REMIniscence of Aldosterone's Role in Myocardial Remodelling

This article refers to ‘Role of aldosterone in mid- and long-term left ventricular remodelling after acute myocardial infarction: The REMI study’ by L. Monzo et al., published in this issue on pages 1742–1752. Myocardial infarctions cause adverse remodelling of the ventricular myocardium.1 Thus, patients suffering from myocardial infarction are always at least at risk of heart failure (stage A).2 Ongoing ventricular remodelling establishes a disease trajectory of increasing structural abnormalities of the cardiac tissue (stage B, imminent heart failure), and may finally result in evident heart failure (stages C and D) – with its high burden of morbidity and mortality.3 Aldosterone levels are elevated after myocardial infarction and the renin–angiotensin–aldosterone system plays a major role in the process of remodelling; its modification has been shown to reduce mortality and morbidity.4-6 The 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure therefore recommend the use of drugs like angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists or angiotensin receptor–neprilysin inhibitors (summarized as renin–angiotensin system [RAS] inhibitors) and mineralocorticoid receptor antagonists (MRA) in addition to beta-blockers as well as sodium–glucose cotransporter 2 inhibitors.7 The current prospective study by Monzo et al.8 investigated the impact of aldosterone levels following a ST-elevation myocardial infarction on mid- and long-term left ventricular remodelling in today's era of frequent RAS inhibitor use. The left ventricular volume indices, both end-systolic (LVESV) and end-diastolic (LVEDV), were utilized as surrogate parameters of myocardial remodelling. Left ventricular volumes were measured by transthoracic echocardiography (index hospitalization, 6-month and long-term follow-up) and cardiac magnetic resonance imaging (index hospitalization and 6-month follow-up). The primary outcome was the change in LVEDV from index hospitalization to 6-month follow-up. Overall, 119 patients were included, all of them 2–4 days after successful percutaneous coronary revascularization. At the 6-month follow-up, LVESV was significantly reduced, but only to a minor degree (−3.4 ml/m2). The authors found a significant association of higher baseline aldosterone levels with greater, for example, worse, volume indices at 6-month follow-up. However, this association lost its significance in the long-term follow-up (mean 6.6 years). The authors conclude that previous findings regarding aldosterone's role in remodelling and thus clinical outcomes are confirmed by their REMI study for the contemporary setting. However, there are several drawbacks of this study that implicate obstacles in its interpretation. First, 250 patients were supposed to be recruited for an 80% power to detect a significant difference of 20% in LVEDV as the primary endpoint between baseline and 6-month follow-up. However, the study failed to do so due to slow patient enrolment, partly because of the single centre design. Only 119 patients were recruited – as a result, the primary endpoint's threshold had to be decreased to 15% change in LVEDV (a 25% reduction). Second, and similarly, only 80 patients were still available for long-term follow-up (with a wide range of 3–9 years). Hence, it comes as no surprise that the association between baseline plasma aldosterone and remodelling did not extend to this point. This renders the interpretation of the neutral long-term results difficult, as it remains completely uncertain whether the effect of aldosterone might level off over time or if low patient numbers are the main driver for this result. Third, the effect size of the association of aldosterone with the volume indices may be significant at the 6-month follow-up – but appears rather miniscule, introducing the ever-appearing controversy between statistical significance and clinical relevance. Finally, small sample sizes bear the risk to make studies vulnerable to competing events in the follow-up, for example, other events impacting volume indices, a risk which can only be partly mitigated by sub-analyses for registered events, but not for non-registered or unknown events. Nevertheless, these straits cannot be hold against the authors, who overall should be applauded for trying to answer this important research question. Most studies in this field struggle with patient recruitment – in parts due to strict enrolment criteria which are necessary to provide sufficient internal validity – highlighting the difficulty to conduct clinical trials in general. Therefore, rather than interpreting the study findings in isolation, and thereby over-pronouncing its limitations, readers should be advised to see them in the context of previous analyses, as the totality of evidence indicates that blocking the aldosterone receptor prevents left ventricular remodelling.9-11 The current study not only confirms this, but, as the primary endpoint was also reached in the subset of patients with left ventricular ejection fraction >40% at the 6-month follow-up, it also provides additional evidence for the use of MRA (and RAS inhibitors) in these patients. Once again, these findings reduce the gap of evidence between heart failure with reduced ejection fraction and heart failure with mildly reduced ejection fraction treatment and may contribute to raising the class of recommendation of RAS inhibitors and MRA in future guidelines. Finally, although this study might have been impacted by obstacles along the way, the authors made a great effort to further explore the impact of aldosterone levels on adverse remodelling in ST-elevation myocardial infarction patients. Hence, this study should be a reminiscence of aldosterone's crucial role in myocardial remodelling to all of us. Conflict of interest: none declared.