Nonischemic myocardial changes detected by cardiac magnetic resonance in critical care patients with sepsis.

To the Editor: We report herein the first in vivo demonstration of a nonischemic myocardial alteration in patients with sepsis using a noninvasive imaging biomarker. Troponin as a nonspecific serum biomarker for cardiac injury is often elevated in patients with sepsis, raising suspicion for acute coronary syndrome (ACS). However, troponin elevation in patients with severe sepsis predicts mortality even in the absence of ACS and irrespective of hemodynamic status (e.g., shock) (1, 2), raising questions as to the mechanism of myocardial injury. Recent postmortem data published in the journal (3) suggest that cardiomyocyte injury occurs in the absence of cell death; however, in vivo evidence supporting nonischemic mechanisms of myocardial injury have not been previously identified. We performed cardiac magnetic resonance imaging (CMR) as part of an Institutional Review Board–approved human subjects protocol in a series of patients with sepsis. CMR is a well-established, clinically available technique that is able to distinguish typical subendocardial injury due to ACS from inflammatory myocardial injury (4). Contemporary techniques afford rapid imaging of myocardial injury, subendocardial infarction, and contractile function with minimal patient cooperation. Targeted patients for enrollment were those who had the diagnosis of sepsis based on established criteria including evidence of a systemic inflammatory response syndrome and source for infection either microbiologically proven, clinically proven, or suspected (5). Exclusion criteria for enrollment were the following: history of known arteriosclerotic coronary artery disease or cardiomyopathy, evidence of ST elevation or new left bundle branch block on electrocardiogram, evidence or history of unstable arrhythmia, presence of any non-MR compatible implant (e.g., pacemaker or defibrillator device), glomerular filtration rate 65 mm Hg, afebrile for >12 hours, and stable or decreasing vasopressor requirement > 12 hours. If mechanically ventilated, stability criteria also included positive end-expiratory pressure < 10 cm H2O and FiO2 < 60%. Patients with PaO2/FiO2 ratios < 200 were excluded. All patients and/or patients’ families provided written informed consent for participation. The protocol included measurement of troponin-I serum level using a high-sensitivity assay (TnI-Ultra and ADVIA Centaur XP immunoanalyzer; Siemens Healthcare Diagnostics (Malvern, PA); upper limit of normal = 0.11 ng/ml) and rapid (<30 min) CMR examination with T2 mapping for myocardial inflammation/injury, cine imaging for left ventricular ejection fraction, and late postgadolinium enhancement (LGE) acquisitions for infarct scar imaging. Myocardial T2 was measured in a mid-short axis cross-section through the left ventricle with measurements made specifically in epicardium and endocardium. Whole myocardium T2 was averaged including both epicardium and endocardium, which was compared with a normal cutoff of <59 ms established in prior studies (6). Left ventricular ejection fraction averaged 53 ± 12% (range: 35–65%). LGE images were independently evaluated by two blinded reviewers and rated by consensus as showing presence/absence of myocardial infarct scar. Fisher’s exact test was used to test agreement between normal/abnormal T2 and normal/abnormal troponin-I. Comparison between myocardial T2 values in patients with sepsis versus those previously reported from 21 healthy subjects (7) was performed using Student’s t test, and intra-patient comparison between endocardial and epicardial T2 values was performed using Wilcoxon’s rank sum test. Table 1 summarizes the clinical characteristics of seven enrolled patients, five of whom had abnormal myocardial T2 (>59 ms; Figure 1). Five of seven had evidence of severe sepsis based on established criteria (8), and none were on pressors or had hemodynamic instability at the time of CMR. There was excellent agreement between normal/abnormal T2 and normal/elevated troponin (R2 = 1.00, P = 0.02). Myocardial T2 in patients with sepsis was significantly higher than that in healthy control subjects (P = 0.02; Figure 1). T2 elevation was consistently higher in epicardium versus endocardium in patients with sepsis (median [interquartile range] difference = 1.2 [0.04–1.42] ms, P = 0.04). LGE showed no evidence of subendocardial infarct scar in any of the patients. TABLE 1. CHARACTERISTICS OF STUDY SUBJECTS Figure 1. T2 maps of the left ventricle (LV) in cross-section are shown in a typical patient with sepsis (A) in comparison to a healthy control subject (B). T2 relaxation time is measured in milliseconds, with longer relaxation times being more abnormal. The scale . Our findings support a nonischemic mechanism of myocardial injury, namely, inflammation and/or tissue acidosis, that can be detected in patients during the acute phase of sepsis. This insight was afforded by in vivo CMR using quantitative myocardial T2 measurement together with LGE, which is used clinically to distinguish between ACS (typified by subendocardial T2 increase and infarct scar by LGE) and myocarditis (marked by epicardial T2 increase and no subendocardial infarct scar). Muscle T2 values are known to increase in direct proportion to [H+] (9), making it a useful biomarker of myocardial acidosis (10). The epicardial predominance of myocardial T2 elevation suggests a nonischemic pattern of injury that may be due to myocardial inflammation or altered myocardial metabolism (acidosis); this is in distinction from myocardial infarction and global hypoperfusion that produce subendocardial injury (11). These findings align with the postmortem findings of Takasu and colleagues (3), which suggest that cardiac dysfunction in sepsis is not caused by cell necrosis or death but potentially reversible mitochondrial injury. This explanation is further supported by a murine model wherein the septic heart was shown to adopt an altered metabolic state associated with increased reliance on anaerobic, non-mitochondrial pathways, which results in tissue (lactic) acidosis (12). Together, these data behoove larger studies to better define the prevalence of myocardial inflammation in the setting of sepsis. If confirmed, therapies for troponin elevation in sepsis distinct from the usual anti-platelet and anti-coagulant approaches used for presumptive ACS should be considered. Given the poor prognosis associated with troponin elevation in sepsis, better delineation of the mechanism of troponin increase is needed to guide appropriate cardioprotective strategies to attenuate organ dysfunction.