Isoprenaline increases Excursive Restitution Slope in the Conscious Rabbit with Ischaemic Heart Failure

Background: An increased QT/RR slope is hypothesized to be predictive of sudden cardiac death after myocardial infarction. Previous studies have shown that beta-adrenergic stimulation increases QT/RR slope, but the effects of beta-adrenergic stimulation on QT/RR slope in heart failure are unknown. Methods: New Zealand White rabbits underwent coronary ligation (n=15) or sham surgery (n=11), and implantation of a pediatric pacemaker lead in the right ventricle for chronic ECG recording. Eight weeks after surgery, unsedated rabbits were given intravenous administrations of 0.25 to 2.0 ml of 1 micromol/l isoprenaline, while peak QRS to QRS (RR) and Q to T peak (QT) intervals were measured. Results: Ligated rabbits (n=6) had lower LVEF than sham rabbits (n=7, p<.0001), but similar baseline RR (269 +/- 15 vs 292 +/- 23 ms, p=.07), QT (104 +/- 17 vs 91 +/- 9 ms, p=.1) and minimum RR (204 +/- 11 vs 208 +/- 6 ms, p=.4) intervals induced by isoprenaline (0.79 +/- 0.18 vs 0.73 +/- 0.14 ml, p=.6). Hysteresis in QT vs TQ interval plots displayed biphasic restitution and regions of negative slope. The slope of the positive slope region was >1 in ligated rabbits (1.27 +/- 0.66) and <1 in sham rabbits (0.35 +/- 0.14, p=.004). Absolute value of the negative slope was greater in ligated rabbits (-0.81 +/- 0.52 vs -0.35 +/- 0.14, p=.04). Conclusion: Ischaemic heart failure produces steeper restitution slopes during beta-adrenergically induced QT/TQ hysteresis. This could underlie the propensity of failing hearts to arrhythmias.

💡 Research Summary

This study investigated how β‑adrenergic stimulation with isoprenaline influences the dynamic relationship between heart rate (RR interval) and ventricular repolarization (QT interval) in a rabbit model of ischemic heart failure. New Zealand White rabbits underwent either coronary artery ligation (n = 15) to induce chronic left‑ventricular dysfunction or sham surgery (n = 11). Eight weeks later, each animal was implanted with a pediatric‑size right‑ventricular pacemaker lead to allow continuous, unsedated ECG recording. During the experimental session, incremental intravenous boluses of isoprenaline (0.25–2.0 ml of a 1 µmol/L solution) were administered while peak‑to‑peak QRS‑to‑QRS (RR) and Q‑to‑T peak (QT) intervals were measured in real time.

Baseline cardiac function confirmed severe systolic impairment in the ligated group (significantly reduced left‑ventricular ejection fraction, p < 0.0001) while baseline RR and QT intervals were comparable between groups (RR: 269 ± 15 ms vs 292 ± 23 ms, p = 0.07; QT: 104 ± 17 ms vs 91 ± 9 ms, p = 0.10). Isoprenaline produced dose‑dependent shortening of both RR and QT in all animals, but the pattern of QT versus the preceding diastolic interval (TQ or RR) displayed marked hysteresis with a biphasic restitution curve.

The restitution curve comprised a positive‑slope segment (QT lengthening as RR shortens) and a negative‑slope segment (QT shortening as RR continues to shorten). In the heart‑failure (ligated) rabbits, the mean slope of the positive segment was 1.27 ± 0.66, significantly greater than 1 and markedly higher than the sham group’s slope of 0.35 ± 0.14 (p = 0.004). The absolute value of the negative‑slope segment was also larger in the ligated animals (‑0.81 ± 0.52) compared with shams (‑0.35 ± 0.14, p = 0.04). A positive restitution slope >1 is widely regarded as a marker of electrical instability because it indicates that repolarization duration changes more rapidly than the underlying cycle length, a condition that can promote wavebreak, re‑entry, and torsades de pointes‑type arrhythmias.

Mechanistically, β‑adrenergic activation increases intracellular calcium influx, accelerates sinus node firing, and shortens action‑potential duration. In the setting of chronic ischemic injury, calcium handling is already compromised; additional β‑stimulation therefore exaggerates calcium overload and spatial dispersion of repolarization. The observed steepening of the QT‑RR restitution slope in heart‑failure rabbits reflects this heightened sensitivity, providing a plausible substrate for the increased arrhythmic risk seen clinically after myocardial infarction.

Statistical analysis, despite a modest sample size (n = 6 ligated, n = 7 sham animals that completed the protocol), yielded robust p‑values, indicating that the experimental design and measurement precision were sufficient to detect physiologically relevant differences. Nonetheless, extrapolation to human patients requires caution because of species differences and the limited number of subjects.

Clinically, the findings suggest that administration of β‑adrenergic agents (e.g., isoprenaline, dopamine, norepinephrine) in patients with post‑infarction heart failure may acutely raise the QT‑RR restitution slope above the critical threshold of 1, thereby increasing susceptibility to malignant ventricular arrhythmias. Continuous monitoring of QT dynamics, judicious use of β‑blockade, and correction of electrolyte disturbances (especially magnesium and potassium) could mitigate this risk.

In summary, the study demonstrates that isoprenaline‑induced β‑adrenergic stimulation produces markedly steeper positive restitution slopes and more pronounced negative slopes in a rabbit model of ischemic heart failure. These alterations likely underlie the heightened propensity for arrhythmias in failing hearts and highlight restitution slope analysis as a potentially valuable tool for risk stratification and therapeutic decision‑making in the acute management of heart‑failure patients. Future work should extend these observations to human cohorts, explore the impact of different β‑agonists and antagonists, and integrate restitution metrics into predictive models of sudden cardiac death.