Response to the letter to the Editor

Response to the letter to the Editor We would like to thank Dr Jolobe for his valuable comments regarding the treatment of diastolic heart failure. Neurohormonal activation plays an important role in the development of diastolic dysfunction. Activation of the renin-angiotensin-aldosterone system (RAAS), particularly direct cardiac effects of angiotensin II and aldosterone, contributes to the pathogenesis and progression of diastolic dysfunction. Hence, there is a strong rationale for the use of agents that antagonize the RAAS, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists in these patients.1 The RAAS has varied roles in the regulation of cardiac function including early receptormediated effects, such as second-messenger generation, and delayed responses, such as protein synthesis and cell growth.2 Angiotensin II and aldosterone appear to have synergistic effects on adverse left ventricular remodeling; hence, both are treatment targets in patients with heart failure. Angiotensin II is an important stimulus for the adrenal glands to release the mineralocorticoid aldosterone. Aldosterone reduces renal excretion of water and sodium, thereby elevating blood pressure. Aldosterone may play a direct role in the myocardium via mineralocorticoid receptors, which modulate the extracellular matrix and promote collagen deposition.3 Aldosterone receptor blockade with spironolactone has been reported to inhibit collagen synthesis and thereby reduce cardiac fibrosis.4 Aldosterone antagonism also improves endothelial function, promotes sodium excretion, and lowers systemic vascular resistance.5 We look forward to the results in several years from the National Institutes of Health TOPCAT trial, which is a multicenter, international, randomized, double-blind, placebocontrolled trial of the aldosterone antagonist, spirono-

lactone, in 4500 adults with heart failure and left ventricular ejection fraction of z45% who were recruited internationally from N250 clinical centers.6,7 We are unaware of any large trial testing torsemide and its possible antialdosterone properties as a specific therapy in diastolic heart failure. Am Heart J 2007;154:e7. 0002-8703/$ - see front matter doi:10.1016/j.ahj.2007.04.018

Kavitha M. Chinnaiyan,, MD Daniel Alexander,, MD Michael Maddens,, MD Peter A. McCullough,, MD, MPH Cardiology, William Beaumont Hospital Royal Oak, MI, USA E-mail: [email protected]

References 1. Chinnaiyan KM, Alexander D, McCullough PA. Role of angiotensin II in the evolution of diastolic heart failure. J Clin Hyper 2005;7:740 - 7. 2. Baker KM, Booz GW, Dostal DE. Cardiac actions of angiotensin II: role of an intracardiac renin-angiotensin system. Annu Rev Physiol 1992;54:227 - 41. 3. Zannad F, Dousset B, Alla F. Treatment of congestive heart failure: interfering the aldosterone–cardiac extracellular matrix relationship. Hypertension 2001;38:1227 - 32. 4. Brilla CG, Masubara L, Weber K. Antifibrotic effects of spironolactone in preventing myocardial fibrosis in systemic arterial hypertension. Am J Cardiol 1993;71:12A - 6A. 5. Farquharson CAJ, Struthers AD. Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation 2000;101:594 - 7. 6. http://topcatstudy.com/protocol.asp. 7. http://www.clinicaltrials.gov/ct/show/NCT00094302?order=1.