ABSTRACT
BACKGROUND: Data are lacking on the relative incidence of thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli (STEC) and atypical HUS (aHUS) in patients presenting with thrombotic microangiopathies (TMAs). METHODS: This was a prospective, cross-sectional, multicentre and non-interventional epidemiological study. Patients fulfilling criteria for TMAs (platelet consumption, microangiopathic haemolytic anaemia and organ dysfunction) were included in the study. The primary objective was to assess the relative incidence of TTP, STEC-HUS, aHUS and 'other' physician-defined diagnoses. The secondary objective was to develop an algorithm to predict a severe deficiency in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity (≤10%) using routine laboratory parameters. A post hoc classification using the recent Kidney Disease: Improving Global Outcomes diagnostic criteria was then undertaken to further classify patient groups. RESULTS: aHUS was diagnosed with a relative incidence of 61%, whereas TTP, STEC-HUS and 'other' were diagnosed in 13, 6 and 20% of patients, respectively. In the post hoc analysis, 27% of patients with a TMA were classified as 'primary aHUS' and 53% as 'secondary aHUS'. Multivariate analysis revealed that severe deficiency in ADAMTS13 activity (≤10%) was unlikely to underlie TMA if platelet and serum creatinine were above threshold values of 30 × 109/L and 1.8 mg/dL, respectively (negative predictive value of 92.3 and 98.1, respectively, if one or both values were above the threshold). CONCLUSIONS: In this study, aHUS was the most common single diagnosis among patients presenting with a TMA. In the absence of an ADAMTS13 activity result, platelet count and serum creatinine may aid in the differential diagnosis.
ABSTRACT
RATIONALE: Myocardial infarction (MI) increases the wall stress in the viable myocardium and initiates early adaptive remodeling in the left ventricle to maintain cardiac output. Later remodeling processes include fibrotic reorganization that eventually leads to cardiac failure. Understanding the mechanisms that support cardiac function in the early phase post MI and identifying the processes that initiate transition to maladaptive remodeling are of major clinical interest. OBJECTIVE: To characterize MI-induced changes in titin-based cardiac myocyte stiffness and to elucidate the role of titin in ventricular remodeling of remote myocardium in the early phase after MI. METHODS AND RESULTS: Titin properties were analyzed in Langendorff-perfused mouse hearts after 20-minute ischemia/60-minute reperfusion (I/R), and mouse hearts that underwent ligature of the left anterior descending coronary artery for 3 or 10 days. Cardiac myocyte passive tension was significantly increased 1 hour after ischemia/reperfusion and 3 and 10 days after left anterior descending coronary artery ligature. The increased passive tension was caused by hypophosphorylation of the titin N2-B unique sequence and hyperphosphorylation of the PEVK (titin domain rich in proline, glutamate, valine, and lysine) region of titin. Blocking of interleukine-6 before left anterior descending coronary artery ligature restored titin-based myocyte tension after MI, suggesting that MI-induced titin stiffening is mediated by elevated levels of the cytokine interleukine-6. We further demonstrate that the early remodeling processes 3 days after MI involve accelerated titin turnover by the ubiquitin-proteasome system. CONCLUSIONS: We conclude that titin-based cardiac myocyte stiffening acutely after MI is partly mediated by interleukine-6 and is an important mechanism of remote myocardium to adapt to the increased mechanical demands after myocardial injury.
