Kenneth N. Litwak

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.

Hemodynamic responses to continuous versus pulsatile mechanical unloading of the failing left ventricle.

Debate exists regarding the merits and limitations of continuous versus pulsatile flow mechanical circulatory support. To characterize the hemodynamic differences between each mode of support, we investigated the acute effects of continuous versus pulsatile unloading of the failing left ventricle in a bovine model. Heart failure was induced in male calves (n = 14). During an acute study, animals were instrumented through thoracotomy for hemodynamic measurement. A continuous flow (n = 8) and/or pulsatile flow (n = 8) left ventricular assist device (LVAD) was implanted and studied during maximum support (∼5 L/min) and moderate support (∼2–3 L/min) modes. Pulse pressure (PP), surplus hemodynamic energy (SHE), and (energy equivalent pressure [EEP]/mean aortic pressure (MAP) − 1) × 100% were derived to characterize hemodynamic energy profiles during the different support modes. Standard hemodynamic parameters of cardiac performance were also derived. Data were analyzed by repeated measures one-way analysis of variance within groups and unpaired Students t-tests across groups. During maximum and moderate continuous unloading, PP, SHE, and (EEP/MAP − 1) × 100% were significantly decreased compared with baseline and compared with pulsatile unloading. As a result, continuous unloading significantly altered left ventricular peak systolic pressure, aortic systolic and diastolic pressure, ±dP/dt, and rate × pressure product, whereas pulsatile unloading preserved a normal profile of physiologic values. As continuous unloading increased, the pressure-volume relationship collapsed, and the aortic valve remained closed. In contrast, as pulsatile unloading increased, a comparable decrease in left ventricular volumes was noted. However, a normal range of left ventricular pressures was preserved. Continuous unloading deranged the physiologic profile of myocardial and vascular hemodynamic energy utilization, whereas pulsatile unloading preserved more normal physiologic values. These findings may have important implications for chronic LVAD therapy.

HeartMate III: pump design for a centrifugal LVAD with a magnetically levitated rotor.

A long-term, compact left ventricular assist device (LVAD), the HeartMate III, has been designed and fabricated, featuring a centrifugal pump with a magnetically levitated rotor. The pump has been optimized by in vitro testing to achieve a design point of 7 L/min against 135 mm Hg at high hydrodynamic efficiency (30%) and to be capable of up to 10 L/min under such a load. Furthermore, the pump has demonstrated no mechanical failures, low hemolysis (4–10 mg/dl plasma free Hb), and low thrombogenicity during six (40, 27, 59, 42, 27, and 49-day) in vivo bovine studies.

Smooth muscle cell hypertrophy of renal cortex arteries with chronic continuous flow left ventricular assist

BACKGROUND Pathophysiology of long-term continuous flow left ventricular assist is not well described. With many of these devices becoming available, it is important to examine for possible pathologic effects. In this study we examined the relationship between diminished pulsatility and pathologic changes in renal cortical arteries. METHODS Twenty-nine calves were implanted with various continuous flow left ventricular assist systems in a left ventricle-descending thoracic aorta bypass configuration. Pulsatility was quantified by pulse pressure and pulsatility index. Pathologic changes of the renal cortex arteries were described and evaluated by medial thickness, medial/vascular cross-sectional area ratio, and smooth muscle cell count, to quantify hypertrophy or hyperplasia. Seven calves, which underwent a sham-implant, were used as controls. RESULTS Systolic arterial pressure, pulse pressure, and pulsatility index were significantly lower and diastolic pressure was significantly higher than before implant in pump-implanted animals. Twenty-three of 29 pumpimplanted calves (79.3%) had medial smooth muscle cell hypertrophy in renal cortex arteries, whereas none of sham-implanted calves had any abnormal lesions. When the pump-implanted calves were grouped according to the presence of smooth muscle cell hypertrophy, there was a clear trend toward lower pump flow rate in calves with lesions. Renal function was within the normal range in all calves. CONCLUSIONS There appears to be a relationship between smooth muscle cell hypertrophy in renal cortex arteries and continuous flow left ventricular assist. Furthermore, although the pathologic changes are likely multifactorial, these lesions appear to be related to lower pump assist rates.

Platelet activation, aggregation, and life span in calves implanted with axial flow ventricular assist devices

BACKGROUND A variety of rotary blood pumps are under development worldwide to serve as chronic ventricular assist devices (VADs). Historically VADs have been associated with thrombotic and thromboembolic complications, yet the ability to evaluate the thrombotic process in preclinical device testing has been limited. METHODS We have developed and applied flow cytometric assays for activated platelets, platelet microaggregates, and platelet life span and consumption to calves implanted with an axial flow VAD and calves undergoing a sham surgical procedure. RESULTS Surgical sham calves had significant increases in circulating activated platelets (p < 0.05) that resolved within 17 days, and no increases in circulating platelet microaggregates. Calves with uneventful VAD implant periods had early transient elevations in platelet microaggregates and prolonged elevations in activated platelets that did not recover to preoperative values during the study. Daily platelet consumption in VAD implanted calves was increased by 20% +/- 3%. Calves with thrombotic deposition within the VAD and elevated thromboembolism observed at autopsy experienced increases in circulating activated platelets and microaggregates at the end of the implant period when VAD flow decreased. CONCLUSIONS This study demonstrates the ability of flow cytometry-based platelet assays to differentiate VAD implant operations from VAD support, and suggests differences that exist between uneventful VAD support and support with complications. These techniques should have value in evaluating other cardiovascular devices undergoing preclinical testing and provide insight into the temporal impact of these devices on the hemostatic system.

Esophageal Luminal Temperature Measurement Underestimates Esophageal Tissue Temperature During Radiofrequency Ablation Within the Canine Left Atrium: Comparison Between 8 mm Tip and Open Irrigation Catheters

Introduction: Evaluation of luminal temperature during left atrial ablation is used clinically; however, luminal temperature does not necessarily reflect temperature within the esophageal wall and poses a risk of atrioesophageal fistula. This animal study evaluates luminal esophageal temperature and its relation to the temperature of the external esophageal tissue during left atrial lesions using the 8 mm solid tip and the open irrigated tip catheters (OIC).

Hemodynamic and pressure-volume responses to continuous and pulsatile ventricular assist in an adult mock circulation

This study investigated the hemodynamic and left ventricular (LV) pressure–volume loop responses to continuous versus pulsatile assist techniques at 50% and 100% bypass flow rates during simulated ventricular pathophysiologic states (normal, failing, recovery) with Starling response behavior in an adult mock circulation. The rationale for this approach was the desire to conduct a preliminary investigation in a well controlled environment that cannot be as easily produced in an animal model or clinical setting. Continuous and pulsatile flow ventricular assist devices (VADs) were connected to ventricular apical and aortic root return cannulae. The mock circulation was instrumented with a pressure–volume conductance catheter for simultaneous measurement of aortic root pressure and LV pressure and volume; a left atrial pressure catheter; a distal aortic pressure catheter; and aortic root, aortic distal, VAD output, and coronary flow probes. Filling pressures (mean left atrial and LV end diastolic) were reduced with each assist technique; continuous assist reduced filling pressures by 50% more than pulsatile. This reduction, however, was at the expense of a higher mean distal aortic pressure and lower diastolic to systolic coronary artery flow ratio. At full bypass flow (100%) for both assist devices, there was a pronounced effect on hemodynamic parameters, whereas the lesser bypass flow (50%) had only a slight influence. Hemodynamic responses to continuous and pulsatile assist during simulated heart failure differed from normal and recovery states. These findings suggest the potential for differences in endocardial perfusion between assist techniques that may warrant further investigation in an in vivo model, the need for controlling the amount of bypass flow, and the importance in considering the choice of in vivo model.

Ex vivo testing of the intravenous membrane oxygenator.

Intravenous oxygenation represents a potential respiratory support modality for patients with acute respiratory failure or with acute exacerbations of chronic respiratory conditions. Our group has been developing an intravenous oxygenator, the IMO, which uses a constrained fiber bundle and a rapidly pulsating balloon within the fiber bundle. Balloon pulsation drives blood flow past the fibers at greater relative velocities than would otherwise exist within the host vessel, and gas exchange rates are enhanced. The purpose of this study was twofold: (1) to characterize the gas exchange performance of the current IMO in an extracorporeal mock vena cava vessel under conditions of known fixed vessel geometry and controlled blood flow rates; and (2) to compare the IMO gas exchange performance to that reported for the clinically tested IVOX device within a comparable ex vivo set-up. The ex vivo flow loop consisted of a 1 inch ID tube as a mock vena cava that was perfused directly from an anesthetized calf at blood flow rates ranging from 1 to 4 1/2 L/min. O2 and CO2 exchange rates were measured for balloon pulsation rates, which ranged from 0 to 180 bpm. Balloon pulsation significantly increased gas exchange, by 200-300% at the lowest blood flow rate and 50-100% at the highest blood flow rate. Balloon pulsation eliminated much if not all of the dependence of the gas exchange rate on blood flow rate as seen in passive oxygenators. This suggests that in clinical application the IMO may exhibit less gas transfer variability due to differences in cardiac output Over the entire flow rate range studied, the CO2 and O2 gas exchange rates of the IMO at maximal balloon pulsation varied from approximately 250 to 350 ml/min/m2. At maximum balloon pulsation the IMO exchanged CO2 and O2 at rates from 50-500% greater, depending upon the blood flow rate, than the exchange rates reported for the IVOX device in ex vivo tests.

Acute hemodynamic efficacy of a 32-ml subcutaneous counterpulsation device in a calf model of diminished cardiac function.

The acute hemodynamic efficacy of an implantable counterpulsation device (CPD) was evaluated. The CPD is a valveless single port, 32-ml stroke volume blood chamber designed to be connected to the human axillary artery using a simple surface surgical procedure. Blood is drawn into the pump during systole and ejected during diastole. The acute hemodynamic effects of the 32-ml CPD were compared to a standard clinical 40-ml intra-aortic balloon pump (IABP) in calves (80 kg, n = 10). The calves were treated by a single oral dose of Monensin to produce a model of diminished cardiac function (DCF). The CPD and IABP produced similar increases in cardiac output (6% CPD vs. 5% IABP, p > 0.5) and reduction in left ventricular external work (14% CPD vs. 13% IABP, p > 0.5) compared to DCF (p < 0.05). However, the ratio of diastolic coronary artery flow to left ventricular external work increase from DCF baseline (p < 0.05) was greater with the CPD compared to the IABP (15% vs. 4%, p < 0.05). The CPD also produced a greater reduction in left ventricular myocardial oxygen consumption from DCF baseline (p < 0.05) compared to the IABP (13% vs. 9%, p < 0.05) despite each device providing similar improvements in cardiac output. There was no early indication of hemolysis, thrombus formation, or vascular injury. The CPD provides hemodynamic efficacy equivalent to an IABP and may become a therapeutic option for patients who may benefit from prolonged counterpulsation.

Arterial heparan sulfate is negatively associated with hyperglycemia and atherosclerosis in diabetic monkeys

BackgroundArterial proteoglycans are implicated in the pathogenesis of atherosclerosis by their ability to trap plasma lipoproteins in the arterial wall and by their influence on cellular migration, adhesion and proliferation. In addition, data have suggested an anti-atherogenic role for heparan sulfate proteoglycans and a pro-atherogenic role for dermatan sulfate proteoglycans. Using a non-human primate model for human diabetes, studies examined diabetes-induced changes in arterial proteoglycans that may increase susceptibility to atherosclerosis.MethodsControl (n = 7) and streptozotocin-induced diabetic (n = 8) cynomolgous monkeys were assessed for hyperglycemia by measurement of plasma glycated hemoglobin (GHb). Thoracic aortas obtained at necropsy, were extracted with 4 M guanidine HCL and proteoglycans were measured as hexuronic acid. Atherosclerosis was measured by enzymatic analysis of extracted tissue cholesterol. Glycosaminoglycan chains of arterial proteoglycans were released with papain, separated by agarose electrophoresis and analysed by scanning densitometry.ResultsTissue cholesterol was positively associated with hexuronic acid content in diabetic arteries (r = .82, p < .025) but not in control arteries. Glycosaminoglycan chain analysis demonstrated that dermatan sulfate was associated with increased tissue cholesterol in both control (r = .8, p < 0.05) and diabetic (r = .8, p < .025) arteries, whereas a negative relationship was observed between heparan sulfate and tissue cholesterol in diabetic arteries only (r = -.7, p < .05). GHb, which was significantly higher in diabetic animals (8.2 ± 0.9 vs 3.8 ± 0.2%, p < .0005) was negatively associated with heparan sulfate in diabetic arteries (r = -.7, p < .05).ConclusionsThese data implicate hyperglycemia induced modifications in arterial proteoglycans that may promote atherosclerosis.