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enalapril in patients with essential hypertension and left ventricular hypertrophy. the 4e-left ventricular hypertrophy study
Effects of Eplerenone, Enalapril, and Eplerenone/ Enalapril in Patients With Essential Hypertension and Left Ventricular Hypertrophy. The 4E-Left Ventricular Hypertrophy Study
Study Question: Are elevations of matrix metalloproteinase (MMP)-2 and MMP-9 in heart donors with intracerebral hemorrhage (ICH) associated with subsequent development of cardiac allograft vasculopathy (CAV)? Methods: The authors evaluated mRNA expressions of MMP-2 and MMP-9 in donor spleen lymphocytes (before transplantation) and in heart biopsies at 1 week after transplantation in 20 recipients from ICH donors and 20 recipients from trauma donors. Patients underwent serial coronary intravascular ultrasound, and interstitial myocardial fibrosis was quantified at 1 year. Results: Heart biopsies from the ICH group showed significant increased expression of MMP-2 (17-fold, p⬍0.0001) and MMP-9 (20-fold, p⬍0.0001) compared with the trauma group. The ICH group showed 1.8-fold (p⬍0.016) increased mRNA expression of MMP-2 and 1.7-fold (p⬍0.015) increased mRNA expression of MMP-9 in the donor spleen lymphocytes, suggesting the presence of systemic activation of MMPs before transplantation. At 1 year, the ICH group showed increased myocardial fibrosis and accelerated CAV. Using multivariable regression analysis, MMP-9 was found to be associated with increased risk for vasculopathy independent of donor age (OR, 2.41; p⬍0.01; 95% CI, 1.24 – 4.69). Conclusions: This is the first report to describe systemic activation of MMP-2 and MMP-9 in donors with intracerebral hemorrhage and subsequent development of CAV. Perspective: Cardiac allograft vasculopathy is a leading cause of death in patients who survive the first posttransplant year. Despite its delayed clinical manifestation and its apparent, albeit poorly understood, immunologic basis (the process only occurs in the transplanted organ’s arterial system), it’s long been known that nonimmunologic events at the time of transplant (donor intracerebral hemorrhage, ischemic time) play an important role in its pathophysiology. This important study will stimulate further investigation into the role of MMPs in CAV and analogous forms of chronic rejection in other solid organ transplants, and may provide future opportunities for therapeutic intervention. KA
Pitt B, Reichek N, Willenbrock R, et al. Circulation 2003;108: 1831– 8. Study Question: Which strategy can best achieve regression of left ventricular hypertrophy (LVH) in hypertension: treatment with eplerenone (a selective aldosterone blocker), enalapril or their combination? Methods: In a 9-month, double-blind, randomized trial, 202 patients with LVH and hypertension received either eplerenone 200 mg daily, enalapril 40 mg daily or eplerenone 200 mg and enalapril 10 mg daily. At week 8, hydrochlorothiazide 12.5–25 mg and/or amlodipine 10 mg was added if diastolic blood pressure was ⬎90 mm Hg. Change in left ventricular (LV) mass as assessed by MRI was the primary end point. Change in blood pressure, reninangiotensin-aldosterone system hormones, albuminuria and safety were also assessed. Results: Eplerenone significantly reduced LV mass from baseline (⫺14.5⫾3.36 g; n⫽50) similarly to enalapril (⫺19.7⫾3.20 g; n⫽54; p⫽0.258), but eplerenone/enalapril (⫺27.2⫾3.39 g; n⫽49) was more effective than eplerenone alone (p⫽0.007). All treatments reduced systolic blood pressure and diastolic blood pressure from baseline (eplerenone, ⫺23.8 and ⫺11.9 mm Hg; enalapril, ⫺24.7 and ⫺3.4 mm Hg; and eplerenone/enalapril, ⫺28.7 and ⫺14.4 mm Hg, p⫽0.048, in systolic blood pressure compared with eplerenone alone). Cough was more common with enalapril than with eplerenone (p⫽0.033), and elevated potassium was more common with eplerenone. Conclusions: Eplerenone was as effective as enalapril in LVH regression and blood pressure control. The combination of eplerenone and enalapril was more effective in reducing LV mass and systolic blood pressure than eplerenone alone. Perspective: The results of this study are consistent with independent effects of angiotensin II and aldosterone on stimulating myocardial hypertrophy in hypertension. As LVH is a potent predictor of cardiovascular outcomes in hypertensives, one would anticipate favorable effects for an aldosterone receptor antagonist, alone and especially in combination with an ACE inhibitor or ARB, on cardiovascular outcomes in hypertension, but this remains to be demonstrated. KA
Adverse Prognosis of Patients With Hypertrophic Cardiomyopathy Who Have Epicardial Coronary Artery Disease Sorajja P, Ommen SR, Nishimura RA, Gersh BJ, Berger PB, Tajik AJ. Circulation 2003;108:2342– 8.
Donor Spontaneous Intracerebral Hemorrhage Is Associated With Systemic Activation of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 and Subsequent Development of Coronary Vasculopathy in the Heart Transplant Recipient
Study Question: Does the presence of epicardial coronary artery disease (CAD) affect long-term prognosis among patients with hypertrophic cardiomyopathy? Methods: The study population comprised 433 patients with a diagnosis of hypertrophic cardiomyopathy referred to the Mayo Clinic between 1972 and 2000 who underwent coronary angiography, were ⱖ21 years, had normal left ventricular ejection fraction and no history of prior surgical
Yamani MH, Starling RC, Cook DJ, et al. Circulation 2003;108: 1724 – 8.
ACC CURRENT JOURNAL REVIEW Feb 2004
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Study Question: Are elevations of matrix metalloproteinase (MMP)-2 and MMP-9 in heart donors with intracerebral hemorrhage (ICH) associated with subsequent development of cardiac allograft vasculopathy (CAV)? Methods: The authors evaluated mRNA expressions of MMP-2 and MMP-9 in donor spleen lymphocytes (before transplantation) and in heart biopsies at 1 week after transplantation in 20 recipients from ICH donors and 20 recipients from trauma donors. Patients underwent serial coronary intravascular ultrasound, and interstitial myocardial fibrosis was quantified at 1 year. Results: Heart biopsies from the ICH group showed significant increased expression of MMP-2 (17-fold, p⬍0.0001) and MMP-9 (20-fold, p⬍0.0001) compared with the trauma group. The ICH group showed 1.8-fold (p⬍0.016) increased mRNA expression of MMP-2 and 1.7-fold (p⬍0.015) increased mRNA expression of MMP-9 in the donor spleen lymphocytes, suggesting the presence of systemic activation of MMPs before transplantation. At 1 year, the ICH group showed increased myocardial fibrosis and accelerated CAV. Using multivariable regression analysis, MMP-9 was found to be associated with increased risk for vasculopathy independent of donor age (OR, 2.41; p⬍0.01; 95% CI, 1.24 – 4.69). Conclusions: This is the first report to describe systemic activation of MMP-2 and MMP-9 in donors with intracerebral hemorrhage and subsequent development of CAV. Perspective: Cardiac allograft vasculopathy is a leading cause of death in patients who survive the first posttransplant year. Despite its delayed clinical manifestation and its apparent, albeit poorly understood, immunologic basis (the process only occurs in the transplanted organ’s arterial system), it’s long been known that nonimmunologic events at the time of transplant (donor intracerebral hemorrhage, ischemic time) play an important role in its pathophysiology. This important study will stimulate further investigation into the role of MMPs in CAV and analogous forms of chronic rejection in other solid organ transplants, and may provide future opportunities for therapeutic intervention. KA
Pitt B, Reichek N, Willenbrock R, et al. Circulation 2003;108: 1831– 8. Study Question: Which strategy can best achieve regression of left ventricular hypertrophy (LVH) in hypertension: treatment with eplerenone (a selective aldosterone blocker), enalapril or their combination? Methods: In a 9-month, double-blind, randomized trial, 202 patients with LVH and hypertension received either eplerenone 200 mg daily, enalapril 40 mg daily or eplerenone 200 mg and enalapril 10 mg daily. At week 8, hydrochlorothiazide 12.5–25 mg and/or amlodipine 10 mg was added if diastolic blood pressure was ⬎90 mm Hg. Change in left ventricular (LV) mass as assessed by MRI was the primary end point. Change in blood pressure, reninangiotensin-aldosterone system hormones, albuminuria and safety were also assessed. Results: Eplerenone significantly reduced LV mass from baseline (⫺14.5⫾3.36 g; n⫽50) similarly to enalapril (⫺19.7⫾3.20 g; n⫽54; p⫽0.258), but eplerenone/enalapril (⫺27.2⫾3.39 g; n⫽49) was more effective than eplerenone alone (p⫽0.007). All treatments reduced systolic blood pressure and diastolic blood pressure from baseline (eplerenone, ⫺23.8 and ⫺11.9 mm Hg; enalapril, ⫺24.7 and ⫺3.4 mm Hg; and eplerenone/enalapril, ⫺28.7 and ⫺14.4 mm Hg, p⫽0.048, in systolic blood pressure compared with eplerenone alone). Cough was more common with enalapril than with eplerenone (p⫽0.033), and elevated potassium was more common with eplerenone. Conclusions: Eplerenone was as effective as enalapril in LVH regression and blood pressure control. The combination of eplerenone and enalapril was more effective in reducing LV mass and systolic blood pressure than eplerenone alone. Perspective: The results of this study are consistent with independent effects of angiotensin II and aldosterone on stimulating myocardial hypertrophy in hypertension. As LVH is a potent predictor of cardiovascular outcomes in hypertensives, one would anticipate favorable effects for an aldosterone receptor antagonist, alone and especially in combination with an ACE inhibitor or ARB, on cardiovascular outcomes in hypertension, but this remains to be demonstrated. KA
Adverse Prognosis of Patients With Hypertrophic Cardiomyopathy Who Have Epicardial Coronary Artery Disease Sorajja P, Ommen SR, Nishimura RA, Gersh BJ, Berger PB, Tajik AJ. Circulation 2003;108:2342– 8.
Donor Spontaneous Intracerebral Hemorrhage Is Associated With Systemic Activation of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9 and Subsequent Development of Coronary Vasculopathy in the Heart Transplant Recipient
Study Question: Does the presence of epicardial coronary artery disease (CAD) affect long-term prognosis among patients with hypertrophic cardiomyopathy? Methods: The study population comprised 433 patients with a diagnosis of hypertrophic cardiomyopathy referred to the Mayo Clinic between 1972 and 2000 who underwent coronary angiography, were ⱖ21 years, had normal left ventricular ejection fraction and no history of prior surgical
Yamani MH, Starling RC, Cook DJ, et al. Circulation 2003;108: 1724 – 8.
ACC CURRENT JOURNAL REVIEW Feb 2004
33