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Biomedical subjects

David A Calhoun

Publications and source records attributed to David A Calhoun.

At least 19 recordsLinked to original sources
PubMed2007

Low-dose aldosterone blockade as a new treatment paradigm for controlling resistant hypertension.

Treatment of resistant hypertension requires confirmation of true resistance, diagnosis and treatment of secondary causes of hypertension, adoption of appropriate lifestyle modifications, and effective use of multidrug antihypertensive regimens. Excessive volume retention often underlies resistant hypertension, so diuretics are generally necessary to achieve blood pressure (BP) goals. Although treatment regimens consisting of 3 or more agents have not been systematically evaluated, the author has found a triple regimen consisting of a thiazide diuretic, a calcium channel blocker, and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) to be generally effective and well tolerated. Although hydrochlorothiazide is more widely used, chlorthalidone provides better BP reduction and should be preferentially used in patients with resistant hypertension, particularly if the patient remains uncontrolled on hydrochlorothiazide. Recent studies have demonstrated that low doses of aldosterone antagonists, when added to multidrug regimens that include a thiazide diuretic and an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, provide significant additional BP reduction, seemingly exceeding what would be expected with addition of alternative classes of agents. The degree of BP reduction induced by aldosterone blockade has been similar in patients with and without evidence of aldosterone excess. Aldosterone antagonists are generally safe and well tolerated. The most common adverse effect of low-dose spironolactone has been breast tenderness, occurring in about 10% of men. Hyperkalemia is uncommon, but can occur, necessitating biochemical monitoring. Risk of hyperkalemia is increased in patients with chronic kidney disease or diabetes, elderly patients, and patients already receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Resistant or difficult-to-treat hypertension.

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.

Alcohol Drinking↗
PubMed2006

Primary aldosteronism: diagnosis and treatment.

Recent studies have indicated a higher prevalence of primary aldosteronism (PA) than reported historically. Aldosterone excess induces sodium and fluid retention with consequential increases in blood pressure. Patients with PA are at an increased risk of developing left ventricular hypertrophy, chronic kidney disease, and endothelial dysfunction. Measurement of the plasma aldosterone/plasma renin activity ratio is an effective screening test for PA. The majority of patients with PA do not have a discernable aldosterone-producing adenoma (APA), and the aldosterone excess is considered idiopathic in etiology and/or attributed to adrenal hyperplasia. Treatment of PA includes medical therapy with mineralocorticoid receptor antagonists and adrenalectomy for patients with a unilateral APA. A reasonable treatment strategy is to attempt medical therapy in all patients with a high plasma aldosterone/PRA ratio and reserve the extensive workup needed to identify an APA for those patients whose hypertension or hypokalemia cannot be controlled medically.

Decision Trees↗
PubMed2006

Aldosterone antagonists: effective add-on therapy for the treatment of resistant hypertension.

Resistant hypertension is defined as blood pressure that remains above target levels despite treatment with three different antihypertensive agents. Cross-sectional analyses and hypertension outcome studies indicate that it is a common clinical problem, which will undoubtedly become increasingly prevalent with an aging and increasingly overweight population. Secondary causes of hypertension are common in patients with resistant hypertension, particularly hyperaldosteronism, with a prevalence of approximately 15-20%. This, however, is likely to be an underestimation of the role excess aldosterone plays in causing resistance to treatment. In subjects with resistant hypertension, suppressed renin levels are common, exceeding 60% in studies conducted by the authors and from centers elsewhere in the world, suggesting occurrence of excess aldosterone beyond cases of true primary aldosteronism. Recent clinical studies indicate that aldosterone antagonists provide significant additional blood pressure reduction when added to treatment regimens of patients with resistant hypertension independent of aldosterone levels. These agents are generally well tolerated. Hyperkalemia is an uncommon complication of aldosterone antagonists, but it can occur. Therefore, biochemical monitoring is necessary, particularly in high-risk patients.

Clinical Trials as Topic↗
PubMed2005

Primary aldosteronism: diagnostic and therapeutic considerations.

Recent evaluations indicate that primary aldosteronism (PA) is common in patients with hypertension. In patients with mild to moderate hypertension the prevalence of PA is 5% to 10%, whereas in subjects with resistant hypertension the prevalence is approximately 20%. As such, PA has become the most common secondary cause of hypertension. Such high prevalence rates are distinctly different from earlier assessments in which PA was found to be rare, with a prevalence of generally less than 1% of hypertensive patients. Why PA is seemingly so much more common now than when first described remains unknown. Accurate identification of PA allows for specific therapy with aldosterone antagonists or with surgical resection of aldosterone-producing adenomas. Determination of the plasma aldosterone to plasma renin activity ratio is an effective screen for PA in that it has a high negative predictive value even in the setting of ongoing antihypertensive therapy. Its specificity, however, is low such that a high ratio is suggestive of PA but must be confirmed by demonstration of high and autonomous secretion of aldosterone.

Adrenalectomy↗
PubMed2005

Aldosterone antagonism: an emerging strategy for effective blood pressure lowering.

Aldosterone antagonists have been available for many decades for the treatment of hypertension, but their use has been mostly limited to patients with classic primary aldosteronism or to combination products with hydrochlorothiazide to minimize risk for hypokalemia. Recently, indications for aldosterone antagonists have been expanded to include congestive heart failure and first-line treatment of mild-to-moderate hypertension. In addition, we have reported that spironolactone has significant antihypertensive benefit when added to existing regimens in patients with resistant hypertension. This benefit was present in patients with and without hyperaldosteronism and was additive to chronic renin-angiotensin blockade with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). Eplerenone, a selective aldosterone antagonist, avoids the androgen and progesterone receptor-related adverse events that sometimes occur with spironolactone, such as breast tenderness, gynecomastia, sexual dysfunction, and menstrual irregularities. In clinical trials, eplerenone has been shown to have antihypertensive benefit in treating mild-to-moderate hypertension similar to other widely used classes of agents. With recent demonstrations of benefit in multiple segments of the hypertensive population, aldosterone antagonists represent emerging opportunity for controlling high blood pressure.

Eplerenone↗
PubMed2005

The role of aldosterone antagonists in the management of resistant hypertension.

Resistant hypertension is an increasingly common problem faced by primary care physicians and specialists and will undoubtedly become even more common as the adult population ages and gains weight. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), at least 8% of subjects were resistant to treatment based on the need for three or more antihypertensive agents. Characteristics of patients with resistant hypertension include being older, black, obese, and diabetic, and having chronic kidney disease as well as untreated sleep apnea. Hyperaldosteronism is common in patients with resistant hypertension, with a prevalence of approximately 20%. This, however, is likely an underestimation of the role aldosterone excess plays in causing drug resistance. In subjects with resistant hypertension, suppressed renin levels are common, exceeding 75% in our studies, suggesting aldosterone excess effects beyond cases of true primary hyperaldosteronism. Recent studies indicate that aldosterone antagonists provide significant blood pressure reduction when added to antihypertensive regimens of patients with resistant hypertension. Interestingly, the blood pressure reduction with use of spironolactone is not limited to patients with hyperaldosteronism, consistent with the concept of aldosterone excess as a continuum from low-renin hypertension with normal aldosterone levels to true primary hyperaldosteronism.

Drug Resistance↗
PubMed2005

Validity of plasma aldosterone-to-renin activity ratio in African American and white subjects with resistant hypertension.

BACKGROUND: Recent reports suggesting that primary aldosteronism (PA) is more common than historically thought have often relied on use of the plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio (ARR) to identify patients with PA. Prior determinations of the validity of the ARR had been generally limited to subjects that could be withdrawn from antihypertensive therapy and to non-African American subjects. METHODS AND RESULTS: The current study was designed to evaluate prospectively the diagnostic value of the ARR in treated African American and white subjects with resistant hypertension. Consecutive subjects referred to a university hypertension clinic for resistant hypertension were evaluated with an early morning ARR and a 24-h urinary aldosterone and sodium. The presence of PA was defined as a suppressed PRA (<1.0 ng/mL/h) and elevated urinary aldosterone excretion (>12 microg/24 h) during high dietary sodium ingestion (>200 mEq/24 h). In 58 subjects, PA was confirmed. The ARR was elevated (>20) in 45 of 58 subjects with PA and in 35 of the 207 patients without PA, resulting in a sensitivity of 78% and specificity of 83% with a corresponding positive predictive value of 56% and a negative predictive value of 93%. Among African American subjects, the ARR was less sensitive than in white subjects (75% v 80%), but it still had a high negative predictive value (92% v 94%). CONCLUSIONS: These data indicate that the ARR is valid as a screening test for PA in African American and white patients on stable antihypertensive treatments, but a high percentage of false-positive results precludes using it for accurate diagnosis of PA.

Black or African American↗
PubMed2004

Impaired endothelium-dependent flow-mediated vasodilation in hypertensive subjects with hyperaldosteronism.

BACKGROUND: Recent studies suggest that aldosterone may impair endothelium-dependent vascular function through suppression of nitric oxide formation. Assessments of forearm blood flow or arterial compliance suggest a similar effect in humans. The present study was designed to determine whether chronic aldosterone excess in subjects with resistant hypertension impairs endothelium-dependent vascular reactivity as indexed by direct assessment of brachial artery flow-mediated dilation (FMD). METHODS AND RESULTS: Consecutive subjects (n=80) with resistant hypertension were prospectively evaluated with an early-morning ratio of plasma aldosterone to plasma renin activity and 24-hour urinary aldosterone and sodium. Changes in brachial artery diameter during reactive hyperemia were measured by high-resolution ultrasound. Hyperaldosteronism was diagnosed on the basis of a renin activity <1.0 ng x mL(-1) x h(-1), urinary aldosterone >12 microg/24 h, and urinary sodium >200 mEq/24 h. FMD was significantly lower in 36 subjects with hyperaldosteronism (1.8+/-1.3% versus 3.9+/-1.9% from baseline; P<0.0001) compared with the 44 subjects without hyperaldosteronism. FMD was negatively and significantly correlated with plasma aldosterone (r=-0.38, P=0.0006), 24-hour urinary aldosterone (r=-0.49, P<0.0001), and ratio of plasma aldosterone to plasma renin activity (r=-0.43, P<0.0001) but was independent of blood pressure, age, and body mass index. In 30 subjects, 3 months of treatment with spironolactone significantly increased FMD (2.5+/-1.7 versus 6.0+/-2.0%; P<0.0001) independently of blood pressure change. CONCLUSIONS: These data demonstrate a strong association between aldosterone excess and impaired endothelial function in human subjects as indexed by flow-mediated arterial vasodilation. These results suggest that chronic aldosteronism may have a blood pressure-independent effect on cardiovascular disease progression in subjects with resistant hypertension.

Adult↗
PubMed2004

Resistant hypertension, obesity, sleep apnea, and aldosterone: theory and therapy.

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.

Aldosterone↗
PubMed2004

Attitudes about and psychosocial outcomes of HFE genotyping for hemochromatosis.

We examined attitudes regarding genetic testing and psychosocial outcomes of HFE genotyping for hemochromatosis. A total of 87 persons with hemochromatosis (patients) (39 women, 48 men), who underwent HFE genotyping, and 50 persons with hypertension (controls) (22 women, 28 men), who had not undergone HFE genotyping, completed a structured interview in which they reported attitudes about benefits and disadvantages of genetic testing and their understanding of genetics and hemochromatosis. Among patients, adherence to treatment for hemochromatosis was assessed. Controls estimated the likelihood of experiencing several potential positive and negative psychosocial outcomes after a positive genetic test. Patients reported their experience pertinent to these outcomes. Patients received information about hemochromatosis when they were diagnosed, and controls read a brief description of hemochromatosis before answering questions. Patients correctly answered 65% of knowledge questions and controls correctly answered 59%. Most participants believed genetic testing is beneficial and described few negative aspects of testing. Controls expected to experience more anxiety, depression, and anger related to a positive genetic test than was reported by patients (p < 0.001). One patient reported discrimination related to the HFE genotype. Most patients were compliant with the iron depletion and maintenance phases of treatment for hemochromatosis. Race, sex, marital status, income, education, barriers to treatment, and knowledge were not significantly associated with adherence to maintenance phlebotomy. We conclude that HFE genotyping appears to be viewed positively and would be generally accepted were it offered as part of a screening program for hemochromatosis. Persons who have not undergone genetic testing may overestimate their emotional responses to a positive test result. In the present hemochromatosis patients, few reported that HFE genotyping was accompanied by negative psychosocial outcomes.

Adult↗
PubMed2004

Aldosterone excretion among subjects with resistant hypertension and symptoms of sleep apnea.

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.

Aldosterone↗