Congenital heart disease (CHD) is the most common birth defect in the United States and affects 1% or 40,000 births/year. The complexity of CHD can range from simple structural abnormalities that affect isolated cardiac structures such as valves or heart walls to complex abnormalities that can lead to severely underdeveloped cardiac structures that require surgical interventions to help with survival.

The Saraf Laboratory is interested in exploring molecular and cellular mechanisms that affect long term outcomes in patients with congenital heart disease and finding therapies to address sequalae associated with CHD such as heart failure and arrhythmia.

Our laboratory uses induced pluripotent stem cell (iPSC) derived cardiomyocytes from patients with CHD as well as genetically modified cells that have mutations, similar to those associated with various forms of CHD. We are using CRISPR-Cas9 gene editing technology to create complex hypomorphic mutations in genes to understand how we can tune gene expression levels to affect severity of CHD.

Our laboratory is funded by the American Heart Association and the National Institutes of Health in addition to intramural and extramural individual grants.

Research Interests

Cellular Physiology of HLHS

Hypoplastic left heart syndrome (HLHS) is one of the most severe forms of CHD with the highest mortality. Structures within the left side of the heart, such as the mitral valve, the left ventricle, aortic valve and the aorta are severely underdeveloped in babies born with HLHS. Mutations in cardiac developmental protein NOTCH1 have a higher incidence in HLHS. We are interested in understanding how intracellular structures are affected in cardiomyocytes of HLHS patients, and the result these abnormalities have on the beating of cardiomyocytes. This information will help us understand how we can change intracellular structures to improve cardiomyocyte structure and function.

Drug Discovery for HLHS

Using our high throughput drug discovery platform, we have established novel screening methods to test drugs that can improve cardiomyocyte physiology and function. Check out our drug discovery center!

 

 

 

 

 

 

Role of Inflammation in CHD comorbidities

Our patient-based studies have shown that inflammatory markers such as TNF-α and IL-6 are mild to moderately elevated in our most complex CHD patients, even when they are doing well clinically. Our laboratory is investigating how inflammation affects outcomes in CHD patients. Understanding the effect of inflammation on CHD outcomes will help us identify biologic factors that cause poor outcomes in CHD patients.

Organ-on-a-chip model for CHD

Cardiomyocytes experience various forces within a beating heart including cyclic elongation when the heart fills with blood (diastole) and contraction facilitated by the cardiomyocyte itself (systole). Our laboratory studies the influence of his cyclic motion using bioreactors custom built to closely emulate the various forces experienced by the cardiomyocyte. These bioreactors enhance the understanding of how the beating heart differentially affects cardiomyocytes in CHD patients versus patients without any abnormalities.

Meet the Team

Anita Saraf, MD, PhD

PRINCIPAL INVESTIGATOR

Assistant Professor of Medicine (Cardiology) and Pediatrics;
McGowan Regenerative Institute

Email: sarafap@upmc.edu

Brian Toma

Email: bpt27@pitt.edu

Shourya Mukherjee

Email: ssm58@pitt.edu

Funding

Publications

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Kazerouninia A, Georgekutty J, Kendsersky P, Byrne RD, Seto B, Chu PY, Wang Y, Rodriguez FH 3rd, Smith C, Saraf A, Lloyd MS, Frischhertz BP, Parekh DR, Ermis PR, Franklin WJ, Lam WW. A Multisite Retrospective Review of Direct Oral Anticoagulants Compared to Warfarin in Adult Fontan Patients. Cardiovasc Drugs Ther. 2022 Jan 13. doi: 10.1007/s10557-021-07298-5. Epub ahead of print. PMID: 35022950.
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Saraf A, Book W. Reply to the Letter to the Editor: “GDF-15 – A matter of the heart or the kidney?”. Int J Cardiol. 2020 Aug 15;313:46. doi: 10.1016/j.ijcard.2020.04.008. PMID: 32517964.

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Saraf, A, Management of Congenital Heart Disease in Adulthood, Chapter for Elsevier Clinical Overviews, In press, Nov 2021.

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Raskind-Hood C, Saraf A, Riehle-Colarusso T, Glidewell J, Gurvitz M, Dunn JE, Lui GK, Van Zutphen A, McGarry C, Hogue CJ, Hoffman T, Rodriguez Iii FH, Book WM. Assessing Pregnancy, Gestational Complications, and Co-morbidities in Women With Congenital Heart Defects (Data from ICD-9-CM Codes in 3 US Surveillance Sites). Am J Cardiol. 2020 Mar 1;125(5):812-819. doi: 10.1016/j.amjcard.2019.12.001. Epub 2019 Dec 9. PMID: 31902476; PMCID: PMC7493054.

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Saraf A, Rampoldi A, Chao M, Li D, Armand L, Hwang H, Liu R, Jha R, Fu H, Maxwell JT, Xu C. Functional and molecular effects of TNF-α on human iPSC-derived cardiomyocytes. Stem Cell Res. 2021 Apr;52:102218. doi: 10.1016/j.scr.2021.102218. Epub 2021 Feb 1. PMID: 33592567; PMCID: PMC8080119.

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Saraf A, De Staercke C, Everitt I, Haouzi A, Ko YA, Jennings S, Kim JH, Rodriguez FH, Kalogeropoulos AP, Quyyumi A, Book W. Biomarker profile in stable Fontan patients. Int J Cardiol. 2020 Apr 15;305:56-62. doi: 10.1016/j.ijcard.2020.01.012. Epub 2020 Jan 9. PMID: 31959411; PMCID: PMC7133708.

View all publications
  1. Kazerouninia A, Georgekutty J, Kendsersky P, Byrne RD, Seto B, Chu PY, Wang Y, Rodriguez FH 3rd, Smith C, Saraf A, Lloyd MS, Frischhertz BP, Parekh DR, Ermis PR, Franklin WJ, Lam WW. A Multisite Retrospective Review of Direct Oral Anticoagulants Compared to Warfarin in Adult Fontan Patients. Cardiovasc Drugs Ther. 2022 Jan 13. doi: 10.1007/s10557-021-07298-5. Epub ahead of print. PMID: 35022950.
  1. Saraf, A, Management of Congenital Heart Disease in Adulthood, Chapter for Elsevier Clinical Overviews, In press, Nov 2021.
  1. Saraf A, Rampoldi A, Chao M, Li D, Armand L, Hwang H, Liu R, Jha R, Fu H, Maxwell JT, Xu C. Functional and molecular effects of TNF-α on human iPSC-derived cardiomyocytes. Stem Cell Res. 2021 Apr;52:102218. doi: 10.1016/j.scr.2021.102218. Epub 2021 Feb 1. PMID: 33592567; PMCID: PMC8080119.
  1. Saraf A, Book W. Reply to the Letter to the Editor: “GDF-15 – A matter of the heart or the kidney?”. Int J Cardiol. 2020 Aug 15;313:46. doi: 10.1016/j.ijcard.2020.04.008. PMID: 32517964.
  1. Saraf A, De Staercke C, Everitt I, Haouzi A, Ko YA, Jennings S, Kim JH, Rodriguez FH, Kalogeropoulos AP, Quyyumi A, Book W. Biomarker profile in stable Fontan patients. Int J Cardiol. 2020 Apr 15;305:56-62. doi: 10.1016/j.ijcard.2020.01.012. Epub 2020 Jan 9. PMID: 31959411; PMCID: PMC7133708.
  1. Raskind-Hood C, Saraf A, Riehle-Colarusso T, Glidewell J, Gurvitz M, Dunn JE, Lui GK, Van Zutphen A, McGarry C, Hogue CJ, Hoffman T, Rodriguez Iii FH, Book WM. Assessing Pregnancy, Gestational Complications, and Co-morbidities in Women With Congenital Heart Defects (Data from ICD-9-CM Codes in 3 US Surveillance Sites). Am J Cardiol. 2020 Mar 1;125(5):812-819. doi: 10.1016/j.amjcard.2019.12.001. Epub 2019 Dec 9. PMID: 31902476; PMCID: PMC7493054.
  1. Saraf A, Rodriguez FH, Peripartum Cardiomyopathy and Heart Failure in Pregnancy. Heart Failure: An Essential Clinical Guide. (Book Chapter), 2020, Accepted.
  1. Saraf A, Book WM, Nelson TJ, Xu C. Hypoplastic left heart syndrome: From bedside to bench and back. J Mol Cell Cardiol. 2019 Oct;135:109-118. doi: 10.1016/j.yjmcc.2019.08.005. Epub 2019 Aug 13. PMID: 31419439.
  1. Peoples JN, Saraf A, Ghazal N, Pham TT, Kwong JQ. Mitochondrial dysfunction and oxidative stress in heart disease. Exp Mol Med. 2019 Dec 19;51(12):1-13. doi: 10.1038/s12276-019-0355-7. PMID: 31857574; PMCID: PMC6923355.
  1. Gentillon C, Li D, Duan M, Yu WM, Preininger MK, Jha R, Rampoldi A, Saraf A, Gibson GC, Qu CK, Brown LA, Xu C. Targeting HIF-1α in combination with PPARα activation and postnatal factors promotes the metabolic maturation of human induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol. 2019 Jul;132:120-135. doi: 10.1016/j.yjmcc.2019.05.003. Epub 2019 May 11. PMID: 31082397; PMCID: PMC6683286.
  1. Rampoldi A, Singh M, Wu Q, Duan M, Jha R, Maxwell JT, Bradner JM, Zhang X, Saraf A, Miller GW, Gibson G, Brown LA, Xu C. Cardiac Toxicity From Ethanol Exposure in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292. doi: 10.1093/toxsci/kfz038. PMID: 31059573; PMCID: PMC6484889.
  1. Bradley EA, Saraf A, Book W. Heart Failure in Women with Congenital Heart Disease. Heart Fail Clin. 2019 Jan;15(1):87-96. doi: 10.1016/j.hfc.2018.08.009. Epub 2018 Oct 24. PMID: 30449383.
  1. Titterington JS, Hung OY, Saraf AP, Wenger NK. Gender differences in acute coronary syndromes: focus on the women with ACS without an obstructing culprit lesion. Expert Rev Cardiovasc Ther. 2018 Apr;16(4):297-304. doi: 10.1080/14779072.2018.1443808. Epub 2018 Mar 7. PMID: 29471698.
  1. Klouda L, Franklin WJ, Saraf A, Parekh DR, Schwartz DD. Neurocognitive and executive functioning in adult survivors of congenital heart disease. Congenit Heart Dis. 2017 Jan;12(1):91-98. doi: 10.1111/chd.12409. Epub 2016 Sep 21. PMID: 27650247.
  1. Gerardin J, Rodriguez III FH, Saraf A, Book W. Heart Transplantation in Adults for Fontan Failure. Progress in Pediatric Cardiology. 2016, September 20; 42:17-22
  1. Book WM, Gerardin J, Saraf A, Marie Valente A, Rodriguez F 3rd. Clinical Phenotypes of Fontan Failure: Implications for Management. Congenit Heart Dis. 2016 Jul;11(4):296-308. doi: 10.1111/chd.12368. Epub 2016 May 26. PMID: 27226033.
  1. Hebson C, Saraf A, Book WM. Risk Assessment and Management of the Mother with Cardiovascular Disease. Clin Perinatol. 2016 Mar;43(1):1-22. doi: 10.1016/j.clp.2015.11.001. PMID: 26876118.
  1. Saraf A, Franklin WJ, Snyder CS, Fraser CD Jr, Salazar JD. Intermittent cyanosis years after a Mustard repair for dextro-transposition of the great arteries. Tex Heart Inst J. 2012;39(5):665-7. PMID: 23109763; PMCID: PMC3461672.
  1. Martins AM, Saraf A, Sousa RA, Alves CM, Mikos AG, Kasper FK, Reis RL. Combination of enzymes and flow perfusion conditions improves osteogenic differentiation of bone marrow stromal cells cultured upon starch/poly(epsilon-caprolactone) fiber meshes. J Biomed Mater Res A. 2010 Sep 15;94(4):1061-9. doi: 10.1002/jbm.a.32785. PMID: 20694973.
  1. Guo X, Liao J, Park H, Saraf A, Raphael RM, Tabata Y, Kasper FK, Mikos AG. Effects of TGF-beta3 and preculture period of osteogenic cells on the chondrogenic differentiation of rabbit marrow mesenchymal stem cells encapsulated in a bilayered hydrogel composite. Acta Biomater. 2010 Aug;6(8):2920-31. doi: 10.1016/j.actbio.2010.02.046. Epub 2010 Mar 1. PMID: 20197126; PMCID: PMC2882985.
  1. Saraf A, Baggett LS, Raphael RM, Kasper FK, Mikos AG. Regulated non-viral gene delivery from coaxial electrospun fiber mesh scaffolds. J Control Release. 2010 Apr 2;143(1):95-103. doi: 10.1016/j.jconrel.2009.12.009. Epub 2009 Dec 16. PMID: 20006660; PMCID: PMC2840180.
  1. Chew SA, Hacker MC, Saraf A, Raphael RM, Kasper FK, Mikos AG. Altering amine basicities in biodegradable branched polycationic polymers for nonviral gene delivery. Biomacromolecules. 2010 Mar 8;11(3):600-9. doi: 10.1021/bm901147k. PMID: 20170180; PMCID: PMC2842827.
  1. Chew SA, Hacker MC, Saraf A, Raphael RM, Kasper FK, Mikos AG. Biodegradable branched polycationic polymers with varying hydrophilic spacers for nonviral gene delivery. Biomacromolecules. 2009 Sep 14;10(9):2436-45. doi: 10.1021/bm9003783. PMID: 19678696; PMCID: PMC2743757.
  1. Saraf A, Lozier G, Haesslein A, Kasper FK, Raphael RM, Baggett LS, Mikos AG. Fabrication of nonwoven coaxial fiber meshes by electrospinning. Tissue Eng Part C Methods. 2009 Sep;15(3):333-344. doi: 10.1089/ten.tec.2008.0422. PMID: 19196125; PMCID: PMC2738761.
  1. Sitharaman B, Zakharian TY, Saraf A, Misra P, Ashcroft J, Pan S, Pham QP, Mikos AG, Wilson LJ, Engler DA. Water-soluble fullerene (C60) derivatives as nonviral gene-delivery vectors. Mol Pharm. 2008 Jul-Aug;5(4):567-78. doi: 10.1021/mp700106w. Epub 2008 May 28. PMID: 18505267; PMCID: PMC2652357.
  1. Saraf A, Hacker MC, Sitharaman B, Grande-Allen KJ, Barry MA, Mikos AG. Synthesis and conformational evaluation of a novel gene delivery vector for human mesenchymal stem cells. Biomacromolecules. 2008 Mar;9(3):818-27. doi: 10.1021/bm701146f. Epub 2008 Feb 5. PMID: 18247565.
  1. Saraf A, Mikos AG. Gene delivery strategies for cartilage tissue engineering. Adv Drug Deliv Rev. 2006 Jul 7;58(4):592-603. doi: 10.1016/j.addr.2006.03.005. PMID: 16766079; PMCID: PMC2702530.
  1. Lu J, Caplan MS, Saraf AP, Li D, Adler L, Liu X, Jilling T. Platelet-activating factor-induced apoptosis is blocked by Bcl-2 in rat intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2004 Feb;286(2):G340-50. doi: 10.1152/ajpgi.00182.2003. Epub 2003 Sep 25. PMID: 14512286.
Dr. Saraf's NCBI Bibliography

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