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Towards Donor Lung Recovery - Gene Expression Changes During Ex Vivo Lung Perfusion
Abstracts S39 range 0-5.2%, n= 2) and lamin A/C (1.4%, range 0.4-3.2%, n= 1) mutations showed a threefold increase in P62 staining. A tenfold positive staining was found in desmosomal mutations (PKP2 and DSP; 3.8%, range 0-10%, n= 3). Phospholamban mutations (8.3%, range 0.8-39%, n= 9) and desminopathies (desmin and Alpha-B crystallin; 18% of cardiomyocytes, range 0.8-48%, n= 2), especially the Alpha-B crystallin mutation (31%, range 11-48%, n= 1), showed the highest number of P62 positive cells. Conclusion: Accumulation of P62 positive protein aggregates is associated with the type of mutation underlying the dilated cardiomyopathy. Titin, lamin A/C and troponin mutations revealed little protein aggregation, whereas desminopathies, phospholamban and desmosomal mutations show abundant aggregates. This suggests that the type of mutation plays an important role in determining distinct mechanisms of cardiomyocyte cell death. 8( 1) Coronary Allograft Arteriosclerosis: Local MicroRNA Modulation Using a Novel Anti-Mir-21-Eluting Stent Prevents in-Stent Restenosis D. Wang ,1 T. Deuse,2 M. Stubbendorff,1 E. Chernogubova,3 R.G. Erben,4 S.M. Eken,3 H. Jin,3 C. Heeger,5 B. Behnisch,6 H. Reichenspurner,2 R.C. Robbins,7 J.M. Spin,8 P.S. Tsao,9 L. Maegdefessel,3 S. Schrepfer.10 1University Heart Center Hamburg, Transplant and Stem Cell Immunobiology Lab (TSI), Hamburg, Germany; 2CT Surgery, University Heart Center Hamburg, Hamburg, Germany; 3Atherosclerosis Research Unit, Karolinska Institute, Stockholm, Sweden; 4Veterinary Medicine, University of Vienna, Vienna, Austria; 5Department of Cardiology Asklepios Clinic St. Georg, Hamburg, Germany; 6Translumina GmbH, Hechingen, Hechingen, Germany; 7CT Surgery, Stanford University, Stanford, CA; 8Veterans Affairs Palo Alto Health Care System, Stanford University, Stanford, CA; [email protected], Stanford University, Stanford, CA; 10Stanford University Transplant and Stem Cell Immunobiology Lab (TSI), Stanford, CA. Purpose: A major cause of organ graft loss after heart transplantation is accelerated coronary allograft arteriosclerosis which is characterized by myointimal proliferation (MH) consisting mainly of smooth muscle cells (SMCs). The central role of microRNAs (miRNAs) in molecular pathophysiology of MH may offer attractive concepts for possible therapeutic interventions. However, since systemic miRNA modulation is feared to cause substantial off-target effects, this would hamper its clinical use. For the first time, we herein report on the feasibility of local miRNA modulation using stent coating. Methods: A humanized animal model, utilizing balloon-injured human internal mammary arteries (IMAs) with or without stent in RNU rats was used (n= 6 per group) and compared to human tissue samples. Of 8 miRNA candidates associated with vascular (patho)physiology, 7 miRNAs were downregulated and only miR-21 was upregulated. Therefore, therapeutic miR-21 repression was attempted using intravenous application of FAM-taggedLNA-anti-miR-21 (anti-21) in our humanized MH-model (n= 7/group). Results: The suppression of vascular miR-21 expression correlated with a reduction of luminal obliteration and the anti-21 effect was dose-dependent. Systemic anti-21 did not impede vessel re-endothelialization. However, miR-21 expression in liver, heart, lung, and kidney were also significantly reduced and serum creatinine was increased. Thus, systemic miRNA modulation caused substantial off-target effects. We sought to assess the feasibility of local miR-21 suppression using anti-21-eluting stents. When compared to bare metal stents, anti-21-coated stents effectively reduced MH. We did not observe any off-target effects with local anti-21 delivery. Conclusion: This is the first study to demonstrate the efficacy of an anti21-eluting stent for the reduction of MH by inhibition of smooth muscle cell proliferation and preservation of ultrastructurally and physiological normal endothelial cells. 8( 2) Human Induced Pluripotent Stem Cells for Tissue Engineered Cardiac Repair S. Pecha ,1 F. Weinberger,2 K. Breckwoldt,2 B. Geertz,2 J. Starbatty,2 A. Hansen,1 H. Reichenspurner,3 T. Eschenhagen.1 1Cardiovascular Surgery, Univ Hospital Hamburg, Hamburg, Germany; 2Experimental Pharmacology and Toxicology, University Medical Center HamburgEppendorf, Hamburg, Germany; 3Cardiovascular Surgery, University Hospital Hamburg, Hamburg, Germany.
Purpose: Myocardial infarction causes unrecoverable loss of cardiomyocytes. Engineered heart tissue (EHT) is an in vitro model of three-dimensional, force generating cardiomyocyte network. In this study we transplanted EHTs from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CM) on cryo-injured guinea pig hearts and investigated whether hiPSC-CM-EHTs support left ventricular function. Methods: Human iPSC were generated by retroviral reprogramming of dermal fibroblasts. Cardiac differentiation of hiPSC was performed by an embryoid body-based three-stage differentiation protocol. EHTs were created from hiPS-CM (5*10^6 cardiomyocytes and 2*10^6 GFP+-HUVECs per EHT). Left ventricular cryo-injury was induced in guinea pigs (n= 21). 7 days after injury EHTs (2 per animal, n= 12) or cell-free constructs (n= 9) were implanted. All animals received immunosuppression. Functional parameters were examined by echocardiography and histology at baseline, before and 28 days after transplantation. Results: HiPSC-CM-EHTs displayed morphological properties of native heart tissue. Cryo-injury resulted in large transmural scars, which were verified histologically. Immunohistochemical staining for dystrophin and MLC2v showed the formation of large islets of cross-striated muscle tissue in the scar. The human origin was demonstrated by fluorescent-in-situ-hybridization. The new myocardium was vascularized with endothelium partly being of human origin. Animals receiving cell-free constructs showed left ventricular dilatation 28 days after transplantation. The EHT-group showed less dilatation (LV end-diastolic diameter 8.9±0.4 mm vs. 9.7±0.7 mm in 28d control [basal 8.1±0.2 mm, 7d post cryo-injury 8.2±0.2 mm]) and significantly better fractional area shortening (42.0±4.5% vs. 23.0±3.2% in 28d control [basal 42.2±1.9%, 7d post cryo-injury 26.1±2.1%]). Conclusion: Transplantation of hiPSC-derived EHTs in a guinea pig cryoinjury model generates new myocardium and improves cardiac function.
8( 3) Towards Donor Lung Recovery - Gene Expression Changes During Ex Vivo Lung Perfusion J.C. Yeung , R. Zamel, X. Bai, T.N. Machuca, M. Liu, M. Cypel, S. Keshavjee. Toronto Lung Transplant Program, University of Toronto, Toronto, ON, Canada. Purpose: Acellular normothermic ex vivo lung perfusion (EVLP) of high-risk donor lungs has resulted in post-transplant clinical outcomes equivalent to current lung transplantation. However, the mechanism of this effect remains unclear. We examined the gene expression changes occurring in human lungs during 12h of EVLP to better explain this phenomenon. Methods: 10 human donor lungs clinically rejected for transplantation were procured using our clinical standard cold preservation. EVLP was performed for 12h and biopsies taken at 0h, 1h, 3h, 6h, 9h, and 12h. mRNA was hybridized to Affymetrix(U133+2.0) microarrays. Robust multi-array average was used for probe summarization and temporal gene changes were identified using the Short Time-series Expression Miner (STEM). The biological consequences of these gene expression changes were analyzed using Ingenuity Pathway Analysis (IPA). Results: All ten lungs completed 12h of EVLP with stable physiological parameters. STEM identified 2585 genes to significantly change expression during EVLP. Despite increases in expression of endothelial markers of inflammation (eg: log ratio 0h-12h of E-selectin= 2.33), circulating cell-specific gene expression fell (eg: log ratio 0h-12h of L-selectin= -2.33,
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The Journal of Heart and Lung Transplantation, Vol 34, No 4S, April 2015
hemoglobin B= -2.75, CD36= -1.33, CCR5= -1.61) during 12h of EVLP, suggesting donor leukocyte washout. Upstream analysis to identify gene expression regulators was confounded by this washout of circulating cells. The overall biological effects of gene expression changes predicted by IPA were cell death (z-score 4.1), cell survival (z= 5.1), cell survival (z= 4.8), invasion of cells (z= 3.3), and formation of epithelial tissue (z= 2.8) at 1h, 3h, 6h, 9h, and 12h, respectively. Conclusion: EVLP acts as a platform for donor lung recovery prior to the subsequent insult of post-implantation reperfusion. Circulating donor leukocytes are washed out of the lung during EVLP and this can potentially interrupt the donor-APC mediated inflammatory response. The gene expression signature of cell death at 1h of EVLP suggests an initial response to clear damaged cells. All subsequent gene expression signatures suggest survival and a proliferative response for repair. At the time of post-implantation reperfusion, EVLP donor lungs will start with this beneficial gene expression signature as opposed to the pro-inflammatory signature of donor lungs stored cold. 8( 4) Long Term Measurements of Aortic Root and Left Ventricular Dimensions in Patients on HeartWare® Ventricular Assist Device - An Explanation for the Development of Aortic Incompetence in Chronic LVAD Support? S.K. Bhagra ,1 C.J. Bhagra,1 N. Wrightson,2 G.A. MacGowan,1 S. Schueler.3 1Cardiology, Freeman Hospital, Newcastle Upon Tyne, United Kingdom; 2Cardipulmonary Transplantation, Freeman Hospital, Newcastle Upon Tyne, United Kingdom; 3Cardiothoracic Surgery, Freeman Hospital, Newcastle Upon Tyne, United Kingdom. Purpose: We investigated the serial changes in left ventricular (LV) dimensions and aortic root size in our adult patient cohort supported by the HeartWare® ventricular assist device (HVAD). We hypothesised that in those who develop mild or more de-novo aortic incompetence (AI) the aortic root dilates whilst LV dimensions remain unchanged. Methods: A retrospective analysis of echocardiograms was performed on those who had HVAD implanted over a 3.5 yr period. 101 HVAD’s were implanted in 96 patients.Echocardiograms performed pre and at 1 and 2 years post were analysed. Only those with native aortic valves and an HVAD for 6 months were included, and grouped into those with none or trace AI or mild or more AI. Results: 84.5% were male, mean age 47+/– 12.6 yrs.Dilated cardiomyopathy was etiology in 53.5%. Mean duration of HVAD support was 624 +/– 359 days. Aortic annulus dimensions significantly increased in both groups at 1 and 2 years (Tables 1,2). At 2 years in those with AI the Sinuses of Valsalva were also larger, p= 0.002. LVEDD significantly reduced in those with no or trace AI at 1 and 2 years but remained unchanged in those with AI at both points. Conclusion: Long term HVAD support leads to dilatation of the aortic annulus, and additional root dilatation in those with mild or more AI overtime. The proximity of the outflow graft insertion to the aortic root with the constant strain of flow may explain these findings. Further studies should focus on alternate insertion sites of the outflow graft, more distant to the aortic root.
Table 1: 1 year
Change in serial aortic root and LV dimensions in those supported out to
Implants = 53Echo = 48
Aortic annulus (mm) Sinus of Valsalva (mm) LV end diastolic dimension (LVEDD, mm) LV end systolic dimension (LVESD, mm)
None or trace AI (n= 35)Mean +/– SDMedian (IQR)
P value
Pre Implant 1 Year 20 (20,22) 22 (21,24) 0.006 29.1 +/– 3.0 67.7 +/– 9.6
28.9 +/– 3.0 60.2 +/v 13.4
60.0 +/– 10.6
52.6 +/– 14.3
0.814 0.012
0.024
Mild or more AI (n= 13) Mean +/– SDMedian (IQR)
P value
Pre Implant 20.0 +/– 2.8 29.1 +/– 2.3 67.5 +/– 10.5
1 Year 22.6 +/– 3.0 30.1 +/– 3.9 64.1 +/– 10.8
60.3 +/– 11.8
58.8 +/– 13.0
0.05 0.5 0.42
0.79
Table 2:
Change in serial aortic root and LV dimensions in those supported out to
2 years Mild or more AI* (n= 8)
None or trace AI (n= 19) Implants = Mean +/– 31Echo = SDMedian (IQR) 27 Pre 1 year Implant Aortic Annulus (mm) Sinus of Valsalva (mm) LVEDD (mm) LVESD (mm)
Mean +/– SDMedian (IQR) 2 Year
P value
Pre 1 Year Implant
2 Year
20.7 +/– 22.7 +/– 23.1 +/– 20.3 +/– 21.8 +/– 23.1 +/– 0.008; 0.013* 2.9 2.2 3.0 3.2 3.1 2.6 29.9 +/– 30.5 +/– 31.3 +/– 29 +/– 3.6 2.9 3.7 2.3
28.8 +/– 31.9 5.5 +/– 7
0.056; 0.002*
67.8 +/– 61.4 +/– 61.7 +/– 65 (57.5, 59 (56, 57.5 (55, 0.008; 73) 64) 62) 0.96* 9.0 12.8 12.7 61 (51,65)55 (39.5, 61 (44, 57 +/– 57.8 +/– 57.3 +/– 0.94; 65.5) 67.5) 0.95* 9.9 8.5 8.5
8( 5) Remission From Stage D Heart Failure (RESTAGE-HF): Early Results From a Prospective Multi-Center Study of Myocardial Recovery E.J. Birks ,1 S. Drakos,2 C. Selzman,3 R. Starling,4 C. Cunningham,5 M. Slaughter,6 D.M. Spevack,7 A. Salahuddin,7 P. Alturi,8 B. Lowes,9 S. Patel,10 D. Farrar,11 F. Kallel,11 J.E. Rame.12 1Cardiovascular Medicine, University of Louisville, Louisville, KY; 2Cardiovascular Medicine, University of Utah, Salt Lake City, UT; 3Cardiovascular Surgery, University of Utah, Salt Lake City, UT; 4Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH; 5Clinical Trials Unit, University of Louisville, Louisville, KY; 6Cardiovascular Surgery, University of Louisville, Louisville, KY; 7Department of Echocardiography, Montefiore, New York, NY; 8Cardiovascular Surgery, University of Pennsylvania, Philadelphia, PA; 9Cardiovascular Medicine, University of Nebraska, Omaha, NE; 10Cardiovascular Medicine, Montefiore, New York, NY; 11Thoratec Corporation, Pleasanton, CA; 12Cardiovascular Medicine, University of Pennsylvania, Philadelphia, PA. Purpose: Although the rate of clinically significant myocardial recovery or “remission “ from advanced heart failure sufficient to allow device explantation is generally considered to be low in the overall population, LVADs are usually implanted as a bridge to transplantation or as destination therapy with little/no attempt at promoting and testing for myocardial recovery. Methods: We designed a multi-center prospective study consisting of a combination of prolonged optimized mechanical unloading with the HeartMate II LVAD together with a standardized protocol of specific pharmacological therapy (designed to induce profound reverse structural remodeling and reduce fibrosis) and regular testing of underlying myocardial function. Pump speed was optimized for maximal unloading early after implant. Echocardiography was performed at low LVAD speed operation at 6000 rpm for 5 and 15 min with a 6 minute walk at 6 weeks, 4, 6, 9 and 12-18 months after implantation. In this report we present initial results from the first 22/40 patients with non ischemic dilated cardiomyopathy enrolled from 5 sites. Results: The mean age was 36 years (19-55), 68% DT, 67% caucasian, and 81% were male. Mean EF pre-LVAD implant was 15% (10-20), EDD 76 mm (59-95), ESD 68 mm (51-89). At implant 61% of the patients were INTERMACS 1&2 and 39% were INTERMACS 3&4. The history of HF was 1-5 years, 3-6 months, and < 3 months in 48%, 33% and 19% of the patients respectively. The average duration of support to date is 222 days (14-445). Two patients expired post-implant at day 14 and 106. Of the remaining 20, so far five patients have reached the study pre-defined explant criteria and have been successfully explanted after a support duration of 265 days (197-417), the rest are ongoing. The median age of the 5 explanted patients is 45 years (42-55), 3 were BTT and 3 were male. Among the explanted patients, one patient committed suicide 2 weeks post-explant due a psychosocial condition, the rest are alive and well. Median duration post explant is 138 days (14-383) to date.
Purpose: Myocardial infarction causes unrecoverable loss of cardiomyocytes. Engineered heart tissue (EHT) is an in vitro model of three-dimensional, force generating cardiomyocyte network. In this study we transplanted EHTs from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CM) on cryo-injured guinea pig hearts and investigated whether hiPSC-CM-EHTs support left ventricular function. Methods: Human iPSC were generated by retroviral reprogramming of dermal fibroblasts. Cardiac differentiation of hiPSC was performed by an embryoid body-based three-stage differentiation protocol. EHTs were created from hiPS-CM (5*10^6 cardiomyocytes and 2*10^6 GFP+-HUVECs per EHT). Left ventricular cryo-injury was induced in guinea pigs (n= 21). 7 days after injury EHTs (2 per animal, n= 12) or cell-free constructs (n= 9) were implanted. All animals received immunosuppression. Functional parameters were examined by echocardiography and histology at baseline, before and 28 days after transplantation. Results: HiPSC-CM-EHTs displayed morphological properties of native heart tissue. Cryo-injury resulted in large transmural scars, which were verified histologically. Immunohistochemical staining for dystrophin and MLC2v showed the formation of large islets of cross-striated muscle tissue in the scar. The human origin was demonstrated by fluorescent-in-situ-hybridization. The new myocardium was vascularized with endothelium partly being of human origin. Animals receiving cell-free constructs showed left ventricular dilatation 28 days after transplantation. The EHT-group showed less dilatation (LV end-diastolic diameter 8.9±0.4 mm vs. 9.7±0.7 mm in 28d control [basal 8.1±0.2 mm, 7d post cryo-injury 8.2±0.2 mm]) and significantly better fractional area shortening (42.0±4.5% vs. 23.0±3.2% in 28d control [basal 42.2±1.9%, 7d post cryo-injury 26.1±2.1%]). Conclusion: Transplantation of hiPSC-derived EHTs in a guinea pig cryoinjury model generates new myocardium and improves cardiac function.
8( 3) Towards Donor Lung Recovery - Gene Expression Changes During Ex Vivo Lung Perfusion J.C. Yeung , R. Zamel, X. Bai, T.N. Machuca, M. Liu, M. Cypel, S. Keshavjee. Toronto Lung Transplant Program, University of Toronto, Toronto, ON, Canada. Purpose: Acellular normothermic ex vivo lung perfusion (EVLP) of high-risk donor lungs has resulted in post-transplant clinical outcomes equivalent to current lung transplantation. However, the mechanism of this effect remains unclear. We examined the gene expression changes occurring in human lungs during 12h of EVLP to better explain this phenomenon. Methods: 10 human donor lungs clinically rejected for transplantation were procured using our clinical standard cold preservation. EVLP was performed for 12h and biopsies taken at 0h, 1h, 3h, 6h, 9h, and 12h. mRNA was hybridized to Affymetrix(U133+2.0) microarrays. Robust multi-array average was used for probe summarization and temporal gene changes were identified using the Short Time-series Expression Miner (STEM). The biological consequences of these gene expression changes were analyzed using Ingenuity Pathway Analysis (IPA). Results: All ten lungs completed 12h of EVLP with stable physiological parameters. STEM identified 2585 genes to significantly change expression during EVLP. Despite increases in expression of endothelial markers of inflammation (eg: log ratio 0h-12h of E-selectin= 2.33), circulating cell-specific gene expression fell (eg: log ratio 0h-12h of L-selectin= -2.33,
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The Journal of Heart and Lung Transplantation, Vol 34, No 4S, April 2015
hemoglobin B= -2.75, CD36= -1.33, CCR5= -1.61) during 12h of EVLP, suggesting donor leukocyte washout. Upstream analysis to identify gene expression regulators was confounded by this washout of circulating cells. The overall biological effects of gene expression changes predicted by IPA were cell death (z-score 4.1), cell survival (z= 5.1), cell survival (z= 4.8), invasion of cells (z= 3.3), and formation of epithelial tissue (z= 2.8) at 1h, 3h, 6h, 9h, and 12h, respectively. Conclusion: EVLP acts as a platform for donor lung recovery prior to the subsequent insult of post-implantation reperfusion. Circulating donor leukocytes are washed out of the lung during EVLP and this can potentially interrupt the donor-APC mediated inflammatory response. The gene expression signature of cell death at 1h of EVLP suggests an initial response to clear damaged cells. All subsequent gene expression signatures suggest survival and a proliferative response for repair. At the time of post-implantation reperfusion, EVLP donor lungs will start with this beneficial gene expression signature as opposed to the pro-inflammatory signature of donor lungs stored cold. 8( 4) Long Term Measurements of Aortic Root and Left Ventricular Dimensions in Patients on HeartWare® Ventricular Assist Device - An Explanation for the Development of Aortic Incompetence in Chronic LVAD Support? S.K. Bhagra ,1 C.J. Bhagra,1 N. Wrightson,2 G.A. MacGowan,1 S. Schueler.3 1Cardiology, Freeman Hospital, Newcastle Upon Tyne, United Kingdom; 2Cardipulmonary Transplantation, Freeman Hospital, Newcastle Upon Tyne, United Kingdom; 3Cardiothoracic Surgery, Freeman Hospital, Newcastle Upon Tyne, United Kingdom. Purpose: We investigated the serial changes in left ventricular (LV) dimensions and aortic root size in our adult patient cohort supported by the HeartWare® ventricular assist device (HVAD). We hypothesised that in those who develop mild or more de-novo aortic incompetence (AI) the aortic root dilates whilst LV dimensions remain unchanged. Methods: A retrospective analysis of echocardiograms was performed on those who had HVAD implanted over a 3.5 yr period. 101 HVAD’s were implanted in 96 patients.Echocardiograms performed pre and at 1 and 2 years post were analysed. Only those with native aortic valves and an HVAD for 6 months were included, and grouped into those with none or trace AI or mild or more AI. Results: 84.5% were male, mean age 47+/– 12.6 yrs.Dilated cardiomyopathy was etiology in 53.5%. Mean duration of HVAD support was 624 +/– 359 days. Aortic annulus dimensions significantly increased in both groups at 1 and 2 years (Tables 1,2). At 2 years in those with AI the Sinuses of Valsalva were also larger, p= 0.002. LVEDD significantly reduced in those with no or trace AI at 1 and 2 years but remained unchanged in those with AI at both points. Conclusion: Long term HVAD support leads to dilatation of the aortic annulus, and additional root dilatation in those with mild or more AI overtime. The proximity of the outflow graft insertion to the aortic root with the constant strain of flow may explain these findings. Further studies should focus on alternate insertion sites of the outflow graft, more distant to the aortic root.
Table 1: 1 year
Change in serial aortic root and LV dimensions in those supported out to
Implants = 53Echo = 48
Aortic annulus (mm) Sinus of Valsalva (mm) LV end diastolic dimension (LVEDD, mm) LV end systolic dimension (LVESD, mm)
None or trace AI (n= 35)Mean +/– SDMedian (IQR)
P value
Pre Implant 1 Year 20 (20,22) 22 (21,24) 0.006 29.1 +/– 3.0 67.7 +/– 9.6
28.9 +/– 3.0 60.2 +/v 13.4
60.0 +/– 10.6
52.6 +/– 14.3
0.814 0.012
0.024
Mild or more AI (n= 13) Mean +/– SDMedian (IQR)
P value
Pre Implant 20.0 +/– 2.8 29.1 +/– 2.3 67.5 +/– 10.5
1 Year 22.6 +/– 3.0 30.1 +/– 3.9 64.1 +/– 10.8
60.3 +/– 11.8
58.8 +/– 13.0
0.05 0.5 0.42
0.79
Table 2:
Change in serial aortic root and LV dimensions in those supported out to
2 years Mild or more AI* (n= 8)
None or trace AI (n= 19) Implants = Mean +/– 31Echo = SDMedian (IQR) 27 Pre 1 year Implant Aortic Annulus (mm) Sinus of Valsalva (mm) LVEDD (mm) LVESD (mm)
Mean +/– SDMedian (IQR) 2 Year
P value
Pre 1 Year Implant
2 Year
20.7 +/– 22.7 +/– 23.1 +/– 20.3 +/– 21.8 +/– 23.1 +/– 0.008; 0.013* 2.9 2.2 3.0 3.2 3.1 2.6 29.9 +/– 30.5 +/– 31.3 +/– 29 +/– 3.6 2.9 3.7 2.3
28.8 +/– 31.9 5.5 +/– 7
0.056; 0.002*
67.8 +/– 61.4 +/– 61.7 +/– 65 (57.5, 59 (56, 57.5 (55, 0.008; 73) 64) 62) 0.96* 9.0 12.8 12.7 61 (51,65)55 (39.5, 61 (44, 57 +/– 57.8 +/– 57.3 +/– 0.94; 65.5) 67.5) 0.95* 9.9 8.5 8.5
8( 5) Remission From Stage D Heart Failure (RESTAGE-HF): Early Results From a Prospective Multi-Center Study of Myocardial Recovery E.J. Birks ,1 S. Drakos,2 C. Selzman,3 R. Starling,4 C. Cunningham,5 M. Slaughter,6 D.M. Spevack,7 A. Salahuddin,7 P. Alturi,8 B. Lowes,9 S. Patel,10 D. Farrar,11 F. Kallel,11 J.E. Rame.12 1Cardiovascular Medicine, University of Louisville, Louisville, KY; 2Cardiovascular Medicine, University of Utah, Salt Lake City, UT; 3Cardiovascular Surgery, University of Utah, Salt Lake City, UT; 4Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH; 5Clinical Trials Unit, University of Louisville, Louisville, KY; 6Cardiovascular Surgery, University of Louisville, Louisville, KY; 7Department of Echocardiography, Montefiore, New York, NY; 8Cardiovascular Surgery, University of Pennsylvania, Philadelphia, PA; 9Cardiovascular Medicine, University of Nebraska, Omaha, NE; 10Cardiovascular Medicine, Montefiore, New York, NY; 11Thoratec Corporation, Pleasanton, CA; 12Cardiovascular Medicine, University of Pennsylvania, Philadelphia, PA. Purpose: Although the rate of clinically significant myocardial recovery or “remission “ from advanced heart failure sufficient to allow device explantation is generally considered to be low in the overall population, LVADs are usually implanted as a bridge to transplantation or as destination therapy with little/no attempt at promoting and testing for myocardial recovery. Methods: We designed a multi-center prospective study consisting of a combination of prolonged optimized mechanical unloading with the HeartMate II LVAD together with a standardized protocol of specific pharmacological therapy (designed to induce profound reverse structural remodeling and reduce fibrosis) and regular testing of underlying myocardial function. Pump speed was optimized for maximal unloading early after implant. Echocardiography was performed at low LVAD speed operation at 6000 rpm for 5 and 15 min with a 6 minute walk at 6 weeks, 4, 6, 9 and 12-18 months after implantation. In this report we present initial results from the first 22/40 patients with non ischemic dilated cardiomyopathy enrolled from 5 sites. Results: The mean age was 36 years (19-55), 68% DT, 67% caucasian, and 81% were male. Mean EF pre-LVAD implant was 15% (10-20), EDD 76 mm (59-95), ESD 68 mm (51-89). At implant 61% of the patients were INTERMACS 1&2 and 39% were INTERMACS 3&4. The history of HF was 1-5 years, 3-6 months, and < 3 months in 48%, 33% and 19% of the patients respectively. The average duration of support to date is 222 days (14-445). Two patients expired post-implant at day 14 and 106. Of the remaining 20, so far five patients have reached the study pre-defined explant criteria and have been successfully explanted after a support duration of 265 days (197-417), the rest are ongoing. The median age of the 5 explanted patients is 45 years (42-55), 3 were BTT and 3 were male. Among the explanted patients, one patient committed suicide 2 weeks post-explant due a psychosocial condition, the rest are alive and well. Median duration post explant is 138 days (14-383) to date.