Effects of early treatment with growth hormone on infarct size, survival, and cardiac gene expression after acute myocardial infarction

Dronedarone improves microvascular flow during atrial fibrillation and reduces the infarct size in acute models of myocardial infarction. However, dronedarone might be harmful in patients with recent decompensated heart failure and increases mortality in patients with permanent atrial fibrillation. A pathophysiological explanation for these discrepant data is lacking. This study investigated the effects of dronedarone on gene and protein expression in the infarcted area and border zone in pigs subjected to anterior ischemia/reperfusion myocardial infarction. The ischemia/reperfusion myocardial infarction was induced in 16 pigs. Eight pigs were treated with dronedarone for 28 days after myocardial infarction, the remaining pigs served as control. Microarray-based transcriptome profiling and 2D-DIGE-based proteome analysis were used to assess the effects of dronedarone on left ventricular gene expression in healthy (LV), infarcted (MI), and border zone tissue. Selected targets were validated by RT-qPCR or immunoblot analyses, with special emphasize given to the transcriptome/proteome overlap. Combined “omics” analysis was performed to identify most significant disease and function charts affected by dronedarone and to establish an integrated network. The levels of 879 (BZ) or 7 (MI) transcripts and 51 (LV) or 15 (BZ) proteins were significantly altered by dronedarone, pointing to a substantial efficacy of dronedarone in the border zone. Transcriptome and proteome data indicate that dronedarone influences post-infarction remodeling processes and identify matricellular proteins as major targets of dronedarone in this setting. This finding is fully supported by the disease and function charts as well as by the integrated network established by combined “omics”. Dronedarone therapy alters myocardial gene expression after acute myocardial infarction with pronounced effects in the border zone. Dronedarone promotes infarct healing via regulation of periostin and might contribute to the limitation of its expansion as well as cardiac rupture. Thus, there are no experimental hints that dronedarone per se has direct harmful effects after MI in ventricular tissue. Impact statement Dronedarone reduced the infarct size in models of acute myocardial infarction (MI). Here, we show that dronedarone attenuates many of the substantial changes in gene expression that are provoked by acute myocardial infarction (AMI) in pigs. Dronedarone modifies the expression of gene panels related to post-infarction cardiac healing and remodeling processes and, most remarkably, this occurs predominantly in the infarction border-zone and much less so in the vital or infarcted myocardium. Combined “omics” identified matricellular proteins and ECM as major dronedarone-regulated targets and emphasizes their relevance for Disease Charts and Tox Function Charts associated with tissue remodeling and cellular movement. The results demonstrate dronedarone’s capability of regulating cardiac repair and remodeling processes specifically in the infarction border zone and identify underlying mechanisms and pathways that might be employed in future therapeutic strategies to improve long-term cardiac tissue function and stability.

Download Full-text

Stem cell-related cardiac gene expression early after murine myocardial infarction

Cardiovascular Research ◽

10.1016/j.cardiores.2006.11.030 ◽

2007 ◽

Vol 73 (4) ◽

pp. 783-793 ◽

Cited By ~ 47

Author(s):

Susanne Vandervelde ◽

Marja J.A. van Luyn ◽

Mark H. Rozenbaum ◽

Arjen H. Petersen ◽

Rene A. Tio ◽

...

Keyword(s):

Gene Expression ◽

Myocardial Infarction ◽

Stem Cell ◽

Cardiac Gene Expression ◽

Cardiac Gene

Download Full-text

Alterations in Cardiac Gene Expression During Ventricular Remodeling Following Experimental Myocardial Infarction

Journal of Molecular and Cellular Cardiology ◽

10.1006/jmcc.1997.0628 ◽

1998 ◽

Vol 30 (3) ◽

pp. 627-637 ◽

Cited By ~ 42

Author(s):

Madhavi Gidh-Jain ◽

Boyu Huang ◽

Praveer Jain ◽

Gregory Gick ◽

Nabil El-Sherif

Keyword(s):

Gene Expression ◽

Myocardial Infarction ◽

Ventricular Remodeling ◽

Experimental Myocardial Infarction ◽

Cardiac Gene Expression ◽

Cardiac Gene

Download Full-text

P2889 Left-ventricular asynchrony after acute myocardial infarction correlates with infarct size

European Heart Journal ◽

10.1016/s0195-668x(03)95667-3 ◽

2003 ◽

Vol 24 (5) ◽

pp. 554

Author(s):

Y ZHANG

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Infarct Size ◽

Left Ventricular ◽

Ventricular Asynchrony ◽

Left Ventricular Asynchrony

Download Full-text

P942 Infarct size and mortality after glucose-insulin-potassium infusion in primary angioplasty for acute myocardial infarction

European Heart Journal ◽

10.1016/s0195-668x(03)94234-5 ◽

2003 ◽

Vol 24 (5) ◽

pp. 156

Author(s):

J VANDERHORST

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Infarct Size ◽

Primary Angioplasty

Download Full-text

Preinfarction Angina and Improved Reperfusion of the Infarct-related Artery

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615557 ◽

1999 ◽

Vol 82 (S 01) ◽

pp. 68-72 ◽

Cited By ~ 2

Author(s):

Alessandro Sciahbasi ◽

Eugenia De Marco ◽

Attilio Maseri ◽

Felicita Andreotti

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Infarct Size ◽

Ischemic Preconditioning ◽

Early Reperfusion ◽

Vast Number ◽

Beneficial Effects ◽

Infarct Related Artery ◽

Cardioprotective Effects ◽

Collateral Vessels

SummaryPreinfarction angina and early reperfusion of the infarct-related artery are major determinants of reduced infarct-size in patients with acute myocardial infarction. The beneficial effects of preinfarction angina on infarct size have been attributed to the development of collateral vessels and/or to post-ischemic myocardial protection. However, recently, a relation has been found between prodromal angina, faster coronary recanalization, and smaller infarcts in patients treated with rt-PA: those with preinfarction angina showed earlier reperfusion (p = 0.006) and a 50% reduction of CKMB-estimated infarct-size (p = 0.009) compared to patients without preinfarction angina. This intriguing observation is consistent with a subsequent observation of higher coronary recanalization rates following thrombolysis in patients with prodromal preinfarction angina compared to patients without antecedent angina. Recent findings in dogs show an enhanced spontaneous lysis of plateletrich coronary thrombi with ischemic preconditioning, which is prevented by adenosine blockade, suggesting an antithrom-botic effect of ischemic metabolites. Understanding the mechanisms responsible for earlier and enhanced coronary recanalization in patients with preinfarction angina may open the way to new reperfusion strategies.A vast number of studies, globally involving ≈17,000 patients with acute myocardial infarction, have unequivocally shown that an infarction preceded by angina evolves into a smaller area of necrosis compared to an infarct not preceded by angina (Table 1) (1). So far, preinfarction angina has been thought to have cardioprotective effects mainly through two mechanisms: collateral perfusion of the infarctzone (2-4), and ischemic preconditioning of the myocardium (5-7). Here we discuss a further mechanism of protection represented by improved reperfusion of the infarct-related artery.

Download Full-text