The literature exploring the utility of advanced echocardiographic techniques (such as deformation imaging) in the diagnosis and prognostication of patients receiving potentially cardiotoxic cancer therapy has involved relatively small trials in the research setting. In this systematic review of the current literature, we describe echocardiographic myocardial deformation parameters in 1,504 patients during or after cancer chemotherapy for 3 clinically-relevant scenarios. The systematic review was performed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using the EMBASE (1974 to November 2013) and MEDLINE (1946 to November 2013) databases. All studies of early myocardial changes with chemotherapy demonstrate that alterations of myocardial deformation precede significant change in left ventricular ejection fraction (LVEF). Using tissue Doppler-based strain imaging, peak systolic longitudinal strain rate has most consistently detected early myocardial changes during therapy, whereas with speckle tracking echocardiography (STE), peak systolic global longitudinal strain (GLS) appears to be the best measure. A 10% to 15% early reduction in GLS by STE during therapy appears to be the most useful parameter for the prediction of cardiotoxicity, defined as a drop in LVEF or heart failure. In late survivors of cancer, measures of global radial and circumferential strain are consistently abnormal, even in the context of normal LVEF, but their clinical value in predicting subsequent ventricular dysfunction or heart failure has not been explored. Thus, this systematic review confirms the value of echocardiographic myocardial deformation parameters for the early detection of myocardial changes and prediction of cardiotoxicity in patients receiving cancer therapy.

Patients with end‐stage renal disease (ESRD) have elevated circulating calcium (Ca) and phosphate (Pi), and exhibit accelerated progression of calcific aortic valve disease (CAVD). We hypothesized that matrix vesicles (MVs) initiate the calcification process in CAVD. Ca induced rat valve interstitial cells (VICs) calcification at 4.5 mM (16.4‐fold; p < 0.05) whereas Pi treatment alone had no effect. Ca (2.7 mM) and Pi (2.5 mM) synergistically induced calcium deposition (10.8‐fold; p < 0.001) in VICs. Ca treatment increased the mRNA of the osteogenic markers Msx2, Runx2, and Alpl (p < 0.01). MVs were harvested by ultracentrifugation from VICs cultured with control or calcification media (containing 2.7 mM Ca and 2.5 mM Pi) for 16 hr. Proteomics analysis revealed the marked enrichment of exosomal proteins, including CD9, CD63, LAMP‐1, and LAMP‐2 and a concomitant up‐regulation of the Annexin family of calcium‐binding proteins. Of particular note Annexin VI was shown to be enriched in calcifying VIC‐derived MVs (51.9‐fold; p < 0.05). Through bioinformatic analysis using Ingenuity Pathway Analysis (IPA), the up‐regulation of canonical signaling pathways relevant to cardiovascular function were identified in calcifying VIC‐derived MVs, including aldosterone, Rho kinase, and metal binding. Further studies using human calcified valve tissue revealed the co‐localization of Annexin VI with areas of MVs in the extracellular matrix by transmission electron microscopy (TEM). Together these findings highlight a critical role for VIC‐derived MVs in CAVD. Furthermore, we identify calcium as a key driver of aortic valve calcification, which may directly underpin the increased susceptibility of ESRD patients to accelerated development of CAVD.

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