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Recovery From Anthracycline Cardiomyopathy After Long-term Support With a Continuous Flow Left Ventricular Assist Device
Recovery From Anthracycline Cardiomyopathy After Long-term Support With a Continuous Flow Left Ventricular Assist Device Mark Freilich, MBBS,a Dion Stub, MBBS,a Donald Esmore, FRACS,b Justin Negri, FRACS,b Robert Salamonsen, FFARACS,c Peter Bergin, FRACP,a Angeline Leet, FRACP,a Meroula Richardson, FRACP,a Andrew Taylor, PhD, FRACP,a John Woodard, PhD,d David Kaye, PhD, FRACP,a and Franklin Rosenfeldt, MD, FRACSb We report the clinical course of a 16-year-old girl in remission from non-Hodgkin’s lymphoma who presented in cardiogenic shock due to a severe anthracycline cardiomyopathy. The patient was initially stabilized using central extracorporeal membrane oxygenation support, followed by conversion to a left ventricular assist device. Unexpected evidence of cardiac recovery 9 months after implant enabled device weaning during a 3-month period, culminating in successful device explantation 1 year after implant. The patient survives 18 months after explant in New York Heart Association class I, on conventional heart failure medical management and metabolic therapy. J Heart Lung Transplant 2009;28:101–3. © 2009 Published by Elsevier Inc. on behalf of the International Society for Heart and Lung Transplantation.
Long-term recovery of heart function after mechanical circulatory support (MCS) is the best of all possible outcomes of left ventricular assist device (LVAD) implantation. Although successful weaning from MCS has been most commonly achieved after acute myocarditis,1 there is intense interest in weaning patients with chronic heart failure due to idiopathic dilated cardiomyopathy (IDC).2 To date, evidence for cardiac recovery in the setting of cytotoxic-induced cardiac failure has been minimal. We report a 16-year-old girl who required LVAD implantation for severe anthracycline cardiomyopathy, followed by removal 1 year later. CASE REPORT A 16-year-old girl in remission from non-Hodgkin’s lymphoma (NHL) presented in cardiogenic shock due to anthracycline-induced cardiomyopathy. The patient had been diagnosed 8 months earlier with large mediastinal B-cell NHL. An echocardiogram on initiation of the chemotherapy regimen showed normal left ventricular systolic function with an ejection fraction of 55%. She received 8 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. The cumulative doses were vincristine, From the aDepartments of Cardiology, bDepartment of Cardiothoracic Surgery, and cIntensive Care Unit, Alfred Hospital, Prahran, Victoria; and dVentracor Pty Ltd, Chatswood, New South Whales, Australia. Submitted July 23, 2008; revised October 7, 2008; accepted October 14, 2008. Reprint requests: Professor F. Rosenfeldt, Department of Cardiothoracic Surgery PO Box 315, Prahran, Victoria 3181. Telephone: 61-3-92763685. Fax: 61-3-9276-2317. E-mail: [email protected] © 2009 Published by Elsevier Inc. on behalf of the International Society for Heart and Lung Transplantation. 1053-2498/09/$–see front matter. doi:10.1016/j.healun.2008.10.002
2.8 mg/m2; doxorubicin, 400 mg/m2; cyclophosphamide, 6,000 mg/m2; and prednisolone and rituximab, 3,000 mg/m2. Episodes of paroxysmal supraventricular tachycardia occurred intermittently during her chemotherapy course, which were not an ongoing issue. Three months after commencing chemotherapy, her left ventricular fractional shortening was 28% on echocardiography, with an ejection fraction of 54% on gated cardiac blood pool scan. After 4 months of therapy, NHL remission was confirmed by positron emission tomography and computed tomography scan. The patient presented 3 months later with 2 weeks of progressive exertional dyspnea that deteriorated rapidly to cardiogenic shock complicated by multiorgan failure. An echocardiogram on admission confirmed severe left ventricular systolic dysfunction with a fractional shortening of 2%, without evidence of a pericardial effusion. She was intubated, ventilated, and initially commenced on high-dose inotropic support and balloon counterpulsation. She progressed, however, to biventricular failure requiring urgent institution of central extracorporeal membrane oxygenation (ECMO). After end-organ recovery during a 6-day period of ECMO support, a VentrAssist LVAD (Ventracor Ltd, Chatswood, NSW, Australia)3 was implanted. Light microscopy of the left ventricular apex revealed patchy cytoplasmic vacuolation without significant fibrosis, inflammation, or malignancy. To assist cardiac recovery, metabolic therapy with coenzyme Q10 (CoQ10; 100 mg, 3 times daily) was initiated by nasogastric tube. She remained in hospital a further 40 days before discharge with warfarin, aspirin, perindopril, and CoQ10 therapy. The patient remained in remission from NHL, and at 9 months after LVAD implant, she was placed on 101
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the waiting list for cardiac transplantation. However, serial echocardiograms during the waiting list period revealed a steady improvement in LV systolic function, with evidence of improved fractional shortening and a decrease in LV diameter (Figure 1). At 11 months after insertion, the decision was made to wean LVAD support to ascertain the degree of myocardial recovery. During the ensuing 6 weeks, LVAD speed was progressively reduced from 2,200 to 1,800 rpm, with no changes in the patient’s clinical status or echocardiographic findings. At 1 year and 13 days after implant, the patient underwent full instrumentation in the operating theater. The patient was partially heparinized. LVAD flows were then reduced to 1,600 rpm (cardiopulmonary resuscitation mode of the device). During a 2-hour observation period, the patient’s hemodynamic values remained stable. The decision was then made to remove the VentrAssist device. The device was explanted, the apical cannulation site was repaired, and an IABP was inserted. Postoperative recovery was uneventful, and the IABP was removed on Day 2 after the reintroduction of perindopril, bisoprolol, and CoQ10 therapies. She was discharged from the intensive care unit on Day 5 and from hospital on Day 17. At 28 months after explant, LV function remains only mildly reduced, with no intercurrent events. The patient remains in New York Heart Association class I on her discharge heart failure medication and metabolic therapy. DISCUSSION Anthracyclines are among the most potent chemotherapeutic agents for the treatment of a wide variety of tumors; however, their usefulness is limited by dose-
Figure 1. After implantation of a left ventricular assist device (LVAD), serial echocardiograms while the patient was on the transplant waiting list revealed a steady improvement in left ventricular systolic function. 1. Extracorporeal membrane oxygenation inserted. 2. Left ventricular assist device inserted. 3. Discharged from the hospital. 4. LVAD removed. LVEDD, left ventricular end-diastolic diameter; FS, fractional shortening.
The Journal of Heart and Lung Transplantation January 2009
related cardiotoxicity. Three stages of toxicity have been identified: acute, early, and late. Acute toxicity may lead to arrhythmias during therapy that is usually self-limiting. Early cardiomyopathy, of which this case is an example, has a peak incidence at 3 months after therapy, but late cardiomyopathy can present years after treatment. The usual outcome is either death or survival after cardiac transplantation. The dose-related cardiomyopathy induced by anthracyclines may be explained largely by the induction of irreversible oxidative damage to cardiac mitochondria. These organelles are highly susceptible to the effects of anthracyclines due to the presence of a unique enzyme (reduced nicotinamide adenine dinucleotide dehydrogenase) in their inner mitochondrial membrane.4 This enzyme reduces anthracyclines to their semi-quinones, ultimately resulting in severe oxidative damage to mitochondrial DNA that leads to reductions in cellular energy production and ultimately to apoptosis of cardiomyocytes. Evidence is increasing that concurrent administration of CoQ10 can prevent or reduce these undesirable side effects.5–7 The lipid-soluble antioxidant CoQ10 is an integral component of the mitochondrial respiratory chain and has successfully been used in the treatment of cardiac failure.8 In this patient, the LVAD was implanted as a bridge to transplant, with a planned 1-year support time in which to confirm remission from the NHL. To have averted or delayed cardiac transplantation avoids the well-known limitations of transplantation, including limited duration of allograft survival and the accompanying risks of immunosuppression. In this patient, perhaps more importantly, the potential for an adverse effect of immunosuppression on her NHL was also avoided. The International Society of Heart and Lung Transplantation (ISHLT) Mechanical Circulatory Support database confirms that only 5% of all reported LVAD implants worldwide effect a myocardial recovery outcome.9 Most reported cases of cardiac recovery have involved volume displacement devices with their inherent volume (fill to empty) mode, facility for complete unloading of the heart, and controlled weaning through rate reduction and modulation of stroke volume.4 Continuous flow devices by their design do not have such advantages, the general belief is that ventricular unloading is incomplete with these devices, hence providing a sub-optimal platform for cardiac recovery. In conclusion, the current case exemplifies 2 important principles relevant to clinical practice. First, mechanical circulatory support of selected patients with cytotoxic-induced cardiomyopathy may identify a subpopulation with the potential for cardiac recovery and a putative role for metabolic therapy. Second, the use of smaller, continuous flow devices is a viable treatment
The Journal of Heart and Lung Transplantation Volume 28, Number 1
modality in this setting, and myocardial recovery is possible. REFERENCES 1. Leprince P, Combes A, Bonnet N, et al. Circulatory support for fulminant myocarditis: consideration for implantation, weaning and explantation. Eur J Cardiothorac Surg 2003;24:399 – 403. 2. Dandel M, Weng Y, Siniawski H, et al. Long-term results in patients with idiopathic dilated cardiomyopathy after weaning from left ventricular assist devices. Circulation.2005;112:1–37. 3. Esmore DS, Kaye D, Salamonen R, et al. Initial clinical experience with the VentrAssist left ventricular assist device: the pilot trial. J Heart Lung Transplant 2008;27:479 – 85. 4. Fisher NG, Marshall AJ. Anthracycline-induced cardiomyopathy. UK Postgrad Med J 1999;75:265– 8.
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5. Van Dalen EC, Caron HN, Dickinson HO, Kremer LC. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 2005;CD003917. 6. Wouters KA, Kremer LC, Miller TL, Herman EH, Lipshultz SE. Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol 2005;131: 561–78. 7. Conklin KA. Coenzyme q10 for prevention of anthracycline induced cardiotoxicity. Integr Cancer Ther 2005;4;110 –30. 8. Sander S, Coleman CI, Patel AA, Kluger I, White CH. The impact of coenzyme Q10 on systolic function in patients with chronic heart failure. J Card Fail 2006;12:464 –72. 9. Deng MC, Edwards LB, Hertz MI, et al. Mechanical Circulatory Support Device Database of the International Society for Heart and Lung Transplantation: third annual report—2005. J Heart Lung Transplant 2005;24:1182–7.
Long-term recovery of heart function after mechanical circulatory support (MCS) is the best of all possible outcomes of left ventricular assist device (LVAD) implantation. Although successful weaning from MCS has been most commonly achieved after acute myocarditis,1 there is intense interest in weaning patients with chronic heart failure due to idiopathic dilated cardiomyopathy (IDC).2 To date, evidence for cardiac recovery in the setting of cytotoxic-induced cardiac failure has been minimal. We report a 16-year-old girl who required LVAD implantation for severe anthracycline cardiomyopathy, followed by removal 1 year later. CASE REPORT A 16-year-old girl in remission from non-Hodgkin’s lymphoma (NHL) presented in cardiogenic shock due to anthracycline-induced cardiomyopathy. The patient had been diagnosed 8 months earlier with large mediastinal B-cell NHL. An echocardiogram on initiation of the chemotherapy regimen showed normal left ventricular systolic function with an ejection fraction of 55%. She received 8 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. The cumulative doses were vincristine, From the aDepartments of Cardiology, bDepartment of Cardiothoracic Surgery, and cIntensive Care Unit, Alfred Hospital, Prahran, Victoria; and dVentracor Pty Ltd, Chatswood, New South Whales, Australia. Submitted July 23, 2008; revised October 7, 2008; accepted October 14, 2008. Reprint requests: Professor F. Rosenfeldt, Department of Cardiothoracic Surgery PO Box 315, Prahran, Victoria 3181. Telephone: 61-3-92763685. Fax: 61-3-9276-2317. E-mail: [email protected] © 2009 Published by Elsevier Inc. on behalf of the International Society for Heart and Lung Transplantation. 1053-2498/09/$–see front matter. doi:10.1016/j.healun.2008.10.002
2.8 mg/m2; doxorubicin, 400 mg/m2; cyclophosphamide, 6,000 mg/m2; and prednisolone and rituximab, 3,000 mg/m2. Episodes of paroxysmal supraventricular tachycardia occurred intermittently during her chemotherapy course, which were not an ongoing issue. Three months after commencing chemotherapy, her left ventricular fractional shortening was 28% on echocardiography, with an ejection fraction of 54% on gated cardiac blood pool scan. After 4 months of therapy, NHL remission was confirmed by positron emission tomography and computed tomography scan. The patient presented 3 months later with 2 weeks of progressive exertional dyspnea that deteriorated rapidly to cardiogenic shock complicated by multiorgan failure. An echocardiogram on admission confirmed severe left ventricular systolic dysfunction with a fractional shortening of 2%, without evidence of a pericardial effusion. She was intubated, ventilated, and initially commenced on high-dose inotropic support and balloon counterpulsation. She progressed, however, to biventricular failure requiring urgent institution of central extracorporeal membrane oxygenation (ECMO). After end-organ recovery during a 6-day period of ECMO support, a VentrAssist LVAD (Ventracor Ltd, Chatswood, NSW, Australia)3 was implanted. Light microscopy of the left ventricular apex revealed patchy cytoplasmic vacuolation without significant fibrosis, inflammation, or malignancy. To assist cardiac recovery, metabolic therapy with coenzyme Q10 (CoQ10; 100 mg, 3 times daily) was initiated by nasogastric tube. She remained in hospital a further 40 days before discharge with warfarin, aspirin, perindopril, and CoQ10 therapy. The patient remained in remission from NHL, and at 9 months after LVAD implant, she was placed on 101
102
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the waiting list for cardiac transplantation. However, serial echocardiograms during the waiting list period revealed a steady improvement in LV systolic function, with evidence of improved fractional shortening and a decrease in LV diameter (Figure 1). At 11 months after insertion, the decision was made to wean LVAD support to ascertain the degree of myocardial recovery. During the ensuing 6 weeks, LVAD speed was progressively reduced from 2,200 to 1,800 rpm, with no changes in the patient’s clinical status or echocardiographic findings. At 1 year and 13 days after implant, the patient underwent full instrumentation in the operating theater. The patient was partially heparinized. LVAD flows were then reduced to 1,600 rpm (cardiopulmonary resuscitation mode of the device). During a 2-hour observation period, the patient’s hemodynamic values remained stable. The decision was then made to remove the VentrAssist device. The device was explanted, the apical cannulation site was repaired, and an IABP was inserted. Postoperative recovery was uneventful, and the IABP was removed on Day 2 after the reintroduction of perindopril, bisoprolol, and CoQ10 therapies. She was discharged from the intensive care unit on Day 5 and from hospital on Day 17. At 28 months after explant, LV function remains only mildly reduced, with no intercurrent events. The patient remains in New York Heart Association class I on her discharge heart failure medication and metabolic therapy. DISCUSSION Anthracyclines are among the most potent chemotherapeutic agents for the treatment of a wide variety of tumors; however, their usefulness is limited by dose-
Figure 1. After implantation of a left ventricular assist device (LVAD), serial echocardiograms while the patient was on the transplant waiting list revealed a steady improvement in left ventricular systolic function. 1. Extracorporeal membrane oxygenation inserted. 2. Left ventricular assist device inserted. 3. Discharged from the hospital. 4. LVAD removed. LVEDD, left ventricular end-diastolic diameter; FS, fractional shortening.
The Journal of Heart and Lung Transplantation January 2009
related cardiotoxicity. Three stages of toxicity have been identified: acute, early, and late. Acute toxicity may lead to arrhythmias during therapy that is usually self-limiting. Early cardiomyopathy, of which this case is an example, has a peak incidence at 3 months after therapy, but late cardiomyopathy can present years after treatment. The usual outcome is either death or survival after cardiac transplantation. The dose-related cardiomyopathy induced by anthracyclines may be explained largely by the induction of irreversible oxidative damage to cardiac mitochondria. These organelles are highly susceptible to the effects of anthracyclines due to the presence of a unique enzyme (reduced nicotinamide adenine dinucleotide dehydrogenase) in their inner mitochondrial membrane.4 This enzyme reduces anthracyclines to their semi-quinones, ultimately resulting in severe oxidative damage to mitochondrial DNA that leads to reductions in cellular energy production and ultimately to apoptosis of cardiomyocytes. Evidence is increasing that concurrent administration of CoQ10 can prevent or reduce these undesirable side effects.5–7 The lipid-soluble antioxidant CoQ10 is an integral component of the mitochondrial respiratory chain and has successfully been used in the treatment of cardiac failure.8 In this patient, the LVAD was implanted as a bridge to transplant, with a planned 1-year support time in which to confirm remission from the NHL. To have averted or delayed cardiac transplantation avoids the well-known limitations of transplantation, including limited duration of allograft survival and the accompanying risks of immunosuppression. In this patient, perhaps more importantly, the potential for an adverse effect of immunosuppression on her NHL was also avoided. The International Society of Heart and Lung Transplantation (ISHLT) Mechanical Circulatory Support database confirms that only 5% of all reported LVAD implants worldwide effect a myocardial recovery outcome.9 Most reported cases of cardiac recovery have involved volume displacement devices with their inherent volume (fill to empty) mode, facility for complete unloading of the heart, and controlled weaning through rate reduction and modulation of stroke volume.4 Continuous flow devices by their design do not have such advantages, the general belief is that ventricular unloading is incomplete with these devices, hence providing a sub-optimal platform for cardiac recovery. In conclusion, the current case exemplifies 2 important principles relevant to clinical practice. First, mechanical circulatory support of selected patients with cytotoxic-induced cardiomyopathy may identify a subpopulation with the potential for cardiac recovery and a putative role for metabolic therapy. Second, the use of smaller, continuous flow devices is a viable treatment
The Journal of Heart and Lung Transplantation Volume 28, Number 1
modality in this setting, and myocardial recovery is possible. REFERENCES 1. Leprince P, Combes A, Bonnet N, et al. Circulatory support for fulminant myocarditis: consideration for implantation, weaning and explantation. Eur J Cardiothorac Surg 2003;24:399 – 403. 2. Dandel M, Weng Y, Siniawski H, et al. Long-term results in patients with idiopathic dilated cardiomyopathy after weaning from left ventricular assist devices. Circulation.2005;112:1–37. 3. Esmore DS, Kaye D, Salamonen R, et al. Initial clinical experience with the VentrAssist left ventricular assist device: the pilot trial. J Heart Lung Transplant 2008;27:479 – 85. 4. Fisher NG, Marshall AJ. Anthracycline-induced cardiomyopathy. UK Postgrad Med J 1999;75:265– 8.
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5. Van Dalen EC, Caron HN, Dickinson HO, Kremer LC. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 2005;CD003917. 6. Wouters KA, Kremer LC, Miller TL, Herman EH, Lipshultz SE. Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol 2005;131: 561–78. 7. Conklin KA. Coenzyme q10 for prevention of anthracycline induced cardiotoxicity. Integr Cancer Ther 2005;4;110 –30. 8. Sander S, Coleman CI, Patel AA, Kluger I, White CH. The impact of coenzyme Q10 on systolic function in patients with chronic heart failure. J Card Fail 2006;12:464 –72. 9. Deng MC, Edwards LB, Hertz MI, et al. Mechanical Circulatory Support Device Database of the International Society for Heart and Lung Transplantation: third annual report—2005. J Heart Lung Transplant 2005;24:1182–7.