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Cholesterol Byproduct Blocks Heart Health Benefits Of Estrogen
New findings by UT Southwestern Medical Center researchers show that a byproduct of cholesterol metabolism interferes with the beneficial effects estrogen has on the cardiovascular system, providing a better understanding of the interplay between cholesterol and estrogen in heart disease.
The results of the study, available online and in the October issue of the journal Nature Medicine, also may explain why hormone replacement therapy fails to protect some postmenopausal women from heart disease, said Dr. David Mangelsdorf, chairman of pharmacology and senior author of the paper.
The researchers found that in rodents, a molecule called 27-hydroxycholesterol, or 27HC, binds to the same receptors in the blood vessels of the heart to which estrogen binds.
The normal result of this estrogen binding is that blood vessel walls remain elastic and dilated, and damage to the vasculature is repaired, among other heart protective effects. Other research has shown that postmenopausal women who no longer produce estrogen lose this protective action and become more susceptible to heart disease.
Based on their animal studies and other experiments, the UT Southwestern researchers determined that when estrogen levels dropped relative to the amount of 27HC circulating in the blood, 27HC reacted and bound to the estrogen receptors in the cardiovascular system and blocked their protective function, primarily by inhibiting the production of nitric oxide. Nitric oxide mediates smooth muscle relaxation in blood vessels, aids cell growth and repair, and prevents thrombosis. Reduced levels of nitric oxide in blood vessels has been linked with high cholesterol and diabetes.
In animals fed a high fat, high cholesterol diet, both cholesterol and 27HC levels were elevated.
"We found that 27HC can effectively inhibit estrogen function in vascular tissue by binding to estrogen receptors," said Dr. Mangelsdorf, a Howard Hughes Medical Institute investigator at UT Southwestern. "This study not only illustrates the damaging effects high cholesterol has on the heart but also supports the notion that the relative levels of 27HC and estrogen in the vasculature are contributing factors to the risk for cardiovascular disease."
In normal premenopausal women, the amount of 27HC generated from cholesterol is relatively low compared to the level of estrogen circulating in the blood, leading to enhanced cardiovascular protection. In contrast, when the level of 27HC is higher relative to estrogen, such as during the postmenopausal period or as a consequence of high cholesterol, the researchers speculate that 27HC out competes estrogen to bind with estrogen receptors, blocking the function of the receptors and resulting in a loss of protection.
"This model may help explain why women are better protected than men from cardiovascular disease until they reach menopause," said Dr. Mangelsdorf.
The findings also may help explain why a large clinical trial that evaluated certain hormone replacement therapies (HRT) in postmenopausal women a component of the 15-year Women's Health Initiative had to be halted in 2002 when the hormones appeared to increase a woman's risk of heart disease.
"In the Women's Health Initiative research program, the women who began taking HRT were an average of 13 years postmenopause," Dr. Manglesdorf said. "By the time they started taking this estrogen again, the damage caused by 27HC binding to the estrogen receptors in the cardiovascular system may already have occurred. Once you lose estrogen's protection for such an extended period of time, you can't get it back."
The researchers also found that 27HC works predominantly on estrogen receptors in the cardiovascular system. When it binds to estrogen receptors in other tissues, such as reproductive tissues, it has no effect on their reproduction-related functions. This property of 27HC makes it a "selective estrogen receptor modulator," or SERM, the first such naturally occurring molecule known to exhibit such selectivity.
"This molecule is remarkable in its selectivity for the vasculature," Dr. Mangelsdorf said. "These findings also validate the estrogen receptor as a possible drug target for manufactured SERMs."
Other UT Southwestern researchers involved in the study were: lead author Dr. Michihisa Umetani, instructor of pharmacology; Dr. Hideharu Domoto, former postdoctoral researcher in pharmacology; Dr. Andrew Gormley, former postdoctoral research fellow in pediatrics; Ivan S. Yuhanna, senior research associate in pediatrics; Dr. Carolyn Cummins, HHMI research associate in pharmacology; and Dr. Philip W. Shaul, professor of pediatrics. Researchers from the New York University School of Medicine and the National Institute of Environmental Health Sciences also contributed.
Aspirin 'resistant' patients at increased risk of cardiovascular event
By BMJ-British Medical Journal, [RxPG] Being resistant to aspirin makes patients four times more likely to suffer a heart attack, stroke or even die from a pre-existing heart condition, according to a study published on bmj.com.
The study relates to patients who are prescribed aspirin long term as a way of preventing clots from forming in the blood.
Patients who are labelled “aspirin resistant” have blood cells (platelets) that are not affected in the same way as those of patients who are responsive to the drug, ie people who are “aspirin sensitive.”
There is currently no agreed method of accurately determining who is and isn’t aspirin resistant and the reasons why someone might be aspirin resistant are currently a cause of controversy.
Relatively few studies have looked at whether aspirin resistance has any impact on clinical outcome so the Canadian authors carried out a review of all the available data to better understand the relationship between the two.
They identified 20 studies, involving 2,930 patients with cardiovascular disease, all of whom had been prescribed aspirin as a way of preventing clots from forming in the blood. 28% were classified as aspirin resistant.
They found that all aspirin resistant patients, regardless of their underlying clinical condition, were at greater risk of suffering a heart attack, stroke or even dying. In particular they found that 39% of aspirin resistant patients compared to 16% of aspirin sensitive patients suffered some sort of cardiovascular event.
They also found that taking other drugs to thin the blood, such as Clopidogrel or Tirofiban, did not provide any benefit to these patients.
The authors conclude that there needs to be further studies on aspirin resistance to identify the most useful test to determine the condition. They also say aspirin resistance: “is a biological entity that should be considered when recommending aspirin as antiplatelet therapy.”
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By Julie Steenhuysen
CHICAGO (Reuters) - People who have a cardiac arrest in the hospital at night or on the weekend are far less likely to survive than those who suffer one during the day, U.S. researchers said on Tuesday.
Studies suggest this may be at least partly because of inadequate staffing at off-peak hours.
The researchers found only 14.7 percent of people whose hearts stop pumping during the night survive, compared with nearly 20 percent of people during the day.
Those who had a cardiac arrest at around 3 p.m. had the survival rate, Dr. Mary Ann Peberdy of Virginia Commonwealth University in Richmond and colleagues reported in the Journal of the American Medical Association.
The only part of the hospital with difference in survival day or night was the emergency department. "That survival difference by time of day was there regardless of where we looked, except in the emergency department," Peberdy said.
She said emergency departments are the one place in hospitals constantly staffed by senior-level physicians.
Cardiac arrest occurs when the heart stops circulating blood. Without cardiopulmonary resuscitation or CPR and often a shock from a defibrillator, patients can die within minutes.
"Doing the right thing and doing it quickly is very important," Peberdy said.
She said studies at individual hospitals suggested staffing played a role in whether a patient survived a cardiac arrest.
Other studies have shown that doctors make more mistakes at night, hospitals have fewer nurses per patient working at night and that fewer experienced supervisors work the night shift.
TIME TRUMPS OTHER FACTORS
Peberdy wanted to see how this affected survival of cardiac arrest. Her team scoured the National Registry of Cardiopulmonary Resuscitation, which included survival data for more than 86,000 adults who had heart attacks in more than 500 U.S. hospitals between January 2000 and February 2007.
They split up the data by time of day, with the day/evening defined as 7 a.m.-10:59 p.m., night as 11 p.m.-6.59 a.m. and weekends starting at 11 p.m. Friday and running through 6.59 a.m. Monday.
"We factored in how sick people were, what their initial rhythms were. None of that overshadowed the time of day," Peberdy said in a telephone interview.
"Weekend nights were pretty much the same as week nights. Weekend days were kind of in between week days and nights," she said.
She said the difference by time of day held regardless of whether a patient was in a bed with a heart monitor or even in the intensive care unit.
"I think the study confirms what some of us have suspected for a while: That how we staff the hospital determines how well patients do," said Dr. Graham Nichol who helps oversee the NRCPR registry for the American Heart Association.
Peberdy said the study suggests hospitals need to focus on improving their resuscitation systems in off-hours.
(Editing by Alan Elsner and Maggie Fox)
MY OPINION : I have seen a few studies claiming Cardiac arrest mortality rates are higher in the night. And the basic aims of these study is to bring into focus the lack of proper treatment or procedures during off-hours like in the nights of weekends. And this study actually proves that inefficiency in procedures actually contributes to increased complications. We cannot change the time of when a supposed cardiac arrest is supposed to happen in a patient. But we can make sure, through intensive education and practice, that people suffering from cardiac arrests in the night should be given the same intensive attention and properly guided procedures even in the wake of night. More attention should be given to Emergency Department staff who work in the night.
And yes properly trained or improperly trained staff play a great role in prognosis. [/b]
Actually, I'm not sure if this should be in the 'Women's health Research, News,Reviews' thread or here. If its inappropriate here, I request the moderator to move it .
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Pregnancy increases risk of acute myocardial infarction
Although acute myocardial infarction (AMI) is rare in women of child-bearing age, pregnancy can increase a woman's risk of heart attack 3- to 4-fold, according to a study published in the July 15, 2008, issue of the Journal of the American College of Cardiology.
Since women today may delay having children until later in life, and advances in reproductive medicine enable older women to conceive, the occurrence of AMI associated with pregnancy is expected to increase.
The study, authored by Arie Roth, M.D., Tel Aviv University in Israel, and Uri Elkayam, M.D., University of Southern California (USC), is a follow up to their initial report released in 1995. The report is based on a review of 103 women with pregnancy-related AMI in the last decade and outlines key recommendations for the diagnosis and treatment of this condition in pregnant women that also considers the health and safety of the developing baby.
"It's extremely important that physicians who take care of women during pregnancy and after delivery be aware of the occasional occurrence of AMI in pregnancy and not overlook symptoms in these young patients," said Dr. Elkayam, who is a professor of Medicine and Obstetrics and Gynecology at USC. "Although many of the standard principles for diagnosing and treating AMI in non-pregnant patients also apply to pregnant women, two patients need to be treated-the mother and her baby-and the health status of both should play a major role in the selection of diagnostic and therapeutic strategies."
Some of the standard diagnostic tests and medications (e.g., ACE inhibitors, angiotensin II receptor blockers (ARBs) and warfarin) used to manage AMI can be harmful to the baby, whether in the womb or through breastfeeding; therefore, their use should take into account potential risks and benefits. There is also limited evidence about the efficacy and safety of other commonly used drugs such as thrombolytic and antiplatelet therapy and devices such as drug-eluting stents, mainly because pregnant patients are routinely excluded from clinical trials.
"The good news is that we've seen a significant drop in maternal deaths related to AMI during and immediately following pregnancy in the last decade," said Dr. Elkayam. "Our initial report indicated a mortality rate of 20 percent, and nearly 40 percent was reported by other studies. In contrast, the new data suggest that only 5 percent to 10 percent of expectant and new mothers who have a heart attack die as a result."
The authors attribute this improvement to increased awareness, more aggressive clinical approaches to treating AMI in general, including standardized hospital protocols for screening and diagnosis, as well as the application of these approaches to pregnant women.
"Interestingly, the mechanism of AMI is somewhat different when it occurs in association with pregnancy. One in four women had a weakening and separation of the walls of the coronary arteries (coronary dissection), which is a rare cause of heart attack in the general population," explains Dr. Elkayam. "Another 13 percent had normal coronary arteries. These findings signify the need to establish the cause of AMI in pregnancy in order to decide on appropriate therapy."
At the same time, many patients reported standard risk factors for AMI, including smoking (45 percent), high cholesterol (24 percent), family history of heart attack (22 percent), high blood pressure (15 percent) and diabetes (11percent). These findings indicate that such risk factors are important even at younger ages and should be diagnosed early and treated aggressively.
Those who experienced AMI within 24 hours before or after delivery are twice as likely to die from heart attack as those who have a cardiac event before labor or postpartum (24 hours to three months after delivery). Overall, the majority of patients with stable AMI had a vaginal delivery, meaning that cesarean section should not be an automatic indication in patients who are stable, according to Dr. Elkayam.
This study is based on an extensive and systematic review of 103 cases of pregnancy-related AMI during the last decade, and compared them to 125 cases diagnosed prior to that time. Patients' ages ranged from 19 to 44 years, and older maternal age was shown to be a risk factor. The majority of patients (72 percent) were older than 30 years, and one in four was older than 35 years of age.
"We felt it was important to reexamine the literature about AMI related to pregnancy and provide updated recommendations for the diagnosis and management of heart attack in this group of women," said Dr. Elkayam.
"It's been encouraging to see improvements in patient outcomes over the last 10 years, and we hope the guidelines presented in this paper will further increase awareness about AMI in pregnancy."
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Yes it's possible to be fit and fat as well!
New research has come up with some surprising revelations about people who are overweight.
The research by scientists from the Albert Einstein College of Medicine in New York, has found that it may be possible to be both fat and healthy.
The researchers say at least half of overweight adults, and almost a third of obese men and women, have normal blood pressure, cholesterol and other measures of heart health.
They say being lean does not necessarily protect people as almost a quarter of normal-weight adults in the U.S. were found in one study to have risk factors for heart disease or diabetes.
The researchers suggest that not enough is known about obesity as a considerable proportion of overweight and obese U.S. adults are metabolically healthy, whereas a considerable proportion of normal-weight adults have a number of cardiometabolic abnormalities.
Researchers Rachel Wildman and Judith Wylie-Rosett who led the study, say their research shows you can still be healthy even if you are obese.
The team of researchers examined data on 5,440 men and women who were examined and filled out questionnaires for the National Health and Nutritional Examination Surveys between 1999 and 2004, the majority did little exercise.
The data revealed that just over 51 percent of those who were overweight, and 31.7 percent of those who were obese, had healthy levels of cholesterol, blood sugar, blood pressure and other measures linked to heart disease, strokes, diabetes and other heart disease.
It also revealed that more than 23 percent of those who were at a healthy weight, according to their body mass index, had two or more unhealthy readings.
While people's diets came under scrutiny the researchers believe the critical factor may be the location of the body fat, which might be as important as how much of it there is.
There is an abundance of research which has demonstrated that having visceral fat, in and among the internal organs, may be more dangerous than having fat on the thighs or buttocks.
The most common way to estimate visceral fat, is by measuring the waist circumference, and it was found that more than 36 percent of the obese people with what should have been dangerously large waists, had healthy blood test results.
The research is published in the journal Archives of Internal Medicine.
My extra notes: I wonder if results would be similar if the study is carried out in India. Our diet is very different from the one usually consumed in the west. It will be interesting to find out what percentage of people in India who have a 'healthy' weight get those unhealthy readings in their blood tests.
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Some Obese Individuals Appear 'Metabolically Healthy,' Without Increased Cardiovascular Risk
Aug. 12, 2008
Some obese individuals do not appear to have an increased risk for heart disease, while some normal-weight individuals experience a cluster of heart risks, according to two reports in the August 11/25 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.
The prevalence of obesity is increasing worldwide, and this epidemic is accompanied by a high incidence of type 2 diabetes mellitus and cardiovascular disease, the authors write as background information in one of the articles.
Research indicates that in addition to overall obesity, the way body fat is distributed may influence risk for heart disease and diabetes. For instance, individuals with fat within the abdominal cavity—estimated by measuring waist size—appear to be at higher risk for insulin resistance (a pre-diabetic condition that occurs when the body fails to respond to the hormone insulin) and for having an unhealthy cardiovascular risk profile.
In one study, Norbert Stefan, M.D., and colleagues at the University of Tübingen, Germany, studied 314 individuals age 18 to 69 (average age 45). The researchers measured participants' total body fat, visceral fat (abdominal fat around the internal organs) and subcutaneous fat (fat under the skin) using magnetic resonance tomography. Insulin resistance was measured using an oral glucose tolerance test. The individuals were then divided into four groups: normal weight, overweight, obese but still sensitive to insulin and obese with insulin resistance.
Those in the overweight and obese groups had more total body and visceral fat than those at a normal weight, and there was no difference between obese groups.
However, obese individuals with insulin resistance had more fat within their skeletal muscles and their livers than obese individuals without insulin resistance. In addition, those who were insulin-resistant had thicker walls in their carotid arteries, an early sign of atherosclerosis (narrowing of the arteries, a heart disease risk factor).
Individuals in the obese–insulin sensitive group did not differ from the normal-weight group in insulin sensitivity or artery wall thickness, the authors note.
"In conclusion, we provide evidence that a metabolically benign obesity can be identified and that it may protect from insulin resistance and atherosclerosis," they write. "Furthermore, our data suggest that ectopic [misplaced] fat accumulation in the liver may be more important than visceral fat in the determination of such a beneficial phenotype in obesity."
In a second study, Rachel P. Wildman, Ph.D., of the Albert Einstein College of Medicine, Bronx, N.Y., and colleagues assessed body weight and cardiometabolic abnormalities (including high blood pressure, elevated triglycerides and low high-density lipoprotein or "good" cholesterol) in 5,440 individuals participating in the National Health and Nutritional Examination Surveys between 1999 and 2004.
Participants were considered metabolically healthy if they had none or one abnormality and metabolically abnormal if they had two or more abnormalities.
"Among U.S. adults 20 years and older, 23.5 percent (approximately 16.3 million adults) of normal-weight adults were metabolically abnormal, whereas 51.3 percent (approximately 35.9 million adults) of overweight adults and 31.7 percent (approximately 19.5 million adults) of obese adults were metabolically healthy," the authors write.
Normal-weight individuals with metabolic abnormalities tended to be older, less physically active and have larger waists than healthy normal-weight individuals. Obese individuals with no metabolic abnormalities were more likely to be younger, black, more physically active and have smaller waists than those with metabolic risk factors.
"These data show that a considerable proportion of overweight and obese U.S. adults are metabolically healthy, whereas a considerable proportion of normal-weight adults express a clustering of cardiometabolic abnormalities," the authors write.
"Further studies into the behavioral, hormonal or biochemical and genetic mechanisms underlying these differential metabolic responses to body size are needed and will likely further the identification of possible obesity intervention targets and improve cardiovascular disease screening tools."
My extra notes: I guess no one knows why this is so.
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Untreated Sleep-Disordered Breathing (SDB) May Triple Risk for Mortality
Author: Laurie Barclay, MD
: Désirée Lie, MD, MSEd
August 1, 2008 — An 18-year follow-up study finds that untreated sleep-disordered breathing (SDB) increases the risk for mortality 3-fold, according to the results of a study reported in the August 1 issue of Sleep.
"...SDB is a treatable but markedly under-diagnosed condition of frequent breathing pauses during sleep," write Terry Young, PhD, from the University of Wisconsin-Madison, and colleagues.
"SDB is linked to incident cardiovascular disease, stroke, and other morbidity. However, the risk of mortality with untreated SDB, determined by polysomnography screening, in the general population has not been established."
The study cohort for this 18-year mortality follow-up study was the population-based Wisconsin Sleep Cohort sample (n = 1522).
Participants had baseline polysomnography to detect SDB, which was characterized by the number of apnea and hypopnea episodes per hour of sleep. Cutoff points at 5, 15, and 30 episodes per hour of sleep identified mild, moderate, and severe SDB, respectively.
All-cause and cardiovascular mortality risks associated with SDB severity levels, after adjustment for potential confounding factors, were estimated with use of Cox proportional hazards regression.
After adjustment for age, sex, body mass index, and other clinical variables, the risk for all-cause mortality significantly increased with SDB severity.
For severe SDB vs no SDB, the adjusted hazard ratio (HR) for all-cause mortality was 3.0 (95% confidence interval [CI], 1.4 - 6.3).
When persons who had been treated with continuous positive airway pressure (CPAP; n = 126) were excluded, the adjusted HR for all-cause mortality with severe SDB vs no SDB was 3.8 (95% CI, 1.6 - 9.0), and the adjusted HR for cardiovascular mortality was 5.2 (95% CI, 1.4 - 19.2). Accounting for daytime sleepiness did not change these results.
"Our findings of a significant, high mortality risk with untreated SDB, independent of age, sex, and BMI [body mass index] underscore the need for heightened clinical recognition and treatment of SDB, indicated by frequent episodes of apnea and hypopnea, irrespective of symptoms of sleepiness," the study authors write.
Limitations of this study include lack of information on consistent CPAP use with time or effectiveness of air pressure level to prevent airway closure, lack of randomization, inability to determine how CPAP contributes to lower death rates, inability to determine how long participants had SDB before their baseline study, and cohort 95% white and all employed at recruitment.
"Although further studies are needed to quantify the proportion of mortality that could be lowered by prevention or treatment of SDB, the results of our study can be applied directly to current health care practice," the study authors conclude.
The National Institutes of Health supported this study. The study authors have disclosed no relevant financial relationships.
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