Immune-Mediated Hypertension and Kidney Injury (page 1111)
Hypertension is a widespread risk factor for many diseases. Although a variety of medications are available, hypertension remains uncontrolled in many treated patients, highlighting a need for novel therapeutic options. Because of the heritability of hypertension, understanding its genetic basis may lead to better treatment and more individualized care. Human genome–wide association studies have nominated many genes for hypertension, and investigation of these genes may uncover novel mechanisms of pathology. One such gene, SH2B3, encodes an intracellular adaptor protein with no clear link to blood pressure regulation. In this issue, we demonstrate that mutation of SH2B3 in the Dahl salt–sensitive rat significantly attenuated hypertension and renal disease. Subsequent bone marrow transplantation between Sh2b3em1Mcwi mutants and Dahl SS rats revealed that the immune cells partly mediated this attenuation of pathology. Furthermore, mutation of SH2B3 significantly increased the percentage of regulatory T cells among circulating and splenic T cells. Regulatory T cells suppress inflammatory signaling of many cell types, and adoptive transfer of regulatory T cells has attenuated pathology in several models of immune-mediated disease. If hypertension is mediated by inflammation, as many recent studies suggest, then elevating the expression of regulatory T cells may prove beneficial by increasing the threshold for immune responses. Further study of SH2B3 and its signaling may reveal targetable pathways that can modulate immune cell differentiation to accommodate patients with inflammatory diseases, including hypertension.
Mineralocorticoid Receptor Blockade Treats Obesity-Related Cardiac Diastolic Dysfunction (page 1082)
Results of the recent Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial were negative about the benefit of mineralocorticoid receptor (MR) antagonism in patients with diastolic heart failure; however, the broad inclusion criteria of TOPCAT may have masked patient subgroups that might benefit from MR antagonism. Obese patients exhibit a high incidence of cardiac diastolic dysfunction, a condition that contributes to increased mortality in this population and for which no evidence-based treatment exists. Because MR antagonists are cardioprotective and obesity is associated with renin–angiotensin–aldosterone system activation, MR blockade holds promise as a treatment for obesity-related diastolic dysfunction. In this issue, Bender et al report that treatment of Zucker obese rats with a low dose of the MR antagonist spironolactone normalized established cardiac diastolic dysfunction associated with reduced cardiac fibrosis and oxidative stress, as well as improved coronary microvascular endothelial function and endothelial insulin signaling. Importantly, the cardiovascular protection reported in this study occurred in the absence of hyperkalemia, an improvement in kidney injury, or changes in blood pressure. This study highlights a context-dependent role of MR signaling as a contributor to obesity-related cardiac diastolic dysfunction and coronary microvascular dysfunction and suggests that the cardiovascular benefit of MR antagonism can be achieved with minimal effect on kidney MR. Thus, these benefits of MR antagonism warrant further clinical evaluation for therapeutic application to these conditions in obese patients.
Peripheral Plasma 18-Oxocortisol in Primary Aldosteronism (page 1096)
Adrenal venous sampling is currently the only reliable method to distinguish unilateral from bilateral disease in primary aldosteronism. We attempted to determine whether peripheral plasma levels of 18-oxocortisol (18oxoF) could contribute to the clinical differentiation between aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism with bilateral adrenal hyperplasia (bilateral hyperaldosteronism) in 234 patients with primary aldosteronism, including computed tomography (CT)–detectable APA (n=113) and bilateral hyperaldosteronism (n=121), all of whom underwent CT and adrenal venous sampling. All aldosteronomas were surgically resected, and the accuracy of diagnosis was clinically and histopathologically confirmed. 18oxoF and 18-hydroxycortisol were measured using liquid chromatographic tandem mass spectrometry. Receiver operating characteristic analysis of 18oxoF discrimination of adenoma from hyperplasia demonstrated a sensitivity/specificity of 0.83/0.99 at a cut-off value of 4.7 ng/dL. 18oxoF levels >6.1 ng/dL were found in 86 of 113 patients with APA (76%) but in none of 121 patients with bilateral hyperaldosteronism, 30 of whom harbored CT-detectable unilateral nonfunctioning nodules in their adrenals. In addition, 18oxoF levels <1.2 ng/dL, the lowest in aldosteronoma, were found in 52 of the 121 (43%) patients with bilateral hyperaldosteronism. Further analysis of 27 patients with CT-undetectable microscopic APAs revealed that 8 of these 27 patients had CT-detectable contralateral adrenal nodules and their highest value of 18oxoF was 4.8 ng/dL below 6.1. The peripheral plasma 18oxoF concentrations served not only to differentiate APAs but also could serve to avoid unnecessary surgery for nonfunctioning adrenocortical nodules concurrent with hyperplasia or microadenoma.
- © 2015 American Heart Association, Inc.