Heart immunoengineering by lentiviral vector-mediated genetic modification during normothermic ex vivo perfusion.

Heart transplantation is associated with major hurdles, including the limited number of available organs for transplantation, the risk of rejection due to genetic discrepancies, and the burden of immunosuppression. In this study, we demonstrated the feasibility of permanent genetic engineering of the heart during ex vivo perfusion. Lentiviral vectors encoding for short hairpin RNAs targeting beta2-microglobulin (shß2m) and class II transactivator (shCIITA) were delivered to the graft during two hours of normothermic EVHP. Highly efficient genetic engineering was indicated by stable reporter gene expression in endothelial cells and cardiomyocytes. Remarkably, swine leucocyte antigen (SLA) class I and SLA class II expression levels were decreased by 66% and 76%, respectively, in the vascular endothelium. Evaluation of lactate, troponin T, and LDH levels in the perfusate and histological analysis showed no additional cell injury or tissue damage caused by lentiviral vectors. Moreover, cytokine secretion profiles (IL-6, IL-8, and TNF-α) of non-transduced and lentiviral vector-transduced hearts were comparable. This study demonstrated the ex vivo generation of genetically engineered hearts without compromising tissue integrity. Downregulation of SLA expression may contribute to reduce the immunogenicity of the heart and support graft survival after allogeneic or xenogeneic transplantation.

Minimally Invasive Approach for Replacement of the Ascending Aorta towards the Proximal Aortic Arch.

Objectives: In recent years, minimally invasive approaches have been used with increasing frequency, even for more complex aortic procedures. However, evidence on the practicability and safety of expanding minimally invasive techniques from isolated operations of the ascending aorta towards more complex operations such as the hemiarch replacement is still scarce to date. Methods: A total of 86 patients undergoing elective surgical replacement of the ascending aorta with (n = 40) or without (n = 46) concomitant proximal aortic arch replacement between 2009 and 2023 were analyzed in a retrospective single-center analysis. Groups were compared regarding operation times, intra- and postoperative complications and long-term survival. Results: Operation times and ventilation times were significantly longer in the hemiarch replacement group. Despite this, no statistically significant differences between the two groups were observed for the duration of the ICU and hospital stay and postoperative complication rates. At ten-year follow-up, overall survival was 82.6% after isolated ascending aorta replacement and 86.3% after hemiarch replacement (p = 0.441). Conclusions: Expanding the indication for minimally invasive aortic surgery towards the proximal aortic arch resulted in comparable postoperative complication rates, length of hospital stay and overall long-term survival compared to the well-established minimally invasive isolated supracommissural ascending aorta replacement.

Intraoperative haemoadsorption for antithrombotic drug removal during cardiac surgery: initial report of the international safe and timely antithrombotic removal (STAR) registry.

Intraoperative antithrombotic drug removal by haemoadsorption is a novel strategy to reduce perioperative bleeding in patients on antithrombotic drugs undergoing cardiac surgery. The international STAR registry reports real-world clinical outcomes associated with this application. All patients underwent cardiac surgery before completing the recommended washout period. The haemoadsorption device was incorporated into the cardiopulmonary bypass (CPB) circuit. Patients on P2Y12 inhibitors comprised group 1, and patients on direct-acting oral anticoagulants (DOAC) group 2. Outcome measurements included bleeding events according to standardised definitions and 24-hour chest-tube-drainage (CTD). 165 patients were included from 8 institutions in Austria, Germany, Sweden, and the UK. Group 1 included 114 patients (62.9 ± 11.6years, 81% male) operated at a mean time of 33.2 h from the last P2Y12 inhibitor dose with a mean CPB duration of 117.1 ± 62.0 min. Group 2 included 51 patients (68.4 ± 9.4years, 53% male), operated at a mean time of 44.6 h after the last DOAC dose, with a CPB duration of 128.6 ± 48.4 min. In Group 1, 15 patients experienced a BARC-4 bleeding event (13%), including 3 reoperations (2.6%). The mean 24-hour CTD was 651 ± 407mL. In Group 2, 8 patients experienced a BARC-4 bleeding event (16%) including 4 reoperations (7.8%). The mean CTD was 675 ± 363mL. This initial report of the ongoing STAR registry shows that the intraoperative use of a haemoadsorption device is simple and safe, and may potentially mitigate the expected high bleeding risk of patients on antithrombotic drugs undergoing cardiac surgery before completion of the recommended washout period.Clinical registration number: ClinicalTrials.gov identifier: NCT05077124.

Hemodynamical Evaluation of a New Surgically Implanted Pulsatile Right Ventricular Assist Device Driven by a Conventional Intra-Aortic Balloon Pump Console.

Severe right heart failure, often overlooked and challenging to manage, has prompted a growing interest in innovative approaches to provide functional support. This study uses experimentation in large porcine models to introduce a novel prototype of a pulsatile mechanical circulatory support device and document its effects when deployed as a right ventricular assist device (RVAD). The pulsatile ventricular assist platform (pVAP), featuring a membrane pump driven by an intra-aortic balloon pump console, actively generates pulsatile flow to propel right ventricular blood into the pulmonary artery. This novel prototype demonstrates promising potential in addressing the challenges of right heart failure management. After preliminary in vitro assessments, the pVAP was tested on seven porcine models in a healthy state and after the induction of right ventricular failure. During the procedure, a set of standard (ie, standard-of-care) hemodynamic measurements was obtained. Additionally, invasive pressure-volume loop analysis was employed to examine left ventricular hemodynamics. Results indicated that activation of the pVAP during right ventricular failure significantly improved systemic hemodynamics and enhanced left ventricular function. This study sheds light on the potential of the pVAP in managing right heart failure.

Risk factors, prevention, and therapy of intraluminal stent thrombosis in frozen elephant trunk prostheses-what we know so far.

Intraluminal thrombus formation (ILT) is a recently discovered and highly clinically relevant complication after frozen elephant trunk implantation in cardiovascular surgery. In this phenomenon, a thrombus forms within the lumen of the stent graft component of the frozen elephant trunk prosthesis and puts the patient at risk for downstream embolization with visceral or lower limb ischemia. Incidence of ILT reported in the currently available studies ranges from 6% to 17% of patients after frozen elephant trunk implantation. Adverse thromboembolic events include acute occlusion of the celiac and superior mesenteric arteries, both renal arteries as well as acute lower limb ischemia due to iliac or femoral artery embolization that not infrequently require interventional or open embolectomy. Therefore, the presence of ILT is associated with increased short-term mortality and morbidity. Currently proposed strategies to avoid ILT formation include a more aggressive anticoagulation management, minimization of postoperative coagulation factor application, and even technical optimizations of the stent graft portion itself. If ILT is manifested, the therapeutic strategies tested to date are long-term escalation of anticoagulation and early endovascular extension of the FET stent graft with overstenting of the intraluminal thrombus. The long-term efficiency of these prophylactic and therapeutic measures has yet to be proven. Nonetheless, all surgeons performing the frozen elephant trunk procedure must be aware of the risk of ILT formation to facilitate a timely diagnosis and therapy.

Antibacterial copper-filled TiO2 coating of cardiovascular implants to prevent infective endocarditis-A pilot study.

BACKGROUND: Infective endocarditis (IE) poses a significant health risk, especially in patients with prosthetic heart valves. Despite advances in treatment, mortality rates remain high. This study aims to investigate the antibacterial properties of a copper titanium dioxide (4× Cu-TiO2) coating on cardiovascular implants against Staphylococcus aureus, a common causative agent of IE. METHODS: Titanium oxide carriers functionalized with copper ions were employed as an antibacterial coating for heart and vascular prostheses. The coating's antibacterial efficacy was assessed using S. aureus ATCC 29213. Microscopic evaluations were conducted on both biological and artificial materials. Antibacterial activity was qualitatively assessed via a modified disc diffusion method and quantitatively measured through colony counts in NaCl suspensions. RESULTS: The coating process was successfully applied to all tested cardiovascular prosthetic materials. Qualitative assessments of antibacterial effectiveness revealed an absence of bacterial growth in the area directly beneath the coated valve. Quantitative evaluations showed a significant reduction in bacterial colonization on coated mechanical valves, with 2.95 × 104 CFU per valve, compared to 1.91 × 105 CFU in control valves. CONCLUSIONS: The 4× Cu-TiO2 coating demonstrated promising antibacterial properties against S. aureus, suggesting its potential as an effective strategy for reducing the risk of bacterial colonization of cardiovascular implants. Further studies are needed to assess the longevity of the coating and its efficacy against other pathogens.

Fully magnetically centrifugal left ventricular assist device and long-term outcomes: the ELEVATE registry.

BACKGROUND AND AIMS: HeartMate 3 (HM3) is a fully magnetically levitated continuous flow left ventricular assist device, which received CE marking in 2015. The ELEVATE Registry was initiated to collect real-world outcomes in patients treated with HM3 post-CE Mark approval. METHODS: A total of 540 subjects implanted at 26 centres between March 2015 and February 2017 were included in this registry. Of these, 463 received the device as a primary implant (primary implant cohort, PIC), 19 as a pump exchange (pump exchange cohort), and in 58 patients, only anonymized survival data were collected (anonymized cohort, AC). Patients in the PIC contributed to the baseline demographics, survival, adverse events, quality of life (QoL) (EuroQoL-5 Dimensions-5 Levels visual analogue scale), and functional capacity (6 min walk distance) assessments, while patients in the AC contributed only to survival. RESULTS: Primary implant cohort patients had a mean age of 56 years and were predominantly male (89%) with 48% ischaemic aetiology. The majority of subjects was designated bridge to transplant (66%) and had INTERMACS Profiles 1-3 (70%). At baseline, the subjects had poor functional capacity (104 ± 140 m) and impaired QoL (35 ± 19 points). The overall survival rate of the PIC was 63.3% and survival free of stroke was 58.1% at 5 years. Significant improvements in functional capacity and QoL were observed and maintained for 5 years (301 ± 131 m and 64 ± 20 points, respectively). CONCLUSIONS: Real-world data from the ELEVATE registry demonstrate an overall survival rate for primary implants of 63.3%. In the PIC, reductions in adverse events for patients in the extended follow-up and improved QoL and functional capacity were observed at 5 years in this patient population with advanced heart failure.

Left ventricular assist device implantation and concomitant mitral valve surgery: A systematic review and meta-analysis.

BACKGROUND: The management of concomitant valvular lesions in patients undergoing left ventricular assist device (LVAD) implantation remains a topic of debate. This systematic review and meta-analysis aimed to evaluate the existing evidence on postoperative outcomes following LVAD implantation, with and without concomitant MV surgery. METHODS: A systematic database search was conducted as per PRISMA guidelines, of original articles comparing LVAD alone to LVAD plus concomitant MV surgery up to February 2023. The primary outcomes assessed were overall mortality and early mortality, while secondary outcomes included stroke, need for right ventricular assist device (RVAD) implantation, postoperative mitral valve regurgitation, major bleeding, and renal dysfunction. RESULTS: The meta-analysis included 10 studies comprising 32 184 patients. It revealed that concomitant MV surgery during LVAD implantation did not significantly affect overall mortality (OR:0.83; 95% CI: 0.53 to 1.29; p = 0.40), early mortality (OR:1.17; 95% CI: 0.63 to 2.17; p = 0.63), stroke, need for RVAD implantation, postoperative mitral valve regurgitation, major bleeding, or renal dysfunction. These findings suggest that concomitant MV surgery appears not to confer additional benefits in terms of these clinical outcomes. CONCLUSION: Based on the available evidence, concomitant MV surgery during LVAD implantation does not appear to have a significant impact on postoperative outcomes. However, decision-making regarding MV surgery should be individualized, considering patient-specific factors and characteristics. Further research with prospective studies focusing on specific patient populations and newer LVAD devices is warranted to provide more robust evidence and guide clinical practice in the management of valvular lesions in LVAD recipients.

Interplay between driveline infection, vessel wall inflammation, cerebrovascular events and mortality in patients with left ventricular assist device.

In patients with left ventricular assist device (LVAD), infections and thrombotic events represent severe complications. We investigated device-specific local and systemic inflammation and its impact on cerebrovascular events (CVE) and mortality. In 118 LVAD patients referred for 18F-FDG-PET/CT, metabolic activity of LVAD components, thoracic aortic wall, lymphoid and hematopoietic organs, was quantified and correlated with clinical characteristics, laboratory findings, and outcome. Driveline infection was detected in 92/118 (78%) patients by 18F-FDG-PET/CT. Activity at the driveline entry site was associated with increased signals in aortic wall (r = 0.32, p < 0.001), spleen (r = 0.20, p = 0.03) and bone marrow (r = 0.20, p = 0.03), indicating systemic interactions. Multivariable analysis revealed independent associations of aortic wall activity with activity of spleen (ß = 0.43, 95% CI 0.18-0.68, p < 0.001) and driveline entry site (ß = 0.04, 95% CI 0.01-0.06, p = 0.001). Twenty-two (19%) patients suffered CVE after PET/CT. In a binary logistic regression analysis metabolic activity at the driveline entry site missed the level of significance as an influencing factor for CVE after adjusting for anticoagulation (OR = 1.16, 95% CI 1-1.33, p = 0.05). Metabolic activity of the subcutaneous driveline (OR = 1.13, 95% CI 1.02-1.24, p = 0.016) emerged as independent risk factor for mortality. Molecular imaging revealed systemic inflammatory interplay between thoracic aorta, hematopoietic organs, and infected device components in LVAD patients, the latter predicting CVE and mortality.

Pre-emptive iron supplementation prevents myocardial iron deficiency and attenuates adverse remodelling after myocardial infarction.

AIMS: Heart failure (HF) after myocardial infarction (MI) is a major cause of morbidity and mortality. We sought to investigate the functional importance of cardiac iron status after MI and the potential of pre-emptive iron supplementation in preventing cardiac iron deficiency (ID) and attenuating left ventricular (LV) remodelling. METHODS AND RESULTS: MI was induced in C57BL/6J male mice by left anterior descending coronary artery ligation. Cardiac iron status in the non-infarcted LV myocardium was dynamically regulated after MI: non-haem iron and ferritin increased at 4 weeks but decreased at 24 weeks after MI. Cardiac ID at 24 weeks was associated with reduced expression of iron-dependent electron transport chain (ETC) Complex I compared with sham-operated mice. Hepcidin expression in the non-infarcted LV myocardium was elevated at 4 weeks and suppressed at 24 weeks. Hepcidin suppression at 24 weeks was accompanied by more abundant expression of membrane-localized ferroportin, the iron exporter, in the non-infarcted LV myocardium. Notably, similarly dysregulated iron homeostasis was observed in LV myocardium from failing human hearts, which displayed lower iron content, reduced hepcidin expression, and increased membrane-bound ferroportin. Injecting ferric carboxymaltose (15 µg/g body weight) intravenously at 12, 16, and 20 weeks after MI preserved cardiac iron content and attenuated LV remodelling and dysfunction at 24 weeks compared with saline-injected mice. CONCLUSION: We demonstrate, for the first time, that dynamic changes in cardiac iron status after MI are associated with local hepcidin suppression, leading to cardiac ID long term after MI. Pre-emptive iron supplementation maintained cardiac iron content and attenuated adverse remodelling after MI. Our results identify the spontaneous development of cardiac ID as a novel disease mechanism and therapeutic target in post-infarction LV remodelling and HF.

Use of left atrial appendage as an autologous tissue source for epicardial micrograft transplantation during LVAD implantation.

We report here the first clinical use of the left atrial appendage (LAA) for epicardial micrograft transplantation during left ventricular assist device (LVAD) implantation. Previously, a sample from the right atrial appendage (RAA) has been available for processing and administering micrograft therapy in cardiac surgery. Both LAA and RAA are rich sources of various types of myocardial cells and are capable of providing both paracrine and cellular support to the failing myocardium. The surgical approach of LAA micrografting facilitates epicardial micrograft therapy dose escalation and treatment of larger myocardial areas than done previously. Moreover, as collection of treated vs. untreated tissues from the recipient heart is possible following LVAD implantation at the time of heart transplantation, the evaluation of the therapy's mechanism of action can be further deciphered at cellular and molecular levels. This LAA modification of the epicardial micrografting technique has the overall potential to facilitate the adoption of cardiac cell therapy during heart surgery.

Changes in eligibility for a subcutaneous cardioverter-defibrillator after implantation of a left ventricular assist device-A prospective analysis.

BACKGROUND: The number of left ventricular assist devices (LVADs) implanted in patients with end-stage heart failure is increasing. In this patient cohort, subcutaneous implantable cardioverter defibrillators (S-ICDs) could be a promising alternative to transvenous ICDs due to lower infection rates and avoidance of venous access. However, eligibility for the S-ICD depends on ECG features that may be influenced by an LVAD. The aim of the present study was a prospective evaluation of S-ICD eligibility before and after LVAD implantation. METHODS: The study recruited all patients presenting at Hannover Medical School for LVAD implantation between 2016 and 2020. S-ICD eligibility was evaluated using the ECG-based and the device-based S-ICD screening test before and after LVAD implantation. RESULTS: Twenty-two patients (57.3 ± 8.7 years of age, 95.5% male) were included in the analysis. The most common underlying diseases were dilated cardiomyopathy (n = 16, 72.7%) and ischemic cardiomyopathy (n = 5, 22.7%). Before LVAD implantation 16 patients were found eligible for the S-ICD according to both screening tests (72.7%), but only 7 patients were eligible after LVAD, 31.8%; p = 0.05). Oversensing due to electromagnetic interference was observed in 6 patients (66.6%) found ineligible for S-ICD after LVAD implantation. A lower S wave amplitude in leads I (p = 0.009), II (p = 0.006) and aVF (p = 0.006) before LVAD implantation was associated with higher rate of S-ICD ineligibility after LVAD implantation. CONCLUSION: LVAD implantation can impair S-ICD eligibility. Patients with lower S wave amplitude in leads I, II and aVF were more likely to be ineligible for S-ICD implantation after LVAD implantation. Thus, S-ICD therapy should be carefully considered in patients who are candidates for LVAD therapy.

Three-month outcomes after the implantation of two HeartMate 3 devices in total artificial heart configuration.

BACKGROUND: Total artificial heart (TAH) implantation is a rarely performed procedure. Contrarily, left ventricular assist device (VAD) implantation is rather common in many centers. As transplantation is quantitatively limited cardiac replacement with artificial hearts is a viable alternative in the treatment of severe biventricular heart failure. An alternative to TAH is the implantation of two VADs in a TAH configuration. We hereby present the first multi-center study on 3-months outcomes of patients treated by cardiectomy and placement of two HeartMate 3s in a TAH configuration. METHODS: We retrospectively investigated a cohort of 15 patients that underwent HM3-TAH-implantation at three international institutions. Follow-up was 3 months after implantation. Baseline, intra- and postoperative parameters as well as survival data and adverse events were collected. RESULTS: A total of 1089 days on HM3-TAH were observed. Thirty-day survival after HM3-TAH implantation was 53% (8/15) and three month survival was 40% (6/15). The longest duration on device was 274 days. Causes of death were multi-organ failure, sepsis, and neurological adverse events. No technical complications were documented. Two patients remained on the device. Four patients (26%) were successfully bridged to transplantation. CONCLUSIONS: The implantation of two HeartMate 3s in a TAH configuration is a last resort and off-label concept in cases of extreme biventricular heart failure. In a diligently selected patient cohort, HM3-TAH implantation is a feasible method to increase the chance of survival in a severely ill patient cohort and successfully bridge patients to heart transplantation that would otherwise have died.

Outcomes of modular cable exchange in HeartMate 3 patients versus conventional driveline repair in HeartMate II patients.

BACKGROUND: Driveline (DL) damages are a common difficulty among ventricular assist devices (VAD). Repairing the electrical fibers inside the DL on a running pump is hazardous and requires technical expertise, which is not easily available on site. A new feature of the HeartMate3 (Abbott, U.S.A.) LVAD is a modular driveline that allows an easy exchange of the DL cord. In this report we analyze our experiences with this feature. METHODS: We performed a retrospective analysis of 302 patients who underwent either HeartMate II or HeartMate 3 implantation between February 2004 and September 2021. Patients were screened for driveline faults and need for exchange or repair of driveline or VAD exchange. Documented were baseline characteristics, reasons for DL or VAD exchange, and complications. Follow-up was three months after the procedure. RESULTS: We present a cohort of 302 patients who underwent either HMII (n = 107;35.4%) or HM 3 (n = 195; 64.5%) implantation. Out of those, 40 patients (40/302; 13.2%) required driveline repair (DLRe) or exchange (DLEx). Out of 107 HMII patients, 9 showed severe DL damages (9/107; 8.4%). Six patients (6/9; 66.6%) underwent DLRe, two patients (2/6; 33.3%) required VAD exchange after DLRe, one patient (1/2;50%) experienced emergency VAD exchange after pump stop. The DLRe procedure in the other four patients (4/6; 66.6%) was successful. Due to damage to the internal driveline two patients (2/9; 22.2%) underwent emergency device exchange and one patient (1/9;11.1%) was listed for transplantation. 31 out 195 HM3 patients underwent exchange of the modular DL. In none of the cases, damages of the internal fibers were the reasons for the exchange. In 100% of the cases, damages of the external coating were the reason for DL exchange. In none of the cases, complications occurred after the exchange procedure. CONCLUSIONS: Driveline damages are a habitual, recurrent complication in VAD patients. The exchange of the modular driveline cable of the HM3 is feasible and safe compared to the conventional DL repair in HMII patients. Risky repair attempts and surgical LVAD exchange due to major damages of the electrical fibers can be avoided successfully by the new feature of HM3 driveline.

Microembolic signal monitoring in patients with HeartMate 3 and HeartWare left ventricular assist devices: Association with antithrombotic treatment and cerebrovascular events.

BACKGROUND: In patients with left ventricular assist devices (LVADs), ischemic and hemorrhagic stroke are dreaded complications. Predictive markers for these events are lacking. This study aimed to investigate the prevalence and predictive value of microembolic signals (MES) for stroke, detected by Transcranial Doppler sonography (TCD) in patients with HeartMate 3 (HM 3) or HeartWare (HW). METHODS: A thirty-minute bilateral TCD monitoring of the middle cerebral artery (MCA) was performed in 62 outpatients with LVAD (HM 3 N = 31, HW N = 31) and 31 healthy controls. Prevalence and quantity of MES were investigated regarding clinical and laboratory parameters. Cerebrovascular events (CVE) were recorded on follow-up at 90 and 180 days. RESULTS: MES were detected in six patients with HM 3, three patients with HW, and three controls. Within the LVAD groups, patients on monotherapy with vitamin-K-antagonist (VKA) without antiplatelet therapy were at risk for a higher count of MES (negative binomial regression: VKA: 1; VKA + ASA: Exp(B) = 0.005, 95%CI 0.001-0.044; VKA + clopidogrel: Exp(B) = 0.012, 95%CI 0.002-0.056). There was no association between the presence of MES and CVE or death on follow-up (p > 0.05). CONCLUSION: For the first time, the prevalence of MES was prospectively investigated in a notable outpatient cohort of patients with HM 3 and HW. Despite optimized properties of the latest LVAD, MES remain detectable depending on antithrombotic therapy. No association between MES and CVE could be detected.