Champion of the Myocardial Imaging Debate: MDCT (For Now)
Technical Competency in Flexible Sigmoidoscopy
Tick Borne and Other Emerging Infectious Diseases
Emergency Room Management of Hypertensive Urgencies and Emergencies
More New Hypertension Guidelines -- But is Anybody Listening?
Hypertension Highlights
Medscape Cardiology 7(2), 2003. © 2003 Medscape
Posted 10/17/2003
Introduction
This month's news relating to hypertension covers a wide range of topics, including brain function, risk of stroke in hypertensive patients with diabetes, The Seventh Report of the National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) Committee response to criticisms, European guidelines, benefits of thiazide-type diuretics, benefits of drinking black tea, US Food and Drug Administration approval of eplerenone, and advances in basic science.
In the area of brain function, a report from the American Heart Association's 57th Annual High Blood Pressure Research Conference appears to confirm the negative effect of hypertension on cognitive function and memory and gives support to the theory that antihypertensive drugs that affect vascular function, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) might favorably affect cognition.
A recent Japanese paper highlights the increased risk of stroke in hypertensive patients with diabetes and stresses the importance of regular oral glucose tolerance testing.
National and international guidelines continue to provoke reactions, and some of the most common criticisms voiced about the JNC 7 report were recently answered by JNC 7 committee members.
In a reversal of the JNC 7 publication process, the short version of the European hypertension guidelines has been published several months after the full version appeared. (The full JNC 7 report is expected this fall.)
Although not strictly relevant to the hypertension guidelines, other benefits of thiazide-type diuretics that might make them more attractive appear to have been confirmed in a Dutch study, notably that they reduce the risk of hip fracture in the elderly, particularly women.
Elderly women might also get a blood pressure-lowering effect from drinking black tea, according to Australian researchers, adding to the extensive list of reported benefits associated with polyphenols found in tea.
An approved therapy for hypertension, the selective aldosterone antagonist eplerenone, has received approval in the United States for the additional indication of heart failure following an acute heart attack. Eplerenone, which has not been marketed to date, is expected to become available in the United States in December.
In basic science, a potential new target for heart failure therapy has been identified in a mouse model of chronic hypertension, and news to encourage even more basic research comes from the announcement of the world's first cloned rats, a species that has been presenting problems in cloning for some time. The new animals will provide new disease models in many fields as well as for drug development.
Decreased Cerebral Blood Flow in Hypertension May Impair Cognition
Hypertension has been associated with cognitive and memory impairment in many studies. Now researchers from the University of Pittsburgh (Pittsburgh, Pennsylvania) have reported that vascular remodeling due to hypertension decreases cerebral blood flow (CBF) during cognition in elderly subjects. J Richard Jennings, PhD, and colleagues reported the results of their study on hypertension and memory impairment at the American Heart Association's 57th Annual High Blood Pressure Research Conference, held September 23-26 in Washington, DC.[1]
Dr. Jennings and his colleagues recruited 59 volunteers, mean age 60 years, with blood pressure < 140/90 mm Hg, and 37 volunteers, mean age 61 years, with hypertension, defined as systolic blood pressure (SBP) >/= 140 mm Hg or diastolic blood pressure (DBP) >/= 90 mm Hg. The hypertensive subjects had a mean blood pressure of 144/84 mm Hg. All the volunteers underwent neuropsychology tests to determine their baseline memory and cognitive abilities. They also had a Doppler ultrasound carotid artery examination, anatomic magnetic resonance imaging (MRI), and quantitative functional imaging using positron emission tomography (PET) with O15 as the positron emitter.
All volunteers took a series of computer-based memory tests, performed while undergoing a PET scan. These exercises tested "running memory" function, skills that often fail with age, such as looking up a telephone number and then walking to another room and dialing the number. The tests involved memorizing squares on a flashing checkerboard while tapping right- or left-hand fingers and performing verbal and spatial working memory tests, as well as a control test. Data were scored for total CBF and CBF within the anterior and posterior watershed areas, posterior parietal, prefrontal, thalamic, and amygdala/hippocampal areas of the brain.
The hypertensive volunteers showed less CBF activation for the flashing checkerboard task involving closure of right-hand fingers, and little change in CBF, particularly in the posterior brain areas, during verbal and spatial memory tests, compared with the increases seen in the normotensive volunteers. These findings were not significantly altered after adjustment for age, alcohol intake, intima media thickness, or MRI indices.
Speaking to the American Heart Association, Dr. Jennings cautioned that the differences between CBF in the hypertensive and normotensive volunteers were subtle and the reasons why some but not all brain regions showed a reduction in activated flow among the hypertensives are not known. Nonetheless, he pointed out that antihypertensive drugs that specifically address vascular changes, such as ACE inhibitors or ARBs, are most likely to increase CBF.
Diabetes With Hypertension a Major Determinant of Silent Cerebral Infarcts
The results of a Japanese study published in the October issue of Stroke suggest that patients with diabetes and hypertension have a significantly increased risk of silent cerebral infarcts (SCIs).[2]
Kazuo Eguchi, MD, and colleagues at Jichi Medical School (Togichi, Japan) performed 24-hour ambulatory blood pressure monitoring and brain MRI in 360 asymptomatic hypertensive patients, 159 of whom had diabetes mellitus. SCIs (>/= 1) were found in 82% of the patients with diabetes compared with 52% of those with hypertension alone, and multiple SCIs (>/= 3) in 62% vs 35%, respectively (both P < .001). Patients were significantly more likely to have >/= 1 SCI if they were older, had diabetes, or had had hypertension for > 10 years, and significantly more likely to have multiple SCIs if additionally they were male or had higher 24-hour SBP.
Patients with diabetes and white-coat hypertension (clinical SBP > 140 mm Hg or DBP > 90 mm Hg but 24-hour SBP < 135 mm Hg and DBP < 80 mm Hg) had more SCIs (mean 2.8 per person) than patients with sustained hypertension (clinical SBP > 140 mm Hg or DBP > 90 mm Hg and 24-hour SBP >/= 135 mm Hg or DBP >/= 80 mm Hg) but no diabetes (mean, 2.3 per person). The highest prevalence of SCIs was seen among patients with diabetes and sustained hypertension (mean 5.2 per person), and the lowest prevalence was seen in the group with white-coat hypertension and no diabetes (mean 1.4 per person).
On the basis of their previous research showing an association between insulin-resistance-related hemostatic abnormality and multiple SCIs in hypertensive patients,[3] Dr. Eguchi and his colleagues suggest that a synergistic effect between hypertension and diabetes mellitus involving hemostatic factors may be responsible for the increased risk of SCIs.
Commenting on their research to the American Heart Association, the publisher of Stroke, Dr. Eguchi stressed the importance of blood pressure control in diabetic patients with hypertension and the necessity for vigilance in hypertensive patients who do not already have diabetes. He recommended that all hypertensive patients take an oral glucose tolerance test at least once annually.
The JNC 7 Committee Replies to Critics
A number of letters criticizing different aspects of JNC 7[4] appear in the September 10 issue of JAMA. Aram V. Chobanian, Boston University Medical Center (Boston, Massachusetts) and Edward J. Roccella PhD, MPH, National Heart, Lung and Blood Institute (Bethesda, Maryland) reply on behalf of the JNC 7 Committee.[5]
One of the critics voices an opinion -- often expressed since the publication of JNC 7 -- that the new classification of prehypertension "threatens to medicalize most of the adult population" and could "place demands on the medical system that could divert resources from those most at risk."[6] To this, Drs. Chobanian and Roccella reply that the term "prehypertension" is intended "to encourage healthy lifestyles to prevent the progressive rise of blood pressure that accompanies increasing age." In reply to the suggestion that JNC 7 should have set a blood pressure goal of 115/75 mm Hg rather than 135/85 mm Hg to further reduce the risks of myocardial infarction, stroke, and cardiovascular disease,[7] they agree that risk would be lower at this blood pressure, but point out that there is no evidence to justify such an aggressive lowering of blood pressure. They point out that achieving the JNC 7 goals as set out in the guidelines will be a major challenge for the medical community.
They also reject another suggestion, that the American College of Physicians' blood pressure goal of 135/85 mm Hg for patients with diabetes may be more achievable than the 130/85 mm Hg set for diabetics by JNC 7.[8]
The author of another letter[9] maintains that JNC 7 should have included guidelines and cautions for long-term management with thiazide diuretics, since the patients on diuretic therapy in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) had a higher incidence of hyperkalemia, hyperglycemia, new-onset diabetes, and a more rapid decline in glomerular filtration rate compared with those on amlodipine or lisinopril.[10] Drs. Chobanian and Roccella say that the metabolic changes associated with diuretic therapy were "relatively minor and did not translate into increased incidence of cardiovascular events," and that therefore the data justify the use of diuretics in patients with hypertension and diabetes. They point out that periodic monitoring of blood chemistries is advisable in all patients with hypertension. There is criticism by other correspondents of JNC 7's "outmoded admonition" that beta-blockers should generally be avoided in patients who have asthma or reactive airways disease, for the reason that the newer agents carry little risk for bronchospasm.[11] The JNC 7 authors stress that this caution was just that and not a prohibition of beta-blockers.
Perceived omissions from JNC 7 include more details about sleep apnea as a treatable cause of hypertension,[12] and information about mind-body therapies, such as autogenic training, biofeedback, meditation, relaxation, guided imagery, and hypnosis.[13] Drs. Chobanian and Roccella confirm that more information about sleep apnea will appear in the full JNC 7 report (due Fall 2003). However, the JNC 7 committee concluded that "evidence for efficacy of mind-body therapies in hypertensive patients remains somewhat unclear," and as such could not be recommended on a broad basis.
Short Version of European Guidelines Now Available\
Unlike the NHBLI, the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) first released the full report of their 2003 hypertension guidelines.[14] Now a summarized version of the hypertension guidelines has been published by the ESC/ESH in the October issue of the Journal of Hypertension.[15] This version is formulated specifically to be useful for primary care physicians and omits the critical assessment of the evidence contained in the full version of the guidelines published in June.
Thiazide Diuretics Protect Against Hip Fractures
Thiazide diuretics, the antihypertensive therapy recommended as first line in most patients in the JNC 7 report, have other, noncardiovascular beneficial effects, Dutch researchers have confirmed. Thiazide diuretics are believed to protect against age-related bone loss and have been reported to protect against hip fractures. However, how long the drugs have to be taken to affect fracture incidence and how long this effect persists after thiazide diuretics are discontinued has been unclear. Now an epidemiologic study has shown that long-term use of thiazide diuretics, including chlorthalidone, reduces the risk of hip fracture during use and up to 4 months after discontinuation. The results of the study are published in the September 16 issue of Annals of Internal Medicine.[16]
The data come from the Rotterdam Study, a prospective, population-based cohort study on the occurrence and determinants of disease and disability in elderly persons. It was carried out in 7891 people aged >/= 55 years living in a single suburb of the Dutch city. Between June 1, 1991, and December 31, 1999, a total of 281 hip fractures occurred among these subjects. Those who had been taking thiazide diuretics for > 365 days showed a 54% lower risk for hip fracture compared with those who had never taken thiazide diuretics (hazard ratio 0.46 [95% CI 0.21-0.96]). A nonstatistically significant risk reduction was found to persist up to 120 days. The protective effect was not thiazide dose dependent. These effects persisted after adjustment for a range of confounders.
Several mechanisms of action have been proposed for the protective effect of thiazide diuretics against hip fracture. It has been suggested that thiazides might reduce renal calcium excretion, creating a positive calcium balance, they may inhibit bone resorption, or they may have a protective effect on bone mineral density. This could not be investigated in the Rotterdam study, since only cross-sectional data were available. However, lead investigator Bruno H. Ch. Stricker, MB, PhD (Erasmus Medical Center, Rotterdam) and his group point out that patients with moderate to high calcium intake all benefited from thiazides, suggesting that creation of a positive calcium intake is not the only mechanism by which thiazides affect hip fracture risk.
While noting that physicians are unlikely to prescribe thiazide diuretics to patients specifically to lower their hip fracture risk, Dr. Stricker and colleagues point to the additional benefits that would be available to older women with hypertension. Few men participated in their study, so the researchers suggest that the effects may be different in men.
Blood Pressure Lower in Elderly Women Who Drink Black Tea
Long-term regular ingestion of black tea appears to have a beneficial effect on blood pressure in elderly women, according to the results of a study reported in the September issue of the Journal of Nutrition.[17] The study also found a relationship of a marker of tea-derived polyphenols with blood pressure.
Researchers from Perth, Western Australia, investigated the relationships of tea intake and a biomarker of exposure to tea-derived polyphenols (4-O-methylgallic acid) with blood pressure in a cross-sectional study of 218 women aged > 70 years. The women were participating in a larger study of oral calcium supplements to prevent osteoporotic fractures.
Blood pressure was measured in the clinic after the subjects had fasted overnight (12 hours), with abstinence from tea, coffee, and alcohol. Mean pressure was calculated from 3 measurements at 1-minute intervals, with the subjects resting in a seated position. All food and beverages were recorded for the 24-hour period prior to the clinic visit. Although consumption of all tea was assessed, nearly all the tea consumed by this population turned out to be black tea with milk added. A 24-hour urinary sample for the 24-hour period corresponding to the dietary recall information was taken for the measurement of 4-O-methylgallic acid.
Mean daily tea intake was 525 mL and mean blood pressure was 138.1/73.5 mm Hg. A trend was seen for SBP and DBP to be lower with higher tea intake (P = .001 and P = .015, respectively) and higher 4-O-methylgallic acid (P = .008 and P < .001, respectively). A 250-mL (1-cup) increase in tea intake was associated with a 2.2-mm Hg lower SBP and a 0.9-mm Hg lower DBP. This association was confirmed by univariate and multivariate analysis, and after adjustment for age, smoking history, BMI, physical activity, and socioeconomic status, the researchers calculated that a population-wide decrease of 2-3 mm Hg would result in a 17% decrease in hypertension, a 6% decrease in the risk of coronary artery disease, and a 15% decrease in the risk of stroke.
Dr. Jonathan M. Hodgson (University of Western Australia) and colleagues believe that their results are consistent with previous suggestions that the blood pressure-lowering effect of tea may be due to its constituent polyphenols. They suggest that the polyphenols may achieve this effect by improving endothelial function, via antioxidant or estrogen-like activity.
Tea is the most widely consumed drink in the world after water. A wide range of health benefits have been attributed to the consumption of both black and green tea, among which are that tea may reduce the risk of coronary heart disease and stroke. The most recent clinical tea-related research reported a cholesterol-lowering effect of black tea in mildly hypercholesterolemic adults.[18]
Eplerenone to Become Available for Heart Failure and Hypertension
On October 8, the US Food and Drug Administration (FDA) announced the approval of the selective aldosterone blocker eplerenone "for improving the survival of congestive heart failure patients following an acute heart attack." Eplerenone was first approved by the FDA for the treatment of hypertension in 2002, but it has not been marketed to date. The manufacturer, Pfizer, has announced that eplerenone will be available through an early-access program in November and marketed in December.
The FDA approval for the heart failure indication was based on the results of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), which compared eplerenone 25-50 mg/day and placebo added to optimal medical therapy in over 6600 patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.[19] The use of eplerenone resulted in a 15% reduction in the risk of death. A 13% reduction in the risk of death from cardiovascular causes or hospitalization for cardiovascular events.
A recently published study reported that eplerenone was as effective as enalapril in left ventricular hypertrophy (LVH) regression and blood pressure control, but that as combined therapy, eplerenone and enalapril were more effective in reducing LV mass and comparing LVH and SBP than eplerenone alone.[20] The 4E-Left Ventricular Hypertrophy Study compared eplerenone 200 mg daily, enalapril 40 mg daily, and eplerenone 200 mg daily plus enalapril 10 mg daily over 9 months in 202 patients with LVH and hypertension. Hydrochlorothiazide 12.5-25 mg and/or amlodipine 10 mg were added at week 8 if DBP was > 90 mm Hg. Eplerenone significantly reduced LV mass from baseline (-14.5±3.36 g) similarly to enalapril (-19.7±3.20 g), but eplerenone/enalapril was more effective (-27.2±3.39 g) than eplerenone alone (P = .007). All treatments reduced blood pressure, but the reduction in SBP with enalapril/eplerenone was significantly greater than with eplerenone alone (-28.7 vs -23.6 mm Hg, P = .033). The most frequent side effect with enalapril was cough and with eplerenone, hyperkalemia.
Potential New Drug Target Identified in Mouse Model
Researchers from the United States and Italy reported in the October 1 issue of The Journal of Clinical Investigation that they have significantly eased heart failure in mice with chronic high blood pressure by disrupting the activity of a single heart protein, PI3Kgamma.[21] Lead author Howard Rockman, MD, Duke University Medical Center (Durham, North Carolina), believes that the study has identified a potential new target for heart drugs and that it may have important clinical implications.
The PI3Kgamma protein was identified earlier by Dr. Rockman's team. The enzyme is required for internalization and recycling of beta-adrenergic receptors on heart cells and disrupting its function preserves the receptors when they are chronically exposed to adrenaline. In heart failure patients, chronic stress leads to an excess of adrenaline that overstimulates beta-adrenergic receptors, resulting in receptor desensitization and loss. Whether this loss in heart failure protects the heart or contributes to the disease has been unresolved.
Dr. Rockman and his colleagues used genetically modified mice that produced an inactive form of PI3Kgamma, thus allowing the beta-adrenergic receptors to remain active when chronically exposed to an adrenaline-like chemical. In normal mice, the same receptors showed a substantial loss of function similar to that occurring in heart failure patients. After 3 months of chronic pressure overload, the mice with inactive PI3Kgamma showed less than half the decline in heart function compared with mice with the active protein. The genetically manipulated mice with high blood pressure also survived longer than normal mice.
"Our study results show that an intervention that maintains functional beta-adrenergic receptors on the heart surface by disrupting PI3Kgamma activity leads to improved heart function, a result supporting the idea that the loss of receptors contributes to heart failure," Dr. Rockman said in a news release. The study has elucidated a key cellular mechanism underlying heart failure and has identified a novel method for stalling progression of the disease, he believes.
Encouraging News for Animal Research
The world's first cloned rats have been produced, paving the way for new animal models of human diseases, including hypertension. The cloned rats were produced by researchers from the Institut National de la Recherche Agronomique (INRA; Jouy en Josas) and genOway (Lyon) in France. Details of how the rats were generated are published in the online version of Science magazine.[22] The researchers have developed a proprietary 1-step cloning procedure using somatic cell nuclear transfer (SCNT). Previously, cloning rats was beset by problems not found in other cloned species, with previous attempts in rats resulting in developmental arrest at the implantation stage.
The French researchers overcame this by stabilizing the oocytes with a protease inhibitor drug, collecting them in the presence of the drug, and performing SCNT within 30 minutes of removal of the drug. The embryos were then implanted into pseudopregnant foster female rats. Live male and female pups were delivered that have grown to adults that are fertile and exhibit no abnormalities. genOway intends to "work on building an international consortium" with the objective of developing knock-out and knock-in rat models in areas such as obesity, diabetes, and neurologic disorders, as well as in cardiovascular areas such as hypertension and atherosclerosis. The company is also working on new, improved models for use in toxicology and pharmacology studies in drug development.
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(1). What is the only other word you can make using all of the letters in the word, "insatiable?"
(2). What is the only other word you can make using all of the letters in the word, "banalities?"
(1). Close the circle, open your minds eye, visit "The Celtic Connection", through the provided link on my page.
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