Daniel J. Goldstein

The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: Executive summary

Institutional Affiliations Co-chairs Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, Georgia Institute of Technology and Morehouse School of Medicine; Pamboukian SV: University of Alabama at Birmingham, Birmingham, Alabama; Teuteberg JJ: University of Pittsburgh, Pittsburgh, Pennsylvania Task force chairs Birks E: University of Louisville, Louisville, Kentucky; Lietz K: Loyola University, Chicago, Maywood, Illinois; Moore SA: Massachusetts General Hospital, Boston, Massachusetts; Morgan JA: Henry Ford Hospital, Detroit, Michigan Contributing writers Arabia F: Mayo Clinic Arizona, Phoenix, Arizona; Bauman ME: University of Alberta, Alberta, Canada; Buchholz HW: University of Alberta, Stollery Children’s Hospital and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada; Deng M: University of California at Los Angeles, Los Angeles, California; Dickstein ML: Columbia University, New York, New York; El-Banayosy A: Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania; Elliot T: Inova Fairfax, Falls Church, Virginia; Goldstein DJ: Montefiore Medical Center, New York, New York; Grady KL: Northwestern University, Chicago, Illinois; Jones K: Alfred Hospital, Melbourne, Australia; Hryniewicz K: Minneapolis Heart Institute, Minneapolis, Minnesota; John R: University of Minnesota, Minneapolis, Minnesota; Kaan A: St. Paul’s Hospital, Vancouver, British Columbia, Canada; Kusne S: Mayo Clinic Arizona, Phoenix, Arizona; Loebe M: Methodist Hospital, Houston, Texas; Massicotte P: University of Alberta, Stollery Children’s Hospital, Edmonton, Alberta, Canada; Moazami N: Minneapolis Heart Institute, Minneapolis, Minnesota; Mohacsi P: University Hospital, Bern, Switzerland; Mooney M: Sentara Norfolk, Virginia Beach, Virginia; Nelson T: Mayo Clinic Arizona, Phoenix, Arizona; Pagani F: University of Michigan, Ann Arbor, Michigan; Perry W: Integris Baptist Health Care, Oklahoma City, Oklahoma; Potapov EV: Deutsches Herzzentrum Berlin, Berlin, Germany; Rame JE: University of Pennsylvania, Philadelphia, Pennsylvania; Russell SD: Johns Hopkins, Baltimore, Maryland; Sorensen EN: University of Maryland, Baltimore, Maryland; Sun B: Minneapolis Heart Institute, Minneapolis, Minnesota; Strueber M: Hannover Medical School, Hanover, Germany Independent reviewers Mangi AA: Yale University School of Medicine, New Haven, Connecticut; Petty MG: University of Minnesota Medical Center, Fairview, Minneapolis, Minnesota; Rogers J: Duke University Medical Center, Durham, North Carolina

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.

Cyclosporine-associated end-stage nephropathy after cardiac transplantation : Incidence and progression

BACKGROUND The salutary immunosuppressive effects of cyclosporine in extending cardiac allograft survival may be curtailed by its nephrotoxic effects. We reviewed our first 9 years of experience with cyclosporine after cardiac transplantation, to evaluate the incidence and progression of cyclosporine-associated end-stage renal failure necessitating chronic hemodialysis. METHODS Retrospective computer-based file review and personal interview when possible. RESULTS The population at risk was comprised of all adult cardiac recipients surviving at least 3 years (n=293). Of these, 19 (6.5%) developed end-stage renal failure requiring chronic hemodialysis. There were 17 men and 2 women (mean age of 45 +/- 11 years). The mean creatinine clearance for the study group decreased by 38% (P<0.001 vs. before transplant) by 6 months after transplantation and by 48% by 3 years postoperatively (P<0.001 vs. before transplant). The mean serum creatinine rose by 80% (P< 0.001 vs. before transplant) by 6 months after transplantation and by 125% by 3 years postoperatively (P<0.001 vs. before transplant). Time elapsed from transplantation to hemodialysis ranged from 3.7 to 9.5 years (mean 6.4 +/- 2). Actuarial 1- year survival after onset of hemodialysis was 75%. CONCLUSIONS Although cyclosporine remains the central immunosuppressive agent for cardiac allograft recipients, its use leads to a greater than one-third decrease in creatinine clearance by 6 months after transplantation and progression to end-stage renal failure, requiring hemodialysis in 6.5% of cardiac transplant recipients. Moreover, these patients are at increased risk of death compared with other cardiac allograft recipients. This data warrants the search of alternative or adjunctive agents that would allow decreased dosing or reduced nephrotoxicity of cyclosporine, while maintaining equivalent survival.

Existence of the Frank-Starling Mechanism in the Failing Human Heart Investigations on the Organ, Tissue, and Sarcomere Levels

BACKGROUND The Frank-Starling mechanism is one of the most important physiological principles for regulation of contractile performance. We therefore studied the question of whether this mechanism may be absent or attenuated in end-stage failing human left ventricular myocardium. METHODS AND RESULTS Different methodological approaches were used to analyze the effects of this mechanism on the organ, tissue, and sarcomere levels: (1) In excised human whole left ventricles (2 donor hearts, 5 failing hearts), diastolic and systolic pressure-volume relationships were obtained. (2) In isolated muscle strip preparations from the left ventricular wall of donor hearts (n = 14) and failing hearts from patients with idiopathic dilated cardiomyopathy (n = 21) and ischemic cardiomyopathy (n = 11), peak developed force was measured at different muscle lengths of the preparation. (3) Skinned fiber preparations were obtained from failing right and left ventricles (n = 12). In all three studies, we clearly observed the existence of the Frank-Starling mechanism: (1) In isolated failing human left ventricles, peak developed isometric pressure is increased when the preload is elevated. (2) Peak developed tension is increased by approximately 50% to 70% (P < .01) in left ventricular preparations of failing and nonfailing ventricles when the muscles are stretched from 90% to 100% optimum length. (3) An increase in sarcomere length leads to a sensitization of contractile proteins of ventricular skinned fiber preparations from failing human hearts. At 1.9-microns sarcomere length, the EC50 value was 5.56 +/- 0.06, and at 2.3 microns it was 5.70 +/- 0.05 (P < .01; n = 7). CONCLUSIONS The Frank-Starling mechanism is maintained in end-stage failing human hearts, whereas significant alterations of diastolic myocardial distensibility are evident in chronic heart failure.

Screening Scale Predicts Patients Successfully Receiving Long-term Implantable Left Ventricular Assist Devices

BACKGROUND Although use of long-term implantable left ventricular assist devices (LVAD) is becoming more popular, further reduction of the mortality rate accompanying device insertion through improved patient selection would make this alternative even more appealing. We sought to develop a scoring system that was based on criteria obtainable at the time of evaluation and predictive of successful early outcome and simple to apply. METHODS AND RESULTS Patients (n = 56) undergoing LVAD insertion between 1990 and 1994 were screened for easily obtainable preoperative risk factors. To test the association between survival and each risk factor, a chi 2 analysis was performed, and relative risks were estimated. Oliguria, ventilator dependence, elevated central venous pressure, elevated prothrombin time, and reoperation stats had low probability values and high estimated relative risks. On the basis of these relations, a risk factor-selection scale (RFSS) (range, 0 to 10) was developed by computing appropriate weights for each risk factor. The distribution of patients for each scale score reveal that with RFSS > or = 5, most device recipients will die (P < .001). The average RFSS (+/- SD) of survivors (n = 42) was 2.45 +/- 1.73 compared with 5.43 +/- 2.85 in nonsurvivors (n = 14) (P < .0001). Univariate logistical regression was also significant (score statistic, 16.2; df = 1; P = .001). CONCLUSIONS The RFSS is simple, easy to apply, and statistically valid. Physicians could use the scale as a starting point in discussing the suitability for LVAD implantation in a specific patient and as a basis for comparing patient outcomes.

A Fully Magnetically Levitated Circulatory Pump for Advanced Heart Failure

Background Continuous‐flow left ventricular assist systems increase the rate of survival among patients with advanced heart failure but are associated with the development of pump thrombosis. We investigated the effects of a new magnetically levitated centrifugal continuous‐flow pump that was engineered to avert thrombosis. Methods We randomly assigned patients with advanced heart failure to receive either the new centrifugal continuous‐flow pump or a commercially available axial continuous‐flow pump. Patients could be enrolled irrespective of the intended goal of pump support (bridge to transplantation or destination therapy). The primary end point was a composite of survival free of disabling stroke (with disabling stroke indicated by a modified Rankin score >3; scores range from 0 to 6, with higher scores indicating more severe disability) or survival free of reoperation to replace or remove the device at 6 months after implantation. The trial was powered for noninferiority testing of the primary end point (noninferiority margin, ‐10 percentage points). Results Of 294 patients, 152 were assigned to the centrifugal‐flow pump group and 142 to the axial‐flow pump group. In the intention‐to‐treat population, the primary end point occurred in 131 patients (86.2%) in the centrifugal‐flow pump group and in 109 (76.8%) in the axial‐flow pump group (absolute difference, 9.4 percentage points; 95% lower confidence boundary, ‐2.1 [P<0.001 for noninferiority]; hazard ratio, 0.55; 95% confidence interval [CI], 0.32 to 0.95 [two‐tailed P=0.04 for superiority]). There were no significant between‐group differences in the rates of death or disabling stroke, but reoperation for pump malfunction was less frequent in the centrifugal‐flow pump group than in the axial‐flow pump group (1 [0.7%] vs. 11 [7.7%]; hazard ratio, 0.08; 95% CI, 0.01 to 0.60; P=0.002). Suspected or confirmed pump thrombosis occurred in no patients in the centrifugal‐flow pump group and in 14 patients (10.1%) in the axial‐flow pump group. Conclusions Among patients with advanced heart failure, implantation of a fully magnetically levitated centrifugal‐flow pump was associated with better outcomes at 6 months than was implantation of an axial‐flow pump, primarily because of the lower rate of reoperation for pump malfunction. (Funded by St. Jude Medical; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755.)

Worldwide Experience With the MicroMed DeBakey Ventricular Assist Device® as a Bridge to Transplantation

Background—Ventricular assist device (VAD) support with pulsatile first generation pumps is a well-established therapy for bridging to transplantation. Shortcomings of this technology include limited applicability to small patients, noise, and high incidence of infection and pump malfunction. A second generation of pumps, spearheaded by the axial flow MicroMed DeBakey VAD®, is in clinical trials and potentially will address these shortcomings. Methods and Results—Between November 13, 1998 and May 7, 2002, 150 patients worldwide underwent placement of the Micromed DeBakey VAD® as a bridge to transplantation. Prospectively acquired data including demographics, adverse events and outcomes was collected. Follow up is 100% with 30.4 patient-years of cumulative support time. Mean age was 48±4 years and 18% were female. Twenty-three percent had prior sternotomy. Preoperatively, 25% were on balloon pump support, 20% had renal insufficiency, and 40% were on at least two inotropes with a mean cardiac index of 1.8 L/min/m2. Mean support time was 75±81 days. Linearized rates (events/patient-year) were: reoperation for bleeding 2.03, hemolysis 0.61, device infection 0.16, thromboembolic event 0.61, pump thrombus 0.61, and pump failure 0.13. Eight-two patients (55%) were either bridged to transplantation, recovery or are ongoing and 68 (45%) have died. Several patients have been supported as outpatients. Conclusions—This initial experience suggests that bridging to transplantation can be successfully approached with a small and quiet axial flow pump that provides low incidence of device infection and pump failure. The incidence of pump thrombus and thromboembolism is being addressed by incorporation of heparin coating to all device surfaces.

Use of aprotinin in LVAD recipients reduces blood loss, blood use, and perioperative mortality

Aprotinin, a bovine protease inhibitor, has been used extensively in patients undergoing cardiac surgical procedures in an effort to minimize blood loss and prevent the complications associated with blood replacement. We sought to evaluate the effect of aprotinin on postoperative blood loss, renal function, and the incidence of right ventricular failure in patients undergoing placement of a TCI Heartmate left ventricular assist device as a bridge to cardiac transplantation. Retrospective data analysis in 142 patients (42 receiving aprotinin and 100 untreated) demonstrated that the use of aprotinin was associated with a significant decrease in postoperative blood loss (p = 0.019) and in the intraoperative packed red blood cell transfusion (p = 0.019) and total blood product (p = 0.016) requirements. A transient, yet significant, increase in the postoperative creatinine level in the aprotinin group (p = 0.0006), but not in blood urea nitrogen level (p = 0.22), was noted. Interestingly, we noted an association between blood loss and the subsequent development of right ventricular failure; patients who required a right ventricular assist device bled significantly more than did those who did not suffer right ventricular failure (p = 0.02). Additionally, aprotinin recipients benefited by a reduction of nearly one half in the incidence of the need for a right ventricular assist device. The incidence of perioperative mortality was reduced in those receiving aprotinin compared with that in untreated patients, (p = 0.05). We conclude that aprotinin is safe and effective in decreasing postoperative blood loss and intraoperative blood product requirements, and in reducing perioperative mortality in patients undergoing left ventricular assist device placement as a bridge to cardiac transplantation.

Outpatient Left Ventricular Assist Device Support: A Destination Rather Than a Bridge

BACKGROUND To evaluate the feasibility and efficacy of outpatient left ventricular assist devices as a bridge to transplantation, we reviewed the initial clinical experience with this modality at our institution. METHODS During January 1993 to November 1995, 12 male and 2 female patients with an average age of 47 +/- 17 years were supported for an average of 117 +/- 24 days with the Thermo Cardiosystems VE wearable left ventricular assist device. Seven patients were discharged home an average of 35 +/- 4 days after implantation. RESULTS No device failures occurred, although 29 controller malfunctions were identified during 1,640 total support days. All patients were able to safely maintain their devices. Outflow graft bleeding and driveline infection were responsible for two readmissions. No long-term anticoagulation treatment was used; one small thromboembolic episode occurred, but without significant long-term sequelae. CONCLUSIONS None of the 7 patients released from the hospital died, and all were able to successfully maintain their devices at home. Hospital discharge of patients supported with left ventricular assist devices has allowed long-term evaluation of this technology, and the findings should prompt study of their use as a long-term alternative treatment to medical management for congestive heart failure.

Circulatory Resuscitation With Left Ventricular Assist Device Support Reduces Interleukins 6 and 8 Levels

BACKGROUND Elevated tumor necrosis factor serum levels have been reported in patients with severe congestive heart failure. This study was designed to characterize the cytokine profile in patients with acute circulatory collapse. METHODS Blood drawn from 14 consecutive patients within 24 hours before undergoing left ventricular assist device placement and after at least 30 days of mechanical assistance or before transplantation was assayed for levels of interleukin 6, interleukin 8, and tumor necrosis factor-alpha. RESULTS Interleukin 6 level was elevated in 11 (79%), interleukin 8 in 10 (71%), and tumor necrosis factor in 2 (14%) of the 14 patients. After hemodynamic recovery, interleukin 6 levels decreased from 33.6 +/- 9 pg/mL to 11.3 +/- 4 pg/mL (p = 0.05) and interleukin 8 levels decreased from 122 +/- 34 pg/mL to 19.7 +/- 8 pg/mL (p = 0.005). Tumor necrosis factor-alpha levels did not vary significantly; they were associated with infection in 2 left ventricular assist device recipients and normalized after left ventricular assist device support. All patients had resolution of circulatory shock after mechanical support and had improvement in parameters of end-organ function. CONCLUSIONS Circulatory shock treated with left ventricular assist device placement is associated with a proinflammatory response similar to that seen in septic shock. The decrease in cytokine serum levels that follows hemodynamic recovery suggests that these cytokines may be markers of tissue damage and may modulate cardiac dysfunction.