5805
J Physiol 591.23 (2013) pp 5805–5806
T R A N S L AT I O N A L P E R S P E C T I V E S
Hypertension: is it more than just a numbers game? Timothy B. Curry Departments of Anesthesiology and Physiology, Mayo Clinic, Rochester, MN 55905, USA
The Journal of Physiology
Email: [email protected]
Hypertension is a major risk factor for cardiovascular disease. Given an ageing population and the fact that the beneficial effects of hypertension treatment continues in octogenarians, the physiological study of blood pressure-lowering drugs in ageing is critical. It is known that sympathetic activity increases with ageing and that sympathetic activity is directly related to blood pressure in older individuals (Hart et al. 2012). In this issue of The Journal of Physiology, Okada et al. (2013) clearly demonstrated that direct renin inhibition by aliskiren had a greater effect on lowering blood pressure without increasing resting muscle sympathetic nerve activity or aldosterone versus the diuretic hydrochlorothiazide in older subjects. Furthermore, aliskiren blunted the sympathetic response to head-up tilt. The authors postulate that hypertensive therapy that does not activate the sympathetic nervous system may have important benefits beyond simply treating numbers. Thiazide diuretics were introduced into clinical practice in 1958 and were used in the landmark Veterans Administration Cooperative trials in the 1960s where blood pressure control was shown to reduce deaths from cardiovascular diseases. The clinical benefits demonstrated in these studies and others such as the SHEP trial firmly established thiazide and thiazide-like drugs as the first-line treatment for hypertension, particularly in older patients (Curb et al. 1996). However, single-drug therapy for hypertension often fails. Despite adequate blood pressure control, the risk of death from cardiovascular disease is increased over time in individuals with treated hypertension (Andersson et al. 1998). Does the treatment of hypertension and its related morbidity fall victim to the redundant nature of physiological systems, or are we treating a symptom and not the cause? As the authors note, it has been postulated that
the elevated risk of cardiovascular disease in treated individuals may be more related to persistent sympathetic activation and they observed an increase in sympathetic activity with thiazides treatment. These results stress the need for the development of new anti-hypertensive drugs and therapies (e.g. renal sympathetic nerve ablation, carotid sinus stimulation) that targets the sympathetic nervous system. These are not new ideas – even the multi-drug regimen used in the initial VA Cooperative studies included the sympatholytic drug reserpine. Drugs such as diuretics and those that target the renin–angiotensin–aldosterone system (RAAS) such as angiotensinconverting enzyme inhibitors (ACE-Is), and angiotensin receptor blockers (ARBs) can paradoxically increase plasma renin activity which results in RAAS-independent increases in angiotensin, aldosterone, blood pressure and sympathetic tone. Development of the first oral form of a competitive inhibitor of the protease renin led to the hope that inhibiting the RAAS upstream would limit reflex sympathetic activation and end-organ damage. Okada et al. have now shown that aliskiren reduces blood pressure without a reflex increase in sympathetic nervous system activity. The clinical implications of these findings are unclear. A relationship between elevated resting sympathetic tone and hypertension and end-organ damage has been shown (Abboud et al. 2012). Given that generic forms of diuretics such as hydrochlorothiazide are far less expensive than aliskiren, it is imperative that benefits unique to direct renin inhibition are found beyond just a reduction in blood pressure, so the focus on sympathetic activation is logical. However, despite early promise, many of the results of the ongoing clinical trials ASPIRE HIGHER research programme, which include aliskiren medication, have been disappointing (Sen et al. 2013). Identifying specific populations who may benefit from reduced sympathetic activity will be essential to understanding the role of this drug in clinical practice. The results of the APOLLO trial, which is designed to measure the effectiveness of aliskiren in older individuals (http://clinicaltrials.gov/show/NCT012592 97), will be of particular relevance to the study by Okada et al.
C 2013 The Authors. The Journal of Physiology C 2013 The Physiological Society
A number of stimulating questions arise from the Okada et al. study. First, are drugs such as a diuretic or ACE-I plus a drug targeting the sympathetic nervous system just as effective as inhibition of renin? Second, how do these drugs affect sympathetic activity during stress? The stress response may be as important as resting sympathetic tone in the development of hypertension (Flaa et al. 2006). Finally, ageing individuals are at a higher risk of iatrogenic orthostatic hypotension and an inability to increase sympathetic tone during postural changes could put these individuals at a greater risk of falls. These data from Okada et al. provide some reassurance that blood pressure is maintained during an orthostatic challenge and that baroreflex gain is unchanged despite the fact that there is less of a sympathetic response. However, high rates of hypotension resulted in an aliskiren combination product being withdrawn from the market. Additionally, a contra-indication of the use of aliskiren plus an ACE-I or ARB has been issued. Further studies are clearly warranted which examine the combined effects of these drugs. In summary, it is clear that just treating numbers doesn’t fully reduce the risks associated with hypertension and the sympathetic nervous system continues to be an important target in the treatment of hypertension. Lifestyle modifications such as weight loss, sodium reduction, exercise and moderation of alcohol are still the mainstays of treatment (and prevention) of hypertension – and they have the advantage of not increasing sympathetic activity. When lifestyle modifications alone do not result in adequate control, the addition of drug therapy can reduce the risk of cardiovascular disease associated with hypertension. Studies such as those by Okada et al. are important to understand how new and existing drugs affect the sympathetic nervous system. However, clinical outcomes will ultimately drive choices in therapy.
References Abboud FM, Harwani SC & Chapleau MW (2012). Hypertension 59, 755–762. Andersson OK, Almgren T, Persson B, Samuelsson O, Hedner T & Wilhelmsen L (1998). BMJ 317, 167–171.
DOI: 10.1113/jphysiol.2013.266254
5806 Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H, Camel G, Davis BR, Frost PH, Gonzalez N, Guthrie G, Oberman A, Rutan GH & Stamler J (1996). JAMA 276, 1886–1892.
Translational Perspectives Flaa A, Mundal HH, Eide I, Kjeldsen S & Rostrup M (2006). Hypertension 47, 396–402. Hart EC, Joyner MJ, Wallin BG & Charkoudian N (2012). J Physiol 590, 2069–2079.
J Physiol 591.23
Okada Y, Jarvis SS, Best SA, Bivens TB, Adams-Huet B, Levine BD & Fu Q (2013). J Physiol 591, 5913–5922. Sen S, Sabirli S, Ozyigit T & Uresin Y (2013). Ther Adv Chronic Dis 4, 232–241.
C 2013 The Authors. The Journal of Physiology C 2013 The Physiological Society
J Physiol 591.23 (2013) pp 5805–5806
T R A N S L AT I O N A L P E R S P E C T I V E S
Hypertension: is it more than just a numbers game? Timothy B. Curry Departments of Anesthesiology and Physiology, Mayo Clinic, Rochester, MN 55905, USA
The Journal of Physiology
Email: [email protected]
Hypertension is a major risk factor for cardiovascular disease. Given an ageing population and the fact that the beneficial effects of hypertension treatment continues in octogenarians, the physiological study of blood pressure-lowering drugs in ageing is critical. It is known that sympathetic activity increases with ageing and that sympathetic activity is directly related to blood pressure in older individuals (Hart et al. 2012). In this issue of The Journal of Physiology, Okada et al. (2013) clearly demonstrated that direct renin inhibition by aliskiren had a greater effect on lowering blood pressure without increasing resting muscle sympathetic nerve activity or aldosterone versus the diuretic hydrochlorothiazide in older subjects. Furthermore, aliskiren blunted the sympathetic response to head-up tilt. The authors postulate that hypertensive therapy that does not activate the sympathetic nervous system may have important benefits beyond simply treating numbers. Thiazide diuretics were introduced into clinical practice in 1958 and were used in the landmark Veterans Administration Cooperative trials in the 1960s where blood pressure control was shown to reduce deaths from cardiovascular diseases. The clinical benefits demonstrated in these studies and others such as the SHEP trial firmly established thiazide and thiazide-like drugs as the first-line treatment for hypertension, particularly in older patients (Curb et al. 1996). However, single-drug therapy for hypertension often fails. Despite adequate blood pressure control, the risk of death from cardiovascular disease is increased over time in individuals with treated hypertension (Andersson et al. 1998). Does the treatment of hypertension and its related morbidity fall victim to the redundant nature of physiological systems, or are we treating a symptom and not the cause? As the authors note, it has been postulated that
the elevated risk of cardiovascular disease in treated individuals may be more related to persistent sympathetic activation and they observed an increase in sympathetic activity with thiazides treatment. These results stress the need for the development of new anti-hypertensive drugs and therapies (e.g. renal sympathetic nerve ablation, carotid sinus stimulation) that targets the sympathetic nervous system. These are not new ideas – even the multi-drug regimen used in the initial VA Cooperative studies included the sympatholytic drug reserpine. Drugs such as diuretics and those that target the renin–angiotensin–aldosterone system (RAAS) such as angiotensinconverting enzyme inhibitors (ACE-Is), and angiotensin receptor blockers (ARBs) can paradoxically increase plasma renin activity which results in RAAS-independent increases in angiotensin, aldosterone, blood pressure and sympathetic tone. Development of the first oral form of a competitive inhibitor of the protease renin led to the hope that inhibiting the RAAS upstream would limit reflex sympathetic activation and end-organ damage. Okada et al. have now shown that aliskiren reduces blood pressure without a reflex increase in sympathetic nervous system activity. The clinical implications of these findings are unclear. A relationship between elevated resting sympathetic tone and hypertension and end-organ damage has been shown (Abboud et al. 2012). Given that generic forms of diuretics such as hydrochlorothiazide are far less expensive than aliskiren, it is imperative that benefits unique to direct renin inhibition are found beyond just a reduction in blood pressure, so the focus on sympathetic activation is logical. However, despite early promise, many of the results of the ongoing clinical trials ASPIRE HIGHER research programme, which include aliskiren medication, have been disappointing (Sen et al. 2013). Identifying specific populations who may benefit from reduced sympathetic activity will be essential to understanding the role of this drug in clinical practice. The results of the APOLLO trial, which is designed to measure the effectiveness of aliskiren in older individuals (http://clinicaltrials.gov/show/NCT012592 97), will be of particular relevance to the study by Okada et al.
C 2013 The Authors. The Journal of Physiology C 2013 The Physiological Society
A number of stimulating questions arise from the Okada et al. study. First, are drugs such as a diuretic or ACE-I plus a drug targeting the sympathetic nervous system just as effective as inhibition of renin? Second, how do these drugs affect sympathetic activity during stress? The stress response may be as important as resting sympathetic tone in the development of hypertension (Flaa et al. 2006). Finally, ageing individuals are at a higher risk of iatrogenic orthostatic hypotension and an inability to increase sympathetic tone during postural changes could put these individuals at a greater risk of falls. These data from Okada et al. provide some reassurance that blood pressure is maintained during an orthostatic challenge and that baroreflex gain is unchanged despite the fact that there is less of a sympathetic response. However, high rates of hypotension resulted in an aliskiren combination product being withdrawn from the market. Additionally, a contra-indication of the use of aliskiren plus an ACE-I or ARB has been issued. Further studies are clearly warranted which examine the combined effects of these drugs. In summary, it is clear that just treating numbers doesn’t fully reduce the risks associated with hypertension and the sympathetic nervous system continues to be an important target in the treatment of hypertension. Lifestyle modifications such as weight loss, sodium reduction, exercise and moderation of alcohol are still the mainstays of treatment (and prevention) of hypertension – and they have the advantage of not increasing sympathetic activity. When lifestyle modifications alone do not result in adequate control, the addition of drug therapy can reduce the risk of cardiovascular disease associated with hypertension. Studies such as those by Okada et al. are important to understand how new and existing drugs affect the sympathetic nervous system. However, clinical outcomes will ultimately drive choices in therapy.
References Abboud FM, Harwani SC & Chapleau MW (2012). Hypertension 59, 755–762. Andersson OK, Almgren T, Persson B, Samuelsson O, Hedner T & Wilhelmsen L (1998). BMJ 317, 167–171.
DOI: 10.1113/jphysiol.2013.266254
5806 Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Black H, Camel G, Davis BR, Frost PH, Gonzalez N, Guthrie G, Oberman A, Rutan GH & Stamler J (1996). JAMA 276, 1886–1892.
Translational Perspectives Flaa A, Mundal HH, Eide I, Kjeldsen S & Rostrup M (2006). Hypertension 47, 396–402. Hart EC, Joyner MJ, Wallin BG & Charkoudian N (2012). J Physiol 590, 2069–2079.
J Physiol 591.23
Okada Y, Jarvis SS, Best SA, Bivens TB, Adams-Huet B, Levine BD & Fu Q (2013). J Physiol 591, 5913–5922. Sen S, Sabirli S, Ozyigit T & Uresin Y (2013). Ther Adv Chronic Dis 4, 232–241.
C 2013 The Authors. The Journal of Physiology C 2013 The Physiological Society
