Imaging Reveals the Connection Between Spontaneous Coronary Plaque Ruptures, Atherothrombosis, and Myocardial Infarctions in HypoE/SRBI^−/− Mice

Abstract

The hyperlipidemic mouse model HypoE/SRBI −/− has been shown to develop occlusive coronary atherosclerosis followed by myocardial infarctions and premature deaths in response to high-fat, highcholesterol diet (HFC). However, the causal connection between myocardial infarctions and atherosclerotic plaque rupture events in the coronary arteries has not been investigated so far. The objective of this study was to assess whether diet-induced coronary plaque ruptures trigger atherothrombotic occlusions, resulting in myocardial infarctions in HFC-fed HypoE/SRBI −/− mice. Methods: HypoE/SRBI −/− mice were characterized with respect to the individual dynamics of myocardial infarctions and features of infarct-related coronary atherosclerosis by serial noninvasive molecular and functional imaging, histopathology, and a pharmaceutical intervention. Detailed histologic analysis of whole mouse hearts was performed when spontaneously occurring acute myocardial infarctions were diagnosed by imaging. Results: Using the imaging-triggered approach, we discovered thrombi in 32 (10.8%) of all 296 atherosclerotic coronary plaques in 14 HFC-fed HypoE/SRBI −/− mice. These thrombi typically were found in arteries presenting with inflammatory plaque phenotypes. Acetylsalicylic acid treatment did not attenuate the development of atherosclerotic coronary plaques but profoundly reduced the incidence of premature deaths, the number of thrombi (7 in 249 plaques), and also the degree of inflammation in the culprit lesions. Conclusion: HFC-induced ruptures of coronary plaques trigger atherothrombosis, vessel occlusions, myocardial infarctions, and sudden death in these mice. Thus, the HypoE/SRBI −/− mouse model mimics major features of human coronary heart disease and might therefore be a valuable model for the investigation of molecular and cellular parameters driving plaque rupture-related events and the development of new interventional approaches.

Hyperglycemia Aggravates Diet-Induced Coronary Artery Disease and Myocardial Infarction in SR-B1-Knockout/ApoE-Hypomorphic Mice

“…Mice that were maintained on normal chow, regardless of treatment with STZ or control citrate buffer, exhibited no obvious clinical signs (other than dramatically increased urination in the STZ treated mice) and survived to the end of the study (14 weeks after initiation of STZ or control citrate buffer treatment; Figure 1C ) at which point, they were euthanized for further analysis. SR-B1-KO/hypoE mice are known to develop HFC diet induced occlusive coronary artery atherosclerosis and fatal myocardial infarction ( Zhang et al, 2005 ; Nakagawa-Toyama et al, 2012 ; Pei et al, 2013 ; Hermann et al, 2016 ; Luk et al, 2016 ). Consistent with this, SR-B1-KO/hypoE mice that had been treated with control citrate buffer and switched to the HFC diet exhibited reduced survival, with a median survival of 11.3 weeks after the start of treatment (8.3 weeks after the start of HFC diet feeding).…”

“…SR-B1-KO/hypoE mice fed the HFC diet develop atherosclerosis in coronary arteries in addition to the aortic sinus ( Zhang et al, 2005 ; Nakagawa-Toyama et al, 2012 ; Pei et al, 2013 ; Hermann et al, 2016 ; Luk et al, 2016 ). We therefore examined the effects of STZ- vs control-treatment on atherosclerosis in coronary arteries in SR-B1-KO/hypoE that had been maintained on chow diet until 14 weeks after the induction of STZ or control- treatment, and in STZ- or control-treated SR-B1-KO/hypoE mice that had been fed the HFC diet beginning 3 weeks after the start of STZ- or control-treatment for a total of 4 weeks of HFC diet feeding ( Figures 4A – G ).…”

“…SR-B1-KO mice containing atherogenic mutations in either apoE ( KO or hypomorphic) or LDLR ( LDLR-KO ) develop either spontaneous (in the case of SR-B1/apoE double KO) or HFC diet-induced (in the case of SR-B1-KO/hypoE or SR-B1/LDLR double KO mice) coronary artery atherosclerosis, myocardial infarction, and dramatically reduced survival ( Braun et al, 2002 , 2003 ; Zhang et al, 2005 ; Karackattu et al, 2006 ; Nakagawa-Toyama et al, 2012 ; Al-Jarallah et al, 2013 ; Fuller et al, 2014 ; Hermann et al, 2016 ; Luk et al, 2016 ; Liao et al, 2017 ). The reduced survival of these mice appears to be associated with myocardial infarction and resulting cardiac conduction and functional abnormalities ( Braun et al, 2002 , 2003 ; Zhang et al, 2005 ; Karackattu et al, 2006 ; Nakagawa-Toyama et al, 2012 ; Al-Jarallah et al, 2013 ; Fuller et al, 2014 ; Hermann et al, 2016 ; Luk et al, 2016 ; Liao et al, 2017 ). In the case of the SR-B1-KO/hypoE and SR-B1/LDLR double KO mice, the timing of the onset of these phenotypes is dependent on the composition of the diet, with respect to fat and cholesterol and other components (such as cholate) which affect the diet’s atherogenicity ( Nakagawa-Toyama et al, 2012 ; Fuller et al, 2014 ).…”

“…For example, Hermann et al (2016) recently reported that coronary arteries from SR-B1-KO/hypoE mice, fed a more atherogenic diet containing cholate, exhibited features of plaque rupture, including intraluminal thrombi and pro-inflammatory phenotypes, and that their distribution corresponded to regions of hearts exhibiting infarction. Administration of acetylsalicylic acid to those mice resulted in no changes in the burden of coronary artery atherosclerosis but a significantly reduced coronary artery inflammation and thrombosis and myocardial infarction and extended survival of the mice ( Hermann et al, 2016 ). In an analogous manner, the increased coronary artery thrombosis detected in the STZ- compared to control-treated mice fed the HFC diet may have contributed to the increased cardiac fibrosis and their reduced survival.…”

“…We and others reported similar results for mice deficient in both SR-B1 and the LDLR ( SR-B1/LDLR double KO mice) fed HFC atherogenic diets ( Fuller et al, 2014 ; Liao et al, 2017 ). SR-B1 KO mice homozygous for a hypomorphic mutant apoE allele ( hypoE ) also develop HFC diet-induced coronary artery atherosclerosis, myocardial infarction, cardiac dysfunction, and reduced survival ( Zhang et al, 2005 ; Nakagawa-Toyama et al, 2012 ; Hermann et al, 2016 ; Luk et al, 2016 ). Taking advantage of the inducible nature of the coronary artery atherosclerosis and myocardial infarction in SR-B1-KO/hypoE mice, we tested whether the induction of hyperglycemia in these mice affected the development of the diet induced coronary heart disease phenotype.…”