Distinct cardiodynamic and molecular characteristics during early and late stages of sepsis-induced myocardial dysfunction.
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.
Chopra
Mani
M
Cardionome Laboratory Department of Biomedical Sciences Baylor College of Dentistry, Texas A&M Health Science Center, 3302 Gaston Avenue, Dallas, TX 75246, USA.
Sharma
Avadhesh C
AC
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*
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