Pyridoxamine protects against mechanical defects in cardiac ageing in rats: studies on load dependence of myocardial relaxation

Abstract

Our team demonstrated in the past that pyridoxamine attenuated arterial stiffening by targeting the pathogenic formation of glycated collagen cross-links in aged rats. Herein, we examined whether pyridoxamine therapy can protect against mechanical defects in myocardial relaxation by improving arterial wave properties and cardiac contractile performance in senescent animals. Fifteen-month-old male Fisher 344 rats were treated daily with pyridoxamine (1 g l(-1) in drinking water) for 5 months and compared with age-matched untreated control animals (20 months old). Arterial wave properties were characterized by wave transit time (τw) and wave reflection factor (Rf). We measured the contractile status of the myocardium in an intact heart as the left ventricular (LV) end-systolic elastance (Ees). Myocardial relaxation was described according to the time constant of the LV isovolumic pressure decay (τe). Pyridoxamine therapy prevented the age-associated prolongation in LV τe and the diminished Ees in senescent rats. The drug also attenuated the age-related augmentation in afterload imposed on the heart, as evidenced by the increased τw and decreased Rf. We found that the LV τe was significantly influenced by both the arterial τw and Rf (τe = 16.3902 + 8.3123 × Rf - 0.4739 × τw; r = 0.7048, P < 0.005). In the meantime, the LV τe and the LV Ees showed a significant inverse linear correlation (τe = 13.9807 - 0.0068 × Ees; r = 0.6451, P < 0.0005). All these findings suggested that long-term treatment with pyridoxamine might ameliorate myocardial relaxation rate, at least partly through its ability to enhance myocardial contractile performance, increase wave transit time and decrease wave reflection factor in aged rats.

Figure 1

Modulus (A) and phase (B) of the aortic input impedance in a 6-month-old rat and the impulse response function curve (C) derived from the filtered aortic input impedance spectra shown in A and B In C, the long vertical arrow shows the discrete reflection peak from the body circulation and the short vertical arrow demonstrates the initial peak as a reference. Half of the time difference between the appearance of the reflected peak and the initial peak approximates the arterial wave transit time (τ_w) in the lower body circulation.

Figure 2

The ascending aortic flow (A) and left ventricular (LV) pressure (B) in the same 6-month-old rat as shown in Fig. 1, and the LV end-systolic pressure–stroke volume (P_es–SV) relationships (C) In B, the dashed pink line represents the isovolumic pressure curve at an end-diastolic volume, which is estimated by fitting a sinusoidal function to the isovolumic portions of the measured LV pressure. In C, drawing a tangential line from the peak LV isovolumic pressure (P_isomax) to the right corner of the pressure-ejected volume loop yields a point referred to as the end-systolic equilibrium point. The dotted-dashed red line connecting P_isomax to the end-systolic equilibrium point constructs the LV P_es–SV relationship, which has a slope of the LV end-systolic elastance (E_es) and a volume intercept of effective LV end-diastolic volume (V_eed).

Figure 3

Calculation of the time constant of the LV isovolumic pressure decay In A, the continuous red line represents the measured LV pressure waveform in the same 6-month-old rat shown in Fig. 1. The dashed green line is its derivative, dP_LV/dt. In B, the time course of the LV isovolumic pressure decline is defined by the pressure point of the peak −dP_LV/dt to 10 mmHg above the end-diastolic pressure. The time constant of the LV isovolumic pressure decay (τ_e) was calculated as the negative inverse slope of the lnP_LV versus t relationship. In this case, the LV τ_e was 9.15 ms, with an r² of 0.9972 and a relative standard error of the estimat of 0.53%.

Figure 4

Effects of ageing and pyridoxamine (PM) on peak LV isovolumic pressure (P_isomax; A), effective LV end-diastolic volume (V_eed; B) and LV end-systolic elastance (E_es; C)

Figure 5

Effects of ageing and PM on peak −dP_LV/dt (A) and LV τ_e (B)

Figure 6

Influences of arterial wave properties and cardiac contractile status on the LV isovolumic pressure relaxation In A, a multiple linear regression was employed to fit the data, taking the time constant of the LV isovolumic pressure decay (τ_e) as the dependent variable and the arterial wave transit time (τ_w) and arterial wave reflection factor (R_f) as the two independent variables. The correlation among the three parameters achieved significance. In B, the LV τ_e and the LV end-systolic elastance (E_es) showed a significant inverse linear correlation.