Effects Of Spironolactone In Larger Dosage On The Autonomic Nervous System And Ventricular Remodeling In Severe Congestive Heart Failure Patients

Objective: Aldosterone has an important role in thepathophysiology of heart failure. Aldosterone promotes theretention of sodium, the loss of potassium, myocardial fibrosis,ventricular remodeling, baroreceptor dysfunction andsympathetic activation. Despite of the outstanding success ofangiotensin-converting enzyme(ACE) inhibitors in thetreatment of congestive heart failure(CHF), the mortality ofCHF patients remains high. It was partly due to the"aldosterone escape phenomenon". Aldosterone-receptorblocker can inhibit the roles of aldosterone. In the RandomizedAldosterone Evaluation Study (RALES), spironolactone(26mg/d) was shown to reduce the mortality and improvecardiac function of CHF patients who had already receivedroutine therapy including ACEI, diuretics, digoxin andβ-blocker. We had tried to use larger dosage ofspironolactone(≥60mg/d) to treat severe CHF patients andreceived good curative effect. This study wants to observe thechanges of heart rate variability(HRV), ventricular remodelingand biochemical parameters after intervention with smaller andlarger dosage of spironolactone, and explores the effects oflarger dosage of spironolactone on autonomic nervous system,ventricular remodeling and the safety of spironolactone.Methods: Sixty-seven patients with CHF(39 men and 28women, age from 44 to 75, mean age 61.9±8.8 years) wererecruited, including ischemic heart disease, idiopathic dilatedcardiomyopathy and hypertensive heart disease. All patientshad NewYork Heart Association(NYHA) Ⅲ～Ⅳclass, LeftVentricular Ejection Fraction(LVEF) ≤35% and LeftVentricular End-Diastolic Diameter(LVEDD) >55mm. Thefollowing patients were excluded: acute coronary syndrome;severe malignant arrhythmia; primary operable valvular heartdisease; congenital heart disease; predominant cardiac rhythmwas non-sinus, second-degree or third-degree atrioventricularblock, bundle branch block or WPW syndrom; severe liver orrenal dysfunction; serum potassium >5.0mmol/L; diabetesmellitus;hyperthy roidism; cancer or any life-threateningdisease. All patients received routine therapy, includinghydrochlorothiazide or furosemide, ACEI or angiotensin Ⅱrecepter blocker (ARB) and/or β-blocker, digoxin for at lasttwo weeks after stable. Spironolactone was not permittedbefore the study. The patients were randomly assigned tosmaller dosage spironolactone group (≤40mg/d) and largerdosage spironolactone group ( ≥60mg/d). Furosemide orpotassium supplements were recommended according to thelevel of serum potassium and water retention, all cardioactivedrugs were unchanged during the study. No patients withdrawnfrom the study unless they had severe adverse events. Thedosage of spironolactone was reduced or diuretics wereadjusted if serum potassium more than 5.0 mmol/L. Patientswere excluded from the study if serum potassium more than5.5 mmol/L or creatine more than 4 mg/dL. HRV and cardiacfunction parameters were measured before and 3 months afterintervention. Electrolytes were measured every week, liver andrenal function were measured the first week and 1, 2, 3 monthsafter intervention, respectively.Time domain analysis was performed using twenty-fourhour continuous ECG recordings. The main time domainanalysis parameters included (1)standard deviation of all RRintervals (SDNN) (2)standard deviation of 5-min mean RRintervals (SDNN) (3)the root mean square of differences ofsuccessive RR intervals (rMSSD).Frequency domain analysis was performed using ECGlab2.0. The main parameters included low-frequency(LF),high-frequency(HF) and LF/HF.The cardiac function parameters were measured bySONOLINE type ultrasonic diagnostic apparatus (SeimensCompany, Germany) using a 2.5MHZ frequency linear arreytransducer, including Left Ventricular End-Systolic Diameter(LVESD), Left Ventricular End-Diastolic Diameter (LVEDD),Left Ventricular Ejection Fraction (LVEF), Left VentricularPosterior Wall Thickness (LVPWT) and IntraventricularSeptation Thickness (IVST). Body surface area (BSA) wascalculated according to their height and weight, and LeftVentricular Mass Index (LVMI) was calculated according toDevereux Formula, at the same time, to caculate LeftVentricular End-Systolic Volume Index (LVESVI) and LeftVentricular End-Diastolic Volume Index (LVEDVI).All the data was analyzed using SPSS11.0 softwarepackage. Measurement data which was normal distribution andhomoscedasticity was denoted by mean±standard deviationand student t test was used to analyze the comparison betweentwo groups and paired t test was used to analyze thecomparison within the group. Chi-square test was used toanalyze categorical data. A P value<0.05 was regarded assignificant.Results:1 The average dosage of spironolactone was 88.2±14.3mg/d in larger dosage group and 25.8±4.2mg/d insmaller dosage group respectively, and similar to the dosageused in RALES, so it can be used as a standard contrast in thelatter.2 There was one patient died of sudden death in larger dosagegroup, one patient withdrawn from study for deterioration ofCHF in smaller dosage group. No lethiferous high serumpotassium occurred in both groups.3 There were no significant differences in baseline databetween two groups including age, sex, NYHA class, HRV,LVEF, LVMI, LVEDVI, LVESVI, serum potassium,magnesium and creatine (Table1).4 After 3 months of therapy, the time domain analysisparameters: SDNN, SDANN, rMSSD and frequency domainanalysis parameter HF were significantly improved comparedwith baseline in both groups (P<0.05), but it was moresignificant in the larger dosage group (P<0.05) (Table2), andthe effects on the HRV indices were greatest from 6:00 to10:00 Am (Fig1,2). There were no significant differences in LFbetween and within both groups.5 After 3 months of therapy, LVEF, LVMI, LVEDVI andLVESVI were all improved compared with baseline in bothgroups (P<0.01), however, did more in the larger dosage groupthan in the smaller group (P<0.05) (Table3).6 After 3 months of therapy, serum potassium, magnesiumand creatine were all increased compared with baseline in bothgroups (P<0.05). There were no significant differences inserum potassium and magnesium between two groups. Thoughserum creatine increased more in larger dosage group than insmaller dosage group, there was no renal dysfunction. Fourpatients developed gynecomastia in larger dosage group whilenone in smaller dosage group (P=0.041).Conclusions:Autonomic nervous system function andventricular remodeling were improved more obviously in largerdosage group than in the smaller group. Although largerdosage spironolactone can increase serum potassium,magnesium and creatine, renal dysfunction and severe high...