Clinical Briefs with Comments from Russell H. Greenfield, MD
With Comments from Russell H. Greenfield, MD. Dr. Greenfield is Clinical Assistant Professor, School of Medicine, University of North Carolina, Chapel Hill, NC; and Visiting Assistant Professor, University of Arizona, College of Medicine, Tucson, AZ.
A Thorny Issue Crataegus and Heart Failure
Source: Zick SM, et al: The effect of Crataegus oxycantha special extract WS 1442 on clinical progression in patients with mild to moderate symptoms of heart failure. Eur J Heart Fail. 2008;10:587-593.
Goal: To determine whether a special extract of Crataegus oxycantha (COE) slows the clinical progression of mild-to-moderate heart failure (HF).
Study Design: Retrospective secondary data analysis from HERB CHF, a randomized, double-blind, placebo-controlled trial.
Subjects: People with NYHA HF Classes II-III of > 3 months duration whose left ventricular ejection fraction (LVEF) was < 40% and whose medication regimen had been essentially stable for a minimum of 3 months (data evaluable on n=111).
Methods: Screening took place at the end of HF clinic visits through the University of Michigan Health System cardiology department. Interested patients were asked to perform a 6-minute walk test, and those who walked between 150-450 m were invited for a baseline visit in 2 weeks, at which time clinically stable patients were asked to repeat the 6-minute walk test. Those who walked between 150-450 m again were randomized, and radionuclide ventriculography performed to assess LVEF. Subjects were then randomized to receive either placebo or 900 mg Crataegus oxycantha Special Extract WS 1442 (COE) in split daily doses for 6 months. Baseline, 3 and 6 month data were analyzed retrospectively from 120 people who had completed the HERB CHF trial. Primary outcome measure was progression of HF (HF death, hospitalization or sustained increase in diuretics; patients with more than one endpoint were counted only once).
Results: Progression of HF occurred in 46.6% of the COE group (odds ratio/OR=1.14) and 43.3% of the placebo group, reflecting no difference between the two groups with respect to the primary outcome in question. COE use was associated with nominally more HF deaths and HF hospitalizations, but less frequent need for increased diuretic compared with placebo. Non-proportional Cox regression analysis, however, showed that those receiving COE were 3.9 times more likely to experience an early HF progression event, with the hazard ratio (HR) decreasing with time. In adjusted analysis, the risk of early HF progression increased to 6.4 in the COE group, again with a declining risk with time. Subgroup analysis of patients with LVEF <35% showed that those who were taking COE were at significantly greater risk (HR=3.2) throughout the entire 6-month study period than those in the placebo group, and not just initially.
Conclusion: COE does not reduce HF progression in patients with mild to moderate HF, and may increase the risk of early HF progression.
Study strengths: Independent verification of product consistency.
Study weaknesses: Compliance measured by pill count; > 25% of participants ended up having an LVEF of > 40% after randomization had already occurred; small sample size; unable to continuously monitor changes in HF medications over the 6 months (only at baseline, 3 and 6 months).
Of note: Crataegus oxycantha has been used to treat cardiovascular disorders since the first century AD and appears to have both antioxidant and anti-inflammatory activity, with some pointing to antidysrhythmic effects, too; subjects were eligible for participation in HERB CHF if they were receiving standard HF therapy (inclusive of a diuretic, an ACE-inhibitor or angiotensin receptor blocker [ARB], and a beta blocker; those diagnosed with NYHA class III HF were also required to receive spironolactone); inflammation and oxidative stress appear to be involved in transcriptional regulatory pathways that lead to HF progression; a single batch of COE was used in this trial, standardized to 84.3 mg of oligomeric proanthocyanidins (OPCs).
We knew that: A significant amount of research suggests that Crataegus oxycantha may be a safe and effective treatment for the management of symptoms and diminished exercise capacity seen in people with mild-to-moderate HF; despite great advances in the management of HF, the clinical course remains that of seeming inescapable worsening; HERB CHF found that COE had a neutral effect on clinical outcomes of people with NYHA II-IV HF; the neurohumoral system is triggered early in HF disease progression.
Comments: Hawthorn has long been a valued herbal remedy, with an avid consumer base in Europe presently consuming it regularly as a "cardiac tonic." Concerns about potential interaction with digitalis glycosides were seemingly answered, and studies of hawthorn that focused on symptom management for those with HF often provided promising results, albeit with nagging questions regarding proper dosage and whether findings would be the same considering that standard HF care differs significantly from when many prior hawthorn trials were performed. Now comes a paper raising the specter of not just ineffectiveness, but actual harm from use of COE early in the disease course. Why would this be? The authors ponder this, too, wondering whether a herb-drug interaction may be at work, but a ready explanation presently escapes us.
Hawthorn has been used successfully with many HF patients, and this paper's results alone are not sufficient evidence for forgoing its use in future similar circumstances; however, the conclusions do make it incumbent upon practitioners who recommend hawthorn to intensify patient follow-up during the initial weeks of therapy in case early clinical deterioration of HF with Crataegus oxycantha as reported here is a newly discovered significant adverse effect.
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Tea for Two? Green Tea and Sleep Apnea
Source: Burckhardt IC, et al. Green tea catechin polyphenols attenuate behavioral and oxidative responses to intermittent hypoxia. Am J Respir Crit Care Med. 2008;177:1135-1141.
Goal: To assess the effects of orally administered green tea polyphenols (GTP) on cognitive, inflammatory and oxidative responses to long-term intermittent hypoxia (IH) during sleep.
Subjects: Young adult Sprague-Dawley rats (n=106).
Methods: Rats were divided into 2 groups, one that was exposed to IH, the other to room air (RA). The animals were housed in identical chambers operated under 12-hour light/dark cycles, while oxygen concentration was continually monitored. Oxygen concentration was regulated so as to provide alternating 90-second intervals of 10% oxygen (IH) and room air (RA) throughout the 12-hour light cycle, with 10 hypoxic events per hour of exposure. During the dark cycle oxygen concentration was maintained at 21%. A commercially available green tea product containing 60% catechins was administered in fresh drinking water for 3 days prior and throughout the > 14 day period of IH exposures. Spatial place learning was assessed using a Morris water maze. At the end of the study period, brain tissue was harvested, and assays for malondialdehyde (MDA, an indicator of lipid peroxidation) and prostaglandin E2 (PGE2) were performed, as were Western blotting, PCR and immunolocalization.
Results: Animals exposed to IH who received plain water had significantly higher brain MDA levels than rats in the RA-water, RA-GTP or IH-GTP groups. The IH-GTP animals had a 33% reduction in MDA compared with IH-water animals, while results for RA-GTP and RA-water were both relatively low (with RA-GTP MDA levels being lowest). PGE2 levels increased only in the IH-water group. IH-water treated animals also performed markedly worse in tests of spatial bias. Other results all showed a tendency towards worsening neural damage from oxidation only in the IH-water group.
Conclusion: Oral GTP minimizes IH-induced spatial learning deficits, and apparently reduces neural susceptibility to IH during sleep, by mitigating IH-induced oxidative stress and inflammation in rodents.
Study strengths: Uniform GTP administration; in-depth laboratory evaluation.
Study weaknesses: Model does not incorporate other important aspects of SDB, including sleep fragmentation and recurring hypercapnia; animal model may not correlate with human findings.
Of note: Green tea contains polyphenols (catechins) that exhibit antioxidant activity and may help reduce specific disease risk; IH with sleep disordered breathing (SDB) increases NADPH oxidase activity in rodents; chronic exposure to IH in rodents replicates many of the features of obstructive sleep apnea (OSA) in humans; people with OSA have increased circulating markers of oxidative stress and inflammation; the hippocampus and prefrontal cortex, both critical to learning and memory, are particularly sensitive to IH during sleep, with damage likely occurring due to oxidative stress and inflammation; in an animal model of global ischemia, EGCG (a highly active green tea polyphenol) was neuroprotective against neuronal damage.
We knew that: OSA is the most severe form of SDB and is characterized by repeated episodes of upper airway obstruction during sleep that induce IH and sleep fragmentation; the IH associated with SDB, including sleep apnea, is associated with neurocognitive deficits such as impaired spatial learning, and is likely caused by increased oxidative stress; untreated OSA can lead to significant cardiovascular, neurocognitive (learning and psychological), and metabolic morbidities.
Comments: The prevalence of SDB is increasing, and in light of seemingly ever-worsening data on rates of obesity, the numbers of people experiencing SDB will likely continue to increase for the foreseeable future. A significant number of people have SDB but have yet to be evaluated for it, diagnosed and offered treatment. Once the diagnosis has been secured, for some the solution becomes part of the problem. Many patients experience benefits from CPAP yet do not continue its use, citing discomfort and noise, among other things. Other use dams and bite blocks, while still others opt for surgical intervention. Indeed, while some people with SDB are not overweight, many are, and appropriate weight management planning is of significant help. The present study adds a potential new layer of help for people with SDB, though a human trial is needed.
SDB is more than merely a nuisance; untreated, it can have severe physiologic and cognitive/psychologic consequences. A healthy diet that includes foods high in polyphenols may help prevent sequelae of untreated or under-treated SDB. Even for those receiving appropriate treatment, polyphenols may turn out to be a useful adjunct. Polyphenols can be found not only in green tea, but also in chocolate, wine, and some fruits and vegetables, but don't be surprised if polyphenol supplements become even more popular.
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Fish for The Blues? Depression and EPA
Source: Fe'art C, et al: Plasma eicosapentaenoic acid is inversely associated with severity of depressive symptomatology in the elderly: data from the Bordeaux sample of the Three-City Study. Am J Clin Nutr. 2008;87:1156-1162.
Goal: To examine the relationship between plasma fatty acid concentrations and severity of depression in elderly French community dwellers.
Study Design: Cross-sectional population-based study (data taken from the Three-City Study, a prospective cohort study of vascular risk factors for dementia).
Subjects: People (average age 74.6 years) from Bordeaux who participated in the Three-City Study cohort (n=1,390 with 547 men).
Methods: A community sample of people over age 65 years was selected from electoral rolls of 3 French cities in 1999-2000, including Bordeaux. Baseline information obtained included sociodemographics, lifestyle including a food frequency questionnaire, symptoms, medical history, blood pressure, use of alcohol and tobacco. Anthropometric data and fasting blood samples were collected, and neuropsychological testing was performed. Cognitive functioning was assessed using the Mini-Mental State Examination (MMSE). Depressive symptomatology (DS) was assessed using the Center for Epidemiologic Studies Depression Scale (CES-D), which was completed during a home interview as performed by specially trained psychologists. Multiple measures of free fatty acids were performed and ratios determined. Cross-sectional analysis of the relationship between plasma fatty acid profile and DS was performed using multilinear regression.
Results: A total of 117 participants were identified to have DS. As compared to controls, subjects with DS were older, more often women who were widowed or single, had lower monthly incomes, were taking antidepressant medication more frequently, had a lower incidence of dyslipidemia, and had lower scores on MMSE. Of all the fatty acids measured, only plasma EPA levels were found to differ between those with DS and the control group, with levels lower in subjects with DS than in controls, and inversely related to severity of DS in subjects using antidepressants when data were adjusted for potential confounders. No statistically significant association between EPA levels and severity of DS was found for people not taking antidepressants, nor was there an identified interaction with specific antidepressant treatment.
Conclusion: Higher plasma levels of EPA are associated with less severe DS in elderly subjects, especially those already taking antidepressant medication.
Study Strengths: Sample size; simultaneous assessment of DS and blood tests; control for numerous confounders.
Study Weaknesses: Data based on CES-D and not clinical diagnosis of depression; no assessment of duration of antidepressant use or length of time of DS; no biological data on inflammatory and oxidative status of subjects.
Of note: Depression amongst the elderly is often under-treated or under-diagnosed; the origins of late-life depression span social, physical, biochemical and psychological domains; the increased prevalence of depression parallels fundamental dietary changes in recent decades; n-3 polyunsaturated fatty acids (PUFAs) have been reported to have a protective effect against depression, and subjects with depression have been reported to have lower levels of n-3 PUFAs; elongase and desaturase enzyme activity important to the formation of n-3 PUFAs decreases with advancing age, translating into an increased importance of dietary sources of essential fatty acids; the CES-D has been reported to be a valid and reliable measure of DS in the elderly; in this trial, the control group included people who were using antidepressant treatment and were no longer depressed; 13 subjects were unable to complete the CES-D due to severe DS; subjects with DS also took more medication than controls (75% were on 5 or more medications, mainly comprised of antidepressants), deemed their health status poorer, and performed worse on the MMSE; red blood cell fatty acid content better reflects long-term PUFA intake than does plasma fatty acid concentration.
We knew that: Older adults are at high risk for depression, and demographic trends would suggest that the age-specific prevalence of this malady will only increase; chronic illness, cognitive impairment, and disability are often accompanied by depression; n-3 PUFAs have anti-inflammatory and vascular effects, and play an important role in neuronal membrane integrity; red blood cell membranes in depressed people show evidence of oxidative damage; n-3 PUFAs have been shown to play an integral role in regulation of the serotonergic system.
Comments: It has long been suggested that a diet high in essential fatty acids can help prevent, or at least modulate, certain maladies. From a mental health perspective, the data on n-3 PUFAs for bipolar disorder have been promising, and results from trials focusing on depression have also largely been suggestive of benefit. Results of the current study support this notion, especially for seniors already being treated with antidepressants, though methodologic barriers limit firmness of the conclusions.
Depression in the elderly is a growing problem, and findings that point to a potential dietary component are both helpful and problematic. If people ate healthier fare across their lifetimes, such as foods high in essential fatty acids, perhaps mood disorders amongst senior citizens would be less severe; however, one of the numerous challenges the elderly face is eating a healthy diet. Many suffer from poor dentition, no longer cook for themselves, or eat mainly alone, which research suggests is associated with less than optimal nutrition. If further study confirms the potential benefits of n-3 PUFAs for the mental health of seniors, it will be additional fodder for practitioners to use to apply political pressure and ensure adequate exposure to such foods, and perhaps supplements, across socioeconomic barriers.
What to do with this article: Keep a copy on your computer.Goal: To determine whether a special extract of Crataegus oxycantha (COE) slows the clinical progression of mild-to-moderate heart failure (HF).
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