IJCS | Volume 31, Nº6, November / December 2018

648 Jorge et al. Myocardial dysfunction and mortality in sepsis Int J Cardiovasc Sci. 2018;31(6)643-651 Review Article systemic vascular resistance, which is initially reduced, pulmonary vascular resistance is increased since the early stages of sepsis by decreased production of NO 48,49 and increased circulating levels of vasoactive substances, such as thromboxane, endothelin, and serotonin. 50-53 An RV with an intrinsic reduction in contractility induced by sepsis becomes more sensitive to the increase in afterload secondary to pulmonary vascular dysfunction 54 and only manages to maintain, at least initially, its systolic function through increased filling pressures provided by an adequate volume resuscitation; with fluid administration, there is an increase in cardiac index, central venous pressure, pulmonary capillary wedge pressure, and indices of end systolic and diastolic RV volumes, despite a progressive reduction in the ejection fraction of this ventricle. 55 The failure of this compensatory mechanism becomes particularly more evident in patients on mechanical ventilation and in the presence of acute lung injury. In the first case, the effects of positive pressure on cardiac function lead to decreased venous return (hindering the increased filling pressures), elevation in pulmonary vascular resistance, and reduction in cardiac output due to increased intrathoracic pressure. 56 In the second, the hyperinflation resulting from recruitment maneuver and the pulmonary collapse due to alveolar filling and protective ventilation strategies using very low tidal volumes can also elevate the pulmonary vascular resistance by an increased autonomic tonus reflex and hypoxic pulmonary vasoconstriction, respectively. 57,58 Regardless of this mechanism of adaptation, the literature has demonstrated an association between right ventricular systolic dysfunction and mortality in sepsis, with studies pointing to a lower RVEF 59,60 and, more recently, to a reduction in peak systolic velocity of the RV free wall on tissue Doppler in patients not surviving to sepsis compared with survivors. 61,62 Vallabhajosyula et al., 63 in a historical cohort study of patients with severe sepsis or septic shock admitted to all intensive care units at Mayo Clinic between January 2007 and December 2014, showed that 55% of the patients met the diagnostic criteria for right ventricular dysfunction and, after adjustment for age, comorbidities, disease severity, presence of septic shock, and mechanical ventilation, concluded that the presence of right ventricular dysfunction was associated with worse survival at 1 year (risk ratio of 1.6, 95% confidence interval [95%CI] 1.2 – 2.1, p = 0.002). 63 More recently, Orde et al. 64 showed that right ventricular dysfunction was present in 32% of the patients with severe sepsis or septic shock evaluated by conventional echocardiography, and that this number rose to 72% when the evaluation was performed with speckle tracking; this “unmasked” dysfunction, especiallywhen severe, was associatedwith a high mortality rate. 64 Biomarkers and sepsis Cardiac troponins (I and T) are important independent predictors of mortality in acute coronary syndrome without ST-segment elevation 65 and other clinical conditions, such as end-stage renal disease, 66 stroke, 67 and pulmonary embolism. 68 The elevation in troponin levels is relatively common in sepsis, occurring in approximately 60% of the patients; 69 even though it is unclear why this happens, the manifestations of myocardial dysfunction that most correlated to the elevation in troponin levels have been recently demonstrated to be diastolic dysfunction and right ventricular dilation. 44 The role of the troponins as a prognostic factor in sepsis is still under debate, with some studies 70-72 having shown negative results in terms of increased mortality, and others concluded otherwise. John et al. 73 showed a higher mortality at 28 days in patients with positive troponin I (32% versus 14%, p < 0.0001),73 while Vallabhajosyula et al., 74 in a retrospective cohort study, observed a relationship between troponin T elevation (≥ 0.01 ng/mL) on admission, in-hospital mortality (odds ratio [OR] 1.6, p = 0.003), and mortality at 1 year (OR 1.4, p = 0.04). 74 BNP and NT-proBNP are two molecules secreted in response to atrial wall stretching and extensively used in the diagnosis and prognosis of heart failure. In the clinical context of sepsis, proinflammatory cytokines are believed to also exert an important role in the elevation of BNP levels. In vitro studies have shown the importance of interleukins 1 and 6 and TNF- α in inducing BNP secretion by cardiomyocytes, 75,76 explaining the higher plasma concentrations of this biomarker even in individuals without heart failure, and its correlation with the levels of C-reactive protein, a traditional marker of inflammatory activity. 77 In sepsis, the interpretation of increased levels of BNP and NT-proBNP can be hampered by the inflammation and other factors like age and renal insufficiency, although studies have demonstrated their importance