Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL.

The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. The SERCA-LVAD trial was one of a program of AAV1/SERCA2a cardiac gene therapy trials including CUPID1, CUPID 2 and AGENT trials. Enroled subjects were randomised to receive a single intracoronary infusion of 1 × 1013 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients at 3 years follow up, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort which may help guide future trial design.

Evidence of clinical efficacy of counterpulsation therapy methods.

Although heart transplantation remains the ultimate treatment for end-stage heart failure, its epidemiological impact is limited by donor organ availability. Surgical and device-based approaches have been introduced with the aim of increasing systemic perfusion and in some circumstances promoting left ventricular recovery by inducing reverse remodelling. Innovative counterpulsation devices based on the established principle of the intra-aortic balloon pump have been developed, and of these, the CardioVad and the C-Pulse System have been introduced in clinical practice with convincing evidence of haemodynamic efficacy. The evolution from pulsatile to continuous-flow left ventricular assist devices has been associated with improved survival rates during the first 2 years of support with the potential of matching heart transplantation outcomes. However, blood contact with the device remains a significant challenge despite the highly sophisticated technology currently available. Innovative extra-vascular counterpulsation devices have been shown to overcome the limitations of the intra-aortic balloon pump and rend the device suitable for prolonged support. Monitoring of the performance of these novel devices is essential, and carotid Doppler ultrasonography is of utility in assessing the haemodynamic performance of the devices in a clinical setting. Computational modelling has played a role in the simulation of these devices and should continue to assist with their optimisation and implementation in clinical practice.

Development of mock circulation models for the assessment of counterpulsation systems.

STUDY OBJECTIVE: This study entailed the development of mock circulation models to assess and compare the haemodynamic efficacy of extra-aortic counterpulsation (using trained skeletal muscle wrapped around the proximal descending aorta) and conventional intra-aortic balloon counterpulsation. DESIGN AND EXPERIMENTAL MATERIALS: Hydraulic Windkessel type lumped parameter models were used either in conjunction with native skeletal muscle or as a dynamic simulation of counterpulsation. The haemodynamic performance of the wrapped latissimus dorsi muscle of the normal sheep was assessed using an artificial load to simulate the pressurised proximal descending aorta. Mock circulation models of counterpulsation comprised Windkessel compliance chambers, laminar flow resistors, a blood analogue, a prosthetic blood pump, and a purpose made hydraulic counterpulsator. MEASUREMENTS AND MAIN RESULTS: An electrically stimulated muscle wrap, 5 cm in length, previously trained for 2 weeks at 3 V and 35 Hz, was assessed for haemodynamic performance in a mock circulation: volume of fluid displaced = 14.1(SD 1.8) ml; pressure increase from 100 mm Hg = 14.9(2.1) mm Hg; external work per contraction cycle = 180(70)mJ; external mean power = 800(100) mW. In a simulation of intra-aortic balloon counterpulsation, haemodynamic benefit (ie, an increase in proximal flow rate and endocardial viability ratio and a reduction in left ventricular stroke power) was assessed with respect to defined parameters. CONCLUSIONS: This paper demonstrates the potential of the mock circulation models both for the investigation of muscle wrap performance and for the comparison of extra-aortic muscle with intra-aortic balloon counterpulsation.

Incidence and clinical management of life-threatening left ventricular assist device failure.

BACKGROUND: Mechanical device failure can be life-threatening and is becoming increasingly important as left ventricular assist devices (LVADs) are being used for longer periods as a bridge to transplantation (period lengthening due to donor shortage) or recovery, or as destination therapy. However, its incidence and clinical management have not been widely studied. METHODS: We investigated the incidence and management of major device failure for a total of 102 Thoratec/TCI HeartMate and Thoratec PVAD devices implanted at our institution since 1995. RESULTS: The cumulative probability of device failure was 6%, 12%, 27% and 64% at 6 months, 1 year, 18 months and 2 years, respectively. Major failure occurred in 8 (7.8%) patients. Four patients presented as emergency cases with vented electric (VE) failure, and 3, with failure due to a seized motor, were supported on the pneumatic driver to explantation, transplantation or device change. Another patient had a ruptured pump diaphragm and was maintained for 12 hours, but died of a Type B aortic dissection. Four patients underwent elective device change, including 2 of a VE pump, 1 with inlet valve regurgitation and fractured power cable at 414 days, and 1 with inlet valve regurgitation at 656 days, all of whom underwent transplantation or explantation. One patient with VE failure was maintained on the pneumatic driver, then underwent Thoratec paracorporeal ventricular assist device (PVAD) implantation and was transplanted. One Thoratec PVAD patient developed LVAD thrombus, underwent pump replacement, and was transplanted. A further patient on the implantable pneumatic (IP) HeartMate developed a pneumoperitoneum due to a leak at the junction of the pneumatic driveline, which was repaired by inserting a new driveline, and underwent heart/kidney transplantation. CONCLUSIONS: Life-threatening mechanical device failure is not uncommon and increases with time, but can be managed successfully in most patients. Improvements in design and manufacture should further enhance outcome with LVADs.

Cardiopulmonary bypass impairs small intestinal transport and increases gut permeability.

Gastrointestinal damage occurs in 0.6% to 2% of patients after cardiopulmonary bypass (CPB), and carries a mortality of 12% to 67%. The incidence of subclinical gastrointestinal damage may be much greater. We examined the effects of nonpulsatile, hypothermic CPB on intestinal absorption and permeability in 41 patients. Bowel mucosal saccharide transport and permeation were evaluated using 100 mL of an oral solution containing 3-O-methyl-D-glucose (0.2 g), D-xylose (0.5 g), L-rhamnose (1.0 g), and lactulose (5.0 g) to assess active carrier-mediated, passive carrier-mediated, transcellular, and paracellular transport, respectively, with a 5-hour urine analysis. Patients were studied before, immediately after, and 5 days after CPB. Immediately after CPB there was a decrease in urinary excretion of 3-O-methyl-D-glucose (from 34% +/- 2.2% to 5.2% +/- 0.7%; p < 0.0001), D-xylose (from 25.4% +/- 1.4% to 4.1% +/- 0.8%; p < 0.0001), and L-rhamnose (from 8.3% +/- 0.6% to 2.6% +/- 0.4%; p < 0.0001). The permeation of 3-O-methyl-D-glucose and D-xylose returned to normal levels 5 days after CPB, but that of L-rhamnose remained significantly below pre-CPB values at 6.6% +/- 0.5% (p = 0.004). However, the permeation of lactulose increased after CPB (from 0.35% +/- 0.04% to 0.59% +/- 0.1%; p = 0.018), and the lactulose/L-rhamnose gut permeability ratio increased markedly (from 0.045 +/- 0.04 to 0.36 +/- 0.08; normal = 0.06 to 0.08; p = 0.004). Patients who had a CPB time of 100 minutes or more had a greater increase in gut permeability (p = 0.049).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of the compliance of the pump housing and cannulas of a paracorporeal pneumatic ventricular assist device on transient pressure characteristics.

The dependence of transient pressure characteristics of a ventricular assist device (VAD) on the compliance of its housing and cannulas was investigated in a mock circulation. The peak rate of change of pressure (dP/dtmax) values was greater in the cannulas than other compartments and was associated with valve closure-induced pressure oscillations. When cannula compliance was increased from 0.0057 to 0.0129 cm3/mm Hg, these values decreased by approximately 20%, and outflow cannula pressure oscillation frequency decreased from 17.5 Hz by 35%. This trend was also apparent in the inflow. A VAD housing compliance increase from 0.0162 to 0.0483 cm3/mm Hg caused a dP/dtmax decrease of 30% in both the blood chamber and the outflow cannula. The effect of this change on the inflow was weaker implying that housing absorbs the energy associated with outflow deceleration more effectively than the inflow. These findings suggest that increasing VAD housing and cannulas compliance can improve hydrodynamic performance.

Endotoxaemia detected during cardiopulmonary bypass with a modified Limulus amoebocyte lysate assay.

Cardiopulmonary bypass (CPB) is associated with blood heparin level fluctuations and a reduction in haematocrit due to crystalloid haemodilution. The effect of these changes on the reliability of the Limulus amoebocyte lysate (LAL) chromogenic microassay for the measurement of plasma endotoxin was assessed in vitro. It was shown that the assay could be significantly compromised by twofold haemodilution which can occur during CPB. The interference effect on the assay caused by CPB-associated heparin was not significant if a comparatively large amount of heparin (25 IU/ml) was added to the blood at the time of sampling. The effect of haemodilution was counteracted by prediluting plasma samples with crystalloid by a factor dependent on the sample haematocrit (to ensure that the proportion of plasma was similar in all samples). A correction was then required to determine the endotoxin level in the original sample. The modified assay was used to determine sequential plasma endotoxin levels in 14 patients undergoing hypothermic nonpulsatile CPB. Endotoxaemia occurred at the time of aortic cross-clamp release and reached a peak of 48.9 +/- 12.9 ng/l shortly before the end of CPB, which was significantly higher than baseline values pre-CPB (p < 0.05). Thereafter, there was a decline in endotoxin levels to 28.9 +/- 13.6 ng/l 24 hours later which was still significantly higher than baseline levels (p < 0.05). Peak endotoxaemia was a predictor of protracted hospital stay when compared with haemodynamic and tissue perfusion parameters.

The effect of cardiopulmonary bypass on gastric and colonic mucosal perfusion: a tonometric assessment.

In a study to assess the potential effect of nonpulsatile hypothermic cardiopulmonary bypass (CPB), intramucosal pH (pHi) of the gastric and colonic mucosae was determined by tonometry (n = 8). During the hypothermic phase of CPB, gastric and colonic pHi did not change significantly. Forty minutes after the start of rewarming, despite increases in the cardiac index and mean arterial blood pressure, gastric pHi fell from 7.53 +/- 0.02 to 7.31 +/- 0.03 (p = 0.017) and colonic pHi fell from 7.50 +/- 0.02 to 7.32 +/- 0.03 (p = 0.028). Forty minutes after the end of CPB both the colonic (p = 0.017) and gastric (p = 0.046) pHi remained depressed below pre-CPB values. The difference in the arterial (pHa) and the gastric mucosal pH changed from -0.097 before CPB to 0.016, 40 minutes after the end of CPB (p = 0.027). This alteration in the pHa-pHi underlines the importance of measuring intramucosal pH by tonometry, since the pHa and pHi may move in opposite directions during episodes of haemodynamic stress. Both the gastric and colonic pHi were found to have a linear correlation with the pHa, although changes in the gastric pHi (r = 0.41, p = 0.018) were more strongly correlated with the pHa than the colonic pHi (r = 0.23, p = 0.19) in the rewarming phase of CPB and the immediate post-CPB period when there was a tendency towards intramucosal acidosis. The development of intramucosal acidosis in the rewarming and immediate post-CPB phases following hypothermic nonpulsatile CPB may impair the gut barrier and predispose patients to the absorption of luminal toxins.

Metabolic analysis of latissimus dorsi coupled to a mock circulation.

A mock circulation system has been used to examine the metabolic and hemodynamic responses of untrained and trained latissimus dorsi muscle in a normal animal model. The metabolic response of untrained latissimus dorsi to differing stimulation regimes runs parallel to its mechanical performance. The ratio of power generated to oxidative capacity (a measure of metabolic efficiency) was maintained to a greater extent in muscle trained for 5 months subjected to specific fatigue tests, falling by only 20% (as opposed to 80% observed in untrained control muscle). This approach to studying metabolic and hemodynamic performance may have relevance when skeletal muscle is used for cardiac assistance.