Autonomic neuro-cardiac profile of electrical, structural and neuronal remodeling in myocardial infarction-induced heart failure

Abstract

Aims: Heart failure is a clinical syndrome typified by abnormal autonomic tone, impaired ventricular function, and increased arrhythmic vulnerability. This study aims to examine electrophysiological, structural and neuronal remodeling following myocardial infarction in a rabbit heart failure model to establish its neuro-cardiac profile.

Methods and results: Weight-matched adult male New Zealand White rabbits (3.2 ± 0.1 kg, n = 25) were randomized to have coronary ligation surgeries (HF group, n = 13) or sham procedures (SHM group, n = 12). Transthoracic echocardiography was performed six weeks post-operatively. On week 8, dual-innervated Langendorff-perfused heart preparations were set up for terminal experiments. Seventeen hearts (HF group, n = 10) underwent ex-vivo cardiac MRI. Twenty-two hearts (HF group, n = 7) were examined histologically. Electrical remodeling and abnormal autonomic profile were evident in HF rabbits with exaggerated sympathetic and attenuated vagal effect on ventricular fibrillation threshold, ventricular refractoriness and restitution curves, in addition to increased spatial restitution dispersion. Histologically, there was significant neuronal enlargement at the heart hila and conus arteriosus in HF. Structural remodeling was characterized by quantifiable myocardial scarring, enlarged left ventricles, altered ventricular geometry and impaired contractility.

Conclusion: In an infarct-induced rabbit heart failure model, extensive structural, neuronal and electrophysiological remodeling in conjunction with abnormal autonomic profile provide substrates for ventricular arrhythmias.

Keywords: Autonomic; Ganglia; Heart failure; Remodeling; Restitution; Ventricular fibrillation.

Graphical abstract

Fig. 1

Examples of ex-vivo T2-weighted 2D slice montage representations (top panels: base; bottom panels; apex) of rabbit heart eight weeks following coronary ligation (1A) with apical scarring (white stain) and wall thinning (loss of tissue)(n = 1 from group of 10 heart failure rabbits), versus eight weeks following sham procedure (1B) with no evidence of apical scarring (n = 1 from group of 7 sham rabbits).

Fig. 2

Comparison of ventricular fibrillation threshold (A) and relative changes from baseline (B) between heart failure (HF)(n = 13) and sham (SHM)(n = 12) groups at baseline (BL), during sympathetic (SNS) and vagal (VNS) stimulations with each condition replicated 3 times. Data analyzed as repeated measures 2-way ANOVA with Bonferroni post-hoc test and presented as mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 3

A Comparison of basal and apical action potential duration-restitution (APDR) between heart failure (HF)(n = 13) and sham (SHM)(n = 12) groups at baseline (BL), during sympathetic (SNS) and vagal (VNS) stimulations with each condition replicated 3 times. Data analyzed as repeated measures 2-way ANOVA with Bonferroni post-hoc test and presented as mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001 B Comparison of relative changes from baseline values in basal and apical action potential duration-restitution (APDR) between heart failure (HF)(n = 13) and sham (SHM)(n = 12) groups during sympathetic (SNS) and vagal (VNS) stimulations with each condition replicated 3 times. Data analyzed as repeated measures 2-way ANOVA with Bonferroni post-hoc test and presented as mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001 C Typical examples of regional restitution (APDR) curves between a heart failure (HF) and sham (SHM) at baseline (3 Ci-ii), during SNS (iii-iv) and VNS (v-vi) with each condition replicated 3 times. APDR curves at base (left panel) and apex (right panel) of SHM and HF hearts were shown (n = 1 from group of 13 HF rabbits, and n = 1 from group of 12 SHM rabbits). D Comparison of relative apico-basal restitution (APDR) dispersion between heart failure (HF) (n = 13) and sham (SHM) (n = 12) groups. Data analyzed as repeated measures 2-way ANOVA with Bonferroni post-hoc test and presented as mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 3

A Comparison of basal and apical action potential duration-restitution (APDR) between heart failure (HF)(n = 13) and sham (SHM)(n = 12) groups at baseline (BL), during sympathetic (SNS) and vagal (VNS) stimulations with each condition replicated 3 times. Data analyzed as repeated measures 2-way ANOVA with Bonferroni post-hoc test and presented as mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001 B Comparison of relative changes from baseline values in basal and apical action potential duration-restitution (APDR) between heart failure (HF)(n = 13) and sham (SHM)(n = 12) groups during sympathetic (SNS) and vagal (VNS) stimulations with each condition replicated 3 times. Data analyzed as repeated measures 2-way ANOVA with Bonferroni post-hoc test and presented as mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001 C Typical examples of regional restitution (APDR) curves between a heart failure (HF) and sham (SHM) at baseline (3 Ci-ii), during SNS (iii-iv) and VNS (v-vi) with each condition replicated 3 times. APDR curves at base (left panel) and apex (right panel) of SHM and HF hearts were shown (n = 1 from group of 13 HF rabbits, and n = 1 from group of 12 SHM rabbits). D Comparison of relative apico-basal restitution (APDR) dispersion between heart failure (HF) (n = 13) and sham (SHM) (n = 12) groups. Data analyzed as repeated measures 2-way ANOVA with Bonferroni post-hoc test and presented as mean ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001.

Fig. 4

A Macrographs illustrating the neuronal enlargement of somata seen in the heart failure group (4Ai and ii)(n = 7) when compared to the control (n = 11) group (4Aiii and iv). Micrograph highlighting the lack of neuronal enlargement in the right atrial region in the heart failure group (4Av). B MI induced morphological changes in neuronal somata within the rabbit ICNS. The average overall cell area was quantified and compared between hearts from CTL (green)(n = 11 (10777), SHM (blue)(n = 4 (3419) and HF (red)(n = 7 (3902)) (4Bi). The average cell area was increased significantly in all regions examined apart from the region of the right atrial ganglionated plexus (4Bii). Representations of the distribution of cell size are shown in Biii, with Biv indicating ganglionic sites and highlighting the right atrial region (red circle). n = number of animals (number of cells). Data are represented as mean ± SEM. Statistical analysis performed with repeated measures two-way ANOVA, with Bonferroni post-hoc test. ns = no significance, ***p < 0.001, ****p < 0.0001. Abbreviations: CA, conus arteriosus; RA, right atrial; vPV, ventral pulmonary veins; RCV – right cranial vena cava; LCV – left cranial vena cava; LPV/MPV/RPV – left, middle, right pulmonary vein; DRA/VRA – dorsal/ventral right atrium; VLA – ventral left atrium; RAu – right auricle. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

A Macrographs illustrating the neuronal enlargement of somata seen in the heart failure group (4Ai and ii)(n = 7) when compared to the control (n = 11) group (4Aiii and iv). Micrograph highlighting the lack of neuronal enlargement in the right atrial region in the heart failure group (4Av). B MI induced morphological changes in neuronal somata within the rabbit ICNS. The average overall cell area was quantified and compared between hearts from CTL (green)(n = 11 (10777), SHM (blue)(n = 4 (3419) and HF (red)(n = 7 (3902)) (4Bi). The average cell area was increased significantly in all regions examined apart from the region of the right atrial ganglionated plexus (4Bii). Representations of the distribution of cell size are shown in Biii, with Biv indicating ganglionic sites and highlighting the right atrial region (red circle). n = number of animals (number of cells). Data are represented as mean ± SEM. Statistical analysis performed with repeated measures two-way ANOVA, with Bonferroni post-hoc test. ns = no significance, ***p < 0.001, ****p < 0.0001. Abbreviations: CA, conus arteriosus; RA, right atrial; vPV, ventral pulmonary veins; RCV – right cranial vena cava; LCV – left cranial vena cava; LPV/MPV/RPV – left, middle, right pulmonary vein; DRA/VRA – dorsal/ventral right atrium; VLA – ventral left atrium; RAu – right auricle. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 5

Macrographs of the rabbit heart illustrating the location of the intrinsic cardiac nerve plexus. The boxed area on the rabbit heart in (a) is enlarged in (b). Images C and D demonstrate examples of right atrial ganglia. Black arrows indicate extrinsic nerves accessing the nerve plexus on the heart hilum in (a) and (b). White arrows indicate examples of intrinsic cardiac neurons with black arrowheads showing interconnecting commissural nerves.