Publications by authors named "Ronglih Liao"

150 Publications

Angiotensin II blockers improve cardiac coronary flow under hemodynamic pressure overload.

Hypertens Res 2021 Feb 10. Epub 2021 Feb 10.

Department of Medicine, Brigham and Women's Hospital Harvard Medical School, Boston, MA, USA.

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.
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http://dx.doi.org/10.1038/s41440-021-00617-1DOI Listing
February 2021

MicroRNA-21 regulates right ventricular remodeling secondary to pulmonary arterial pressure overload.

J Mol Cell Cardiol 2021 05 4;154:106-114. Epub 2021 Feb 4.

Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America; Stanford Cardiovascular Institute, Department of Medicine, Stanford University School of Medicine, CA, United States of America. Electronic address:

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.
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http://dx.doi.org/10.1016/j.yjmcc.2021.01.003DOI Listing
May 2021

UBXN7 cofactor of CRL3 and CRL2 ubiquitin ligase complexes mediates reciprocal regulation of NRF2 and HIF-1α proteins.

Biochim Biophys Acta Mol Cell Res 2021 Apr 12;1868(4):118963. Epub 2021 Jan 12.

Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 12722 Research Parkway Orlando, FL 32826, United States of America. Electronic address:

UBXN7 is a cofactor protein that provides a scaffold for both CRL3 and CRL2 ubiquitin ligase complexes involved in the regulation of the NRF2 and HIF-1α protein levels respectively. NRF2 and HIF-1α are surveillance transcription factors that orchestrate the cellular response to oxidative stress (NRF2) or to hypoxia (HIF-1α). Since mitochondria are the main oxygen sensors as well as the principal producers of ROS, it can be presumed that they may be able to modulate the activity of CRL3 and CRL2 complexes in response to stress. We have uncovered a new mechanism of such regulation that involves the UBXN7 cofactor protein and its regulation by mitochondrial MUL1 E3 ubiquitin ligase. High level of UBXN7 leads to HIF-1α accumulation, whereas low level of UBXN7 correlates with an increase in NRF2 protein. The reciprocal regulation of HIF-1α and NRF2 by UBXN7 is coordinated under conditions of oxidative stress or hypoxia. In addition, this molecular mechanism leads to different metabolic states; high level of UBXN7 and accumulation of HIF-1α support glycolysis, whereas inactivation of UBXN7 and activation of NRF2 confer increased OXPHOS. We describe a new mechanism by which MUL1 E3 ubiquitin ligase modulates the UBXN7 cofactor protein level and provides a reciprocal regulation of CRL3 and CRL2 ubiquitin ligase complexes. Furthermore, we delineate how this regulation is reflected in NRF2 and HIF-1α accumulation and determines the metabolic state as well as the adaptive response to mitochondrial stress.
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http://dx.doi.org/10.1016/j.bbamcr.2021.118963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882025PMC
April 2021

Thomas L. Force, MD: 1951-2020: A Brilliant Physician-Scientist Gone Too Soon.

Circ Res 2021 Jan 7;128(1):6-7. Epub 2021 Jan 7.

Cardiovascular Research Center (S.R.H.), Lewis Katz School of Medicine, Temple University, Philadelphia, PA.

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http://dx.doi.org/10.1161/CIRCRESAHA.120.318673DOI Listing
January 2021

Serum high-density lipoprotein cholesterol serves as a prognostic marker for light-chain cardiac amyloidosis.

Int J Cardiol 2021 Feb 17;325:96-102. Epub 2020 Oct 17.

Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China; Center of Rare Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, PR China. Electronic address:

Background: Oxidative stress and inflammation are central in the pathophysiology of light-chain amyloid cardiomyopathy (AL-CM). High-density lipoprotein cholesterol (HDLC) is an antioxidant and acts as an anti-inflammatory regulator. In this study, the prognostic value of serum HDL-C was explored in AL-CM.

Method: In this prospective single-center study, two hundred consecutive patients with biopsy-confirmed light-chain amyloidosis (AL) and cardiac involvement were enrolled. Patients were classified into low or normal serum HDL-C groups (HDL-C < 40 mg/dL and HDL-C ≥ 40 mg/dL, respectively). Univariate and multivariate Cox models were used to identify predictors of survival. Kaplan-Meier analysis was performed to compare survival between patients with low or normal serum HDL-C.

Results: Patients with low serum HDL-C were more likely to present with higher levels of cardiac troponin-T (123.4 ng/L vs. 79.1 ng/L, p = 0.026) and higher levels of N-terminal pro-B-type natriuretic peptide (9146 pg/mL vs. 4945 pg/mL, p = 0.011). Patients were followed for a median follow-up period of 19 months, in which 118 (59%) patients died. The median overall survival times for patients with low or normal serum HDL-C were 7 and 16 months, respectively (p = 0.002). Multivariate analysis demonstrated that serum HDL-C (HR 0.984, 95% CI 0.973-0.994, p = 0.003) was independently associated with prognosis, after adjusting for nephrotic syndrome, hepatic involvement, nutritional state, renal function, SBP, DBP, serum uric acid, total cholesterol, Mayo AL 2004 stage, and treatment with chemotherapy.

Conclusions: HDL-C is a novel serum biomarker for disease severity and prognosis in light-chain cardiac amyloidosis.
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http://dx.doi.org/10.1016/j.ijcard.2020.10.034DOI Listing
February 2021

Modeling Secondary Iron Overload Cardiomyopathy with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Cell Rep 2020 07;32(2):107886

Stanford Cardiovascular Institute, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA 94305, USA; Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305 USA. Electronic address:

Excessive iron accumulation in the heart causes iron overload cardiomyopathy (IOC), which initially presents as diastolic dysfunction and arrhythmia but progresses to systolic dysfunction and end-stage heart failure when left untreated. However, the mechanisms of iron-related cardiac injury and how iron accumulates in human cardiomyocytes are not well understood. Herein, using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we model IOC and screen for drugs to rescue the iron overload phenotypes. Human iPSC-CMs under excess iron exposure recapitulate early-stage IOC, including oxidative stress, arrhythmia, and contractile dysfunction. We find that iron-induced changes in calcium kinetics play a critical role in dysregulation of CM functions. We identify that ebselen, a selective divalent metal transporter 1 (DMT1) inhibitor and antioxidant, could prevent the observed iron overload phenotypes, supporting the role of DMT1 in iron uptake into the human myocardium. These results suggest that ebselen may be a potential preventive and therapeutic agent for treating patients with secondary iron overload.
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http://dx.doi.org/10.1016/j.celrep.2020.107886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553857PMC
July 2020

Improved Quantification of Cardiac Amyloid Burden in Systemic Light Chain Amyloidosis: Redefining Early Disease?

JACC Cardiovasc Imaging 2020 06 13;13(6):1325-1336. Epub 2020 May 13.

Department of Medicine, Division of Cardiology, Cardiac Amyloidosis Program, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Radiology, Division of Nuclear Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Medicine and Radiology, CV Imaging Program, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address:

Objectives: The purpose of this study was to determine phenotypes characterizing cardiac involvement in AL amyloidosis by using direct (fluorine-18-labeled florbetapir {[F]florbetapir} positron emission tomography [PET]/computed tomography) and indirect (echocardiography and cardiac magnetic resonance [CMR]) imaging biomarkers of AL amyloidosis.

Background: Cardiac involvement in systemic light chain amyloidosis (AL) is the main determinant of prognosis and, therefore, guides management. The hypothesis of this study was that myocardial AL deposits and expansion of extracellular volume (ECV) could be identified before increases in N-terminal pro-B-type natriuretic peptide or wall thickness.

Methods: A total of 45 subjects were prospectively enrolled in 3 groups: 25 with active AL amyloidosis with cardiac involvement (active-CA), 10 with active AL amyloidosis without cardiac involvement by conventional criteria (active-non-CA), and 10 with AL amyloidosis with cardiac involvement in remission for at least 1 year (remission-CA). All subjects underwent echocardiography, CMR, and [F]florbetapir PET/CT to evaluate cardiac amyloid burden.

Results: The active-CA group demonstrated the largest myocardial AL amyloid burden, quantified by [F]florbetapir retention index (RI) 0.110 (interquartile range [IQR]: 0.078 to 0.139) min, and the lowest cardiac function by global longitudinal strain (GLS), median GLS -11% (IQR: -8% to -13%). The remission-CA group had expanded extracellular volume (ECV) and [F]florbetapir RI of 0.097 (IQR: 0.070 to 0.124 min), and abnormal GLS despite hematologic remission for >1 year. The active-non-CA cohort had evidence of cardiac amyloid deposition by advanced imaging metrics in 50% of the subjects; cardiac involvement was identified by late gadolinium enhancement in 20%, elevated ECV in 20%, and elevated [F]florbetapir RI in 50%.

Conclusions: Evidence of cardiac amyloid infiltration was found based on direct and indirect imaging biomarkers in subjects without CA by conventional criteria. The findings from [F]florbetapir PET imaging provided insight into the preclinical disease process and on the basis of interpretation of expanded ECV on CMR and have important implications for future research and clinical management of AL amyloidosis. (Molecular Imaging of Primary Amyloid Cardiomyopathy [MICA]; NCT02641145).
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http://dx.doi.org/10.1016/j.jcmg.2020.02.025DOI Listing
June 2020

Outcomes in Patients With Cardiac Amyloidosis Undergoing Heart Transplantation.

JACC Heart Fail 2020 06 6;8(6):461-468. Epub 2020 May 6.

Stanford Amyloid Center, Stanford University School of Medicine, Stanford, California. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jchf.2019.12.013DOI Listing
June 2020

Localized Antileptin Therapy Prevents Aortic Root Dilatation and Preserves Left Ventricular Systolic Function in a Murine Model of Marfan Syndrome.

J Am Heart Assoc 2020 05 7;9(10):e014761. Epub 2020 May 7.

Department of Vascular Surgery Sheba Medical Center Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel.

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 mice underwent periaortic application of low-dose leptin antagonist at the aortic root. Treatment abolished medial degeneration and prevented increase in aortic root diameter (<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 (<0.01, <0.05, <0.001, and <0.001, respectively). Leptin and angiotensin-converting enzyme 1 expression levels in left ventricular cardiomyocytes were also decreased (<0.001) and coincided with prevention of left ventricular hypertrophy and aortic and mitral valve leaflet thickening (<0.01 and <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.
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http://dx.doi.org/10.1161/JAHA.119.014761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660857PMC
May 2020

High-Frequency Ultrasound Echocardiography to Assess Zebrafish Cardiac Function.

J Vis Exp 2020 03 12(157). Epub 2020 Mar 12.

Stanford Cardiovascular Institute, Stanford University;

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.
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http://dx.doi.org/10.3791/60976DOI Listing
March 2020

Mitochondrial MUL1 E3 ubiquitin ligase regulates Hypoxia Inducible Factor (HIF-1α) and metabolic reprogramming by modulating the UBXN7 cofactor protein.

Sci Rep 2020 01 31;10(1):1609. Epub 2020 Jan 31.

Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, 12722, Research Parkway Orlando, FL, 32826, USA.

MUL1 is a multifunctional E3 ubiquitin ligase anchored in the outer mitochondrial membrane with its RING finger domain facing the cytoplasm. MUL1 participates in various biological pathways involved in apoptosis, mitochondrial dynamics, and innate immune response. The unique topology of MUL1 enables it to "sense" mitochondrial stress in the intermembrane mitochondrial space and convey these signals through the ubiquitination of specific cytoplasmic substrates. We have identified UBXN7, the cofactor protein of the CRL2 ligase complex, as a specific substrate of MUL1 ligase. CRL2 ligase complex regulates HIF-1α protein levels under aerobic (normoxia) or anaerobic (hypoxia) conditions. Inactivation of MUL1 ligase leads to accumulation of UBXN7, with concomitant increase in HIF-1α protein levels, reduction in oxidative phosphorylation, and increased glycolysis. We describe a novel pathway that originates in the mitochondria and operates upstream of the CRL2 ligase complex. Furthermore, we delineate the mechanism by which the mitochondria, through MUL1 ligase, can inhibit the CRL2 complex leading to high HIF-1α protein levels and a metabolic shift to glycolysis under normoxic conditions.
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http://dx.doi.org/10.1038/s41598-020-58484-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994496PMC
January 2020

Natural Compound Library Screening Identifies New Molecules for the Treatment of Cardiac Fibrosis and Diastolic Dysfunction.

Circulation 2020 03 17;141(9):751-767. Epub 2020 Jan 17.

Institute for Pathology, Nephropathology Unit (J.H.B., J.S.), Hannover Medical School, Germany.

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 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.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.042559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050799PMC
March 2020

Harnessing Cardiac Regeneration as a Potential Therapeutic Strategy for AL Cardiac Amyloidosis.

Curr Cardiol Rep 2020 01 13;22(1). Epub 2020 Jan 13.

Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.

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.
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http://dx.doi.org/10.1007/s11886-020-1252-3DOI Listing
January 2020

Quantitative [F]florbetapir PET/CT may identify lung involvement in patients with systemic AL amyloidosis.

Eur J Nucl Med Mol Imaging 2020 07 5;47(8):1998-2009. Epub 2019 Dec 5.

Division of Nuclear Medicine, Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA.

Purpose: The clinical diagnosis of pulmonary involvement in individuals with systemic AL amyloidosis remains challenging. [F]florbetapir imaging has previously identified AL amyloid deposits in the heart and extra-cardiac organs. The aim of this study is to determine quantitative [F]florbetapir pulmonary kinetics to identify pulmonary involvement in individuals with systemic AL amyloidosis.

Methods: We prospectively enrolled 58 subjects with biopsy-proven AL amyloidosis and 9 control subjects (5 without amyloidosis and 4 with ATTR cardiac amyloidosis). Pulmonary [F]florbetapir uptake was evaluated visually and quantified as distribution volume of specific binding (Vs) derived from compartmental analysis and simpler semiquantitative metrics of maximum standardized uptake values (SUVmax), retention index (RI), and target-to-blood ratio (TBR).

Results: On visual analysis, pulmonary tracer uptake was absent in most AL subjects (40/58, 69%); 12% (7/58) of AL subjects demonstrated intense bilateral homogeneous tracer uptake. In this group, compared to the control group, Vs (median Vs 30-fold higher, 9.79 vs. 0.26, p < 0.001), TBR (median TBR 12.0 vs. 1.71, p < 0.001), and RI (median RI 0.310 vs. 0.033, p < 0.001) were substantially higher. Notably, the AL group without visually apparent pulmonary [F]florbetapir uptake also demonstrated a > 3-fold higher Vs compared to the control group (median 0.99 vs. 0.26, p < 0.001). Vs was independently related to left ventricular SUVmax, a marker of cardiac AL deposition, but not to ejection fraction, a marker of cardiac dysfunction. Also, intense [F]florbetapir lung uptake was not related to [C]acetate lung uptake, suggesting that intense [F]florbetapir lung uptake represents AL amyloidosis rather than heart failure.

Conclusions: [F]florbetapir PET/CT offers the potential to noninvasively identify pulmonary AL amyloidosis, and its clinical relevance warrants further study.
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http://dx.doi.org/10.1007/s00259-019-04627-7DOI Listing
July 2020

A single combination gene therapy treats multiple age-related diseases.

Proc Natl Acad Sci U S A 2019 11 4;116(47):23505-23511. Epub 2019 Nov 4.

Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115;

Comorbidity is common as age increases, and currently prescribed treatments often ignore the interconnectedness of the involved age-related diseases. The presence of any one such disease usually increases the risk of having others, and new approaches will be more effective at increasing an individual's health span by taking this systems-level view into account. In this study, we developed gene therapies based on 3 longevity associated genes (fibroblast growth factor 21 [FGF21], αKlotho, soluble form of mouse transforming growth factor-β receptor 2 [sTGFβR2]) delivered using adeno-associated viruses and explored their ability to mitigate 4 age-related diseases: obesity, type II diabetes, heart failure, and renal failure. Individually and combinatorially, we applied these therapies to disease-specific mouse models and found that this set of diverse pathologies could be effectively treated and in some cases, even reversed with a single dose. We observed a 58% increase in heart function in ascending aortic constriction ensuing heart failure, a 38% reduction in α-smooth muscle actin (αSMA) expression, and a 75% reduction in renal medullary atrophy in mice subjected to unilateral ureteral obstruction and a complete reversal of obesity and diabetes phenotypes in mice fed a constant high-fat diet. Crucially, we discovered that a single formulation combining 2 separate therapies into 1 was able to treat all 4 diseases. These results emphasize the promise of gene therapy for treating diverse age-related ailments and demonstrate the potential of combination gene therapy that may improve health span and longevity by addressing multiple diseases at once.
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http://dx.doi.org/10.1073/pnas.1910073116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876218PMC
November 2019

Alteration in ventricular pressure stimulates cardiac repair and remodeling.

J Mol Cell Cardiol 2019 08 17;133:174-187. Epub 2019 Jun 17.

Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America; Cardiovascular Research Institute, Stanford University School of Medicine, Stanford, CA, United States of America. Electronic address:

The mammalian heart undergoes complex structural and functional remodeling to compensate for stresses such as pressure overload. While studies suggest that, at best, the adult mammalian heart is capable of very limited regeneration arising from the proliferation of existing cardiomyocytes, how myocardial stress affects endogenous cardiac regeneration or repair is unknown. To define the relationship between left ventricular afterload and cardiac repair, we induced left ventricle pressure overload in adult mice by constriction of the ascending aorta (AAC). One week following AAC, we normalized ventricular afterload in a subset of animals through removal of the aortic constriction (de-AAC). Subsequent monitoring of cardiomyocyte cell cycle activity via thymidine analog labeling revealed that an acute increase in ventricular afterload induced cardiomyocyte proliferation. Intriguingly, a release in ventricular overload (de-AAC) further increases cardiomyocyte proliferation. Following both AAC and de-AAC, thymidine analog-positive cardiomyocytes exhibited characteristics of newly generated cardiomyocytes, including single diploid nuclei and reduced cell size as compared to age-matched, sham-operated adult mouse myocytes. Notably, those smaller cardiomyocytes frequently resided alongside one another, consistent with local stimulation of cellular proliferation. Collectively, our data demonstrate that adult cardiomyocyte proliferation can be locally stimulated by an acute increase or decrease of ventricular pressure, and this mode of stimulation can be harnessed to promote cardiac repair.
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http://dx.doi.org/10.1016/j.yjmcc.2019.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698254PMC
August 2019

Zebrafish model of amyloid light chain cardiotoxicity: regeneration versus degeneration.

Am J Physiol Heart Circ Physiol 2019 05 15;316(5):H1158-H1166. Epub 2019 Mar 15.

Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts.

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. 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.
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http://dx.doi.org/10.1152/ajpheart.00788.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580397PMC
May 2019

Convergences of Life Sciences and Engineering in Understanding and Treating Heart Failure.

Circ Res 2019 01;124(1):161-169

Stanford Cardiovascular Institute, Department of Medicine, Stanford University School of Medicine, CA (R.L., J.C.W.).

On March 1 and 2, 2018, the National Institutes of Health 2018 Progenitor Cell Translational Consortium, Cardiovascular Bioengineering Symposium, was held at the University of Alabama at Birmingham. Convergence of life sciences and engineering to advance the understanding and treatment of heart failure was the theme of the meeting. Over 150 attendees were present, and >40 scientists presented their latest work on engineering human functional myocardium for disease modeling, drug development, and heart failure research. The scientists, engineers, and physicians in the field of cardiovascular sciences met and discussed the most recent advances in their work and proposed future strategies for overcoming the major roadblocks of cardiovascular bioengineering and therapy. Particular emphasis was given for manipulation and using of stem/progenitor cells, biomaterials, and methods to provide molecular, chemical, and mechanical cues to cells to influence their identity and fate in vitro and in vivo. Collectively, these works are profoundly impacting and progressing toward deciphering the mechanisms and developing novel treatments for left ventricular dysfunction of failing hearts. Here, we present some important perspectives that emerged from this meeting.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.314216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350935PMC
January 2019

Mortality From Heart Failure and Dementia in the United States: CDC WONDER 1999-2016.

J Card Fail 2019 Feb 22;25(2):125-129. Epub 2018 Nov 22.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts; Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts; Cardiac Amyloidosis Program, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address:

Background: Heart failure and dementia are diseases of the elderly that result in billions of dollars in annual health care expenditure. With the aging of the United States population and increasing evidence of shared risk factors, there is a need to understand the conditions' shared contributions to nationwide mortality. The objectives of this study were to estimate the burden of mortality from heart failure and dementia and characterize the demographics of affected individuals.

Methods And Results: This retrospective study used National Vital Statistics Data from 1999 to 2016 provided by the Centers for Disease Control and International Classification of Diseases (10th edition) codes for heart failure and dementia as defined by the Medicare Chronic Conditions Data Warehouse. From 1999 to 2016, deaths contributed to by both heart failure and dementia totaled 214,706 and constituted 4.00% of all heart failure deaths and 9.04% of all dementia deaths. Women were more affected than men, with higher age-adjusted mortality rates (per 1,000,000 person-years): 38.67 (95% confidence interval [CI] 38.47-38.87) versus 32.90 (95% CI 32.65-33.15; P < .001). Whites were affected more than blacks, with age-adjusted mortality rates (per 1,000,000 person-years) of 38.00 (95% CI 37.83-38.16) versus 31.06 (95% CI 30.54-31.59; P < .001). However, under the age of 65 years, higher crude mortality rates (per 1,000,000 person-years) were reported in men (0.20, 95% CI 0.18-0.22) compared with women (0.15, 95% CI 0.13-0.16; P < .001).

Conclusions: This study provides insight into temporal trends and nationwide mortality rates reported for heart failure and dementia. Our results suggest a disproportionate burden on populations over 85 years of age, whites, and women.
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http://dx.doi.org/10.1016/j.cardfail.2018.11.012DOI Listing
February 2019

Geographic Disparities in Reported US Amyloidosis Mortality From 1979 to 2015: Potential Underdetection of Cardiac Amyloidosis.

JAMA Cardiol 2018 09;3(9):865-870

Cardiac Amyloidosis Program, Division of Cardiology, Department of Medicine, Heart & Vascular Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: Cardiac amyloidosis is an underdiagnosed disease and is highly fatal when untreated. Early diagnosis and treatment with the emerging novel therapies significantly improve survival. A comprehensive analysis of amyloidosis-related mortality is critical to appreciate the nature and distribution of underdiagnosis and improve disease detection.

Objective: To evaluate the temporal and regional trends in age-adjusted amyloidosis-related mortality among men and women of various races/ethnicities in the United States.

Design, Setting, And Participants: In this observational cohort study, death certificate information from the Centers for Disease Control and Prevention's Wide-ranging ONline Data for Epidemiologic Research database and the National Vital Statistics System from 1979 to 2015 was analyzed. A total of 30 764 individuals in the United States with amyloidosis listed as the underlying cause of death and 26 591 individuals with amyloidosis listed as a contributing cause of death were analyzed.

Exposures: Region of residence.

Main Outcomes And Measures: Age-adjusted mortality rate from amyloidosis per 1 000 000 population stratified by year, sex, race/ethnicity, and state and county of residence.

Results: Of the 30 764 individuals with amyloidosis listed as the underlying cause of death, 17 421 (56.6%) were men and 27 312 (88.8%) were 55 years or older. From 1979 to 2015, the reported overall mean age-adjusted mortality rate from amyloidosis as the underlying cause of death doubled from 1.77 to 3.96 per 1 000 000 population (2.32 to 5.43 in men and 1.35 to 2.80 in women). Black men had the highest mortality rate (12.36 per 1 000 000), followed by black women (6.48 per 1 000 000). Amyloidosis contributed to age-adjusted mortality rates as high as 31.73 per 1 000 000 in certain counties. Most southern states reported the lowest US mortality rates despite having the highest proportions of black individuals.

Conclusions And Relevance: The increased reported mortality over time and in proximity to amyloidosis centers more likely reflects an overall increase in disease diagnosis rather than increased lethality. The reported amyloidosis mortality is highly variable in different US regions. The lack of higher reported mortality rates in states with a greater proportion of black residents suggests underdiagnosis of amyloidosis, including cardiac forms of the disease, in many areas of the United States. Better understanding of the determinants of geographic and racial disparity in the reporting of amyloidosis deaths are warranted.
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http://dx.doi.org/10.1001/jamacardio.2018.2093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233639PMC
September 2018

Guidelines for experimental models of myocardial ischemia and infarction.

Am J Physiol Heart Circ Physiol 2018 04 12;314(4):H812-H838. Epub 2018 Jan 12.

Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School , Essen , Germany.

Myocardial infarction is a prevalent major cardiovascular event that arises from myocardial ischemia with or without reperfusion, and basic and translational research is needed to better understand its underlying mechanisms and consequences for cardiac structure and function. Ischemia underlies a broad range of clinical scenarios ranging from angina to hibernation to permanent occlusion, and while reperfusion is mandatory for salvage from ischemic injury, reperfusion also inflicts injury on its own. In this consensus statement, we present recommendations for animal models of myocardial ischemia and infarction. With increasing awareness of the need for rigor and reproducibility in designing and performing scientific research to ensure validation of results, the goal of this review is to provide best practice information regarding myocardial ischemia-reperfusion and infarction models. Listen to this article's corresponding podcast at ajpheart.podbean.com/e/guidelines-for-experimental-models-of-myocardial-ischemia-and-infarction/.
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http://dx.doi.org/10.1152/ajpheart.00335.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966768PMC
April 2018

Cardiac macrophages promote diastolic dysfunction.

J Exp Med 2018 02 16;215(2):423-440. Epub 2018 Jan 16.

Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA

Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen. In humans, we observed a parallel constellation of hematopoietic activation: circulating myeloid cells are more frequent, and splenic F-FDG PET/CT imaging signal correlates with echocardiographic indices of diastolic dysfunction. While diastolic dysfunction develops, cardiac macrophages produce IL-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. Deletion of IL-10 in macrophages improves diastolic function. These data imply expansion and phenotypic changes of cardiac macrophages as therapeutic targets for cardiac fibrosis leading to diastolic dysfunction.
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http://dx.doi.org/10.1084/jem.20171274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789416PMC
February 2018

Oxygen-Generating Photo-Cross-Linkable Hydrogels Support Cardiac Progenitor Cell Survival by Reducing Hypoxia-Induced Necrosis.

ACS Biomater Sci Eng 2017 Sep 20;3(9):1964-1971. Epub 2016 Jun 20.

Biomaterials Innovation Research Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, Massachusetts 02139, United States.

Oxygen is essential to cell survival and tissue function. Not surprisingly, ischemia resulting from myocardial infarction induces cell death and tissue necrosis. Attempts to regenerate myocardial tissue with cell based therapies exacerbate the hypoxic stress by further increasing the metabolic burden. In consequence, implanted tissue engineered cardiac tissues suffer from hypoxia-induced cell death. Here, we report on the generation of oxygen-generating hydrogels composed of calcium peroxide (CPO) laden gelatin methacryloyl (GelMA). CPO-GelMA hydrogels released significant amounts of oxygen for over a period of 5 days under hypoxic conditions (1% O). The released oxygen proved sufficient to relieve the metabolic stress of cardiac side population cells that were encapsulated within CPO-GelMA hydrogels. In particular, incorporation of CPO in GelMA hydrogels strongly enhanced cell viability as compared to GelMA-only hydrogels. Importantly, CPO-based oxygen generation reduced cell death by limiting hypoxia-induced necrosis. The current study demonstrates that CPO based oxygen-generating hydrogels could be used to transiently provide oxygen to cardiac cells under ischemic conditions. Therefore, oxygen generating materials such as CPO-GelMA can improve cell-based therapies aimed at treatment or regeneration of infarcted myocardial tissue.
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http://dx.doi.org/10.1021/acsbiomaterials.6b00109DOI Listing
September 2017

Amyloid Cardiomyopathy: Disease on the Rise.

Circ Res 2017 06;120(12):1865-1867

From the Divisions of Genetics and Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1161/CIRCRESAHA.117.310643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584551PMC
June 2017

From the BCVS Chair.

Authors:
Ronglih Liao

Circ Res 2017 05;120(11):1707-1708

From the Divisions of Genetics and Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

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http://dx.doi.org/10.1161/CIRCRESAHA.117.310524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774628PMC
May 2017

Simultaneous electrical recording of cardiac electrophysiology and contraction on chip.

Lab Chip 2017 05;17(10):1732-1739

Engineering Directorate, Lawrence Livermore National Laboratory, Livermore, California 94550, USA.

Prevailing commercialized cardiac platforms for in vitro drug development utilize planar microelectrode arrays to map action potentials, or impedance sensing to record contraction in real time, but cannot record both functions on the same chip with high spatial resolution. Here we report a novel cardiac platform that can record cardiac tissue adhesion, electrophysiology, and contractility on the same chip. The platform integrates two independent yet interpenetrating sensor arrays: a microelectrode array for field potential readouts and an interdigitated electrode array for impedance readouts. Together, these arrays provide real-time, non-invasive data acquisition of both cardiac electrophysiology and contractility under physiological conditions and under drug stimuli. Human induced pluripotent stem cell-derived cardiomyocytes were cultured as a model system, and used to validate the platform with an excitation-contraction decoupling chemical. Preliminary data using the platform to investigate the effect of the drug norepinephrine are combined with computational efforts. This platform provides a quantitative and predictive assay system that can potentially be used for comprehensive assessment of cardiac toxicity earlier in the drug discovery process.
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http://dx.doi.org/10.1039/c7lc00210fDOI Listing
May 2017

Theranostic Nucleic Acid Binding Nanoprobe Exerts Anti-inflammatory and Cytoprotective Effects in Ischemic Injury.

Theranostics 2017 8;7(4):814-825. Epub 2017 Feb 8.

Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston MA;; Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston MA.

Extracellular nucleic acids are proinflammatory molecules that have been implicated in a diverse range of diseases. We report here the development of a multivalent nucleic acid scavenging nanoprobe, where the fluorochrome thiazole orange (TO) is conjugated to a polymeric 40 kDa dextran carrier. Dextran-TO (Dex-TO) has nanomolar affinity for mammalian and bacterial nucleic acids and attenuates the production of inflammatory cytokines from activated macrophages exposed to DNA and RNA. Mice with myocardial ischemia reperfusion that were treated with Dex-TO showed a decrease in myocardial macrophage infiltration at 24 hours (p<0.05) and a decrease in infarct size (18% ± 9%, p<0.01) on day 7. Dex-TO allows sites of injury to be identified with fluorescence imaging, while simultaneously exerting an anti-inflammatory and cytoprotective effect. Dex-TO could be of significant diagnostic and therapeutic (theranostic) utility in a broad range of conditions including ischemia, trauma, burns, sepsis and autoimmune disease.
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http://dx.doi.org/10.7150/thno.17366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381246PMC
October 2017

Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics.

Cancer Cell 2017 01 22;31(1):142-156. Epub 2016 Dec 22.

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Mayer 430, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA. Electronic address:

It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 profiling, we find that mitochondria of many adult somatic tissues, including brain, heart, and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities.
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http://dx.doi.org/10.1016/j.ccell.2016.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363285PMC
January 2017

AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy.

J Am Coll Cardiol 2016 09;68(12):1323-41

Brigham and Women's Hospital Cardiac Amyloidosis Program, Harvard Medical School and Department of Medicine, Section of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts; Department of Radiology, Division of Nuclear Medicine and Molecular Imaging, Harvard Medical School, Boston, Massachusetts.

The amyloidoses are a group of protein-folding disorders in which ≥1 organ is infiltrated by proteinaceous deposits known as amyloid. The deposits are derived from 1 of several amyloidogenic precursor proteins, and the prognosis of the disease is determined both by the organ(s) involved and the type of amyloid. Amyloid involvement of the heart (cardiac amyloidosis) carries the worst prognosis of any involved organ, and light-chain (AL) amyloidosis is the most serious form of the disease. The last decade has seen considerable progress in understanding the amyloidoses. In this review, current and novel approaches to the diagnosis and treatment of cardiac amyloidosis are discussed, with particular reference to AL amyloidosis in the heart.
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http://dx.doi.org/10.1016/j.jacc.2016.06.053DOI Listing
September 2016