Limits...
Changes in Myocardial Composition and Conduction Properties in Rat Heart Failure Model Induced by Chronic Volume Overload

View Article: PubMed Central - PubMed

ABSTRACT

Volume overload leads to development of eccentric cardiac hypertrophy and heart failure. In our previous report, we have shown myocyte hypertrophy with no fibrosis and decrease in gap junctional coupling via connexin43 in a rat model of aorto-caval fistula at 21 weeks. Here we set to analyze the electrophysiological and protein expression changes in the left ventricle and correlate them with phenotypic severity based upon ventricles to body weight ratio. ECG analysis showed increased amplitude and duration of the P wave, prolongation of PR and QRS interval, ST segment elevation and decreased T wave amplitude in the fistula group. Optical mapping showed a prolongation of action potential duration in the hypertrophied hearts. Minimal conduction velocity (CV) showed a bell-shaped curve, with a significant increase in the mild cases and there was a negative correlation of both minimal and maximal CV with heart to body weight ratio. Since the CV is influenced by gap junctional coupling as well as the autonomic nervous system, we measured the amounts of tyrosine hydroxylase (TH) and choline acetyl transferase (ChAT) as a proxy for sympathetic and parasympathetic innervation, respectively. At the protein level, we confirmed a significant decrease in total and phosphorylated connexin43 that was proportional to the level of hypertrophy, and similarly decreased levels of TH and ChAT. Even at a single time-point, severity of morphological phenotype correlates with progression of molecular and electrophysiological changes, with the most hypertrophied hearts showing the most severe changes that might be related to arrhythmogenesis.

No MeSH data available.


Related in: MedlinePlus

Correlation analysis of anisotropy of conduction (A) and QRS voltage (B) with connexin43 amount in the ACF rats. With decreasing connexin43 expression that represents increasing phenotypic severity within the ACF group, there is an increase in conduction anisotropy and amplitude of QRS voltage. N = 9 samples from the ACF group (3 for each sub-group), r, Pearson's correlation coefficient. Line represents linear regression.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4997968&req=5

Figure 4: Correlation analysis of anisotropy of conduction (A) and QRS voltage (B) with connexin43 amount in the ACF rats. With decreasing connexin43 expression that represents increasing phenotypic severity within the ACF group, there is an increase in conduction anisotropy and amplitude of QRS voltage. N = 9 samples from the ACF group (3 for each sub-group), r, Pearson's correlation coefficient. Line represents linear regression.

Mentions: Western blotting (Figure 3) detected a significant decrease in both total and phosphorylated connexin43 protein in the ACF hearts, consistent with the previous results (Benes et al., 2011a). Phenotype severity (HBWR) inversely correlated with both connexin43 or P-connexin43 densities with the most enlarged hearts showing the most pronounced decrease (Figure 3). Total connexin43 amount was strongly negatively correlated with biventricular weight (R = −0.92, p = 0.0004); interestingly, less with the left (R = −0.55, p = 0.1177) and more with the right (R = −0.77, p = 0.0277) ventricular weight. Total connexin43 was also negatively correlated with anisotropy ratio (R = −0.70, p = 0.0348) and QRS sum amplitude (R = −0.67, p = 0.05; Figure 4). This suggests strongly a critical role of this gap junctional protein in myocardial conduction properties, together with changes in ion channels responsible for the changes in APD. Similar behavior was observed for the phosphorylated connexin. Interestingly, correlation coefficient between these two isoforms was only 0.63 (p = 0.06), suggesting that the amount of connexin43 and its phosphorylation might be regulated by separate mechanisms. The ratio of these isoforms mildly (0.49, p = 0.1771) correlated with the QRS duration.


Changes in Myocardial Composition and Conduction Properties in Rat Heart Failure Model Induced by Chronic Volume Overload
Correlation analysis of anisotropy of conduction (A) and QRS voltage (B) with connexin43 amount in the ACF rats. With decreasing connexin43 expression that represents increasing phenotypic severity within the ACF group, there is an increase in conduction anisotropy and amplitude of QRS voltage. N = 9 samples from the ACF group (3 for each sub-group), r, Pearson's correlation coefficient. Line represents linear regression.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4997968&req=5

Figure 4: Correlation analysis of anisotropy of conduction (A) and QRS voltage (B) with connexin43 amount in the ACF rats. With decreasing connexin43 expression that represents increasing phenotypic severity within the ACF group, there is an increase in conduction anisotropy and amplitude of QRS voltage. N = 9 samples from the ACF group (3 for each sub-group), r, Pearson's correlation coefficient. Line represents linear regression.
Mentions: Western blotting (Figure 3) detected a significant decrease in both total and phosphorylated connexin43 protein in the ACF hearts, consistent with the previous results (Benes et al., 2011a). Phenotype severity (HBWR) inversely correlated with both connexin43 or P-connexin43 densities with the most enlarged hearts showing the most pronounced decrease (Figure 3). Total connexin43 amount was strongly negatively correlated with biventricular weight (R = −0.92, p = 0.0004); interestingly, less with the left (R = −0.55, p = 0.1177) and more with the right (R = −0.77, p = 0.0277) ventricular weight. Total connexin43 was also negatively correlated with anisotropy ratio (R = −0.70, p = 0.0348) and QRS sum amplitude (R = −0.67, p = 0.05; Figure 4). This suggests strongly a critical role of this gap junctional protein in myocardial conduction properties, together with changes in ion channels responsible for the changes in APD. Similar behavior was observed for the phosphorylated connexin. Interestingly, correlation coefficient between these two isoforms was only 0.63 (p = 0.06), suggesting that the amount of connexin43 and its phosphorylation might be regulated by separate mechanisms. The ratio of these isoforms mildly (0.49, p = 0.1771) correlated with the QRS duration.

View Article: PubMed Central - PubMed

ABSTRACT

Volume overload leads to development of eccentric cardiac hypertrophy and heart failure. In our previous report, we have shown myocyte hypertrophy with no fibrosis and decrease in gap junctional coupling via connexin43 in a rat model of aorto-caval fistula at 21 weeks. Here we set to analyze the electrophysiological and protein expression changes in the left ventricle and correlate them with phenotypic severity based upon ventricles to body weight ratio. ECG analysis showed increased amplitude and duration of the P wave, prolongation of PR and QRS interval, ST segment elevation and decreased T wave amplitude in the fistula group. Optical mapping showed a prolongation of action potential duration in the hypertrophied hearts. Minimal conduction velocity (CV) showed a bell-shaped curve, with a significant increase in the mild cases and there was a negative correlation of both minimal and maximal CV with heart to body weight ratio. Since the CV is influenced by gap junctional coupling as well as the autonomic nervous system, we measured the amounts of tyrosine hydroxylase (TH) and choline acetyl transferase (ChAT) as a proxy for sympathetic and parasympathetic innervation, respectively. At the protein level, we confirmed a significant decrease in total and phosphorylated connexin43 that was proportional to the level of hypertrophy, and similarly decreased levels of TH and ChAT. Even at a single time-point, severity of morphological phenotype correlates with progression of molecular and electrophysiological changes, with the most hypertrophied hearts showing the most severe changes that might be related to arrhythmogenesis.

No MeSH data available.


Related in: MedlinePlus