Potential role of poly(adenosine 5'-diphosphate-ribose) polymerase activation in the pathogenesis of myocardial contractile dysfunction associated with human septic shock.

OBJECTIVE: Sepsis is associated with increased production of superoxide and nitric oxide, with consequent peroxynitrite generation. Cardiodepression is induced in the heart during oxidative stress associated with septic shock. Oxidative and nitrosative stress can lead to activation of the nuclear enzyme poly(adenosine 5'-diphosphate [ADP]-ribose) polymerase (PARP), with subsequent loss of myocardial contractile function. The aim of the study was to investigate whether cardiodepression found in septic patients is associated with plasma markers of myocardial necrosis and with myocardial PARP activation. DESIGN: Prospective and observational study. SETTING: University hospital intensive care unit for clinical and surgical patients. PATIENTS: Twenty-five patients older than 18 yrs presenting with severe sepsis or septic shock. Patients with history of chronic heart failure, cancer, coronary artery disease, diabetes, or acquired immune deficiency syndrome were excluded. INTERVENTIONS: Patients were followed for 28 days, and biochemical and hemodynamic data were collected on days 1, 3, and 6 of sepsis. The groups were survivors and nonsurvivors, defined only after the end of clinical patient evolution. Heart sections from patients who died were analyzed with hematoxylin-eosin and Picro Sirius-Red immunostaining and with electron microscopy. MEASUREMENTS AND MAIN RESULTS: The study population included 25 individuals, of whom 12 (48%) died during the 6 days of follow-up. The initial data of the inflammation marker C-reactive protein and Acute Physiologic and Chronic Health. Evaluation severity were similar in both groups (nonsurvivors, 26 +/- 2; survivors, 24 +/- 5; NS). Overall, an increase in plasma troponin level was related to increased mortality risk. In patients who died, significant myocardial damage was detected, and histologic analysis of heart sections showed inflammatory infiltration, increased collagen deposition, and derangement of mitochondrial cristae. Immunohistochemical staining for poly(ADP-ribose) (PAR), the product of activated PARP, was demonstrated in septic hearts. There was a positive correlation between PAR staining densitometry and troponin I (r(2) = 0.73; p < .05), and the correlation of PAR staining densitometry and left ventricular systolic stroke work index was r(2) = 0.33 (p = .0509). CONCLUSION: There is significant PARP activation in the hearts of septic patients with impaired cardiac function. We hypothesize that PARP activation may be partly responsible for the cardiac depression seen in humans with severe sepsis.