Citations

Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult. This approach will be vital in keeping patients on these life-saving therapies and may be applicable to other tyrosine kinase inhibitors as well. In this review, we provide a comprehensive overview of the preclinical and clinical side effects of pazopanib with a focus on the mechanisms responsible for its toxicity to the cardiovascular system.

Background Ossabaw pigs are unique miniature swine with genetic predisposition to develop metabolic syndrome and coronary atherosclerosis after extended periods receiving atherogenic diets. We have hypothesized that transgenic Ossabaw swine expressing chimp PCSK9 (proprotein convertase subtilisin‐like/kexin type 9) containing the D374Y gain of function would develop familial hypercholesterolemia and coronary artery plaques more rapidly than Landrace swine with the same transgene. Methods and Results Ossabaw and Landrace PCSK9 gain‐of‐function founders were generated by Sleeping Beauty transposition and cloning. Histopathologic findings in the Ossabaw founder animal showed more advanced plaques and higher stenosis than in the Landrace founder, underscoring the Ossabaw genetic predisposition to atherosclerosis. We chose to further characterize the Ossabaw PCSK9 gain‐of‐function animals receiving standard or atherogenic diets in a 6‐month longitudinal study using computed tomography, magnetic resonance (MR) imaging, intravascular ultrasound, and optical coherence tomography, followed by pathological analysis of atherosclerosis focused on the coronary arteries. The Ossabaw model was consistently hypercholesterolemic, with or without dietary challenge, and by 6 months had consistent and diffuse fibrofatty or fibroatheromatous plaques with necrosis, overlying fibrous caps, and calcification in up to 10% of coronary plaques. Conclusions The Ossabaw PCSK9 gain‐of‐function model provides consistent and robust disease development in a time frame that is practical for use in preclinical therapeutic evaluation to drive innovation. Although no animal model perfectly mimics the human condition, this genetic large‐animal model is a novel tool for testing therapeutic interventions in the context of developing and advanced coronary artery disease.

Anaplastic thyroid carcinoma (ATC) is almost universally fatal. Elevated keratin-8 (KRT8) protein expression is an established diagnostic cancer biomarker in several epithelial cancers (but not ATC). Several keratins, including KRT8, have been suggested to have a role in cell biology beyond that of structural cytoskeletal proteins. Here, we provide evidence that KRT8 plays a direct role in the growth of ATCs. Genomic and transcriptomic analysis of >5000 patients demonstrates that KRT8 mutation and copy number amplification are frequently evident in epithelial-derived cancers. Carcinomas arising from diverse tissues exhibit KRT8 mRNA and protein overexpression when compared to normal tissue levels. Similarly, in a panel of patient-derived ATC cell lines and patient tumors, KRT8 expression shows a similar pattern. sh-RNA-mediated KRT8 knockdown in these cell lines increases apoptosis, whereas forced overexpression of KRT8 confers resistance to apoptosis under peroxide-induced cell stress conditions. We further show that KRT8 protein binds to annexin A2, a protein known to mediate apoptosis as well as the redox pathway.

Blood pressure (BP) reactivity is predictive of the development of cardiovascular disease. We hypothesized that the BP response at the onset of isometric handgrip exercise would occur earlier and to a lesser degree in individuals who underwent bariatric surgery compared with obese adults and that the reliance on total peripheral resistance (TPR) would be attenuated. Twenty-six individuals (7 nonobese, 11 obese, 8 postbariatric surgery) completed isometric handgrip exercise (40% maximum voluntary contraction) to exhaustion. Heart rate (HR, ECG) and arterial BP (brachial catheter) were measured continuously. Stroke volume was estimated from the pressure waveform, and cardiac output (CO) and TPR were calculated. Peak change, time to peak, and rate of rise in BP were assessed during the first 30 s of exercise. Obese adults exhibited a slower rise in BP and higher peak BP at exercise onset compared with nonobese controls ( P < 0.05). Peak BP and the rate of rise were not different between individuals who underwent bariatric surgery and nonobese controls ( P > 0.05). Nonobese controls exhibited an exercise-mediated increase in CO, whereas obese adults increased TPR ( P < 0.05). The increases in CO and TPR were less apparent in individuals who underwent bariatric surgery ( P > 0.05). In contrast to obese adults, individuals who underwent bariatric surgery exhibit a rapid rise in BP at exercise onset. This rapid increase in BP is associated with a fall in TPR and results in lower peak BP at the onset of isometric exercise. These data suggest that bariatric surgery improves BP reactivity via changes in the time course of hemodynamic responses. NEW & NOTEWORTHY Bariatric surgery has been shown to reduce the blood pressure (BP) response to isometric handgrip exercise. By examining the time course of the BP response to exercise, we found, in contrast to obese adults, individuals who underwent bariatric surgery exhibit a rapid rise in BP at exercise onset, which is associated with a fall in total peripheral resistance and results in lower peak BP at the onset of isometric exercise. These data suggest that bariatric surgery improves BP reactivity via reflex autonomic adjustments.

A pulse ([14C]palmitate)-chase ([3H]palmitate) approach was used to study intramuscular triglyceride (imTG) fatty acid and plasma free fatty acid (FFA) kinetics during exercise at ∼45% peak O2consumption in 12 adults. Vastus lateralis muscle was biopsied before and after 90 min of bicycle exercise;3H2O production, breath14CO2excretion and lipid oxidation (indirect calorimetry) rates were measured during exercise. Results: during exercise, 8.2 ± 1.2 and 8.4 ± 0.7 μmol · kg−1· min−1of imTG fatty acids and plasma FFA, respectively, were oxidized according to isotopic measurements. The sum of these two values was not different ( P = 0.6) from lipid oxidation by indirect calorimetry (15.4 ± 1.6 μmol · kg−1· min−1); the isotopic and indirect calorimetry values were correlated ( r = 0.79, P < 0.005). During exercise, imTG turnover rate was 0.32 ± 0.07%/min (6.0 ± 2.0 μmol of imTG · kg wet muscle−1· min−1) and plasma FFA were incorporated into imTG at a rate of 0.7 ± 0.1 μmol · kg wet muscle−1· min−1. The imTG pool size did not change during exercise. This pulse-chase, dual tracer appears to be a reasonable approach to measure oxidation and synthesis kinetics of imTG.