common process of progressive ventricular hypertrophy, enlargement, and cavity distortion over time.1 The underlying molecular, cellular, and interstitial changes in the myocardium have been studied extensively in patients with heart failure.2 Less is known about the mechanisms of reverse remodeling. In the study by Birks et al., significant improvement in clinical status was associated with a decrease in the size of the ventricular cavity, along with functional changes in the myocardium. Have Birks et al. also examined structural changes in the myocardium? Specifically, has the interstitial and replacement fibrosis seen during implantation of the device changed over the course of therapy? If so, this could imply that fibrosis can be reversed.

Viorel G. Florea, M.D., Ph.D.
University of Minnesota, Minneapolis, MN 55455
flore022@umn.edu

2 References

1. 1

   Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling -- concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J Am Coll Cardiol 2000;35:569-582
   CrossRef | Web of Science | Medline

2. 2

   Anand IS, Florea VG. Alterations in ventricular structure: role of left ventricular remodeling. In: Mann DL. Heart failure: a companion to Braunwald's Heart Disease. Philadelphia: Saunders, 2004:229-45.
   

To the Editor:

Birks et al. show that heart failure secondary to nonischemic cardiomyopathy could be reversed with the combined use of a left ventricular assist device and clenbuterol.

A major limitation of this study is the lack of a control group. It is well documented that patients with myocarditis,1 peripartum cardiomyopathy,2 and tako-tsubo cardiomyopathy3 may have spontaneous improvement in left ventricular function, and this cannot be ruled out as an explanation for the improvement described by Birks et al. Although patients with evidence of myocarditis on myocardial biopsy were excluded in their study, the sensitivity of biopsy for the diagnosis of myocarditis is limited.4 The authors appropriately excluded patients with irreversible myocardial damage such as ischemic cardiomyopathy, and it is not surprising that a patient with anthracycline-induced cardiomyopathy did not benefit.

The important clinical question of whether the approach of Birks et al. results in a likelihood of improvement in left ventricular function that exceeds the likelihood of improvement with conservative therapy can be answered only by performing a randomized, controlled trial.

David Rott, M.D.
David Leibowitz, M.D.
Hadassah Hebrew University Medical Center, Jerusalem 91240, Israel

4 References

1. 1

   Mahrholdt H, Wagner A, Deluigi CC, et al. Presentation, patterns of myocardial damage, and clinical course of viral myocarditis. Circulation 2006;114:1581-1590
   CrossRef | Web of Science | Medline

2. 2

   Cetta F, Michels VV. The natural history and spectrum of idiopathic dilated cardiomyopathy, including HIV and peripartum cardiomyopathy. Curr Opin Cardiol 1995;10:332-338
   CrossRef | Web of Science | Medline

3. 3

   Sharkey SW, Lesser JR, Zenovich AG, et al. Acute and reversible cardiomyopathy provoked by stress in women from the United States. Circulation 2005;111:472-479
   CrossRef | Web of Science | Medline

4. 4

   Grogan M, Redfield MM, Bailey KR, et al. Long-term outcome of patients with biopsy-proved myocarditis: comparison with idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1995;26:80-84
   CrossRef | Web of Science | Medline

To the Editor:

Myocardial recovery after partial unloading by means of a left ventricular assist device and drug therapy is arguably one of the most fascinating developments in cardiac surgery. Birks et al. report a recovery rate of 46%, which is substantially higher than the rates reported in previous studies (5%, 24%, and 11%). However, from an intention-to-treat perspective, the recovery rate in the study by Birks et al. should be 33.3% (9 of 27 patients). Although lower than the one reported, it still considerably exceeds the rates in previous studies and is no less impressive.

Gert J. Vanderwilt, Ph.D.
University Medical Center St. Radboud, 6500 HB Nijmegen, the Netherlands

Author/Editor Response

With regard to the comments of Hetzer et al., the significantly higher rate of recovery observed in our series than that previously reported after implantation of left ventricular assist devices is not due to patient selection. All our patients had severe heart failure while receiving inotropic support, with impending or actual multiorgan failure, including Patient 11, who had an ejection fraction of 15% and acidosis. It is well known that isolated measurements of cardiac output can be misleading in inotrope-dependent patients. With regard to the ejection fraction and apical hypokinesis after explantation, all our patients undergo removal of the inflow cannula with formal repair of the apex, which might explain the differences between our patients and those in whom the inflow cannula is left in place. We share the enthusiasm of Hetzer et al. with regard to long-term recovery.

We agree with Dr. Burniston that it is important to combine the use of clenbuterol with β₁-adrenergic–receptor antagonists. With regard to the dosage, we believe it should be carefully adjusted to maintain the heart rate below 100 beats per minute while the patient is monitored for skeletal muscle pain and creatine kinase levels are measured. It is well known that dosages of drugs used in small-animal models cannot be applied to humans.

Dr. Florea points out the importance of studying structural and molecular changes in the myocardium in an attempt to define the mechanisms of recovery. This has been a major focus of investigation in our patients.1-4 With regard to fibrosis, we have observed significant diminution in the collagen volume fraction (unpublished data). However, previous studies5 have outlined the critical importance of cross-linking of collagen in remodeling, which needs to be studied.

The concern of Drs. Rott and Leibowitz regarding inclusion of patients known to have a high rate of spontaneous recovery does not apply to our series. We excluded patients with myocarditis, and none of our patients had the apical ballooning syndrome (“tako-tsubo”), which is easily recognizable. As explained in our article and in the literature, patients with advanced peripartum cardiomyopathy have the same poor prognosis that others have. The use of a randomized control group was precluded by the critical condition of our patients, who required urgent mechanical support.

The statement by Dr. Vanderwilt that from an intention-to-treat perspective the rate of recovery is 33% is incorrect; he included patients with ischemic heart disease and those who died after explantation, including the late death due to carcinoma of the lung. We agree with Dr. Vanderwilt that recovery after implantation of a left ventricular assist device could be one of the important developments in cardiac surgery.

Magdi H. Yacoub, F.R.S.
Emma J. Birks, Ph.D., M.R.C.P.
Royal Brompton and Harefield National Health Service Trust, Harefield UB9 6JH, United Kingdom
m.yacoub@ic.ac.uk

5 References

1. 1

   Terracciano CMN, Hardy J, Birks EJ, Khaghani A, Banner NR, Yacoub MH. Clinical recovery from end-stage heart failure using left ventricular assist device and pharmacologic therapy correlates with increased sarcoplasmic reticulum calcium content but not with regression of cellular hypertrophy. Circulation 2004;109:2263-2265
   CrossRef | Web of Science | Medline

2. 2

   Birks EJ, Hall JL, Barton PJR, et al. Gene profiling changes in cytoskeletal proteins during clinical recovery following left ventricular-assist device support. Circulation 2005;112:Suppl I:I-57
   

3. 3

   Barton PJR, Felkin LE, Birks EJ, et al. Myocardial insulin-like growth factor-I gene expression during recovery from heart failure following combined left ventricular assist device and clenbuterol therapy. Circulation 2005;112:Suppl I:I-46
   

4. 4

   Hall JL, Birks EJ, Grindle S, et al. Molecular signature of recovery following combination left ventricular assist device (LVAD) support and pharmacologic therapy. Eur Heart J (in press).
   

5. 5

   Badenhorst D, Maseko M, Tsotetsi OJ, et al. Cross-linking influences the impact of quantitative changes in myocardial collagen on cardiac stiffness and remodelling in hypertension in rats. Cardiovasc Res 2003;57:632-641
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Peter D. Wearden, Elizabeth D. Blume. 2012. Mechanical Circulatory Support in Pediatrics. , 206-219.
   CrossRef

2. 2

   M. Dandel, Y. Weng, H. Siniawski, A. Stepanenko, T. Krabatsch, E. Potapov, H. B. Lehmkuhl, C. Knosalla, R. Hetzer. (2011) Heart failure reversal by ventricular unloading in patients with chronic cardiomyopathy: criteria for weaning from ventricular assist devices. European Heart Journal 32:9, 1148-1160
   CrossRef