Plasma neurohormonal expression in LVAD patients: toward hormone-guided therapeutic assessment

The Journal of Heart and Lung Transplantation Volume 22, Number 1S

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373 CHANGES IN COLLAGEN CONTENT OF THE MYOCARDIUM BY UNLOADING WITH A CARDIAC ASSIST DEVICE J. Mueller,1 H. Liang,1 Y. Weng,1 M. Pasic,1 R. Pregla,1 P. Fu,1 G. Wallukat,2 R. Hetzer,1 1Cardiac Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany; 2Max-Delbrueck-Zentrum, Berlin, Germany

372 NOVACOR LEFT VENTRICULAR ASSIST BRIDGE TO TRANSPLANT: NO SENSITIZATION OR EXCESS REJECTION AS COMPARED TO UNSUPPORTED PATIENTS D.A. Baran, I.D. Galin, R. Correa, R. DeAsla, P. Seissler, M. Chan, M.C. Courtney, D. Spielvogel, S.L. Lansman, A.L. Gass, Zena and Michael Wiener Cardiovascular Institute, Mt. Sinai Hospital, New York, NY Background: The use of ventricular assist devices (VAD) has been associated with allosensitization as well as increased rejection after cardiac transplant. We reviewed our 15-year experience with the Novacor VAD (Worldheart Inc, Canada), as a bridge to transplant (BTT). Methods: From 1986 to 2002, 48 Novacor VADs were placed of which 39 were as a BTT. 25 patients (64 %) survived to transplantation. During the same period, 213 inotrope-dependent patients were transplanted. Immune reactivity was assessed by serial panel reactive antibody (PRA) tests. Rejection frequency was compared between the VAD and non-VAD group. Immunosuppression was similar between groups (either cyclosporine or tacrolimus- based regimens). Results: The mean PRA pre- and post- VAD-placement were 12.7 ⫾ 11.8 % and 16.1 ⫾ 11.7 % respectively (p⫽NS). Biopsy frequency in the first post-transplant year was similar in both groups (14.3 ⫾ 5.1 vs. 16.0 ⫾ 5.0, p⫽NS). ISHLT 3A or 3B rejection occured at 0.97 ⫾ 1.4 and 0.90 ⫾ 1.2 per non-VAD, and VAD-supported patient respectively (p⫽NS). Rejection is detailed in the table below (all comparisons p⫽NS). One, 3- and 5-year post-transplant survival data are similar by log-rank statistic. An early mortality hazard was noted in VAD patients undergoing transplant. Overall survival for VAD-supported patients was 76.2, 69.8, and 57.1 % at 1-, 3-, and 5-years post-transplant. Conditional survival for VAD patients after the initial 7 days post-op was 84.2, 77.2, and 63.2 % at 1-, 3-, and 5-years post-transplant. Conclusion: Use of the Novacor VAD is not associated with allosensitization. Furthermore, the rejection profile is similar between VAD recipients and a large cohort of non-VAD patients. The long-term survival of BTT patients is comparable to non-VAD patients. 1st Year Post-Transplant Biopsy Results (ISHLT Grade) Pre-Transplant Support

Percent Grade 0/1A/1B

Percent Grade 2

Percent Grade 3A/3B

Inotrope Alone (n ⫽ 213) Novacor LVAD (n ⫽ 23)

81.9 ⫾ 15.5% 81.2 ⫾ 15.5%

12.3 ⫾ 13.6% 12.4 ⫾ 11.2%

5.7 ⫾ 8.3% 6.4 ⫾ 9.2%

All comparisons between non-VAD and VAD-supported patients p ⫽ NS.

Introduction: To examine the effect of ventricular assist devices (VAD) on collagen content of the myocardium (MY) we analyzed tissue samples at implantation (TSIM) and at explantation (TSEX) of the VAD from the same heart (N⫽8). We compared these results with the collagen data from the MY of patients at implantation who were later weaned from the VAD (no transplantation) due to cardiac improvement (N⫽10; TSWE) and with tissue samples from unused donor hearts (N⫽13, TSUN). Methods: At implantation the core sample and at explantation a sample of the left ventricle was taken for analysis of collagen. Results: Total collagen: Significantly (P⫽.014) less at implantation than at explantation (TSIM 8.7 ⫾ 6.1 / TSEX 13 ⫾ 7). Neutral salt-soluble collagen: Significantly less at implantation than at explantation (TSIM 3.2 ⫾ 1.8 / TSEX 4.7 ⫾ 2.1). At the time of weaning significantly (P⫽.001) more than in the unused donor hearts (TSWE 5.6 ⫾ 1.1 / TSUN 3.6 ⫾ .5). Acid soluble collagen: Significantly (P⫽.0001) less at implantation than in the MY of unused donor hearts (TSIM .2 ⫾ .2 / TSUN 1.8 ⫾ .5). Total hydroxyproline: At implantation, significantly less than at explantation (TSIM .6 ⫾ .5 / TSEX 1.6 ⫾ .9). Insoluble hydroxyproline: Significantly (P⫽.002) more in the MY at weaning than in the MY of unused donor hearts (TSWE .37 ⫾ .19 / TSUN .13 ⫾ .11). All other analyzed collagens did not differ among the groups. In the tissue of the MY taken at implantation (TSIM) only the acid-soluble collagen was found to be diminished as compared to the MY of unused donor hearts (TSUN). Conclusions: The pronounced differences in collagen content were seen between implantation and explantation. However, unloading of the heart by an assist device did not lead to a normalization of the collagen profile. 374 PLASMA NEUROHORMONAL EXPRESSION IN LVAD PATIENTS: TOWARD HORMONE-GUIDED THERAPEUTIC ASSESSMENT L.O. Thompson, M. Loebe, C.A. Skrabal, K.A. Youker, G.P. Noon, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX Objective: Brain natriuretic peptide (BNP) has been firmly established as a marker of left ventricular (LV) function. Similarly, endothelin-1 (ET-1), angiotensin II (AT II) and noradrenaline (NOR) have been shown to be of diagnostic and prognostic value in the treatment of congestive heart failure patients. The aim of this study was to analyze relationships between plasma levels of these neurohormones and LV function in LVAD recipients to determine the usefulness of serial hormonal expression in the assessment of cardiac functional rehabilitation in the LVAD setting. Methods: Plasma levels of BNP, ET-1, AT II and NOR were measured in 24 patients in end-stage CHF directly before and up to18 weeks after implantation with various devices. Patients were grouped according to device employed and etiology of heart disease (ischemic or dilated cardiomyopathy, ICMP/DCMP). Echocardiographic indices corresponding to the time of serial hormonal measurement were then evaluated.

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Results: No differences were noted preoperatively between groups. LVAD therapy significantly improved LV ejection fraction (EF%: 21%⫾3.8% to 37%⫾11.39%) and cardiac output (CO: 3.49⫾1.3 to 7.3⫾0.2 l/m) in all patients with intergroup differences; other parameters were not appreciably altered. After an initial precipitous decline, BNP, ET-1 and NOR serum levels remained significantly lower in all patients. BNP and ET-1 exhibited a striking parallelism. Both manifested a bi-phasic tendency and their trendlines revealed an inverse proportionality to corresponding EF% measurements. In contrast, no discernible pattern could be seen with AT II. Several patients (n⫽5) exhibited either no attenuation or an increase in BNP plasma levels. All were ICMP patients; most (4/5) suffered from right heart failure postoperatively and showed decreased or unchanged EF%. Conclusions: Plasma BNP and ET-1 levels strongly correlate with the status of LV function. Alterations in these levels during LVAD support may be of potential use as a therapeutic indicator. 375 THE EFFECT ON MICROVASCULAR FUNCTION OF COMBINED MECHANICAL CIRCULATORY SUPPORT AND PHARMACOLOGICAL THERAPY DURING INDUCTION OF MYOCARDIAL RECOVERY P. Tansley,1 M. Yacoub,1 O. Rimoldi,2 E. Birks,1 J. Hardy,1 M. Hipkin,1 C. Bowles,1 D. Dutka,2 P. Camici,2 1National Heart Lung Institute, Harefield Hospital, Harefield, Middlesex, United Kingdom; 2MRC Clinical Sciences Centre, Hammersmith Hospital, London, United Kingdom Low myocardial blood flow (MBF) and coronary flow reserve (CFR) from microvascular dysfunction are independent prognostic risk factors in dilated cardiomyopathy (DCM). The influence of left ventricular (LV) unloading using left ventricular assist device (LVAD) support on basal MBF and CFR has not been adequately defined. We studied 11 patients with deteriorating end stage DCM (NYHA class IV) during LVAD support combined with pharmacological therapy in a recovery program. MBF (ml/min/g) was measured with PET using 15-O labelled water at rest during device support (T1), at rest 15 min after the device was switched off following heparinization (T2), followed by hyperemia induced by a 140 mg/kg/min i.v. adenosine infusion. Rate pressure product was constant at T1 and T2. CFR was calculated as hyperemic MBF/rest MBF. Data are reported as mean⫾SD. At a mean of 317⫾193 days after LVAD implantation, mean MBF was 0.95⫾0.30 at T1 and slightly increased to 1.15⫾0.36 at T2 (p⫽ns). Mean MBF at T1 was found to be similar to the mean MBF of 11 age and gender matched normal controls 0.91⫾0.13 measured using the same technique (T1 vs controls p⫽ns). However, mean MBF at T2 was significantly higher than the control group (T2 vs controls p⬍0.05). CFR with the device off (n⫽6) was 1.83⫾1.17 compared to 4.02⫾0.82 in the 11 normal controls. In conclusion, this study has shown relatively increased basal MBF during LVAD support that could be due to an increased transmyocardial pressure gradient throughout the cardiac cycle and a reduction in LV oxygen demand. CFR however, remained impaired. These findings could have implications regarding the relationship between MBF and demand during LVAD support, the capacity of the myocardium to recover and prognosis. 376 DECLINING ADVERSE EVENT AND MORTALITY RATES OVER IMPLANT DURATION WITH THE NOVACOR LVAS: IMPLICATIONS FOR DESTINATION THERAPY

The Journal of Heart and Lung Transplantation January 2003 J.G. Rogers, M.K. Pasque, Washington University School of Medicine, St. Louis, MO Background: The Novacor威 LVAS is an implantable pulsatile left ventricular assist device with an eighteen-year worldwide clinical history in end-stage heart failure patients treated with optimal medical therapy pre-implant. A worldwide implant registry includes 982 LVAS recipients of the current implant configuration with durations to 4.3 years. Of these, 221 LVAS recipients as well as 49 control patients participated in North American clinical studies. We wanted to determine the adverse event (AE) rates and survival using combined data from these groups. Methods: Clinical data were retrospectively reviewed. AE data available from the clinical studies were analyzed for linearized rates by time period. Survival data from the clinical studies and the registry were evaluated utilizing a Bayesian statistical methodology, providing a means of analyzing recent observations in the context of prior experience. Results: Analysis of AE data for 270 patients (221 implants, 13% women) found that: (1) clinical AEs are highest in the early period of device support, particularly within the first thirty days post-implant, (2) there is no increasing AE risk for LVAS recipients over time for at least two years and (3) the total linearized AE rate for Novacor LVAS recipients is less than half (42%) of the total linearized AE rate for control patients. The relative reduction of mortality risk is 78.5% (standard deviation 7.2%) at one year and is similar across time to at least two years. The probability that LVAS survival is not superior to optimal conventional medical therapy is ⬍0.0005. Conclusions: AE rates in LVAS recipients demonstrate a positive benefit-to-risk ratio in comparison to controls and across time. There appears to be a compelling survival advantage. Implications for destination therapy are encouraging. 377 RELIABILITY OF THE NOVACOR LVAS: IMPLICATIONS FOR DESTINATION THERAPY U. Livi, Department of Cardiovascular Sciences, General Hospital S. Maria Della Misericordia, Udine, Italy As LVAS use evolves from bridge-to-transplant (BTT) to destination therapy (DT), the demonstrated high reliability and multi-year durability of the Novacor LVAS assume increasing importance. There have been no deaths attributed to device failure in 1349 total implants (including 113 implants over 1 year duration, 25 over 2 years, 9 over 3 years and 3 over 4 years). Only 16 implanted pumps (1.2%) have required replacement, for all causes. In addition, there have been four cases (0.3%) of priority transplant. Excluding instances of driveline accident, mismanagement or valve infection, there have been only ten pump replacements and three priority transplants, yielding KaplanMeier freedom from device replacement of 99.3%, 88.2% and 80.8% at 1, 2 and 3 years, respectively, and a correspondingly low linearized rate of pump replacement (below 0.1 replacements per patient year in the third year of implantation). Clinical experience has been consistent with in vitro endurance test results. In an in vitro test-to-failure evaluation of the current N100PC system, 12 systems ran an average of 4.2 years (3.04 to 5.59). Demonstrated reliability (Weibull analysis, Maximum Likelihood Estimate) was 99.99%, 99.4% and 92.7% for 1, 2 and 3-year mission times, respectively. There were no random device failures. Rather, the test revealed a single, predictable, noncatastrophic device wearout mechanism – main bearing wear – that is progressive and can be proactively and noninvasively monitored and diagnosed. Consistent with these results, the most common reason for clinical pump replacement was bearing wearout. The wear signature characterized in the in vitro test