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Translational research goes both ways: lessons from clinical studies
1Prince Henry's Institute of Medical Research, Clayton, Victoria, Australia. john.funder@princehenrys.org
Clinical and Experimental Pharmacology & Physiology
|March 1, 2008
Summary
This study challenges the traditional view of aldosterone's role in hypertension and heart failure, suggesting cortisol may activate mineralocorticoid receptors (MR) in certain conditions. Translational research in cardiovascular disease requires a bidirectional approach.
Area of Science:
- Endocrinology
- Cardiovascular Research
- Genetics
Background:
- Current understanding posits aldosterone drives hypertension via salt/water balance and deleterious effects in essential hypertension and heart failure.
- Mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) are thought to share a common ancestor.
- Translational research is traditionally viewed as a benchtop-to-bedside progression.
Purpose of the Study:
- To re-evaluate the established roles of aldosterone and mineralocorticoid receptors (MR) in cardiovascular conditions.
- To explore the evolutionary origins of MR and its relationship with other steroid hormone receptors.
- To investigate the primary drivers of MR activation in patients with essential hypertension and heart failure.
Main Methods:
- Meta-analysis of clinical trials involving MR blockade (eplerenone) in essential hypertension.
- Re-examination of sequence data for MR and related steroid hormone receptors.
- Analysis of clinical trial data from heart failure and essential hypertension studies, focusing on baseline aldosterone and sodium levels.
Main Results:
- Meta-analysis of eplerenone trials showed no correlation between blood pressure response and electrolyte changes (plasma K).
- Sequence data and analysis of an MR mutant gene suggest MR diverged earlier from a common ancestor than previously thought.
- In clinical trials for heart failure and essential hypertension, low baseline aldosterone and normal sodium status indicate cortisol, not aldosterone, is likely responsible for MR activation.
Conclusions:
- Aldosterone may not be the primary driver of MR activation in all cases of essential hypertension and heart failure.
- The evolutionary history of MR suggests a distinct lineage.
- Translational research in cardiovascular and endocrine fields must adopt a bidirectional perspective, moving from bedside to benchtop as well as benchtop to bedside.
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