Arnar Geirsson MD

Clinical Instructor in Surgery (Section of Cardiac Surgery); Director, Minimally Invasive Cardiac Surgery

Research Interests

Role of micro RNAs in cardiac remodeling; Cardiac regeneration; TGF-beta signaling in degenerative mitral valve disease; Pathology of thoracic aortic aneurysm


Research Summary

The role of micro RNAs in the failing heart and cardiac remodeling.

The molecular mechanism and specifically gene regulation in cardiac remodeling following ischemic insult remain elusive. Neurohormonal factors, ventricular wall stress, alteration in cytoskeletal proteins, desensitization to adrenergic signaling, oxidative stress, cytokines and apoptosis are involved. Micro RNAs (miRNA) have over the last few years been identified as an important mechanism of negative gene regulation and have a role in diverse regulatory pathways.

Cardiac regeneration and role in post myocardial infarction remodeling.

The initial hypothesis or questions that we would like to answer is: Is cardiac regeneration initiated and then halted in mammalian hearts following injury? Are above genes transiently expressed following myocardial infarction and if so what prevents full regeneration of the heart in mammals? Is it possible, by reactivating regenerative mechanisms, to induce native response where the body itself will restore injured heart back to normal function. Research aims will include mouse model of myocardial infarction and development of transgenic mice overexpressing msp1 and msx genes.

MHC suppression in trophoblasts

Recently funded as R21 AI069724-01 by NIH. MHC suppression as a model for transplant. Preliminary data indicate that negative gene regulation through micro RNA and Dicer pathway is involved with TncRNA potentially acting as a precursor of a micro RNA. Research plans includes: Confirmatory studies to demonstrate the involvement of the Dicer pathway. Micro RNA cloning. Analysis of miRNA expression profile in trophoblast. Potential targets involved in MHC regulation will be analysed with corresponding upregulated miRNA for potential miRNA:mRNA interaction.


Extensive Research Description

1. The role of micro RNAs in the failing heart and cardiac remodeling.
The molecular mechanism and specifically gene regulation in cardiac remodeling following ischemic insult remain elusive. Neurohormonal factors, ventricular wall stress, alteration in cytoskeletal proteins, desensitization to adrenergic signaling, oxidative stress, cytokines and apoptosis are involved. Micro RNAs (miRNA) have over the last few years been identified as an important mechanism of negative gene regulation and have a role in diverse regulatory pathways. They are highly conserved across species. They function as molecular switches and fail-safe mechanism to silence unwanted mRNA but are probably more important in fine-tuning of various regulatory pathways. Recently miRNA have clearly been shown to have important role in cardiogenesis and in pathogenesis of cardiac hypertrophy and advanced heart failure. Specific aims include assessing miRNA expression profile in infarcted and adjcent myocardium. Murine model of myocardial infarction will be used. Additionally inducible cardiac specific Dicer knockout mouse will be generated and phenotype assessed for gene expression and function.

2. Cardiac regeneration and role in post myocardial infarction remodeling.
Repeated ischemic insult results in scar tissue formation and cardiac remodeling that eventually has unfavorable cardiac outcome. Various approaches have been attempted to inhibit or ameliorate this response, including medical, mechanical and cell therapy with only moderate success. Zebrafish and newts can fully regenerate their hearts following surgical amputation of 20-30% of ventricular mass including the apex resulting in normally functioning heart without any evidence of scar formation. This true regeneration involves complex set of de novo mechanisms including dedifferentiation of post-mitotic cells, cell proliferation, pattern generation and transdifferentiation of adult specialized cells to rebuild body parts after amputation or injury. The molecular mechanism involved has just started to be identified and includes zebrafish orthologues of msp1, msxB, msxC, Notch1 and deltaC. The initial hypothesis or questions that we would like to answer is: Is cardiac regeneration initiated and then halted in mammalian hearts following injury? Are above genes transiently expressed following myocardial infarction and if so what prevents full regeneration of the heart in mammals? Is it possible, by reactivating regenerative mechanisms, to induce native response where the body itself will restore injured heart back to normal function. Research aims will include mouse model of myocardial infarction and development of transgenic mice overexpressing msp1 and msx genes.

3. MHC suppression in trophoblasts
Recently funded as R21 AI069724-01 by NIH. MHC suppression as a model for transplant tolerance.
Dissecting the mechanism of action of a 481 nt trophoblast RNA (TncRNA) that suppresses MHC class II expression. We have demonstrated that it involves suppression of CIITA promoter III (constitutive) and IV (inducible) activity probably acting as a regulatory RNA. Preliminary data indicate that negative gene regulation through micro RNA and Dicer pathway is involved with TncRNA potentially acting as a precursor of a micro RNA. Research plans includes: Confirmatory studies to demonstrate the involvement of the Dicer pathway. Micro RNA cloning. Analysis of miRNA expression profile in trophoblast. Potential targets involved in MHC regulation will be analysed with corresponding upregulated miRNA for potential miRNA:mRNA interaction.


Selected Publications

  • Sabet W. Hashim, Samuel J. Youssef, Bassem Ayyash, Anthony J Rousou, Sigurdur Ragnarsson, Susan Collazo, Arnar Geirsson. Pseudo-Prolapse of the Anterior Leaflet in Chronic Ischemic Mitral Regurgitation: Identification and Repair. Journal of Thoracic and Cardiovascular Surgery. In press, 2011.
  • Amir H. Lebastchi, Lingfen Qin, Salman F. Khan, Jing Zhou, Arnar Geirsson, Richard W. Kim, Wei Li, George Tellides. Activation of human vascular cells decreases their expression of transforming growth factor-beta. Atherosclerosis. In press, 2011.
  • Amy Gallo, Ahmad Saad, Rahmat Ali, Alan Dardik, George Tellides, Arnar Geirsson. Circulating interferon-?-inducible CXCR3 ligands are elevated in humans with aortic aneurysm and CXCR3 is necessary for aneurysm formation in mice. Journal of Thoracic and Cardiovascular Surgery. In press, 2011.
  • Frederik H.W. Jonker, Felix J.V. Schlosser, Arnar Geirsson, Bauer E. Sumpio, Frans L. Moll, Bart E. Muhs, Endograft Collapse after Thoracic Endovascular Aortic Repair. Journal of Endovascular Therapy. 17;725-734, 2010.
  • Halla Vidarsdottir, Sigurdur Blondal, Hordur Alfredsson, Arnar Geirsson, Tomas Gudbjartsson. Oesophageal perforations in Iceland– A whole population study on incidence, aetiology and surgical outcome. The Thoracic and Cardiovascular Surgeon. 58;476-480, 2010.
  • Usman Ahmad, Rahmat Ali, Amir Lebastchi, Lingfeng Qin, Sheng-fu L. Lo, Alexander O. Yakimov, Salman F. Khan, Jonathan C. Choy, Arnar Geirsson, Jordan S. Pober, George Tellides. Interferon-? Primes Intact Human Coronary Arteries and Cultured Coronary Smooth Muscle Cells to dsRNA and self-RNA Induced Inflammatory Responses by Upregulating TLR3 and MDA5. Journal of Immunology. 185;1283-1294, 2010.
  • John GT. Augoustides, Arnar Geirsson, Wilson Y. Szeto, Elizabeth K. Walsh, Brittany Cornelius, Alberto Pochettino, Joseph E. Bavaria. Observational study of mortality risk stratification by ischemic presentation in patients with acute type A aortic dissection: the Penn classification. Nature Clinical Practice Cardiovascular Medicine. 6;1-7, 2009.
  • Arnar Geirsson, Joseph E. Bavaria, Daniel Swarr, Martin G. Keane, Y. Joseph Woo, Wilson Y. Szeto and Alberto Pochettino. Fate of the Residual Distal and Proximal Aorta after Acute Type A Dissection Repair using Contemporary Surgical Reconstruction Algorithm. Annals of Thoracic Surgery. 84;1955-64, 2007.
  • Wilson Y. Szeto, Joseph E. Bavaria, Frank W Bowen, Arnar Geirsson, Clark W. Hargrove, Alberto Pochettino. Reoperative Aortic Root Replacement in Patients With Previous Aortic Surgery. Annals of Thoracic Surgery. 84;1592-8, 2007.
  • Arnar Geirsson, Alberto Pochettino, Wilson Y. Szeto, Michael L. McGarvey, Martin G. Keane, John G. Augoustides, Y. Joseph Woo, and Joseph E. Bavaria. The significance of malperfusion syndromes following contemporary surgical repair for acute type A aortic dissection: outcomes and need for additional revascularizations. European Journal of Cardio-Thoracic Surgery. 32;255-62, 2007.

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