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Found in Translation
Journal of Cardiac Failure Vol. 17 No. 10 2011
Editorial Comment
Found in Translation PAUL A. SOBOTKA, MD,1 AND STEVEN R. GOLDSMITH, MD2 Mounds View and Minneapolis, Minnesota
Georges Cuvier laid the foundations of reductionism in 1798 with the claim of being able to discern the entirety of an organism from the structure of a single bone. He thereby helped set in motion the slow and inexorable decline of whole-body or integrative physiology. In this issue of the Journal of Cardiac Failure, Galiwango et al report an elegant experiment relating historically established physiology of the sympathorenal axis to the treatment of congestion in human heart failure.1 The study is elegant both in execution and in its translation of established wholeanimal physiology to human disease. The report reminds us that ‘‘translational research’’ includes the translation of experimentally established whole-body physiology to humans and of the critical importance of continuing clinical physiologic research conducted by the informed and astute clinician. The management of congestion in heart failure has been almost entirely based on the opinions of experts recommending dietary salt restriction and the prudent use of loop and thiazide diuretics. More recently, the option of mechanical removal of salt and water has emerged. Data on the relative merits of different diuretic agents as well as detailed information regarding how best to use these agents are almost entirely lacking. A very interesting approach to maximizing the decongestive benefit of loop diuretics, taking into account the role of upright position and activity in mediating renal sympathetic efferent signals, is reported in this issue of the Journal.1 Galiwango et al. report that simply changing the timing of diuretic dosing in relation to posture and activity markedly altered the diuretic and natriuretic responses to furosemide. Total urine volume and urine sodium were considerably greater if patients received the same dose of furosemide while remaining recumbent for 90 minutes,as opposed to assuming the sitting posture combined with light activity. Because both
plasma norepinephrine and plasma renin activity were, as expected, higher during the sitting and exercise experiments, the mechanism of the attenuated diuretic and natriuretic responses presumably was due to differences in activation of renal sympathetic nerves. This experiment is exciting because of its potential clinical applications and for its implications for further device and pharmacologic therapy specifically targeting renal sympathetic efferent signaling as a congestion strategy. Also, the experiment itself represents an elegant translation of preclinical research to the bedside. The renal sympathetic nervous system has been identified as a major contributor to the development of congestion. Sympathetic nerves to the kidney terminate in the blood vessels, the juxtaglomerular apparatus, and the renal tubules.2 Stimulation of the sympathetic efferent nerves causes increased renin release,3 increased sodium reabsorption,4 and reduced renal blood flow.5 The increase in sodium retention and a rightward shift of the pressure natriuresis curve, is a necessary component of the development of fluid retention and congestion. Not surprisingly, the totality of pharmacologic strategy associated with improved outcome in heart failure also likely affects the consequences of renal sympathetic efferent activity. Pharmacologic strategies of proven benefit in heart failure, at least in the subset of heart failure patients with a low ejection fraction, are known to reduce the consequences of renal sympathetic efferent signals. This is clearly true for angiotensin II and the alpha-adrenergic component of carvedilol. It is likely also true for aldosterone and digoxin (the latter having been shown to potentiate renal sympathoinhibition in response to increased intracardiac volume). It is plausible that these effects may contribute to the overall survival benefit of neurohormonally directed therapies and to the benefits of digoxin on reducing admissions for heart failure, which typically are due to congestion. It is also plausible that changes in renal sympathetic tone would affect the response to diuretic agents in patients with heart failure. This presumably is the mechanism by which the diuretic and natriuretic responses to furosemide were enhanced in the supine position as reported in the study under comment. Interestingly, although the natriuretic and diuretic responses to furosemide were enhanced in the supine position, there were no changes in glomerular filtration rate or
From the 1Medtronic, Mounds View, Minnesota and 2Cardiology Division, Hennepin County Medical Center, Minneapolis, Minnesota. Reprint requests: Steven R. Goldsmith, MD, Cardiology Division, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415. Tel: 612-873-2876; Fax: 612-904-4224. E-mail: [email protected] See page 805 for disclosure information. 1071-9164/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2011.09.001
804
Found in Translation
renal plasma flow. This is, however, consistent with the known physiology of renal sympathetic efferent stimulation, in which sodium reabsorption4 has been shown to be enhanced at very low frequencies of stimulation, whereas higher levels of activity are required to increase trigger renin release3 and actually decrease renal blood flow and glomerular filtration rate.5,6 The patients in the present study were all treated with neurohormonal inhibitory therapy, however, and the implications of this baseline therapy for the overall renal response to an increase in sympathetic activity and plasma renin activity, as confirmed by the plasma norepinephrine and plasma renin activity levels, is not known, although in hypertension this physiology is well described.7e9 The presence of the background therapy was clearly not adequate, however, to interfere with the potent effects of posture and activity on the overall diuretic and natriuretic response to furosemide. This elegant and simple experiment, translating well established integrative physiology to the human clinical condition, is a marvel. Human experimental physiologists, often suffering in the ignobility of the basement laboratory and with low-priority research funding, have largely disappeared. Yet the implications of this experiment, performed by clinical researchers well grounded in basic sympathorenal physiology, may have profound implications for how diuretics are used in the treatment of heart failure. It would follow from the results of this experiment that if upright posture and activity attenuates the response to diuretics, presumably through the mechanism of an increase in renal sympathetic tone, then we ought to recommend that our patients take their morning medications, return to bed, and wait until the signal from their bladder, full of salty urine, summons them to eliminate that urine and then to begin their day. Any subsequent dose ought similarly to be followed by a period of supine or semirecumbent rest. It would not be difficult to design a simple study comparing the clinical, renal, and decongestive effects of fixed doses of diuretics given in the standard uncontrolled manner versus one with these strict prescriptions for posture and exercise. Would it not be fascinating, based on this elegant translation of established whole-body physiology to the treatment of human disease, if some portion of natriuretic and diuretic resistance could be reduced, and as a result the risk of congestion also reduced? Such a strategy might help to limit the doses of diuretics needed and consequently
Sobotka and Goldsmith
805
the exposure of the patient to the many known potential problems with these agents. At a minimum, these observations should be taken into account in studies of newer approaches to modulating renal sympathetic tone. Studies like this one should cause us to be grateful that not all human integrative physiologists have gone the way of Cuvier’s dinosaurs, and to remember that far from being lost, many important messages may well be found in successful translational research conducted by clinicians studying real patients with real diseases. Disclosures Paul A. Sobotka is an employee of Medtronic, Minneapolis, Minnesota, was chief medial officer of Ardian, Mountain View, California, and receives royalties from Symplicity sales. He provides medical advice to Ardelyx, Fremont, California. Steven R. Goldsmith reports no potential conflicts.
References 1. Galiwango PJ, McReynolds A, Ivanov J, Chan CT, Floras JS. Activity with ambulation attenuates diuretic responsiveness in chronic heart failure. J Card Fail 2011;17:797e803. 2. Barajas L. Innervation of the renal cortex. Fed Proc 1978;37:1192e201. 3. Zanchetti AS. Neural regulation of renin release: experimental evidence and clinical implications in arterial hypertension. Circ 1977;56:691e8. 4. Bell-Reuss E, Trevino DL, Gottschalk CW. Effect of renal sympathetic nerve stimulation on proximal water and sodium reabsorption. J Clin Invest 1976;57:1104e7. 5. Kirchheim H, Ehmke H, Persson P. Sympathetic modulation of renal hemodynamics, renin release and sodium excretion. Klin Wochenschr 1989;67:858e64. 6. Kon V. Neural control of renal circulation. Miner Electrolyte Metab 1989;15:33e43. 7. Esler M, Jennings G, Lambert G. Noradrenaline release and the pathophysiology of primary human hypertension. Am J Hypertens 1989;2: 140Se6S. 8. Esler M, Jennings G, Biviano B, Lambert G, Hasking G. Mechanism of elevated plasma noradrenaline in the course of essential hypertension. J Cardiovasc Pharmacol 1986;8(Suppl 5):S39e43. 9. Schlaich MP, Lambert E, Kaye DM, Krozowski Z, Campbell DJ, Lambert G, et al. Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine reuptake, and angiotensin neuromodulation. Hypertension 2004;43:169e75.
Editorial Comment
Found in Translation PAUL A. SOBOTKA, MD,1 AND STEVEN R. GOLDSMITH, MD2 Mounds View and Minneapolis, Minnesota
Georges Cuvier laid the foundations of reductionism in 1798 with the claim of being able to discern the entirety of an organism from the structure of a single bone. He thereby helped set in motion the slow and inexorable decline of whole-body or integrative physiology. In this issue of the Journal of Cardiac Failure, Galiwango et al report an elegant experiment relating historically established physiology of the sympathorenal axis to the treatment of congestion in human heart failure.1 The study is elegant both in execution and in its translation of established wholeanimal physiology to human disease. The report reminds us that ‘‘translational research’’ includes the translation of experimentally established whole-body physiology to humans and of the critical importance of continuing clinical physiologic research conducted by the informed and astute clinician. The management of congestion in heart failure has been almost entirely based on the opinions of experts recommending dietary salt restriction and the prudent use of loop and thiazide diuretics. More recently, the option of mechanical removal of salt and water has emerged. Data on the relative merits of different diuretic agents as well as detailed information regarding how best to use these agents are almost entirely lacking. A very interesting approach to maximizing the decongestive benefit of loop diuretics, taking into account the role of upright position and activity in mediating renal sympathetic efferent signals, is reported in this issue of the Journal.1 Galiwango et al. report that simply changing the timing of diuretic dosing in relation to posture and activity markedly altered the diuretic and natriuretic responses to furosemide. Total urine volume and urine sodium were considerably greater if patients received the same dose of furosemide while remaining recumbent for 90 minutes,as opposed to assuming the sitting posture combined with light activity. Because both
plasma norepinephrine and plasma renin activity were, as expected, higher during the sitting and exercise experiments, the mechanism of the attenuated diuretic and natriuretic responses presumably was due to differences in activation of renal sympathetic nerves. This experiment is exciting because of its potential clinical applications and for its implications for further device and pharmacologic therapy specifically targeting renal sympathetic efferent signaling as a congestion strategy. Also, the experiment itself represents an elegant translation of preclinical research to the bedside. The renal sympathetic nervous system has been identified as a major contributor to the development of congestion. Sympathetic nerves to the kidney terminate in the blood vessels, the juxtaglomerular apparatus, and the renal tubules.2 Stimulation of the sympathetic efferent nerves causes increased renin release,3 increased sodium reabsorption,4 and reduced renal blood flow.5 The increase in sodium retention and a rightward shift of the pressure natriuresis curve, is a necessary component of the development of fluid retention and congestion. Not surprisingly, the totality of pharmacologic strategy associated with improved outcome in heart failure also likely affects the consequences of renal sympathetic efferent activity. Pharmacologic strategies of proven benefit in heart failure, at least in the subset of heart failure patients with a low ejection fraction, are known to reduce the consequences of renal sympathetic efferent signals. This is clearly true for angiotensin II and the alpha-adrenergic component of carvedilol. It is likely also true for aldosterone and digoxin (the latter having been shown to potentiate renal sympathoinhibition in response to increased intracardiac volume). It is plausible that these effects may contribute to the overall survival benefit of neurohormonally directed therapies and to the benefits of digoxin on reducing admissions for heart failure, which typically are due to congestion. It is also plausible that changes in renal sympathetic tone would affect the response to diuretic agents in patients with heart failure. This presumably is the mechanism by which the diuretic and natriuretic responses to furosemide were enhanced in the supine position as reported in the study under comment. Interestingly, although the natriuretic and diuretic responses to furosemide were enhanced in the supine position, there were no changes in glomerular filtration rate or
From the 1Medtronic, Mounds View, Minnesota and 2Cardiology Division, Hennepin County Medical Center, Minneapolis, Minnesota. Reprint requests: Steven R. Goldsmith, MD, Cardiology Division, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415. Tel: 612-873-2876; Fax: 612-904-4224. E-mail: [email protected] See page 805 for disclosure information. 1071-9164/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2011.09.001
804
Found in Translation
renal plasma flow. This is, however, consistent with the known physiology of renal sympathetic efferent stimulation, in which sodium reabsorption4 has been shown to be enhanced at very low frequencies of stimulation, whereas higher levels of activity are required to increase trigger renin release3 and actually decrease renal blood flow and glomerular filtration rate.5,6 The patients in the present study were all treated with neurohormonal inhibitory therapy, however, and the implications of this baseline therapy for the overall renal response to an increase in sympathetic activity and plasma renin activity, as confirmed by the plasma norepinephrine and plasma renin activity levels, is not known, although in hypertension this physiology is well described.7e9 The presence of the background therapy was clearly not adequate, however, to interfere with the potent effects of posture and activity on the overall diuretic and natriuretic response to furosemide. This elegant and simple experiment, translating well established integrative physiology to the human clinical condition, is a marvel. Human experimental physiologists, often suffering in the ignobility of the basement laboratory and with low-priority research funding, have largely disappeared. Yet the implications of this experiment, performed by clinical researchers well grounded in basic sympathorenal physiology, may have profound implications for how diuretics are used in the treatment of heart failure. It would follow from the results of this experiment that if upright posture and activity attenuates the response to diuretics, presumably through the mechanism of an increase in renal sympathetic tone, then we ought to recommend that our patients take their morning medications, return to bed, and wait until the signal from their bladder, full of salty urine, summons them to eliminate that urine and then to begin their day. Any subsequent dose ought similarly to be followed by a period of supine or semirecumbent rest. It would not be difficult to design a simple study comparing the clinical, renal, and decongestive effects of fixed doses of diuretics given in the standard uncontrolled manner versus one with these strict prescriptions for posture and exercise. Would it not be fascinating, based on this elegant translation of established whole-body physiology to the treatment of human disease, if some portion of natriuretic and diuretic resistance could be reduced, and as a result the risk of congestion also reduced? Such a strategy might help to limit the doses of diuretics needed and consequently
Sobotka and Goldsmith
805
the exposure of the patient to the many known potential problems with these agents. At a minimum, these observations should be taken into account in studies of newer approaches to modulating renal sympathetic tone. Studies like this one should cause us to be grateful that not all human integrative physiologists have gone the way of Cuvier’s dinosaurs, and to remember that far from being lost, many important messages may well be found in successful translational research conducted by clinicians studying real patients with real diseases. Disclosures Paul A. Sobotka is an employee of Medtronic, Minneapolis, Minnesota, was chief medial officer of Ardian, Mountain View, California, and receives royalties from Symplicity sales. He provides medical advice to Ardelyx, Fremont, California. Steven R. Goldsmith reports no potential conflicts.
References 1. Galiwango PJ, McReynolds A, Ivanov J, Chan CT, Floras JS. Activity with ambulation attenuates diuretic responsiveness in chronic heart failure. J Card Fail 2011;17:797e803. 2. Barajas L. Innervation of the renal cortex. Fed Proc 1978;37:1192e201. 3. Zanchetti AS. Neural regulation of renin release: experimental evidence and clinical implications in arterial hypertension. Circ 1977;56:691e8. 4. Bell-Reuss E, Trevino DL, Gottschalk CW. Effect of renal sympathetic nerve stimulation on proximal water and sodium reabsorption. J Clin Invest 1976;57:1104e7. 5. Kirchheim H, Ehmke H, Persson P. Sympathetic modulation of renal hemodynamics, renin release and sodium excretion. Klin Wochenschr 1989;67:858e64. 6. Kon V. Neural control of renal circulation. Miner Electrolyte Metab 1989;15:33e43. 7. Esler M, Jennings G, Lambert G. Noradrenaline release and the pathophysiology of primary human hypertension. Am J Hypertens 1989;2: 140Se6S. 8. Esler M, Jennings G, Biviano B, Lambert G, Hasking G. Mechanism of elevated plasma noradrenaline in the course of essential hypertension. J Cardiovasc Pharmacol 1986;8(Suppl 5):S39e43. 9. Schlaich MP, Lambert E, Kaye DM, Krozowski Z, Campbell DJ, Lambert G, et al. Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine reuptake, and angiotensin neuromodulation. Hypertension 2004;43:169e75.