Cognitive impairment in heart failure: A protective role for angiotensin-(1-7)

Abstract

Patients with congestive heart failure (CHF) have increased hospital readmission rates and mortality if they are concomitantly diagnosed with cognitive decline and memory loss. Accordingly, we developed a preclinical model of CHF-induced cognitive impairment with the goal of developing novel protective therapies against CHF related cognitive decline. CHF was induced by ligation of the left coronary artery to instigate a myocardial infarction (MI). By 4- and 8-weeks post-MI, CHF mice had approximately a 50% and 70% decline in ejection fraction as measured by echocardiography. At both 4- and 8-weeks post-MI, spatial memory performance in CHF mice as tested using the Morris water task was significantly impaired as compared with sham. In addition, CHF mice had significantly worse performance on object recognition when compared with shams as measured by discrimination ratios during the novel object recognition NOR task. At 8-weeks post-MI, a subgroup of CHF mice were given Angiotensin (Ang)-(1-7) (50mcg/kg/hr) subcutaneously for 4 weeks. Following 3 weeks treatment with systemic Ang-(1-7), the CHF mice NOR discrimination ratios were similar to shams and significantly better than the performance of CHF mice treated with saline. Ang-(1-7) also improved spatial memory in CHF mice as compared with shams. Ang-(1-7) had no effect on cardiac function. Inflammatory biomarker studies from plasma revealed a pattern of neuroprotection that may underlie the observed improvements in cognition. These results demonstrate a preclinical mouse model of CHF that exhibits both spatial memory and object recognition dysfunction. Furthermore, this CHF-induced cognitive impairment is attenuated by treatment with systemic Ang-(1-7). (PsycINFO Database Record

Figure 1.

Time-line for the course of the experiments for the two cohorts. See the online article for the color version of this figure.

Figure 2.

Cardiac histology and morphometry in sham and congestive heart failure (CHF) mice. (A) Representative images of H&E stained hearts in longitudinal sections of sham and CHF mice. (B) Representative M-mode images of sham and MI mice treated with either saline or Ang-(1–7). From M-mode images, parameters of ventricular chamber dimensions and function were determined. See the online article for the color version of this figure.

Figure 3.

Echocardiographic parameters of ventricular function and morphometry in sham and congestive heart failure (CHF) mice with and without Ang-(1–7). (A) LVIDs is lateral ventricular internal diameter at end-systole; (B) LVPWs is LV posterior wall thickness at end-systole; and (C) Percent ejection fraction (EF%). Data presented as mean ± S.E.M. Experimental group numbers are as follows, Sham + Saline, n = 5; Sham + Ang-(1–7), n = 7; MI + Saline, n = 8; MI + Ang-(1–7), n = 5. #p < .05 from baseline; #p < .05 from Sham group.)

Figure 4.

Novel object recognition (NOR) task performance of sham and congestive heart failure (CHF) mice. (A) Mean discrimination ratios, taken from the first 2 min of “test phase” of CHF and sham mice 4-weeks post-MI. A positive score indicates more time spent with the novel object while a negative score indicates more time spent with the familiar object. A zero score indicates a null preference. CHF mice (n = 5) had significantly lower discriminations compared with shams (n = 5; −.43 ± .05 vs. +0.16 ± .1, F(1, 7) = 27.4, p = .001, ANOVA). * = p < .05. (B) Effects of Ang-(1–7) treatment on novel object recognition (NOR) task performance in CHF and sham mice. Following 3 weeks treatment with systemic Ang-(1–7), CHF mice (n = 6) NOR discrimination ratios were similar to shams (n = 3) and significantly greater than the CHF mice treated with saline (n = 4, * p < .05). CHF saline treated animals DRatios were significantly less that Sham animals (p < .05).

Figure 5.

Total object exploration time similar in congestive heart failure (CHF) and Sham mice. Total time spent exploring the two identical objects was not different between the three groups suggesting (A) similar levels of interest in environment exploration. (B) During the familiarization phase with two identical objects, there was a null preference for the tw identical objects for CHF + Ang(1–7) mice, the CHF + saline mice and the Sham + Ang(1–7) mice (0.002 ± 0.03, −0.05 ± 0.02, 0.019 ± 0.05, respectively). These results suggest that there was no difference in object preference for identical objects during the familiarization phase.

Figure 6.

Spatial version of the Morris water task performance of congestive heart failure (CHF) and sham mice. (A) Examples of swim paths for a sham and CHF mouse on Day 3 testing. The sham mouse, as seen in the upper plot, takes a significantly shorter path to the hidden platform compared with the CHF mouse (lower plot). (B) The mean corrected integrated path lengths (CIPL) for CHF (n = 10) and sham (n = 4) mice at 4-weeks post-MI. The paths taken by the CHF mice were significantly longer on Days 2, 3, and 4 compared with the sham group, * p < .05. These results suggest that CHF induces spatial memory loss. See the online article for the color version of this figure.

Figure 7.

Reversal version of Morris water task performance of congestive heart failure (CHF) and sham mice. The mean corrected integrated path lengths (CIPL) for CHF (n = 10) and sham (n = 4) mice at 8-weeks post-MI. The CIPL in the CHF mice was significantly longer on Days 2 and 4 compared with the sham group. * p < .05.

Figure 8.

Visual acuity and swim speed are similar in congestive heart failure (CHF) and sham mice tested with the Morris swim task. (A) There were no differences between the CHF and sham mice in ability to find the elevated platform suggesting that the visual acuity are the same in CHF and sham mice. (B) The average swim speed of the CHF (n = 10, filled histogram) and sham mice (n = 4, open histogram) 8-weeks postsurgery were similar.

Figure 9.

Effects of Ang-(1–7) treatment on Morris swim task performance in congestive heart failure (CHF) and sham mice. The mean corrected integrated path lengths (CIPL) for CHF + Ang-(1–7) (n = 6), CHF + saline (n = 3), and sham + Ang-(1–7) (n = 4) mice 12-weeks post-MI. CHF + Ang-(1–7) mice (n = 6) showed significant improvement in spatial memory on the first day of the swim task and performed similarly to sham mice (n = 4), * p < .05 for CHF + Ang-(1–7) compared to CHF-saline and sham.

Figure 10.

Effects of Ang-(1–7) treatment on serum inflammatory biomarkers in the 2nd Cohort. (A) CXCL12, (B) CXCL13, (C) CCL2, (D) IL-1ra, (E) G-CSF, (F) IL-16, (G) sICAM. * p < .05. See the online article for the color version of this figure.

Figure 11.

Effects of Ang-(1–7) treatment on serum inflammatory biomarkers in early disease at 2-weeks post-MI and 1-week Ang-(1–7) treatment. (A) G-CSF, (B) IL1α, (C) IP10, (D) MIP1α, (E) MIP2. * p < .05. See the online article for the color version of this figure.