Sudden Onset Iron Overload Cardiomyopathy After Liver Transplantation.

Iron overload cardiomyopathy has been described in patients who develop acute heart failure after liver transplantation but few reports of this are available. We present a case of a patient with end-stage liver disease who underwent a deceased donor liver transplantation and developed acute onset systolic heart failure with reduced left ventricular ejection fraction. A cardiac magnetic resonance image demonstrated late gadolinium enhancement with diffuse enhancement globally and T1 mapping with severely decreased pre-contrast T1 values suggesting iron overload cardiomyopathy. The patient was treated with iron chelating therapy as well as heart failure guideline-directed medical therapy with subsequent improvement in cardiac function on follow-up magnetic resonance images. Despite our patient's diagnosis of iron overload cardiomyopathy, her iron studies showed normal serum iron and ferritin levels and no evidence of hepatic iron deposition in the transplanted liver.

Fulminant myocarditis following coronavirus disease 2019 vaccination: a case report.

BACKGROUND: The BNT162b2 vaccine received emergency use authorization from the U.S. Food and Drug Administration for the prevention of severe coronavirus disease 2019 (COVID-19) infection. We report a case of biopsy and magnetic resonance imaging (MRI)-proven severe myocarditis that developed in a previously healthy individual within days of receiving the first dose of the BNT162b2 COVID-19 vaccine. CASE SUMMARY: An 80-year-old female with no significant cardiac history presented with cardiogenic shock and biopsy-proven fulminant myocarditis within 12 days of receiving the BNT162b2 COVID-19 vaccine. She required temporary mechanical circulatory support, inotropic agents, and high-dose steroids for stabilization and management. Ultimately, her cardiac function recovered, and she was discharged in stable condition after 2 weeks of hospitalization. A repeat cardiac MRI 3 months after her initial presentation demonstrated stable biventricular function and continued improvement in myocardial inflammation. DISCUSSION: Fulminant myocarditis is a rare complication of vaccination. Clinicians should stay vigilant to recognize this rare, but potentially deadly complication. Due to the high morbidity and mortality associated with COVID-19 infection, the clinical benefits of the BNT162b2 vaccine greatly outweighs the risks of complications.

Cardiac Transplantation and the Use of Cannabis.

Cardiac transplantation requires the careful allocation of a limited number of precious organs. Therefore, it is critical to select candidates that will receive the greatest anticipated medical benefit but will also serve as the best stewards of the organ. Individual transplant teams have established prerequisites pertaining to recreational drug, tobacco, alcohol, and controlled substance use in potential organ recipients and post-transplantation. Legalization of cannabis and implementation of its prescription-based use for the management of patients with chronic conditions have been increasing over the past years. Center requirements regarding abstinence from recreational and medical cannabis use vary due to rapidly changing state regulations, as well as the lack of clinical safety data in this population. This is evident by the results of the multicenter survey presented in this paper. Developing uniform guidelines around cannabis use will be imperative not only for providers but also for patients.

A case of AL amyloidosis presenting with refractory ventricular fibrillation.

A 66-year-old male with recent diagnosis of heart failure with reduced ejection fraction was referred to our institution for management of cardiogenic/vasodilatory shock. During his evaluation, he suffered a sudden cardiac arrest from refractory ventricular tachycardia/fibrillation (VT/VF) despite normal electrolytes and no evidence of prior ventricular arrhythmias. He was placed on rescue peripheral veno-arterial extracorporeal membrane oxygenation support (VA-ECMO) for 4 days and was decannulated without end-organ damage. Continued workup revealed Mayo stage IV immunoglobulin light chain (AL) amyloidosis. Unfortunately, he developed acute cerebellar hemorrhage several days later. Autopsy findings were consistent with AL amyloidosis, with extensive cardiac fibrosis and amyloid deposition in the myocardium and vasculature. While the most common cause of cardiac death in patients with amyloidosis is severe bradycardia and pulseless electrical activity, sustained ventricular arrhythmias have been reported. The use of implantable cardioverter defibrillators (ICD) is highly debated in this population given the lack of survival benefit. Our patient also developed refractory VT/VF arrest, and ICD shocks would not have rescued him while causing significant distress. Emergent VA-ECMO cannulation allowed us to make a diagnosis, yet this intervention cannot be routinely recommended given the limited survival of patients with AL amyloidosis.

First Successful LVAD Implantation After BioVentrix Revivent TC Ventricular Reshaping.

The Revivent TC System (BioVentrix Inc, San Ramon, CA) enables a less invasive approach for left ventricular reshaping and scar exclusion in selected patients with ischemic cardiomyopathy. Although the system is designed to improve quality of life and to promote reverse remodeling, patients can still progress to end-stage heart failure requiring advanced therapies. This report describes a case of left ventricular assist device surgery in a patient 16 months after Revivent System implantation. The planning process and surgical technique proved to be complex. This case report can help provide guidance to advanced heart failure teams who encounter patients with the Revivent System who require left ventricular assist device support.

Porcine Model of the Arterial Switch Operation: Implications for Unique Strategies in the Management of Hypoplastic Left Ventricles.

There are no reports on the performance of the arterial switch operation (ASO) in a normal heart with normally related great vessels. The objective of this study was to determine whether the ASO could be performed in a healthy animal model. Cardiopulmonary bypass (CPB) and coronary translocation techniques were used to perform ASO in neonatal piglets or a staged ASO with prior main pulmonary artery (PA) banding. Primary ASO was performed in four neonatal piglets. Coronary translocation was effective with angiograms confirming patency. Piglets could not be weaned from CPB due to right ventricle (RV) dysfunction. To improve RV function for the ASO, nine piglets had PA banding. All survived the procedure. Post-banding RV pressure increased from a mean of 20.3 ± 2.2 mmHg to 36.5 ± 7.3 mmHg (p = 0.007). At 58 ± 1 days post-banding, piglets underwent cardiac MRIs revealing RV hypertrophy, and RV pressure overload with mildly reduced RV function. Catheterization confirmed RV systolic pressures of 84.0 ± 6.7 mmHg with LV systolic pressure 83.3 ± 6.7 mmHg (p = 0.43). The remaining five PA banded piglets underwent ASO at 51 ± 0 days post-banding. Three of five were weaned from bypass with patent coronary arteries and adequate RV function. We were able to successfully perform an arterial switch with documented patent coronary arteries on standard anatomy great vessels in a healthy animal model. To our knowledge this is the first time this procedure has been successfully performed. The model may have implications for studying the failing systemic RV, and may support a novel approach for management of borderline, pulsatile left ventricles.

Cardiac patient-specific three-dimensional models as surgical planning tools.

BACKGROUND: Three-dimensional printing is an additive manufacturing method that builds objects from digitally generated computational models. Core technologies behind three-dimensional printing are evolving rapidly with major advances in materials, resolution, and speed that enable greater realism and higher accuracy. These improvements have led to novel applications of these processes in the medical field. METHODS: The process of going from a medical image data set (computed tomography, magnetic resonance imaging, ultrasound) to a physical three-dimensional print includes several steps that are described. Medical images originate from Digital Imaging and Communications in Medicine files or data sets, the current standard for storing and transmitting medical images. Via Digital Imaging and Communications in Medicine manipulation software packages, a segmentation process, and manual intervention by an expert user, three-dimensional digital and printed models can be constructed in great detail. RESULTS: Cardiovascular medicine is one of the fastest growing applications for medical three-dimensional printing. The technology is more frequently being used for patient and clinician education, preprocedural planning, and medical device design and prototyping. We report on three case studies, describing how our three-dimensional printing has contributed to the care of cardiac patients at the University of Minnesota. CONCLUSION: Medical applications of computational three-dimensional modeling and printing are already extensive and growing rapidly and are routinely used for visualizing complex anatomies from patient imaging files to plan surgeries and create surgical simulators. Studies are needed to determine whether three-dimensional printed models are cost effective and can consistently improve clinical outcomes before they become part of routine clinical practice.

Sox7 Regulates Lineage Decisions in Cardiovascular Progenitor Cells.

Specification of the mesodermal lineages requires a complex set of morphogenetic events orchestrated by interconnected signaling pathways and gene regulatory networks. The transcription factor Sox7 has critical functions in differentiation of multiple mesodermal lineages, including cardiac, endothelial, and hematopoietic. Using a doxycycline-inducible mouse embryonic stem cell line, we have previously shown that expression of Sox7 in cardiovascular progenitor cells promotes expansion of endothelial progenitor cells (EPCs). In this study, we show that the ability of Sox7 to promote endothelial cell fate occurs at the expense of the cardiac lineage. Using ChIP-Seq coupled with ATAC-Seq we identify downstream target genes of Sox7 in cardiovascular progenitor cells and by integrating these data with transcriptomic analyses, we define Sox7-dependent gene programs specific to cardiac and EPCs. Furthermore, we demonstrate a protein-protein interaction between SOX7 and GATA4 and provide evidence that SOX7 interferes with the transcriptional activity of GATA4 on cardiac genes. In addition, we show that Sox7 modulates WNT and BMP signaling during cardiovascular differentiation. Our data represent the first genome-wide analysis of Sox7 function and reveal a critical role for Sox7 in regulating signaling pathways that affect cardiovascular progenitor cell differentiation.

Safety and prognostic value of regadenoson stress cardiovascular magnetic resonance imaging in heart transplant recipients.

BACKGROUND: There is a critical need for non-invasive methods to detect coronary allograft vasculopathy and to risk stratify heart transplant recipients. Vasodilator stress testing using cardiovascular magnetic resonance imaging (CMR) is a promising technique for this purpose. We aimed to evaluate the safety and the prognostic value of regadenoson stress CMR in heart transplant recipients. METHODS: To evaluate the safety, we assessed adverse effects in a retrospective matched cohort study of consecutive heart transplant recipients who underwent regadenoson stress CMR matched in a 2:1 ratio to age- and gender-matched non-heart transplant patients. To evaluate the prognostic value, we compared the outcomes of patients with abnormal vs. normal regadenoson stress CMRs using a composite endpoint of myocardial infarction, percutaneous intervention, cardiac hospitalization, retransplantation or death. RESULTS: For the safety analysis, 234 regadenoson stress CMR studies were included - 78 performed in 57 heart transplant recipients and 156 performed in non-heart transplant patients. Those in heart transplant recipients were performed at a median of 2.74 years after transplantation. Thirty-four (44%) CMR studies were performed in the first two years after heart transplantation. There were no differences in the rates of adverse effects between heart transplant recipients and non-heart transplant patients. To study the prognostic value of regadenoson stress CMRs, 20 heart transplant recipients with abnormal regadenoson stress CMRs were compared to 37 with normal regadenoson stress CMRs. An abnormal regadenoson stress CMR was associated with a significantly higher incidence of the composite endpoint compared with a normal regadenoson stress CMR (3-year cumulative incidence estimates of 32.1% vs. 12.7%, p = 0.034). CONCLUSIONS: Regadenoson stress CMR is safe and well tolerated in heart transplant recipients, with no incidence of sinus node dysfunction or high-degree atrioventricular block, including in the first two years after heart transplantation. An abnormal regadenoson stress CMR identifies heart transplant recipients at a higher risk for major adverse cardiovascular events.

Impact of 30 Day Readmission After Left Ventricular Assist Device Implantation.

Early readmission (within 30 days) after left ventricular assist device (LVAD) implantation might be a marker for increased mortality. We retrospectively reviewed the records of 277 adults who underwent continuous-flow LVAD implantation from 2005 through 2015 at our institution. The baseline characteristics of patients who were (versus were not) readmitted within 30 days after LVAD implantation were compared. To assess the impact of 30 day readmission on long-term survival, we used multivariate Cox regression. We also compared the cardiac transplant rate between the two groups. Of the 277 patients, 217 (78.3%) underwent LVAD implantation as a bridge-to-transplant; 76 (27.4%) of the 277 were readmitted within 30 days. The most common reason for readmission was volume overload (23.6%), followed by gastrointestinal bleeding (15.8%). Male gender, previous smoking, a higher baseline creatinine level, higher Model for End Stage Liver Disease Excluding INR (MELD-XI) score, and postoperative gastrointestinal bleeding or stroke were each associated with 30 day readmission. In our final multivariate model, increased mortality was also associated with 30 day readmission (hazard ratio, 1.60; 95% confidence interval, 1.1-2.5). Among the 217 bridge-to-transplant patients, the cardiac transplant rate was similar between the two groups: 18.7 transplants per patient-year among those who were readmitted within 30 days versus 19.7 transplants per patient-year among those who were not (p = 0.26). Among our study patients, 30 day readmission after LVAD implantation was frequent and was associated with increased mortality. It is currently unclear whether the general health of those patients was a factor and whether efforts to reduce 30 day readmission would favorably affect longer-term patient outcomes.

Impact of Cardiovascular Magnetic Resonance Imaging on Identifying the Etiology of Cardiomyopathy in Patients Undergoing Cardiac Transplantation.

Errors in identifying the etiology of cardiomyopathy have been described in patients undergoing cardiac transplantation. There are increasing data that cardiovascular magnetic resonance imaging (CMR) provides unique diagnostic information in heart failure. We investigated the association of the performance of CMR prior to cardiac transplantation with rates of errors in identifying the etiology of cardiomyopathy. We compared pre-transplantation clinical diagnoses with post-transplantation pathology diagnoses obtained from the explanted native hearts. Among 338 patients, there were 23 (7%) errors in identifying the etiology of cardiomyopathy. Of these, 22 (96%) occurred in patients with pre-transplantation clinical diagnoses of non-ischemic cardiomyopathy (NICM). Only 61/338 (18%) had CMRs prior to transplantation. There was no significant association between the performance of CMR and errors in the entire study cohort (p = 0.093). Among patients with pre-transplantation clinical diagnoses of NICM, there was a significant inverse association between the performance of CMR and errors (2.4% vs. 14.6% in patients with and without CMR respectively; p = 0.030). In conclusion, CMR was underutilized prior to cardiac transplantation. In patients with pre-transplantation clinical diagnoses of NICM - in whom 96% of errors in identifying the etiology of cardiomyopathy occurred - the performance of CMR was associated with significantly fewer errors.

Etv2 rescues Flk1 mutant embryoid bodies.

Independent mouse knockouts of Etv2 and Flk1 are embryonic lethal and lack hematopoietic and endothelial lineages. We previously reported that Flk1 activates Etv2 in the initiation of hematopoiesis and vasculogenesis. However, Flk1 and its ligand VEGF are expressed throughout development, from E7.0 to adulthood, whereas Etv2 is expressed only transiently during embryogenesis. These observations suggest a complex regulatory interaction between Flk1 and Etv2. To further examine the Flk1 and Etv2 regulatory interaction, we transduced Etv2 and Flk1 mutant ES cells with viral integrants that inducibly overexpress Flk1 or Etv2. We demonstrated that forced expression of Etv2 rescued the hematopoietic and endothelial potential of differentiating Flk1 and Etv2 mutant cells. We further discovered that forced expression of Flk1 can rescue that of the Flk1, but not Etv2 mutant cells. Therefore, we conclude that the requirement for Flk1 can be bypassed by expressing Etv2, supporting the notion that disruption of Etv2 expression is responsible for the early phenotypes of the Etv2 and Flk1 mutant embryos.

Bone-marrow-derived side population cells for myocardial regeneration.

Bone-marrow-derived stem cells have displayed the potential for myocardial regeneration in animal models as well as in clinical trials. Unfractionated bone marrow mononuclear cell (MNC) population is a heterogeneous group of cells known to include a number of stem cell populations. Cells in the side population (SP) fraction have a high capacity for differentiation into multiple lineages. In the current study, we investigated the role of murine and human bone-marrow-derived side population cells in myocardial regeneration. In these studies, we show that mouse bone-marrow-derived SP cells expressed the contractile protein, alpha-actinin, following culture with neonatal cardiomyocytes and after delivery into the myocardium following injury. Moreover, the number of green-fluorescent-protein-positive cells, of bone marrow side population origin, increased progressively within the injured myocardium over 90 days. Transcriptome analysis of these bone marrow cells reveals a pattern of expression consistent with immature cardiomyocytes. Additionally, the differentiation capacity of human granulocyte colony-stimulating factor stimulated peripheral blood stem cells were assessed following injection into injured rat myocardium. Bone marrow mononuclear cell and side population cells were both readily identified within the rat myocardium 1 month following injection. These human cells expressed human-specific cardiac troponin I as determined by immunohistochemistry as well as numerous cardiac transcripts as determined by polymerase chain reaction. Both human bone marrow mononuclear cells and human side population cells augmented cardiac systolic function following a modest drop in function as a result of cryoinjury. The augmentation of cardiac function following injection of side population cells occurred earlier than with bone marrow mononuclear cells despite the fact that the number of side population cells used was one tenth that of bone marrow mononuclear cells (9 x 10(5) cells per heart in the MNC group compared to 9 x 10(4) per heart in the SP group). These results support the hypotheses that rodent and human-bone-marrow derived side population cells are capable of acquiring a cardiac fate and that human bone-marrow-derived side population cells are superior to unfractionated bone marrow mononuclear cells in augmenting left ventricular systolic function following cryoinjury.

Review of stem cell-based therapy for the treatment of cardiovascular disease.

Cardiovascular disease remains the number one cause of mortality in the United States. Nearly 2,400 Americans die of cardiovascular disease each day, an average of 1 every 37 s. One in three Americans has been diagnosed with one or more forms of cardiovascular disease. Most recent estimates show that, in the United States alone, 16 million people have coronary artery disease and 5.3 million have been diagnosed with heart failure. Unlike other forms of cardiovascular disease, heart failure is often the end-stage of a cardiovascular disease, frequently coronary artery disease. The 1-year mortality of people diagnosed with heart failure remains a sobering 20%. Heart failure is also very costly. The estimated direct and indirect cost of heart failure in the US for 2008 is 34.8 billion dollars. Therefore, advanced treatment options for these populations could greatly impact patient health outcomes and cost savings. Even with the advancements in pharmacologic therapies and improvements in mechanical support devices, the only definitive treatment for advanced heart failure remains heart transplantation. Given the limited availability of donor organs for use in orthotopic heart transplantation, alternative therapies including stem cell-based therapies have been explored. The past decade has seen an explosion of activity of the field of cardiac regeneration. New scientific techniques and discoveries have allowed rapid advancements but there have also been conflicting opinions and results. The concept of cardiac regeneration is now commonly accepted but the exact mechanisms and extent of regeneration is greatly debated. Several candidate cell populations, both cardiac and extracardiac, have been reported to be capable of cardiac regeneration. However, some studies question if these cell populations actually differentiate into cardiomyocytes but rather function through paracrine effects or through cell fusion. Despite these challenges, the field has also begun translating the preclinical animal studies into human clinical trials using several cell types for the treatment of many clinical disease states. This review will highlight the preclinical animal studies and review the results of the published clinical trials.

Ponce de Leon's Fountain: stem cells and the regenerating heart.

Despite current pharmacologic and whole organ transplantation strategies, advanced heart failure remains a common and deadly disease. Limited availability of donor organs for use in orthotopic heart transplantation has prompted the examination of alternative therapies, including cell transfer strategies. Stem cell populations have been identified in virtually all postnatal tissues with the exception of the heart, and these stem cells function in the maintenance and regeneration of the respective tissues. Recent studies challenge preexisting notions regarding cardiac repair and suggest that the heart is capable of limited regeneration through the activation of resident cardiac stem cells or the recruitment of stem cell populations from other tissues such as the bone marrow. This review highlights animal models that have the capacity for myocardial regeneration and examines potential sources of stem cell populations that may participate in tissue regeneration. While some authors view these cell-based strategies as a Fountain of Youth for the myopathic heart, future studies will decipher the regulatory mechanisms of stem cell populations and serve as a prelude to stem cell-based strategies.

Persistent expression of the ATP-binding cassette transporter, Abcg2, identifies cardiac SP cells in the developing and adult heart.

Stem cells are important in the maintenance and repair of adult tissues. A population of cells, termed side population (SP) cells, has stem cell characteristics as they have been shown to contribute to diverse lineages. In this study, we confirm that Abcg2 is a determinant of the SP cell phenotype. Therefore, we examined Abcg2 expression during murine embryogenesis and observed robust expression in the blood islands of the E8.5 yolk sac and in developing tissues including the heart. During the latter stages of embryogenesis, Abcg2 identifies a rare cell population in the developing organs. We further establish that the adult heart contains an Abcg2 expressing SP cell population and these progenitor cells are capable of proliferation and differentiation. We define the molecular signature of cardiac SP cells and compare it to embryonic stem cells and adult cardiomyocytes using emerging technologies. We propose that the cardiac SP cell population functions as a progenitor cell population for the development, maintenance, and repair of the heart.

Stem cell biology and therapeutic applications.

PURPOSE OF REVIEW: Chronic diseases are common and deadly. Stem cell therapies have received intense interest for the repopulation of damaged or diseased tissues. A detailed understanding of the similarities and differences between embryonic stem cells and somatic stem cells will enhance our understanding of mechanisms of tissue repair or cellular augmentation. In addition, emerging technologies will be useful in the definition of the molecular regulation of the respective stem cell populations. RECENT FINDINGS: A number of postnatal tissues have a population of somatic stem cells, which function in the maintenance and repair of tissues. Using molecular technologies these somatic stem cell populations have been shown to be pluripotent when placed in a permissive environment. Recent studies have utilized emerging technologies to define a molecular signature of embryonic stem cells and selected somatic stem cell populations. These strategies will be useful for the definition of a molecular program that promotes a stem cell phenotype (i.e. stemness phenotype). SUMMARY: Recent studies suggest that embryonic and somatic stem cell populations hold promise as sources for tissue engineering. The use of cell biological and molecular technologies will enhance our understanding of embryonic and somatic stem cell populations and their molecular regulatory events that promote multipotentiation.