Autonomous Aldosterone Production and Left Ventricular Hypertrophy.

In general, for the same level of blood pressure (BP), patients with primary aldosteronism (PA) carry a poorer prognosis than those with essential hypertension. This could result from there being more left ventricular hypertrophy (LVH) in patients with PA. It has been difficult to demonstrate in human studies an effect of aldosterone on the heart or, to be more specific, for an increase in aldosterone production to cause LVH. That is until now. In the current issue of Hypertension, Ohno et al present findings from the JPAS (Japan Primary Aldosteronism Study), a large cohort of patients with PA. The original JPAS cohort included 2814 patients from 29 medical centers across Japan over the years 2006 to 2017. In the present study, the authors analyzed data from 1186 patients, all of whom had received an echocardiogram. A fortuitous feature of the clinical evaluation was a confirmatory test, intended to substantiate the diagnosis of PA. One or the other of 2 tests was performed on each patient: The captopril challenge test or the saline infusion test. Both tests, by giving the ACE (angiotensin-converting enzyme) inhibitor or saline infusion, remove or significantly diminish the regulation of aldosterone production by angiotensin II. The prevailing plasma aldosterone concentrations (PAC) were considered to be representative of autonomous aldosterone production, that is, secretion of aldosterone beyond what is dictated by angiotensin II. As Ohno et al showed, it was this nonsuppressible portion of aldosterone production that was implicated for the increased risk of cardiomegaly. The article presented 3 key findings: First and foremost, left ventricular mass index (LVMI) was positively associated with PAC measured at the end of either captopril challenge test or saline infusion test. Second, hypokalemia was related to the presence of LVH, suggesting that a higher level of aldosterone, one sufficient to lower potassium concentrations, could significantly increase the risk of LVH. Finally, patients that had been treated for PA, either with adrenalectomy or by MR (mineralocorticoid receptor) antagonists (MRA), and then underwent a subsequent echocardiogram within 6 to 9 months after the initiation of the treatment demonstrated significantly decreased LVMI and systolic BP from baseline. With these findings, the study has presented perhaps the most compelling evidence to date of an interaction of aldosterone with hypertrophy of the heart in a clinical population of PA. The findings give credence to the notion that aldosterone can influence the heart in ways beyond its sodium-retaining properties that affect BP. In PA, aldosterone-induced cardiac remodeling represents a significant risk that should not be overlooked. MR has a ubiquitous presence in human tissues. In the kidney, aldosterone acts on the epithelial sodium channel, which mediates sodium reabsorption and potassium secretion. An excess of aldosterone, therefore, could activate epithelial sodium channel and cause extracellular volume expansion and BP elevation and thus increasing the risk of LVH. Conversely, SPRINT (Systolic Blood Pressure Intervention Trial) showed that aggressively reducing BP resulted in a significant reduction in the rates of new LVH, and higher rates of regression in those with existing LVH. But MR also exists in nonepithelial tissues, including the heart, where aldosterone’s influences could be independent of its BP effect. Animal models have shown that aldosterone treatment led to LVH and that removal of aldosterone by adrenalectomy or MRA had reduced the cardiac and renal damage without significantly altering BP. Human studies largely corroborate the findings from animal experiments. Rossi and colleagues reported that aldosterone excess was associated with increased LV mass and wall thickness in patients with aldosterone-producing adenomas. Pitt et al showed that in hypertensive patients with LVH, an MRA (eplerenone 200 mg/day) was about as effective as an ACE inhibitor (enalapril 10 mg/day) in reducing LV mass; a combination of eplerenone and enalapril lowered BP more than each of the individual drugs alone. Both drugs, of course, reduce exposure to aldosterone. Their cardiovascular benefits would seem to be derived not solely from the drugs’ BP-lowering effects. As others have observed, the risk of LVH arises when aldosterone production becomes autonomous and unresponsive to the modulation of salt, and by extension, angiotensin II. By linking the autonomous production of aldosterone to LVMI, the current study has highlighted the cardiovascular consequences of PA. Evidence from the present study strongly suggests dual pathways of influence result in LVH in (Figure). In contrast to angiotensin II–regulated aldosterone production by the normal adrenal, the nonsuppressible aldosterone production in PA leads to hypertrophied cardiomyocytes, through elevated BP, as well as what may be direct effect by aldosterone. The opinions expressed in this article are not necessarily those of the American Heart Association. From the Indiana University Center for Aging Research (W.T.) and Department of Medicine (J.H.P.), Indiana University School of Medicine, Indianapolis. Correspondence to J. Howard Pratt, MD, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202. Email johpratt@iu.edu Autonomous Aldosterone Production and Left Ventricular Hypertrophy