Molecular basis of takotsubo syndrome
Introduction Takotsubo syndrome (TTS), also known as the “Broken Heart Syndrome” or “Apical Ballooning Syndrome is defined by its characteristic anomaly: when the heart contracts during systole, the apex of the heart dilates as the base of the heart contracts. Severe TTS can lead to cardiogenic shock and death in 3–4% of patients. There is no standard medical therapy for TTS because the mechanism underlying the development of the syndrome is unknown. Our goal is to determine the molecular mechanisms of TTS as a first step towards better treatment plans and outcomes. Methods Our model of TTS is a Kv1.5 null mouse, with compromised coronary metabolic dilation, subjected to transaortic constriction (TAC). Two weeks after TAC, when Kv1.5 null mouse showed profound apical ballooning during ventricular contraction (echocardiography), myocardial blood flow (MBF) was measured by contrast echocardiography in the base and apex of the left ventricle of mice under control conditions and during acute administration of norepinephrine to increase cardiac work. Hearts were collected and gene expression (RNA deep sequencing) in both the apex and the base were performed and followed by bioinformatic analysis. Wild type (WT) and unstressed Kv1.5 null mice were used as controls. To increase the scientific rigor, we purposefully analyzed RNA expression from different animals with Real‐Time‐PCR, to confirm the sequencing data. Results A total of 3875 genes were identified by differentially expressed between TTS vs unstressed Kv1.5 null hearts. Gene Set Enrichment Analysis shows many families of genes downregulated (metabolism) and upregulated (inflammation, hypoxia, apoptosis) in the apical (ballooning) area of the heart in TTS (compared to the base of the heart). RT‐qPCR revealed significant upregulation of the genes for Postn, Lox, and C920009B18Rik (p<0.01) and down‐regulation of the genes Ucp3, Acaa2, Pfkb1, Mir133a‐2 (p<0.05). These significant changes in expression were also shown in the apex of TTS hearts as compared to the apex of control Kv1.5 null hearts (p<0.01). We also found that in the mice with TTS, MBF was lower in the apex than in the base. Conclusion Our results suggest that the apex of the heart in TTS is receiving insufficient perfusion compared to the base, which may be one of the root problems in TTS. There is significant upregulation of structural genes in the apex of TTS hearts versus their bases and the apexes of normal hearts, whereas there is a significant downregulation of genes playing roles in metabolism. This confirms the importance of these specific genes in the development of the anomaly shown in TTS.
Chandler S;Joshi H;Hoff E;Patel K;Ohanyan V;Kiedrowski M;Chilian W;Dong F
Faseb Journal
2020
2020-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1096/fasebj.2020.34.s1.02623" target="_blank" rel="noreferrer noopener">10.1096/fasebj.2020.34.s1.02623</a>
Myocardial CXCR4 expression is required for mesenchymal stem cell mediated repair following acute myocardial infarction.
Mice; Myocardium; Cells; Receptors; Proteins; Animal Studies; Cell Physiology; Cardiovascular System Physiology; Myocardial Infarction; Myocardial Infarction – Therapy; Stem Cells – Metabolism; Cytokines – Metabolism; Cell Surface – Metabolism; Myocardial Infarction – Pathology; Apoptosis – Physiology; Cell Movement – Physiology; Cell Surface; Coronary Circulation – Physiology; Gene Expression – Physiology; Stem Cells – Transplantation
BACKGROUND: Overexpression of stromal cell-derived factor-1 in injured tissue leads to improved end-organ function. In this study, we quantify the local trophic effects of mesenchymal stem cell (MSC) stromal cell-derived factor-1 release on the effects of MSC engraftment in the myocardium after acute myocardial infarction. METHODS AND RESULTS: Conditional cardiac myocyte CXCR4 (CM-CXCR4) null mice were generated by use of tamoxifen-inducible cardiac-specific cre by crossing CXCR4 floxed with MCM-cre mouse. Studies were performed in littermates with (CM-CXCR4 null) or without (control) tamoxifen injection 3 weeks before acute myocardial infarction. One day after acute myocardial infarction, mice received 100 000 MSC or saline via tail vein. We show [alpha]-myosin heavy chain MerCreMer and the MLC-2v promoters are active in cardiac progenitor cells. MSC engraftment in wild-type mice decreased terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling positive CM (-44%, P\textless0.01), increased cardiac progenitor cell recruitment (100.9%, P\textless0.01), and increased cardiac myosin-positive area (39%, P\textless0.05) at 4, 7, and 21 days after acute myocardial infarction, respectively. MSC in wild-type mice resulted in 107.4% (P\textless0.05) increase in ejection fraction in comparison with 25.9% (P=NS) increase in CM-CXCR4 null mice. These differences occurred despite equivalent increases (16%) in vascular density in response to MSC infusion in wild-type and CM-CXCR4 null mice. CONCLUSIONS: These data demonstrate that the local trophic effects of MSC require cardiac progenitor cell and CM-CXCR4 expression and are mediated by MSC stromal cell-derived factor-1 secretion. Our results further demonstrate and quantify for the first time a specific paracrine mechanism of MSC engraftment. In the absence of CM-CXCR4 expression, there is a significant loss of functional benefit in MSC-mediated repair despite equal increases in vascular density.
Dong F; Harvey J; Finan A; Weber K; Agarwal U; Penn M S
Circulation
2012
2012-07-17
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/circulationaha.111.082453" target="_blank" rel="noreferrer noopener">10.1161/circulationaha.111.082453</a>
Role of SDF:CXCR4 in diet-induced cardiac injury
Introduction Diabetic cardiomyopathy (DCM) is a major cardiovascular complication in patients with diabetes and is defined as ventricular dysfunction (in diabetes) independent of coronary artery disease. In this study, we define a novel role for the SDF‐1: CXCR4 axis in diabetes‐associated myocardial dysfunction. Methods Wild‐type mice were randomly assigned to a high fat high sugar diet (HFHS) or control diet (LF) for 14 months. Serial echocardiography was used to assess cardiac function. The hSDF‐1 plasmid was injected into the LV wall of HFHS mice 7 months and 14 months after HFHS diet. The mRNA levels in the hearts were quantified by qPCR. Results HFHS‐fed mice (vs. control diet) showed significantly increased deceleration time (diastolic dysfunction) 7 months after HFHS diet and decreased Ejection Fraction (EF) (systolic dysfunction) 14 months after the HFHS diet. We observed a significant increase in cardiac myocytes surface area and a decrease in vascular density in the hearts of HFHS mice. HFHS‐fed mice showed decreased P‐selectin, E‐selectin expression and increased CXCR4, Resistin, and DDR2 expression in the heart. There is no significant improvement in diastolic function after the SDF‐1 injection at 7 month. However, direct myocardial injection of hSDF‐1 plasmid led to a significant improvement in EF compared to the control group. To determine the role of CM CXCR4 in hyperglycemia associated cardiac injury, we quantified cardiac function and survival rate in HFHS‐fed CM‐CXCR4 null mice. We observed a significantly increased mortality rate before 14 months on HFHS fed CM‐CXCR4 null mice compare to HFHS‐fed control mice. Conclusion HFHS diet induces diastolic dysfunction in the short term then systolic dysfunction after a long term. SDF‐1 treatment ameliorates systolic dysfunction but not diastolic dysfunction. Our data suggest that cardiac myocyte expression of CXCR4 has an important role in diabetes‐associated cardiac injury.
Dong F;Patel K;Kiedrowski M;Penn M
Faseb Journal
2020
2020-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1096/fasebj.2020.34.s1.01787" target="_blank" rel="noreferrer noopener">10.1096/fasebj.2020.34.s1.01787</a>
Early Up-regulation Of Myocardial Cxcr4 Expression Is Critical For Cardiac Improvement With Chemical Preconditioning In Acute Myocardial Infarction
Cardiac regeneration; Cardiovascular System & Cardiology; heart failure; Myocardial infarction
Kamath M; Kiedrowski M; Weber K; Forudi F; Penn M S; Dong F
Circulation
2013
2013-11
Journal Article or Conference Abstract Publication
n/a
Stem cells for myocardial regeneration.
Animals; Clinical Trials as Topic/trends; Humans; Myocardial Infarction/pathology/physiopathology/*surgery; Regeneration/*physiology; Regenerative Medicine/*trends; Stem Cell Transplantation/*trends
The field of cardiovascular regenerative medicine has made significant strides over the past decade. Clinical trials have demonstrated benefit in acute myocardial infarction (AMI) and chronic heart failure (CHF). As the field has matured, it has defined novel biology and invented an array of therapeutic strategies that are currently under development. In this brief review, we attempt to conceptualize the knowledge to date as well as examine how this knowledge has been translated to various therapeutic strategies.
Penn M S; Dong F; Klein S; Mayorga M E
Clinical pharmacology and therapeutics
2011
2011-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/clpt.2011.196" target="_blank" rel="noreferrer noopener">10.1038/clpt.2011.196</a>