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The Role of Aldosterone and Aldosterone Blockade in Cardiovascular Disease Gary E Sander, MD, PhD., FACC Professor, Tulane - New Orleans The Contemporary View Myocardial Fibrosis Thrombotic Phenomena Vascular Fibrosis DELETERIOUS EFFECTS OF ALDOSTERONE Catecholamine Potentiation Sodium Retention Ventricular Arrhythmias Potassium and Magnesium Loss Central Pressor Effects Endothelial Dysfunction Cardiac and vascular damage* Hypertension, Heart Failure, Ischemia, Ventricular Dysfunction, Arrhythmia, Edema, Stroke, End-Stage Renal Disease Delyani, Exp Opin Invest Drug 1998. Zannad, Eur Heart J 1995. Brown et al, Hypertension 1998. * In the absence of aldosterone-receptor blockade, aldosterone may cause cardiac and vascular damage. Aldosterone Stimulates Myocardial Fibrosis in Animal Model Plasma Unilateral renal artery stenosis Angiotensin II Aldosterone HB P Yes LVH Fibrosis Yes Yes Fibrosi s Aldosterone infusion in uninephric rat Angiotensin II Aldosterone Yes Yes Yes Fibrosi s Infrarenal aortic banding Angiotensin II Aldosterone Yes Yes No No fibrosis HBP = high blood pressure, LVH = left ventricular hypertrophy Brilla et al, Circ Res 1990. Aldosterone Correlates With Increased LV Mass 45 r=0.559 p<0.001 40 35 30 Aldosterone (ng/dL) 25 20 15 10 5 0 0 50 100 150 Left ventricular mass index (g/m2) Duprez et al, Am J Cardiol 1993. 200 250 Aldosterone Correlates With Decreased Large-Artery Compliance 30 25 20 Plasma aldosterone 15 (ng/dL) 10 r=0.795 p<0.002 5 0 0 0.5 1.0 1.5 2.0 2.5 Proximal arterial compliance (mL/mmHg) Duprez et al, Eur Heart J 1998. Enalapril/Epleronone Combination SBP (mm Hg) DBP (mm Hg) LVM (gm) epleronone -24 -12 -15 enalapril -25 -13 -20 combination -29 -14 -27 The Role of Spironolactone in the Treatment of Patients with Refractory Hypertension Inclusion: • • • • essential HTN ≥ 6 months Clinical and mean ABP > 140/90 on ≥ 2 drugs No prior treatment with spironolactone No renal insufficiency Results • after 1 month of therapy, 23/25 patients had clinical BP < 140/90 • ABPM after 1 month: 152±2/86±2 128±2/76±2 Ouzan et al Am J Hypertens 2002:15:333-9 Aldosterone Synthesis Escape • Aldosterone levels may fall initially in response to ACE inhibition or angiotensin-II receptor blockade, but return to normal or above baseline levels (“escape”) by 12 weeks1 • Multiple homeostatic mechanisms exist to preserve mineralocorticoid activity2,3 • Regulators of aldosterone secretion include potassium, angiotensin II, ACTH, and other minor stimulants3 1Staessen et al, J Endocrinol 1981. Am J Cardiol 1993. 3Zannad, Eur Heart J 1995. 2Weber, Diuretic use, progressive heart failure, and death in patients in the studies of left ventricular dysfunction (SOLVD) Event rate per 100 patient years None PSD only Non-PSD Only Both p Hosp for HF 2.2 (237) 4.6(9) 8.0 (480) 5.0 (47) 0.0008 CV Death 4.7 (517) 7.1 (15) 12.1 (801) 7.9 (78) 0.0001 All-Cause mortality 5.4 (594) 7.6 (16) 13.6 (900) 8.8 (87) <10-5 Hosp for, or death from, HF 3.1 (341) 5.7 (12) 9.7 (640) 6.4 (63) 0.0004 Domanski et al JACC 2003;42:705-8. Estimated Risks, With 95% Confidence Intervals, for Patients Taking Only Non-PSDs and Those Taking PSDs Relative to the Risk of Patients Taking No Diuretics at Baseline None PSD p Value Non-PSD Only p Value Hospitalization for HF 1.00 1.03 (0.75–1.41) 0.86 1.38 (1.11–1.71) 0.003 Death from CV disease 1.00 0.95 (0.75–1.20) 0.67 1.28 (1.09–1.50) 0.002 Death from all causes 1.00 0.93 (0.75–1.16) 0.52 1.28 (1.19–1.49) 0.0008 Hosp or death from HF 1.00 0.99 (0.76–1.30) 0.95 1.31 (1.09–1.57) 0.0004 Domanski et al JACC 2003;42:705-8. Effect of spironolactone on cardiacsympathetic nerve activity and left ventricular remodeling in patients with dilated cardiomyopathy Kasama et al JACC 2003;41:574-81 Correlation between the changes in the 123I-MIBG scintigraphic findings and changes in left ventricular end-diastolic volume (LVEDV) after six months of spironolactone treatment in 15 patients with dilated cardiomyopathy. Delta LVEDV = LVEDV value after six months − pretreatment value of LVEDV; delta TDS = total defect score (TDS) value after six months − pretreatment value of TDS; delta H/M RATIO = H/M ratio after six months − pretreatment value of H/M ratio; delta WR = washout rate (WR) value after six months − pretreatment value of WR. Effect Of Spironolactone On Cardiac Sympathetic Nerve Activity And Left Ventricular Remodeling In Patients With Dilated Cardiomyopathy Kasama et al JACC 2003;41:574-81 CONCLUSIONS Spironolactone improves cardiac sympathetic nerve activity and LV remodeling in patients with DCM Dose-Dependent Effect of Spironolactone in Heart Failure Control Group (n=46) Variable Baseline Follow-Up Spironolactone (n=47) Baseline Follow-Up LVEDV (ml) 257 ± 80 253 ± 89 275 ± 104 251 ± 105 LVESV (ml) 173 ± 71 168 ± 79 188 ± 94 171 ± 97 LVEF (%) 34 ± 7 34 ± 9 33 ± 7 36 ± 9 P < 0.05 for all Cicoira et al JACC 2002;40:304-10. Dose-Dependent Effect of Spironolactone in Heart Failure Cicoira et al JACC 2002;40:304-10. Immediate Administration of Mineralocorticoid Receptor Antagonist Spironolactone Prevents Post-Infarct Left Ventricular Remodeling Associated With Suppression of a Marker of Myocardial Collagen Synthesis in Patients With First Anterior Acute Myocardial Infarction Hayashi et al. Circulation 2003;107:2559-2565 • To evaluate the effect of mineralocorticoid receptor antagonist (MRA) spironolactone on post-infarct LV remodeling, 134 patients with first anterior acute myocardial infarction were randomly divided into the MRA (n=65) or non-MRA (n=69) groups after revascularization. • All patients were administered angiotensin-converting enzyme (ACE) inhibitor and study drug just after revascularization. • Left ventriculography with contrast medium was performed at the acute stage and after 1 month to evaluate LV remodeling. • ALD was measured at aortic root and coronary sinus. There was no difference in the baseline characteristics including infarct size and LV performance between the two groups. Top, Changes in the LVEF, LVEDVI, LVESVI in the two randomized treatment groups from baseline to 1 month later. Bottom, Absolute change (value at 1 month-baseline) in LVEF, LVEDVI, and LVESVI. P<0.05; P<0.01; P<0.0001: difference between baseline and 1-month values (within each group). Beneficial Neurohormonal Profile Of Spironolactone In Severe Congestive Heart Failure: Results From The RALES Neurohumoral Substudy Rousseau et al JACC 2002;40:1596-1601 CONCLUSIONS • Andosterone antagonism appears to reduce inflammation and to preserve endothelial functional and tissue structural integrity in a number of pathophysiological states • Caution is required in the patient with diabetes, particularly in the presence of reduced renal function/Type IV RTA • Avoid combinations with potassium, other Ksparing diruetics, and NSAIDS