Current methods of protein detection are insensitive to detecting subtle changes in oncoprotein activation that underlie critical cancer signaling processes. The requirement for large numbers of cells precludes serial tumor sampling for assessing a response to therapeutics. Therefore, we have developed a nano-fluidic proteomic immunoassay (NIA) to quantify total and low abundance protein isoforms in 4 nanoliters of lysate. Our method could quantify levels of MYC and BCL2 proteins in Burkitt’s versus follicular lymphoma; identify changes in activation of ERK1/2, MEK1, STAT3/5, JNK and caspase 3 in imatinib-treated chronic myelogeneous leukemia (CML) cells; measure a novel change in phosphorylation of an ERK2 isomer in CML patients who responded to imatinib; and detect a decrease in STAT3/5 phosphorylation in lymphoma patients treated with atorvastatin. Therefore, we have described a novel and highly sensitive method for interrogating oncoprotein expression and phosphorylation in clinical specimens for the development of new therapeutics for cancer.

Background: Myocardial injury, defined by elevated troponin levels, is associated with adverse outcome in patients with coronavirus disease 2019 (COVID-19). The frequency of cardiac injury remains highly uncertain and confounded in current publications; myocarditis is one of several mechanisms that have been proposed. Methods: We prospectively assessed patients with myocardial injury hospitalized for COVID-19 using transthoracic echocardiography, cardiac magnetic resonance imaging, and endomyocardial biopsy. Results: Eighteen patients with COVID-19 and myocardial injury were included in this study. Echocardiography revealed normal to mildly reduced left ventricular ejection fraction of 52.5% (46.5%–60.5%) but moderately to severely reduced left ventricular global longitudinal strain of −11.2% (−7.6% to −15.1%). Cardiac magnetic resonance showed any myocardial tissue injury defined by elevated T1, extracellular volume, or late gadolinium enhancement with a nonischemic pattern in 16 patients (83.3%). Seven patients (38.9%) demonstrated myocardial edema in addition to tissue injury fulfilling the Lake-Louise criteria for myocarditis. Combining cardiac magnetic resonance with speckle tracking echocardiography demonstrated functional or morphological cardiac changes in 100% of investigated patients. Endomyocardial biopsy was conducted in 5 patients and revealed enhanced macrophage numbers in all 5 patients in addition to lymphocytic myocarditis in 1 patient. SARS-CoV-2 RNA was not detected in any biopsy by quantitative real-time polymerase chain reaction. Finally, follow-up measurements of left ventricular global longitudinal strain revealed significant improvement after a median of 52.0 days (−11.2% [−9.2% to −14.7%] versus −15.6% [−12.5% to −19.6%] at follow-up; P =0.041). Conclusions: In this small cohort of COVID-19 patients with elevated troponin levels, myocardial injury was evidenced by reduced echocardiographic left ventricular strain, myocarditis patterns on cardiac magnetic resonance, and enhanced macrophage numbers but not predominantly lymphocytic myocarditis in endomyocardial biopsies.

Cardiogenic shock is still a major driver of mortality on intensive care units and complicates ∼10% of acute coronary syndromes with contemporary mortality rates up to 50%. In the meantime, percutaneous circulatory support devices, in particular venoarterial extracorporeal membrane oxygenation (VA-ECMO), have emerged as an established salvage intervention for patients in cardiogenic shock. Venoarterial extracorporeal membrane oxygenation provides temporary circulatory support until other treatments are effective and enables recovery or serves as a bridge to ventricular assist devices, heart transplantation, or decision-making. In this critical care perspective, we provide a concise overview of VA-ECMO utilization in cardiogenic shock, considering rationale, critical care management, as well as weaning aspects. We supplement previous literature by focusing on therapeutic issues related to the vicious circle of retrograde aortic VA-ECMO flow, increased left ventricular (LV) afterload, insufficient LV unloading, and severe pulmonary congestion limiting prognosis in a relevant proportion of patients receiving VA-ECMO treatment. We will outline different modifications in percutaneous mechanical circulatory support to meet this challenge. Besides a strategy of running ECMO at lowest possible flow rates, novel therapeutic options including the combination of VA-ECMO with percutaneous microaxial pumps or implementation of a venoarteriovenous-ECMO configuration based on an additional venous cannula supplying towards pulmonary circulation are most promising among LV unloading and venting strategies. The latter may even combine the advantages of venovenous and venoarterial ECMO therapy, providing potent respiratory and circulatory support at the same time. However, whether VA-ECMO can reduce mortality has to be evaluated in the urgently needed, ongoing prospective randomized studies EURO-SHOCK (NCT03813134), ANCHOR (NCT04184635), and ECLS-SHOCK (NCT03637205). These studies will provide the opportunity to investigate indication, mode, and effect of LV unloading in dedicated sub-analyses. In future, the Heart Teams should aim at conducting a dedicated randomized trial comparing VA-ECMO support with vs. without LV unloading strategies in patients with cardiogenic shock.

Purpose SARS-COV-2 infection can develop into a multi-organ disease. Although pathophysiological mechanisms of COVID-19-associated myocardial injury have been studied throughout the pandemic course in 2019, its morphological characterisation is still unclear. With this study, we aimed to characterise echocardiographic patterns of ventricular function in patients with COVID-19-associated myocardial injury. Methods We prospectively assessed 32 patients hospitalised with COVID-19 and presence or absence of elevated high sensitive troponin T (hsTNT+ vs. hsTNT-) by comprehensive three-dimensional (3D) and strain echocardiography. Results A minority (34.3%) of patients had normal ventricular function, whereas 65.7% had left and/or right ventricular dysfunction defined by impaired left and/or right ventricular ejection fraction and strain measurements. Concomitant biventricular dysfunction was common in hsTNT+ patients. We observed impaired left ventricular (LV) global longitudinal strain (GLS) in patients with myocardial injury (-13.9% vs. -17.7% for hsTNT+ vs. hsTNT-, p = 0.005) but preserved LV ejection fraction (52% vs. 59%, p = 0.074). Further, in these patients, right ventricular (RV) systolic function was impaired with lower RV ejection fraction (40% vs. 49%, p = 0.001) and reduced RV free wall strain (-18.5% vs. -28.3%, p = 0.003). Myocardial dysfunction partially recovered in hsTNT + patients after 52 days of follow-up. In particular, LV-GLS and RV-FWS significantly improved from baseline to follow-up (LV-GLS: -13.9% to -16.5%, p = 0.013; RV-FWS: -18.5% to -22.3%, p = 0.037). Conclusion In patients with COVID-19-associated myocardial injury, comprehensive 3D and strain echocardiography revealed LV dysfunction by GLS and RV dysfunction, which partially resolved at 2-month follow-up. Trial registration COVID-19 Registry of the LMU University Hospital Munich (CORKUM), WHO trial ID DRKS00021225.