Metastatic renal cell carcinoma to heart: cardiac surgery versus cardiotoxicity of kinase inhibitors Free

Your case report concerning cardiac metastasis of renal cell carcinoma (RCC) is of great importance as it constitutes a rare complication with difficult treatment [1]. Indeed, metastatic RCC is highly resistant to cytotoxic agents, hormones, and radiotherapy. However, immunochemotherapy, antiangiogenesis agents, and molecular targeting have been investigated as alternative treatment in order to improve the outcome in advanced RCC. Specifically, chemotherapy with kinase inhibitors (KIs) provide targeted therapy inhibiting the causal or contributory kinases driving tumor progression, while leaving the function of other kinases intact. This class of therapeutics has had some remarkable successes, as sunitinib and sorafenib have significantly contributed to the management of renal cell carcinoma.

Unfortunately, cardiotoxicity, often manifest as left ventricular dysfunction and/or heart failure, has ensued after the use of KIs in patients. Several mechanisms leading to cardiotoxicity have been proposed. Sunitinib, which was initially developed primarily to inhibit vascular endothelial growth factor receptors (VEGFRs) 1–3, platelet-derived growth factor receptors (PDGFRs) á/â, and c-Kit, has been predicted to inhibit at least 50 kinases [2]. In cultured cardiomyocytes, sunitinib induced loss of mitochondrial membrane potential and energy rundown [3]. Typically, when energy stores drop in the cardiomyocyte, a kinase called AMP-activated protein kinase (AMPK) is activated, leading to increased energy generation and decreased energy utilization. However, AMPK was not activated in the energy-stressed cardiomyocytes. In fact, AMPK activity was reduced in hearts of sunitinibtreated mice and cardiomyocytes in culture, and this was due to potent and direct inhibition of AMPK by sunitinib [2, 3].

Secondly, studies in mouse models have suggested that angiogenesis is key to maintaining cardiac homeostasis in response to pressure overload, which, taken together with the significant hypertension induced by VEGFR inhibitors, might explain, in part, the LV dysfunction seen with sunitinib [4]. More recently, PDGFRâ, another target of sunitinib, was also found to be critical for angiogenesis, and deletion of the gene in mice led to heart failure when the mice were exposed to high-pressure loads [5].

Finally, it remains unclear whether LV dysfunction with KIs is attributable to myocyte loss (and therefore largely irreversible) or myocyte dysfunction (potentially reversible).

Despite these promising chemotherapeutic approaches, the treatment of metastatic RCC remains ineffective. Surgical resection plays a major role in the palliation of isolated metastatic disease as in your case. While combination therapy that includes surgery and chemotherapy may constitute the best chance of palliation or even cure of this perplexing complication.

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