Regional expression of inflammatory and cardiac remodelling genes in a rat model of takotsubo cardiomyopathy

Introduction Takotsubo cardiomyopathy (TTC) is an acute heart failure syndrome with a typical left ventricular ’ballooning‘ and in-hospital mortality rates of 4%–5%. Human studies have shown that structural changes occur in the TTC myocyte and extracellular matrix, such as oedema and fibrosis. In this study an animal model has been used to investigate the expression of genes involved in cardiac inflammation, fibrosis and hypertrophy in the acute stage of TTC. Methods TTC was induced by intraperitoneal injection of a single dose of isoprenaline (100 mg/kg) in 2–4 months old female Sprague Dawley rats (259 ± 48 g). Our previous studies revealed a TTC-like apical ballooning of the left ventricle at day 3 after injection, which resolved at day 7. Accordingly, the left ventricle was collected from control and TTC rats (n=10) on day 3 and separated in to apex, mid-cavity and base. Total RNA was isolated and reverse transcribed to cDNA before gene expression was analysed by real-time PCR. Transcript levels were normalised for HPRT using the delta Ct method and expressed as fold-change relative to control for each region. Results Relative to control, there was a 9-fold increase in Collagen type 1 alpha 1 (Col1a1) mRNA levels in the apex (p=0.006) and mid-cavity (p=0.002) regions and a 3-fold increase in the base (p=0.02) of the TTC rat heart. Similarly, a 3-fold increase in alpha skeletal actin 1 (aSKA1) transcript in the apex (p=0.009) and mid-cavity (p=0.002) regions was observed with no significant difference found in the base. Expression of CD68 was increased 5-fold in the base (p Conclusion In the acute stage a marked upregulation of a global inflammatory response occurs in the TTC rat heart with increased transcription of macrophage marker CD68 evident in all regions. This is accompanied by region-dependent upregulation of myocardial fibrosis occurring most strikingly in the previously akinetic regions and less so in the previously hyperkinetic base. Likewise upregulatory pathways of myocyte hypertrophy are evident in the apex and mid-cavity regions, but not in the base. This suggests that cardiac remodelling manifests at the transcriptional level as early as 3 days following cardiac insult indicating an acute heart failure phenotype in the TTC rat.