- Email: [email protected]
Low rate of cardiac recovery despite cellular recovery during LVAD support: results from the LVAD working group
S52
Abstracts
J. Segovia, L. Alonso-Pulpo ´ n, P. Ortiz, J. Jime´nez-Mazuecos, F. Alfonso, J. Escaned, R. Herna ´ ndez-Antolı´n, C. Macaya, Cardiac Transplant Unit, Clı´nica Puerta de Hierro, Madrid, Spain; Interventional Cardiology Dept, Hosp. Clı´nico, Madrid, Spain Graft vessel disease (GVD) is a frequent and letal late complication of heart transplantation (HTx). The only effective treatment for severe GVD is retransplantation, an option not available for most patients. In recently published trials using intracoronary ultrasound (ICUS), TORinhibitors sirolimus and everolimus have proved their efficacy in the prevention of initial stages of GVD. We designed a prospective, randomized, unicentric preliminary study in order to evaluate the role of sirolimus in the treatment of established GVD. Method: HTx recipients with more than 50% angiographic stenosis in at least one major coronary vessel were randomized in a 2:1 fashion to receive either sirolimus in combination with low-dose cyclosporine ⫾ prednisone or to maintain their basal immunosuppression (cyclosporine, MMF or azathioprine ⫾ prednisone). Basal coronary study of 3–5 coronary segments with a 30 MHz ICUS catheter with automated pull-back at a speed of 0.5 mm/s is performed. A second ICUS study of the same coronary segments will take plece 6 ⫾ 2 months later. The primary endpoint of the study is the difference in the volume of coronary lesions in the same coronary segments when comparing both studies. Secondary endpoints include other ICUS parameters (maximal intimal thickness, crossectional plaque area, intimal index, luminal and external vessel dimensions), as well as clinical efficacy and safety variables. Twenty patients have been included in the study after signing informed consent. All basal and most (80%) post-intervention ICUS studies have been performed already. The last procedure is scheduled for January 2004. A total number of 70 – 80 coronary segments will be compared: 50 –55 segments in 14 patients in sirolimus arm, and 20 –25 segments in 6 patients in the control group. Quantitative, parallel, off-line analysis of both ICUS studies will be performed by two expert cardiologists unaware of treatment allocation of each patient. Data analysis will be ready by March 2004. 30 LOW RATE OF CARDIAC RECOVERY DESPITE CELLULAR RECOVERY DURING LVAD SUPPORT: RESULTS FROM THE LVAD WORKING GROUP S. Maybaum,1 O.H. Frazier,2 R. Starling,3 L. Miller,4 S. Murali,5 K. Aaronson,6 K. Margulies,7 S. Xydas,1 S. McRee,8 G. Torre,8 1 Columbia Univ, NY, NY; 2Texas Heart Inst, Houston, TX; 3The Cleveland Clin, Cleveland, OH; 4Univ of Minn, Minneapolis, MN; 5 Univ of Pitt, Pittsburgh, PA; 6Univ of Mich, Ann Arbor, MI; 7 Temple Univ, Philadelphia, PA; 8Baylor Coll of Med, Houston, TX Background: The rate of cardiac recovery during LVAD support is unknown. The LVAD Working Group is a multicenter prospective study aiming to define the rate, time course and durability of recovery during LVAD support. Methods: Patients undergo monthly evaluation, including echo at full and reduced LVAD flow and exercise testing. Hemodynamic stress testing is performed in patients with improved resting function. Myocardial tissue samples from implant and explant are analyzed. Results: 64 patients with HF for 58 ⫾ 70 months underwent LVAD implant over 14 months. Duration of LVAD support was 165.6 ⫾ 85 days. 32 patients have been transplanted, 6 have expired and 22 remain on LVAD support. After 30 days, there was significant improvement in left ventricular (LV) ejection fraction (35.4 ⫾ 14.1% vs 16.6 ⫾ 6.9) and reduction in LVEDD (4.8 ⫾ 1.0 cm vs 7.2 ⫾ 1.2) and LV mass (198 ⫾ 82 g vs 321 ⫾ 118) vs pre-LVAD (all p ⬍ .001). 36% of patients had LVEF ⬎ 40% with device flow reduced to 4 L/min at 30 days. LVEF peaked at 30 days and then plateaued while LV mass
The Journal of Heart and Lung Transplantation February 2004
decreased with time. No differences were seen between ischemic (44%) and non-ischemic (56%) patients. With longer support, there was significant improvement in peak oxygen consumption (13.4 ⫾ 4.1 vs 19.1 ⫾ 6.4 ml/kg/min, 30 vs 120 days, p ⬍ .01). Thirteen patients (20%) with improved resting function underwent hemodynamic stress testing and 4 patients (6.3%) with acute HF (⬍30 days) underwent explantation and have normal LV function after 20 –27 weeks. No patients with chronic HF underwent LVAD explantation. Tissue analysis revealed a significant drop in myocyte size, collagen content and cardiac TNF in all patients studied (implant vs explant, p ⬍ .01 for all variables). Conclusions: While cellular recovery and improvement in LV function is seen with LVAD support, the degree of recovery is insufficient for explantation in chronic HF. The addition of novel medical therapies may modify these results. 31 MECHANICAL UNLOADING REVERSES ALTERATIONS IN CYTOSKELETAL PROTEINS IN THE FAILING HUMAN HEART L.A. Aquila-Pastir,1 P.M. McCarthy,2 J.B. Young,1 C.S. Moravec,1 1 Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH; 2Thoracic and Cardiovascular Surgery, Cleveland Clinic Foundation, Cleveland, OH The cytoskeleton maintains the size and shape of cardiac myocytes, and may participate in intracellular signaling. Data from our lab (J Mol Cell Cardiol 34:1513–1523, 2002) and others suggest that cytoskeletal alterations may have structural and functional ramifications during human hypertrophy and heart failure. If these alterations are reversible, they may have therapeutic implications. We tested the hypothesis that mechanical unloading of the failing human heart with a left ventricular assist device (LVAD) would cause reversal of alterations in the cytoskeletal proteins vinculin, desmin, and -tubulin, using a combination of immunofluorescence and quantitative immunoblotting on 8 nonfailing (NF), 10 hypertrophied (H), 7 failing and 12 LVAD (L) supported human hearts. Desmin protein was significantly increased in F vs NF, both by immunoblotting and confocal microscopy, and the increases were reversed in L. Vinculin protein was not quantitatively different in H or F, but staining for vinculin at the intercalated discs was significantly decreased in H and absent in F (vs NF), and this pattern was consistently reversed in L. -tubulin quantitation was not different in H or F vs NF, but the density of the -tubulin network was significantly increased in F vs NF, and was reversed by L. Increased density of staining with no change in protein quantitation suggests increased polymerization of -tubulin in F, and reversal following LVAD. Data from this study suggest that alterations in the intracellular scaffolding structure of the cardiac myocyte during human heart failure are reversible and may thus serve as a therapeutic target. 32 SUSTAINED REVERSAL OF ELECTRICAL REMODELING DURING AND AFTER LEFT VENTRICULAR ASSIST DEVICE (LVAD) SUPPORT J. Hardy,1 C. Terracciano,1 P. Tansley,1 E. Birks,1 C. Bowles,1 A. Khaghani,1 N. Banner,1 M. Yacoub,1 1Cardiothoracic Surgery, Harefield Hospital, Harefield, Middlesex, United Kingdom Electrical remodeling (prolonged QT interval) is common in severe heart failure and is associated with increased mortality. Use of LVADs results in reversal of structural and electrical remodeling in patients bridged to transplant. The relationship between structural and electrical remodeling as well as changes in electrical remodeling follow-
Abstracts
J. Segovia, L. Alonso-Pulpo ´ n, P. Ortiz, J. Jime´nez-Mazuecos, F. Alfonso, J. Escaned, R. Herna ´ ndez-Antolı´n, C. Macaya, Cardiac Transplant Unit, Clı´nica Puerta de Hierro, Madrid, Spain; Interventional Cardiology Dept, Hosp. Clı´nico, Madrid, Spain Graft vessel disease (GVD) is a frequent and letal late complication of heart transplantation (HTx). The only effective treatment for severe GVD is retransplantation, an option not available for most patients. In recently published trials using intracoronary ultrasound (ICUS), TORinhibitors sirolimus and everolimus have proved their efficacy in the prevention of initial stages of GVD. We designed a prospective, randomized, unicentric preliminary study in order to evaluate the role of sirolimus in the treatment of established GVD. Method: HTx recipients with more than 50% angiographic stenosis in at least one major coronary vessel were randomized in a 2:1 fashion to receive either sirolimus in combination with low-dose cyclosporine ⫾ prednisone or to maintain their basal immunosuppression (cyclosporine, MMF or azathioprine ⫾ prednisone). Basal coronary study of 3–5 coronary segments with a 30 MHz ICUS catheter with automated pull-back at a speed of 0.5 mm/s is performed. A second ICUS study of the same coronary segments will take plece 6 ⫾ 2 months later. The primary endpoint of the study is the difference in the volume of coronary lesions in the same coronary segments when comparing both studies. Secondary endpoints include other ICUS parameters (maximal intimal thickness, crossectional plaque area, intimal index, luminal and external vessel dimensions), as well as clinical efficacy and safety variables. Twenty patients have been included in the study after signing informed consent. All basal and most (80%) post-intervention ICUS studies have been performed already. The last procedure is scheduled for January 2004. A total number of 70 – 80 coronary segments will be compared: 50 –55 segments in 14 patients in sirolimus arm, and 20 –25 segments in 6 patients in the control group. Quantitative, parallel, off-line analysis of both ICUS studies will be performed by two expert cardiologists unaware of treatment allocation of each patient. Data analysis will be ready by March 2004. 30 LOW RATE OF CARDIAC RECOVERY DESPITE CELLULAR RECOVERY DURING LVAD SUPPORT: RESULTS FROM THE LVAD WORKING GROUP S. Maybaum,1 O.H. Frazier,2 R. Starling,3 L. Miller,4 S. Murali,5 K. Aaronson,6 K. Margulies,7 S. Xydas,1 S. McRee,8 G. Torre,8 1 Columbia Univ, NY, NY; 2Texas Heart Inst, Houston, TX; 3The Cleveland Clin, Cleveland, OH; 4Univ of Minn, Minneapolis, MN; 5 Univ of Pitt, Pittsburgh, PA; 6Univ of Mich, Ann Arbor, MI; 7 Temple Univ, Philadelphia, PA; 8Baylor Coll of Med, Houston, TX Background: The rate of cardiac recovery during LVAD support is unknown. The LVAD Working Group is a multicenter prospective study aiming to define the rate, time course and durability of recovery during LVAD support. Methods: Patients undergo monthly evaluation, including echo at full and reduced LVAD flow and exercise testing. Hemodynamic stress testing is performed in patients with improved resting function. Myocardial tissue samples from implant and explant are analyzed. Results: 64 patients with HF for 58 ⫾ 70 months underwent LVAD implant over 14 months. Duration of LVAD support was 165.6 ⫾ 85 days. 32 patients have been transplanted, 6 have expired and 22 remain on LVAD support. After 30 days, there was significant improvement in left ventricular (LV) ejection fraction (35.4 ⫾ 14.1% vs 16.6 ⫾ 6.9) and reduction in LVEDD (4.8 ⫾ 1.0 cm vs 7.2 ⫾ 1.2) and LV mass (198 ⫾ 82 g vs 321 ⫾ 118) vs pre-LVAD (all p ⬍ .001). 36% of patients had LVEF ⬎ 40% with device flow reduced to 4 L/min at 30 days. LVEF peaked at 30 days and then plateaued while LV mass
The Journal of Heart and Lung Transplantation February 2004
decreased with time. No differences were seen between ischemic (44%) and non-ischemic (56%) patients. With longer support, there was significant improvement in peak oxygen consumption (13.4 ⫾ 4.1 vs 19.1 ⫾ 6.4 ml/kg/min, 30 vs 120 days, p ⬍ .01). Thirteen patients (20%) with improved resting function underwent hemodynamic stress testing and 4 patients (6.3%) with acute HF (⬍30 days) underwent explantation and have normal LV function after 20 –27 weeks. No patients with chronic HF underwent LVAD explantation. Tissue analysis revealed a significant drop in myocyte size, collagen content and cardiac TNF in all patients studied (implant vs explant, p ⬍ .01 for all variables). Conclusions: While cellular recovery and improvement in LV function is seen with LVAD support, the degree of recovery is insufficient for explantation in chronic HF. The addition of novel medical therapies may modify these results. 31 MECHANICAL UNLOADING REVERSES ALTERATIONS IN CYTOSKELETAL PROTEINS IN THE FAILING HUMAN HEART L.A. Aquila-Pastir,1 P.M. McCarthy,2 J.B. Young,1 C.S. Moravec,1 1 Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH; 2Thoracic and Cardiovascular Surgery, Cleveland Clinic Foundation, Cleveland, OH The cytoskeleton maintains the size and shape of cardiac myocytes, and may participate in intracellular signaling. Data from our lab (J Mol Cell Cardiol 34:1513–1523, 2002) and others suggest that cytoskeletal alterations may have structural and functional ramifications during human hypertrophy and heart failure. If these alterations are reversible, they may have therapeutic implications. We tested the hypothesis that mechanical unloading of the failing human heart with a left ventricular assist device (LVAD) would cause reversal of alterations in the cytoskeletal proteins vinculin, desmin, and -tubulin, using a combination of immunofluorescence and quantitative immunoblotting on 8 nonfailing (NF), 10 hypertrophied (H), 7 failing and 12 LVAD (L) supported human hearts. Desmin protein was significantly increased in F vs NF, both by immunoblotting and confocal microscopy, and the increases were reversed in L. Vinculin protein was not quantitatively different in H or F, but staining for vinculin at the intercalated discs was significantly decreased in H and absent in F (vs NF), and this pattern was consistently reversed in L. -tubulin quantitation was not different in H or F vs NF, but the density of the -tubulin network was significantly increased in F vs NF, and was reversed by L. Increased density of staining with no change in protein quantitation suggests increased polymerization of -tubulin in F, and reversal following LVAD. Data from this study suggest that alterations in the intracellular scaffolding structure of the cardiac myocyte during human heart failure are reversible and may thus serve as a therapeutic target. 32 SUSTAINED REVERSAL OF ELECTRICAL REMODELING DURING AND AFTER LEFT VENTRICULAR ASSIST DEVICE (LVAD) SUPPORT J. Hardy,1 C. Terracciano,1 P. Tansley,1 E. Birks,1 C. Bowles,1 A. Khaghani,1 N. Banner,1 M. Yacoub,1 1Cardiothoracic Surgery, Harefield Hospital, Harefield, Middlesex, United Kingdom Electrical remodeling (prolonged QT interval) is common in severe heart failure and is associated with increased mortality. Use of LVADs results in reversal of structural and electrical remodeling in patients bridged to transplant. The relationship between structural and electrical remodeling as well as changes in electrical remodeling follow-