Inhibition of myocardial cathepsin-L release during reperfusion following myocardial infarction improves cardiac function and reduces infarct size.

AIMS: Identifying novel mediators of lethal myocardial reperfusion injury that can be targeted during primary percutaneous coronary intervention (PPCI) is key to limiting the progression of patients with ST-elevation myocardial infarction (STEMI) to heart failure. Here, we show through parallel clinical and integrative preclinical studies the significance of the protease cathepsin-L on cardiac function during reperfusion injury. METHODS AND RESULTS: We found that direct cardiac release of cathepsin-L in STEMI patients (n = 76) immediately post-PPCI leads to elevated serum cathepsin-L levels and that serum levels of cathepsin-L in the first 24 h post-reperfusion are associated with reduced cardiac contractile function and increased infarct size. Preclinical studies demonstrate that inhibition of cathepsin-L release following reperfusion injury with CAA0225 reduces infarct size and improves cardiac contractile function by limiting abnormal cardiomyocyte calcium handling and apoptosis. CONCLUSION: Our findings suggest that cathepsin-L is a novel therapeutic target that could be exploited clinically to counteract the deleterious effects of acute reperfusion injury after an acute STEMI.

Thermodilution-derived temperature recovery time: a novel predictor of microvascular reperfusion and prognosis after myocardial infarction.

BACKGROUND: Novel parameters that detect failed microvascular reperfusion might identify better the patients likely to benefit from adjunctive treatments during primary percutaneous coronary intervention (PCI). AIMS: The aim of this study was to test the hypothesis that a novel invasive parameter, the thermodilution-derived temperature recovery time (TRT), would be associated with microvascular obstruction (MVO) and prognosis. METHODS: TRT was derived and validated in two independent ST-elevation myocardial infarction populations and was measured immediately post PCI. TRT was defined as the duration (seconds) from the nadir of the hyperaemic thermodilution curve to 20% from baseline body temperature. MVO extent (% left ventricular mass) was assessed by cardiovascular magnetic resonance imaging at 2-7 days. RESULTS: In the retrospective derivation cohort (n=271, mean age 60±12 years, 72% male), higher TRT was associated with more MVO (coefficient: 4.09 [95% CI: 2.70-5.48], p<0.001), independently of IMR >32, CFR ≤2, hyperaemic Tmn >median, thermodilution waveform, age and ischaemic time. At five years, higher TRT was multivariably associated with all-cause death/heart failure hospitalisation (OR 4.14 [95% CI: 2.08-8.25], p<0.001) and major adverse cardiac events (OR 4.05 [95% CI: 2.00-8.21], p<0.001). In the validation population (n=144, mean age 59±11 years, 80% male), the findings were confirmed prospectively. CONCLUSIONS: TRT represents a novel diagnostic advance for predicting MVO and prognosis. ClinicalTrials.gov Identifiers: NCT02072850 & NCT02257294 Visual summary. Thermodilution-derived temperature recovery time (TRT): a novel predictor of microvascular reperfusion & prognosis after STEMI. CMR: cardiovascular magnetic resonance; MACE: major adverse cardiac events; MVO: microvascular obstruction; PCI: percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction.

Severe left ventricular systolic dysfunction in a patient with a typical haemolytic-uraemic syndrome treated with rituximab-coincidence or cause?

A 26-year-old female with haemolytic-uraemic syndrome (HUS) refractory to daily plasma exchange was successfully treated with rituximab. Subsequent testing confirmed the presence of mutations in genes encoding complement factor I and CD46. On Day 32 she developed pulmonary oedema, and echocardiography demonstrated severe left ventricular systolic dysfunction. There was no evidence of recent myocardial infarction. Cardiac involvement has been reported, not only in thrombotic thrombocytopaenic purpura (TTP) but also with rituximab therapy. However, it is unclear if atypical HUS is also associated with cardiac disease. We recommend echocardiography in all patients with TTP-HUS and in any patients commencing treatment with rituximab.