Mineralocorticoid receptor antagonists for heart failure

The review ‘Mineralocorticoid Receptor Antagonists for Heart failure’ [1] is a comprehensive, useful and balanced survey of the field. It provides an excellent summary for clinicians and scientists alike of the basic physiology of aldosterone and mineralocorticoid receptors. What follows are snapshots of the RALES, EPHESUS and EMPHASIS trials, followed by a linear and logical analysis of when antagonists should be used in heart failure, when they are inappropriately prescribed, and when they should be used and are not.

That said, it seems churlish to offer any suggestions about what else might have been included: it is a sizeable review, and there is nothing superfluous in the text. It seems even more churlish to take issue in terms merely of emphasis. These two rubrics can be fairly summarily dealt with, and the major part of this commentary will attempt to broaden the discussion beyond the focus of the review, from heart failure to hypertension.

To get the churlishness out of the way, the review might have profitably spent a sentence or two more on GPR30, long considered – against all the evidence – to be a membrane estrogen receptor, and shown by Ross Feldman and his colleagues [2] to be a (very) high affinity membrane-binding site for aldosterone. GPR30 is a receptor in that it can mediate intracellular effects of aldosterone at subnanomolar concentrations; whether it is truly a membrane mineralocorticoid receptor, that is, able to be selectively activated by aldosterone, rather than a fairly promiscuous corticosteroid-binding species (such as the classical mineralocorticoid receptor) is yet to be established.

Two other points are the counter-intuitive finding that mice selectively mineralocorticoid receptor null in macrophages do not show an elevated blood pressure (BP) on DOCA/salt, in addition to the (expected) lessening of perivascular cardiac fibrosis [3]; the second is the inverse agonist action of spironolactone [4]. The first may be of importance in highlighting the little explored link between the cardiovascular and immune systems, and make people wonder; the second, preliminary data notwithstanding, overturns the long-held notion that antagonists act by excluding agonists from mineralocorticoid receptors. The demonstration – in animal studies, in Langendorf preparations – that spironolactone can be protective in the absence of any other steroid is clear evidence that how we envisage antagonist action needs to be radically reconsidered.

Finally, in the churlish arena, is the question of the ectopic production of aldosterone (or other mineralocorticoid receptor active steroids) in the heart and blood vessels. Studies on both sides of the Atlantic – in the opinion of this author [5] – finally lay to rest cardiac synthesis; implicit from these careful studies is the heady combination of very low level contamination and forty plus PCR cycles in the reported sightings. When one considers the fastidious architecture – inner and outer mitochondrial membranes, and so on – of adrenal corticosteroidogenesis, allowing substrate for subsequent enzymes to reach necessarily high concentration, the burden of proof needs more than PCR ‘evidence’ of steroidogenic enzymes, at levels 0.1 – 0.01% of those in whole adrenal; here endeth the first lesson.

Now for something completely different. For obvious reasons, the major clinical trials – RALES, EPHESUS, EMPHASIS, and the yet to be completed TOPCAT – are done in heart failure. Heart failure – most obviously in RALES – is a progressive and lethal disease, and both mortality and morbidity data are appropriate and satisfactory end points. In the realm of hypertension, a well-substantiated cardiovascular risk factor, things are different: morbidity rather than mortality data are the norm. Even when differences are impressive – the four to fourteen times higher levels of atrial fibrillation, stroke and nonfatal myocardial infarction in patients with longstanding primary aldosteronism than in age-, sex- and BP-matched essential hypertensives [6] – such morbidity markers are prognostic, not definitive of mortality. What this has meant is that trials of mineralocorticoid antagonists in hypertension have been small, with far less dramatic outcomes: reductions in BP or proteinuria, translated into reduction in risk factors for deleterious cardiovascular outcomes.

Such differences notwithstanding, the prime area for expanding the use of mineralocorticoid receptor antagonists would appear to be in hypertension. Some minor mathematics need to be considered in justification of this claim. As noted above, heart failure is a progressive and lethal disease, increasingly as a terminal event given modern methods of cardiovascular protection/salvage, and with an average shortening of lifespan more than that of cancer. In many countries, it is also the commonest cause of recurrent hospital admissions. Hypertension on the other hand affects ∼ 20% of the population, is commonly seen relatively early in the now generally extended lifespan, and is a cardiovascular risk in itself, but not necessarily a death sentence.

As a drug target for mineralocorticoid receptors, what differences it has over heart failure are four things, as follows. First, it is preventative, rather than palliative. Second, it should be given for 30 years, not (on average from RALES) 30 months. Third, patients are on average much younger and thus far less likely to have co-morbidities or excluding factors (elevated serum creatinine or plasma (K+)). Finally, is the sheer weight of numbers: for every one patient in heart failure, there are 10 hypertensives.

There are powerful reasons for considering a mineralocorticoid receptor antagonist as part of first-line therapy in hypertension. In uncomplicated essential hypertension, when titrated to effect, it is an excellent BP lowering agent, and can be safely prescribed in terms of hyperkalemia [7]. More importantly, it is uniquely vasoprotective in essential hypertensive patients with or without diabetes [8]. For patients with resistant hypertension – BP remaining elevated despite three conventional agents including a diuretic – low dose spironolactone as an adjuvant has been shown to produce remarkable falls in BP, of the order of 20 – 30mmHg systolic and 15 – 20 mmHg diastolic [9].

Low-dose spironolactone – an inverse agonist, not a ‘blocker’ – is, however, of most importance in the ∼ 10% of hypertensive patients who have autonomous aldosterone secretion or primary aldosteronism. In no country in the world are > 1% of subjects with primary aldosterone ever diagnosed as such and appropriately treated. True, the recommended treatment for the third of the total with unilateral hypersecretion is laparoscopic adrenalectomy [10]: there are, however, data that at 5 years in such patients there are no significant differences between medical and surgical treatment [11]. For the majority of patients with primary aldosteronism due to bilateral adrenal hyperplasia, medical treatment with mineralocorticoid receptor antagonists is, of course, the treatment of choice.

The problem is that cardiologists are understandably driven by survival as an outcome, and thus the attention has focussed on heart failure. The guidelines for the management of primary aldosteronism are written by endocrinologists, but not those for hypertension. In essential hypertension, mineralocorticoid receptor blockade is uniquely vasculoprotective. In resistant hypertension, it is uniquely effective in lowering BP. In the 99% of subjects with occult primary aldosteronism, given its record of increased morbidity over essential hypertension, low dose mineralocorticoid receptor antagonists from the outset are game-changing. Whatever the cause of the elevated BP – essential, resistant or primary aldosteronism – mineralocorticoid receptor antagonists need to be part of first-line antihypertensive therapy.

Declaration of interest

The author declares no conflict of interest and has received no payment in preparation of this manuscript.