Despite substantial clinical advances over the past 65 years, cardiovascular disease remains the leading cause of death in America. The past 15 years has witnessed major basic and translational ...interest in the use of stem and precursor cells as a therapeutic agent for chronically injured organs. Among the cell types under investigation, adult mesenchymal stem cells are widely studied, and in early stage, clinical studies show promise for repair and regeneration of cardiac tissues. The ability of mesenchymal stem cells to differentiate into mesoderm- and nonmesoderm-derived tissues, their immunomodulatory effects, their availability, and their key role in maintaining and replenishing endogenous stem cell niches have rendered them one of the most heavily investigated and clinically tested type of stem cell. Accumulating data from preclinical and early phase clinical trials document their safety when delivered as either autologous or allogeneic forms in a range of cardiovascular diseases, but also importantly define parameters of clinical efficacy that justify further investigation in larger clinical trials. Here, we review the biology of mesenchymal stem cells, their interaction with endogenous molecular and cellular pathways, and their modulation of immune responses. Additionally, we discuss factors that enhance their proliferative and regenerative ability and factors that may hinder their effectiveness in the clinical setting.
Inflammatory Cardiomyopathic Syndromes Trachtenberg, Barry H; Hare, Joshua M
Circulation research,
2017-September-15, Letnik:
121, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Inflammatory activation occurs in nearly all forms of myocardial injury. In contrast, inflammatory cardiomyopathies refer to a diverse group of disorders in which inflammation of the heart (or ...myocarditis) is the proximate cause of myocardial dysfunction, causing injury that can range from a fully recoverable syndrome to one that leads to chronic remodeling and dilated cardiomyopathy. The most common cause of inflammatory cardiomyopathies in developed countries is lymphocytic myocarditis most commonly caused by a viral pathogenesis. In Latin America, cardiomyopathy caused by Chagas disease is endemic. The true incidence of myocarditis is unknown to the limited utilization and the poor sensitivity of endomyocardial biopsies (especially for patchy diseases such as lymphocytic myocarditis and sarcoidosis) using the gold-standard Dallas criteria. Emerging immunohistochemistry criteria and molecular diagnostic techniques are being developed that will improve diagnostic yield, provide additional clues into the pathophysiology, and offer an application of precision medicine to these important syndromes. Immunosuppression is recommended for patients with cardiac sarcoidosis, giant cell myocarditis, and myocarditis associated with connective tissue disorders and may be beneficial in chronic viral myocarditis once virus is cleared. Further trials of immunosuppression, antiviral, and immunomodulating therapies are needed. Together, with new molecular-based diagnostics and therapies tailored to specific pathogeneses, the outcome of patients with these disorders may improve.
RATIONALE:Myocardial infarction (MI) is a leading cause of death worldwide. Because endogenous cardiac repair mechanisms are not sufficient for meaningful tissue regeneration, MI results in loss of ...cardiac tissue and detrimental remodeling events. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression in a sequence dependent manner. Our previous data indicate that miRNAs are dysregulated in response to ischemic injury of the heart and actively contribute to cardiac remodeling after MI.
OBJECTIVE:This study was designed to determine whether miRNAs are dysregulated on ischemic damage in porcine cardiac tissues and whether locked nucleic acid (LNA)-modified anti-miR chemistries can target cardiac expressed miRNAs to therapeutically inhibit miR-15 on ischemic injury.
METHODS AND RESULTS:Our data indicate that the miR-15 family, which includes 6 closely related miRNAs, is regulated in the infarcted region of the heart in response to ischemia-reperfusion injury in mice and pigs. LNA-modified chemistries can effectively silence miR-15 family members in vitro and render cardiomyocytes resistant to hypoxia-induced cardiomyocyte cell death. Correspondingly, systemic delivery of miR-15 anti-miRs dose-dependently represses miR-15 in cardiac tissue of both mice and pigs, whereas therapeutic targeting of miR-15 in mice reduces infarct size and cardiac remodeling and enhances cardiac function in response to MI.
CONCLUSIONS:Oligonucleotide-based therapies using LNA-modified chemistries for modulating cardiac miRNAs in the setting of heart disease are efficacious and validate miR-15 as a potential therapeutic target for the manipulation of cardiac remodeling and function in the setting of ischemic injury.
Mesenchymal stem cells (MSCs) are broadly distributed cells that retain postnatal capacity for self-renewal and multilineage differentiation. MSCs evade immune detection, secrete an array of ...anti-inflammatory and anti-fibrotic mediators, and very importantly activate resident precursors. These properties form the basis for the strategy of clinical application of cell-based therapeutics for inflammatory and fibrotic conditions. In cardiovascular medicine, administration of autologous or allogeneic MSCs in patients with ischemic and nonischemic cardiomyopathy holds significant promise. Numerous preclinical studies of ischemic and nonischemic cardiomyopathy employing MSC-based therapy have demonstrated that the properties of reducing fibrosis, stimulating angiogenesis, and cardiomyogenesis have led to improvements in the structure and function of remodeled ventricles. Further attempts have been made to augment MSCs' effects through genetic modification and cell preconditioning. Progression of MSC therapy to early clinical trials has supported their role in improving cardiac structure and function, functional capacity, and patient quality of life. Emerging data have supported larger clinical trials that have been either completed or are currently underway. Mechanistically, MSC therapy is thought to benefit the heart by stimulating innate anti-fibrotic and regenerative responses. The mechanisms of action involve paracrine signaling, cell-cell interactions, and fusion with resident cells. Trans-differentiation of MSCs to bona fide cardiomyocytes and coronary vessels is also thought to occur, although at a nonphysiological level. Recently, MSC-based tissue engineering for cardiovascular disease has been examined with quite encouraging results. This review discusses MSCs from their basic biological characteristics to their role as a promising therapeutic strategy for clinical cardiovascular disease.
Administration of mesenchymal stem cells (MSCs) to diseased hearts improves cardiac function and reduces scar size. These effects occur via the stimulation of endogenous repair mechanisms, including ...regulation of immune responses, tissue perfusion, inhibition of fibrosis, and proliferation of resident cardiac cells, although rare events of transdifferentiation into cardiomyocytes and vascular components are also described in animal models. While these improvements demonstrate the potential of stem cell therapy, the goal of full cardiac recovery has yet to be realized in either preclinical or clinical studies. To reach this goal, novel cell-based therapeutic approaches are needed. Ongoing studies include cell combinations, incorporation of MSCs into biomaterials, or pre-conditioning or genetic manipulation of MSCs to boost their release of paracrine factors, such as exosomes, growth factors, microRNAs, etc. All of these approaches can augment therapeutic efficacy. Further study of the optimal route of administration, the correct dose, the best cell population(s), and timing for treatment are parameters that still need to be addressed in order to achieve the goal of complete cardiac regeneration. Despite significant progress, many challenges remain.
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Administering mesenchymal stem cells (MSCs) to the injured heart improves cardiac function and reduces scar size, primarily by stimulating endogenous repair mechanisms. We review the progress, challenges, and potential of MSC-based therapy, and we propose that combining MSCs with other cell type(s) improves therapeutic efficacy.
Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic ...targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibroblast growth factor (FGF) 23 rise progressively in CKD and induce LVH through an unknown FGF receptor (FGFR)-dependent mechanism. Here, we report that FGF23 exclusively activates FGFR4 on cardiac myocytes to stimulate phospholipase Cγ/calcineurin/nuclear factor of activated T cell signaling. A specific FGFR4-blocking antibody inhibits FGF23-induced hypertrophy of isolated cardiac myocytes and attenuates LVH in rats with CKD. Mice lacking FGFR4 do not develop LVH in response to elevated FGF23, whereas knockin mice carrying an FGFR4 gain-of-function mutation spontaneously develop LVH. Thus, FGF23 promotes LVH by activating FGFR4, thereby establishing FGFR4 as a pharmacological target for reducing cardiovascular risk in CKD.
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•In the absence of α-klotho, FGF23 induces binding of FGFR4 to PLCγ•FGF23 activates calcineurin/NFAT signaling in cardiac myocytes via FGFR4•FGFR4 blockade protects CKD rats with high serum FGF23 from cardiac hypertrophy•Knockin mice carrying a FGFR4 gain-of-function mutation develop cardiac hypertrophy
Grabner et al. reveal that FGFR4 mediates the pro-hypertrophic cardiac effects of FGF23, a phosphate-regulating hormone elevated in patients with chronic kidney disease (CKD). Activation of FGFR4/calcineurin/NFAT signaling is sufficient to induce cardiac hypertrophy in mice, while FGFR4 blockade attenuates cardiac hypertrophy in a rat model of CKD.
Given the rising prevalence of cardiovascular disease worldwide and the limited therapeutic options for severe heart failure, novel technologies that harness the regenerative capacity of the heart ...are sorely needed. The therapeutic use of stem cells has the potential to reverse myocardial injury and improve cardiac function, in contrast to most current medical therapies that only mitigate heart failure symptoms. Nearly 2 decades and >200 trials for cardiovascular disease have revealed that most cell types are safe; however, their efficacy remains controversial, limiting the transition of this therapy from investigation to practice. Lessons learned from these initial studies are driving the design of new clinical trials; higher fidelity of cell isolation techniques, standardization of conditions, more consistent use of state of the art measurement techniques, and assessment of multiple end points to garner insights into the efficacy of stem cells. Translation to clinical trials has almost outpaced our mechanistic understanding, and individual patient factors likely play a large role in stem cell efficacy. Therefore, careful analysis of dosing, delivery methods, and the ideal patient populations is necessary to translate cell therapy from research to practice. We are at a pivotal stage in the field in which information from many relatively small clinical trials must guide carefully executed efficacy trials. Larger efficacy trials are being launched to answer questions about older, first-generation stem cell therapeutics, while novel, second-generation products are being introduced into the clinical realm. This review critically examines the current state of clinical research on cell-based therapies for cardiovascular disease, highlighting the controversies in the field, improvements in clinical trial design, and the application of exciting new cell products.
Mesenchymal stem cells (MSCs) are a prototypical adult stem cell with capacity for self-renewal and differentiation with a broad tissue distribution. Initially described in bone marrow, MSCs have the ...capacity to differentiate into mesoderm- and nonmesoderm-derived tissues. The endogenous role for MSCs is maintenance of stem cell niches (classically the hematopoietic), and as such, MSCs participate in organ homeostasis, wound healing, and successful aging. From a therapeutic perspective, and facilitated by the ease of preparation and immunologic privilege, MSCs are emerging as an extremely promising therapeutic agent for tissue regeneration. Studies in animal models of myocardial infarction have demonstrated the ability of transplanted MSCs to engraft and differentiate into cardiomyocytes and vasculature cells, recruit endogenous cardiac stem cells, and secrete a wide array of paracrine factors. Together, these properties can be harnessed to both prevent and reverse remodeling in the ischemically injured ventricle. In proof-of-concept and phase I clinical trials, MSC therapy improved left ventricular function, induced reverse remodeling, and decreased scar size. This article reviews the current understanding of MSC biology, mechanism of action in cardiac repair, translational findings, and early clinical trial data of MSC therapy for cardiac disease.
Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory ...cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.
Objectives Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI). Background Bone ...marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support. Methods We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n = 53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points. Results Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p = 0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p = 0.003) in the hMSC-treated patients. Global symptom score in all patients (p = 0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling. Conclusions Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells MSC to Treat Acute Myocardial Infarction; NCT00114452 )
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