Chronic Akt1 Deficiency Attenuates Adverse Remodeling and Enhances Angiogenesis After Myocardial Infarction

Abstract

Background— Akt1 is a key signaling molecule in multiple cell types, including endothelial cells. Accordingly, Akt1 was proposed as a therapeutic target for ischemic injury in the context of myocardial infarction (MI). The aim of this study was to use multimodal in vivo imaging to investigate the impact of systemic Akt1 deficiency on cardiac function and angiogenesis before and after MI. Methods and Results— In vivo cardiac MRI was performed before and at days 1, 8, 15, and 29 to 30 after MI induction for wild-type, heterozygous, and Akt1-deficient mice. Noninfarcted hearts were imaged using ex vivo stereomicroscopy and microcomputed tomography. Histological examination was performed for noninfarcted hearts and for hearts at days 8 and 29 to 30 after MI. MRI revealed mildly decreased baseline cardiac function in Akt1 null mice, whereas ex vivo stereomicroscopy and microcomputed tomography revealed substantially reduced coronary macrovasculature. After MI, Akt1 –/– mice demonstrated significantly attenuated ventricular remodeling and a smaller decrease in ejection fraction. At 8 days after MI, a larger functional capillary network at the remote and border zone, accompanied by reduced scar extension, preserved cardiac function, and enhanced border zone wall thickening, was observed in Akt1 –/– mice when compared with littermate controls. Conclusions— Using multimodal imaging to probe the role of Akt1 in cardiac function and remodeling after MI, this study revealed reduced adverse remodeling in Akt1-deficient mice after MI. Augmented myocardial angiogenesis coupled with a more functional myocardial capillary network may facilitate revascularization and therefore be responsible for preservation of infarcted myocardium.

Cardio-Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Reveals Molecular Signatures of Endogenous Fibrosis and Exogenous Contrast Media

“…Changes in FS during the process of infarct healing paralleled the time course of scar formation and maturation as established by previous histological studies 18 including those from our institution. 13 In addition, high-density scar in myocardial regions of interest demonstrating heightened FS was confirmed histologically in all samples. Clinically, cardioCEST of myocardial fibrosis could enable diagnosis and risk stratification of large high-risk patient cohorts currently contraindicated to LGE.…”

3D Imaging and Quantitative Analysis of Vascular Networks: A Comparison of Ultramicroscopy and Micro-Computed Tomography

“…Micro-CT imaging has been used by several groups to analyze the murine heart's arterial vasculature. Vessel geometry and total vessel length of the murine coronary network 39 , 40 , 41 , 42 have been determined in 2D down to a diameter of 45 µm 39 . Recently, lumen distribution of murine coronary arteries (24-240 µm diameter) have been calculated with the help of several different algorithms 42 .…”

Noninvasive mapping of endothelial dysfunction in myocardial ischemia by magnetic resonance imaging using an albumin‐based contrast agent

“…Magnetic resonance imaging (MRI) is a minimally invasive and high‐resolution imaging technique that is now widely used for cardiac imaging in both clinical practice and preclinical research . Late gadolinium‐enhanced magnetic resonance imaging (LGE‐MRI) using clinically available low‐molecular‐weight gadolinium‐based contrast agents yields hyperintense regions as a standard technique for the quantification of infarct size . Low‐molecular‐weight intravascular contrast agents, such as gadopentetate dimeglumine (GdDTPA), change myocardial tissue relaxation by diffusion exchange from the intravascular to extravascular space, and vice versa, at the capillary level .…”

“…4 Late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) using clinically available low-molecular-weight gadolinium-based contrast agents yields hyperintense regions as a standard technique for the quantification of infarct size. 5,6 Low-molecular-weight intravascular contrast agents, such as gadopentetate dimeglumine (GdDTPA), change myocardial tissue relaxation by diffusion exchange from the intravascular to extravascular space, and vice versa, at the capillary level. 7,8 However, this assumption is invalid for larger molecules, such as albumin used here.…”