Eric A. Rose

Reversal of chronic ventricular dilation in patients with end-stage cardiomyopathy by prolonged mechanical unloading.

BACKGROUND Ventricular dilation, indexed by marked shifts toward larger volumes of the end-diastolic pressure-volume relation (EDPVR), has been considered to represent an irreversible aspect of ventricular remodeling in end-stage heart failure. However, we hypothesized that such dilation could be reversed with sufficient hemodynamic unloading, such as can be provided by a left ventricular assist device (LVAD). METHODS AND RESULTS The EDPVRs of hearts from seven patients with end-stage idiopathic cardiomyopathy and comparable baseline hemodynamics were measured ex vivo at the time of cardiac transplantation; these were compared with EDPVRs from three normal human hearts that were technically unsuitable for transplantation. Four of the patients received optimal medical therapy; three of the patients, who deteriorated on optimal therapy, underwent LVAD support for approximately 4 months. Compared with the normal hearts, EDPVRs of hearts from medically treated patients were shifted toward markedly larger volumes. In contrast, EDPVRs of hearts from LVAD patients were similar to those of normal hearts. CONCLUSIONS Chronic hemodynamic unloading of sufficient magnitude and duration can result in reversal of chamber enlargement and normalization of cardiac structure as indexed by the EDPVR, both important aspects of remodeling, even in the most advanced stages of heart failure.

Selection and Treatment of Candidates for Heart Transplantation A Statement for Health Professionals From the Committee on Heart Failure and Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association

Improved outcome of heart failure in response to medical therapy, coupled with a critical shortage of donor organs, makes it imperative to restrict heart transplantation to patients who are most disabled by heart failure and who are likely to derive the maximum benefit from transplantation. Hemodynamic and functional indexes of prognosis are helpful in identifying these patients. Stratification of ambulatory heart failure patients by objective criteria, such as peak exercise oxygen consumption, has improved ability to select appropriate adult patients for heart transplantation. Such patients will have a poor prognosis despite optimal medical therapy. When determining the impact of individual comorbid conditions on a patients candidacy for heart transplantation, the detrimental effects of each condition on posttransplantation outcome should be weighed. Evaluation of patients with severe heart failure should be done by a multidisciplinary team that is expert in management of heart failure, performance of cardiac surgery in patients with low left ventricular ejection fraction, and transplantation. Potential heart transplant candidates should be reevaluated on a regular basis to assess continued need for transplantation. Long-term management of heart failure should include continuity of care by an experienced physician, optimal dosing in conventional therapy, and periodic reevaluation of left ventricular function and exercise capacity. The outcome of high-risk conventional cardiovascular surgery should be weighed against that of transplantation in patients with ischemic and valvular heart disease. Establishment of regional specialized heart failure centers may improve access to optimal medical therapy and new promising medical and surgical treatments for these patients as well as stimulate investigative efforts to accelerate progress in this critical area.

Low Incidence of Myocardial Recovery After Left Ventricular Assist Device Implantation in Patients With Chronic Heart Failure

BACKGROUND Mechanical, histological, and biochemical improvement has been described in patients after left ventricular assist device (LVAD) support. Explantation of the LVADs without heart transplantation has been described in selected patients who received this therapy as a bridge to transplantation. METHODS AND RESULTS A retrospective review of patients receiving a mechanical bridge to transplantation at Columbia Presbyterian Hospital after July 21, 1991, was performed to determine the incidence of patients in whom the device was successfully explanted. From August 1, 1996, to February 1, 1998, we prospectively attempted to identify potential explant candidates by the use of exercise testing. During this time, we recruited 39 consecutive patients after insertion of the Thermo Cardiosystems vented electric device to participate in the following study. Approximately 3 months after device implantation, a maximal exercise test with hemodynamic monitoring and respiratory gas analysis was performed with the LVAD in the automated mode. The electric device was interfaced with a pneumatic console such that the rate could be decreased to 20 cycles/min. Hemodynamic measurements were recorded as the device rate was decreased. A repeat exercise test was then performed if the patient remained hemodynamically stable. A retrospective chart review of 111 LVAD recipients at our institution identified only 5 successful explant patients. Eighteen of the 39 patients were studied. Fifteen patients exercised with maximal device support. At peak exercise, VO2 averaged 14.5+/-3.6 mL. kg-1. min-1; LVAD flow, 8.0+/-1.3 L/min; Fick cardiac output, 11.4+/-3.3 L/min; and pulmonary capillary wedge pressure, 13+/-4 mm Hg. Seven patients remained normotensive and could exercise at a fixed rate of 20 cycles/min. In these patients, peak VO2 declined from 17.3+/-3.9 to 13.0+/-6.1 mL. kg-1. min-1. In one of these patients, the device was explanted. CONCLUSIONS Significant myocardial recovery after LVAD therapy in patients with end-stage congestive heart failure occurs in a small percentage of patients. Most of these patients have dilated cardiomyopathy. Exercise testing may be a useful modality to identify those patients in whom the device can be explanted.

Multicenter clinical evaluation of the HeartMate 1000 IP left ventricular assist device

The Thermo Cardiosystems Inc (Woburn, MA) HeartMate 1000 IP left ventricular assist device (LVAD) has been evaluated as a bridge to transplantation in 34 patients for up to 324 days at seven clinical centers in the United States. Sixty-five percent of the patients underwent transplantation, 80% of whom were discharged from the hospital. Six additional control patients, transplant candidates who met the entrance criteria but who did not receive the device, were also included in the study. Although 3 (50%) of the control patients received transplants, all 6 died within 77 days of having met the LVAD inclusion criteria (100% mortality). Complications resulting from use of the device were comparable with those previously reported for all ventricular assist devices, except for thromboembolic events: bleeding, 39%; infection, 25%; and right heart failure, 21%. No device-related thromboembolic events occurred, although 1 patient experienced an event related to a mechanical aortic valve in the native heart. None of the complications had a significant negative association with outcome of the patient except for right heart failure. All survivors had a significant improvement in hepatic function before transplantation. Total bilirubin values were reduced by 60% during LVAD support. No significant differences were observed when total bilirubin values were compared at 30 and 60 days after LVAD support and at 30 and 60 days after transplantation in a cohort of 15 patients (p greater than 0.05). The improvement in renal function was less predictable than that of hepatic function. Creatinine values decreased significantly before transplantation; however, the values measured at 30 and 60 days after transplantation were higher than those measured at the same intervals after LVAD support had been initiated, and this increase is presumably related to the immunosuppressive drugs. In conclusion, the HeartMate 1000 IP LVAD has been shown to be effective in supporting end-stage cardiomyopathy patients to transplantation. Thromboembolism, previously regarded as a serious complication with such devices, has not been a problem with this device. Additional patients are being enrolled into the study to further document the safety and effectiveness of this technology.

The REMATCH trial: rationale, design, and end points

BACKGROUND Because left ventricular assist devices have recently been approved by the Food and Drug Administration to support the circulation of patients with end-stage heart failure awaiting cardiac transplantation, these devices are increasingly being considered as a potential alternative to biologic cardiac replacement. The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial is a multicenter study supported by the National Heart, Lung, and Blood Institute to compare long-term implantation of left ventricular assist devices with optimal medical management for patients with end-stage heart failure who require, but do not qualify to receive cardiac transplantation. METHODS We discuss the rationale for conducting REMATCH, the obstacles to designing this and other randomized surgical trials, the lessons learned in conducting the multicenter pilot study, and the features of the REMATCH study design (objectives, target population, treatments, end points, analysis, and trial organization). CONCLUSIONS We consider what will be learned from REMATCH, expectations for expanding the use of left ventricular assist devices, and future directions for assessing clinical procedures.

Persistent allopeptide reactivity and epitope spreading in chronic rejection of organ allografts.

The role of the indirect allorecognition pathway in acute allograft rejection has been documented both in organ recipients and in experimental models. However, it is unknown whether self-restricted recognition of donor alloantigens also contributes to chronic allograft rejection. The aim of this study was to determine the relationship between allopeptide reactivity, epitope spreading, and chronic rejection. Using synthetic peptides corresponding to the hypervariable region of 32 HLA-DR alleles, we have followed the specificity of self-restricted T cell alloresponses to the donor in a population of 34 heart allograft recipients. T cells from sequential samples of blood collected from the patients up to 36 mo after transplantation were studied in limiting dilution analysis for allopeptide reactivity. The incidence of coronary artery vasculopathy (CAV) was significantly higher in patients who displayed persistent alloreactivity late after transplantation than in patients who showed no alloreactivity after the first 6 mo after transplantation. Both intra- and intermolecular spreading of epitopes was observed with an increased frequency in patients developing CAV in less than 2 yr, compared with patients without CAV; this suggests that diversification of the immune response against the graft contributes to chronic rejection. These data provide a strategy for identifying patients at risk of developing CAV and a rationale for therapeutic intervention aimed to prevent the progression of the rejection process.

Improved mortality and rehabilitation of transplant candidates treated with a long-term implantable left ventricular assist system

ObjectiveThis nonrandomized study using concurrent controls was performed to determine whether the HeartMate implantable pneumatic (IP) left ventricular assist system (LVAS) could provide sufficient hemodynamic support to allow rehabilitation of severely debilitated transplant candidates and to evaluate whether such support reduced mortality before and after transplantation. MethodsOutcomes of 75 LVAS patients were compared with outcomes of 33 control patients (not treated with an LVAS) at 17 centers in the United States. All patients were transplant candidates who met the following hemodynamic criteria: pulmonary capillary wedge pressure ≥ 20 mm Hg with a systolic blood pressure ≤ 80 mm Hg or a cardiac index ≤ 2.0 L/minute/m2. In addition, none of the patients met predetermined exclusion criteria. ResultsMore LVAS patients than control patients survived to transplantation: 53 (71%) versus 12 (36%) (p = 0.001); and more LVAS patients were alive at 1 year: 48 (91%) versus 8 (67%) (p = 0.0001). The time to transplantation was longer in the group supported with the LVAS (average, 76 days; range, <1–344 days) than in the control group (average, 12 days; range, 1–72 days). In the LVAS group, the average pump index (2.77 L/minute/m2) throughout support was 50% greater than the corresponding cardiac index (1.86 L/minute/m2) at implantation (p = 0.0001). In addition, 58% of LVAS patients with renal dysfunction survived, compared with 16% of the control patients (p < 0.001). ConclusionsThe LVAS provided adequate hemodynamic support and was effective in rehabilitating patients based on improved renal, hepatic, and physical capacity assessments over time. In the LVAS

Management of vasodilatory shock after cardiac surgery: Identification of predisposing factors and use of a novel pressor agent

BACKGROUND Cardiopulmonary bypass can be associated with vasodilatory hypotension requiring pressor support. We have previously found arginine vasopressin to be a remarkably effective pressor in a variety of vasodilatory shock states. We investigated the incidence and clinical predictors of vasodilatory shock in a general population of cardiac surgical patients and the effects of low-dose arginine vasopressin as treatment of this syndrome in patients with heart failure. METHODS Patients undergoing cardiopulmonary bypass (n = 145) were studied prospectively. Preoperative ejection fraction, medications, and perioperative hemodynamics were recorded, and postbypass serum arginine vasopressin levels were measured. Vasodilatory shock was defined as a mean arterial pressure lower than 70 mm Hg, a cardiac index greater than 2.5 L/min/m2, and norepinephrine dependence. Predictors of vasodilatory shock were investigated by logistic regression analysis. The hemodynamic responses of patients who received arginine vasopressin infusions for vasodilatory shock after cardiopulmonary bypass for left ventricular assist device placement or heart transplantation were analyzed retrospectively. RESULTS Eleven of 145 general cardiac surgery patients (8%) met criteria for postbypass vasodilatory shock. By multivariate analysis, an ejection fraction lower than 0.35 and angiotensin-converting enzyme inhibitor use were independent predictors of postbypass vasodilatory shock (relative risks of 9.1 and 11.9, respectively). Vasodilatory shock was associated with inappropriately low serum arginine vasopressin concentrations (12.0 +/- 6.6 pg/mL). Retrospective analysis found 40 patients with postbypass vasodilatory shock who received low-dose arginine vasopressin infusions, resulting in increased mean arterial pressure and decreased norepinephrine requirements. CONCLUSIONS Low ejection fraction and angiotensin-converting enzyme inhibitor use are risk factors for postbypass vasodilatory shock, and this syndrome is associated with vasopressin deficiency. In patients exhibiting this syndrome after high-risk cardiac operations, replacement of arginine vasopressin increases blood pressure and reduces catecholamine pressor requirements.

INDIRECT RECOGNITION OF DONOR HLA-DR PEPTIDES IN ORGAN ALLOGRAFT REJECTION

To determine whether indirect allorecognition is involved in heart allograft rejection T cells obtained from peripheral blood and graft biopsy tissues were expanded in the presence of IL-2 and tested in limiting dilution analysis (LDA) for reactivity to synthetic peptides corresponding to the hypervariable regions of the mismatched HLA-DR antigen(s) of the donor. Serial studies of 32 patients showed that T cell reactivity to donor allopeptides was strongly associated with episodes of acute rejection. The frequency of allopeptide reactive T cells was 10-50-fold higher in the graft than in the periphery indicating that T cells activated via the indirect allorecognition pathway participate actively in acute allograft rejection. In recipients carrying a graft differing by two HLA-DR alleles the response appeared to target only one of the mismatched antigens of the donor. Indirect allorecognition was restricted by a single HLA-DR antigen of the host and directed against one immunodominant peptide of donor HLA-DR protein. However, intermolecular spreading was demonstrated in patients with multiple rejection episodes by showing that they develop allopeptide reactivity against the second HLA-DR antigen. These data imply that early treatment to suppress T cell responses through the indirect pathway of allorecognition, such as tolerance induction to the dominant donor determinant, may be required to prevent amplification and perpetuation of the rejection process.

Bridge experience with long-term implantable left ventricular assist devices: Are they an alternative to transplantation?

BACKGROUND If long-term use of left ventricular assist devices (LVADs) as bridges to transplantation is successful, the issue of permanent device implantation in lieu of transplantation could be addressed through the creation of appropriately designed trials. Our medium-term experience with both pneumatically and electrically powered ThermoCardiosystems LVADs is presented to outline the benefits and limitations of device support in lieu of transplantation. METHODS AND RESULTS Detailed records were kept prospectively for all patients undergoing LVAD insertion. Fifty-eight LVADs were inserted over 5 years, with a survival rate of 74%. Mean patient age was 50 years, and duration of support averaged 98 days. Although common, both preexisting infection and infection during LVAD support were not associated with increased mortality or decreased rate of successful transplantation. Thromboembolic complications were rare, occurring in only three patients (5%) despite the absence of anticoagulation. Ventricular arrhythmias were well tolerated in all patients except in cases of early perioperative right ventricular failure, with no deaths. Right ventricular failure occurred in one third of patients and was managed in a small percentage by right ventricular assist device (RVAD) support and/or inhaled nitric oxide therapy. There were no serious device malfunctions, but five graft-related hemorrhages resulted in two deaths. Finally, a variety of noncardiac surgical procedures were performed in LVAD recipients, with no major morbidity and mortality. CONCLUSIONS Over all, our medium-term experience with implantable LVAD support is encouraging. Although additional areas of investigation exist, improvements in patients selection and management together with device alterations that have reduced the thromboembolic incidence and facilitated patient rehabilitation lead us to believe that a prospective, randomized trial is indicated to study the role that LVADs may have as an alternative to medical management.