Subtotal ablation and hyperthermia in the adrenal cortex
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Primary aldosteronism (PA) accounts for 5–12% of all hypertension and confers a higher risk for cardiovascular and cerebrovascular complications compared to age and blood pressure (BP) matched essential hypertension. PA is caused by autonomous aldosterone secretion from unilateral (40%) or bilateral (60%) sources. The current definitive management for unilateral PA is surgical laparoscopic adrenalectomy. Bilateral disease is not currently definitively managed but rather treated pharmacologically using mineralocorticoid receptor antagonists.. Currently, the option of surgery is limited to 30% of individuals with unilateral disease due to the collateral resection of normal cortex. Adrenalectomy is very rarely considered for those with bilateral disease. Therefore, there exists a need for improved definitive options for management of bilateral and unilateral PA which selectively removes or disrupts the diseased tissue causing aldosterone excess, while also preserving normal adrenocortical tissue. Proposed herein, is a novel image-guided adrenal thermal therapy approach to definitively manage PA. The hyperthermia dosimetry that induces cell death in both H295R and HAC15 adrenocortical cancer cell lines was assessed to inform ablation therapy applications. In both cell lines cell death via necrosis occurred following 500C exposure for 15 and 30 minutes. In those cells exposed to sublethal exposures of hyperthermia a heat shock response was induced, indicated by increased protein expression of HSP90 and HSP70. The effects of sublethal hyperthermia at 420C and 450C on steroidogenesis was next investigated in H295R and HAC15 cell lines. This study assessed which steroidogenic pathways and enzymes are most sensitive to hyperthermia. Hyperthermia of 450C exposure for 30 minutes was found to decrease CYP17A1 and HSD3B2 protein expression in both cell lines. While under the same conditions StaR was decreased in H295Rs and increased in HAC15 cells. CYP11B2 remained stable under all treatments. Sublethal hyperthermia was found to significantly inhibit cortisol output but aldosterone output remained intact. Finally, an in-vivo swine model was used to investigate the feasibility and safety of subtotal adrenal ablation. From this it was found that subtotal ablation of the adrenal could be achieved whereby the selectively ablated zone was disrupted while the nontargeted tissue remained unaffected. The only safety concern raised was due to transient elevated blood pressure during the procedure caused by medullary degranulation and the release of catecholamines. Ultimately, these data identify a novel strategy to provide definitive adrenocortical sparing treatment to patients with primary aldosteronism, and additionally provides a molecular understanding as to how this is achieved.