Michael A. Sobieski

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.

Role of RBM25/LUC7L3 in Abnormal Cardiac Sodium Channel Splicing Regulation in Human Heart Failure

Background— Human heart failure is associated with decreased cardiac voltage-gated Na+ channel current (encoded by SCN5A), and the changes have been implicated in the increased risk of sudden death in heart failure. Nevertheless, the mechanism of SCN5A downregulation is unclear. A number of human diseases are associated with alternative mRNA splicing, which has received comparatively little attention in the study of cardiac disease. Splicing factor expression profiles during human heart failure and a specific splicing pathway for SCN5A regulation were explored in this study. Methods and Results— Gene array comparisons between normal human and heart failure tissues demonstrated that 17 splicing factors, associated with all major spliceosome components, were upregulated. Two of these splicing factors, RBM25 and LUC7L3, were elevated in human heart failure tissue and mediated truncation of SCN5A mRNA in both Jurkat cells and human embryonic stem cell–derived cardiomyocytes. RBM25/LUC7L3-mediated abnormal SCN5A mRNA splicing reduced Na+ channel current 91.1±9.3% to a range known to cause sudden death. Overexpression of either splicing factor resulted in an increase in truncated mRNA and a concomitant decrease in the full-length SCN5A transcript. Conclusions— Of the 17 mRNA splicing factors upregulated in heart failure, RBM25 and LUC7L3 were sufficient to explain the increase in truncated forms and the reduction in full-length Na+ channel transcript. Because the reduction in channels was in the range known to be associated with sudden death, interruption of this abnormal mRNA processing may reduce arrhythmic risk in heart failure.

Fibrinolytic activation during long-term support with the HeartMate II left ventricular assist device.

Human physiologic responses to pulsatile left ventricular assist devices (LVADs) are well understood; responses to the newer continuous flow pumps are not. Therefore, we evaluated the long-term effects of continuous flow LVAD support on fibrinolytic activation. Twelve recipients of an axial flow LVAD as destination therapy were assessed for fibrinolytic activation at 1, 3, 6, 9, and 12 months postimplantation. The fibrinolytic response and changes were assessed in terms of fibrinogen, D-dimer, plasma free hemoglobin, international normalized ratio (INR), and red blood cell (RBC) sedimentation rate. Bleeding and thromboembolic events were recorded. All fibrinolytic response parameters were elevated at baseline; mean RBC sedimentation rate was 51.8 mm/h, mean D-dimer was 3.95 nmol/L, and the mean fibrinogen was 356 mg/dl. The D-dimer and fibrinogen levels increased after LVAD implantation but returned to near-normal levels by 12 months. Red blood cell sedimentation rates increased indicating ongoing inflammation. Plasma free hemoglobin values decreased and remained low, an indicator of low shear rates and hemolysis. Three nonfatal bleeding events but no thromboembolic events were observed. Fibrinolytic responses initially increase after LVAD implantation but then gradually normalize.

Rotary pumps and diminished pulsatility: do we need a pulse?

Ventricular assist devices (VADs) have been successfully used as a bridge to heart transplant and destination therapy (DT) for congestive heart failure (HF) patients. Recently, continuous flow VAD (CVAD) has emerged as an attractive clinical option for long-term mechanical support of HF patients, with bridge-to-transplant outcomes comparable with pulsatile flow VAD (PVAD). Continuous flow VADs are smaller, more reliable, and less complex than the first-generation PVAD. Despite the widespread clinical use, CVAD support has been associated with gastrointestinal bleeding, hemorrhagic strokes, and aortic valve insufficiency. Speculation that diminished arterial pressure pulsatility associated with continuous flow devices may be contributing to these complications has sparked much debate over CVAD support. Studies comparing pulsatile flow and continuous flow (CF) support have presented conflicting findings, and the relevance to CVAD as DT is uncertain due to variations in device operation, support duration, and the criteria used to quantify pulsatility. Currently, there is interest in developing control algorithms for CVAD to increase the delivered pulsatility as a strategy to mitigate adverse event risks associated with CVAD therapy. There may also be the added benefit of specific control strategies for managing CVAD therapy, potentially improving the rate of myocardial recovery and successful weaning of mechanical circulatory support.

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.

Reducing the effects of the systemic inflammatory response to cardiopulmonary bypass: can single dose steroids blunt systemic inflammatory response syndrome?

The use of cardiopulmonary bypass (CPB) is associated with the development of a significant systemic inflammatory response syndrome (SIRS) which can affect patient outcomes. Multiple pathways are involved in initiating and maintaining SIRS. We studied whether a single dose of steroids (dexamethasone) after the induction of anesthesia could blunt the SIRS from CPB. A prospective, randomized, double-blinded, placebo control trial of 28 patients (13 study vs. 15 control). The study group received 100 mg of dexamethasone whereas the control group received sterile saline. Inclusion criteria were the following: elective coronary artery bypass grafting, less than 80 years old, normal ejection fraction, no acute myocardial infarction. Serum levels of C3a, interleukin (IL)-6, and plasma norepinephrine (PNE) were measured after intubation, 30 minutes after initiation of CPB, 24 and 72 hours after termination of bypass. The study group demonstrated significantly lower levels of IL-6 (p = 0.0005) at 24 hours and PNE (p = 0.05) at 72 hours post-CPB. There were no differences in the C3a levels between the groups. No infections occurred in either group. A single dose of dexamethasone reduces IL-6 and PNE levels associated with CPB. Despite the significant reductions in IL-6 and PNE, there was no effect on clinical outcomes. Additional studies are needed to demonstrate a clinically significant effect on patient outcomes.

Home Discharge Experience With the Thoratec Tlc-ii Portable Driver

With the growing success and expanded use of ventricular assist devices, home discharge with independent ambulation and self-care are now important issues. We describe our initial home discharge experience with the Thoratec TLC-II portable drive. Patients discharged home were required to have five outpatient excursions (three monitored) before discharge and were seen weekly after discharge. Between August 2000 and December 2004, 14 patients (average age, 57 years) were placed on the TLC-II portable driver. One patient on the TLC-II portable driver had left ventricular assist device removal after 50 days of support but before discharge. Thirteen patients were discharged from the hospital with average time at home of 62 days (range, 16 to 243 days). After discharge, the TLC-II portable driver was maintained in the auto mode at average settings of 78 beat rate, 5.1 L/min flow rate, 204 mm Hg ejection pressure, and –8.4 mm Hg fill vacuum. A total of 5852 alarms (average, 6.7 per day) were recorded with 2373 battery reminders (41%), 1922 occlusion alarms during sleep (33%), and 1461 no-fill signals (25%). There were no readmissions for device malfunction, emergency battery utilization or back-up unit use. These results demonstrate that the Thoratec TLC-II portable driver is safe, reliable, and can be effectively managed at home.

Rotary pump speed modulation for generating pulsatile flow and phasic left ventricular volume unloading in a bovine model of chronic ischemic heart failure

BACKGROUND Rotary blood pumps operate at a constant speed (rpm) that diminishes vascular pulsatility and variation in ventricular end-systolic and end-diastolic volumes, which may contribute to adverse events, including aortic insufficiency and gastrointestinal bleeding. In this study, pump speed modulation algorithms for generating pulsatility and variation in ventricular end-systolic and end-diastolic volumes were investigated in an ischemic heart failure (IHF) bovine model (n = 10) using a clinically implanted centrifugal-flow left ventricular assist device (LVAD). METHODS Hemodynamic and hematologic measurements were recorded during IHF baseline, constant pumps speeds, and asynchronous (19-60 cycles/min) and synchronous (copulse and counterpulse) pump speed modulation profiles using low relative pulse speed (±25%) of 3,200 ± 800 rpm and high relative pulse speed (±38%) of 2,900 ± 1,100 rpm. End-organ perfusion, hemodynamics, and pump parameters were measured to characterize pulsatility, myocardial workload, and LVAD performance for each speed modulation profile. RESULTS Speed modulation profiles augmented aortic pulse pressure, surplus hemodynamic energy, and end-organ perfusion (p < 0.01) compared with operation at constant speed. Left ventricular external work and myocardial oxygen consumption were significantly reduced compared with IHF baseline (p < 0.01) but at the expense of higher LVAD power consumption. CONCLUSIONS Pump speed modulation increases pulsatility and improves cardiac function and end-organ perfusion, but the asynchronous mode provides the technologic advantage of sensorless control. Investigation of asynchronous pump speed modulation during long-term support is warranted to test the hypothesis that operating an LVAD with speed modulation will minimize adverse events in patients supported by an LVAD that may be associated with long-term operation at a constant pump speed.

Defining pulsatility during continuous-flow ventricular assist device support

Continuous-flow ventricular assist devices (CVADs) have gained widespread use as an effective clinical therapy for patients with advanced-stage heart failure. Axial and centrifugal CVADs have been successfully used as bridge-to-transplant and destination therapy. CVADs are smaller, more reliable, and less complex than the first-generation pulsatile-flow ventricular assist devices. Despite their recent clinical success, arteriovenous malformations, gastrointestinal bleeding, hemorrhagic strokes, aortic valve insufficiency, and valve fusion have been reported in heart failure patients supported by CVADs. It has been hypothesized that diminished arterial pressure and flow pulsatility delivered by CVAD may be a contributing factor to these adverse events. Subsequently, the clinical significance of vascular pulsatility continues to be highly debated. Studies comparing pulsatile-flow and continuous-flow support have presented conflicting findings, largely due to variations in device operation, support duration, and the criteria used to quantify pulsatility. Traditional measurements of pulse pressure and pulsatility index are less effective at quantifying pulsatility for mechanically derived flows, particularly with the growing trend of CVAD speed modulation to achieve various pulsatile flow patterns. Kinetic measurements of energy equivalent pressure and surplus hemodynamic energy can better quantify pulsatile energies, yet technologic and conceptual challenges are impeding their clinical adaption. A review of methods for quantifying vascular pulsatility and their application as a research tool for investigating physiologic responses to CVAD support are presented.

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.