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. 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). 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). Our work describes an imaging marker using cine ASL-CMR with a potential to monitor vascular and myocardial remodelling in HCM.

中文翻译：

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心血管磁共振检测肥厚性心肌病小鼠模型中的微血管功能障碍

肥厚型心肌病 (HCM) 相关的心肌血管重构可能导致心肌供血减少和随后的心脏功能逐渐丧失。这个过程很难观察，因此它们之间的联系尚不清楚。在这里，我们使用非侵入性心肌血流敏感 CMR 来显示自然发生的 HCM 小鼠模型中静息心肌灌注的损害。我们使用了一种小鼠模型（DBA/2 J；D2 小鼠品系），该模型自发携带两个最易感的 HCM 基因——Mybpc3 和 Myh7 的变异，并具有人类 HCM 的关键特征。C57BL/6 J (B6) 用作参考菌株。具有 B6 或 D2 背景的小鼠（雄性：n = 4，雌性：n = 4）在 9.4 T 时接受了 cine-CMR 进行功能评估。在舒张末期通过 cine-CMR 测量左心室 (LV) 壁厚。定量心肌灌注图（男性：n = 5，女性：每组 n = 5）从静止的动脉自旋标记（电影 ASL-CMR）中获得。基于 LV 心肌中心室的 LV 分割模型，通过描绘不同的感兴趣区域来测量心肌灌注值。在 CMR 后立即取出小鼠心脏进行组织学评估，以确认心肌间质纤维化（每组 n = 8）和小血管重塑如血管密度（每组 n = 6）和血管周围纤维化（n = 每组 8 人）。D2 小鼠的 LV 肥厚比 B6 小鼠更明显（雄性：D2 LV 壁厚 = 1.3 ± 0.1 毫米 vs B6 LV 壁厚 = 1.0 ± 0.0 毫米，p < 0.001；雌性：D2 LV 壁厚 = 1.0 ± 0.1 毫米与 B6 LV 壁厚 = 0.8 ± 0.1 毫米，p < 0.01）。D2 小鼠的静息全局心肌灌注（心肌血流量；MBF）低于 B6 小鼠（舒张末期：D2 MBFglobal = 7.5 ± 0.6 vs B6 MBFglobal = 9.3 ± 1.6 ml/g/min，p < 0.05；结束-收缩期：D2 MBFglobal = 6.6 ± 0.8 vs B6 MBFglobal = 8.2 ± 2.6 ml/g/min，p < 0.01）。观察到这种心肌微血管功能障碍并与局部 MBF 减少有关，主要是在心肌的室间隔和下部区域。免疫荧光显示 D2 中的血管密度数量低于 B6（D2 毛细血管 = 31.0 ± 3.8% 与 B6 毛细血管 = 40.7 ± 4.6%，p < 0.05）。D2 LV 与 B6 LV 小鼠的心肌胶原体积分数 (CVF) 显着更高（D2 CVF = 3.7 ± 1.4% 与 B6 CVF = 1.7 ± 0.7%，p < 0.01）。此外，在 D2 中发现血管周围纤维化 (PFR) 的比率高于 B6 小鼠（D2 PFR = 2.3 ± 1.0%，B6 PFR = 0.8 ± 0.4%，p < 0.01）。我们的工作描述了一种使用电影 ASL-CMR 的成像标记物，它具有监测 HCM 中血管和心肌重塑的潜力。