title: Distinct cardiodynamic and molecular characteristics during early and late stages of sepsis-induced myocardial dysfunction.
abstract: We hypothesized that progressive decline in myocardial performance would correlate with upregulation of markers for apoptotic mechanisms following increased duration of polymicrobial sepsis in the rat. Male Sprague-Dawley rats (350-400 g) were randomized into sham, 1-, 3- and 7-day sepsis groups. Each septic rat received 200 mg/kg cecal inoculum intraperitoneally (i.p). The post-mortem analysis showed a severely inflamed peritoneum with the presence of pus in all septic animals that was directly proportional to the duration of sepsis. We observed 10, 33 and 42% mortality in the 1-, 3- and 7-day sepsis groups, respectively. Septic animals at 3 and 7 days exhibited an increased wet lung/total body weight and heart weight/total body weight. A significant increase in total cardiac troponin I (cTnI) and C Reactive Protein (CRP) and endothelin-1 (ET-1) was also observed with an increased duration of sepsis. Myocardial ET-1 concentration in the 7-day post-sepsis group was significantly elevated compared to the sham and 1-day post-sepsis groups. Sepsis also produced a significant decrease in the mean arterial pressure in the 7-day post-sepsis group and tachycardia in the 1-, 3-, and 7-day post-sepsis groups compared to the sham group. A significant prolongation of the left ventricular isovolumic relaxation rate constant, tau, and left ventricular end-diastolic pressure in the 1-, 3- and 7-day post-sepsis groups compared to the sham group was observed. In addition, a significant decrease in the rates of left ventricular relaxation (-dP/dt) and contraction (+dP/dt) in the 3- and 7-day post-sepsis groups compared to the sham and 1-day post-sepsis group was observed. Sepsis produced a significant upregulation in the expression of myocardial TRADD, cytosolic active caspase-3, the Bax/Bcl(2) ratio, and the mitochondrial release of cytochrome C in the 3- and 7-day post-sepsis groups. We observed a progressive increase in the number of TUNEL positive nuclei, cytosolic caspase-3 activation and co-localization of PARP in the nuclei at 1, 3 and 7 days post-sepsis. These data suggest that the progression of sepsis from 1 day to 3-7 days produce distinct cardiodynamic characteristics with a more profound effect during later stages. The sepsis-induced decline in myocardial performance correlates with the induction of myocardial apoptosis.
authors.affiliation: Cardionome Laboratory Department of Biomedical Sciences Baylor College of Dentistry, Texas A&M Health Science Center, 3302 Gaston Avenue, Dallas, TX 75246, USA.
authors.forename: Mani
authors.initials: M
authors.lastname: Chopra
authors.forename: Avadhesh C
authors.initials: AC
authors.lastname: Sharma
mesh_terms: D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D016232:Endothelins / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D006339:Heart Rate; D007022:Hypotension / Q000209:etiology / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D013492:Suppuration / Q000378:metabolism / Q000503:physiopathology; D015996:Survival Rate; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism; D013610:Tachycardia / Q000378:metabolism / Q000503:physiopathology; D019210:Troponin I / Q000378:metabolism; D018754:Ventricular Dysfunction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D016232:Endothelins; D019253:Proto-Oncogene Proteins c-bcl-2; D053199:TNF Receptor-Associated Death Domain Protein; D019210:Troponin I; D051028:bcl-2-Associated X Protein; D002097:C-Reactive Protein; D045304:Cytochromes c; D011065:Poly(ADP-ribose) Polymerases; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3