Flow Optimization, Management, and Prevention of LV Distention during VA-ECMO

Cardiogenic shock (CS) still carries an unacceptably high mortality (30–60%), despite several therapeutic approaches; the SHOCK II trial questioned the benefit of intra-aortic balloon pump (IABP), while IMPRESS and CULPRIT-SHOCK trials confirmed heterogeneity in disease spectrum and patient selection for acute myocardial infarction-related CS requiring acute mechanical circulatory support (AMCS). The heterogeneity of devices employed as AMCS, including temporary micro-axial flow pumps (Impella), percutaneous bypass (TandemHeart), and extracorporeal life support (VA-ECMO), contributed to the actual dramatic scenario, where CS is defined clinically rather than hemodynamically. To date, the role of VA-ECMO is emerging as rapid strategy to mitigate mortality rates of severe refractory states, despite the lack of data regarding the best practices of management and flows control. VA-ECMO’s flow represents the “dose” of treatment and higher flows are less tolerated percutaneously requiring, to prevent deleterious pulmonary edema and ventricular distention, additional approaches such as pulmonary, left atrial, or left ventricular unloading. Any efforts have to be directed to (1) determine adequate management of patients on VA-ECMO, (2) define the safer duration of VA-ECMO support, and (3) establish algorithms and techniques to predict and obtain stable weaning from ECMO or ensure fast transition to durable VAD and/or heart transplant

Human Cardiac Progenitor Cell-Derived Extracellular Vesicles Exhibit Promising Potential for Supporting Cardiac Repair in Vitro

Although human Cardiac Progenitor Cells (hCPCs) are not retained by host myocardium they still improve cardiac function when injected into schemic heart. Emerging evidence supports the hypothesis that hCPC beneficial effects are induced by paracrine action on resident cells. Extracellular vesicles (EVs) are an intriguing mechanism of cell communication based on the transport and transfer of peptides, lipids, and nucleic acids that have the potential to modulate signaling pathways, cell growth, migration, mand proliferation of recipient cells. We hypothesize that EVs are involved in the paracrine effects elicited by hCPCs and held accountable for the response of the infarcted myocardium to hCPC-based cell therapy. To test this theory, we collected EVs released by hCPCs isolated from healthy myocardium and evaluated the effects they elicited when administered to resident hCPC and cardiac fibroblasts (CFs) isolated from patients with post-ischemic end-stage heart failure. Evidence emerging from our study indicated that hCPC-derived EVs impacted upon proliferation and survival of hCPCs residing in the ischemic heart and regulated the synthesis and deposition of extracellular-matrix by CFs. These findings suggest that beneficial effects exerted by hCPC injection are, at least to some extent, ascribable to the delivery of signals conveyed by EVs

Biological properties of cardiac stem cells in normal and pathological conditions - matrix makes a difference

Cardiac cells and extracellular matrix (ECM) are reciprocally related and their characteristics are modified in response to developmental or pathophysiological cues. Adult human cardiac tissue regeneration mediated by cardiac stem cells (CSCs) is strictly regulated and, hypothetically, impaired by the ECM-CSC signalling in the pathological conditions. To test this hypothesis, we isolated cardiac fibroblasts (CFs) and CSCs from the atria of age-matched adult human normal (n=9) and pathological hearts (ischemic cardiomyopathy, n=11). The CFs were cultured in order to obtain ECM coating and conditioned medium, which were characterized by immunoblotting and ELISA, respectively. Next, we examined the effects of CF-derived ECM and CF-conditioned medium on normal and pathological CSC proliferation, apoptosis, and migration in vitro. The ECM produced by CFs from normal heart was composed mainly of fibronectin, laminin α2 and collagen I, while that produced by CFs from hearts with ischemic cardiomyopathy contained also laminin α1 and tenascin X. Compared to the normal CF-conditioned medium, that conditioned by pathological CFs contained twice as much IGF1 and HGF, and it stimulated proliferation and migration, while reducing apoptosis of CSCs. In the presence of pathological CF-derived ECM, there was a nearly 2-fold increase (p<0.05) in proliferation of normal and pathological CSCs, when compared to normal CF-derived ECM. Moreover, pathological CF-derived ECM reduced CSC apoptosis, specifically in cells from pathological heart. However, in the same conditions, the migration of pathological CSCs was significantly lower. These results indicate that the activity of CFs and its modification in chronic ischemic conditions determines biological properties of CSCs. Such an influence should be taken into consideration when attempting ischemic cardiac tissue stem cell-based regeneration

Glycated ACE2 reduces anti-remodeling effects of renin-angiotensin system inhibition in human diabetic hearts

High glycated-hemoglobin (HbA1c) levels correlated with an elevated risk of adverse cardiovascular outcomes despite renin-angiotensin system (RAS) inhibition in type-2 diabetic (T2DM) patients with reduced ejection fraction. Using the routine biopsies of non-T2DM heart transplanted (HTX) in T2DM recipients, we evaluated whether the diabetic milieu modulates glycosylated ACE2 (GlycACE2) levels in cardiomyocytes, known to be affected by non-enzymatic glycosylation, and the relationship with glycemic control

Heart Transplantation

One of the most challenging scientific steps of the modern era has been the ability to replace, functionally or anatomically, the failing heart, and in December 2017 we celebrated the 50th anniversary of the world's first human heart transplant. Despite a long and troubled hystory, heart transplantation has dramatically expanded over time, and is currently the ""gold standard"" solution in terms of treatment of refractory end-stage heart failure. Thanks to the contributions by well-known experts in the field, the goal of this book is to provide a framework for successful transplant program development and management. The text reflects the global collective efforts of those who have dedicated countless energy to achieving a better understanding of the details that will ultimately yield better outcomes in terms of teamwork

The epigenetic promise to improve prognosis of heart failure and heart transplantation

Heart transplantation is still the only possible life-saving treatment for end-stage heart failure, the critical epilogue of several cardiac diseases. Epigenetic mechanisms are being intensively investigated because they could contribute to establishing innovative diagnostic and predictive biomarkers, as well as ground-breaking therapies both for heart failure and heart transplantation rejection. DNA methylation and histone modifications can modulate the innate and adaptive immune response by acting on the expression of immune-related genes that, in turn, are crucial determinants of transplantation outcome. Epigenetic drugs acting on methylation and histone-modification pathways may modulate Treg activity by acting as immunosuppressive agents. Moreover, the identification of non-invasive and reliable epigenetic biomarkers for the prediction of allograft rejection and for monitoring immunosuppressive therapies represents an attractive perspective in the management of transplanted patients. MiRNAs seem to fit particularly well to this purpose because they are differently expressed in patients at high and low risk of rejection and are detectable in biological fluids besides biopsies. Although increasing evidence supports the involvement of epigenetic tags in heart failure and transplantation, further short and long-term clinical studies are needed to translate the possible available findings into clinical setting

Mini-organs forum: how to advance organoid technology to organ transplant community

The generation of human mini-organs, the so-called organoids, is one of the biggest scientific advances in regenerative medicine. This technology exploits traditional three-dimensional culture techniques that support cell-autonomous self-organization responses of stem cells to derive micrometer to millimeter size versions of human organs. The convergence of the organoid technology with organ transplantation is still in its infancy but this alliance is expected to open new venues to change the way we conduct both transplant and organoid research. In this Forum we provide a summary on early achievements facilitating organoid derivation and culture. We further discuss on early advances of organoid transplantation also offering a comprehensive overview of current limitations and challenges to instruct organoid maturation. We expect that this Forum sets the ground for initial discussions between stem cell biologists, bioengineers, and the transplant community to better direct organoid basic research to advance the organ transplantation field

Task force groups of Transplant International: working together to globally connect the transplant community of tomorrow

In the last decades, we have advanced from a situation where transplantation was the unique solution of end-stage organ failure into a thrilling era in which regenerative therapies and organ reconditioning are opening new avenues in our area of health care