Curr Hypertens Rep (2015) 17: 18 DOI 10.1007/s11906-014-0530-0
HYPERTENSION AND METABOLIC SYNDROME (JR SOWERS AND A WHALEY-CONNELL, SECTION EDITORS)
Natriuretic Peptides as a Novel Target in Resistant Hypertension Pratik Patel & Horng H. Chen
Published online: 10 March 2015 # Springer Science+Business Media New York 2015
Abstract Resistant hypertension is defined as blood pressure not under goal despite being on at least three antihypertensives. Resistant hypertension is associated with significant cardiovascular morbidity and mortality. Currently, the mainstay for the treatment of resistant hypertension is lifestyle modification and antihypertensive drugs. Natriuretic peptides play an important role in regulating cardiovascular hemodynamics and sodium and fluid homeostasis including blood pressure control. They hold a promising potential for treatment of resistant hypertension.
Resistant Hypertension Resistant hypertension is defined as blood pressure that is not under goal target while being on at least three antihypertensive medications and includes patients with blood pressure under control on four or more antihypertensive medications [1]. Resistant hypertension differs from uncontrolled hypertension in that the latter can result from true resistant hypertension, poor compliance, or inadequate dosing of antihypertensives [1]. Furthermore, resistant hypertension must be differentiated from pseudoresistance, which can result from poor blood pressure measurement technique and white coat hypertension [1].
Keywords Resistant hypertension . Natriuretic peptides . Chronic kidney diseases Prevalence and Incidence of Resistant Hypertension
Introduction Resistant hypertension is defined as blood pressure not under goal despite being on at least three antihypertensive medications. It is associated with increased risk for cardiovascular morbidity and mortality. Natriuretic peptides (NPs) are hormones secreted from the heart and vasculature in response to both pressure and volume overload. With their multifaceted biological actions on the heart, vasculature, kidney, adrenal gland, and the sympathetic system, NPs play an important role in blood pressure control as well as fluid and electrolyte balance. In this paper, we will review the promising potential therapeutic role of NPs in resistant hypertension. This article is part of the Topical Collection on Hypertension and Metabolic Syndrome P. Patel Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA H. H. Chen (*) Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected]
Prevalence estimates of resistant hypertension vary from 10 % to 30 % of patients with hypertension (Table 1). The data from the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2008 reported that 8.9 % of adults with hypertension in USA met criteria for resistant hypertension [4•]. The ALLHAT trial showed that after follow up of 4.9 years, 27 % of patients with uncontrolled blood pressure were on three or more medications, meeting the criteria for resistant hypertension [2]. The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study (n=10,700), which is a prospective cohort study, estimated that the prevalence of resistant hypertension was 15.8, 24.9, and 33.4 % for those participants with estimated glomerular filtration rate (GFR)≥60, 45–59, and 75 years, left ventricular hypertrophy, and obesity were associated with poor systolic blood pressure control [9]. In the ALLHAT trial, the strongest risk factor for resistant hypertension was chronic kidney disease defined as serum creatinine of ≥1.5 mg/dL [10]. In addition, the study also showed that African Americans and women were less likely to have their blood pressure under control [10]. Medications that can contribute to high blood pressure include NSAIDs, sympathomimetic drugs like decongestants, stimulants like methylphenidate, oral contraceptives, and glucocorticoids [1]. Secondary causes of hypertension can mask resistant hypertension. These include obstructive sleep apnea, chronic kidney disease, renal artery stenosis, diabetes mellitus, primary hyperaldosteronism, Cushing’s syndrome, and pheochromocytoma [1]. Pathophysiology The exact pathophysiology of resistant hypertension remains unknown, but it is likely multifactorial in nature, involving both genetic and environmental factors. The CYP3A5 gene, which codes for 11 β-hydroxysteroid dehydrogenase type 2
27 % on ≥3 antihypertensives, controlled
15.8 % uncontrolled BP on ≥3 antihypertensives or ≥4 antihypertensives regardless of BP control 8.9 % on ≥3 antihypertensives, controlled or ≥4 antihypertensives, uncontrolled 15.9–28 % on ≥3 antihypertensives, controlled 11.8 % on ≥4 antihypertensives, uncontrolled
enzyme, plays an important role in the metabolism of cortisol in the kidney. A study showed that among blacks, a single nucleotide polymorphism in this gene was more common in hypertensives as compared with normotensives [11]. Older age, male sex, obesity, renal dysfunction, and insulin resistance are all associated with resistant hypertension [12, 13]. Increased sympathetic activation also contributes to resistant hypertension. Increased sympathetic activation is seen with aging, obesity, and sleep apnea, which are all associated with resistant hypertension [14]. Furthermore, the kidney plays an important role in resistant hypertension. Efferent fibers from the brain to the kidney innervate peripheral segments of the renal cortex and glomerular arterioles. Sympathetic stimulation leads to enhanced renin release, increased sodium and water reabsorption, and reduced renal blood flow and GFR [15]. Sympathetic afferent fibers from the kidney to the brain regulate sympathetic outflow from the brain [15]. Both sympathetic efferent and afferent systems are involved in resistant hypertension [15]. Renin-angiotensin-aldosterone system (RAAS) also stimulates the central sympathetic nervous system by acting on mineralocorticoid receptors in neurons of paraventricular nuclei [16]. High systemic vascular resistance, expanded plasma volume, elevated aldosterone level, and renin suppression is seen in patients with resistant hypertension [14, 17]. Higher circulating leptin level, a hormone secreted from adipose tissue, has been shown to be associated with elevated blood pressure in patients with uncontrolled resistant hypertension [16]. To summarize, underlying mechanisms for resistant hypertension are multifactorial.
Curr Hypertens Rep (2015) 17: 18
Prognosis Patients with resistant hypertension are at higher risk for cardiovascular disease. A prospective cohort study of 436 hypertensive patients with chronic kidney disease, of which 22.9 % had truly resistant hypertension, found increased risk for cardiovascular events (HR 1.98 95 % CI 1.14–3.43) and renal events (HR 2.66 95 % CI 1.62–4.37) over a follow up of 57 months [18]. A retrospective cohort study of 3960 patients with resistant hypertension showed increased risk for cardiovascular events (HR 1.47; 95 % CI 1.33–1.62; p
HYPERTENSION AND METABOLIC SYNDROME (JR SOWERS AND A WHALEY-CONNELL, SECTION EDITORS)
Natriuretic Peptides as a Novel Target in Resistant Hypertension Pratik Patel & Horng H. Chen
Published online: 10 March 2015 # Springer Science+Business Media New York 2015
Abstract Resistant hypertension is defined as blood pressure not under goal despite being on at least three antihypertensives. Resistant hypertension is associated with significant cardiovascular morbidity and mortality. Currently, the mainstay for the treatment of resistant hypertension is lifestyle modification and antihypertensive drugs. Natriuretic peptides play an important role in regulating cardiovascular hemodynamics and sodium and fluid homeostasis including blood pressure control. They hold a promising potential for treatment of resistant hypertension.
Resistant Hypertension Resistant hypertension is defined as blood pressure that is not under goal target while being on at least three antihypertensive medications and includes patients with blood pressure under control on four or more antihypertensive medications [1]. Resistant hypertension differs from uncontrolled hypertension in that the latter can result from true resistant hypertension, poor compliance, or inadequate dosing of antihypertensives [1]. Furthermore, resistant hypertension must be differentiated from pseudoresistance, which can result from poor blood pressure measurement technique and white coat hypertension [1].
Keywords Resistant hypertension . Natriuretic peptides . Chronic kidney diseases Prevalence and Incidence of Resistant Hypertension
Introduction Resistant hypertension is defined as blood pressure not under goal despite being on at least three antihypertensive medications. It is associated with increased risk for cardiovascular morbidity and mortality. Natriuretic peptides (NPs) are hormones secreted from the heart and vasculature in response to both pressure and volume overload. With their multifaceted biological actions on the heart, vasculature, kidney, adrenal gland, and the sympathetic system, NPs play an important role in blood pressure control as well as fluid and electrolyte balance. In this paper, we will review the promising potential therapeutic role of NPs in resistant hypertension. This article is part of the Topical Collection on Hypertension and Metabolic Syndrome P. Patel Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA H. H. Chen (*) Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected]
Prevalence estimates of resistant hypertension vary from 10 % to 30 % of patients with hypertension (Table 1). The data from the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2008 reported that 8.9 % of adults with hypertension in USA met criteria for resistant hypertension [4•]. The ALLHAT trial showed that after follow up of 4.9 years, 27 % of patients with uncontrolled blood pressure were on three or more medications, meeting the criteria for resistant hypertension [2]. The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study (n=10,700), which is a prospective cohort study, estimated that the prevalence of resistant hypertension was 15.8, 24.9, and 33.4 % for those participants with estimated glomerular filtration rate (GFR)≥60, 45–59, and 75 years, left ventricular hypertrophy, and obesity were associated with poor systolic blood pressure control [9]. In the ALLHAT trial, the strongest risk factor for resistant hypertension was chronic kidney disease defined as serum creatinine of ≥1.5 mg/dL [10]. In addition, the study also showed that African Americans and women were less likely to have their blood pressure under control [10]. Medications that can contribute to high blood pressure include NSAIDs, sympathomimetic drugs like decongestants, stimulants like methylphenidate, oral contraceptives, and glucocorticoids [1]. Secondary causes of hypertension can mask resistant hypertension. These include obstructive sleep apnea, chronic kidney disease, renal artery stenosis, diabetes mellitus, primary hyperaldosteronism, Cushing’s syndrome, and pheochromocytoma [1]. Pathophysiology The exact pathophysiology of resistant hypertension remains unknown, but it is likely multifactorial in nature, involving both genetic and environmental factors. The CYP3A5 gene, which codes for 11 β-hydroxysteroid dehydrogenase type 2
27 % on ≥3 antihypertensives, controlled
15.8 % uncontrolled BP on ≥3 antihypertensives or ≥4 antihypertensives regardless of BP control 8.9 % on ≥3 antihypertensives, controlled or ≥4 antihypertensives, uncontrolled 15.9–28 % on ≥3 antihypertensives, controlled 11.8 % on ≥4 antihypertensives, uncontrolled
enzyme, plays an important role in the metabolism of cortisol in the kidney. A study showed that among blacks, a single nucleotide polymorphism in this gene was more common in hypertensives as compared with normotensives [11]. Older age, male sex, obesity, renal dysfunction, and insulin resistance are all associated with resistant hypertension [12, 13]. Increased sympathetic activation also contributes to resistant hypertension. Increased sympathetic activation is seen with aging, obesity, and sleep apnea, which are all associated with resistant hypertension [14]. Furthermore, the kidney plays an important role in resistant hypertension. Efferent fibers from the brain to the kidney innervate peripheral segments of the renal cortex and glomerular arterioles. Sympathetic stimulation leads to enhanced renin release, increased sodium and water reabsorption, and reduced renal blood flow and GFR [15]. Sympathetic afferent fibers from the kidney to the brain regulate sympathetic outflow from the brain [15]. Both sympathetic efferent and afferent systems are involved in resistant hypertension [15]. Renin-angiotensin-aldosterone system (RAAS) also stimulates the central sympathetic nervous system by acting on mineralocorticoid receptors in neurons of paraventricular nuclei [16]. High systemic vascular resistance, expanded plasma volume, elevated aldosterone level, and renin suppression is seen in patients with resistant hypertension [14, 17]. Higher circulating leptin level, a hormone secreted from adipose tissue, has been shown to be associated with elevated blood pressure in patients with uncontrolled resistant hypertension [16]. To summarize, underlying mechanisms for resistant hypertension are multifactorial.
Curr Hypertens Rep (2015) 17: 18
Prognosis Patients with resistant hypertension are at higher risk for cardiovascular disease. A prospective cohort study of 436 hypertensive patients with chronic kidney disease, of which 22.9 % had truly resistant hypertension, found increased risk for cardiovascular events (HR 1.98 95 % CI 1.14–3.43) and renal events (HR 2.66 95 % CI 1.62–4.37) over a follow up of 57 months [18]. A retrospective cohort study of 3960 patients with resistant hypertension showed increased risk for cardiovascular events (HR 1.47; 95 % CI 1.33–1.62; p
