Development of a Flexible Sensor-Integrated Tissue Patch to Monitor Early Organ Rejection Processes Using Impedance Spectroscopy.

Heart failure represents a primary cause of hospitalization and mortality in both developed and developing countries, often necessitating heart transplantation as the only viable recovery path. Despite advances in transplantation medicine, organ rejection remains a significant post-operative challenge, traditionally monitored through invasive endomyocardial biopsies (EMB). This study introduces a rapid prototyping approach to organ rejection monitoring via a sensor-integrated flexible patch, employing electrical impedance spectroscopy (EIS) for the non-invasive, continuous assessment of resistive and capacitive changes indicative of tissue rejection processes. Utilizing titanium-dioxide-coated electrodes for contactless impedance sensing, this method aims to mitigate the limitations associated with EMB, including procedural risks and the psychological burden on patients. The biosensor's design features, including electrode passivation and three-dimensional microelectrode protrusions, facilitate effective monitoring of cardiac rejection by aligning with the heart's curvature and responding to muscle contractions. Evaluation of sensor performance utilized SPICE simulations, scanning electron microscopy, and cyclic voltammetry, alongside experimental validation using chicken heart tissue to simulate healthy and rejected states. The study highlights the potential of EIS in reducing the need for invasive biopsy procedures and offering a promising avenue for early detection and monitoring of organ rejection, with implications for patient care and healthcare resource utilization.

Late Right Heart Failure After Left Ventricular Assist Device Implantation: Contemporary Insights and Future Perspectives.

Late right heart failure (RHF) is increasingly recognized in patients with long-term left ventricular assist device (LVAD) support and is associated with decreased survival and increased incidence of adverse events such as gastrointestinal bleeding and stroke. Progression of right ventricular (RV) dysfunction to clinical syndrome of late RHF in patients supported with LVAD is dependent on the severity of pre-existing RV dysfunction, persistent or worsening left- or right-sided valvular heart disease, pulmonary hypertension, inadequate or excessive left ventricular unloading, and/or progression of the underlying cardiac disease. RHF likely represents a continuum of risk with early presentation and progression to late RHF. However, de novo RHF develops in a subset of patients leading to increased diuretic requirement, arrhythmias, renal and hepatic dysfunction, and heart failure hospitalizations. The distinction between isolated late RHF and RHF due to left-sided contributions is lacking in registry studies and should be the focus of future registry data collection. Potential management strategies include optimization of RV preload and afterload, neurohormonal blockade, LVAD speed optimization, and treatment of concomitant valvular disease. In this review, the authors discuss definition, pathophysiology, prevention, and management of late RHF.

Time in Therapeutic Range Significantly Impacts Survival and Adverse Events in Destination Therapy Patients.

The study aim was to examine the impact time in therapeutic range (TTR, International Normalized Ratio [INR] 2.0-3.0) has on survival and adverse events in patients receiving the HeartWare HVAD System in the ENDURANCE and ENDURANCE Supplemental Trials. Evaluable subjects (n = 495) had >1 INR value recorded 1-24 months postimplant and were categorized as: low TTR (10-39%), moderate TTR (40-69%), and high TTR (≥70%). Baseline characteristics, adverse events, and survival were analyzed. Low TTR patients experienced higher rates of major bleeding (1.69 vs. 0.54 events per patient year [EPPY]; p < 0.001), GI bleeding (1.22 vs. 0.38 EPPY; p < 0.001), stroke (0.47 vs. 0.17 EPPY; p < 0.001), thrombus requiring exchange (0.05 vs. 0.01 EPPY; p = 0.02), infection (1.44 vs. 0.69 EPPY; p < 0.001), and renal dysfunction (0.23 vs. 0.05 EPPY; p < 0.001) compared with high TTR. Moderate TTR had higher rates of major bleeding (0.75 vs. 0.54 EPPY; p < 0.001), thrombus requiring exchange (0.05 vs. 0.01 EPPY; p = 0.007), cardiac arrhythmia (0.32 vs. 0.24 EPPY; p = 0.04), and infection (0.90 vs. 0.69 EPPY; p = 0.001) compared with high TTR. Two year survival was greater among moderate and high versus low cohorts (Log-rank p = 0.001). The significant reduction in morbidity and mortality in destination therapy (DT) HVAD patients with well-controlled TTR (≥70%) emphasizes the importance of vigilant anticoagulation management.

Two-Year Follow Up of the LATERAL Clinical Trial: A Focus on Adverse Events.

BACKGROUND: The LATERAL trial validated the safety and efficacy of the thoracotomy approach for implantation of the HeartWare HVAD System, leading to Food and Drug Administration approval. We sought to analyze 24-month adverse event (AE) rates, including a temporal analysis of the risk profile, associated with the thoracotomy approach for the HVAD system. METHODS: AEs from the LATERAL trial were evaluated over 2 years postimplant. Data was obtained from the Interagency Registry for Mechanically Assisted Circulatory Support database for 144 enrolled United States and Canadian patients. Temporal AE profiles were expressed as events per patient year. RESULTS: During 162.5 patient years of support, there were 25 driveline infections (0.15 events per patient year), 50 gastrointestinal bleeds (0.31 events per patient year), and 21 strokes (0.13 events per patient year). Longitudinal AE analysis at follow-up intervals of <30 and 30 to 180 days, and 6 to 12 and 12 to 24 months revealed the highest AE rate at <30 days, with a decrease in total AEs within the first 6 months. After 6 months, most AE rates either stabilized or decreased through 2 years, including a 95% overall freedom from disabling stroke. CONCLUSIONS: Two-year follow-up of the LATERAL trial revealed a favorable morbidity profile in patients supported with the HVAD system, as AE rates were more likely to occur in the first 30 days postimplant, and overall AE rates were significantly reduced after 6 months. Importantly, 2-year freedom from disabling stroke was 95%. These data further support the improving AE profile of patients on long-term HVAD support. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02268942.

Cost of Thoracotomy Approach: An Analysis of the LATERAL Trial.

BACKGROUND: Less invasive techniques for left ventricular assist device implantation have been increasingly prevalent over past years and have been associated with improved clinical outcomes. The procedural economic impact of these techniques remains unknown. We sought to study and report economic outcomes associated with the thoracotomy implantation approach. METHODS: The LATERAL clinical trial evaluated the safety and efficacy of the thoracotomy approach for implantation of the HeartWare centrifugal-flow ventricular assist device system (HVAD). We collected UB-04 forms in parallel to the trial, allowing analysis of index hospitalization costs. All charges were converted to costs using hospital-specific cost-to-charge ratios and were subsequently compared with Medicare cost data for the same period (2015-2016). Because thoracotomy implants were off-label for all left ventricular assist devices during that period, the Medicare cohort was assumed to consist predominately of traditional sternotomy patients. RESULTS: Thoracotomy patients demonstrated decreased costs compared with sternotomy patients during the index hospitalization. Mean total index hospitalization costs for thoracotomy were $204,107 per patient, corresponding to 21.6% reduction (P < .001) and $56,385 savings per procedure compared with sternotomy. Across almost all cost categories, thoracotomy implants were less costly. CONCLUSIONS: In LATERAL, a clinical trial evaluating the safety and efficacy of the thoracotomy approach for HVAD, costs were lower than those reported in Medicare patient claims occurring over the same period. Because Medicare data can be presumed to consist of predominately sternotomy procedures, thoracotomy appears less expensive than traditional sternotomy.

Detecting Suspected Pump Thrombosis in Left Ventricular Assist Devices via Acoustic Analysis.

OBJECTIVE: Left ventricular assist devices (LVADs) fail in up to 10% of patients due to the development of pump thrombosis. Remote monitoring of patients with LVADs can enable early detection and, subsequently, treatment and prevention of pump thrombosis. We assessed whether acoustical signals measured on the chest of patients with LVADs, combined with machine learning algorithms, can be used for detecting pump thrombosis. METHODS: 13 centrifugal pump (HVAD) recipients were enrolled in the study. When hospitalized for suspected pump thrombosis, clinical data and acoustical recordings were obtained at admission, prior to and after administration of thrombolytic therapy, and every 24 hours until laboratory and pump parameters normalized. First, we selected the most important features among our feature set using LDH-based correlation analysis. Then using these features, we trained a logistic regression model and determined our decision threshold to differentiate between thrombosis and non-thrombosis episodes. RESULTS: Accuracy, sensitivity and precision were calculated to be 88.9%, 90.9% and 83.3%, respectively. When tested on the post-thrombolysis data, our algorithm suggested possible pump abnormalities that were not identified by the reference pump power or biomarker abnormalities. SIGNIFICANCE: We showed that the acoustical signatures of LVADs can be an index of mechanical deterioration and, when combined with machine learning algorithms, provide clinical decision support regarding the presence of pump thrombosis.

Evaluation of a lateral thoracotomy implant approach for a centrifugal-flow left ventricular assist device: The LATERAL clinical trial.

BACKGROUND: The HeartWare centrifugal-flow ventricular assist device system (HVAD) is a viable option for treatment of advanced heart failure. There is a growing trend toward the use of less invasive techniques in cardiac surgery, and the thoracotomy technique for HVAD implantation may provide benefits not available with conventional approaches. METHODS: The LATERAL trial is a multicenter, prospective, non-randomized, single-arm trial that utilized data from 144 patients enrolled in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database at 26 centers in the United States and Canada. The primary composite end-point was success at 180 days defined as alive on the originally implanted device and free from disabling stroke (modified Rankin Scale score >3), transplanted or explanted for recovery. The key secondary end-point was mean length of initial hospital stay. RESULTS: The primary end-point was successfully achieved in 88.1% of patients and was significantly greater than the pre-defined performance goal of 77.5% set from historical sternotomy data (p = 0.0012). The key secondary end-point-mean length of initial hospital stay -was 18 days and was significantly shorter than the pre-defined performance goal of 26.1 days obtained from historical sternotomy data (p < 0.0001). The adverse event profile further demonstrated the safety of the thoracotomy approach. The overall patient survival was good, and bleeding requiring reoperation was significantly less frequent than that observed in previous studies using the sternotomy approach. CONCLUSIONS: This prospective clinical trial provides validation that implantation of the HVAD system via the thoracotomy approach used in the LATERAL study represents a safe and effective alternative to median sternotomy in selected patients intended for a bridge-to-transplant indication.

Feasibility and utility of intraoperative epicardial scar characterization during left ventricular assist device implantation.

INTRODUCTION: Ventricular arrhythmias (VA) after left ventricular assist device (LVAD) placement are associated with increased morbidity and mortality. We sought to assess epicardial voltage characteristics at the time of LVAD implantation and investigate relationships between scar burden and postimplant VA. METHODS AND RESULTS: Consecutive patients underwent open chest epicardial electroanatomic mapping immediately before LVAD implantation. Areas of low voltage and sites with local abnormal potentials were identified. Patients were followed prospectively for postimplant VA and clinical outcomes. Between 2015 and 2017, 36 patients underwent high-density intraoperative epicardial voltage mapping; 15 had complete maps suitable for analysis. Mapping required a median of 11.8 (interquartile range [IQR], 8.5-12.7) minutes, with a median of 2650 (IQR, 2139-3191) points sampled per patient. Over a median follow-up of 311 (IQR, 168-469) postoperative days, four patients (27%) experienced sustained VA. Patients with postimplant VA were more likely to have had preimplant implantable cardioverter defibrillator shocks (100% vs 27%; P = 0.03), ventricular tachycardia storm (75% vs 9%; P = 0.03), and lower ejection fraction (13.5 vs 19.0%, P = 0.05). Patients with postimplant VA also had a significantly higher burden of epicardial low bipolar voltage points: 55.4% vs 24.9% of points were less than 0.5 mV (P = 0.01), and 88.9% vs 63.7% of points less than 1.5 mV (P = 0.004). CONCLUSIONS: Intraoperative high-density epicardial mapping during LVAD implantation is safe and efficient, facilitating characterization of a potentially arrhythmogenic substrate. An increased burden of the epicardial scar may be associated with a higher incidence of postimplant VA. The role of empiric intraoperative epicardial ablation to mitigate risk of postimplant VA requires further study.

Intraoperative identification and treatment of a giant right coronary artery aneurysm.

Giant coronary artery aneurysms are rare, difficult to diagnose, and have variable clinical presentations and treatment options. We demonstrate a case of a patient presenting with acute onset chest pain and signs of cardiac tamponade who then underwent a computed tomography pulmonary embolus protocol and was found to have hemopericardium with accumulation of contrast adjacent to the aorta. She then underwent emergent sternotomy and was found to have a large hemorrhagic mass on the right ventricle, which upon further dissection was determined to be a giant right coronary artery aneurysm with a site of contained rupture. Given the acuity of the presentation and the circumstances in which the giant coronary aneurysm was identified, the decision was made to ligate and bypass the affected coronary artery.

Giant right coronary artery aneurysm presenting as cardiac tamponade.

Giant coronary artery aneurysms are rare and have variable presentations, which range from an incidental finding to sudden death. We report a case of a female presenting with chest pain and signs of cardiac tamponade who underwent a computed tomography (CT) pulmonary embolus protocol and was found to have haemopericardium with accumulation of contrast adjacent to the aorta. She underwent emergent sternotomy and was found to have a ruptured giant right coronary artery aneurysm, which was ligated and bypassed. This report highlights the difficulty of diagnosing a ruptured giant coronary artery aneurysm via CT and provides valuable information on an atypical presentation.

Increased Thromboembolic Events With Dabigatran Compared With Vitamin K Antagonism in Left Ventricular Assist Device Patients: A Randomized Controlled Pilot Trial.

BACKGROUND: Left ventricular assist device-supported patients are usually anticoagulated with a combination of aspirin and vitamin K antagonists. Long-term vitamin K antagonist therapy can be complicated by unstable international normalized ratio values and patient-related compliance problems. Therefore, direct thrombin inhibitors may represent an alternative to vitamin K antagonists. METHODS AND RESULTS: Thirty HeartWare ventricular assist device patients with stable renal function were planned for this prospective, randomized, open-label, single-center study. Patients were randomized to receive either phenprocoumon or dabigatran in addition to aspirin for long-term anticoagulation. Treatment duration was scheduled for 1 year and stopped after observation of a primary end point. Dabigatran dose was 110 and 75 mg BID in patients with normal or impaired renal function (glomerular filtration rate >80 mL/min or between 80 and 30 mL/min, respectively). The study was stopped prematurely for safety reasons after 16 patients (61±8 years, 1 female) were randomized. Thromboembolic events occurred in 4 subjects receiving dabigatran (50%) and in 1 receiving phenprocoumon (13%; P=0.28). No major bleeding was recorded, and no patient died during the study. Median time to treatment termination was significantly shorter in dabigatran patients (8.5 versus 12.0 months; P=0.015). CONCLUSIONS: Thromboembolic events on dabigatran led to early termination of a randomized controlled trial of dabigatran versus phenprocoumon in left ventricular assist device patients. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT02872649.

Ventricular assist devices for treatment of acute heart failure and chronic heart failure.

Despite therapeutic advances that improve longevity and quality of life, heart failure (HF) remains a relentless disease. At the end stage of HF, patients may become eligible for mechanical circulatory support (MCS) for the indications of stabilising acute cardiogenic shock or for chronic HF management. MCS use is growing rapidly in the USA and some countries of the European Union, especially in transplant-ineligible patients. In others, it remains largely a tool to stabilise patients until heart transplant. MCS comprises a heterogeneous group of temporary and durable devices which augment or replace the pumping function of one or both ventricles, with postimplant 2 year survival rivalling that of transplant in selected, lower-risk patients. In transplant-eligible and non-transplant-eligible patients, improvement in end-organ perfusion, functional capacity and quality of life have been noted. Even for optimal candidates, however, there are a host of potential complications that require constant vigilance of a coordinated care team. Recently, there has been official recognition of the importance of palliative care expertise in advance care planning preimplant and management of patients with ventricular assist devices at the end of their lives.

Lack of donor and recipient age interaction in cardiac transplantation.

BACKGROUND: The proportion of older donors and recipients is constantly rising in heart transplantation (HTX). The impact of age on different outcomes after HTX has been studied; however, effects of interaction between donor and recipient age remain elusive. METHODS: This retrospective cohort study comprised 1,190 patients who underwent HTX between 1984 and 2011 at the Medical University Vienna. Multivariable models consisted of a basic set that included donor age, recipient age, and transplant eras and were adjusted for 2 sets of 6 possible confounders and 3 mediator variables. Cox models were used to estimate the risk of death. To search for age-related effects on the development of cardiac allograft vasculopathy (CAV), we applied cause-specific Cox models and proportional sub-distribution hazard models for competing risk data. RESULTS: Survival was 80%, 77%, 69%, and 56% after 1, 2, 5, and 10 years, respectively. Donor age (hazard ratio [HR], 1.1; 95% confidence interval [CI], 1.0-1.2), recipient age (HR, 1.1; 95% CI, 1.0-1.2), admission from intensive care unit to HTX (HR, 1.5; 95% CI, 1.2-1.9), and diabetes (HR, 1.4; 95% CI, 1.1-1.7) were identified as significant independent risk factors for death. Significant risk factors for CAV were donor age (HR, 1.4; 95% CI, 1.3-1.5) and male recipient sex (HR, 1.5; 95% CI, 1.0-2.2). Recipient age was inversely associated with initiation of CAV (HR, 0.8; 95% CI, 0.8-1.0). Analysis of the interaction between donor and recipient age was not significant for death (p = 0.8) or CAV (p = 0.6). CONCLUSIONS: We found no interaction between donor and recipient age negatively affecting mortality and CAV. The identified independent risk factors may have implications for allocation strategies in elderly recipients.

Extended in vivo evaluation of a miniaturized axial flow pump with a novel inflow cannula for a minimal invasive implantation procedure.

BACKGROUND: Minimally invasive techniques are desirable to minimize surgical trauma during left ventricular assist device (LVAD) implantation. This is particularly challenging for full-flow support. In this study, a minimally invasive implantation technique was developed for a microaxial rotary pump. The system was evaluated in a chronic sheep model. METHODS: A HeartWare MVAD (HeartWare, Miami Lakes, FL) pump (length, 50 mm; diameter, 21 mm; maximum flow, 7-8 liters/min) was combined with a novel inflow cannula, including a new flow-optimized tip. The device was implanted into sheep (range, 60-80 kg, mean, 71.6 ± 6.8 kg) through a right-sided minithoracotomy. The inflow cannula was inserted through the superior pulmonary vein, passing through the left atrium into the left ventricle. Scheduled implant period was 30 days for 8 sheep and 100 days for 3 sheep. Mean support flow was set to half of the nominal cardiac output. RESULTS: Six of 8 sheep finished the scheduled 30-day investigation period (one failed due to early non-pump-related post-operative bleeding and one due to prototype controller failure). The 3 sheep scheduled for 100 days reached the study end point. Peak pump flows of up to 6.9 liters/min were achieved. At necropsy, no signs of mitral valve lesions or thrombus formation around the cannula, the tip, or the insertion site were observed, except for valve leaflet erosion in 1 animal, where the cannula had been entangled in the sub-valvular chords due to lack of ultrasound monitoring. CONCLUSIONS: The minimally invasive implantation technique using the HeartWare MVAD pump, together with a new cannula, provided excellent results in a chronic animal model.

Low-level-laser irradiation induces photorelaxation in coronary arteries and overcomes vasospasm of internal thoracic arteries.

BACKGROUND AND OBJECTIVE: As low-level laser irradiation (LLLI) seems to induce vasodilation besides many other known biological effects, LLLI has been increasingly used in therapy of medical conditions with various irradiation parameters. The aim of this study was to investigate the effect of LLLI on photorelaxation of human coronary and internal thoracic arteries (ITA). MATERIALS AND METHODS: Thirty vessel segments of ITA used for routine coronary artery bypass grafting as well as left anterior descending coronary arteries (LAD) of patients undergoing cardiac transplantation were cut into 4-mm rings stored in a modified Krebs-Henseleit solution and evaluated in a myograph. Both types of vessel segments were irradiated by a semiconductor non-thermal GaAs diode laser operating at a wavelength of 680 nm. After precontraction with thromboxane agonist U44619, respective relaxation responses were evaluated and compared to pharmacological dilatation induced by substance P. RESULTS: Mean pharmacological vasodilation by substance P was 22.6 ± 3.3%, 12.8 ± 1.4%, and 20.4 ± 3.2% in macroscopic healthy LAD, LAD with atheromatous plaque, and ITA, respectively. Average photorelaxation induced by LLLI was 16.5 ± 2.0%, 1.9 ± 1.7%, and 6.8 ± 4.7%, accordingly. Vasodilatatory responses induced either by substance P or administration of LLLI were significantly decreased in LAD with atheromatous plaque (P < 0.0001). Vasospasms of ITA segments occurring during experiments could be abandoned when LLLI was administered. CONCLUSION: Macroscopic healthy LAD exposed to LLLI revealed significant photorelaxation. With the administration of LLLI, 73% of the maximal obtainable effect by an endothelium-dependent vasodilator could be reached. Furthermore, LLLI has the potential to overcome vasospasms of ITA.