Mitochondrial Biomarkers in Patients with ST-Elevation Myocardial Infarction and Their Potential Prognostic Implications: A Prospective Observational Study

Background: Mitochondrial biomarkers have been investigated in different critical settings, including ST-elevation myocardial infarction (STEMI). Whether they provide prognostic information in STEMI, complementary to troponins, has not been fully elucidated. We prospectively explored the in-hospital and long-term prognostic implications of cytochrome c and cell-free mitochondrial DNA (mtDNA) in STEMI patients undergoing primary percutaneous coronary intervention. Methods: We measured cytochrome c and mtDNA at admission in 466 patients. Patients were grouped according to mitochondrial biomarkers detection: group 1 (−/−; no biomarker detected; n = 28); group 2 (−/+; only one biomarker detected; n = 283); group 3 (+/+; both biomarkers detected; n = 155). A composite of in-hospital mortality, cardiogenic shock, and acute pulmonary edema was the primary endpoint. Four-year all-cause mortality was the secondary endpoint. Results: Progressively lower left ventricular ejection fractions (52 ± 8%, 49 ± 8%, 47 ± 9%; p = 0.006) and higher troponin I peaks (54 ± 44, 73 ± 66, 106 ± 81 ng/mL; p = 0.001) were found across the groups. An increase in primary (4%, 14%, 19%; p = 0.03) and secondary (10%, 15%, 23%; p = 0.02) endpoint rate was observed going from group 1 to group 3. The adjusted odds ratio increment of the primary endpoint from one group to the next was 1.65 (95% CI 1.04–2.61; p = 0.03), while the adjusted hazard ratio increment of the secondary endpoint was 1.55 (95% CI 1.12–2.52; p = 0.03). The addition of study group allocation to admission troponin I reclassified 12% and 22% of patients for the primary and secondary endpoint, respectively. Conclusions: Detection of mitochondrial biomarkers is common in STEMI and seems to be associated with in-hospital and long-term outcome independently of troponin

Mitochondrial Biomarkers in Patients with ST-Elevation Myocardial Infarction and Their Potential Prognostic Implications: A Prospective Observational Study

Background: Mitochondrial biomarkers have been investigated in different critical settings, including ST-elevation myocardial infarction (STEMI). Whether they provide prognostic information in STEMI, complementary to troponins, has not been fully elucidated. We prospectively explored the in-hospital and long-term prognostic implications of cytochrome c and cell-free mitochondrial DNA (mtDNA) in STEMI patients undergoing primary percutaneous coronary intervention. Methods: We measured cytochrome c and mtDNA at admission in 466 patients. Patients were grouped according to mitochondrial biomarkers detection: group 1 (−/−; no biomarker detected; n = 28); group 2 (−/+; only one biomarker detected; n = 283); group 3 (+/+; both biomarkers detected; n = 155). A composite of in-hospital mortality, cardiogenic shock, and acute pulmonary edema was the primary endpoint. Four-year all-cause mortality was the secondary endpoint. Results: Progressively lower left ventricular ejection fractions (52 ± 8%, 49 ± 8%, 47 ± 9%; p = 0.006) and higher troponin I peaks (54 ± 44, 73 ± 66, 106 ± 81 ng/mL; p = 0.001) were found across the groups. An increase in primary (4%, 14%, 19%; p = 0.03) and secondary (10%, 15%, 23%; p = 0.02) endpoint rate was observed going from group 1 to group 3. The adjusted odds ratio increment of the primary endpoint from one group to the next was 1.65 (95% CI 1.04–2.61; p = 0.03), while the adjusted hazard ratio increment of the secondary endpoint was 1.55 (95% CI 1.12–2.52; p = 0.03). The addition of study group allocation to admission troponin I reclassified 12% and 22% of patients for the primary and secondary endpoint, respectively. Conclusions: Detection of mitochondrial biomarkers is common in STEMI and seems to be associated with in-hospital and long-term outcome independently of troponin

Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein-Protein Interactions

We developed a new class of inhibitors of protein-protein interactions of the SHP2 phosphatase, which is pivotal in cell signaling and represents a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective for disease-associated SHP2 mutants. Considering that pathogenic lesions cause signaling hyperactivation due to increased levels of SHP2 association with cognate proteins, we developed peptide-based molecules with nanomolar affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation, and an affinity for pathogenic variants of SHP2 that is 2-20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant (D61G) in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool for investigating the role of protein-protein interactions in the function of SHP2