Effect of spironolactone on the progression of coronary calcification in peritoneal dialysis patients: a pilot study / Efeito da espironolactona na progressão da calcificação coronariana em pacientes em diálise peritoneal: um estudo piloto

ABSTRACT Introduction: There is evidence that aldosterone plays a role in the pathogenesis of vascular calcification. The aim of this study was to evaluate the effect of spironolactone, a mineralocorticoid receptor antagonist, on the progression of coronary calcification (CC) in peritoneal dialysis patients and to identify the factors involved in this progression. Methods: Thirty-three patients with a coronary calcium score (CCS) ≥ 30, detected through multi-detector computed tomography (MDCT) and expressed in Agatston units, were randomly assigned to a group receiving 25mg spironolactone per day for 12 months (spironolactone group) and a control group not receiving this drug. The primary outcome was a percentage change in CCS from baseline to end of the study (relative progression), when a further MDCT was conducted. Patients who had progression of CC were compared with those who did not progress. Results: Sixteen patients, seven in the spironolactone group and nine in the control group, concluded the study. The relative progression of the CCS was similar in both groups, 17.2% and 27.5% in the spironolactone and control groups respectively. Fifty-seven percent of the treated patients and 67% of those in the control group presented progression in the CC scores (p = 0.697). Progressor patients differed from non-progressors because they presented higher levels of calcium and low-density lipoprotein cholesterol and lower levels of albumin. Conclusion: In peritoneal dialysis patients, spironolactone did not attenuate the progression of CC. However, large-scale studies are needed to confirm this observation. Disorders of mineral metabolism and dyslipidemia are involved in the progression of CC.

RESUMO Introdução: Existem evidências de que a aldosterona exerça um papel na patogênese da calcificação vascular. O objetivo deste estudo foi avaliar o efeito da espironolactona, um antagonista do receptor mineralocorticoide, na progressão da calcificação coronariana (CC) de pacientes em diálise peritoneal, e identificar os fatores envolvidos nessa progressão. Métodos: Trinta e três pacientes com escore de cálcio coronariano (ECC) ≥ 30, detectado por tomografia computadorizada com múltiplos detectores (TCMD) e expresso em unidades de Agatston, foram randomizados para um grupo que recebeu 25 mg de espironolactona por dia durante 12 meses (grupo espironolactona) e um grupo controle que não recebeu este medicamento. O desfecho primário foi a mudança percentual do ECC do início para o final do estudo (progressão relativa), quando uma nova TCMD foi realizada. Os pacientes que tiveram progressão de CC foram comparados com aqueles que não progrediram. Resultados: Dezesseis pacientes, sete no grupo espironolactona e nove no grupo controle, concluíram o estudo. A progressão relativa do ECC foi semelhante nos dois grupos, 17,2% e 27,5% nos grupos espironolactona e controle, respectivamente. Cinquenta e sete por cento dos pacientes tratados e 67% daqueles no grupo controle apresentaram progressão nos escores de CC (p = 0,697). Os pacientes progressores diferiram dos não progressores porque apresentaram níveis séricos mais elevados de cálcio e LDL-colesterol e menores níveis de albumina. Conclusão: Em pacientes em diálise peritoneal, a espironolactona não atenuou a progressão da CC. No entanto, estudos em grande escala são necessários para confirmar essa observação. Distúrbios do metabolismo mineral e dislipidemia estão envolvidos na progressão da CC.

Hormonal therapy with estradiol and drospirenone improves endothelium-dependent vasodilation in the coronary bed of ovariectomized spontaneously hypertensive rats

Drospirenone (DRSP) is a progestin with anti-aldosterone properties and it reduces blood pressure in hypertensive women. However, the effects of DRSP on endothelium-dependent coronary vasodilation have not been evaluated. This study investigated the effects of combined therapy with estrogen (E2) and DRSP on endothelium-dependent vasodilation of the coronary bed of ovariectomized (OVX) spontaneously hypertensive rats. Female spontaneously hypertensive rats (n=87) at 12 weeks of age were randomly divided into sham operated (Sham), OVX, OVX treated with E2 (E2), and OVX treated with E2 and DRSP (E2+DRSP) groups. Hemodynamic parameters were directly evaluated by catheter insertion into the femoral artery. Endothelium-dependent vasodilation in response to bradykinin in the coronary arterial bed was assessed using isolated hearts according to a modified Langendorff method. Coronary protein expression of endothelial nitric oxide synthase and estrogen receptor alpha (ER-α) was assessed by Western blotting. Histological slices of coronary arteries were stained with hematoxylin and eosin, and morphometric parameters were analyzed. Oxidative stress was assessed in situ by dihydroethidium fluorescence. Ovariectomy increased systolic blood pressure, which was only prevented by E2+DRSP treatment. Estrogen deficiency caused endothelial dysfunction, which was prevented by both treatments. However, the vasodilator response in the E2+DRSP group was significantly higher at the three highest concentrations compared with the OVX group. Reduced ER-α expression in OVX rats was restored by both treatments. Morphometric parameters and oxidative stress were augmented by OVX and reduced by E2 and E2+DRSP treatments. Hormonal therapy with E2 and DRSP may be an important therapeutic option in the prevention of coronary heart disease in hypertensive post-menopausal women.

Expression of NAD(P)H Oxidase Subunits and Their Contribution to Cardiovascular Damage in Aldosterone/Salt-Induced Hypertensive Rat

NAD(P)H oxidase plays an important role in hypertension and its complication in aldosterone-salt rat. We questioned whether NAD(P)H oxidase subunit expression and activity are modulated by aldosterone and whether this is associated with target- organ damage. Rats were infused with aldosterone (0.75 microgram/hr/day) for 6 weeks and were given 0.9% NaCl+/-losartan (30 mg/kg/day), spironolactone (200 mg/kg/ day), and apocynin (1.5 mM/L). Aldosterone-salt hypertension was prevented completely by spironolactone and modestly by losartan and apocynin. Aldosterone increased aortic NAD(P)H oxidase activity by 34% and spironolactone and losartan inhibited the activity. Aortic expression of the subunits p47(phox), gp91(phox), and p22(phox) increased in aldosterone-infused rats by 5.5, 4.7, and 3.2-fold, respectively, which was decreased completely by spironolactone and partially by losartan and apocynin. Therefore, the increased expression of NAD(P)H oxidase may contribute to cardiovascular damage in aldosterone-salt hypertension through the increased expression of each subunit.

Aldosterone receptor antagonists induce favorable cardiac remodeling in diastolic heart failure patients / Antagonistas de receptores de aldosterona inducen remodelación cardiaca favorable en pacientes con insuficiencia cardiaca diastólica

Background. Serum levels of aldosterone in heart failure are increased up to 20 times compared to normal subjects. After an acute myocardial infarction, aldosterone increases progressively as well as interstitial fibrosis and collagen synthesis from cardiac fibroblasts, forming a patchy heterogeneous interstitial collagen matrix that affects ventricular function. Even if angiotensine converting enzyme inhibitors (ACEI) or angiotensin II receptor antagonists (ARA) can reduce aldosterone levels early during treatment, they increase again after a 12 week treatment. The aim of this study was to evaluate the changes in structure and function of the left ventricle in symptomatic (NYHA I-III) diastolic heart failure patients receiving an aldosterone receptor antagonist. Methods. Twenty-eight subjects with diastolic heart failure, on BB, ACEI and/or ARA were randomized to receive spironolactone (group A) on a mean dose of 37.5 mg once a day (n =14, age 63.7 ± 21.6 years and body mass index, BMI 27.5 ± 9.4), or not (group B, n = 14, Age 64.8 ± 11.9, BMI 26.9 ± 4.7). All patients were followed-up for a mean of 13.79 ± 0.99 months. Results. Group A showed a 42.8% ischemic origin of heart failure, while in group B was 55% (p = 0.2). No other co-morbidities were significativelly different among both groups. Mean percentage of changes by echocardiogram was as follows: Interventricular septum (IVS) -12.2 ± 11% vs. 1.3 ± 15.2 (p = 0.03), pulmonary systolic artery pressure (PSAP was 0.99 ± 3.8% vs. 10.5 ± 9.1, p = 0.05). Other parameters did not show statistically significant differences. Conclusion. Aldosterone receptor antagonists reduce or avoid increasing of PSAP and inducing a favorable remodeling of the left ventricle, especially in the IVS in diastolic heart failure patients.

Antecedentes. En pacientes con insuficiencia cardiaca existen aumentos de aldosterona hasta 20 veces mayores que en sujetos control. Después de un infarto miocárdico la aldosterona aumenta progresivamente, así como la fibrosis intersticial y la síntesis de colágena por fibroblastos cardiacos, provocando parches intersticiales heterogéneos en la matriz de colágena que afecta la función ventricular. El tratamiento inicial con inhibidores de enzima convertidora de angiotensina (IECA) y/o antagonistas de receptores de angiotensina II (ARA) puede reducir estos niveles; sin embargo, aumentan nuevamente después de 12 semanas de tratamiento. El propósito de este estudio fue evaluar los cambios estructurales y funcionales en el ventrículo izquierdo en pacientes con insuficiencia diastólica tratados con ARA angiotensina (NYHAI-III). Métodos. Veintiocho pacientes con insuficiencia cardiaca diastólica en tratamiento con BB, IECA y/o ARA se aleatorizaron a recibir una dosis media de 37.5 mg una vez al día de espironolactona (grupo A) (n - 14, edad 63.7 ± 0 21.6 años e índice masa corporal IMC 27.5 ± 9.4), o no (grupo B, n =14, edad 64.8 ± 11.9, IMC 26.9 ± 4.7). Todos los pacientes fueron seguidos por 13.79 ± 0.99 meses. Resultados. De los pacientes del grupo A, 42.8% y el 55 del grupo B (p = 0.2), tenían cardiopatía isquémica. No se encontraron diferencias significativas en otras comorbilidades. El porcentaje promedio de cambios en el ecocardiograma se observó en septum interventricular (SIV) -12.2 ± 11% vs. 1.3 ± 15.3% (p = 0.02), y la presión sistólica de la arteria pulmonar (PSAP, 0.99 ± 3.8% vs. 10.5 ± 9.1, p = 0.05, para los grupos A y B, respectivamente). Los otros parámetros no mostraron diferencias estadísticamente significativas. Conclusión. El tratamiento con antagonistas de receptores de aldosterona disminuye o limita aumentos de PSAP e inducen una remodelación favorable del ventrículo izquierdo, especialmente del SIV en pacientes con insuficiencia cardiaca diastólica.