Search

Your search keyword '"Margulies, Kenneth B."' showing total 1,277 results
Start Over Author "Margulies, Kenneth B."
1,277 results on '"Margulies, Kenneth B."'

1. Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy

Author

Zheng, Sean L., Henry, Albert, Cannie, Douglas, Lee, Michael, Miller, David, McGurk, Kathryn A., Bond, Isabelle, Xu, Xiao, Issa, Hanane, Francis, Catherine, De Marvao, Antonio, Theotokis, Pantazis I., Buchan, Rachel J., Speed, Doug, Abner, Erik, Adams, Lance, Aragam, Krishna G., Ärnlöv, Johan, Raja, Anna Axelsson, Backman, Joshua D., Baksi, John, Barton, Paul J. R., Biddinger, Kiran J., Boersma, Eric, Brandimarto, Jeffrey, Brunak, Søren, Bundgaard, Henning, Carey, David J., Charron, Philippe, Cook, James P., Cook, Stuart A., Denaxas, Spiros, Deleuze, Jean-François, Doney, Alexander S., Elliott, Perry, Erikstrup, Christian, Esko, Tõnu, Farber-Eger, Eric H., Finan, Chris, Garnier, Sophie, Ghouse, Jonas, Giedraitis, Vilmantas, Guðbjartsson, Daniel F., Haggerty, Christopher M., Halliday, Brian P., Helgadottir, Anna, Hemingway, Harry, Hillege, Hans L., Kardys, Isabella, Lind, Lars, Lindgren, Cecilia M., Lowery, Brandon D., Manisty, Charlotte, Margulies, Kenneth B., Moon, James C., Mordi, Ify R., Morley, Michael P., Morris, Andrew D., Morris, Andrew P., Morton, Lori, Noursadeghi, Mahdad, Ostrowski, Sisse R., Owens, Anjali T., Palmer, Colin N. A., Pantazis, Antonis, Pedersen, Ole B. V., Prasad, Sanjay K., Shekhar, Akshay, Smelser, Diane T., Srinivasan, Sundararajan, Stefansson, Kari, Sveinbjörnsson, Garðar, Syrris, Petros, Tammesoo, Mari-Liis, Tayal, Upasana, Teder-Laving, Maris, Thorgeirsson, Guðmundur, Thorsteinsdottir, Unnur, Tragante, Vinicius, Trégouët, David-Alexandre, Treibel, Thomas A., Ullum, Henrik, Valdes, Ana M., van Setten, Jessica, van Vugt, Marion, Veluchamy, Abirami, Verschuren, W. M. Monique, Villard, Eric, Yang, Yifan, Asselbergs, Folkert W., Cappola, Thomas P., Dube, Marie-Pierre, Dunn, Michael E., Ellinor, Patrick T., Hingorani, Aroon D., Lang, Chim C., Samani, Nilesh J., Shah, Svati H., Smith, J. Gustav, Vasan, Ramachandran S., O’Regan, Declan P., Holm, Hilma, Noseda, Michela, Wells, Quinn, Ware, James S., and Lumbers, R. Thomas

Published
2024
Full Text
View/download PDF

2. Cardiac NAD+ depletion in mice promotes hypertrophic cardiomyopathy and arrhythmias prior to impaired bioenergetics

Author

Doan, Khanh V., Luongo, Timothy S., Ts’olo, Thato T., Lee, Won Dong, Frederick, David W., Mukherjee, Sarmistha, Adzika, Gabriel K., Perry, Caroline E., Gaspar, Ryan B., Walker, Nicole, Blair, Megan C., Bye, Nicole, Davis, James G., Holman, Corey D., Chu, Qingwei, Wang, Lin, Rabinowitz, Joshua D., Kelly, Daniel P., Cappola, Thomas P., Margulies, Kenneth B., and Baur, Joseph A.

Published
2024
Full Text
View/download PDF

7. Genome-wide fetalization of enhancer architecture in heart disease

Author

Spurrell, Cailyn H, Barozzi, Iros, Kosicki, Michael, Mannion, Brandon J, Blow, Matthew J, Fukuda-Yuzawa, Yoko, Slaven, Neil, Afzal, Sarah Y, Akiyama, Jennifer A, Afzal, Veena, Tran, Stella, Plajzer-Frick, Ingrid, Novak, Catherine S, Kato, Momoe, Lee, Elizabeth A, Garvin, Tyler H, Pham, Quan T, Kronshage, Anne N, Lisgo, Steven, Bristow, James, Cappola, Thomas P, Morley, Michael P, Margulies, Kenneth B, Pennacchio, Len A, Dickel, Diane E, and Visel, Axel

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Pediatric, Cardiovascular, Human Genome, Rare Diseases, Heart Disease, 1.1 Normal biological development and functioning, Adult, Cardiomyopathy, Dilated, Enhancer Elements, Genetic, Epigenome, Epigenomics, Humans, Transcription Factors, CP: Molecular biology, RNA-seq, enhancers, fetalization, genomics, hIP-seq, heart disease, regulatory elements, transgenic assay, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

Heart disease is associated with re-expression of key transcription factors normally active only during prenatal development of the heart. However, the impact of this reactivation on the regulatory landscape in heart disease is unclear. Here, we use RNA-seq and ChIP-seq targeting a histone modification associated with active transcriptional enhancers to generate genome-wide enhancer maps from left ventricle tissue from up to 26 healthy controls, 18 individuals with idiopathic dilated cardiomyopathy (DCM), and five fetal hearts. Healthy individuals have a highly reproducible epigenomic landscape, consisting of more than 33,000 predicted heart enhancers. In contrast, we observe reproducible disease-associated changes in activity at 6,850 predicted heart enhancers. Combined analysis of adult and fetal samples reveals that the heart disease epigenome and transcriptome both acquire fetal-like characteristics, with 3,400 individual enhancers sharing fetal regulatory properties. We also provide a comprehensive data resource (http://heart.lbl.gov) for the mechanistic exploration of DCM etiology.

Published
2022

8. The evolving use of biomarkers in heart transplantation: Consensus of an expert panel

Author

Kobashigawa, Jon, Hall, Shelly, Agbor-Enoh, Sean, Bray, Robert, Cadeiras, Martin, Chang, Patty, Chih, Sharon, Eisen, Howie, Farr, Maryjane, Fine, Barry, Ghafourian, Kambiz, Halloran, Phil, Jackson, Annette M, Kao, Andrew, Khush, Kiran K, Madabhushi, Anant, Margulies, Kenneth B, Sani, Maryam Mojarrad, Patel, Jignesh K, Patel, Nikhil, Peyster, Eliot, Parwani, Anil, Pinney, Sean, Schlendorf, Kelley, Shah, Keyur, Shah, Palak, Stehlik, Josef, Tambur, Anat, Zeevi, Adriana, Hall, Shelley, Jackson, Annette M., Khush, Kiran K., Margulies, Kenneth B., and Patel, Jignesh K.

Published
2023
Full Text
View/download PDF

10. Label-Free Visualization and Quantification of Biochemical Markers of Atherosclerotic Plaque Progression Using Intravascular Fluorescence Lifetime

Author

Bec, Julien, Vela, Deborah, Phipps, Jennifer E, Agung, Michael, Unger, Jakob, Margulies, Kenneth B, Southard, Jeffrey A, Buja, L Maximilian, and Marcu, Laura

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Atherosclerosis, Heart Disease - Coronary Heart Disease, Aging, Cardiovascular, Heart Disease, Biomarkers, Coronary Artery Disease, Coronary Vessels, Humans, Optical Imaging, Plaque, Atherosclerotic, Predictive Value of Tests, Ultrasonography, Interventional, atherosclerosis, coronary artery disease, imaging, inflammation, lipids and cholesterol, percutaneous coronary intervention, ultrasonography, ultrasound, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

ObjectivesThis study aimed to systematically investigate whether plaque autofluorescence properties assessed with intravascular fluorescence lifetime imaging (FLIm) can provide qualitative and quantitative information about intimal composition and improve the characterization of atherosclerosis lesions.BackgroundDespite advances in cardiovascular diagnostics, the analytic tools and imaging technologies currently available have limited capabilities for evaluating in situ biochemical changes associated with luminal surface features. Earlier studies of small number of samples have shown differences among the autofluorescence lifetime signature of well-defined lesions, but a systematic pixel-level evaluation of fluorescence signatures associated with various histological features is lacking and needed to better understand the origins of fluorescence contrast.MethodsHuman coronary artery segments (n = 32) were analyzed with a bimodal catheter system combining multispectral FLIm with intravascular ultrasonography compatible with in vivo coronary imaging. Various histological components present along the luminal surface (200-μm depth) were systematically tabulated (12 sectors) from each serial histological section (n = 204). Morphological information provided by ultrasonography allowed for the accurate registration of imaging data with histology data. The relationships between histological findings and FLIm parameters obtained from 3 spectral channels at each measurement location (n = 33,980) were characterized.ResultsOur findings indicate that fluorescence lifetime from different spectral bands can be used to quantitatively predict the superficial presence of macrophage foam cells (mFCs) (area under the receiver-operator characteristic curve: 0.94) and extracellular lipid content in advanced lesions (lifetime increase in 540-nm band), detect superficial calcium (lifetime decrease in 450-nm band area under the receiver-operator characteristic curve: 0.90), and possibly detect lesions consistent with active plaque formation such as pathological intimal thickening and healed thrombus regions (lifetime increase in 390-nm band).ConclusionsOur findings indicate that autofluorescence lifetime provides valuable information for characterizing atherosclerotic lesions in coronary arteries. Specifically, FLIm can be used to identify key phenomena linked with plaque progression (e.g., peroxidized-lipid-rich mFC accumulation and recent plaque formation).

Published
2021

11. The HFSA Advanced Heart Failure and Transplant Cardiology Fellowship Consensus Conference

Author

DRAZNER, MARK H., AMBARDEKAR, AMRUT V., BERLACHER, KATHRYN, BLUMER, VANESSA, CHATUR, SAFIA, CHENG, RICHARD, CHENG, RICHARD K., GRANDIN, E. WILSON, GORODESKI, EIRAN Z., KATARIA, RACHNA, KATZ, JASON N., KITTLESON, MICHELLE M., KRISHNAMOORTHY, ARUN, LALA, ANURADHA, LENNEMAN, ANDREW J., LOHR, NICOLE L., MARGULIES, KENNETH B., MENTZ, ROBERT J., REZA, NOSHEEN, WILCOX, JANE, YOUMANS, QUENTIN R., ZIEROTH, SHELLEY, and TEERLINK, JOHN R.

Published
2024
Full Text
View/download PDF

13. Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes

Author

Shah, Parisha P, Lv, Wenjian, Rhoades, Joshua H, Poleshko, Andrey, Abbey, Deepti, Caporizzo, Matthew A, Linares-Saldana, Ricardo, Heffler, Julie G, Sayed, Nazish, Thomas, Dilip, Wang, Qiaohong, Stanton, Liam J, Bedi, Kenneth, Morley, Michael P, Cappola, Thomas P, Owens, Anjali T, Margulies, Kenneth B, Frank, David B, Wu, Joseph C, Rader, Daniel J, Yang, Wenli, Prosser, Benjamin L, Musunuru, Kiran, and Jain, Rajan

Subjects
Cardiovascular, Stem Cell Research - Induced Pluripotent Stem Cell, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research, Heart Disease, Genetics, Aetiology, 2.1 Biological and endogenous factors, Cardiomyopathy, Dilated, Chromatin, Humans, Induced Pluripotent Stem Cells, Lamin Type A, Mutation, Myocytes, Cardiac, genome organization, hiPSC, laminopathy, peripheral heterochromatin, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Pathogenic mutations in LAMIN A/C (LMNA) cause abnormal nuclear structure and laminopathies. These diseases have myriad tissue-specific phenotypes, including dilated cardiomyopathy (DCM), but how LMNA mutations result in tissue-restricted disease phenotypes remains unclear. We introduced LMNA mutations from individuals with DCM into human induced pluripotent stem cells (hiPSCs) and found that hiPSC-derived cardiomyocytes, in contrast to hepatocytes or adipocytes, exhibit aberrant nuclear morphology and specific disruptions in peripheral chromatin. Disrupted regions were enriched for transcriptionally active genes and regions with lower LAMIN B1 contact frequency. The lamina-chromatin interactions disrupted in mutant cardiomyocytes were enriched for genes associated with non-myocyte lineages and correlated with higher expression of those genes. Myocardium from individuals with LMNA variants similarly showed aberrant expression of non-myocyte pathways. We propose that the lamina network safeguards cellular identity and that pathogenic LMNA variants disrupt peripheral chromatin with specific epigenetic and molecular characteristics, causing misexpression of genes normally expressed in other cell types.

Published
2021

14. Truncated titin protein in dilated cardiomyopathy incorporates into the sarcomere and transmits force

Author

McAfee, Quentin, Caporizzo, Matthew A., Uchida, Keita, Bedi, Kenneth C., Jr., Margulies, Kenneth B., Arany, Zolt, and Prosser, Benjamin L.

Subjects
Cardiomyopathy, Dilated -- Causes of -- Development and progression -- Genetic aspects, Cardiovascular research, Muscle proteins -- Health aspects -- Genetic aspects, Striated muscle -- Genetic aspects -- Health aspects, Genetic variation -- Research, Health care industry
Abstract

To the Editor: Dilated cardiomyopathy (DCM) and peripartum cardiomyopathy frequently associate with heterozygous truncating variants in TTN (TTNtvs) (1). TTN codes for titin, a spring-like protein that spans the sarcomere [...]

Published
2024

16. Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity

Author

Ozcan, Mualla, Guo, Zhen, Valenzuela Ripoll, Carla, Diab, Ahmed, Picataggi, Antonino, Rawnsley, David, Lotfinaghsh, Aynaz, Bergom, Carmen, Szymanski, Jeff, Hwang, Daniel, Asnani, Aarti, Kosiborod, Mikhail, Zheng, Jie, Hayashi, Robert J., Woodard, Pamela K., Kovacs, Attila, Margulies, Kenneth B., Schilling, Joel, Razani, Babak, Diwan, Abhinav, and Javaheri, Ali

Published
2023
Full Text
View/download PDF

17. Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Author

Shah, Sonia, Henry, Albert, Roselli, Carolina, Lin, Honghuang, Sveinbjörnsson, Garðar, Fatemifar, Ghazaleh, Hedman, Åsa K, Wilk, Jemma B, Morley, Michael P, Chaffin, Mark D, Helgadottir, Anna, Verweij, Niek, Dehghan, Abbas, Almgren, Peter, Andersson, Charlotte, Aragam, Krishna G, Ärnlöv, Johan, Backman, Joshua D, Biggs, Mary L, Bloom, Heather L, Brandimarto, Jeffrey, Brown, Michael R, Buckbinder, Leonard, Carey, David J, Chasman, Daniel I, Chen, Xing, Chen, Xu, Chung, Jonathan, Chutkow, William, Cook, James P, Delgado, Graciela E, Denaxas, Spiros, Doney, Alexander S, Dörr, Marcus, Dudley, Samuel C, Dunn, Michael E, Engström, Gunnar, Esko, Tõnu, Felix, Stephan B, Finan, Chris, Ford, Ian, Ghanbari, Mohsen, Ghasemi, Sahar, Giedraitis, Vilmantas, Giulianini, Franco, Gottdiener, John S, Gross, Stefan, Guðbjartsson, Daníel F, Gutmann, Rebecca, Haggerty, Christopher M, van der Harst, Pim, Hyde, Craig L, Ingelsson, Erik, Jukema, J Wouter, Kavousi, Maryam, Khaw, Kay-Tee, Kleber, Marcus E, Køber, Lars, Koekemoer, Andrea, Langenberg, Claudia, Lind, Lars, Lindgren, Cecilia M, London, Barry, Lotta, Luca A, Lovering, Ruth C, Luan, Jian'an, Magnusson, Patrik, Mahajan, Anubha, Margulies, Kenneth B, März, Winfried, Melander, Olle, Mordi, Ify R, Morgan, Thomas, Morris, Andrew D, Morris, Andrew P, Morrison, Alanna C, Nagle, Michael W, Nelson, Christopher P, Niessner, Alexander, Niiranen, Teemu, O'Donoghue, Michelle L, Owens, Anjali T, Palmer, Colin NA, Parry, Helen M, Perola, Markus, Portilla-Fernandez, Eliana, Psaty, Bruce M, Regeneron Genetics Center, Rice, Kenneth M, Ridker, Paul M, Romaine, Simon PR, Rotter, Jerome I, Salo, Perttu, Salomaa, Veikko, van Setten, Jessica, Shalaby, Alaa A, Smelser, Diane T, Smith, Nicholas L, Stender, Steen, and Stott, David J

Subjects
Regeneron Genetics Center, Humans, Atrial Fibrillation, Cardiomyopathies, Microfilament Proteins, Adaptor Proteins, Signal Transducing, Carrier Proteins, Muscle Proteins, Risk Factors, Case-Control Studies, Ventricular Function, Left, Cyclin-Dependent Kinase Inhibitor p21, Apoptosis Regulatory Proteins, Coronary Artery Disease, Heart Failure, Genome-Wide Association Study, Mendelian Randomization Analysis, Adaptor Proteins, Signal Transducing, Ventricular Function, Left
Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Published
2020

18. Investigating Origins of FLIm Contrast in Atherosclerotic Lesions Using Combined FLIm-Raman Spectroscopy

Author

Bec, Julien, Shaik, Tanveer Ahmed, Krafft, Christoph, Bocklitz, Thomas W, Alfonso-Garcia, Alba, Margulies, Kenneth B, Popp, Jürgen, and Marcu, Laura

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Atherosclerosis, Biomedical Imaging, Prevention, Cardiovascular, imaging, spectroscopy, atherosclerosis, Raman spectroscopy, FLIm, time resolved fluorescence, Cardiovascular medicine and haematology
Abstract

Background: Fluorescence lifetime imaging (FLIm) is a spectroscopic imaging technique able to characterize the composition of luminal surface of arterial vessels. Studies of human coronary samples demonstrated that distinct atherosclerotic lesion types are characterized by FLIm features associate with distinct tissue molecular makeup. While conventional histology has provided indications about potential sources of molecular contrast, specific information about the origin of FLIm signals is lacking. Here we investigate whether Raman spectroscopy, a technique able to evaluate chemical content of biological samples, can provide additional insight into the origin of FLIm contrast. Methods: Six human coronary artery samples were imaged using FLIm (355 nm excitation)-Raman spectroscopy (785 nm excitation) via a multimodal fiber optic probe. The spatial distribution of molecular contrast in FLIm images was analyzed in relationship with histological findings. Raman data was investigated using an endmember technique and compared with histological findings. A descriptive modeling approach based on multivariate regression was used to identify Raman bands related with changes in lifetime in four spectral channels (violet: 387/35 nm, blue: 443/29 nm, green: 546/38 nm, and red: 628/53 nm). Results: Fluorescence lifetime variations in the violet, blue and green spectral bands were observed for distinct areas of each tissue sample associated with distinct pathologies. Analysis of Raman signals from areas associated with normal, pathological intimal thickening, and fibrocalcific regions demonstrated the presence of hydroxyapatite, collagenous proteins, carotene, cholesterol, and triglycerides. The FLIm and Raman descriptive modeling analysis indicated that lifetime increase in the violet spectral band was associated with increased presence of cholesterol and carotenes, a new finding consistent with LDL accumulation in atherosclerotic lesions, and not with collagen proteins, as expected from earlier studies. Conclusions: The systematic, quantitative analysis of the multimodal FLIm-Raman dataset using a descriptive modeling approach led to the identification of LDL accumulation as the primary source of lifetime contrast in atherosclerotic lesions in the violet spectral range. Earlier FLIm validation studies relying on histopathological findings had associated this contrast to increased collagen content, also present in advanced lesions, thus demonstrating the benefits of alternative validation methods.

Published
2020

19. Apolipoprotein M Attenuates Anthracycline Cardiotoxicity and Lysosomal Injury

Author

Guo, Zhen, Valenzuela Ripoll, Carla, Picataggi, Antonino, Rawnsley, David R., Ozcan, Mualla, Chirinos, Julio A., Chendamarai, Ezhilarasi, Girardi, Amanda, Riehl, Terrence, Evie, Hosannah, Diab, Ahmed, Kovacs, Attila, Hyrc, Krzysztof, Ma, Xiucui, Asnani, Aarti, Shewale, Swapnil V., Scherrer-Crosbie, Marielle, Cowart, Lauren Ashley, Parks, John S., Zhao, Lei, Gordon, David, Ramirez-Valle, Francisco, Margulies, Kenneth B., Cappola, Thomas P., Desai, Ankit A., Pedersen, Lauren N., Bergom, Carmen, Stitziel, Nathan O., Rettig, Michael P., DiPersio, John F., Hajny, Stefan, Christoffersen, Christina, Diwan, Abhinav, and Javaheri, Ali

Published
2023
Full Text
View/download PDF

26. Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy

Author

Chaffin, Mark, Papangeli, Irinna, Simonson, Bridget, Akkad, Amer-Denis, Hill, Matthew C., Arduini, Alessandro, Fleming, Stephen J., Melanson, Michelle, Hayat, Sikander, Kost-Alimova, Maria, Atwa, Ondine, Ye, Jiangchuan, Bedi, Jr, Kenneth C., Nahrendorf, Matthias, Kaushik, Virendar K., Stegmann, Christian M., Margulies, Kenneth B., Tucker, Nathan R., and Ellinor, Patrick T.

Published
2022
Full Text
View/download PDF

27. Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Author

Cordero, Pablo, Parikh, Victoria N, Chin, Elizabeth T, Erbilgin, Ayca, Gloudemans, Michael J, Shang, Ching, Huang, Yong, Chang, Alex C, Smith, Kevin S, Dewey, Frederick, Zaleta, Kathia, Morley, Michael, Brandimarto, Jeff, Glazer, Nicole, Waggott, Daryl, Pavlovic, Aleksandra, Zhao, Mingming, Moravec, Christine S, Tang, WH Wilson, Skreen, Jamie, Malloy, Christine, Hannenhalli, Sridhar, Li, Hongzhe, Ritter, Scott, Li, Mingyao, Bernstein, Daniel, Connolly, Andrew, Hakonarson, Hakon, Lusis, Aldons J, Margulies, Kenneth B, Depaoli-Roach, Anna A, Montgomery, Stephen B, Wheeler, Matthew T, Cappola, Thomas, and Ashley, Euan A

Subjects
Biological Sciences, Genetics, Human Genome, Biotechnology, Heart Disease, Cardiovascular, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Animals, Benzeneacetamides, Cells, Cultured, Datasets as Topic, Disease Models, Animal, Female, Gene Expression Profiling, Gene Expression Regulation, Gene Knockdown Techniques, Gene Regulatory Networks, Genome-Wide Association Study, Heart Failure, Humans, Male, Metabolic Networks and Pathways, Mice, Mice, Knockout, Middle Aged, Myocytes, Cardiac, Phosphoprotein Phosphatases, Primary Cell Culture, Pyridines, Quantitative Trait Loci, Rats, Rats, Sprague-Dawley, Sequence Analysis, RNA
Abstract

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.

Published
2019

28. Genome-Wide Fetalization of Enhancer Architecture in Heart Disease

Author

Spurrell, Cailyn H, Barozzi, Iros, Mannion, Brandon J, Blow, Matthew J, Fukuda-Yuzawa, Yoko, Afzal, Sarah Y, Akiyama, Jennifer A, Afzal, Veena, Tran, Stella, Plajzer-Frick, Ingrid, Novak, Catherine S, Kato, Momoe, Lee, Elizabeth, Garvin, Tyler H, Pham, Quan T, Harrington, Anne N, Lisgo, Steven, Bristow, James, Cappola, Thomas P, Morley, Michael P, Margulies, Kenneth B, Pennacchio, Len A, Dickel, Diane E, and Visel, Axel

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Heart Disease, Rare Diseases, Human Genome, Cardiovascular, Underpinning research, 1.1 Normal biological development and functioning
Abstract

Heart disease is associated with re-expression of key transcription factors normally active only during prenatal development of the heart. However, the impact of this reactivation on the genome-wide regulatory landscape in heart disease has remained obscure. Here we show that pervasive epigenomic changes occur in heart disease, with thousands of regulatory sequences reacquiring fetal-like chromatin signatures. We used RNA-seq and ChIP-seq targeting a histone modification associated with active transcriptional enhancers to generate genome-wide enhancer maps from left ventricle tissue from 18 healthy controls and 18 individuals with idiopathic dilated cardiomyopathy (DCM). Healthy individuals had a highly reproducible epigenomic landscape, consisting of more than 31,000 predicted heart enhancers. In contrast, we observed reproducible disease-associated gains or losses of activity at more than 7,500 predicted heart enhancers. Next, we profiled human fetal heart tissue by ChIP-seq and RNA-seq. Comparison with adult tissues revealed that the heart disease epigenome and transcrip-tome both shift toward a fetal-like state, with 3,400 individual enhancers sharing fetal regulatory properties. Our results demonstrate widespread epigenomic changes in DCM, and we provide a comprehensive data resource ( http://heart.lbl.gov ) for the mechanistic exploration of heart disease etiology.

Published
2019

29. Extra-cardiac BCAA catabolism lowers blood pressure and protects from heart failure

Author

Murashige, Danielle, Jung, Jae Woo, Neinast, Michael D., Levin, Michael G., Chu, Qingwei, Lambert, Jonathan P., Garbincius, Joanne F., Kim, Boa, Hoshino, Atsushi, Marti-Pamies, Ingrid, McDaid, Kendra S., Shewale, Swapnil V., Flam, Emily, Yang, Steven, Roberts, Emilia, Li, Li, Morley, Michael P., Bedi, Kenneth C., Jr., Hyman, Matthew C., Frankel, David S., Margulies, Kenneth B., Assoian, Richard K., Elrod, John W., Jang, Cholsoon, Rabinowitz, Joshua D., and Arany, Zoltan

Published
2022
Full Text
View/download PDF

32. Debulking different Corona (SARS-CoV-2 delta, omicron, OC43) and Influenza (H1N1, H3N2) virus strains by plant viral trap proteins in chewing gums to decrease infection and transmission

Author

Daniell, Henry, Nair, Smruti K., Guan, Hancheng, Guo, Yuwei, Kulchar, Rachel J., Torres, Marcelo D.T., Shahed-Al-Mahmud, Md., Wakade, Geetanjali, Liu, Yo-Min, Marques, Andrew D., Graham-Wooten, Jevon, Zhou, Wan, Wang, Ping, Molugu, Sudheer K., de Araujo, William R., de la Fuente-Nunez, Cesar, Ma, Che, Short, William R., Tebas, Pablo, Margulies, Kenneth B., Bushman, Frederic D., Mante, Francis K., Ricciardi, Robert P., Collman, Ronald G., and Wolff, Mark S.

Published
2022
Full Text
View/download PDF

34. Genome-wide association and multi-trait analyses characterize the common genetic architecture of heart failure

Author

Levin, Michael G., Tsao, Noah L., Singhal, Pankhuri, Liu, Chang, Vy, Ha My T., Paranjpe, Ishan, Backman, Joshua D., Bellomo, Tiffany R., Bone, William P., Biddinger, Kiran J., Hui, Qin, Dikilitas, Ozan, Satterfield, Benjamin A., Yang, Yifan, Morley, Michael P., Bradford, Yuki, Burke, Megan, Reza, Nosheen, Charest, Brian, Judy, Renae L., Puckelwartz, Megan J., Hakonarson, Hakon, Khan, Atlas, Kottyan, Leah C., Kullo, Iftikhar, Luo, Yuan, McNally, Elizabeth M., Rasmussen-Torvik, Laura J., Day, Sharlene M., Do, Ron, Phillips, Lawrence S., Ellinor, Patrick T., Nadkarni, Girish N., Ritchie, Marylyn D., Arany, Zoltan, Cappola, Thomas P., Margulies, Kenneth B., Aragam, Krishna G., Haggerty, Christopher M., Joseph, Jacob, Sun, Yan V., Voight, Benjamin F., and Damrauer, Scott M.

Published
2022
Full Text
View/download PDF

37. TRAF2, an Innate Immune Sensor, Reciprocally Regulates Mitophagy and Inflammation to Maintain Cardiac Myocyte Homeostasis

Author

Ma, Xiucui, Rawnsley, David R., Kovacs, Attila, Islam, Moydul, Murphy, John T., Zhao, Chen, Kumari, Minu, Foroughi, Layla, Liu, Haiyan, Qi, Kevin, Diwan, Aaradhya, Hyrc, Krzysztof, Evans, Sarah, Satoh, Takashi, French, Brent A., Margulies, Kenneth B., Javaheri, Ali, Razani, Babak, Mann, Douglas L., Mani, Kartik, and Diwan, Abhinav

Published
2022
Full Text
View/download PDF

39. Common Coding Variants in SCN10A Are Associated With the Nav1.8 Late Current and Cardiac Conduction

Author

Macri, Vincenzo, Brody, Jennifer A, Arking, Dan E, Hucker, William J, Yin, Xiaoyan, Lin, Honghuang, Mills, Robert W, Sinner, Moritz F, Lubitz, Steven A, Liu, Ching-Ti, Morrison, Alanna C, Alonso, Alvaro, Li, Ning, Fedorov, Vadim V, Janssen, Paul M, Bis, Joshua C, Heckbert, Susan R, Dolmatova, Elena V, Lumley, Thomas, Sitlani, Colleen M, Cupples, L Adrienne, Pulit, Sara L, Newton-Cheh, Christopher, Barnard, John, Smith, Jonathan D, Van Wagoner, David R, Chung, Mina K, Vlahakes, Gus J, O'Donnell, Christopher J, Rotter, Jerome I, Margulies, Kenneth B, Morley, Michael P, Cappola, Thomas P, Benjamin, Emelia J, Muzny, Donna, Gibbs, Richard A, Jackson, Rebecca D, Magnani, Jared W, Herndon, Caroline N, Rich, Stephen S, Psaty, Bruce M, Milan, David J, Boerwinkle, Eric, Mohler, Peter J, Sotoodehnia, Nona, and Ellinor, Patrick T

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Genetics, Heart Disease, Biotechnology, Cardiovascular, Aetiology, 2.1 Biological and endogenous factors, Biophysical Phenomena, Electrocardiography, Genetic Association Studies, Haplotypes, Heart Conduction System, Humans, Ion Channel Gating, Mutation, Missense, NAV1.8 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Quantitative Trait Loci, atrial fibrillation, electrocardiography, haplotypes, Na plus channels, population genetics, Na+ channels, genetics, population, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology
Abstract

BACKGROUND:Genetic variants at the SCN5A/SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized. METHODS:We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology. RESULTS:We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium (r  2=0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, P=1.52×10-14) and QRS intervals (rs6599251, QRS β=-0.73; P=1.2×10-4), respectively. Although these variants were not associated with SCN5A or SCN10A expression in human atrial tissue (n=490), they were in high linkage disequilibrium (r  2≥0.72) with a common SCN10A missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, P=0.03, and I962V+V1073A, 22.4±0.8%, P=0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, P=0.03). CONCLUSIONS:Our findings suggest an association between genetic variation in SCN10A, the late sodium current, and alterations in cardiac conduction.

Published
2018

40. Perinuclear damage from nuclear envelope deterioration elicits stress responses that contribute to LMNA cardiomyopathy

Author

Sikder, Kunal, primary, Phillips, Elizabeth, additional, Zhong, Zhijiu, additional, Wang, Nadan, additional, Saunders, Jasmine, additional, Mothy, David, additional, Kossenkov, Andrew, additional, Schneider, Timothy, additional, Nichtova, Zuzana, additional, Csordas, Gyorgy, additional, Margulies, Kenneth B., additional, and Choi, Jason C., additional

Published
2024
Full Text
View/download PDF

42. In vivo label-free structural and biochemical imaging of coronary arteries using an integrated ultrasound and multispectral fluorescence lifetime catheter system.

Author

Bec, Julien, Phipps, Jennifer E, Gorpas, Dimitris, Ma, Dinglong, Fatakdawala, Hussain, Margulies, Kenneth B, Southard, Jeffrey A, and Marcu, Laura

Subjects
Animals, Swine, Humans, Ultrasonography, Histocytochemistry, Coronary Artery Disease, Cardiac Catheterization, Optical Imaging
Abstract

Existing clinical intravascular imaging modalities are not capable of accurate detection of critical plaque pathophysiology in the coronary arteries. This study reports the first intravascular catheter combining intravascular ultrasound (IVUS) with multispectral fluorescence lifetime imaging (FLIm) that enables label-free simultaneous assessment of morphological and biochemical features of coronary vessels in vivo. A 3.7 Fr catheter with a fiber-optic channel was constructed based on a 40 MHz clinical IVUS catheter. The ability to safely acquire co-registered FLIm-IVUS data in vivo using Dextran40 solution flushing was demonstrated in swine coronary arteries. FLIm parameters from the arterial wall were consistent with the emission of fluorophores present in healthy arterial wall (collagen, elastin). Additionally, structural and biochemical features from atherosclerotic lesions were acquired in ex vivo human coronary samples and corroborated with histological findings. Current results show that FLIm parameters linked to the amount of structural proteins (e.g. collagen, elastin) and lipids (e.g. foam cells, extracellular lipids) in the first 200 μm of the intima provide important biochemical information that can supplement IVUS data for a comprehensive assessment of plaques pathophysiology. The unique FLIm-IVUS system evaluated here has the potential to provide a comprehensive insight into atherosclerotic lesion formation, diagnostics and response to therapy.

Published
2017

43. Integrating Clinical Phenotype With Multiomics Analyses of Human Cardiac Tissue Unveils Divergent Metabolic Remodeling in Genotype-Positive and Genotype-Negative Patients With Hypertrophic Cardiomyopathy

Author

Onderzoek Precision medicine, Nollet, Edgar E., Schuldt, Maike, Sequeira, Vasco, Binek, Aleksandra, Pham, Thang V., Schoonvelde, Stephan A.C., Jansen, Mark, Schomakers, Bauke V., van Weeghel, Michel, Vaz, Fred M., Houtkooper, Riekelt H., Van Eyk, Jennifer E., Jimenez, Connie R., Michels, Michelle, Bedi, Kenneth C., Margulies, Kenneth B., dos Remedios, Cristobal G., Kuster, Diederik W.D., van der Velden, Jolanda, Onderzoek Precision medicine, Nollet, Edgar E., Schuldt, Maike, Sequeira, Vasco, Binek, Aleksandra, Pham, Thang V., Schoonvelde, Stephan A.C., Jansen, Mark, Schomakers, Bauke V., van Weeghel, Michel, Vaz, Fred M., Houtkooper, Riekelt H., Van Eyk, Jennifer E., Jimenez, Connie R., Michels, Michelle, Bedi, Kenneth C., Margulies, Kenneth B., dos Remedios, Cristobal G., Kuster, Diederik W.D., and van der Velden, Jolanda

Published
2024

44. Integrating Clinical Phenotype With Multiomics Analyses of Human Cardiac Tissue Unveils Divergent Metabolic Remodeling in Genotype-Positive and Genotype-Negative Patients With Hypertrophic Cardiomyopathy

Author

Nollet, Edgar E., Schuldt, Maike, Sequeira, Vasco, Binek, Aleksandra, Pham, Thang V., Schoonvelde, Stephan A.C., Jansen, Mark, Schomakers, Bauke V., van Weeghel, Michel, Vaz, Fred M., Houtkooper, Riekelt H., Van Eyk, Jennifer E., Jimenez, Connie R., Michels, Michelle, Bedi, Kenneth C., Margulies, Kenneth B., dos Remedios, Cristobal G., Kuster, Diederik W.D., van der Velden, Jolanda, Nollet, Edgar E., Schuldt, Maike, Sequeira, Vasco, Binek, Aleksandra, Pham, Thang V., Schoonvelde, Stephan A.C., Jansen, Mark, Schomakers, Bauke V., van Weeghel, Michel, Vaz, Fred M., Houtkooper, Riekelt H., Van Eyk, Jennifer E., Jimenez, Connie R., Michels, Michelle, Bedi, Kenneth C., Margulies, Kenneth B., dos Remedios, Cristobal G., Kuster, Diederik W.D., and van der Velden, Jolanda

Abstract

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by sarcomere gene mutations (genotype-positive HCM) in ≈50% of patients and occurs in the absence of mutations (genotype-negative HCM) in the other half of patients. We explored how alterations in the metabolomic and lipidomic landscape are involved in cardiac remodeling in both patient groups. METHODS: We performed proteomics, metabolomics, and lipidomics on myectomy samples (genotype-positive N=19; genotype-negative N=22; and genotype unknown N=6) from clinically well-phenotyped patients with HCM and on cardiac tissue samples from sex- and age-matched and body mass index-matched nonfailing donors (N=20). These data sets were integrated to comprehensively map changes in lipid-handling and energy metabolism pathways. By linking metabolomic and lipidomic data to variability in clinical data, we explored patient group-specific associations between cardiac and metabolic remodeling. RESULTS:HCM myectomy samples exhibited (1) increased glucose and glycogen metabolism, (2) downregulation of fatty acid oxidation, and (3) reduced ceramide formation and lipid storage. In genotype-negative patients, septal hypertrophy and diastolic dysfunction correlated with lowering of acylcarnitines, redox metabolites, amino acids, pentose phosphate pathway intermediates, purines, and pyrimidines. In contrast, redox metabolites, amino acids, pentose phosphate pathway intermediates, purines, and pyrimidines were positively associated with septal hypertrophy and diastolic impairment in genotype-positive patients. CONCLUSIONS: We provide novel insights into both general and genotype-specific metabolic changes in HCM. Distinct metabolic alterations underlie cardiac disease progression in genotype-negative and genotype-positive patients with HCM.

Published
2024

50. Comparing Raman and fluorescence lifetime spectroscopy from human atherosclerotic lesions using a bimodal probe

Author

Dochow, Sebastian, Fatakdawala, Hussain, Phipps, Jennifer E, Ma, Dinglong, Bocklitz, Thomas, Schmitt, Michael, Bishop, John W, Margulies, Kenneth B, Marcu, Laura, and Popp, Jürgen

Subjects
Analytical Chemistry, Medicinal and Biomolecular Chemistry, Chemical Sciences, Bioengineering, Biomedical Imaging, Clinical Research, Cardiovascular, Atherosclerosis, Coronary Vessels, Humans, Myocardium, Optical Imaging, Spectrometry, Fluorescence, Spectrum Analysis, Raman, fluorescence lifetime, Raman spectroscopy, bimodal, imaging, fiber probes, atherosclerosis, Optical Physics, Medical Biotechnology, Optoelectronics & Photonics, Analytical chemistry, Medicinal and biomolecular chemistry
Abstract

Fluorescence lifetime imaging (FLIm) and Raman spectroscopy are two promising methods to support morphological intravascular imaging techniques with chemical contrast. Both approaches are complementary and may also be used in combination with OCT/IVUS to add chemical specificity to these morphologic intravascular imaging modalities. In this contribution, both modalities were simultaneously acquired from two human coronary specimens using a bimodal probe. A previously trained SVM model was used to interpret the fluorescence lifetime data; integrated band intensities displayed in RGB false color images were used to interpret the Raman data. Both modalities demonstrate unique strengths and weaknesses and these will be discussed in comparison to histologic analyses from the two coronary arteries imaged.

Published
2016

Catalog

Books, media, physical & digital resources
See catalog results