Heart failure (HF) describes a heterogenous complex spectrum of pathological conditions that results in structural and functional remodeling leading to subsequent impairment of cardiac function, including either systolic dysfunction, diastolic dysfunction, or both. Several factors chronically lead to HF, including cardiac volume and pressure overload that may result from hypertension, valvular lesions, acute, or chronic ischemic injuries. Major forms of HF include hypertrophic, dilated, and restrictive cardiomyopathy. The severity of cardiomyopathy can be impacted by other comorbidities such as diabetes or obesity and external stress factors. Age is another major contributor, and the number of patients with HF is rising worldwide in part due to an increase in the aged population. HF can occur with reduced ejection fraction (HF with reduced ejection fraction), that is, the overall cardiac function is compromised, and typically the left ventricular ejection fraction is lower than 40%. In some cases of HF, the ejection fraction is preserved (HF with preserved ejection fraction). Animal models play a critical role in facilitating the understanding of molecular mechanisms of how hearts fail. This review aims to summarize and describe the strengths, limitations, and outcomes of both small and large animal models of HF with reduced ejection fraction that are currently used in basic and translational research. The driving defect is a failure of the heart to adequately supply the tissues with blood due to impaired filling or pumping. An accurate model of HF with reduced ejection fraction would encompass the symptoms (fatigue, dyspnea, exercise intolerance, and edema) along with the pathology (collagen fibrosis, ventricular hypertrophy) and ultimately exhibit a decrease in cardiac output. Although countless experimental studies have been published, no model completely recapitulates the full human disease. Therefore, it is critical to evaluate the strength and weakness of each animal model to allow better selection of what animal models to use to address the scientific question proposed.

Background: Neonatal mammalian hearts have the unique characteristic to fully repair and regenerate following injury. This discovery has led to visionary endeavors to understand and subsequently reawaken regeneration processes in the human adult heart that are lost after birth, contributing to heart failure and death after ischemic insults. In utero exposure to tobacco smoke has detrimental effects on fetal development and growth. However, the consequences of prenatal exposure to cigarette smoke on murine neonate’s cardiac regeneration have never been explored. Methods: To study the impact of cigarette smoke during the entire pregnancy on cardiac regeneration in the offspring, plugged female wild type C57LB/6J mice were exposed either to cigarette smoke (n=6) or filtered air (control, n=6). Two days after birth, 5 pups from each litter were assigned to the two experimental groups: Myocardial infarction (MI) and sham. Detrimental effects of in utero exposure to tobacco smoke on the recovery of cardiac function following MI surgery were followed using two-dimensional speckle tracking echocardiography and strain imaging. To investigate the underlying mechanism, cardiac tissue of the infarct and remote zone was collected for non-coding RNA analysis. Results: In utero exposure to cigarette smoke significantly compromised cardiac regeneration in neonates. At both early and late time points in the phase of cardiac repair, hearts of neonates exposed to cigarette smoke during pregnancy showed a marked impairment of cardiac regenerative potential. In particular, ejection fraction, fractional area change and shortening, as well as left ventricular internal diameter during systole remained pathologically changed following MI insult in the smoked group until the very endpoint. Conclusions: Collectively, we here provide evidence that in utero exposure to cigarette smoke strongly compromises cardiac regeneration in the newborn offspring. This result reinforces smoking cessation during pregnancy. Additionally, understanding the changes in non-coding RNA expression in a setting of preserved versus disrupted repair of the heart might be an important first step towards the identification of key cellular processes in cardiac regeneration after injury.

Amyloid light chain (AL) amyloidosis results from tissue deposition of clonal light chains, most commonly produced by clonal plasma cells. AL amyloidosis is closely associated with multiple myeloma (MM), another disease which arises from clonal plasma cell proliferation. Here we aim to identify gene signatures to distinguish AL cardiomyopathy (AL-CM) risk in MM patients. We utilized publicly available data sets and applied Graph Cluster Perturbation approach to cluster the co-expression networks based on pathways in MM and AL-CM utilizing 225 samples from four datasets: GSE42955 study (12 dilated CM, 12 ischemic CM and 5 control LV human heart tissues), GSE95077 study (16 amiloride drug treated/untreated myeloma cell line samples), GSE24128 study (16 newly diagnosed AL with monoclonal plasma cell samples over- or under-expressing cyclin D1), and GSE6477 study (76 primary bone marrow samples from hyper-diploid myeloma patients and 80 non-hyperdiploid MM patients). From these data sets, the networks for extracellular matrix organization, immune system, innate immune system, metabolism, and neutrophil degranulation pathways for MM and amyloid CM were extracted. Summary: Ranking of the perturbed genes based on pathways similarity index in MM and AL resulted in a panel of genes: CD44, NRAS, GRAP2, CTLA4, GSN, CCND1, NFKB1, and IRF1 (p= <0.01). As shown in Figure , the high hazard ratio of this gene cluster in MM with AL-CM (3.76; p=0.021) compared to MM without CM (0.96; p=0.032) suggests the potential of this gene panel to distinguish high or low risk groups in MM based on survival.

We have previously described the discovery and development of GAIM (general amyloid interaction motif)-Ig (immunoglobulin) fusions as therapeutic candidates for neurodegenerative indications [1,2]....

The ability to use light to stimulate mammalian cells has significantly augmented our understanding of electrically excitable tissues in health and disease, paving the way toward various novel applications in the research and therapeutic fields. Here, we demonstrate full optogenetic control of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). We simultaneously introduced channelrhodopsin-2 (ChR2) and a third-generation halorhodopsin (NpHR3) into hiPSC via a polycistronic lentiviral vector. Via directed differentiation, we created opsinexpressing cardiomyocytes. To quantify the impact of photostimulation on these cells, we assessed evoked electrical and mechanical signals. With the application of blue (470 nm) and yellow (580 nm) light, we show both activation and inhibition of cardiomyocyte contractions, respectively. To illustrate the utility of our system, we have synchronized our light-sensitive cardiomyocytes with discarded primary human heart tissue, in vitro. In addition, we have created threedimensional optogenetic engineered heart muscle (o-EHM) that can be activated and inhibited with light; this offers a way to immediately and orthogonally synchronize this muscle with native heart rhythms. Our system provides insight into whether hiPSC-CM have the potential to be synchronized to recipient hearts in vivo upon therapeutic delivery, either as individual cardiomyocytes or as a component of engineered muscle.

Cardiac dysfunction is the most frequent cause of morbidity and mortality in amyloid light chain (AL) amyloidosis caused by a clonal immunoglobulin light chain (LC). Previously published transgenic animal models of AL amyloidosis have not recapitulated the key phenotype of cardiac dysfunction seen in AL amyloidosis, which has limited our understanding of the disease mechanisms in vivo, as well as the development of targeted AL therapeutics. We have developed a transgenic zebrafish model in which a λ LC derived from a patient with AL amyloidosis is conditionally expressed in the liver under the control of the Gal4 upstream activation sequence enhancer system. Circulating LC levels of 125 µg/ml in these transgenic zebrafish are comparable to median pathological serum LC levels. Functional analysis links abnormal contractile function with evidence of cellular and molecular proteotoxicity in the heart, including increased cell death and autophagy. However, despite pathological and functional phenotypes analogous to human AL, the lifespan of the transgenic fish is comparable to control fish without the expressed AL-LC transgene. Nuclear labeling experiments suggest increased cardiac proliferation in the transgenic fish, which can be counteracted by treatment with a small molecule proliferation inhibitor leading to increased zebrafish mortality because of cardiac apoptosis and functional deterioration. This transgenic zebrafish model provides a platform to study underlying AL disease mechanisms in vivo further. NEW & NOTEWORTHY Heart failure is a major cause of mortality in amyloid light (AL) amyloidosis, yet it has been difficult to model in animals. We report the generation of a transgenic zebrafish model for AL amyloidosis with pathological concentration of circulating human light chain protein that results in cardiac dysfunction. The light chain toxicity triggers regeneration in the zebrafish heart resulting in functional compensation early in life, but with age develops into cardiac dysfunction.

HomeCirculation ResearchVol. 120, No. 12Amyloid Cardiomyopathy Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBAmyloid CardiomyopathyDisease on the Rise Ronglih Liao and Jennifer E. Ward Ronglih LiaoRonglih Liao From the Divisions of Genetics and Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. and Jennifer E. WardJennifer E. Ward From the Divisions of Genetics and Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Originally published9 Jun 2017https://doi.org/10.1161/CIRCRESAHA.117.310643Circulation Research. 2017;120:1865–1867Amyloidoses represent a group of human degenerative diseases characterized by the deposition of aggregates of abnormally folded proteins in single or multi-organs. Whereas neurological amyloidoses, such as Alzheimer and Parkinson disease, have received the greatest recognition, there also exists many systemic amyloidoses that affect many target organs, including the heart.Cardiac amyloidosis is primarily associated with the systemic production and release of many amyloidogenic proteins, notably immunoglobulin light chain or transthyretin (TTR). AL (light chain amyloidosis) is the result of a clonal plasma cell dyscrasia and production of amyloidgenic light chain proteins. TTR amyloidosis may result from normal wild-type amyloidogenic TTR protein as seen in the elderly (known as senile systemic amyloidosis or ATTRwt) or from mutations in the TTR protein (ATTRm) as in familial amyloid cardiomyopathy.1,2 Cardiac deposition of amyloidogenic proteins often results in an aggressive form of heart disease with resulting cardiac failure that is largely resistant to many common heart failure therapies. Although once thought to be a rare disease, cardiac amyloidosis is more recently acknowledged to be much more common. For instance, AL amyloidosis, the most frequent cause of systemic amyloidosis in the developed world, has an incidence similar to that of Hodgkin lymphoma or chronic myelogenous leukemia and was widely underdiagnosed because of its ambiguous presentation and rapid mortality. Similarly, autopsy studies have identified significant cardiac deposition of wild-type TTR deposition in over 25% of individuals >80 years of age.3 Physician education, along with now widely accessible assays for diagnosis and monitoring (such as the Freelite serum-free LC assay), and improved cardiac imaging have contributed to the increase in diagnosis. In addition to ultrasound echocardiography and late gadolinium enhancement by cardiac magnetic resonance imaging,4 newer imaging modalities with 99mTc-pyrophosphate4,5 and florbetapir6 have improved detection, monitoring of disease progression, and treatment response in cardiac amyloidosis. With these imaging modalities becoming more widely accessible, it is likely that the identification of cardiac amyloidosis will only continue to increase. It is also likely that these noninvasive imaging methods will now be used to even screen people at elevated risk factors for developing cardiac amyloidoses, including patients with monoclonal gammopathy of undetermined significance and smoldering multiple myeloma at risk for AL amyloidosis, as well as asymptomatic gene carriers7 and African Americans who carry the TTR V122I mutation,8 who are at risk for TTR amyloidosis. Even in diseases thought to be localized, such as Alzheimer disease, APP (amyloid β precursor protein)-derived Aβ protein has been found in the heart.9 With over 10% of the population over the age of 65 years currently experiencing Alzheimer disease and only expected to increase, the potential rise in cardiac amyloidosis and secondary cardiac morbidity may also rise markedly.Given the projected rise in cardiac amyloidoses, in addition to improving diagnosis and monitoring through imaging, there is a great need to develop targeted therapies. Such therapies must antagonize not only the amyloid fibrils which cause physical damage to the heart but also the prefibrillar misfolded proteins which are proteotoxic, and the deleterious signaling pathways are triggered by these misfolded proteins. Development of such therapies will require greater understanding of the basic mechanisms of cardiac amyloidosis. Fortunately, greater research efforts are already underway. There has been a steady increase in publications with the keywords heart and amyloidosis over the past 10 years (Figure [A]). Compared with the history of research in Alzheimer disease (Figure [B]), cardiac amyloidosis appears to mirror the early 1980s—when increased recognition of the disease burden spurred greater research efforts. Interestingly, the number of publications in amyloid research seems to follow the kinetics of amyloid fibril formation with a lag phase now giving rise to a growth/elongation phase and eventually an equilibrium phase (Figure [C]).Download figureDownload PowerPointFigure. A, The number of publications using the keywords heart and amyloidosis. There has been a clear trend of increased publication in cardiac amyloidosis since the mid 2000s with suggestion of exponential growth of research in this area. B, The number of publications using the keyword Alzheimer's disease in PubMed increased dramatically in the late 1970s, reaching the current plateau of ≈6000 papers per year. Notably, the National Institute on Aging was established in 1974 and began funding Alzheimer's Disease Centers at medical institutions across the country in 1984. This exponential increase of research publications in Alzheimer disease resembles. C, The established kinetics of amyloid fibril formation showing a lag/nucleation phase, elongation/growth phase, and equilibrium phase.Although the root cause of amyloid diseases is well established, namely the production (or over production) of precursor proteins that misfold, aggregate, and form amyloid fibrils in distal tissues, there are still many other basic questions that remain unanswered. On a protein level, the structure of the prefibrillar protein in the circulation and in different tissues has not been clearly defined for LC and TTR or has the effect of post-translational modifications. On an organ level, we do not understand the variable organ tropism observed with patients with AL amyloidosis. Likewise, patients with ATTRwt do not typically develop the debilitating neuropathy frequently present in many of the familial forms of ATTRm, although there is only a single amino acid difference in the mutant protein. The interaction between the prefibrillar proteins and local tissue environment at the site of the amyloid deposit is poorly understood. On an organism level, the contribution of other host factors, such as inflammation, aging, genetics, and sex (ATTRwt nearly exclusively affects men), remains to be addressed. One shortcoming that has slowed investigation of these basic science questions and the development of targeted therapeutics has been the lack of appropriate animal models that recapitulates the primary cardiac phenotypes and other diverse disease pathology observed in humans. The history of animal models in the neurological amyloid diseases, mainly Alzheimer disease, has revealed that development of animal models is a long process with dozens of different models, each manifesting only a portion of the components (cause, symptoms, behavior, physiology, and pathology) of a multi-factorial disease.10 Although models that replicate only a partial phenotype allow for focused study of specific factors and their contribution to particular phenotype, such models also give rise to false discovery and artifact. The lack of ideal models may be 1 potential explanation as to why many therapeutics are effective in preclinical animal studies only to fail in human trials. Many attempts have been made to generate appropriate animal models for AL amyloidosis from mouse to fish to worms.11–14 Most such models have been limited in achieving proper phenotype or pathology. Mouse models of TTR have been able to modestly recapitulate some phenotype with minimal pathology or pathology without a cardiac phenotype.15 Solely overexpressing the amyloidogenic precursor protein has been insufficient in inducing the full spectrum of disease in any species. In the test tube, amyloid fibrils can be generated from precursor proteins in the absence of other factors, but nonphysiological conditions are necessary to cause fibril formation on a laboratory timescale (pH, ionic strength, heat, and agitation all forms of in vitro stress). Similar to the multiple-hit hypothesis in carcinogenesis, multiple hits may be required for the pathogenesis of amyloidosis or a perfect storm of underlying factors. What are these other hits? One important but poorly understood hit is the contribution of natural aging. Many cardiac amyloidoses are aging-associated diseases. In the case of TTR, circulating protein is present from birth but only causes significant amyloid aggregation and tissue injury decades later. Whether stress, injury, or local tissue inflammation contributes to amyloidogenic aggregation and deposition remains unknown. The age-related changes include but are not limited to oxidative stress, local tissue inflammation, mitochondrial dysfunction, and metabolic dysregulation, all of which may affect protein folding/misfolding and subsequent tissue amyloid deposition, and represent key topics for future research. In the absence of high-fidelity animal models, there is a greater need for close collaboration and data sharing among major cardiac amyloid clinical centers nationally and internationally to promote human-based research for revealing disease mechanisms, to develop novel and personalized treatment strategies, and to train the next generations of scientists, physicians, and physician scientists.As basic science and clinical research enters the growth phase of cardiac amyloidosis, it will be imperative that the response to the rising prevalence of disease is the wider adaptation of sensitive imaging modalities, earlier diagnosis, and development of targeted therapies. Because of the complexity of disease and diversity in phenotype, it is likely that effective therapy will necessitate precision-based approaches. Only through a more definitive understanding of disease mechanisms will such therapies become a reality, and the disease will again return a rarity.AcknowledgmentsWe acknowledge the immense contributions of the late Drs Carl Apstein and David Seldin, including their inspiration, support, and encouragement for so many in the pursuit of amyloid research. We would also like to acknowledge the support of the Brigham and Women's Hospital Cardiac Amyloid Program and The Amyloidosis Center at Boston University School of Medicine.Sources of FundingThis work was supported by National Institution of Health grants HL088533, HL112831, and HL128135; American Heart Association 16CSA28880004; and The Demarest Lloyd Jr Foundation.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Ronglih Liao, PhD, Cardiac Muscle Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, 77 Ave Louis Pasteur, NRB 431, Boston, MA 02115. E-mail [email protected]References1. Falk RH, Alexander KM, Liao R, Dorbala S. AL (Light-Chain) cardiac amyloidosis: a review of diagnosis and therapy.J Am Coll Cardiol. 2016; 68:1323–1341. doi: 10.1016/j.jacc.2016.06.053.CrossrefMedlineGoogle Scholar2. Connors LH, Sam F, Skinner M, Salinaro F, Sun F, Ruberg FL, Berk JL, Seldin DC. Heart failure resulting from age-related cardiac amyloid disease associated with wild-type transthyretin: a prospective, observational cohort study.Circulation. 2016; 133:282–290. doi: 10.1161/CIRCULATIONAHA.115.018852.LinkGoogle Scholar3. Tanskanen M, Peuralinna T, Polvikoski T, Notkola IL, Sulkava R, Hardy J, Singleton A, Kiuru-Enari S, Paetau A, Tienari PJ, Myllykangas L. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study.Ann Med. 2008; 40:232–239. doi: 10.1080/07853890701842988.CrossrefMedlineGoogle Scholar4. Fontana M, Chung R, Hawkins PN, Moon JC. Cardiovascular magnetic resonance for amyloidosis.Heart Fail Rev. 2015; 20:133–144. doi: 10.1007/s10741-014-9470-7.CrossrefMedlineGoogle Scholar5. Castano A, Haq M, Narotsky DL, Goldsmith J, Weinberg RL, Morgenstern R, Pozniakoff T, Ruberg FL, Miller EJ, Berk JL, Dispenzieri A, Grogan M, Johnson G, Bokhari S, Maurer MS. Multicenter study of planar technetium 99m pyrophosphate cardiac imaging: predicting survival for patients with ATTR cardiac amyloidosis.JAMA Cardiol. 2016; 1:880–889. doi: 10.1001/jamacardio.2016.2839.CrossrefMedlineGoogle Scholar6. Park MA, Padera RF, Belanger A, Dubey S, Hwang DH, Veeranna V, Falk RH, Di Carli MF, Dorbala S. 18F-florbetapir binds specifically to myocardial light chain and transthyretin amyloid deposits: autoradiography study.Circ Cardiovasc Imaging. 2015; 8:e002954.LinkGoogle Scholar7. Haq M, Pawar S, Berk JL, Miller EJ, Ruberg FL. Can 99m-Tc-pyrophosphate aid in early detection of cardiac involvement in asymptomatic variant TTR amyloidosis? [published online ahead of print August 20, 2016].JACC Cardiovasc Imaging. doi: 10.1016/j.jcmg.2016.06.003. http://www.imaging.onlinejacc.org/content/early/2016/11/23/j.jcmg.2016.06.003?sso=1&ssoredirect_count=1&access_token=.Google Scholar8. Quarta CC, Buxbaum JN, Shah AM, Falk RH, Claggett B, Kitzman DW, Mosley TH, Butler KR, Boerwinkle E, Solomon SD. The amyloidogenic V122I transthyretin variant in elderly black Americans.N Engl J Med. 2015; 372:21–29. doi: 10.1056/NEJMoa1404852.CrossrefMedlineGoogle Scholar9. Troncone L, Luciani M, Coggins M, Wilker EH, Ho CY, Codispoti KE, Frosch MP, Kayed R, Del Monte F. Aβ amyloid pathology affects the hearts of patients with Alzheimer's disease: mind the heart.J Am Coll Cardiol. 2016; 68:2395–2407. doi: 10.1016/j.jacc.2016.08.073.CrossrefMedlineGoogle Scholar10. Drummond E, Wisniewski T. Alzheimer's disease: experimental models and reality.Acta Neuropathol. 2017; 133:155–175. doi: 10.1007/s00401-016-1662-x.CrossrefMedlineGoogle Scholar11. Diomede L, Rognoni P, Lavatelli F, Romeo M, del Favero E, Cantù L, Ghibaudi E, di Fonzo A, Corbelli A, Fiordaliso F, Palladini G, Valentini V, Perfetti V, Salmona M, Merlini G. A Caenorhabditis elegans-based assay recognizes immunoglobulin light chains causing heart amyloidosis.Blood. 2014; 123:3543–3552. doi: 10.1182/blood-2013-10-525634.CrossrefMedlineGoogle Scholar12. Mishra S, Guan J, Plovie E, Seldin DC, Connors LH, Merlini G, Falk RH, MacRae CA, Liao R. Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish.Am J Physiol Heart Circ Physiol. 2013; 305:H95–H103. doi: 10.1152/ajpheart.00186.2013.CrossrefMedlineGoogle Scholar13. Solomon A, Weiss DT, Pepys MB. Induction in mice of human light-chain-associated amyloidosis.Am J Pathol. 1992; 140:629–637.MedlineGoogle Scholar14. Ward JE, Ren R, Toraldo G, Soohoo P, Guan J, O'Hara C, Jasuja R, Trinkaus-Randall V, Liao R, Connors LH, Seldin DC. Doxycycline reduces fibril formation in a transgenic mouse model of AL amyloidosis.Blood. 2011; 118:6610–6617. doi: 10.1182/blood-2011-04-351643.CrossrefMedlineGoogle Scholar15. Teng MH, Yin JY, Vidal R, Ghiso J, Kumar A, Rabenou R, Shah A, Jacobson DR, Tagoe C, Gallo G, Buxbaum J. Amyloid and nonfibrillar deposits in mice transgenic for wild-type human transthyretin: a possible model for senile systemic amyloidosis.Lab Invest. 2001; 81:385–396.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Göbel S, Hobohm L, Desuki A, Gori T, Münzel T, Claudio R, Wenzel P and Keller K (2022) Impact of cardiac amyloidosis on outcomes of patients hospitalized with heart failure, European Journal of Internal Medicine, 10.1016/j.ejim.2022.05.013, Online publication date: 1-May-2022. Quaggin-Smith J, Wehbe R and Holly T (2021) Incidental detection of ATTR cardiac amyloidosis, Journal of Nuclear Cardiology, 10.1007/s12350-020-02467-9, 29:3, (1030-1033), Online publication date: 1-Jun-2022. Dittloff K, Iezzi A, Zhong J, Mohindra P, Desai T and Russell B (2021) Transthyretin amyloid fibrils alter primary fibroblast structure, function, and inflammatory gene expression, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00073.2021, 321:1, (H149-H160), Online publication date: 1-Jul-2021. Yakupova E, Bobylev A, Bobyleva L and Vikhlyantsev I (2019) Study of the complement activation by amyloid aggregates of smooth muscle titin in vitro , Journal of Immunoassay and Immunochemistry, 10.1080/15321819.2019.1694943, 41:2, (132-143), Online publication date: 3-Mar-2020. McVeigh T and Tennyson C (2020) Understanding and recognizing cardiac amyloidosis, Journal of the American Academy of Physician Assistants, 10.1097/01.JAA.0000697236.11386.3a, 33:10, (16-20), Online publication date: 1-Oct-2020. Kocher F, Kaser A, Escher F, Doerler J, Zaruba M, Messner M, Mussner‐Seeber C, Mayr A, Ulmer H, Schneiderbauer‐Porod S, Ebner C and Poelzl G (2020) Heart failure from ATTRwt amyloid cardiomyopathy is associated with poor prognosis, ESC Heart Failure, 10.1002/ehf2.12986, 7:6, (3919-3928), Online publication date: 1-Dec-2020. Ablasser K, Verheyen N, Glantschnig T, Agnetti G and Rainer P Unfolding Cardiac Amyloidosis –From Pathophysiology to Cure, Current Medicinal Chemistry, 10.2174/0929867325666180104153338, 26:16, (2865-2878) Manolis A, Manolis A, Manolis T and Melita H (2019) Cardiac amyloidosis: An underdiagnosed/underappreciated disease, European Journal of Internal Medicine, 10.1016/j.ejim.2019.07.022, 67, (1-13), Online publication date: 1-Sep-2019. Shityakov S, Hayashi K, Störk S, Scheper V, Lenarz T and Förster C (2021) The Conspicuous Link between Ear, Brain and Heart–Could Neurotrophin-Treatment of Age-Related Hearing Loss Help Prevent Alzheimer's Disease and Associated Amyloid Cardiomyopathy?, Biomolecules, 10.3390/biom11060900, 11:6, (900) Magalhães S, Almeida I, Martins F, Camões F, Soares A, Goodfellow B, Rebelo S and Nunes A (2021) FTIR Spectroscopy as a Tool to Study Age-Related Changes in Cardiac and Skeletal Muscle of Female C57BL/6J Mice, Molecules, 10.3390/molecules26216410, 26:21, (6410) June 9, 2017Vol 120, Issue 12 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.117.310643PMID: 28596171 Originally publishedJune 9, 2017 Keywordsmutationamyloidgadoliniumheart failureagingPDF download Advertisement SubjectsBasic Science ResearchCardiomyopathyHeart FailureMyocardial BiologyPathophysiology

Amyloidoses represent a group of human degenerative diseases characterized by the deposition of aggregates of abnormally folded proteins in single or multi-organs. Whereas neurological amyloidoses, such as Alzheimer and Parkinson disease, have received the greatest recognition, there also exists many systemic amyloidoses that affect many target organs, including the heart.

Interferon-alpha (IFN-α) has been identified as a neurotoxin that plays a prominent role in human immunodeficiency virus (HIV)-associated neurocognitive disorders and HIV encephalitis (HIVE) pathology. IFN-α is associated with cognitive dysfunction in other inflammatory diseases where IFN-α is upregulated. Trials of monoclonal anti-IFN-α antibodies have been generally disappointing possibly due to high specificity to limited IFN-α subtypes and low affinity. We investigated a novel IFN-α inhibitor, B18R, in an HIVE/severe combined immunodeficiency (SCID) mouse model. Immunostaining for B18R in systemically treated HIVE/SCID mice suggested the ability of B18R to cross the blood-brain barrier (BBB). Real-time PCR indicated that B18R treatment resulted in a decrease in gene expression associated with IFN-α signaling in the brain. Mice treated with B18R were found to have decreased mouse mononuclear phagocytes and significant retention of neuronal arborization compared to untreated HIVE/SCID mice. Increased mononuclear phagocytes and decreased neuronal arborization are key features of HIVE. These results suggest that B18R crosses the BBB, blocks IFN-α signaling, and it prevents key features of HIVE pathology. These data suggest that the high affinity and broad IFN-α subtype specificity of B18R make it a viable alternative to monoclonal antibodies for the inhibition of IFN-α in the immune-suppressed environment.

AL cardiomyopathy leading to heart failure (HF) represents a significant cause of morbidity and mortality in systemic amyloidosis. However, the paucity of robust in vivo models of AL-induced cardiac dysfunction has limited our ability to probe the mechanisms of AL heart disease. To address this problem, we have developed a model of AL HF in zebrafish embryos by injection of in vitro transcribed mRNA encoding amyloidogenic light chain (aLC) into fertilized oocytes. We demonstrate that expression of aLC causes cardiomyopathy in developing zebrafish without significantly impairing extracardiac development. The cardiac ventricle of embryos expressing aLC exhibit impaired contractility, smaller size, and increased myocardial thickness which result in congestion and edema, features paralleling the clinical manifestations of amyloid cardiomyopathy. Phosphorylated p38, a marker of oxidative stress, was increased in response to aLC expression. No evidence of amyloid fibril deposition was identified. Thus, expression of aLC mRNA in zebrafish results in cardio toxic effects without fibril deposition. This is consistent with prior evidence indicating that aLC oligomers mediate cardiac dysfunction in vitro. This model will allow exploration of amyloid pathophysiology and testing of interventions to reduce and reverse the deleterious effects of amyloidosis on myocardial function.

Systemic AL amyloidosis results from the aggregation of an amyloidogenic immunoglobulin (Ig) light chain (LC) usually produced by a plasma cell clone in the bone marrow. AL is the most rapidly fatal of the systemic amyloidoses, as amyloid fibrils can rapidly accumulate in tissues including the heart, kidneys, autonomic or peripheral nervous systems, gastrointestinal tract, and liver. Chemotherapy is used to eradicate the cellular source of the amyloidogenic precursor. Currently, there are no therapies that target the process of LC aggregation, fibril formation, or organ damage. We developed transgenic mice expressing an amyloidogenic λ6 LC using the cytomegalovirus (CMV) promoter to circumvent the disruption of B cell development by premature expression of recombined LC. The CMV-λ6 transgenic mice develop neurologic dysfunction and Congophilic amyloid deposits in the stomach. Amyloid deposition was inhibited in vivo by the antibiotic doxycycline. In vitro studies demonstrated that doxycycline directly disrupted the formation of recombinant LC fibrils. Furthermore, treatment of ex vivo LC amyloid fibrils with doxycycline reduced the number of intact fibrils and led to the formation of large disordered aggregates. The CMV-λ6 transgenic model replicates the process of AL amyloidosis and is useful for testing the antifibril potential of orally available agents.

J. E. Ward1,2, P. SooHoo1,3, G. Toraldo2, R. Jasuja2, L. H. Connors1,4, C. O'Hara1,3, & D. C. Seldin1,21Department of Pathology, Boston University, Gerry Amyloid Research Laboratory, Boston Univers...

Amyloid light chain (AL) amyloidosis is a rare hematologic disorder characterized by the accumulation of a misfolded monoclonal immunoglobulin (Ig) light chain (LC) as fibrillar protein deposits. Current treatments, including cytotoxic chemotherapy and immunomodulatory therapy, are directed at killing the plasma cells that produce the LCs, but have significant toxicity for other cell types. We have designed small interfering RNAs (siRNAs) targeting the amyloidogenic LC messenger RNA (mRNA) in order to reduce expression of the amyloid precursor protein. Using nanomolar concentrations of siRNAs, we have inhibited synthesis of LC in transfected cells in vitro in a dose-dependent fashion. Furthermore, in an in vivo plasmacytoma mouse model of AL amyloidosis, we have demonstrated that these siRNAs can significantly reduce local production and circulating levels of LC. This model system highlights the therapeutic potential of siRNA for AL amyloidosis.

Patients with primary (AL) cardiac amyloidosis suffer from progressive cardiomyopathy with a median survival of less than 8 months and a 5-year survival of <10%. Contributing to this poor prognosis is the fact that these patients generally do not tolerate standard heart failure therapies. The molecular mechanisms underlying this deadly form of heart disease remain unclear. Although interstitial amyloid fibril deposition of Ig light chain proteins is a major cause of cardiac dysfunction in AL cardiac amyloidosis, we have previously shown that amyloid precursor proteins directly impair cardiac function at the cellular and isolated organ levels, independent of fibril formation. In this study, we report that amyloidogenic light chain (AL-LC) proteins provoke oxidative stress, cellular dysfunction, and apoptosis in isolated adult cardiomyocytes through activation of p38 mitogen-activated protein kinase (MAPK). AL-LC–induced p38 activation was found to be independent of the upstream MAPK kinase, MKK3/6, and instead depends upon transforming growth factor-β-activated protein kinase-1 binding protein-1 (TAB1)-mediated p38α MAPK autophosphorylation. Treatment of cardiomyocytes with SB203580, a selective p38 MAPK inhibitor, significantly attenuated AL-LC–induced oxidative stress, cellular dysfunction, and apoptosis. Our data provide a unique mechanistic insight into the pathogenesis of AL-LC cardiac toxicity and suggest that TAB1-mediated p38α MAPK autophosphorylation may serve as an important event leading to cardiac dysfunction and subsequent heart failure.

AL amyloidosis is a rare, sporadic disorder characterized by the accumulation of misfolded monoclonal immunoglobulin light chains (LC) as systemic amyloid deposits. Current therapies primarily include chemotherapies targeted at killing the plasma cells, often having toxic side effects for the patients. We have designed siRNAs targeted at either the variable (VL) or the constant regions (CL) of the LC to reduce amyloidogenic precursor protein expression in the producing cells. The strategy of targeting the unique VL is to develop sequence-specific siRNAs; alternatively, by targeting shared sequences in CL, siRNAs may be effective for sets of patients sharing the same LC family. Using picomolar concentrations of siRNAs, we have reduced LC protein levels in transfected cells in vitro in a dose-dependent fashion. In an in vivo tumor transplant mouse model of AL amyloidosis we have shown we can decrease the local and circulating LC levels. In this model, SP2/0 plasmacytoma cells stably expressing human amyloidogenic LCs are injected subcutaneously, and allowed to form a tumor. Once the tumor is the appropriate size, In Vivo Electroporation (IVEP) is used to deliver the siRNA oligos into the cells. By examining tumor and serum samples 48 hours post treatment, we have shown the siRNAs can significantly decrease the amount of LC in a sequence-specific manner. This model system highlights the therapeutic potential of siRNA for this disease. In conclusion, siRNA appears to be a viable potential therapy for AL amyloidosis.

Arthur R. BradwellThe Binding Site, Ltd., San Diego, 2006285 pp., $75.00ISBN-10: 0-70442-529-7ISBN-13: 978-0-70442-529-3Students of basic immunology are taught that immunoglobulins exist as heterot...

Acquired loss of functional von Willebrand factor (VWF) has been termed the acquired von Willebrand syndrome (AVWS). AVWS is a rare adult‐onset bleeding diathesis that is clinically similar to congenital von Willebrand disease (VWD), and occurs with a variety of autoimmune, lymphoproliferative, or myeloproliferative disorders. We have identified four patients with AVWS in association with immunoglobulin light chain (AL) amyloidosis. These patients, lacking any pre‐existing or family history of abnormal bleeding, developed cutaneous, mucosal, or gastrointestinal bleeding in the course of their disease without deficiency of clotting factor X or other factors; the activated partial thromboplastin time (aPTT) was prolonged in three out of the four cases. Despite normal VWF antigen levels, VWF ristocetin cofactor activity (VWF:RCo) was low. Electrophoresis patterns of high molecular weight (HMW) VWF multimers were abnormal in two of the four cases. Two of the patients were treated with high‐dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) and achieved hematologic remission. In these two patients, the bleeding diathesis improved and the coagulation parameters normalized, confirming a causal relationship between the plasma cell dyscrasia and the AVWS. AVWS should be considered in AL amyloidosis patients with hemorrhagic diatheses and normal clotting factor levels. Am. J. Hematol., 2007. © 2007 Wiley‐Liss, Inc.

Easy bruising is a common clinical symptom in primary (AL) amyloidosis, and can occur through multiple mechanisms. Infiltration of amyloid fibrils into thin-walled capillaries leads to mechanical fragility predisposing to petechiae and purpura, with periorbital “raccoon-eye” purpura being pathognomonic of AL amyloidosis. Another mechanism predisposing to bleeding in AL amyloidosis is adsorption of coagulation factors to amyloid fibrils. In 1977, Furie et al. reported (New England Journal of Medicine) that elevation of the clotting times is most commonly due to deficiency of factor X, and other investigators have since reported deficiencies of factors II, V, IX, or XIII. We have demonstrated that remission of the underlying plasma cell dyscrasia after high dose melphalan chemotherapy and autologous stem cell transplantation can lead to remission of the acquired factor X deficiency (Choufani et al., Blood 2001). From 2000–2004, four amyloidosis patients presented to Boston University Medical Center with bleeding and a prolonged activated partial thromboplastin time (aPTT), but with no such factor deficiency. Instead, they were found to have abnormal von Willebrand ristocetin cofactor (vWF:RCo) and/or factor VIII (FVIII:C) activities, with normal vWF antigen (vWF:Ag), consistent with a functional defect in von Willebrand factor (vWF). None of the patients had a prior history or family history consistent with congenital von Willebrand's disease, thus they were diagnosed with acquired von Willebrand syndrome (AvWS). AvWS has most often been reported in association with other lymphoproliferative or myeloproliferative disorders. The aPTT was prolonged in three out of the four cases. Loss of high molecular weight multimers (HMWM) was observed in two of the four cases. Two of the patients were treated with high-dose intravenous melphalan followed by autologous stem cell transplantation and achieved remission of their underlying plasma cell disease; in addition, the bleeding diathesis ceased and the coagulation parameters normalized, indicating reversal of the AvWS with effective treatment of AL amyloidosis.