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High-dose versus low-dose losartan in patients with heart failure
Correspondence
I am grateful for John McMahon Sr’s comment. There was no room in my essay for the full citation. It makes my point well. The absence of an explicit “right not to know” policy, coupled with a detailed code dealing with the provision of information, raises the presumption that patients must have a bare minimum of information. That presumption is strengthened by the cited section, which does not seem to countenance the possibility that the “quantity” of information that must be provided might in some cases be zero. If the American Medical Association thinks that there might be some such cases, it would be very helpful if they identified them. I declare that I have no conflicts of interest.
Charles Foster [email protected] Ethox Centre, University of Oxford, Oxford OX3 7LF, UK
dependent uricosuric effects of losartan in the HEAAL study. We declare that we have no conflicts of interest.
*Seok-Min Kang, Jaewon Oh, Namki Hong [email protected] Yonsei University College of Medicine, Yonsei University Medical Center, Shin-Chon dong Seo-Dae-Mun gu, Seoul 120-752, South Korea 1
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Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet 2009; 374: 1840–48. Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation 2003; 107: 1991–97. Fauvel JP, Velon S, Berra N, et al. Effects of losartan on renal function in patients with essential hypertension. J Cardiovasc Pharmacol 1996; 28: 259–63. Elliott WJ, Calhoun DA, DeLucca PT, et al. Losartan versus valsartan in the treatment of patients with mild to moderate essential hypertension: data from a multicenter, randomized, double-blind, 12-week trial. Clin Ther 2001; 23: 1166–79.
The HEAAL investigators (Nov 28, p 1840)1 show that high-dose losartan, compared with low-dose losartan, can reduce mortality and readmission to hospital in patients with heart failure. The dose-dependent sideeffects of losartan such as renal impairment, hypotension, and hyperkalaemia were more common in the high-dose group. Hyperuricaemia has been shown to be a strong, independent marker of poor prognosis in patients with congestive heart failure.2 Losartan can decrease uric acid concentrations, whereas other angiotensin-receptor blockers cannot.3,4 The uricosuric effect of losartan may be related to the mechanisms of clinical benefit, so it would be interesting to know whether there were any dosewww.thelancet.com Vol 375 March 27, 2010
I declare that I have no conflicts of interest.
Adnan Erol [email protected]
Marvin Konstam and colleagues conclude that high-dose losartan improves clinical outcomes in patients with heart failure. In an attempt to explain the mechanism behind the success of higher doses of angiotensin receptor blockers (ARBs) in heart failure, they propose that higher doses provide more complete inhibition of angiotensin effects at the AT1 receptor or increased stimulation of the AT2 receptor. The recent identification of different classes of cardiac progenitor cells has suggested that the heart is not a terminally differentiated, postmitotic organ but an organ regulated by stem-cell compartments. Additionally, the discovery of stem cells in the pathological human heart points to a paradigm shift in the biology of the heart and puts forward potential therapeutic strategies for the failing heart.2 A local renin-angiotensin system exists in cardiac progenitor cells. The formation of angiotensin II is enhanced in these cells in the course of heart 1
High-dose versus lowdose losartan in patients with heart failure
failure. Reactive oxygen and nitrogen species generated by angiotensin II produce DNA damage, leading to senescence of cardiac progenitor cells.3 Stimulation of the AT2 receptor exerts inhibitory modulation of oxidative stress and prevents senescence via both inhibition of AT1-receptormediated signalling and its own signalling mechanism.4,5 Indeed, angiotensin II, in the presence of chronic and complete blockade of the AT1 receptor, increases the expression of AT2 receptors.4 In other words, both AT2-receptor signalling and AT1receptor blockade are necessary for preventing senescence of cardiac progenitor cells.5 Taken together, ARBs, losartan in particular, with the support of the HEAAL study,1 could have distinct potential in the prevention and treatment of heart failure.
Department of Internal Medicine, Erol Project Development House for the Disorders of Energy Metabolism, Silivri, Istanbul, Turkey 1
2
3
4
5
Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet 2009; 374: 1840–48. Bearzi C, Rota M, Hosoda T, et al. Human cardiac stem cells. Proc Natl Acad Sci USA 2007; 104: 14068–73. Gonzalez A, Rota M, Nurzynska D, et al. Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan. Circ Res 2008; 102: 597–606. Jones ES, Vinh A, McCarthy CA, Gaspari TA, Widdop RE. AT2 receptors: functional relevance in cardiovascular disease. Pharmacol Ther 2008; 120: 292–316. Min L-J, Mogi M, Iwanami J, et al. Angiotensin II type 2 receptor deletion enhances vascular senescence by methyl methanesulfonate sensitive 2 inhibition. Hypertension 2008; 51: 1339–44.
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Authors’ reply
Authors’ reply We appreciate Seok-Min Kang and colleagues’ comments on our results and, specifically, regarding a potential clinical role for the uricosuric effects of losartan. Uric acid concentrations were measured at baseline and during multiple on-treatment time points 1079
I am grateful for John McMahon Sr’s comment. There was no room in my essay for the full citation. It makes my point well. The absence of an explicit “right not to know” policy, coupled with a detailed code dealing with the provision of information, raises the presumption that patients must have a bare minimum of information. That presumption is strengthened by the cited section, which does not seem to countenance the possibility that the “quantity” of information that must be provided might in some cases be zero. If the American Medical Association thinks that there might be some such cases, it would be very helpful if they identified them. I declare that I have no conflicts of interest.
Charles Foster [email protected] Ethox Centre, University of Oxford, Oxford OX3 7LF, UK
dependent uricosuric effects of losartan in the HEAAL study. We declare that we have no conflicts of interest.
*Seok-Min Kang, Jaewon Oh, Namki Hong [email protected] Yonsei University College of Medicine, Yonsei University Medical Center, Shin-Chon dong Seo-Dae-Mun gu, Seoul 120-752, South Korea 1
2
3
4
Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet 2009; 374: 1840–48. Anker SD, Doehner W, Rauchhaus M, et al. Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging. Circulation 2003; 107: 1991–97. Fauvel JP, Velon S, Berra N, et al. Effects of losartan on renal function in patients with essential hypertension. J Cardiovasc Pharmacol 1996; 28: 259–63. Elliott WJ, Calhoun DA, DeLucca PT, et al. Losartan versus valsartan in the treatment of patients with mild to moderate essential hypertension: data from a multicenter, randomized, double-blind, 12-week trial. Clin Ther 2001; 23: 1166–79.
The HEAAL investigators (Nov 28, p 1840)1 show that high-dose losartan, compared with low-dose losartan, can reduce mortality and readmission to hospital in patients with heart failure. The dose-dependent sideeffects of losartan such as renal impairment, hypotension, and hyperkalaemia were more common in the high-dose group. Hyperuricaemia has been shown to be a strong, independent marker of poor prognosis in patients with congestive heart failure.2 Losartan can decrease uric acid concentrations, whereas other angiotensin-receptor blockers cannot.3,4 The uricosuric effect of losartan may be related to the mechanisms of clinical benefit, so it would be interesting to know whether there were any dosewww.thelancet.com Vol 375 March 27, 2010
I declare that I have no conflicts of interest.
Adnan Erol [email protected]
Marvin Konstam and colleagues conclude that high-dose losartan improves clinical outcomes in patients with heart failure. In an attempt to explain the mechanism behind the success of higher doses of angiotensin receptor blockers (ARBs) in heart failure, they propose that higher doses provide more complete inhibition of angiotensin effects at the AT1 receptor or increased stimulation of the AT2 receptor. The recent identification of different classes of cardiac progenitor cells has suggested that the heart is not a terminally differentiated, postmitotic organ but an organ regulated by stem-cell compartments. Additionally, the discovery of stem cells in the pathological human heart points to a paradigm shift in the biology of the heart and puts forward potential therapeutic strategies for the failing heart.2 A local renin-angiotensin system exists in cardiac progenitor cells. The formation of angiotensin II is enhanced in these cells in the course of heart 1
High-dose versus lowdose losartan in patients with heart failure
failure. Reactive oxygen and nitrogen species generated by angiotensin II produce DNA damage, leading to senescence of cardiac progenitor cells.3 Stimulation of the AT2 receptor exerts inhibitory modulation of oxidative stress and prevents senescence via both inhibition of AT1-receptormediated signalling and its own signalling mechanism.4,5 Indeed, angiotensin II, in the presence of chronic and complete blockade of the AT1 receptor, increases the expression of AT2 receptors.4 In other words, both AT2-receptor signalling and AT1receptor blockade are necessary for preventing senescence of cardiac progenitor cells.5 Taken together, ARBs, losartan in particular, with the support of the HEAAL study,1 could have distinct potential in the prevention and treatment of heart failure.
Department of Internal Medicine, Erol Project Development House for the Disorders of Energy Metabolism, Silivri, Istanbul, Turkey 1
2
3
4
5
Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet 2009; 374: 1840–48. Bearzi C, Rota M, Hosoda T, et al. Human cardiac stem cells. Proc Natl Acad Sci USA 2007; 104: 14068–73. Gonzalez A, Rota M, Nurzynska D, et al. Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan. Circ Res 2008; 102: 597–606. Jones ES, Vinh A, McCarthy CA, Gaspari TA, Widdop RE. AT2 receptors: functional relevance in cardiovascular disease. Pharmacol Ther 2008; 120: 292–316. Min L-J, Mogi M, Iwanami J, et al. Angiotensin II type 2 receptor deletion enhances vascular senescence by methyl methanesulfonate sensitive 2 inhibition. Hypertension 2008; 51: 1339–44.
Science Photo Library
Authors’ reply
Authors’ reply We appreciate Seok-Min Kang and colleagues’ comments on our results and, specifically, regarding a potential clinical role for the uricosuric effects of losartan. Uric acid concentrations were measured at baseline and during multiple on-treatment time points 1079