The potential for unintended drug induced changes in cardiac contractility is a major concern in medicines development. Whilst direct left ventricular pressure (LVP) measurement is the gold standard for measuring cardiac contractility in vivo, it is resource intensive and poses a welfare burden on research animals. In contrast, arterial blood pressure (BP) measurement has fewer challenges. Symmetric Projection Attractor Reconstruction (SPAR) is a signal processing technique which transforms physiological time-series signals into a corresponding visual image ('attractor'), amplifying morphology changes within physiological waveforms. It was hypothesized that SPAR analysis of BP signals would provide a surrogate measure of cardiac contractility by specifically amplifying the maximum slope of the systolic upstroke. BP (abdominal aorta) signals obtained from beagle dogs, treated with positive and negative inotropes, were retrospectively analysed to identify signal features that correlated with the maximum upslope of the LVP signal from simultaneously acquired LVP recordings. SPAR transformation of BP signals quantified drug induced changes in the maximum slope of the systolic upstroke. We identified key SPAR metrics that provided >0.8 correlation with the LVP maximum upslope, outperforming the BP systolic upstroke alone. This was observed for all 4 different drugs, doses and time points evaluated across studies. Thus, we conclude that the SPAR measures derived from the BP signal could be used as a first pass in vivo screen to flag any risk of drug induced changes in cardiac contractility during the conduct of non-clinical medicines development, potentially reducing or replacing the need to perform direct left ventricular measurements.
Keywords: Blood pressure; Blood pressure systolic upstroke; Cardiac contractility; Left ventricular pressure; Methods; Negative inotrope; Positive inotrope; Signal processing technique; Symmetric Projection Attractor Reconstruction.
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