Sleep Apnea Syndromes: Calhoun DA

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM, Anonymous00014. · No affiliation provided · Circulation. · Pubmed #18574054 links to  free full text

Abstract: Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM. · No affiliation provided · Hypertension. · Pubmed #18391085 links to  free full text

Abstract: Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.

Pimenta E, Calhoun DA, Oparil S. · Department of Hypertension and Nephrology, Dante Pazzanese Institute of Cardiology, Sao Paulo, SP, Brazil. · Prog Cardiovasc Dis. · Pubmed #19249443 No free full text.

Abstract: Obstructive sleep apnea, aldosterone excess, and resistant hypertension are common comorbidities in obese patients. The mechanisms that link these conditions are not fully elucidated, but sympathetic nervous system activation, sodium retention, renin-angiotensin-aldosterone system stimulation, endothelial dysfunction, and increased production of reactive oxidative species may be contributing factors. Patients diagnosed with this triad should be treated with low-salt diet, weight-loss counseling, and continuous positive airway pressure, as well as aggressive antihypertensive therapy, usually with multiple agents, including a mineralocorticoid receptor antagonist. Patients with aldosterone-producing adenoma may require adrenalectomy.

Pimenta E, Calhoun DA, Oparil S. · Departamento de Hipertensão Arterial e Nefrologia, Instituto Dante Pazzanese de Cardiologia, São Paulo, SP, Brasil. · Arq Bras Cardiol. · Pubmed #17664996 links to  free full text

This publication has no abstract.

Calhoun DA. · Vascular Biology and Hypertension Program, Center for Sleep/Wake Disorders, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · J Clin Hypertens (Greenwich). · Pubmed #16522995 No free full text.

Abstract: Resistant hypertension, defined as uncontrolled hypertension on three medications, is becoming an increasingly common problem. In most cases, blood pressure remains elevated because of persistently high systolic blood pressure levels. Common characteristics of patients with resistant hypertension include older age, obesity, excessive dietary salt ingestion, and presence of sleep apnea. The evaluation of patients with resistant hypertension is focused on identifying contributing and secondary causes of hypertension. Treatment should include both lifestyle changes (weight loss, exercise, dietary salt restriction) and the use of effective multidrug regimens, including a diuretic. Recent data indicate that aldosterone antagonists may be effective when added to existing antihypertensive regimens even in the absence of primary aldosteronism.

Goodfriend TL, Calhoun DA. · Research Service, William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Madison, WI 53705, USA. · Hypertension. · Pubmed #14732721 links to  free full text

Abstract: Hypertension resistant to 2 antihypertensive drugs is more common among obese patients than among lean patients. The case we describe and the observations we report suggest that refractoriness among obese hypertensives is frequently caused by obstructive sleep apnea and/or inappropriately high plasma aldosterone levels. In other words, obese hypertensives may have sleep apnea, obese hypertensives without sleep apnea may have inappropriately elevated levels of plasma aldosterone, and a surprising number of obese patients with sleep apnea also have elevated levels of aldosterone. The mechanisms by which obesity and obstructive sleep apnea increase aldosterone levels and raise blood pressure are not understood, but sympathetic nervous system activation and production of nonclassical adrenal stimuli are two possibilities. Obstructive sleep apnea can be detected with a careful history and various sleep studies. Inappropriately elevated aldosterone levels can be detected by measuring the ratio of plasma aldosterone concentration to plasma renin activity. Successful treatment of these resistant hypertensives often can be achieved by devices that provide positive pressure to the upper airway to correct obstructive sleep apnea and by incorporating an aldosterone antagonist in the therapeutic regimen.

Pratt-Ubunama MN, Nishizaka MK, Boedefeld RL, Cofield SS, Harding SM, Calhoun DA. · Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA. · Chest. · Pubmed #17296647 links to  free full text

Abstract: OBJECTIVE: Obstructive sleep apnea (OSA) and primary aldosteronism are common in subjects with resistant hypertension; it is unknown, however, if the two disorders are causally related. This study relates plasma aldosterone and renin levels to OSA severity in subjects with resistant hypertension, and in those with equally severe OSA but without resistant hypertension serving as control subjects. METHODS: Seventy-one consecutive subjects referred to the University of Alabama at Birmingham (UAB) for resistant hypertension (BP uncontrolled on three medications) and 29 control subjects referred to UAB Sleep Disorders Center for suspected OSA were prospectively evaluated by an early morning plasma aldosterone concentration (PAC) and renin level, and by overnight, attended polysomnography. RESULTS: OSA (apnea-hypopnea index [AHI] > or = 5/h) was present in 85% of subjects with resistant hypertension. In these subjects, PAC correlated with AHI (rho = 0.44, p = 0.0002) but not renin concentration. Median PAC was significantly lower in control subjects compared to subjects with resistant hypertension (5.5 ng/dL vs 11.0 ng/dL, p < 0.05) and not related to AHI. In male subjects compared to female subjects with resistant hypertension, OSA was more common (90% vs 77%) and more severe (median AHI, 20.8/h vs 10.8/h; p = 0.01), and median PAC was significantly higher (12.0 ng/dL vs 8.8 ng/dL, p = 0.006). CONCLUSION: OSA is extremely common in subjects with resistant hypertension. A significant correlation between PAC and OSA severity is observed in subjects with resistant hypertension but not in control subjects. While cause and effect cannot be inferred, the data suggest that aldosterone excess may contribute to OSA severity.

Calhoun DA, Nishizaka MK, Zaman MA, Harding SM. · Veterans Affairs Medical Center, University of Alabama at Birmingham, Birmingham, AL 35294-0007, USA. · Chest. · Pubmed #14718429 links to  free full text

Abstract: OBJECTIVE: The severity of obstructive sleep apnea (OSA) correlates with the difficulty of controlling BP. The mechanism, however, by which sleep apnea contributes to the development of resistant hypertension remains obscure. Having observed a high prevalence of OSA among hypertensive subjects with primary hyperaldosteronism, we hypothesized a possible association between sleep apnea and aldosterone excretion. DESIGN: In consecutive subjects referred to a university clinic for resistant hypertension, we prospectively determined plasma renin activity (PRA), plasma aldosterone concentration (PAC), and 24-h urinary aldosterone excretion during high dietary salt ingestion. In addition, all subjects completed the Berlin Questionnaire, a survey designed to identify subjects at risk of having sleep apnea. Primary hyperaldosteronism (PA) was defined as a PRA < 1.0 ng/mL/h and 24-h urinary aldosterone excretion > 12 micro g during high urinary sodium excretion (> 200 mEq/24 h). RESULTS: Of the 114 subjects evaluated, 72 subjects had a high probability and 42 subjects had a low probability of having sleep apnea based on their responses to the Berlin Questionnaire. Subjects at high risk for sleep apnea were almost two times more likely to have PA diagnosed (36 vs 19%, p < 0.05), tended to have lower PRA (1.2 +/- 1.8 ng/mL/h vs 1.9 +/- 4.1 ng/mL/h), and had significantly greater 24-h urinary aldosterone excretion (13.6 +/- 9.6 micro g vs 9.8 +/- 7.6 micro g, p < 0.05) compared to subjects at low risk of sleep apnea. CONCLUSION: These data provide evidence of increased aldosterone excretion in subjects with resistant hypertension and symptoms of sleep apnea. While the causality of this association is unknown, it is hypothesized that sleep apnea contributes to the development of resistant hypertension by stimulating aldosterone excretion.

Alper AB, Calhoun DA. · Vascular Biology and Hypertension Program, 933 South 19th Street, University of Alabama, Birmingham, Alabama 35242, USA. · Curr Hypertens Rep. · Pubmed #10981097 No free full text.

Abstract: Refractory or resistant hypertension is conventionally defined as systolic or diastolic blood pressure that remains uncontrolled despite sustained therapy with at least three different classes of antihypertensive agents. Refractory hypertension is estimated to affect less than 5% of the general population with hypertension; however, its prevalence increases with increasing severity of blood pressure. Patients presenting with refractory hypertension usually have progressed from mild, to moderate, to severe hypertension because of lack of or inadequate treatment. Other common contributing factors include obesity, medical nonadherence, suboptimal medical regimens, excessive dietary salt ingestion, secondary forms of hypertension, sleep apnea, and ingestion of substances that interfere with treatment. Combination therapy that includes appropriate doses of a diuretic is recommended for treatment of refractory hypertension. Use of fixed-dose combinations enhances compliance through cost savings, more convenient dosing, and reduced pill burdens.