Noninvasive Evaluation Of Cardiorenal Syndrome By Molecular And Functional Magnetic Resonance Imaging

Part IMyocardial inflammation and anti-inflammatory therapy by Ramipril in a rat model of type 4 cardiorenal syndrome Objective:Type 4 cardiorenal syndrome(CRS)is a life-threatening world health problem in which chronic kidney disease leads to progressive cardiovascular disease.The aim of this study was to detect cardiac inflammation in a rat model of type 4 CRS,and to evaluate the role of Ramipril in cardiac inflammation.Materials and Methods:A rat model of 5/6 subtotal nephrectomy(SNx)was performed to induce primary renal injury.After 4 weeks,all surviving rats were randomly divided into 2 groups and administered vehicle(SNx + Veh,n = 20)or Ramipril(SNx + Ram,n = 20)for an additional 12 weeks.A group of sham-operated rats(sham,n = 20)was used as the control.Renal function and myocardial function were evaluated in all rats.Histopathology,PCR and Western blot were conducted in the myocardium on week 16 to assess myocardial inflammation and fibrosis.Results:Significantly increased serum creatinine and urea nitrogen were observed in the SNx+ Veh group compared with the sham group,which were significantly improved after Ramipril treatment(P<0.05).Chronic kidney dysfunction caused significant myocardial inflammation dominated by substantial infiltration of monocyte-macrophages and upregulation of pro-inflammatory cytokines such as TNF-?,IL-6 and MCP-1,accompanied by myocardial fibrosis,while Ramipril treatment significantly attenuated myocardial inflammation and fibrosis.Conclusions:Myocardial inflammation is a crucial pathogenic mechanism in the setting of type 4 CRS,and Ramipril was sufficient to inhibit myocardial inflammation in this progression.Visualizing myocardial inflammation in a rat model of type 4 cardiorenal syndrome by dual-modality molecular imagingObjective:The aim of this study was to evaluate cardiac inflammation in a rat model of type 4 cardiorenal syndrome(CRS)noninvasively by magneto-fluorescent nanoparticle(MNP)enhanced dual-modality molecular imaging.Materials and Methods:A rat model of type 4 CRS was performed by 5/6 subtotal nephrectomy(SNx).After 4 weeks,the surviving rats were randomly divided into 2 groups and administered vehicle(SNx + Veh,n= 10)or Ramipril(SNx + Ram,n = 10)for an additional 12 weeks.A group of sham-operated rats(sham,n = 10)was used as the control.To monitor macrophage infiltration in the myocardium,a dual-modality MNP was synthesized by combining ultrasmall superparamagnetic iron oxide nanoparticle and Rhodamine B.In vivo T2*-weighted cardiac MRI was performed on week 16,followed by ex vivo optical imaging.Histological analyses were performed to detect MNP labeled macrophages in inflamed hearts.Results:Cardiac MRI showed a remarkable negative contrast in the myocardium post-MNP compared with pre-MNP in the SNx + Veh group(P<0.05),which was not detectable in the sham group and less pronounced in the SNx + Ram group.The signal intensity in optical imaging was significantly higher in the SNx + Veh group compared with sham-operated and drug-treated groups(P<0.05).Prussian blue and CD68 staining showed the colocalization of iron accumulation and macrophages,and the colocalization of macrophages and Rhodamine B in fluorescence imaging demonstrated the specific targeting profile of MNPs to the macrophages.Conclusions:This dual-modality strategy was feasible for noninvasively assessing myocardial inflammation and monitoring therapeutic efficacy in type 4 CRS.Part IIIRenal hypoxia in experimental myocardial infarctions of different sizes in a mouse model of type 1 cardiorenal syndromeObjective:Acute myocardial infarction(MI)affects renal function,and this interdependent relationship has been termed type 1 cardiorenal syndrome(CRS).However,the pathophysiological changes of renal hypoxia following MI is still poorly understood.The aim of this study was to detect renal oxygenation in experimental MIs of different sizes in a mouse model,and to evaluate the putative role of renal hypoxia in renal tubulointerstitial injury.Materials and Methods:Male C57BL/6J mice were randomly subjected to MI surgery with different locations of left anterior descending coronary artery occlusion or sham surgery.The survived mice were sorted into three groups,i.e.,one group with large size of MI(MI-L,n ?48),one with small size of MI(MI-S,n = 48),and a third group with the sham operation(sham,n = 36).Cardiac and renal function were evaluated,and histological staining and Western blot analyses were performed to evaluate tissue hypoxia and kidney injury before and 7,28 and 60 days after MI.Results:Worse cardiac function was observed in mice with larger MIs,which contributed to lower kidney function.Renal hypoxia-inducible factor(HIF)-la was significantly increased after MI from day 7 to 60 in the MI-L group compared with the sham and MI-S group(P<0.05).Furthermore,increased level of renal kidney injury molecule(KIM)-1 was observed in the MI-L group compared with the sham and MI-S group(P<0.05),and renal KIM-1 was positively correlated with HIF-1?(R2 = 0.68,P<0.001).Conclusions:Renal hypoxia after MI is an essential mechanism of type 1 CRS,and larger MIs lead to lower intrarenal oxygenation,which is a potential risk factor for progressive renal tubulointerstitial injury.Part IVNoninvasive identification of renal hypoxia in experimental myocardial infarctions of different sizes by using BOLD-MRI in a mouse model Objective:The aim of this study was to test the feasibility of identifying renal hypoxia following myocardial infarctions(MIs)of different sizes using blood oxygen level-dependent(BOLD)magnetic resonance imaging(MRI).Materials and Methods:Male C57BL/6J mice were randomly subjected to MI surgery with different locations of left anterior descending coronary artery occlusion or sham surgery,and all MI mice were imaged by late gadolinium enhancement on day 1 to confirm the infarct size.The survived mice with screened infarct sizes were sorted into three groups,i.e.,one group with large size of MI(MI-L,n = 48),one with small size of MI(MI-S,n = 48),and a third group with the sham operation(sham,n = 36),defined as the exposure of the heart but no ligation.Renal BOLD-MRI was conducted before and 1,7,14,28 and 60 days after MI,and immunohistochemical staining of renal hypoxia-inducible factor(HIF)-la was performed to evaluate renal tissue hypoxia.Results:Significantly elevated R2*was detected in the MI groups compared with the sham group from day 1 to 60 in both the renal cortex and medulla(P<0.05),and R2*was higher in the MI-L group than in the MI-S group(P<0.05).Renal HIF-la was significantly increased after MI from day 7 to 60 in the MI-L group compared with the sham and MI-S group(P<0.05),which was linearly correlated with R2*in both the renal cortex(R2 = 0.56,P<0.001)and medulla(R2 = 0.63,P<0.001).Conclusions:The magnitude of renal hypoxia after MIs of different sizes can be noninvasively measured by BOLD-MRI.