Coronary flow velocity (CFV) is reduced in pathologic cardiac hypertrophy. This functional reduction is linked to adverse cardiac remodeling, hypertension and fibrosis, and angiotensin II (AngII) is a key molecular player. Angiotensin receptor blockers (ARBs) are known to attenuate adverse cardiac remodeling and fibrosis following increased afterload, while the mechanism by which these drugs offer clinical benefits and regulate hemodynamics remains unknown. To establish a direct connection between coronary flow changes and angiotensin-induced hypertension, we used a Doppler echocardiographic method in two distinct disease models. First, we performed serial echocardiography to visualize coronary flow and assess heart function in patients newly diagnosed with hypertension and currently on ARBs or calcium channel blockers (CCBs). CFV improved significantly in the hypertensive patients after 12 weeks of ARB treatment but not in those treated with CCBs. Second, using murine models of pressure overload, including Ang II infusion and aortic banding, we mimicked the clinical conditions of Ang II- and mechanical stress-induced hypertension, respectively. Both Ang II infusion and aortic banding increased the end-systolic pressure-volume relationship and cardiac fibrosis, but interestingly, only Ang II infusion resulted in a significant reduction in CFV and corresponding activation of pressure-sensitive proteins, including connective tissue growth factor, hypoxia-inducible factor 1α and signal transducer and activator of transcription 3. These data support the existence of a molecular and functional link between AngII-induced hemodynamic remodeling and alterations in coronary vasculature, which, in part, can explain the clinical benefit of ARB treatment in hypertensive patients.

Introduction: Heart failure with preserved ejection fraction (HFpEF) presents a unique challenge in cardiology due to its diverse etiology and clinical presentation. Our study introduces a cutting-edge integrated deep learning model that combines multi-dimensional datasets, encompassing genetic variants from GWAS, cardiac structural and functional assessments from MRI, and electrophysiological data from ECGs, along with comorbidity profiles including CKD and LFT. Research Questions: Can a deep learning model that integrates multi-dimensional datasets accurately predict HFpEF risk? How does the inclusion of different types of data (genetic, MRI, comorbidity) affect the model's predictive accuracy? Goals: To develop a deep learning model that accurately predicts HFpEF risk To assess the impact of different types of data on the model's predictive accuracy. Methods: The model employs a graph convolutional multi-model deep learning approach to dissect the intricate interplay between genetic variants from GWAS, cardiac structural and functional assessments from MRI, electrophysiological data from ECGs, and comorbidity profiles including CKD and LFT. Results: The baseline genetic model achieved a PRS of 2.04 and an outcome accuracy of 81%. The incorporation of MRI features improved the outcome accuracy to 85.91%. The inclusion of comorbidities such as CKD and T2D resulted in the highest outcome accuracy of 88.57%. Discussion: The results suggest that the inclusion of MRI features and comorbidities improves the model's predictive accuracy. This model holds significant promise for clinical adoption and the advancement of personalized treatment strategies.

Myocardial infarction (MI) is a significant cardiovascular disease that restricts blood flow, resulting in massive cell death and leading to stiff and noncontractile fibrotic scar tissue formation. Recently, sustained oxygen release in the MI area has shown regeneration ability; however, improving its therapeutic efficiency for regenerative medicine remains challenging. Here, a combinatorial strategy for cardiac repair by developing cardioprotective and oxygenating hybrid hydrogels that locally sustain the release of stromal cell-derived factor-1 alpha (SDF) and oxygen for simultaneous activation of neovascularization at the infarct area is presented. A sustained release of oxygen and SDF from injectable, mechanically robust, and tissue-adhesive silk-based hybrid hydrogels is achieved. Enhanced endothelialization under normoxia and anoxia is observed. Furthermore, there is a marked improvement in vascularization that leads to an increment in cardiomyocyte survival by approximate to 30% and a reduction of the fibrotic scar formation in an MI animal rodent model. Improved left ventricular systolic and diastolic functions by approximate to 10% and 20%, respectively, with a approximate to 25% higher ejection fraction on day 7 are also observed. Therefore, local delivery of therapeutic oxygenating and cardioprotective hydrogels demonstrates beneficial effects on cardiac functional recovery for reparative therapy. A combinatorial strategy for cardiac repair is presented by developing cardioprotective and oxygenating hybrid hydrogels composed of silk fibroin and tyramine-alginate that locally sustain the release of stromal cell-derived factor-1 alpha and oxygen for enhanced cardiomyocyte survival and vascularization. These therapeutic hydrogels demonstrate beneficial effects on cardiac functional recovery in a myocardial infarction rodent model and hold promise for reparative therapy. image

Background: An effective pharmacological therapy yet exists to mitigate mitral regurgitation (MR) progression before surgical interventions. Angiotensin receptor-neprilysin inhibitor (ARNI) has shown benefits in patients with heart failure (HF) with reduced ejection fraction but whether it can reduce degenerative MR induced HF remains unknown. Aim: To test the efficacy of ARNI in improving cardiac function in degenerative MR -induced HF. Methods and Results: Using a novel rat model of degenerative MR, we found that in degenerative MR rats treated with ARNI, left ventricular function and atrial fibrillation (AF) inducibility significantly improved compared with those treated with valsartan only (fractional shortening 61.78±7.26% v.s. 55.07±6.63%). Also, the AF inducibility dropped from 83% to 25% in MR rats treated with ARNI than to 58.3% in those treated with valsartan. ARNI treatment demonstrated significant attenuation of fibrosis, apoptosis and expressions of endoplasmic reticulum (ER) stress and inflammatory-associated proteins in left ventricular tissues compared to valsartan. In a shear stress model, the treatment of ARNI on cardiomyocytes mitigated the flow triggered activities of both ER released calcium signaling and store-operated calcium entry. Parallelly, we prospectively included 65 patients with degenerative MR receiving valsartan or ARNI and followed Holter electrocardiography and echocardiography. Notably, compared with degenerative MR patients receiving valsartan, those prescribed with ARNI demonstrated significant improvement of AF burden and left ventricular function. Conclusions: Degenerative MR-induced cardiovascular dysfunction including fibrosis and ER stress, were more effectively attenuated by ARNI treatment than by valsartan alone.

Background: Patients with pulmonary arterial hypertension (PAH) often experience adverse outcomes primarily due to right ventricular (RV) dysfunction. However, the intricate relationship between pulmonary circulation and RV remodeling remains largely unexplored. Exosomal microRNAs (miRNAs) function as paracrine signaling mediators in diverse diseases. Aims: To investigate the ability of exosomal miRNAs derived from pulmonary endothelial cells to transmit signals affecting cardiomyocytes. Methods and Results: Utilizing next-generation sequencing, we identified several target miRNAs by analyzing exosome samples obtained through right-heart catheterization. Notably, exosomal miR-21 exhibited the highest expression in the pulmonary circulation (Figure 1) . Under hypoxic conditions, the expression of miR-21 increased in human pulmonary endothelial cells (HPECs) and in exosomes derived from their conditioned medium. Treatment with these exosomes enhanced miR-21 expression and concurrently mitigated apoptosis in hypoxia-exposed cardiomyocytes. Likewise, miR-21 demonstrated a protective role against hypoxia-induced injuries and apoptosis, involving the SPRY-2/p-ERK and PTEN/Akt pathways. In a murine model of sugen/hypoxia-induced PAH, mice lacking miR-21 (miR-21 -/- ) exhibited more severe RV dysfunction, altered hemodynamics, and increased fibrosis compared to wild-type (WT) mice. Employing a parabiosis model, pairs consisting of WT and miR-21 -/- mice were shielded from RV dysfunction, whereas pairs of miR-21 -/- mice displayed exacerbated RV function (Figure 2) . Conclusion: Hypoxia stimulates the production of exosomal miR-21 in both HPECs and their microenvironment, subsequently mitigating apoptosis in cardiomyocytes (Figure 3) . Our findings propose endothelial cell-derived exosomal miR-21 as a promising therapeutic target for PAH.

Epicardial delivery of human follistatin-like 1 protein (FSTL1) induces significant cardiac benefit following a myocardial infarction (MI). However, the optimal dosing regimen for maximal therapeutic benefit has not yet been elucidated. To investigate the impact of multiple FSTL1 doses, without the confounding effects of multiple surgical procedures for multidose delivery, alternative delivery strategies are needed. Here, we use an epicardial reservoir that allows non-invasive delivery of additional doses after implantation to investigate the impact of single, double, and triple FSTL1 dose regimens in a rat model of MI. Multidose delivery of FSTL1 improves ejection fraction (3 doses), fractional shortening (1, 2 and 3 doses), and chamber stiffness (2 doses) 28 days after MI. Histologically, multiple FSTL1 doses increase ventricular wall thickness (2 and 3 doses) and reduce infarct size (1, 2, and 3 doses). We also demonstrate a dose-dependent increase in blood vessel number and density in the infarct zone, with three FSTL1 doses leading to the highest improvements. This study shows that multidose delivery of FSTL1 improves cardiac function, healing, and angiogenesis following MI. The epicardial delivery platform used here may be essential in optimizing dosing regimens of various bioagent combinations for a range of clinical indications.

The stressed right ventricle (RV) is particularly susceptible to producing and accumulating reactive oxygen species, leading to extracellular matrix deposition and secretion of natriuretic peptides. The role of specific enzymes with antioxidative capacity, like glutathione peroxidase 3 (GPx3), in RV pathogenesis is currently unknown. Here, we use a murine model of pulmonary artery banding (PAB) to study the role of GPx3 in isolated RV pathology. Compared with wild-type (WT) mice undergoing PAB surgery, GPx3-deficient PAB mice presented with higher RV systolic pressure and higher LV eccentricity indices. PAB-induced changes in Fulton's Index, RV free wall thickness, and RV fractional area change were more pronounced in GPx3-deficient mice compared with WT controls. Adverse RV remodeling was enhanced in GPx3-deficient PAB animals, evidenced by increased RV expression levels of connective tissue growth factor (CTGF), transforming growth factor-β (TGF-β), and atrial natriuretic peptide (ANP). In summary, GPx3 deficiency exacerbates maladaptive RV remodeling and causes signs of RV dysfunction.

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.

Epicardial delivery of human follistatin-like 1 protein (FSTL1) induces significant cardiac benefit following a myocardial infarction (MI). However, the optimal dosing regimen for maximal therapeutic benefit has not yet been elucidated. To investigate the impact of multiple FSTL1 doses, without the confounding effects of multiple surgical procedures for multidose delivery, alternative delivery strategies are needed. Here, we use an epicardial reservoir that allows non-invasive delivery of additional doses after implantation to investigate the impact of single, double, and triple FSTL1 dose regimens in a rat model of MI. Multidose delivery of FSTL1 improves ejection fraction (3 doses), fractional shortening (1, 2 and 3 doses), and chamber stiffness (2 doses) 28 days after MI. Histologically, multiple FSTL1 doses increase ventricular wall thickness (2 and 3 doses) and reduce infarct size (1, 2, and 3 doses). We also demonstrate a dose-dependent increase in blood vessel number and density in the infarct zone, with three FSTL1 doses leading to the highest improvements. This study shows that multidose delivery of FSTL1 improves cardiac function, healing, and angiogenesis following MI. The epicardial delivery platform used here may be essential in optimizing dosing regimens of various bioagent combinations for a range of clinical indications.

Right ventricular (RV) function is a critical determinant of survival in patients with pulmonary arterial hypertension (PAH). While miR-21 is known to associate with vascular remodeling in small animal models of PAH, its role in RV remodeling in large animal models has not been characterized. Herein, we investigated the role of miR-21 in RV dysfunction using a sheep model of PAH secondary to pulmonary arterial constriction (PAC). RV structural and functional remodeling were examined using ultrasound imaging. Our results showed that post PAC, RV strain significantly decreased at the basal region compared with t the control. Moreover, such dysfunction was accompanied by increases in miR-21 levels. To determine the role of miR-21 in RV remodeling secondary to PAC, we investigated the molecular alteration secondary to phenylephrine induced hypertrophy and miR21 overexpression in vitro using neonatal rat ventricular myocytes (NRVMs). We found that overexpression of miR-21 in the setting of hypertrophic stimulation augmented only the expression of proteins critical for mitosis but not cytokinesis. Strikingly, this molecular alteration was associated with an eccentric cellular hypertrophic phenotype similar to what we observed in vivo PAC animal model in sheep. Importantly, this hypertrophic change was diminished upon suppressing miR-21 in NRVMs. Collectively, our in vitro and in vivo data demonstrate that miR-21 is a critical contributor in the development of RV dysfunction and could represent a novel therapeutic target for PAH associated RV dysfunction.

BackgroundMitral regurgitation (MR) is a major contributor for heart failure (HF) and atrial fibrillation. Despite the advancement of MR surgeries, an effective medical therapy to mitigate MR progression is lacking. Sodium glucose cotransporter 2 inhibitors, a new class of antidiabetic drugs, has shown measurable benefits in reduction of HF hospitalization and cardiovascular mortality but the mechanism is unclear. We hypothesized that dapagliflozin (DAPA), a sodium glucose cotransporter 2 inhibitor, can improve cardiac hemodynamics in MR‐induced HF.Methods and ResultsUsing a novel, mini‐invasive technique, we established a MR model in rats, in which MR induced left heart dilatation and functional decline. Half of the rats were randomized to be administered with DAPA at 10 mg/kg per day for 6 weeks. After evaluation of electrocardiography and echocardiography, hemodynamic studies were performed, followed by postmortem tissue analyses. Results showed that DAPA partially rescued MR‐induced impairment including partial restoration of left ventricular ejection fraction and end‐systolic pressure volume relationship. Despite no significant changes in electrocardiography at rest, rats treated with DAPA exhibited lower inducibility and decreased duration of pacing‐induced atrial fibrillation. DAPA also significantly attenuated cardiac fibrosis, cardiac expression of apoptosis, and endoplasmic reticulum stress‐associated proteins.ConclusionsDAPA was able to suppress cardiac fibrosis and endoplasmic reticulum stress and improve hemodynamics in an MR‐induced HF rat model. The demonstrated DAPA effect on the heart and its association with key molecular contributors in eliciting its cardio‐protective function, provides a plausible point of DAPA as a potential strategy for MR‐induced HF.

The induction of in vivo reprogramming toward pluripotency has been demonstrated in several tissues utilizing either transgenic inducible mice or gene delivery approaches. However, the effects of exogenous reprogramming factor expression in the mammalian heart have not been previously reported. The present study aims to investigate the response of cardiac cells to ectopic Oct3/4, Sox2, Klf4, and cMyc (OSKM) expression in vivo using a non-integrating adenoviral vector. Direct intramyocardial injection of this vector achieves effective and transient OSKM overexpression in the healthy heart and after myocardial infarction. The expression of these factors induces transient upregulation of a number of endogenous pluripotency (endo-Oct3/4, Gdf3) and reprogramming related (Cdh1, Fut4) genes, confirming the induction of cell reprogramming. Despite the initiation of reprogramming, markers of fully de-differentiated cells including Nanog remain silenced, consistent with a partially reprogrammed state. Furthermore, no indications of tumorigenesis or teratoma formation are observed. Overall, these data suggest that adenoviral mediated OSKM delivery can be utilized to induce partial in vivo reprogramming. However, the absence of any clear regenerative effects after myocardial infarction indicates that further optimization of vector mediated reprogramming strategies is essential to overcome barriers to therapeutic efficacy.

Background Marfan syndrome (MFS) is a genetically transmitted connective tissue disorder characterized by aortic root dilatation, dissection, and rupture. Molecularly, MFS pathological features have been shown to be driven by increased angiotensin II in the aortic wall. Using an angiotensin II-driven aneurysm mouse model, we have recently demonstrated that local inhibition of leptin activity restricts aneurysm formation in the ascending and abdominal aorta. As we observed de novo leptin synthesis in the ascending aortic aneurysm wall of patients with MFS, we hypothesized that local counteracting of leptin activity in MFS may also prevent aortic cardiovascular complications in this context. Methods and Results Fbn1C1039G/+ mice underwent periaortic application of low-dose leptin antagonist at the aortic root. Treatment abolished medial degeneration and prevented increase in aortic root diameter (P<0.001). High levels of leptin, transforming growth factor β1, Phosphorylated Small mothers against decapentaplegic 2, and angiotensin-converting enzyme 1 observed in saline-treated MFS mice were downregulated in leptin antagonist-treated animals (P<0.01, P<0.05, P<0.001, and P<0.001, respectively). Leptin and angiotensin-converting enzyme 1 expression levels in left ventricular cardiomyocytes were also decreased (P<0.001) and coincided with prevention of left ventricular hypertrophy and aortic and mitral valve leaflet thickening (P<0.01 and P<0.05, respectively) and systolic function preservation. Conclusions Local, periaortic application of leptin antagonist prevented aortic root dilatation and left ventricular valve remodeling, preserving left ventricular systolic function in an MFS mouse model. Our results suggest that local inhibition of leptin may constitute a novel, stand-alone approach to prevent MFS aortic root aneurysms and potentially other similar angiotensin II-driven aortic pathological features.

Dapagliflozin (DAPA) -- a sodium glucose cotransporter 2 (SGLT2) inhibitor, is approved for treatments of diabetic patients. DAPA-HF trial disclosed its benefits in symptomatic heart failure but the underlying mechanism remains largely unknown. In this longitudinal and prospective study, we investigated changes of left ventricular (LV) functions including speckle tracking in diabetic patients free from symptomatic heart failure post DAPA treatment. Using streptozotocin-induce diabetic rat model, we measured the effects of DAPA on myocardial function. In patients with diabetes, following six months of DAPA, despite no significant changes LV ejection fraction, the diastolic function and longitudinal strain improved. Likewise, compared to control, the diabetic rat heart developed pronounced fibrosis, a decline in strain and overall hemodynamics, all of which were mitigated by DAPA treatment. In contrast, despite insulin exerting a glucose lowering effect, it failed to improve myocardial function and fibrosis. In our in vitro study, under high glucose cardiomyocytes showed significant activations of apoptosis, reactive oxygen species and ER stress associated proteins, which were attenuated by the co-incubation of DAPA. Mechanistically, DAPA suppressed ER stress, reduced myocardial fibrosis and improved overall function. The results can lead to further improvement in management of LV function in diabetic patients.

The zebrafish (Danio rerio) has become a very popular model organism in cardiovascular research, including human cardiac diseases, largely due to its embryonic transparency, genetic tractability, and amenity to rapid, high-throughput studies. However, the loss of transparency limits heart function analysis at the adult stage, which complicates modeling of age-related heart conditions. To overcome such limitations, high-frequency ultrasound echocardiography in zebrafish is emerging as a viable option. Here, we present a detailed protocol to assess cardiac function in adult zebrafish by non-invasive echocardiography using high-frequency ultrasound. The method allows visualization and analysis of zebrafish heart dimension and quantification of important functional parameters, including heart rate, stroke volume, cardiac output, and ejection fraction. In this method, the fish are anesthetized and kept underwater and can be recovered after the procedure. Although high-frequency ultrasound is an expensive technology, the same imaging platform can be used for different species (e.g., murine and zebrafish) by adapting different transducers. Zebrafish echocardiography is a robust method for cardiac phenotyping, useful in the validation and characterization of disease models, particularly late-onset diseases; drug screens; and studies of heart injury, recovery, and regenerative capacity.

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.

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.

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.