Cardiac hypertrophy and failure give rise to disability and death on account of arrhythmias and pump failure. However, the cardiac phenotype can vary widely. Here we used a rabbit (NZW) model of volume and pressure overload of the left ventricle (LV) – two degrees of volume overload were induced.1 Aortic regurgitation was induced by catheter in anaesthetised rabbits (ketamine 25 mg/kg i.m. with 2.5% isoflurane in O2) to give increases in aortic pulse pressure of ~100% in the acute heart failure group (AHF, n=8) and ~50% in the chronic hypertrophy group (CHT, n=8). After 3 weeks, pressure overload was induced by abdominal aortic banding. The rabbits were kept for 8 (AHF) or 78 (CHT) weeks. Study was conducted in accordance with the Animals (Scientific Procedures) Act 1986. After sacrifice, ion channel transcript expression in different parts of the heart was measured using quantitative PCR (differences tested using 2-way ANOVA). The AHF but not the CHT group showed evidence of heart failure – serous cavity effusions and pulmonary congestion. Echocardiography showed increased LV internal dimensions in both groups. At termination, fractional shortening was reduced to ~25% in the AHF group and preserved at ~35% in the CHT group. Intrinsic heart rate was slower and the PR interval and QRS duration were prolonged in the AHF group while unchanged in the CHT group. The CHT group, however, showed 75% incidence of ventricular arrhythmias after autonomic blockade. In the AHF group, marked remodelling was seen mainly in the sinoatrial node (SAN) and left Purkinje fibres with 12 and 19 out of 25 transcripts studied downregulated (and 1 upregulated in SAN). LV displayed 5 upregulated (Nav1.5, Kir2.1, SUR2a, NCX1, RYR2) and 1 downregulated (KChIP2) transcripts. Surprisingly, there were no changes in the right ventricle (RV) in the AHF group. In contrast, changes in the CHT group occurred more evenly throughout the heart. The RV showed the most striking remodelling with upregulation of Nav1.5, Cav1.2 and Cav3.1 and most K+ channels; only Kv1.4 was downregulated. The right Purkinje fibres displayed upregulation of 2 Ca2+ channels, 4 K+ channels, RYR3 and SERCA2a. The SAN had 3 channel subunits downregulated (Cav1.3, KChIP2, KvLQT1). Right atrium showed reduction of 2 K+ channels and 2 gap junction channels, and upregulation of HCN4. LV showed upregulation of Cav1.3, Cav3.1 and RYR3. In conclusion, difference in the severity of volume overload has produced 2 distinct models with contrasting responses at whole animal and mRNA levels. More severe overload causes acute HF with major downregulation of ion channels in the SAN and left Purkinje fibres, possibly induced by stretch. Less severe volume overload leads to compensated hypertrophy with a more uniform response, and in particular upregulation of gene expression in the RV and right Purkinje fibres.