Regulation of collagen and prolyl-4-hydroxylase during ventricular assist device (VAD) support: collagen regulation depends on the degree of remodelling at the time of VAD-implantation

Purpose: The upregulation of the extracellular matrix is a hallmark of heart failure (HF). During VAD-support highly controversal data were published so far, revealing upregulation, no regulation or even downregulation of the collagen fraction during VAD-support. We therefore analysed in a comparable high number of patients 4-hydroxyproline (4OHP) and the regulation of the prolyl-4-hydroxylase (P4H), which is a key enzyme for synthesis of collagen within the myocardium.

Methods: 4OHP was measured in 10mg transmural tissue as previously published. The α1- and β-subunit of P4H was analysed by realtime-RTPCR and western-blotting, respectively. We analysed rejected donor hearts (NF; n=30), HF-patients (pre-VAD; n=160) and paired samples pre- and post-VAD-support (n=53). P4H was analysed in 10 NF, and 10 paired samples of VAD-patients.

Results: 4OHP was in NF, pre-VAD and post-VAD [nmol/mg tissue]: 6.7±2.02; 15.13±10.22 and 16.78±7.9, respectively. Pre-VAD-samples had significantly higher 4OHP-concentrations versus NF (p<0.0001), whereas pre-VAD and post-VAD samples were not different. Surprisingly, about 15% of preVAD-samples were equal or below the upper percenticle of NF-hearts (75UPNF), indicating a moderate remodelling. However, ratios of paired samples post-VAD/pre-VAD could be fitted by a non-linear correlation (r²=0.45), indicating that preVAD-samples with 4OHP not higher than 75UPNF upregulated collagen during VAD-support. The α1- and β-subunit of P4H were increased in HF-samples and not downregulated by VAD-support. The P4Hα1-mRNA even increased during VAD (p<0.05).

Conclusion: In those hearts with a limited remodelling at the time of VAD-implantation the initiation of fibrosis development can not be stopped by mechanical unloading.