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Objectives: The purpose of this study is to report outcomes after heart transplantation in patients with cardiac amyloidosis based on a large single-center experience., Background: Cardiac amyloidosis causes significant morbidity and mortality, often leading to restrictive cardiomyopathy, progressive heart failure, and death. Historically, heart transplantation outcomes have been worse in patients with cardiac amyloidosis compared with other heart failure populations, in part due to the systemic nature of the disease. However, several case series have suggested that transplantation outcomes may be better in the contemporary era, likely in part due to the availability of more effective light chain suppressive therapies for light chain amyloidosis., Methods: This study examined all patients seen between 2004 and 2017, either at the Stanford University Medical Center or the Kaiser Permanente Santa Clara Medical Center, who were diagnosed with cardiac amyloidosis and ultimately underwent heart transplantation. This study examined pre-transplantation characteristics and post-transplantation outcomes in this group compared with the overall transplantation population at our center., Results: During the study period, 31 patients (13 with light chain amyloidosis and 18 with transthyretin [ATTR] amyloidosis) underwent heart transplantation. Patients with ATTR amyloidosis were older, were more likely to be male, had worse baseline renal function, and had longer waitlist times compared with both patients with light chain amyloidosis and the overall transplantation population. Post-transplantation, there were no differences in post-operative bleeding, renal failure, infection, rejection, or malignancy. There was no significant difference in mortality between patients who underwent heart transplantation for amyloid cardiomyopathy and patients who underwent heart transplantation for all other indications., Conclusions: In carefully selected patients with cardiac amyloidosis, heart transplantation can be an effective therapeutic option with outcomes similar to those transplanted for other causes of heart failure., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Myocardial fibrosis is a hallmark of cardiac remodeling and functionally involved in heart failure development, a leading cause of deaths worldwide. Clinically, no therapeutic strategy is available that specifically attenuates maladaptive responses of cardiac fibroblasts, the effector cells of fibrosis in the heart. Therefore, our aim was to develop novel antifibrotic therapeutics based on naturally derived substance library screens for the treatment of cardiac fibrosis., Methods: Antifibrotic drug candidates were identified by functional screening of 480 chemically diverse natural compounds in primary human cardiac fibroblasts, subsequent validation, and mechanistic in vitro and in vivo studies. Hits were analyzed for dose-dependent inhibition of proliferation of human cardiac fibroblasts, modulation of apoptosis, and extracellular matrix expression. In vitro findings were confirmed in vivo with an angiotensin II-mediated murine model of cardiac fibrosis in both preventive and therapeutic settings, as well as in the Dahl salt-sensitive rat model. To investigate the mechanism underlying the antifibrotic potential of the lead compounds, treatment-dependent changes in the noncoding RNAome in primary human cardiac fibroblasts were analyzed by RNA deep sequencing., Results: High-throughput natural compound library screening identified 15 substances with antiproliferative effects in human cardiac fibroblasts. Using multiple in vitro fibrosis assays and stringent selection algorithms, we identified the steroid bufalin (from Chinese toad venom) and the alkaloid lycorine (from Amaryllidaceae species) to be effective antifibrotic molecules both in vitro and in vivo, leading to improvement in diastolic function in 2 hypertension-dependent rodent models of cardiac fibrosis. Administration at effective doses did not change plasma damage markers or the morphology of kidney and liver, providing the first toxicological safety data. Using next-generation sequencing, we identified the conserved microRNA 671-5p and downstream the antifibrotic selenoprotein P1 as common effectors of the antifibrotic compounds., Conclusions: We identified the molecules bufalin and lycorine as drug candidates for therapeutic applications in cardiac fibrosis and diastolic dysfunction.

Cardiac amyloidosis is a potentially deadly disease characterized by progressive infiltration of amyloid fibrils, and it is increasingly recognized as an underdiagnosed but important cause of heart failure. Given its unique pathogenesis, there are key differences in the management of cardiac amyloidosis compared with other forms of heart failure. Moreover, the 2 common forms of cardiac amyloidosis, transthyretin and light-chain amyloidosis, are distinct entities with varying clinical manifestations and prognoses, leading to the need for tailored approaches to management. In the past decade, there have been many significant advances in the diagnosis and treatment of both forms of cardiac amyloidosis. For example, in selected cases, transthyretin cardiac amyloidosis can be diagnosed noninvasively with the use of bone scintigraphy imaging, avoiding the need for a biopsy. Effective, more targeted therapies have been developed for both transthyretin and light-chain amyloidosis. However, these treatments are much more effective in early stages of disease before significant end-organ amyloid deposition has occurred. Consequently, it is increasingly imperative that clinicians aggressively screen at-risk groups, identify early signs of disease, and initiate treatment. Finally, once thought to be ill advised, heart transplantation should be considered in carefully selected patients with end-stage cardiac amyloidosis, because transplant outcomes in these patients is now similar to other those for other cardiomyopathies. Given these and other recent changes in clinical practice, this article discusses several key considerations for the clinical care of patients with cardiac amyloidosis., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Cardiac regeneration has received much attention as a possible means to treat various forms of cardiac injury. This review will explore the field of cardiac regeneration by highlighting the existing animal models, describing the involved molecular pathways, and discussing attempts to harness cardiac regeneration to treat cardiomyopathies., Recent Findings: Light chain cardiac amyloidosis is a degenerative disease characterized by progressive heart failure due to amyloid fibril deposition and light chain-mediated cardiotoxicity. Recent findings in a zebrafish model of light chain amyloidosis suggest that cardiac regenerative confers a protective effect against this disease. Cardiac regeneration remains an intriguing potential tool for treating cardiovascular disease. Degenerative diseases, such as light chain cardiac amyloidosis, may be particularly suited for therapeutic interventions that target cardiac regeneration. Further studies are needed to translate preclinical findings for cardiac regeneration into effective therapies.

Light chain amyloidosis is a deadly disease in which a monoclonal plasma cell dyscrasia produces misfolded immunoglobulin light chains (AL) that aggregate and form rigid amyloid fibrils. The amyloid deposits infiltrate one or more organs, leading to injury and severe dysfunction. The degree of cardiac involvement is a major driver of morbidity and mortality. Early diagnosis and treatment are crucial to prevent irreversible end-organ damage and improve overall survival. Treatment of AL cardiac amyloidosis involves eliminating the underlying plasma cell dyscrasia with chemotherapy and pursuing supportive heart failure management., (Copyright © 2019 Elsevier Inc. All rights reserved.)