Elevated cardiac tissue level of aldosterone and mineralocorticoid receptor in diastolic heart failure: beneficial effects of mineralocorticoid receptor blocker

Abstract

Cardiac aldosterone levels have not been evaluated in diastolic heart failure (DHF), and its roles in this type of heart failure remain unclear. This study aimed to detect cardiac aldosterone by use of a liquid chromatographic-mass spectrometric method and to assess the effects of mineralocorticoid receptor blockade on hypertensive DHF. Dahl salt-sensitive rats fed 8% NaCl diet from 7 wk (hypertensive DHF model) were divided at 13 wk into three groups: those treated with subdepressor doses of eplerenone (12.5 or 40 mg x kg(-1) x day(-1)) and an untreated group. Dahl salt-sensitive rats fed 0.3% NaCl diet served as controls. Cardiac aldosterone was detected in the DHF rats but not in the control rats, with increased ventricular levels of mineralocorticoid receptor. Cardiac levels of 11-deoxycorticosterone, corticosterone, and 11-dehydrocorticosterone were not different between the control and DHF rats, but the tissue level of corticosterone that has an affinity to mineralocorticoid receptor was 1,000 times as high as that of aldosterone. Aldosterone synthase activity and CYP11B2 mRNA were undetectable in the ventricular tissue of the DHF rats. Administration of eplerenone attenuated ventricular hypertrophy, ventricular fibrosis, myocardial stiffening, and relaxation abnormality, leading to the prevention of overt DHF. In summary, the myocardial aldosterone level increased in the DHF rats. However, its value was extremely low compared with corticosterone, and no evidence for enhancement of intrinsic myocardial aldosterone production was found. The upregulation of mineralocorticoid receptor may play a central role in the pathogenesis of DHF, and blockade of mineralocorticoid receptor is likely an effective therapeutic regimen of DHF.

The Metabolic Effects of Mineralocorticoid Receptor Antagonists in Heart Failure Patients

“…It is well known that HF development associates with increased expression of central and peripheral mineralocorticoid receptors. Moreover, cardiac and vascular imbalance between natriuretic peptides and aldosterone, toward increased MR signalling, contributes to adverse cardiovascular remodeling in response to pressure overload, ischemia / reperfusion, inflammation [19]. All these findings explain the innate pathophysiological mechanisms of extracellular matrix remodelling, inducing of oxidative stress, as well as development of endothelial dysfunction via aldosterone-induced pathway [19,20].…”

“…Moreover, cardiac and vascular imbalance between natriuretic peptides and aldosterone, toward increased MR signalling, contributes to adverse cardiovascular remodeling in response to pressure overload, ischemia / reperfusion, inflammation [19]. All these findings explain the innate pathophysiological mechanisms of extracellular matrix remodelling, inducing of oxidative stress, as well as development of endothelial dysfunction via aldosterone-induced pathway [19,20]. In fact, vascular inflammation resulted in aldosterone over production and attenuated by different originated chemo attractants, apoptotic fragments and oxidative stress components plays a pivotal role in tissue injury in CV diseases [21,22].…”

Aplicaciones y proyecciones de los antagonistas del receptor de mineralocorticoides en el tratamiento de patologías cardiovasculares

“…Ensayos clínicos en pacientes con IC y disfunción sistólica muestran mejoras de la función diastólica dentro de sus hallazgos ecocardiográficos 23 . Estudios experimentales en ratas hipertensas que desarrollan ICD han demostrado un aumento de la expresión del RM miocárdica 24 . En el mismo modelo, se señaló que los ARM son capaces de inhibir el remodelamiento miocárdico y prevenir el desarrollo de ICD 24 .…”

“…Estudios experimentales en ratas hipertensas que desarrollan ICD han demostrado un aumento de la expresión del RM miocárdica 24 . En el mismo modelo, se señaló que los ARM son capaces de inhibir el remodelamiento miocárdico y prevenir el desarrollo de ICD 24 . Ensayos clínicos, de pequeño tamaño muestral, en pacientes con ICD que recibieron junto al tratamiento convencional canrenona, espironolactona o eplerenona demostraron una mejora de los parámetros ecocardiográficos de disfunción diastólica, con mejoras en la sintomatología y la calidad de vida, y sin modificar significativamente los valores de masa ventricular, presión arterial o capacidad aeróbica respecto a grupos control [25][26][27][28][29] .…”

History of Hypertension and Eplerenone in Patients With Acute Myocardial Infarction Complicated by Heart Failure

“…21,22 HF is associated with an upregulation of mineralocorticoid receptors and aldosterone with an increase in myocardial calcium channel expression. [23][24][25][26] Recently, AMI has been shown to cause electric remodeling before mechanical remodeling and LV hypertrophy. 27 The increase in intracellular calcium associated with electric remodeling has been suggested to increase the risk of ventricular arrhythmias and SCD.…”