Magnetic resonance imaging analysis of cardiac cycle events in diabetic rats: the effect of angiotensin-converting enzyme inhibition

Abstract

Non-invasive magnetic resonance imaging (MRI) was used to characterize changes in left and right ventricular cardiac cycles following induction of experimental, streptozotocin (STZ)-induced, diabetes in male Wistar rats at different ages. The effects of the angiotensin-converting enzyme (ACE) inhibitor captopril upon such chronic physiological changes were then evaluated, also for the first time. Diabetes was induced at the age of 7 weeks in two experimental groups, of which one group was subsequently maintained on captopril (2 g l(-1))-containing drinking water, and at 10 and 13 weeks in two further groups. The fifth group provided age-matched controls. All groups (each n = 4 animals) were scanned consistently at 16 weeks, in parallel with timings used in earlier studies that employed this experimental model. Cine magnetic resonance (MR) image acquisition provided transverse sections through both ventricles at twelve time points covering systole and most of diastole. These yielded reconstructions of cardiac anatomy used to derive critical functional indices and their dependence upon time following the triggering electrocardiographic R waves. The left and right ventricular end-diastolic (EDV), end-systolic (ESV) and stroke volumes (SV), and ejection fractions (EF) calculated from each, control and experimental, group showed matching values. This confirmed a necessary condition requiring balanced right and left ventricular outputs and further suggested that STZ-induced diabetes produced physiological changes in both ventricles. Absolute left and right ventricular SVs were significantly altered in all diabetic animals; EDVs and EFs significantly altered in animals diabetic from 7 and 10 but not 13 weeks. When normalized to body weight, left and right ventricular SVs had significantly altered in animals diabetic from 7 and 10 weeks but not 13 weeks. Normalized left ventricular EDVs were also significantly altered in animals diabetic from 7 and 10 weeks. However, normalized right ventricular EDVs were significantly altered only in animals made diabetic from 7 weeks. Diabetic hearts showed major kinetic changes in left and right ventricular contraction (ejection) and relaxation (filling). Both the initial rates of volume change (dV/dt) in both ventricles and the plots of dV/dt values through the cardiac cycle demonstrated more gradual developments of tension during systole and relaxation during diastole. Estimates of the derived left ventricular performance parameters of cardiac output, cardiac power output and stroke work in control animals were comparable with human values when normalized to both body (or cardiac) weight and heart rate. All deteriorated with diabetes. Comparisons of experimental groups diabetic from 7 weeks demonstrated that captopril treatment relieved the alterations in critical volumes, dependence of SV upon EDV, kinetics of systolic contraction and diastolic relaxation and in the derived indicators of ventricular performance. This study represents the first demonstration using non-invasive MRI of early, chronic changes in diastolic filling and systolic ejection in both the left and the right ventricles and of their amelioration by ACE inhibition following STZ-induction of diabetes in intact experimental animals.

Figure 1. Typical transverse MR sections obtained from the heart of a normal control rat (A), and rats made diabetic from 13 (B), 10 (C) and 7 weeks (D) to give disease histories of 3, 6 and 9 weeks respectively, and a captopril-treated diabetic rat with a disease history of 9 weeks (E)

All rats were scanned at 16 weeks. The weight of the normal rat was 340 g and those of the diabetic rats were 230, 275, 330 and 245 g for the rat made diabetic at 7, 10 and 13 weeks and the captopril-treated rat, respectively. The heart rates were continuously monitored throughout imaging sessions; intrinsic heart rates were 315 ± 4 beats min⁻¹ for the normal rat and 290 ± 4, 300 ± 6, 307 ± 4 and 300 ± 4 beats min⁻¹ for the four diabetic rats, respectively. The sections were taken perpendicular to the principal cardiac axis at one spatial slice at typically twelve time points during the cardiac cycle. These time points are indicated in the upper left corner of each panel and correspond to the delay after the trigger, taken from the R wave of the electrocardiogram (ECG), at which the signal was acquired. Each image is the average of two signals obtained at corresponding points in the cardiac cycle following the R wave. LV and RV indicate left and right ventricles, respectively, and C and W indicate chest cavity and chest wall, respectively. Slice thickness was 1.50 mm for the normal control rat and 1.44 mm for the four diabetic rats. Field of view (FOV) was 5 cm for the normal control rat and 4.5 cm for the four diabetic rats. With an image matrix of 128 pixels × 128 pixels, the nominal in-plane resolution was approximately 351.6–390.6 μm pixel⁻¹. The effective repeat time (TR) was approximately 13 ms and the echo time (TE) was 4.3 ms.

Figure 2. Epi- (squares), endo- (circles) and myocardial (triangles) left ventricular (LV) volume curves

Epi-, endo- and myocardial left ventricular (LV) volume curves obtained from the transverse MRI images of the control group (A), and rats diabetic from 13 (B; n = 4), 10 (C; n = 4) and 7 weeks (D; n = 4), and the captopril-treated diabetic group (E; n = 4 rats) (disease durations 3, 6, 9 and 9 weeks, respectively). All the experimental animals were male Wistar rats aged 16 weeks at the time of scanning. The average body weight of the control group (n = 4 in each case) was 351.3 ± 9.7 g and those of the four diabetic groups were 235 ± 8.4, 282.5 ± 6.6, 335 ± 8.4 and 247.5 ± 15.5 g, respectively. The heart rate was continuously monitored throughout the imaging session giving average intrinsic heart rates of 322 ± 9 beats min⁻¹ for the control rats and 280 ± 6, 280 ± 7, 318 ± 7, and 311 ± 10 beats min⁻¹ for respective diabetic groups.

Figure 3. Epi- (squares), endo- (circles), and myocardial (triangles) right ventricular (RV) volume curves

Epi-, endo- and myocardial right ventricular (RV) volume curves obtained from the transverse MRI images of the control group (A), and rats diabetic from 13 (B), 10 (C) and 7 weeks (D), and the captopril-treated diabetic group (E) (disease durations 3, 6, 9 and 9 weeks, respectively). Experimental details as summarized in the legend to Fig. 2.

Figure 4. Left (LV) and right ventricular (RV) stroke volumes (SVs) versus end-diastolic volume (EDV)

Comparative plots of MRI-measured left (A) and right (B) ventricular stroke volumes (SVs) and end-diastolic volumes (EDVs) of the five experimental groups. Data from rats diabetic from 7 and 10 weeks suggested impaired left and right ventricular diastolic and systolic function.

Figure 5. MRI measurements of left and right ventricular volumes and ejection fraction (EF)

Comparative plots of left (LV) and right ventricular (RV) end-diastolic volumes (EDVs) (A), end-systolic volumes (ESVs) (B), stroke volumes (SVs) (C) and ejection fractions (EFs) (D) in the five experimental groups.

Figure 6. Plots of left and right ventricular dV/dt

Block diagrams displaying left (filled bars) and right (open bars) ventricular volume changes with respect to time during the 12 studied time points through the cardiac cycle obtained from the normal control group (A), and rats diabetic from 13 (B), 10 (C) and 7 weeks (D), and the captopril-treated diabetic group (E) (disease durations 3, 6, 9 and 9 weeks, respectively). Each bar represents the average dV/dt ± s.e.m. between two consecutive time points through the cardiac cycle. Negative dV/dts represent contraction of the cardiac walls during systole and positive dV/dts represent their relaxation. The first bar represents dV/dt between the 1st and 2nd studied time points during the cardiac cycle with the first point timed typically 8 ms after the trigger pulse from the electrocardiographic R wave and 21 ms for the second point. The remaining bars represent dV/dts between volume points successively obtained 21, 34, 47, 60, 73, 86, 99, 112, 125, 138 and 151 ms following the R wave.