Harvey S. Borovetz

HeartMate II Left Ventricular Assist System: From Concept to First Clinical Use

The HeartMate II left ventricular assist device (LVAD) (ThermoCardiosystems, Inc, Woburn, MA) has evolved from 1991 when a partnership was struck between the McGowan Center of the University of Pittsburgh and Nimbus Company. Early iterations were conceptually based on axial-flow mini-pumps (Hemopump) and began with purge bearings. As the project developed, so did the understanding of new bearings, computational fluid design and flow visualization, and speed control algorithms. The acquisition of Nimbus by ThermoCardiosystems, Inc (TCI) sped developments of cannulas, controller, and power/monitor units. The system has been successfully tested in more than 40 calves since 1997 and the first human implant occurred in July 2000. Multicenter safety and feasibility trials are planned for Europe and soon thereafter a trial will be started in the United States to test 6-month survival in end-stage heart failure.

The National Heart, Lung, and Blood Institute Pediatric Circulatory Support Program

Options for the circulatory support of pediatric patients under the age of 5 years are currently limited to short-term extracorporeal devices, the use of which is often complicated by infection, bleeding, and thromboembolism. Recognizing this void, the National Heart, Lung, and Blood Institute solicited proposals for the development of novel circulatory support systems for infants and children from 2 to 25 kg with congenital or acquired cardiovascular disease. Five contracts were awarded to develop a family of devices that includes (1) an implantable mixed-flow ventricular assist device designed specifically for patients up to 2 years of age, (2) another mixed-flow ventricular assist device that can be implanted intravascularly or extravascularly depending on patient size, (3) compact integrated pediatric cardiopulmonary assist systems, (4) apically implanted axial-flow ventricular assist devices, and (5) pulsatile-flow ventricular assist devices. The common objective for these devices is to reliably provide circulatory support for infants and children while minimizing risks related to infection, bleeding, and thromboembolism. The devices are expected to be ready for clinical studies at the conclusion of the awards in 2009.

Chronic mechanical circulatory support: Rehabilitation, low morbidity, and superior survival

Because of donor scarcity, 12 (39%) of a series of 31 Novacor left ventricular assist system recipients required mechanical circulatory support for an average of 125 days before transplantation (range, 61 to 303 days). Ten received a heart transplant and all survived to discharge. Two died of infection before transplantation after 93 and 303 days of support. Significant reductions were noted from preimplantation values of right and left cardiac filling pressures. Right ventricular ejection fraction and cardiac index increased. The 4-month actuarial freedom from infection during support was 75%. Three patients benefited from chronic outpatient housing for 5, 18, and 131 days, respectively, with improvements in quality of life measures. Ten chronically supported patients participated in an intensive rehabilitative exercise program resulting in an improvement of New York Heart Association class from IV to I in 9 patients. Mean oxygen consumption, which was 10 mL.kg-1.min-1 30 days after implantation (mean exercise time, 10 minutes) had risen to 15 mL.kg-1.min-1 before transplantation (mean exercise time, 16 minutes). This series suggests that long-term circulatory support is compatible with low morbidity, significant physical and hemodynamic rehabilitation, and an outpatient setting.

Experience with univentricular support in mortally ill cardiac transplant candidates

Between July 1987 and March 1989, 11 patients underwent left ventricular support with the Novacor left ventricular assist system irrespective of apparent degree of right ventricular failure. The first 2 patients died of multisystem organ failure while on support. All the remaining patients survived the support period, and actuarial survival after transplantation was 100% at 6 months and 89% at 1 year. In no patient did bacterial infection develop during support or after transplantation. Right ventricular ejection fraction before implantation of the left ventricular assist system was lower than 15% in 6 of 8 patients, yet it increased twofold during left ventricular support. The need for excessive inotropic support (2 patients) or temporary (four days) mechanical right ventricular support (2 patients) while on the left ventricular support system appeared to be related to elevated pulmonary vascular resistance during support in association with large preimplantation ventricular volumes. It appears that even patients with compromised right ventricular performance can be supported long term with a left ventricular assist device. Patients with elevated pulmonary vascular resistance may require temporary right ventricular support.

The National, Heart, Lung, and Blood Institute Pediatric Circulatory Support Program: A Summary of the 5-year Experience

The Pediatric Circulatory Support Program (PCSP) of the National Heart, Lung, and Blood Institute (NHLBI) was established to fund the development of novel circulatory support devices for children with medically refractory heart failure.1 Before this, developers of circulatory support devices found little incentive to enter the pediatric market because of the small patient numbers that are generally insufficient to justify the significant costs required to develop these devices. As a result of the lack of availability of new devices for circulatory support of pediatric patients, extracorporeal membrane oxygenation (ECMO), which first had been used clinically in the 1960s, remained the most commonly used modality to support these critically ill children during the next 40 years.2 The most attractive feature of ECMO for pediatric circulatory support is its ability to be used in even the smallest infants and neonates. However, ECMO support is characterized by thromboembolic complications and sepsis in a significant percentage of patients.3 Perhaps most importantly, ECMO has generally only been suitable for short-term support, limiting its usefulness as a bridge to transplantation, and the size and extracorporeal configuration of the system components usually limit its use to the intensive care unit setting and preclude ambulation and rehabilitation during support. In recognition of the limitations of the existing devices for pediatric mechanical circulatory support and the limitations for the entry of device companies into the pediatric market, the NHLBI established the PCSP to “perform basic and applied research to develop novel circulatory assist devices or other bioengineered systems for infants and children with congenital and acquired cardiovascular disease who experience cardiopulmonary failure and circulatory collapse.”4 Because the PCSP was a development program for new devices to address a broad goal (circulatory support for pediatric heart …

Temporary Use of the Jarvik-7 Total Artificial Heart before Transplantation

Between October 24, 1985, and July 31, 1986, the Jarvik-7 total artificial heart was implanted into six moribund patients in an attempt to test its potential as a bridge from almost certain death to cardiac transplantation. Four of these patients are now well and at home after implantation of the device and subsequent cardiac transplantation. Before transplantation, one patient died with sepsis and multiorgan failure that preceded implantation of the artificial heart. Another patient died with acute rejection 60 days after cardiac transplantation. Fifty-two days of total mechanical support with the artificial heart were accumulated in these six patients, and although the device worked flawlessly and no clinically apparent thromboembolic events occurred, each artificial heart contained areas of macroscopic aggregations of platelets and thrombi. The results of this trial indicate that in properly selected cases, direct benefit to the patient can be obtained when the Jarvik-7 artificial heart is used as a bridge to transplantation.

Decrease in red blood cell deformability caused by hypothermia, hemodilution, and mechanical stress: Factors related to cardiopulmonary bypass

During extracorporeal circulation in cardiopulmonary bypass (CPB) surgery, blood is exposed to anomalous mechanical and environmental factors, such as high shear stress, turbulence, decreased oncotic pressure caused by dilution of plasma, and moderate and especially deep hypothermia widely applied during CPB in infants. These factors cause damage to the red blood cells (RBCs), which is manifest by immediate and delayed hemolysis and by changes in the mechanical properties of RBCs. These changes include, in particular, decrease in RBC deformability impeding the passage of RBCs through the microvessels and may contribute to the complications associated with CPB surgery. We investigated in vitro the independent and combined effects of hypothermia, plasma dilution, and mechanical stress on deformability of bovine RBCs. Our studies showed each of these factors to cause a significant decrease in the deformability of RBCs, especially acting synergistically. The impairment of RBC deformability caused by hypothermia was found to be more pronounced for RBCs suspended in phosphate buffered saline (PBS) than for RBCs suspended in plasma. The decrease in RBC deformability caused by mechanical stress was significantly exacerbated by dilution of plasma with PBS. In summary, results of our in vitro study strongly point to a possible detrimental consequence of conventional CPB arising from increased RBC rigidity, which may lead to impaired microcirculation and tissue oxygen supply.

Identification of elastic properties of homogeneous, orthotropic vascular segments in distension

Characterization of the constitutive behavior of normal and pathological blood vessel segments could provide the clinician with a means to predict the onset and assess the severity of certain vascular maladies. Many of the constitutive models that have been proposed to date either fail to properly consider certain features of the anatomic structure and function of vascular tissue or are so mathematically complex that their utilization is intractable. We have developed a material identification technique that first required the adaptation and validation of a constitutive law describing the nonlinear, three-dimensional behavior of orthotropic, compressible, hyperelastic vascular segments. By coupling a nonlinear finite element program and experimental data with a robust nonlinear least-squares regression algorithm, a set of elastic parameters (moduli) is obtained. Regressions on data for a canine carotid artery and rabbit infrarenal aorta yielded coefficients of variation of 0.21 and 0.08, respectively. The estimated moduli demonstrated certain trends found by other investigators: both the canine carotid artery and rabbit aorta were found to be stiffer radially than circumferentially, and the former was found to be stiffer circumferentially than longitudinally. Using these material constants and measured arterial pressures, the stress distribution was computed for each specimen. The predicted radial stress was consistent with a transmural variation of approximately--p (applied luminal pressure) to approximately zero in both specimens, while the circumferential stresses ranged from 2.2p to 0.7p for the canine carotid, and from 6.4p to 3.7p for the rabbit aorta. The stress distributions qualitatively agreed with those reported in previous investigations, as well as with certain physiologic observations. Based on the results of our two sample cases, we believe that our technique could be beneficial to the assessment of the three-dimensional, anisotropic behavior of vascular tissue.

Hemodynamics and low density lipoprotein metabolism. Rates of low density lipoprotein incorporation and degradation along medial and lateral walls of the rabbit aorto-iliac bifurcation.

We have investigated whether arterial wall low density lipoprotein (LDL) metabolism in areas of disturbed flow differs from the metabolism in adjacent regions of undisturbed flow. Using the rabbit aorto-iliac bifurcation as a model, we examined the rates of LDL incorporation and catabolism in vivo and correlated them to the arterial flow patterns in these regions. The trapped ligand method was used to quantitate the rates of LDL incorporation and degradation over a 20-hour period in three hemodynamic zones of the daughter iliac branch: 1) a region of flow separation where the shearing forces are elevated along the medial wall and reduced along the lateral wall, 2) a transition region where the flow patterns begin to approach the fully established situation, and 3) a unidirectional flow region with symmetric fluid shearing forces along the medial and lateral walls. Our results indicate an elevated rate of LDL incorporation into the lateral versus the medial wall in the proximal zone of flow separation (5.2 +/- 0.8 nl/mg/hr vs. 3.7 +/- 0.5 nl/mg/hr, p less than 0.01). A similar elevation in the degradation rate of the lateral over the medial wall of this most proximal zone was also observed (2.1 +/- 0.4 vs. 1.4 +/- 0.2, p less than 0.05). No such differences were observed regarding LDL incorporation and degradation in the transitional or unidirectional hemodynamic zones. These results suggest that modifications in arterial wall LDL incorporation and catabolism are induced by hemodynamic forces. The implications of these findings for the formation of the atherosclerotic lesion are discussed.

Computational fluid dynamics analysis of blade tip clearances on hemodynamic performance and blood damage in a centrifugal ventricular assist device.

An important challenge facing the design of turbodynamic ventricular assist devices (VADs) intended for long-term support is the optimization of the flow path geometry to maximize hydraulic performance while minimizing shear-stress-induced hemolysis and thrombosis. For unshrouded centrifugal, mixed-flow and axial-flow blood pumps, the complex flow patterns within the blade tip clearance between the lengthwise upper surface of the rotating impeller blades and the stationary pump housing have a dramatic effect on both the hydrodynamic performance and the blood damage production. Detailed computational fluid dynamics (CFD) analyses were performed in this study to investigate such flow behavior in blade tip clearance region for a centrifugal blood pump representing a scaled-up version of a prototype pediatric VAD. Nominal flow conditions were analyzed at a flow rate of 2.5 L/min and rotor speed of 3000 rpm with three blade tip clearances of 50, 100, and 200 microm. CFD simulations predicted a decrease in the averaged tip leakage flow rate and an increase in pump head and axial thrust with decreasing blade tip clearances from 200 to 50 microm. The predicted hemolysis, however, exhibited a unimodal relationship, having a minimum at 100 microm compared to 50 microm and 200 microm. Experimental data corroborate these predictions. Detailed flow patterns observed in this study revealed interesting fluid dynamic features associated with the blade tip clearances, such as the generation and dissipation of tip leakage vortex and its interaction with the primary flow in the blade-blade passages. Quantitative calculations suggested the existence of an optimal blade tip clearance by which hydraulic efficiency can be maximized and hemolysis minimized.