Cardiovascular magnetic resonance detects the progression of impaired myocardial perfusion reserve and increased left-ventricular mass in mice fed a high-fat diet

Abstract

BackgroundImpaired myocardial perfusion reserve (MPR) is prevalent in obesity and diabetes, even in the absence of obstructive coronary artery disease (CAD), and is prognostic of adverse events. We sought to establish the time course of reduced MPR and to investigate associated vascular and tissue properties in mice fed a high-fat diet (HFD), as they are an emerging model of human obesity, diabetes, and reduced MPR without obstructive CAD.MethodsC57Bl/6 mice fed a HFD or a low-fat diet (control) were imaged at 6, 12, 18 and 24 weeks post-diet. The cardiovascular magnetic resonance (CMR) protocol included multi-slice cine imaging to assess ejection fraction (EF), left-ventricular (LV) mass, LV wall thickness (LVWT), and LV volumes, and first-pass perfusion CMR to quantify MPR. Coronary vascular reactivity, aortic atherosclerosis, myocardial capillary density and tissue fibrosis were also assessed.ResultsBody weight was increased in HFD mice at 6–24 weeks post-diet (p < 0.05 vs. control). MPR in HFD mice was reduced and LV mass and LVWT were increased in HFD mice at 18 and 24 weeks post-diet (p < 0.05 vs. control). Coronary arteriolar vascular reactivity to adenosine and acetylcholine were reduced in HFD mice (p < 0.05 vs. control). There were no significant differences in cardiac volumes, EF, or capillary density measurements between the two groups. Histology showed interstitial fibrosis in HFD and no aortic atherosclerosis in either group.ConclusionsC57Bl/6 mice fed a HFD for 18–24 weeks have progressively increased LV mass and impaired MPR with fibrosis, normal capillary density and no aortic plaque. These results establish C57Bl/6 mice fed a HFD for 18–24 weeks as a model of impaired MPR without obstructive CAD due to obesity and diabetes.

Isolated perfused working hearts provide valuable additional information during phenotypic assessment of the diabetic mouse heart

“…The reported incidence of systolic and diastolic dysfunction is, however, inconsistent. Systolic dysfunction has been reported following feeding regimes that varied from 4–6 [ 33 ; 35 ] to 15–16 weeks [ 19 ; 32 ; 36 ], while the present study and other studies report no evidence of systolic dysfunction after 20–24 weeks [ 15 ; 27 ; 31 ; 37 ; 38 ]. In general, diastolic dysfunction is considered to advance prior to the development of systolic dysfunction, and although some studies [ 17 ; 27 ; 34 ] support this by showing impaired diastolic dysfunction without systolic dysfunction, the duration of HFD feeding required to evoke diastolic impairments remains unclear.…”

“…Diet-induced obese (DIO) mouse models are currently in extensive use in diabetic cardiomyopathy research as they recapitulate aspects of the metabolic syndrome associated with human obesity, and because they are comparable to commonly used genetically modified models. The reported cardiac phenotype from DIO models range from no change in cardiac function [ 12 – 15 ] to more severe remodelling and dysfunction [ 16 – 19 ]. Although, these differences may be linked to the variations between feeding protocols (nutritional composition of the diet and feeding initiation and duration) and the mouse strain used [ 20 ], there is also reason to believe that the techniques and modalities used for cardiac phenotyping influence the observed functional outcome.…”

Quantitative cardiovascular magnetic resonance perfusion imaging identifies reduced flow reserve in microvascular coronary artery disease

“…The subjects had an increased LV mass index and BMI, but neither accounted for the reduced MPR. Coronary arteriolar vasomotor dysfunction in response to adenosine is likely a contributing factor, as our group has demonstrated abnormal vasodilatory response of arterioles to graded doses of adenosine in a murine model of MVD [ 24 ].…”

Guidelines for measuring cardiac physiology in mice

“…At high myocardial blood flow during vasodilation, arterial spin labeling may be more suitable, due to superior image quality and lower user variability. First-pass perfusion MRI has a substantial speed advantage and has successfully been applied in mouse MI models ( 34 , 178 ), cardiac hypertrophy ( 186 ), and obesity ( 128 , 130 ).…”