Cardiovascular magnetic resonance detects microvascular dysfunction in a mouse model of hypertrophic cardiomyopathy
Min-Chi Ku1,2, Frank Kober3, Yi-Ching Lai4
1Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle Strasse 10, 13125, Berlin, Germany. min-chi.ku@mdc-berlin.de.
Insights
Hypertrophic cardiomyopathy (HCM) is linked to reduced blood flow and cardiac function loss. This study used non-invasive imaging to show impaired resting myocardial perfusion in a mouse model of HCM, offering a new imaging marker.
Area of Science:
- Cardiovascular Research
- Medical Imaging
- Mouse Models
Background:
- Hypertrophic cardiomyopathy (HCM) involves vascular remodeling, potentially reducing myocardial blood supply and cardiac function.
- The precise connection between vascular changes and functional decline in HCM has been difficult to ascertain.
- Non-invasive imaging techniques are crucial for observing these processes.
Purpose of the Study:
- To investigate myocardial blood flow and vascular remodeling in a naturally occurring mouse model of HCM.
- To assess the utility of non-invasive cardiac magnetic resonance imaging (CMR) for detecting perfusion deficits in HCM.
- To correlate imaging findings with histological evidence of fibrosis and vascular changes.
Main Methods:
- Utilized a DBA/2J (D2) mouse model with spontaneous HCM-related gene variants and C57BL/6J (B6) as a reference strain.
- Employed cine-CMR at 9.4T for functional assessment and cine arterial spin labeling (ASL-CMR) for quantitative myocardial perfusion mapping at rest.
- Conducted histological analyses for myocardial interstitial fibrosis, vessel density, and perivascular fibrosis.
Main Results:
- D2 mice exhibited significantly greater left ventricular (LV) hypertrophy compared to B6 mice.
- Resting global myocardial blood flow (MBF) was significantly reduced in D2 mice.
- Histological examination revealed decreased vessel density and increased myocardial collagen volume fraction and perivascular fibrosis in D2 mice.
Conclusions:
- Cine ASL-CMR can detect impaired resting myocardial perfusion in a mouse model of HCM.
- The study highlights a link between vascular remodeling, reduced perfusion, and fibrotic changes in HCM.
- This imaging approach shows potential as a marker for monitoring vascular and myocardial remodeling in HCM.
Background:
Hypertrophic cardiomyopathy (HCM) related myocardial vascular remodelling may lead to the reduction of myocardial blood supply and a subsequent progressive loss of cardiac function. This process has been difficult to observe and thus their connection remains unclear. Here we used non-invasive myocardial blood flow sensitive CMR to show an impairment of resting myocardial perfusion in a mouse model of naturally occurring HCM.
Methods:
We used a mouse model (DBA/2 J; D2 mouse strain) that spontaneously carries variants in the two most susceptible HCM genes-Mybpc3 and Myh7 and bears the key features of human HCM. The C57BL/6 J (B6) was used as a reference strain. Mice with either B6 or D2 backgrounds (male: n = 4, female: n = 4) underwent cine-CMR for functional assessment at 9.4 T. Left ventricular (LV) wall thickness was measured in end diastolic phase by cine-CMR. Quantitative myocardial perfusion maps (male: n = 5, female: n = 5 in each group) were acquired from arterial spin labelling (cine ASL-CMR) at rest. Myocardial perfusion values were measured by delineating different regions of interest based on the LV segmentation model in the mid ventricle of the LV myocardium. Directly after the CMR, the mouse hearts were removed for histological assessments to confirm the incidence of myocardial interstitial fibrosis (n = 8 in each group) and small vessel remodelling such as vessel density (n = 6 in each group) and perivascular fibrosis (n = 8 in each group).
Results:
LV hypertrophy was more pronounced in D2 than in B6 mice (male: D2 LV wall thickness = 1.3 ± 0.1 mm vs B6 LV wall thickness = 1.0 ± 0.0 mm, p < 0.001; female: D2 LV wall thickness = 1.0 ± 0.1 mm vs B6 LV wall thickness = 0.8 ± 0.1 mm, p < 0.01). The resting global myocardial perfusion (myocardial blood flow; MBF) was lower in D2 than in B6 mice (end-diastole: D2 MBFglobal = 7.5 ± 0.6 vs B6 MBFglobal = 9.3 ± 1.6 ml/g/min, p < 0.05; end-systole: D2 MBFglobal = 6.6 ± 0.8 vs B6 MBFglobal = 8.2 ± 2.6 ml/g/min, p < 0.01). This myocardial microvascular dysfunction was observed and associated with a reduction in regional MBF, mainly in the interventricular septal and inferior areas of the myocardium. Immunofluorescence revealed a lower number of vessel densities in D2 than in B6 (D2 capillary = 31.0 ± 3.8% vs B6 capillary = 40.7 ± 4.6%, p < 0.05). Myocardial collagen volume fraction (CVF) was significantly higher in D2 LV versus B6 LV mice (D2 CVF = 3.7 ± 1.4% vs B6 CVF = 1.7 ± 0.7%, p < 0.01). Furthermore, a higher ratio of perivascular fibrosis (PFR) was found in D2 than in B6 mice (D2 PFR = 2.3 ± 1.0%, B6 PFR = 0.8 ± 0.4%, p < 0.01).
Conclusions:
Our work describes an imaging marker using cine ASL-CMR with a potential to monitor vascular and myocardial remodelling in HCM.
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