Diagnosis, Diagnostic Tools, and Risk Stratification for Contemporary Treatment of Pulmonary Embolism.

Pulmonary embolism (PE) is quite common and is associated with significant morbidity and mortality. It is estimated that it is the cause of approximately 100,000 annual deaths in the United States. With great variability in presenting symptoms of PE, poor recognition of PE can be fatal. As such, many risk scores have been created to identify the sickest patients. Choosing the appropriate imaging modality is also critical. Invasive pulmonary angiography was once the gold standard to establish the diagnosis. With the advent of nuclear imaging, V/Q scans, invasive angiography has been phased out for diagnosing acute PE. At present, the standard for diagnosis of acute PE is computed tomography pulmonary angiography. In select patient cohorts, nuclear studies remain the modality of choice. Once the diagnosis of acute PE is established, there is a broad spectrum of severity in outcome which has led to substantial focus and development of risk stratification prediction models. We will discuss making the proper diagnosis with contemporary diagnostic tools and risk stratifying patients with PE to receive the correct treatment.

Pulmonary Embolism Complicated With Cardiopulmonary Arrest Treated With Combination of Thrombolytics and Aspiration Thrombectomy.

Systemic thrombolytic therapy is frequently used in the treatment of massive pulmonary embolism. We describe a case of pulseless electrical activity arrest, refractory obstructive shock in the setting of massive pulmonary embolism despite tissue plasminogen activator that was successfully treated with catheter-directed aspiration thrombectomy. (Level of Difficulty: Intermediate.).

Hemodynamic and Clinical Determinants of Left Atrial Enlargement in Liver Transplant Candidates.

New-onset heart failure is a frequent complication after orthotopic liver transplantation (OLT). Left atrial enlargement (LAE) may be a sign of occult left heart disease. Our primary objective was to determine invasive hemodynamic and clinical predictors of LAE and then investigate its effect on post-transplant outcomes. Of 609 subjects who received OLT between January 1, 2010, and October 1, 2018, 145 who underwent preoperative right-sided cardiac catheterization and transthoracic echocardiography were included. Seventy-eight subjects (54%) had pretransplant LAE. Those with LAE had significantly lower systemic vascular resistance with higher cardiac and stroke volume index (61.0 vs 51.7 ml/m2; p <0.001), but there was no difference in pulmonary artery wedge pressure. There was a linear relation between left atrial volume index and stroke volume index (R2 = 0.490, p<0.001), but not pulmonary artery wedge pressure. The presence of severe LAE was associated with a reduced likelihood (hazard ratio = 0.26, p = 0.033) of reaching the composite end point of new-onset systolic heart failure, heart failure hospitalization, or heart failure death within 12 months post-transplant. There was also a significant reduction in LAE after transplantation (p = 0.013). In conclusion, LAE was common in OLT recipients and was more closely associated with stroke volume than left heart filling pressures. The presence of LAE was associated with a reduced likelihood of reaching composite outcomes and tended to regress after transplant.

From Coronaries to Cirrhosis: The Role of Percutaneous Coronary Intervention and Dual Antiplatelet Therapy in End-Stage Liver Disease.

Drug-eluting stents (DES) have superior efficacy compared with bare metal stents (BMS) for treatment of coronary artery lesions. However, BMS continue to play an important role in percutaneous coronary intervention for patients who are at a high bleeding risk, because they require a shorter duration of dual antiplatelet therapy. However, new developments in DES and understanding of the optimal time required for dual antiplatelet therapy after percutaneous coronary intervention may further limit the use of BMS. Furthermore, the use of dual antiplatelet therapy is complicated in patients with cirrhosis, who may have coagulopathy. In this article, we present the case of a patient with cirrhosis and end-stage chronic liver disease with coronary artery disease and a proximal left anterior descending stenosis who received a DES and had multiple episodes of gastrointestinal bleeding. We review the literature addressing DES and BMS in patients at high risk of bleeding. We also review the optimal duration of dual antiplatelet therapy.

c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells.

The ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific "client" proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Hsp90 remain unknown. Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity, enhances Hsp90 interaction with kinase clients, and compromises the chaperoning of non-kinase clients such as glucocorticoid receptor and CFTR. Suggesting a regulatory paradigm, we also find that Y223 phosphorylation leads to ubiquitination and degradation of hAha1 in the proteasome. Finally, pharmacologic inhibition of c-Abl prevents hAha1 interaction with Hsp90, thereby hypersensitizing cancer cells to Hsp90 inhibitors both in vitro and ex vivo.

Molecular mechanisms of tissue inhibitor of metalloproteinase 2 in the tumor microenvironment.

There has been a recent paradigm shift in the way we target cancer, drawing a greater focus on the role of the tumor microenvironment (TME) in cancer development, progression and metastasis. Within the TME, there is a crosstalk in signaling and communication between the malignant cells and the surrounding extracellular matrix. Matrix metalloproteinases (MMPs) are zinc-dependent endoproteases that have the ability to degrade the matrix surrounding a tumor and mediate tumor growth, angiogenesis and metastatic disease. Their endogenous inhibitors, the Tissue Inhibitors of Metalloproteinases (TIMPs), primarily function to prevent degradation of the ECM via inhibition of MMPs. However, recent studies demonstrate that TIMP family members also possess MMP-independent functions. One TIMP member in particular, TIMP-2, has many distinct properties and functions, that occur independent of MMP inhibition, including the inhibition of tumor growth and reduction of angiogenesis through decreased endothelial cell proliferation and migration. The MMP-independent molecular mechanisms and signaling pathways elicited by TIMP-2 in the TME are described in this review.