Mickey S. Ising

Miniaturization of Mechanical Circulatory Support Systems

Heart failure (HF) is increasing worldwide and represents a major burden in terms of health care resources and costs. Despite advances in medical care, prognosis with HF remains poor, especially in advanced stages. The large patient population with advanced HF and the limited number of donor organs stimulated the development of mechanical circulatory support (MCS) devices as a bridge to transplant and for destination therapy. However, MCS devices require a major operative intervention, cardiopulmonary bypass, and blood component exposure, which have been associated with significant adverse event rates, and long recovery periods. Miniaturization of MCS devices and the development of an efficient and reliable transcutaneous energy transfer system may provide the vehicle to overcome these limitations and usher in a new clinical paradigm in heart failure therapy by enabling less invasive beating heart surgical procedures for implantation, reduce cost, and improve patient outcomes and quality of life. Further, it is anticipated that future ventricular assist device technology will allow for a much wider application of the therapy in the treatment of heart failure including its use for myocardial recovery and as a platform for support for cell therapy in addition to permanent long-term support.

Destination Therapy: One-Year Outcomes in Patients With a Body Mass Index Greater Than 30

Left ventricular assist devices (LVADs) are slowly gaining acceptance as the treatment of choice in appropriately selected patients with end-stage heart failure who are not transplant candidates. Obesity is a well-known risk factor for increased cardiovascular morbidity and mortality, and frequently can be the reason some patients are turned down for heart transplantation. Because of this experience in transplant patients, many centers have also been reluctant to offer these patients an LVAD for destination therapy (DT). Subsequently, the 1-year outcomes of obese patients receiving LVADs for DT at our center were reviewed. Fifty-eight consecutive patients (83% men) were implanted with HeartMate XVE (n = 22) or HeartMate II (n = 36) LVAD. Patients were divided into normal (body mass index [BMI] <or= 30 kg/m(2), n = 38) and obese (BMI >or= 30 kg/m(2), n = 20) groups according to their BMI. Preoperatively, there were statistically significant differences (P < 0.05) between normal and obese groups in age (65.9 years vs. 54.7 years), weight (72.9 kg vs. 107.5 kg), BMI (24.1 kg/m(2) vs. 35.2 kg/m(2)), and incidence of diabetes (37% vs. 60%). At 1-year follow-up, there were no statistically significant differences (P > 0.5) between normal and obese groups: creatinine levels (1.4 vs. 1.5), New York Heart Association classification (1.2 vs. 1.6), and survival (63% vs. 65%). Our initial results demonstrate that morbidly obese patients with end-stage heart failure with a contraindication for transplant may successfully undergo implantation of an LVAD for DT.

Thoughts and Progress: Miniaturization of Mechanical Circulatory Support Systems

Heart failure (HF) is increasing worldwide and represents a major burden in terms of health care resources and costs. Despite advances in medical care, prognosis with HF remains poor, especially in advanced stages. The large patient population with advanced HF and the limited number of donor organs stimulated the development of mechanical circulatory support (MCS) devices as a bridge to transplant and for destination therapy. However, MCS devices require a major operative intervention, cardiopulmonary bypass, and blood component exposure, which have been associated with significant adverse event rates, and long recovery periods. Miniaturization of MCS devices and the development of an efficient and reliable transcutaneous energy transfer system may provide the vehicle to overcome these limitations and usher in a new clinical paradigm in heart failure therapy by enabling less invasive beating heart surgical procedures for implantation, reduce cost, and improve patient outcomes and quality of life. Further, it is anticipated that future ventricular assist device technology will allow for a much wider application of the therapy in the treatment of heart failure including its use for myocardial recovery and as a platform for support for cell therapy in addition to permanent long-term support.

Cavopulmonary Assist for the Failing Fontan Circulation: Impact of Ventricular Function on Mechanical Support Strategy

Mechanical circulatory support—either ventricular assist device (VAD, left-sided systemic support) or cavopulmonary assist device (CPAD, right-sided support)—has been suggested as treatment for Fontan failure. The selection of left- versus right-sided support for failing Fontan has not been previously defined. Computer simulation and mock circulation models of pediatric Fontan patients (15–25 kg) with diastolic, systolic, and combined systolic and diastolic dysfunction were developed. The global circulatory response to assisted Fontan flow using VAD (HeartWare HVAD, Miami Lakes, FL) support, CPAD (Viscous Impeller Pump, Indianapolis, IN) support, and combined VAD and CPAD support was evaluated. Cavopulmonary assist improves failing Fontan circulation during diastolic dysfunction but preserved systolic function. In the presence of systolic dysfunction and elevated ventricular end-diastolic pressure (VEDP), VAD support augments cardiac output and diminishes VEDP, while increased preload with cavopulmonary assist may worsen circulatory status. Fontan circulation can be stabilized to biventricular values with modest cavopulmonary assist during diastolic dysfunction. Systemic VAD support may be preferable to maintain systemic output during systolic dysfunction. Both systemic and cavopulmonary support may provide best outcome during combined systolic and diastolic dysfunction. These findings may be useful to guide clinical cavopulmonary assist strategies in failing Fontan circulations.

Blood Trauma Testing of CentriMag and RotaFlow Centrifugal Flow Devices: A Pilot Study

Mechanical circulatory assist devices that provide temporary support in heart failure patients are needed to enable recovery or provide a bridge to decision. Minimizing risk of blood damage (i.e., hemolysis) with these devices is critical, especially if the length of support needs to be extended. Hematologic responses of the RotaFlow (Maquet) and CentriMag (Thoratec) temporary support devices were characterized in an in vitro feasibility study. Paired static mock flow loops primed with fresh bovine blood (700 mL, hematocrit [Hct] = 25 ± 3%, heparin titrated for activated clotting time >300 s) pooled from a single-source donor were used to test hematologic responses to RotaFlow (n = 2) and CentriMag (n = 2) simultaneously. Pump differential pressures, temperature, and flow were maintained at 250 ± 10 mm Hg, 25 ± 2°C, and 4.2 ± 0.25 L/min, respectively. Blood samples (3 mL) were collected at 0, 60, 120, 180, 240, 300, and 360 min after starting pumps in accordance with recommended Food and Drug Administration and American Society for Testing and Materials guidelines. The CentriMag operated at a higher average pump speed (3425 rpm) than the RotaFlow (3000 rpm) while maintaining similar constant flow rates (4.2 L/min). Hematologic indicators of blood trauma (hemoglobin, Hct, platelet count, plasma free hemoglobin, and white blood cell) for all measured time points as well as normalized and modified indices of hemolysis were similar (RotaFlow: normalized index of hemolysis [NIH] =  0.021 ± 0.003 g/100 L, modified index of hemolysis [MIH] = 3.28 ± 0.52 mg/mg compared to CentriMag: NIH =  0.041 ± 0.010 g/100 L, MIH = 6.08 ± 1.45 mg/mg). In this feasibility study, the blood trauma performance of the RotaFlow was similar or better than the CentriMag device under clinically equivalent, worst-case test conditions. The RotaFlow device may be a more cost-effective alternative to the CentriMag.

Blood Trauma Testing For Mechanical Circulatory Support Devices

Preclinical hemolysis testing is a critical requirement toward demonstrating device safety for U.S. Food and Drug Administration (FDA) 510(k) approval of mechanical circulatory support devices (MCSD). FDA and ASTM (formerly known as the American Society for Testing and Materials) have published guidelines to assist industry with developing study protocols. However, there can be significant variability in experimental procedures, study design, and reporting of data that makes comparison of test and predicate devices a challenge. To overcome these limitations, we present a hemolysis testing protocol developed to enable standardization of hemolysis testing while adhering to FDA and ASTM guidelines. Static mock flow loops primed with fresh bovine blood (600 mL, Hematocrit = 27±5%, heparin titrated for ACT >300 sec) from a single-source donor were created as a platform for investigating test and predicate devices. MCSD differential pressure and temperature were maintained at 80 mmHg and 25°±2° C. Blood samples (3 ml) were collected at 0, 5, 90, 180, 270, 360 minutes to measure CBC and plasma free hemoglobin. This protocol led to 510(k) approval of two adult MCSD and has been used to test novel cannulae and a pediatric MCSD. Standardization of hemolysis testing procedures and transparency of results may enable better blood trauma characterization of MCS devices to facilitate the FDA 510(k) and PMA submission processes and improve clinical outcomes.

Heart Transplant Survival Based on Recipient and Donor Risk Scoring: A UNOS Database Analysis.

Unlike the lung allocation score, currently, there is no quantitative scoring system available for patients on heart transplant waiting list. By using United Network for Organ Sharing (UNOS) data, we aim to generate a scoring system based on the recipient and donor risk factors to predict posttransplant survival. Available UNOS data were queried between 2005 and 2013 for heart transplant recipients aged ≥18 years to create separate cox-proportional hazard models for recipient and donor risk scoring. On the basis of risk scores, recipients were divided into five groups and donors into three groups. Kaplan–Meier curves were used for survival. Total 17,131 patients had heart transplant within specified time period. Major factors within high-risk groups were body mass index > 30 kg/m2 (46%), mean pulmonary artery pressure >30 mmHg (65%), creatinine > 1.5 mg% (63%), bilirubin > 1.5 mg% (54%), noncontinuous-flow left ventricular assist devices (45%) for recipients and gender mismatch (81%) and ischemia time >4 hours (88%) for donors. Survival in recipient groups 1, 2, 3, 4, and 5 at 5 years was 81, 80, 77, 74, and 62%, respectively, and in donor groups 1, 2, and 3 at 5 years was 79, 77, and 70%, respectively (p < 0.001). Combining donor and recipient groups based on scoring showed acceptable survival in low-risk recipients with high-risk donor (75% at 5 years). A higher recipient and donor risk score are associated with worse long-term survival. A low-risk recipient transplanted with high-risk donor has acceptable survival at 5 years, but high-risk recipient combined with a high-risk donor has marginal results. Using an objective scoring system could help get the best results when utilizing high-risk donors.

Feasibility of Pump Speed Modulation for Restoring Vascular Pulsatility with Rotary Blood Pumps.

Continuous flow (CF) left ventricular assist devices (LVAD) diminish vascular pressure pulsatility, which may be associated with clinically reported adverse events including gastrointestinal bleeding, aortic valve insufficiency, and hemorrhagic stroke. Three candidate CF LVAD pump speed modulation algorithms designed to augment aortic pulsatility were evaluated in mock flow loop and ischemic heart failure (IHF) bovine models by quantifying hemodynamic performance as a function of mean pump speed, modulation amplitude, and timing. Asynchronous and synchronous copulsation (high revolutions per minute [RPM] during systole, low RPM during diastole) and counterpulsation (low RPM during systole, high RPM during diastole) algorithms were tested for defined modulation amplitudes (±300, ±500, ±800, and ±1,100 RPM) and frequencies (18.75, 37.5, and 60 cycles/minute) at low (2,900 RPM) and high (3,200 RPM) mean LVAD speeds. In the mock flow loop model, asynchronous, synchronous copulsation, and synchronous counterpulsation algorithms each increased pulse pressure (&Dgr;P = 931%, 210%, and 98% and reduced left ventricular external work (LVEW = 20%, 22%, 16%). Similar improvements in vascular pulsatility (1,142%) and LVEW (40%) were observed in the IHF bovine model. Asynchronous modulation produces the largest vascular pulsatility with the advantage of not requiring sensor(s) for timing pump speed modulation, facilitating potential clinical implementation.

Flow modulation algorithms for intra-aortic rotary blood pumps to minimize coronary steal.

Intra-aortic rotary blood pumps (IARBPs) have been used for partial cardiac support during cardiogenic shock, myocardial infarction, percutaneous coronary intervention, and potentially viable for long-term circulatory support. Intra-aortic rotary blood pump support continuously removes volume from the aortic root, which lowers left ventricular preload, external work (LVEW), and improves end-organ perfusion. However, IARBP support diminishes aortic root pressure and coronary artery. It may also create “coronary steal,” which may produce a myocardial hypoxic state adversely affecting patient outcomes. Our objective was to develop IARBP flow modulation algorithms to eliminate coronary steal and improve the myocardial supply-demand ratio without compromising the clinical benefits of restored end-organ perfusion and reduced LVEW. The hemodynamic responses of the native ventricle, coronary, and systemic vasculature to timing and synchronization of IARBP flow modulation (cyclic variation of pump flow) were investigated using a clinical heart failure (HF) computer simulation model. A total of more than 150 combinations of varying pulse widths and time-shifts to modulate IARBP flow were tested at mean IARBP flow rates of 2, 3, and 4 L/min, and compared with HF baseline values (no IARBP support). Increasing IARBP support augmented cardiac output and diminished LVEW. Nonmodulated IARBP support significantly diminished mean diastolic coronary flow (−49%) and myocardial supply-demand ratio (−12%) compared with HF baseline. Intra-aortic rotary blood pump flow modulation increased mean diastolic coronary flow (+17%) and myocardial supply-demand ratio (+24%) compared with nonmodulated IARBP (constant flow). Modulation and synchronization of IARBP support augmented coronary artery perfusion and myocardial supply-demand ratio in simulated clinical HF while also restoring end-organ perfusion and reducing LVEW. Implementation of IARBP support with flow modulation may prevent myocardial hypoxia and improve patient outcomes. However, even with flow modulation, IARBP support provides a smaller improvement in myocardial supply demand ratio compared to ventricular assist devices and intra-aortic balloon pumps.

Use of drug intoxicated donors for lung transplant: Impact on survival outcomes

The number of increasing deaths due to the opioid epidemic has led to a potential greater supply of organ donors. There is hesitancy to use drug intoxicated donors, and we evaluated their impact on post‐transplant survival.