Daniel Bernstein

Stanford University, Palo Alto, California, United States

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Publications (182)1096.3 Total impact

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    ABSTRACT: The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regeneration, either basally or upon transgenic overexpression. Application of the human Fstl1 protein (FSTL1) via an epicardial patch stimulates cell cycle entry and division of pre-existing cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. The data suggest that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodelling following myocardial infarction in humans.
    Nature 09/2015; advance online publication. DOI:10.1038/nature15372 · 41.46 Impact Factor
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  • Sushma Reddy · Daniel Bernstein
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    ABSTRACT: The right ventricle (RV) is uniquely at risk in many patients with repaired or palliated congenital heart disease (CHD) such as tetralogy of Fallot, corrected transposition, single right ventricle, and in those with pulmonary hypertension. These patients live with abnormal cardiac loading conditions throughout their life, predisposing them to right heart failure. Standard heart failure therapies, developed to treat left ventricular failure, have failed to improve function or survival in patients with RV failure, suggesting a divergence in the molecular mechanisms of right versus left ventricular failure. As surgical techniques for repair of the most complex forms of RV-affecting CHDs continue to improve, more children with CHD will survive into adulthood. Long-term survival and quality of life will ultimately depend on our ability to preserve RV function. The purpose of this review is to highlight the differences between the right and left ventricular responses to stress, our current knowledge of how the RV adapts to the unique hemodynamic stressors experienced by patients with CHD, and the need to better understand the molecular mechanisms of RV failure, providing new targets for the development of RV-specific heart failure therapeutics.
    Current opinion in pediatrics 08/2015; 27(5). DOI:10.1097/MOP.0000000000000268 · 2.53 Impact Factor
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    ABSTRACT: Single-center data on pediatric heart transplantation spanning long time frames is sparse. We attempted to analyze how risk profile and pediatric heart transplant survival outcomes at a large center changed over time. We divided 320 pediatric heart transplants done at Stanford University between 1974 and 2014 into three groups by era: the first 20 years (95 transplants), the subsequent 10 years (87 transplants), and the most recent 10 years (138 transplants). Differences in age at transplant, indication, mechanical support, and survival were analyzed. Follow-up was 100% complete. Average age at time of transplantation was 10.4 years, 11.9 years, and 5.6 years in eras 1, 2, and 3, respectively. The percentage of infants who received transplants by era was 21%, 7%, and 18%, respectively. The indication of end-stage congenital heart disease vs cardiomyopathy was 24%, 22%, and 49%, respectively. Only 1 patient (1%) was on mechanical support at transplant in era 1 compared with 15% in era 2 and 30% in era 3. Overall survival was 72% at 5 years and 57% at 10 years. Long-term survival increased significantly with each subsequent era. Patients with cardiomyopathy generally had a survival advantage over those with congenital heart disease. The risk profile of pediatric transplant patients in our institution has increased over time. In the last 10 years, median age has decreased and ventricular assist device support has increased dramatically. Transplantation for end-stage congenital heart disease is increasingly common. Despite this, long-term survival has significantly and consistently improved. Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.
    The Annals of thoracic surgery 07/2015; 100(3). DOI:10.1016/j.athoracsur.2015.05.111 · 3.85 Impact Factor
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    ABSTRACT: Biomaterials are extensively used to restore damaged tissues, in the forms of implants (e.g., tissue engineered scaffolds) or biomedical devices (e.g., pacemakers). Once in contact with the physiological environment, nanostructured biomaterials undergo modifications as a result of endogenous proteins binding to their surface. The formation of this macromolecular coating complex, known as “protein corona,” onto the surface of nanoparticles and its effect on cell–particle interactions are currently under intense investigation. In striking contrast, protein corona constructs within nanostructured porous tissue engineering scaffolds remain poorly characterized. As organismal systems are highly dynamic, it is conceivable that the formation of distinct protein corona on implanted scaffolds might itself modulate cell–extracellular matrix interactions. Here, it is reported that corona complexes formed onto the fibrils of engineered collagen scaffolds display specific, distinct, and reproducible compositions that are a signature of the tissue microenvironment as well as being indicative of the subject's health condition. Protein corona formed on collagen matrices modulated cellular secretome in a context-specific manner ex vivo, demonstrating their role in regulating scaffold–cellular interactions. Together, these findings underscore the importance of custom-designing personalized nanostructured biomaterials, according to the biological milieu and disease state. The use of protein corona as in situ biosensor of temporal and local biomarkers is proposed.
    Advanced Functional Materials 06/2015; DOI:10.1002/adfm.201500875 · 11.81 Impact Factor
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    ABSTRACT: Pulmonary arterial hypertension is characterized by endothelial dysregulation, but global changes in gene expression have not been related to perturbations in function. RNA sequencing was utilized to discriminate changes in transcriptomes of endothelial cells cultured from lungs of patients with idiopathic pulmonary arterial hypertension vs. controls and to assess the functional significance of major differentially expressed transcripts. The endothelial transcriptomes from seven control and six idiopathic pulmonary arterial hypertension patients' lungs were analyzed. Differentially expressed genes were related to BMPR2 signaling. Those downregulated were assessed for function in cultured cells, and in a transgenic mouse. Fold-differences in ten genes were significant (p<0.05), four increased and six decreased in patients vs. No patient was mutant for BMPR2. However, knockdown of BMPR2 by siRNA in control pulmonary arterial endothelial cells recapitulated six/ten patient-related gene changes, including decreased collagen IV (COL4A1, COL4A2) and ephrinA1 (EFNA1). Reduction of BMPR2 regulated transcripts was related to decreased β-catenin. Reducing COL4A1, COL4A2 and EFNA1 by siRNA inhibited pulmonary endothelial adhesion, migration and tube formation. In mice null for the EFNA1 receptor, EphA2, vs. controls, VEGF receptor blockade and hypoxia caused more severe pulmonary hypertension, judged by elevated right ventricular systolic pressure, right ventricular hypertrophy and loss of small arteries. The novel relationship between BMPR2 dysfunction and reduced expression of endothelial COL4 and EFNA1 may underlie vulnerability to injury in pulmonary arterial hypertension.
    American Journal of Respiratory and Critical Care Medicine 06/2015; 192(3). DOI:10.1164/rccm.201408-1528OC · 13.00 Impact Factor
  • The Journal of Heart and Lung Transplantation 04/2015; 34(4):S161. DOI:10.1016/j.healun.2015.01.437 · 6.65 Impact Factor
  • The Journal of Heart and Lung Transplantation 04/2015; 34(4):S22. DOI:10.1016/j.healun.2015.01.047 · 6.65 Impact Factor
  • The Journal of Heart and Lung Transplantation 04/2015; 34(4):S169. DOI:10.1016/j.healun.2015.01.459 · 6.65 Impact Factor
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    Circulation 03/2015; DOI:10.1161/CIR.0000000000000190 · 14.43 Impact Factor
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    Circulation 03/2015; 132(6). DOI:10.1161/CIR.0000000000000199 · 14.43 Impact Factor
  • Journal of the American College of Cardiology 03/2015; 66(6). DOI:10.1016/j.jacc.2015.03.006 · 16.50 Impact Factor
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    ABSTRACT: Nanoparticle-mediated sustained delivery of therapeutics is one of the highly effective and increasingly utilized applications of nanomedicine. Here, we report the development and application of a drug delivery system consisting of polyethylene glycol (PEG)-conjugated liposomal nanoparticles as an efficient in vivo delivery approach for [Pyr1]-apelin-13 polypeptide. Apelin is an adipokine that regulates a variety of biological functions including cardiac hypertrophy and hypertrophy-induced heart failure. The clinical use of apelin has been greatly impaired by its remarkably short half-life in circulation. Here, we investigate whether [Pyr1]-apelin-13 encapsulation in liposome nanocarriers, conjugated with PEG polymer on their surface, can prolong apelin stability in the blood stream and potentiate apelin beneficial effects in cardiac function. Atomic force microscopy and dynamic light scattering were used to assess the structure and size distribution of drug-laden nanoparticles. [Pyr1]-apelin-13 encapsulation in PEGylated liposomal nanocarriers resulted in sustained and extended drug release both in vitro and in vivo. Moreover, intraperitoneal injection of [Pyr1]-apelin-13 nanocarriers in a mouse model of pressure-overload induced heart failure demonstrated a sustainable long-term effect of [Pyr1]-apelin-13 in preventing cardiac dysfunction. We concluded that this engineered nanocarrier system can serve as a delivery platform for treating heart injuries through sustained bioavailability of cardioprotective therapeutics.
    Biomaterials 01/2015; 37:289-298. DOI:10.1016/j.biomaterials.2014.08.045 · 8.56 Impact Factor
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    ABSTRACT: Many children who undergo heart transplantation will survive into adulthood. We sought to examine the QOL and capacity for achievement in long-term adult survivors of pediatric heart transplantation. Adults >18 yr of age who received transplants as children (≤18 yr old) and had survived for at least 10 yr post-transplant completed two self-report questionnaires: (i) Ferrans & Powers QLI, in which life satisfaction is reported as an overall score and in four subscale domains and is then indexed from 0 (very dissatisfied) to 1 (very satisfied); and (ii) a "Metrics of Life Achievement" questionnaire regarding income, education, relationships, housing status, and access to health care. A total of 20 subjects completed the survey. The overall mean QLI score was 0.77 ± 0.16. Subjects were most satisfied in the family domain (0.84 ± 0.21) and least satisfied in the psychological/spiritual domain (0.7 ± 0.28). Satisfaction in the domains of health/functioning and socioeconomic were intermediate at 0.78 and 0.76, respectively. Most respondents had graduated from high school, reported a median annual income >$50 000/yr, and lived independently. Adult survivors of pediatric heart transplant report a good QOL and demonstrate the ability to obtain an education, work, and live independently.
    Pediatric Transplantation 11/2014; 33(4). DOI:10.1111/petr.12384 · 1.44 Impact Factor
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    ABSTRACT: The proteasome inhibitor bortezomib has been used with variable success in the treatment of AMR following heart transplant. There is limited experience with this agent as a pretransplant desensitizing therapy. We report a case of successful HLA desensitization with a bortezomib-based protocol prior to successful heart transplantation. A nine-yr-old boy with dilated cardiomyopathy, not initially sensitized to HLA (cPRA of zero), required three days of ECMO, followed by implantation of a Heartmate II LVAD. Within six wk, the patient developed de novo class I IgG and C1q complement-fixing HLA antibodies with a cPRA of 100%. Two doses of IVIG (2 g/kg) failed to reduce antibody levels, although two courses of a novel desensitization protocol consisting of rituximab (375 mg/m(2) ), bortezomib (1.3 mg/m(2) × 5 doses), and plasmapheresis reduced his cPRA to 0% and 87% by the C1q and IgG assays, respectively. He underwent heart transplantation nearly two months later. The patient is now >one yr post-transplant, is free of both AMR and ACR, and has no detectable donor-specific antibodies by IgG or C1q. Proteasome inhibition with bortezomib and plasmapheresis may be an effective therapy for HLA desensitization pretransplant.
    Pediatric Transplantation 09/2014; 18(8). DOI:10.1111/petr.12347 · 1.44 Impact Factor
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    ABSTRACT: The role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodelling. An estimated 70% of mouse genes undergo antisense transcription, including myosin heavy chain 7 (Myh7), which encodes molecular motor proteins for heart contraction. Here we identify a cluster of lncRNA transcripts from Myh7 loci and demonstrate a new lncRNA-chromatin mechanism for heart failure. In mice, these transcripts, which we named myosin heavy-chain-associated RNA transcripts (Myheart, or Mhrt), are cardiac-specific and abundant in adult hearts. Pathological stress activates the Brg1-Hdac-Parp chromatin repressor complex to inhibit Mhrt transcription in the heart. Such stress-induced Mhrt repression is essential for cardiomyopathy to develop: restoring Mhrt to the pre-stress level protects the heart from hypertrophy and failure. Mhrt antagonizes the function of Brg1, a chromatin-remodelling factor that is activated by stress to trigger aberrant gene expression and cardiac myopathy. Mhrt prevents Brg1 from recognizing its genomic DNA targets, thus inhibiting chromatin targeting and gene regulation by Brg1. It does so by binding to the helicase domain of Brg1, a domain that is crucial for tethering Brg1 to chromatinized DNA targets. Brg1 helicase has dual nucleic-acid-binding specificities: it is capable of binding lncRNA (Mhrt) and chromatinized-but not naked-DNA. This dual-binding feature of helicase enables a competitive inhibition mechanism by which Mhrt sequesters Brg1 from its genomic DNA targets to prevent chromatin remodelling. A Mhrt-Brg1 feedback circuit is thus crucial for heart function. Human MHRT also originates from MYH7 loci and is repressed in various types of myopathic hearts, suggesting a conserved lncRNA mechanism in human cardiomyopathy. Our studies identify a cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatin-remodelling factors, and establish a new paradigm for lncRNA-chromatin interaction.
    Nature 08/2014; 514(7520). DOI:10.1038/nature13596 · 41.46 Impact Factor
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    Gwanghyun Jung · Daniel Bernstein
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    ABSTRACT: Opinion statement: Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent a powerful new model system to study the basic mechanisms of inherited cardiomyopathies. hiPSC-CMs have been utilized to model several cardiovascular diseases, achieving the most success in the inherited arrhythmias, including long QT and Timothy syndromes (Moretti et al. N Engl J Med. 363:1397-409, 2010; Yazawa et al. Nature. 471:230-4, 2011) and arrhythmogenic right ventricular dysplasia (ARVD) (Ma et al. Eur Heart J. 34:1122-33, 2013). Recently, studies have applied hiPSC-CMs to the study of both dilated (DCM) (Sun et al. Sci Transl Med. 4:130ra47, 2012) and hypertrophic (HCM) cardiomyopathies (Lan et al. Cell Stem Cell. 12:101-13, 2013; Carvajal-Vergara et al. Nature. 465:808-12, 2010), providing new insights into basic mechanisms of disease. However, hiPSC-CMs do not recapitulate many of the structural and functional aspects of mature human cardiomyocytes, instead mirroring an immature - embryonic or fetal - phenotype. Much work remains in order to better understand these differences, as well as to develop methods to induce hiPSC-CMs into a fully mature phenotype. Despite these limitations, hiPSC-CMs represent the best current in vitro correlate of the human heart and an invaluable tool in the search for mechanisms underlying cardiomyopathy and for screening new pharmacologic therapies.
    Current Treatment Options in Cardiovascular Medicine 07/2014; 16(7):320. DOI:10.1007/s11936-014-0320-7
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    ABSTRACT: Monitoring allograft health is an important component of posttransplant therapy. Endomyocardial biopsy is the current gold standard for cardiac allograft monitoring but is an expensive and invasive procedure. Proof of principle of a universal, noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA (cfdDNA) was recently demonstrated in a small retrospective cohort. We present the results of a prospective cohort study (65 patients, 565 samples) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation. Circulating cell-free DNA was purified from plasma and sequenced (mean depth, 1.2 giga-base pairs) to quantify the fraction of cfdDNA. Through a comparison with endomyocardial biopsy results, we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation, with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself. This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk, discomfort, and expense of an invasive biopsy.
    Science translational medicine 06/2014; 6(241):241ra77. DOI:10.1126/scitranslmed.3007803 · 15.84 Impact Factor
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    ABSTRACT: Earlier studies have indicated that the pharmacokinetics of mycophenolic acid (MPA) is influenced by polymorphisms of ABCC2, which encodes for the membrane transporter MRP2. The ABCC2 rs717620 A allele has been associated with enterohepatic recirculation of MPA, and our previous work had correlated the discontinuance of MPA with this allele in pediatric heart transplant patients. Therefore, we hypothesized that the ABCC2 rs717620 A allele would be associated with poorer outcomes including rejection with hemodynamic compromise (RHC), graft failure, and death in the pediatric heart transplant (PHTx) population receiving MPA. PHTx recipients from 6 institutions in the Pediatric Heart Transplantation Study (PHTS) from the period of 1993-2009, receiving MPA therapy, were genotyped for ABCC2 rs717620. Genotyping was accomplished by direct sequencing. Demographic and outcome data were limited to the data routinely collected as part of the PHTS and included RHC and mortality. Two hundred ninety patients were identified who received MPA at some point post transplantation, of which 200 carried the GG genotype, 81 carried the AG genotype, and 9 carried the AA genotype. Follow-up time after transplantation was 6 years. RHC occurred in 76 patients and 18 patients died. In the 281 patients followed up more than 1 year, late RHC (>1 year post transplantation) occurred in 42 patients. While both RHC and late RHC were associated with the ABCC2 rs717620 GG genotype (hazard ratios: 1.80 and 4.57, respectively, p<0.05) in all patients, this association was not significant in PHTx patients receiving only MPA as the antiproliferative agent from the time of transplant (n=142). ABCC2 rs717620 polymorphisms varied within racial groups. As a candidate gene assessment, the ABCC2 rs717620 AG and AA genotypes may be associated with improved, rather than poorer, RHC in PHTx patients receiving MPA therapy. ABCC2 rs717620 polymorphisms should be included in any expanded pharmacogenomic analysis of outcomes after pediatric heart transplantation.
    04/2014; 19(1):16-24. DOI:10.5863/1551-6776-19.1.16
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    ABSTRACT: Due to the limited self-renewal capacity of cardiomyocytes, the mammalian heart exhibits impaired regeneration and insufficient ability to restore heart function after injury. Cardiovascular tissue engineering is currently considered as a promising alternative therapy to restore the structure and function of the failing heart. Recent evidence suggests that the epicardium may play critical roles in regulation of myocardial development and regeneration. One of the mechanisms that has been proposed for the restorative effect of the epicardium is the specific physiomechanical cues that this layer provides to the cardiac cells. In this article we explore whether a new generation of epicardium-mimicking, acellular matrices can be utilized to enhance cardiac healing after injury. The matrix consists of a dense collagen scaffold with optimized biomechanical properties approaching those of embryonic epicardium. Grafting the epicardial patch onto the ischemic myocardium—promptly after the incidence of infarct—resulted in preserved contractility, attenuated ventricular remodeling, diminished fibrosis, and vascularization within the injured tissue in the adult murine heart.
    04/2014; 5(3):193-197. DOI:10.4161/bioe.27751

Publication Stats

4k Citations
1,096.30 Total Impact Points


  • 1991–2015
    • Stanford University
      • • Department of Pediatrics
      • • Division of Pediatric Cardiology
      • • Department of Pathology
      • • Department of Medicine
      Palo Alto, California, United States
  • 2013
    • University of Texas at Dallas
      Richardson, Texas, United States
  • 1991–2012
    • Stanford Medicine
      • • Department of Pediatrics
      • • Division of Pediatric Cardiology
      Stanford, California, United States
  • 2010
    • Lucile Packard Children’s Hospital at Stanford
      Palo Alto, California, United States
  • 2007
    • University of Pittsburgh
      • Department of Pathology
      Pittsburgh, PA, United States
  • 2003
    • University of Toronto
      Toronto, Ontario, Canada
  • 1997
    • Childrens Hospital of Pittsburgh
      Pittsburgh, Pennsylvania, United States