Danielle L. Brunjes
Columbia University Medical Center
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Featured researches published by Danielle L. Brunjes.
JCI insight | 2017
Ruiping Ji; Hirokazu Akashi; Konstantinos Drosatos; Xianghai Liao; Hongfeng Jiang; Peter J. Kennel; Danielle L. Brunjes; Estibaliz Castillero; Xiaokan Zhang; Lily Y Deng; Shunichi Homma; Isaac George; Hiroo Takayama; Yoshifumi Naka; Ira J. Goldberg; P. Christian Schulze
Abnormal lipid metabolism may contribute to myocardial injury and remodeling. To determine whether accumulation of very long-chain ceramides occurs in human failing myocardium, we analyzed myocardial tissue and serum from patients with severe heart failure (HF) undergoing placement of left ventricular assist devices and controls. Lipidomic analysis revealed increased total and very long-chain ceramides in myocardium and serum of patients with advanced HF. After unloading, these changes showed partial reversibility. Following myocardial infarction (MI), serine palmitoyl transferase (SPT), the rate-limiting enzyme of the de novo pathway of ceramide synthesis, and ceramides were found increased. Blockade of SPT by the specific inhibitor myriocin reduced ceramide accumulation in ischemic cardiomyopathy and decreased C16, C24:1, and C24 ceramides. SPT inhibition also reduced ventricular remodeling, fibrosis, and macrophage content following MI. Further, genetic deletion of the SPTLC2 gene preserved cardiac function following MI. Finally, in vitro studies revealed that changes in ceramide synthesis are linked to hypoxia and inflammation. In conclusion, cardiac ceramides accumulate in the failing myocardium, and increased levels are detectable in circulation. Inhibition of de novo ceramide synthesis reduces cardiac remodeling. Thus, increased de novo ceramide synthesis contributes to progressive pathologic cardiac remodeling and dysfunction.
Journal of Heart and Lung Transplantation | 2016
Mike Lee; H. Akashi; Tomoko S. Kato; Hiroo Takayama; Christina Wu; Katherine Xu; Elias Collado; Matthew P. Weber; Peter J. Kennel; Danielle L. Brunjes; Ruiping Ji; Yoshifumi Naka; Isaac George; Donna Mancini; Maryjane Farr; P. Christian Schulze
BACKGROUND Left ventricular assist devices are increasingly being used in patients with advanced heart failure as both destination therapy and bridge to transplant. We aimed to identify histomorphometric, structural and inflammatory changes after pulsatile- and continuous-flow left ventricular assist device placement. METHODS Clinical and echocardiographic data were collected from medical records. Aortic wall diameter, cellularity and inflammation were assessed by immunohistochemistry on aortic tissue collected at left ventricular assist device placement and at explantation during heart transplantation. Expression of adhesion molecules was quantified by Western blot. RESULTS Decellularization of the aortic tunica media was observed in patients receiving continuous-flow support. Both device types showed an increased inflammatory response after left ventricular assist device placement with variable T-cell and macrophage accumulations and increased expression of vascular E-selectin, ICAM and VCAM in the aortic wall. CONCLUSIONS Left ventricular assist device implantation is associated with distinct vascular derangements with development of vascular inflammation. These changes are pronounced in patients on continuous-flow left ventricular assist and associated with aortic media decellularization. The present findings help to explain the progressive aortic root dilation and vascular dysfunction in patients after continuous-flow device placement.
Circulation-heart Failure | 2015
Christina Wu; Tomoko S. Kato; Ruiping Ji; Cynthia Zizola; Danielle L. Brunjes; Yue Deng; Hirokazu Akashi; Hilary F. Armstrong; Peter J. Kennel; Tiffany Thomas; Daniel E. Forman; Jennifer Hall; Aalap Chokshi; Matthew N. Bartels; Donna Mancini; David S. Seres; P. Christian Schulze
Background—Skeletal muscle dysfunction and exercise intolerance are clinical hallmarks of patients with heart failure. These have been linked to a progressive catabolic state, skeletal muscle inflammation, and impaired oxidative metabolism. Previous studies suggest beneficial effects of &ohgr;-3 polyunsaturated fatty acids and glutamine on exercise performance and muscle protein balance. Methods and Results—In a randomized double-blind, placebo-controlled trial, 31 patients with heart failure were randomized to either L-alanyl-L-glutamine (8 g/d) and polyunsaturated fatty acid (6.5 g/d) or placebo (safflower oil and milk powder) for 3 months. Cardiopulmonary exercise testing, dual-energy x-ray absorptiometry, 6-minute walk test, hand grip strength, functional muscle testing, echocardiography, and quality of life and lateral quadriceps muscle biopsy were performed at baseline and at follow-up. Oxidative capacity and metabolic gene expression were analyzed on muscle biopsies. No differences in muscle function, echocardiography, 6-minute walk test, or hand grip strength and a nonsignificant increase in peak VO2 in the treatment group were found. Lean body mass increased and quality of life improved in the active treatment group. Molecular analysis revealed no differences in muscle fiber composition, fiber cross-sectional area, gene expression of metabolic marker genes (PGC1&agr;, CPT1, PDK4, and GLUT4), and skeletal muscle oxidative capacity. Conclusions—The combined supplementation of L-alanyl-L-glutamine and polyunsaturated fatty acid did not improve exercise performance or muscle function but increased lean body mass and quality of life in patients with chronic stable heart failure. These findings suggest potentially beneficial effects of high-dose nutritional polyunsaturated fatty acids and amino acid supplementations in patients with chronic stable heart failure. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01534663.
Journal of Cardiac Failure | 2016
Danielle L. Brunjes; Adam Castano; Autumn Clemons; Jonah Rubin; Mathew S. Maurer
Wild-type transthyretin cardiac amyloidosis (ATTRwt), formerly called senile cardiac amyloidosis (SCA), is almost exclusively a disorder of older adults. As the population ages, the diagnosis of ATTRwt will increase, making it the most common form of cardiac amyloidosis. An important precondition to reduce underdiagnosis and misdiagnosis is to maintain a high index of suspicion for cardiac amyloidosis. Several clues can be gleaned from the clinical history, physical exam, electrocardiography, and noninvasive imaging techniques. Nuclear scintigraphy agents using 99mTc-phosphate derivatives combined with assessment for monoclonal proteins are eliminating the need for tissue confirmation in ATTR. Morbidity and mortality from ATTRwt cardiac amyloid is high and the emergence of numerous therapies based on a biologic understanding of the pathophysiology of this condition, including drugs to inhibit the synthesis of TTR, stabilize TTR, and degrade or extract amyloid, provides new hope for those afflicted. This review briefly covers the epidemiology, pathophysiology, and clinical manifestations, as well as diagnostic strategies and treatment, of ATTR in older adults.
Circulation | 2018
Xiaokan Zhang; Ruiping Ji; Xianghai Liao; Estibaliz Castillero; Peter J. Kennel; Danielle L. Brunjes; Marcus Franz; Sven Möbius-Winkler; Konstantinos Drosatos; Isaac George; Emily I. Chen; P.C. Colombo; P. Christian Schulze
Background: Heart failure leads to mitochondrial dysfunction and metabolic abnormalities of the failing myocardium coupled with an energy-depleted state and cardiac remodeling. The mitochondrial deacetylase sirtuin 3 (SIRT3) plays a pivotal role in the maintenance of mitochondrial function through regulating the mitochondrial acetylome. It is interesting to note that unique cardiac and systemic microRNAs have been shown to play an important role in cardiac remodeling by modulating key signaling elements in the myocardium. Methods: Cellular signaling was analyzed in human cardiomyocyte-like AC16 cells, and acetylation levels in rodent models of SIRT3–/–and transgenic microRNA-195 (miR-195) overexpression were compared with wild type. Luciferase assays, Western blotting, immunoprecipitation assays, and echocardiographic analysis were performed. Enzymatic activities of pyruvate dehydrogenase (PDH) and ATP synthase were measured. Results: In failing human myocardium, we observed induction of miR-195 along with decreased expression of the mitochondrial deacetylase SIRT3 that was associated with increased global protein acetylation. We further investigated the role of miR-195 in SIRT3-mediated metabolic processes and its impact on regulating enzymes involved in deacetylation. Proteomic analysis of the total acetylome showed increased overall acetylation, and specific lysine acetylation of 2 central mitochondrial metabolic enzymes, PDH and ATP synthase, as well. miR-195 downregulates SIRT3 expression through direct 3′-untranslated region targeting. Treatments with either sirtuin inhibitor nicotinamide, small interfering RNA–mediated SIRT3 knockdown or miR-195 overexpression enhanced acetylation of PDH complex and ATP synthase. This effect diminished PDH and ATP synthase activity and impaired mitochondrial respiration.SIRT3–/– and miR-195 transgenic mice consistently showed enhanced global protein acetylation, including PDH complex and ATP synthase, associated with decreased enzymatic activity. Conclusions: Altogether, these data suggest that increased levels of miR-195 in failing myocardium regulate a novel pathway that involves direct SIRT3 suppression and enzymatic inhibition via increased acetylation of PDH and ATP synthase that are essential for cardiac energy metabolism.
Circulation | 2018
Alexander Kushnir; Gaetano Santulli; Steven Reiken; Ellie J. Coromilas; Sarah J. Godfrey; Danielle L. Brunjes; P.C. Colombo; M. Yuzefpolskaya; Seth I. Sokol; Richard N. Kitsis; Andrew R. Marks
Background: Advances in congestive heart failure (CHF) management depend on biomarkers for monitoring disease progression and therapeutic response. During systole, intracellular Ca2+ is released from the sarcoplasmic reticulum into the cytoplasm through type-2 ryanodine receptor/Ca2+ release channels. In CHF, chronically elevated circulating catecholamine levels cause pathological remodeling of type-2 ryanodine receptor/Ca2+ release channels resulting in diastolic sarcoplasmic reticulum Ca2+ leak and decreased myocardial contractility. Similarly, skeletal muscle contraction requires sarcoplasmic reticulum Ca2+ release through type-1 ryanodine receptors (RyR1), and chronically elevated catecholamine levels in CHF cause RyR1-mediated sarcoplasmic reticulum Ca2+ leak, contributing to myopathy and weakness. Circulating B-lymphocytes express RyR1 and catecholamine-responsive signaling cascades, making them a potential surrogate for defects in intracellular Ca2+ handling because of leaky RyR channels in CHF. Methods: Whole blood was collected from patients with CHF, CHF following left-ventricular assist device implant, and controls. Blood was also collected from mice with ischemic CHF, ischemic CHF+S107 (a drug that specifically reduces RyR channel Ca2+ leak), and wild-type controls. Channel macromolecular complex was assessed by immunostaining RyR1 immunoprecipitated from lymphocyte-enriched preparations. RyR1 Ca2+ leak was assessed using flow cytometry to measure Ca2+ fluorescence in B-lymphocytes in the absence and presence of RyR1 agonists that empty RyR1 Ca2+ stores within the endoplasmic reticulum. Results: Circulating B-lymphocytes from humans and mice with CHF exhibited remodeled RyR1 and decreased endoplasmic reticulum Ca2+ stores, consistent with chronic intracellular Ca2+ leak. This Ca2+ leak correlated with circulating catecholamine levels. The intracellular Ca2+ leak was significantly reduced in mice treated with the Rycal S107. Patients with CHF treated with left-ventricular assist devices exhibited a heterogeneous response. Conclusions: In CHF, B-lymphocytes exhibit remodeled leaky RyR1 channels and decreased endoplasmic reticulum Ca2+ stores consistent with chronic intracellular Ca2+ leak. RyR1-mediated Ca2+ leak in B-lymphocytes assessed using flow cytometry provides a surrogate measure of intracellular Ca2+ handling and systemic sympathetic burden, presenting a novel biomarker for monitoring response to pharmacological and mechanical CHF therapy.
Journal of Cardiac Failure | 2016
Danielle L. Brunjes; Mark Dunlop; Christina Wu; Meaghan Jones; Tomoko S. Kato; Peter J. Kennel; Hilary F. Armstrong; Tse Hwei Choo; Matthew N. Bartels; Daniel E. Forman; Donna Mancini; P. Christian Schulze
BACKGROUND Heart failure (HF)-related exercise intolerance is thought to be perpetuated by peripheral skeletal muscle functional, structural, and metabolic abnormalities. We analyzed specific dynamics of muscle contraction in patients with HF compared with healthy, sedentary controls. METHODS Isometric and isokinetic muscle parameters were measured in the dominant upper and lower limbs of 45 HF patients and 15 healthy age-matched controls. Measurements included peak torque normalized to body weight, work normalized to body weight, power, time to peak torque, and acceleration and deceleration to maximum strength times. Body morphometry (dual energy X-ray absorptiometry scan) and circulating fatty acids and ceramides (lipodomics) were analyzed in a subset of subjects (18 HF and 9 controls). RESULTS Extension and flexion time-to-peak torque was longer in the lower limbs of HF patients. Furthermore, acceleration and deceleration times in the lower limbs were also prolonged in HF subjects. HF subjects had increased adiposity and decreased lean muscle mass compared with controls. Decreased circulating unsaturated fatty acids and increased ceramides were found in subjects with HF. CONCLUSIONS Delayed torque development suggests skeletal muscle impairments that may reflect abnormal neuromuscular functional coupling. These impairments may be further compounded by increased adiposity and inflammation associated with increased ceramides.
Journal of the American College of Cardiology | 2018
Allyson Checkley; Samantha Kile; Loretta Kristofek; Danielle L. Brunjes; William Bolgar; Vinay Thohan; Maryjane Farr; Jonathan D. Rich
Continuous intravenous (IV) inotropic therapy is used in advanced heart failure (HF) patients awaiting transplant/ventricular assist device (VAD) or for palliation. We investigated contemporary outcomes of therapy in the home. This is a multicenter, prospective, observational registry study of HF
Journal of Heart and Lung Transplantation | 2017
Peter J. Kennel; Amit Saha; Dawn Maldonado; Raymond C. Givens; Danielle L. Brunjes; Estibaliz Castillero; Xiaokan Zhang; Ruiping Ji; Alexandre Yahi; Isaac George; Donna Mancini; Antonius Koller; Barry Fine; Emmanuel Zorn; P.C. Colombo; Nicholas P. Tatonetti; Emily I. Chen; P. Christian Schulze
Journal of Heart and Lung Transplantation | 2018
F. Castagna; A. Pinsino; J. Nwokocha; Danielle L. Brunjes; Eric J. Stöhr; Barry J. McDonnell; John R. Cockcroft; C.M. McEniery; M.F. Pineda; A.R. Garan; V.K. Topkara; R. Te-Frey; Hiroo Takayama; Koji Takeda; Y. Naka; P.C. Colombo; M. Yuzefpolskaya