Myocardial Oedema as a Consequence of Viral Infection and Persistence-A Narrative Review with Focus on COVID-19 and Post COVID Sequelae.

Microvascular integrity is a critical factor in myocardial fluid homeostasis. The subtle equilibrium between capillary filtration and lymphatic fluid removal is disturbed during pathological processes leading to inflammation, but also in hypoxia or due to alterations in vascular perfusion and coagulability. The degradation of the glycocalyx as the main component of the endothelial filtration barrier as well as pericyte disintegration results in the accumulation of interstitial and intracellular water. Moreover, lymphatic dysfunction evokes an increase in metabolic waste products, cytokines and inflammatory cells in the interstitial space contributing to myocardial oedema formation. This leads to myocardial stiffness and impaired contractility, eventually resulting in cardiomyocyte apoptosis, myocardial remodelling and fibrosis. The following article reviews pathophysiological inflammatory processes leading to myocardial oedema including myocarditis, ischaemia-reperfusion injury and viral infections with a special focus on the pathomechanisms evoked by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In addition, clinical implications including potential long-term effects due to viral persistence (long COVID), as well as treatment options, are discussed.

Early outcomes after isolated aortic valve replacement with rapid deployment aortic valve.

OBJECTIVE: Minimal access aortic valve replacement is associated with favorable clinical outcomes; however, several meta-analyses have reported significantly longer crossclamp times compared with a full sternotomy. We examined the procedural and early safety outcomes after isolated rapid deployment aortic valve replacement by surgical approach in patients enrolled in the Surgical Treatment of Aortic Stenosis With a Next Generation Surgical Aortic Valve trial. METHODS: The Surgical Treatment of Aortic Stenosis With a Next Generation Surgical Aortic Valve trial was a prospective, multicenter, single-arm study, with successful implants in 287 patients with aortic valve stenosis who underwent rapid deployment aortic valve replacement using the EDWARDS INTUITY Valve System (Edwards Lifesciences, Irvine, Calif). Patients were evaluated perioperatively for procedural times and technical success rates; at discharge, for hospital length of stay; and, at 30 days, for early adverse events. RESULTS: A total of 158 patients underwent isolated aortic valve replacement through a full sternotomy (n = 71), upper hemisternotomy (n = 77), or right anterior thoracotomy (n = 10). Mean age at baseline was 75.7 ± 7.2 years. Mean aortic crossclamp and cardiopulmonary bypass times (minutes) were similar for full sternotomy and upper hemisternotomy, 43.5 ± 32.5/71.6 ± 41.8 and 43.1 ± 13.1/69.6 ± 19.1, respectively, and significantly longer for right anterior thoracotomy, 88.3 ± 18.6/122.2 ± 22.1 (P < .000). Early adverse event rates were similar, and in-hospital mortality rates were low regardless of surgical approach. CONCLUSIONS: These data suggest that isolated rapid deployment aortic valve replacement through an upper hemisternotomy can lead to shorter crossclamp times than has been reported historically in the literature. This may facilitate minimal access aortic valve replacement by eliminating the issue of prolonged crossclamp times. Further, low in-hospital mortality and new permanent pacemaker implant rates were observed regardless of surgical approach.

Three-year hemodynamic performance, left ventricular mass regression, and prosthetic-patient mismatch after rapid deployment aortic valve replacement in 287 patients.

OBJECTIVE: Superior aortic valve hemodynamic performance can accelerate left ventricular mass regression and enhance survival and functional status after surgical aortic valve replacement. This can be achieved by rapid deployment aortic valve replacement using a subannular balloon-expandable stent frame, which functionally widens and reshapes the left ventricular outflow tract, to ensure a larger effective orifice area compared with conventional surgical valves. We report the intermediate-term follow-up data from a large series of patients enrolled in the Surgical Treatment of Aortic Stenosis With a Next Generation Surgical Aortic Valve (TRITON) trial. METHODS: In a prospective, multicenter (6 European hospitals), single-arm study, 287 patients with aortic stenosis underwent rapid deployment aortic valve replacement using a stented trileaflet bovine pericardial bioprosthesis. Core laboratory echocardiography was performed at baseline, discharge, and 3 months, 1 year, and 3 years after rapid deployment aortic valve replacement. RESULTS: The mean patient age was 75.7 ± 6.7 years (range, 45-93; 49.1% women). The mean aortic valve gradient significantly decreased from discharge to 3 years of follow-up. The mean effective orifice area remained stable from discharge to 3 years. At 1 year, the left ventricular mass index had decreased by 14% (P < .0001) and at 3 years by 16% (P < .0001) compared with at discharge. The prevalence of severe patient-prosthesis mismatch was 3% at discharge and remained stable during the follow-up period. CONCLUSIONS: In a large series of elderly patients with symptomatic severe aortic stenosis, rapid deployment aortic valve replacement using a subannular balloon-expandable stent frame demonstrated excellent hemodynamic performance and significant left ventricular mass regression. With continued follow-up, future studies will establish whether these favorable structural changes correlate with improvement in long-term survival and functional status.

One-year outcomes of the Surgical Treatment of Aortic Stenosis With a Next Generation Surgical Aortic Valve (TRITON) trial: a prospective multicenter study of rapid-deployment aortic valve replacement with the EDWARDS INTUITY Valve System.

OBJECTIVES: A new class of rapid-deployment aortic valves has emerged with the potential to simplify minimally invasive aortic surgery and reduce crossclamp and cardiopulmonary bypass times. We report the 1-year clinical outcomes of aortic valve replacement with the EDWARDS INTUITY Valve System (Edwards Lifesciences LLC, Irvine, Calif) in the Surgical Treatment of Aortic Stenosis With a Next Generation Surgical Aortic Valve (TRITON) trial. METHODS: Seventeen surgeons from 6 European centers treated 152 consecutive patients with aortic stenosis requiring valve replacement in a prospective, single-arm trial. A stented trileaflet bovine pericardial bioprosthesis with a balloon-expandable, cloth-covered stent frame at the inflow aspect was implanted in 146 patients (mean age, 75.5 ± 6.7 years; 52.7% were female). Five valve sizes were evaluated (19-27 mm); 58.9% of cases had isolated aortic valve replacement, and 41.1% of cases involved concomitant procedures. Minimally invasive surgical approaches occurred in 48.8% of the isolated aortic valve replacements. Patients were followed at discharge, 3 months, and 1 year postoperatively. RESULTS: Implantation success was 96.1% (146/152), early valve-related mortality was 1.4% (2/146), and cumulative survival was 92.5% at a mean follow-up of 9.8 ± 5.1 months. Crossclamp time for isolated aortic valve replacement was 41.1 ± 10.6 minutes. Independent core laboratory-adjudicated mean effective orifice area and aortic valve pressure gradient were 1.7 ± 0.2 cm(2) and 8.8 ± 3.0 mm Hg at 3 months, and 1.7 ± 0.2 cm(2) and 8.4 ± 3.4 mm Hg at 1 year, respectively. CONCLUSIONS: Implantation of the EDWARDS INTUITY Valve System is feasible, safe, and efficacious for aortic valve replacement. Aortic crossclamp and cardiopulmonary bypass times were reduced compared with those for conventional aortic valve replacement. Early hemodynamic performance was excellent and remained so up to 1 year.

Antithymocyte globulin induction therapy improves survival in lung transplantation for cystic fibrosis.

Cystic fibrosis (CF) is an inherited condition that leads to respiratory failure and is the third most common indication for adult bilateral lung transplantation (LuTX). In contrast to other lung diseases, the immune system of CF patients is up-regulated and we therefore hypothesized that these patients would benefit from induction therapy. In the current study, we investigated the impact of antithymocyte globulin (ATG) induction therapy in CF patients after LuTX. One hundred and forty six patients who underwent LuTX for CF at our centre between January 1999 and December 2010 were included in the study and retrospectively analysed. They were divided into two groups according to the immunosuppressive protocol: group-A (n = 103) with and group-B (n = 43) without induction therapy on top of the basic calcineurin inhibitor based triple immunosuppression with mycophenolate mofetil and steroids. Perioperative survival was significantly better in the ATG group, a benefit sustained for the entire follow-up. ATG induction resulted in a significantly lower incidence of acute rejections without an increase in infectious complications. Taken together, our results indicate that ATG induction therapy confers a significant survival benefit in CF patients undergoing LuTX and reduces rejection. We advocate the use of induction therapy in this patient cohort.

Downregulation of the CXC chemokine receptor 4/stromal cell-derived factor 1 pathway enhances myocardial neovascularization, cardiomyocyte survival, and functional recovery after myocardial infarction.

OBJECTIVES: Although adequate numbers of hematopoietic progenitor cells reside in the human bone marrow, the extent of endogenous neovascularization after myocardial infarction remains insufficient. The aim of this study was to identify the role of the CXC chemokine receptor 4/stromal cell-derived factor 1 axis in the mobilization and homing of hematopoietic progenitor cells in the ischemic heart. METHODS: Human bone marrow-derived hematopoietic progenitor cells or saline were injected systemically into athymic nude rats 48 hours after myocardial infarction. Myocardial and bone marrow expression of stromal cell-derived factor 1 and chemotaxis of hematopoietic progenitor cells were measured in vitro in the presence or absence of stromal cell-derived factor 1. The role of the CXC chemokine receptor 4/stromal cell-derived factor 1 axis was investigated by means of antibody blockade or systemic administration of granulocyte colony-stimulating factor. Morphologic analysis included measurement of the infarct area, capillary density, and apoptosis, whereas left ventricular function was measured by means of echocardiographic analysis. RESULTS: Expression of postinfarct stromal cell-derived factor 1 was increased by 67% in the bone marrow and decreased by 43% in myocardium. Disruption of bone marrow stromal cell-derived factor 1/CXC chemokine receptor 4 interactions by antibody blockade resulted in a redirection of human hematopoietic progenitor cells from the bone marrow to the ischemic heart and augmented neovascularization and cardiomyocyte survival. Similarly, systemic administration of granulocyte colony-stimulating factor to block CXC chemokine receptor 4/stromal cell-derived factor 1 interaction resulted in increased mobilization and homing of hematopoietic progenitor cells to the ischemic heart, which translated to augmented myocardial neovascularization, prevention of apoptosis, and improved cardiac function. CONCLUSIONS: Bone marrow stromal cell-derived factor 1 upregulation after myocardial ischemia prevents mobilization of endogenous hematopoietic progenitor cells. We provide evidence that disruption of stromal cell-derived factor 1/CXC chemokine receptor 4 interactions allows redirection of hematopoietic progenitor cells to ischemic myocardium and enhances recovery of left ventricular function.

Ex-vivo expanded umbilical cord blood stem cells retain capacity for myocardial regeneration.

BACKGROUND: Umbilical cord blood (UCB) is a source of human hematopoietic precursor cells (HPCs), a stem cell (SC) type that has been used in several trials for myocardial repair. A certain minimal number of cells is required for measurable regeneration and a major challenge of SC-based regenerative therapy constitutes ex-vivo expansion of the primitive cell compartment. The aim of this study was to investigate the ex-vivo expansion potential of UCB-derived HPCs and the ability of these expanded cells to migrate to the site of damage and improve ventricular function in a rodent model of myocardial infarction (MI). METHODS AND RESULTS: UCB-derived HPCs, defined by coexpression of CD133 and CD34, were expanded using various cytokine combinations. MI was induced by left anterior descending artery ligation in nude rats. Cells were injected intravenously 2 days after infarction. The combination of SC factor, thrombopoietin, flt3-ligand and interleukin-6 was found to be the most effective for inducing proliferation of HPCs. The migratory capacity of expanded HPCs was similar to that of non-expanded HPCs and improvement of ejection fraction was significant in both groups, with a relative increase of >60%. CONCLUSIONS: UCB-derived HPCs can be reproducibly expanded ex-vivo and retain their potential to improve cardiac function post-MI. (Circ J 2010; 74: 188 - 194).

Stem cells and cardiac regeneration.

Despite many advances in cardiovascular medicine, heart failure (HF) remains the leading cause of death in developed countries affecting at least 10 million people in Western Europe alone. The poor long-term prognosis of HF patients, and immense public health implications has fuelled interest in finding new therapeutic modalities. Recent observations of the beneficial effect of stem cells on the damaged heart in animal experiments have generated tremendous excitement and stimulated clinical studies suggesting that this approach is feasible, safe, and potentially effective in humans. Cell-based myocardial regeneration is currently explored for a wide range of cardiac disease states, including acute and chronic ischemic myocardial damage, cardiomyopathy and as biological heart pacemakers. The aim of the present manuscript is to review the work that has been done to establish the role of stem cells in cardiac repair, give an update on the clinical trials performed so far, as well as to discuss critically the controversies, challenges and future surrounding this novel therapeutic concept.

Down-regulation of plasminogen activator inhibitor 1 expression promotes myocardial neovascularization by bone marrow progenitors.

Human adult bone marrow-derived endothelial progenitors, or angioblasts, induce neovascularization of infarcted myocardium via mechanisms involving both cell surface urokinase-type plasminogen activator, and interactions between beta integrins and tissue vitronectin. Because each of these processes is regulated by plasminogen activator inhibitor (PAI)-1, we selectively down-regulated PAI-1 mRNA in the adult heart to examine the effects on postinfarct neovascularization and myocardial function. Sequence-specific catalytic DNA enzymes inhibited rat PAI-1 mRNA and protein expression in peri-infarct endothelium within 48 h of administration, and maintained down-regulation for at least 2 wk. PAI-1 inhibition enhanced vitronectin-dependent transendothelial migration of human bone marrow-derived CD34+ cells, and resulted in a striking augmentation of angioblast-dependent neovascularization. Development of large, thin-walled vessels at the peri-infarct region was accompanied by induction of proliferation and regeneration of endogenous cardiomyocytes and functional cardiac recovery. These results identify a causal relationship between elevated PAI-1 levels and poor outcome in patients with myocardial infarction through mechanisms that directly inhibit bone marrow-dependent neovascularization. Strategies that reduce myocardial PAI-1 expression appear capable of enhancing cardiac neovascularization, regeneration, and functional recovery after ischemic insult.

Extensive coagulation monitoring in patients after implantation of the MicroMed Debakey continuous flow axial pump.

Ventricular assist device (VAD) implantation is associated with impaired primary hemostasis and thromboembolic complications. Recently, a new generation of implantable continuous flow axial pumps was introduced into clinical application. To study the potential thrombogenic properties of this type of pump, we applied extensive platelet monitoring was applied. In our institution, 13 patients received the MicroMed DeBakey VAD as a bridge to transplantation. Routine coagulation tests (platelet count, activated partial thromboplastin time, prothrombin time, antithrombin III activity) and platelet function tests (whole blood aggregometry, thrombelastography, flow cytometry) were performed. No clinically relevant thromboembolic events were detected. No correlation was found between global function tests, platelet aggregation, and thrombelastography. No correlation was detected between platelet activation and hemolysis parameters. Platelet aggregation and coagulation index were significantly suppressed early after operation. A subsequent phase of hyper-aggregability, starting around day 6, suggested the initiation of antiaggregation therapy. Platelet activation markers were upregulated in the postoperative period but were returned to preoperative levels after initiation of aspirin. In contrast to routine coagulation monitoring, platelet function tests reflect in detail the coagulation status of blood pump recipients and the efficiency of antiaggregation therapy. Aspirin and dipyridamole therapy in addition to oral anticoagulation using phenprocoumon may contribute to platelet function and clot mechanics restoration and is, therefore, recommended for patients after VAD implantation.

Myocardial neovascularization by adult bone marrow-derived angioblasts: strategies for improvement of cardiomyocyte function.

In the pre-natal period, hemangioblasts derived from the human ventral aorta give rise to cellular elements involved in both hematopoiesis and vasculogenesis, resulting in formation of the primitive capillary network. Endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts are also present in human adult bone marrow, and can be used to induce infarct bed vasculogenesis and angiogenesis after experimental myocardial infarction. The neovascularization results in decreased apoptosis of hypertrophied myocytes in the peri-infarct region, long-term salvage and survival of viable myocardium, reduction in collagen deposition, and sustained improvement in cardiac function. Autologous angioblasts may also be useful in cellular therapy strategies aiming to regenerate myocardial tissue after established heart failure. It is likely that protocols using cardiomyocyte/mesenchymal stem cells will require balanced co-administration of angioblasts to provide vascular structures for supply of oxygen and nutrients to both the chronically ischemic, endogenous myocardium and to the newly-implanted cardiomyocytes. Future studies will need to address the timing, relative concentrations, source and route of delivery of each of these cellular populations in animal models of acute and chronic myocardial ischemia.

New directions in strategies using cell therapy for heart disease.

Congestive heart failure remains a major public health problem and is frequently the end result of cardiomyocyte apoptosis and fibrous replacement after myocardial infarction, a process referred to as left ventricular remodeling. Cardiomyocytes undergo terminal differentiation soon after birth and are generally considered to irreversibly withdraw from the cell cycle. In response to ischemic insult adult cardiomyocytes undergo cellular hypertrophy, nuclear ploidy, and a high degree of apoptosis. A small number of human cardiomyocytes retain the capacity to proliferate and regenerate in response to ischemic injury. However, whether these cells are derived from a resident pool of cardiomyocyte stem cells or from a renewable source of circulating bone marrow-derived stem cells that home to the damaged myocardium is at present not known. Replacement and regeneration of functional cardiac muscle after an ischemic insult to the heart could be achieved by either stimulating proliferation of endogenous mature cardiomyocytes or resident cardiac stem cells or by implanting exogenous donor-derived or allogeneic cells such as fetal or embryonic cardiomyocyte precursors, bone marrow derived mesenchymal stem cells, or skeletal myoblasts. The newly formed cardiomyocytes must integrate precisely into the existing myocardial wall in order to augment synchronized contractility and avoid potentially life-threatening alterations in the electrical conduction of the heart. A major impediment to survival of the implanted cells is altered immunogenicity by prolonged ex vivo culture conditions. In addition, concurrent myocardial revascularization is required to ensure viability of the repaired region and prevent further scar tissue formation. Human adult bone marrow contains endothelial precursors which resemble embryonic angioblasts and can be used to induce infarct bed neovascularization after experimental myocardial infarction. This results in protection of cardiomyocytes against apoptosis, induction of cardiomyocyte proliferation and regeneration, long-term salvage and survival of viable myocardium, prevention of left ventricular remodeling, and sustained improvement in cardiac function. It is reasonable to anticipate that cell therapy strategies for ischemic heart disease will need to incorporate (a) a renewable source of proliferating, functional cardiomyocytes, and (b) angioblasts to generate a network of capillaries and larger size blood vessels for supply of oxygen and nutrients to both the chronically ischemic endogenous myocardium and to the newly implanted cardiomyocytes

Long-term results of CMV hyperimmune globulin prophylaxis in 377 heart transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) has emerged as the most important pathogen to affect the post-operative course after heart transplantation. We performed a retrospective analysis to evaluate the efficiency of CMV hyperimmune globulin (CMVIG) prophylaxis in preventing CMV disease in aggressively immunosuppressed patients after heart transplantation. METHODS: We studied 377 heart transplant recipients who received quadruple-immunosuppressive therapy and CMVIG as sole CMV prophylaxis. The study population was categorized into 4 groups according to donor and recipient CMV serology at the time of transplantation (D+/R+, D+/R-, D-/R+, D-/R-) and was monitored for CMV immediate early antigen in peripheral blood cells, in urine sediments, and in throat washings; for the presence of serum CMV immunoglobulin M and CMV immunoglobulin G; and for clinical evidence of CMV-related symptoms. In addition, we compared the incidence of cardiac allograft vasculopathy and infection among the groups. RESULTS: During the first 5 years after transplantation, CMV disease developed in 79 patients (20.96%). Comparison among the groups showed significantly increased risk for CMV disease in allograft recipients of organs from seropositive donors (D+, 27.31%; D-, 11.33%; p = 0.0003). We observed 6 CMV-associated deaths, all in CMV-antibody-negative recipients. Additionally CMV-positive recipients had a greater incidence of cardiac allograft vasculopathy (p = 0.048), and a greater overall infection rate (p = 0.0034). CONCLUSIONS: Cytomegalovirus hyperimmune globulin administration prevents CMV disease and infection in aggressively immunosuppressed heart transplant recipients. Because fatal CMV disease in CMV-negative recipients of organs from seropositive donors could not be prevented with CMVIG alone, we recommend the additional use of prophylactic ganciclovir in this CMV-mismatched population.

Surgical treatment of acute type A dissection: is rupture a risk factor?

BACKGROUND: The purpose of this study was to evaluate the significance of aortic rupture on clinical outcome in patients after aortic repair for acute type A dissection. METHODS: One hundred and twenty patients underwent aortic operations with resection of the intimal tear and open distal anastomosis. Median age was 60 years (range 16 to 87); 78 were male. Thirty-six patients had only ascending aortic replacement, 82 had hemiarch repair, and 2 had the entire arch replaced. Retrograde cerebral perfusion was utilized in 66 patients (53%). Rupture defined as free blood in the pericardial space was present in 60 patients (50%). Univariate and multivariate analyses were performed to assess the risk factors for mortality and neurologic dysfunction. RESULTS: Overall hospital mortality rate was 24.2% +/- 4.0% (+/- 70% confidence level) but did not differ between patients with aortic rupture or without (p = 0.83). The incidence of permanent neurologic dysfunction was 9.4% overall, 10.5% with rupture and 8.3% without rupture (p = 0.75). Multivariate analysis revealed absence of retrograde cerebral perfusion and any postoperative complication as statistically significant indicators for in-hospital mortality (p < 0.05). Overall 1- and 5-year survival was 85.3% and 33.7%; among discharged patients, survival in the nonruptured group was 89% and 37%, versus 81% and 31% in the ruptured group (p = 0.01). CONCLUSIONS: Aortic rupture at the time of surgery does not increase the risk of hospital mortality or permanent neurologic complications in patients with acute type A dissections. However, aortic rupture at the time of surgery does influence long-term survival.