RxPG News : CHF

New technology to identify compounds that triggers heart failure

Sat, 28 Nov 2009 13:52:27 PST

( from http://www.rxpgnews.com ) A breakthrough will help identify compounds implicated in heart failure more rapidly, says a new study.

The technology, developed by University of Minnesota's David Thomas and Razvan Cornea and Celladon Corporation's Krisztina Zsebo, allows for quicker screening of compounds linked with proteins implicated in heart failure.

Chronic heart failure is the leading medical cause of hospitalisation and is expected to cost the US healthcare system $ 37.2 billion in 2009 alone.

About 5.7 million people in the US have heart failure, and it contributes to or causes some 290,000 deaths annually.

Fluorescence resonance energy transfer - is used to measure disruption of the calcium regulatory system, which has long been implicated in cardiovascular disease.

This will provide key information on a particular drugs' likelihood of success early in the screening process.

'Dr. Cornea and I, along with our students, have worked for more than a decade developing methods for preparing membranes from purified components, and using FRET to detect changes in protein interactions,' Thomas said, according to a Minnesota release.

'Scientists from Celladon saw the potential for drug discovery, and this resulted in a breakthrough that has added an exciting new dimension to our research programme.'

However, developing new treatments is an extremely costly and time-consuming process, taking nearly a decade to gain regulatory approval and requiring hundreds of millions of dollars, the release added.

Arousal disorder in patients with cardiac failure?

Thu, 01 Jan 2009 12:13:10 PST

( from http://www.rxpgnews.com ) A study in the Jan. 1 issue of the journal Sleep demonstrates that the frequent arousals from sleep that occur in heart failure patients with central sleep apnoea (CSA) may reflect the presence of another underlying arousal disorder rather than being a defensive mechanism to terminate apnoeas.

Principal investigator, Douglas Bradley, professor of medicine at the University of Toronto said that researchers involved in the study were surprised that using CPAP to alleviate CSA had no effect on arousals and no effect on sleep structure.

Bradley said, "These results indicate that unlike OSA, arousals from sleep in CSA are not protective, but probably have the opposite effect: they appear to be causative. This finding suggests that future studies should explore preventing arousals from sleep in order to treat CSA."

Results indicate that after three months of treatment with continuous positive airway pressure (CPAP) therapy, heart failure patients with CSA show no significant improvement in the frequency of their arousals or in their sleep structure even though breathing pauses are significantly reduced by 55 percent from 35.4 central apneas and hypopnoeas per hour to 16.1 events per hour. Arousals remain high (24.3 arousals per hour on CPAP compared to 28.8 at baseline), total sleep time stays the same at 318 minutes, and sleep efficiency remains low at 70 percent.

Data were analyzed from 205 heart failure patients with CSA who were enrolled in the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnoea and Heart Failure trial, a prospective, randomized, multicenter clinical trial. Participants were between 18 and 79 years of age, and they were randomly assigned to a CPAP treatment group (97 members) or a control group (108 members). CSA was defined as an apnoea-hypopnoea index (AHI) of 15 or more with more than 50 percent of apneas and hypopneas central in nature. Members of both groups were assessed by overnight polysomnography at baseline and again after three months. Participants in the treatment group were instructed to use CPAP nightly for six or more hours, and their actual usage time was 4.6 hours per day.

According to the authors, arousals in patients with obstructive sleep apnoea (OSA) are considered to be an important defense mechanism to terminate apnoeas, and treating OSA with CPAP immediately reduces the frequency of arousals. In contrast, arousals in heart failure patients with CSA often occur several breaths after apnoea termination.

The authors suggest that hear failure patients with CSA may have a "predisposition to hyperarousability," and in some there may be an underlying arousal disorder accompanied by sleep disruption that is neither a consequence of CSA nor of impaired cardiac function. In heart failure patients with CSA, arousal from sleep may be incidental to, or play a causative role in, the development of CSA by rendering the respiratory control system unstable. Thus factors other than sleep apnoea such as pulmonary congestion during the night, other comorbidities, or medications, may explain the frequent arousals that heart failure patients experience.

Exercise improves life for heart failure patients

Sun, 16 Nov 2008 11:31:16 PST

( from http://www.rxpgnews.com ) Washington, Nov 13 - Heart failure patients who regularly exercised felt better than similar patients who did not work out regularly, say Duke University Medical Centre researchers after a new study.

These findings go a long way toward addressing concerns about the value of exercise for the five million patients in the US with heart failure.

'The HF-ACTION study shows that exercise is not only safe for patients, but also helps to improve the quality of their lives, overall,' said Kathryn Flynn, researcher at Duke Clinical Research Institute - and co-author of the study.

HF-ACTION is the largest clinical trial to date examining the value of exercise in the treatment of heart failure. Investigators enrolled 2,331 patients with moderate to severe heart failure at 82 sites throughout the US, Canada and France from 2003 to 2008.

The regimen consisted of three months of supervised aerobic training on a bicycle or treadmill, followed by instruction for continued home-based training, according to a Duke release.

Researchers set the exercise goal at five 40-minute workouts, or 200 minutes of exercise per week. Participants reached about 60 percent of that goal after one year.

Participants had significant heart failure upon entering the study. Ninety-five percent were taking medications for heart failure, such as ACE-inhibitors or beta-blockers, and 40 percent were using mechanical devices to boost their hearts' ability to pump or to treat arrythmias -.

The average age of the patients was 59 while 28 percent were women.

Upon enrolment, patients filled out the Kansas City Cardiomyopathy Questionnaire -, a 23-item measure shown to be responsive to underlying clinical changes in patients with heart failure.

At three months, patients in both groups showed improvement, with patients in the usual care group registering a three-point gain on the KCCQ score and those in the exercise group showing a five-point gain. Previous reports had defined a five-point gain as clinically significant.

Researchers also found that a higher percentage of those in the exercise group experienced more robust gains. At three months, 54 percent of those in the exercise group saw a five-point gain in overall KCCQ score, while only 28 percent of those in the usual care group met that goal.

These findings were presented at the annual meeting of the American Heart Association's Scientific Sessions 2008.

Gene therapy trial for advanced heart failure promising

Wed, 12 Nov 2008 13:29:06 PST

( from http://www.rxpgnews.com ) Washington, Nov 11 - The first clinical trial of gene therapy for advanced heart failure has shown promising results.

It is a technique for correcting defective genes responsible for the disease by inserting genes into a patient's cells and tissues.

Seven of nine patients given the drug showed improvements over six months in several areas. Two patients did not show improvements.

This approach under CUPID's phase-I trials was shown to have an acceptable safety profile, validated by an independent safety committee and by study investigators.

CUPID stands for calcium up-regulation by percutaneous administration of gene therapy in cardiac disease.

Enrolled patients underwent cardiac catheterisation, to introduce an engineered gene to stimulate enzyme production to help the heart pump more efficiently.

'We are encouraged that this therapy has the potential to help patients with advanced heart failure,' said Donna Mancini, the study's principal investigator and professor of medicine at Columbia University.

More than five million people in the US have heart failure. Patients with severe form of the disease have trouble breathing because the heart muscle is not strong enough to pump fluid out of their lungs.

Approximately 70 percent die of the disease within 10 years, and the five-year survival rate is less than 50 percent.

New York-Presbyterian Hospital / Columbia University Medical Centre was the first to offer the therapy in the New York City area.

The hospital is now recruiting 46 patients for the Phase II CUPID trial to further assess safety and effectiveness in patients with advanced heart failure, said a Columbia press release.

The phase-II randomized, double-blind, placebo-controlled clinical trial will compare the therapy at two- or three-dose levels with placebo.

Data from Phase I trial were presented at the American Heart Association - Scientific Sessions in New Orleans.

Longer anthracycline therapy reduces heart failure in adult cancer patients

Wed, 22 Nov 2006 23:33:20 PST

( from http://www.rxpgnews.com ) Stretching out a dose of chemotherapy over six or more hours may reduce the risk of heart problems caused by certain commonly used cancer drugs, according to a new review of recent research.

Anthracycline drugs like daunorubicin and doxorubicin are used to treat many types of solid tumors and blood cancers such as leukemias in adults and children.

Anthracycline therapy can be very successful at controlling cancer, but heart damage caused by anthracycline treatment “is a considerable and serious problem,” said Dr. Elvira van Dalen of the Emma Children’s Hospital in the Netherlands.

She and her colleagues found that the rates of heart failure among adult patients receiving anthracycline therapy were significantly lower when the patients had an infusion of the drug that lasted six or more hours, compared to shorter infusions times.

In five studies involving 557 patients, the longer treatment cut the risk of heart failure by nearly 75 percent compared to the risk in patients who received the short treatment.

van Dalen said the prolonged dose of six hours or more “might be justified” if a patient is at high risk of heart damage or needs a high cumulative dose of the chemotherapy.

The review appears in the latest issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

In some of the studies, the prolonged dose also reduced the risk of less severe problems such as weakened heart function. Patients had the same chance of survival and tumor shrinkage whether they received the long or short therapies, the Cochrane researchers found.

“It should be emphasized that the majority of the patients included in these studies were adults with advanced solid tumors,” van Dalen and colleagues said, noting that there are few good studies about the length of anthracycline treatment in children.

Among the children in the study, there was no difference in heart damage between the long and short treatments “and no information on survival and tumor shrinkage was available,” van Dalen said.

Recent studies have shown that the toxic heart effects of anthracycline therapy can have lasting effects on children’s health. Dr. Stephen Lipshulz, a pediatric cancer specialist at the University of Miami, said childhood cancer survivors “may be at significant risk of serious cardiovascular problems at a much younger age," than researchers believed a few years ago.

Lipshulz’s work suggests many childhood cancer survivors suffer from enlarged hearts and prematurely hardened arteries, due at least in part from their chemotherapy. “It’s alarming that we’ve found such dramatic heart damage and blood vessel risk in some survivors who are just 10 or 15 years from treatment,” he said.

Seven-point system gauges seriousness of heart failure in elderly

Fri, 10 Nov 2006 17:05:37 PST

( from http://www.rxpgnews.com ) A simple points system may soon help guide treatment of elderly heart failure patients. Researchers at Washington University School of Medicine in St. Louis found that by counting how many of seven easy-to-obtain health factors a patient has, physicians can estimate the patient's risk of dying.

The points system may steer doctors toward considering more aggressive treatments such as implantable defibrillators and pacemakers for those at low risk of death. However, elderly patients with a high risk may want to avoid stressful and unnecessary medical intervention and may benefit most from palliative or hospice care.

"It has typically been very difficult to predict how long a person hospitalized with heart failure may survive," says senior author Michael W. Rich, M.D., associate professor of medicine and a geriatric cardiologist at Barnes-Jewish Hospital. "That has made it hard for the treating physician to know how aggressive to be with therapy."

Heart failure afflicts about 5 million people in the United States, hospitalizing more than a million patients each year. The incidence of heart failure increases with age, and with people 65 and older becoming the fastest growing segment of the population, the personal and financial burden of heart failure will likely increase.

In their study, which followed 282 elderly heart failure patients for up to 14 years, the researchers identified seven factors that most affect patient survival:

* advanced age
* a history of dementia (contributes to a host of conditions related to the inability to properly care for oneself)
* coronary artery disease (arteries that supply blood to the heart muscle are hardened and narrowed)
* peripheral vascular disease (similar to coronary artery disease but involving blood vessels outside of the heart and brain)
* low sodium in the blood (an indication of neurohormonal imbalance)
* high urea in the blood (a reflection of poor cardiac output that affects kidney function)
* low blood pressure (a result of weakened heart function).

The study, published in the September 25th issue of the Archives of Internal Medicine, showed that patients with four or more of the risk factors had a low probability of surviving longer than six months. But if patients had none or just one of the factors, they had a good chance of living five years or more. Patients with two to three factors were likely to live at least a year. The patients in the study received a variety of treatments as determined by their physicians.

"The system is easy to use, and the variables don't require any specialized testing -- they are part of routine medical histories or basic lab tests," Rich says. "If the system can be validated by further studies, it can play a role in helping physicians tailor care to individual patients. If a person has a limited life expectancy, it may not be in his or her best interest to recommend invasive, uncomfortable or risky procedures. On the other hand, an elderly person with only one risk factor could potentially be considered a good candidate for an aggressive treatment such as a defibrillator."

Other factors that might have been expected to affect survival, such as the amount of blood the heart can eject during pumping or a patient's body mass index, didn't seem to influence survival times. Rich emphasizes that each of the factors identified has been linked in previous studies to poor prognosis in heart failure patients.

"We didn't find any new risk factors, which means there's good data to support that these factors truly are predictive," Rich says. "We've pinpointed the seven that are the most predictive and shown that the number of risk factors can give a reasonable estimate of the probability of living for six, 12 or 60 months."

The researchers next aim to better identify the heart failure patients not likely to survive six months so that they can be referred for hospice care.

"Hospice is very nurturing for both patients and family members," Rich says. "There is considerable evidence that patients derive significant benefit from it. If we can predict mortality within six months, we can more easily establish eligibility for hospice care."

Famotidine may help to slow progression of chronic heart failure

Wed, 27 Sep 2006 00:21:37 PST

( from http://www.rxpgnews.com ) An over-the-counter medication used to treat heartburn and acid reflux also appears to help decrease the debilitating effects of chronic heart failure, preliminary research shows. But more testing must be done before the drug is recommended for use by heart failure patients, doctors say.

According to the research, the same type of chemical reaction that allows stomach acid to cause heartburn and create ulcers also appears to damage and weaken diseased hearts. Blocking this process with the drug famotidine (Pepcid) may help to slow the progression of chronic heart failure (CHF).

The research, conducted by the National Cardiovascular Center in Suitra, Japan, appears in the Oct. 3, 2006 edition of the Journal of the American College of Cardiology. Lead researcher Masafumi Kitakaze, MD, PhD, said although the initial results look promising, more research is needed.

"We performed the present prospective study with only 50 CHF patients," said Dr. Kitakaze, director of the Cardiovascular Division and vice president of the Research and Clinical Center at the National Cardiovascular Center. "Now we need to conduct a large-scale trial to confirm the present findings. The large-scale trial based on the results our present research may not help current heart failure patients because it takes time, but we hope it helps our children and grandchildren and others in the future."

Gary Francis, MD, did not participate in the research, but is a cardiologist and heart failure expert at Ohio's Cleveland Clinic. He, too, cautions that the benefits of famotidine for CHF patients remain unclear.

"At this point, we don't know whether it would help," said Dr. Francis, head of the Section of Clinical Cardiology at Cleveland Clinic. "In addition, there is an expense involved, and we're not certain what the dose should be or what the safety would be of larger doses if they were necessary.

"I certainly would not recommend that patients go out and start taking Pepcid three times a day or anything like that," he said.

Still, the research is important because it opens a new avenue of study in the ongoing effort to treat chronic heart failure, said Dr. Francis, who co-wrote an editorial that will be published in conjunction with Dr. Kitakaze's research. Heart failure, which affects an estimated 23 million people worldwide, occurs when the heart is unable to pump as effectively as it should, resulting in shortness of breath, swelling in the legs and ankles, and other health issues.

For the current study, Dr. Kitakaze and his colleagues at Japan's National Cardiovascular Center began with a unique hypothesis. Based on previous research, they speculated that blocking the effects of a specific chemical released by damaged heart cells would slow the development of heart failure. This chemical, one of several types of histamines produced by the body, also contributes to chronic heartburn and stomach ulcers. Famotidine is a histamine blocker, which prevents the chemical from binding to its receptor and causing problems.

To prove their theory, the researchers began by searching existing medical data for patients being treated for both chronic heart failure and gastroesophageal reflux disease (GERD). As suspected, the patients taking famotidine for their stomach problems seemed to have less-severe heart failure symptoms than patients using other types of stomach remedies. But could heart health really be linked to a stomach medication?

To find out, the researchers designed a prospective study in which 25 patients with both medical conditions were given famotidine and 25 patients were given an alternate heartburn medication called teprenone. (Instead of blocking histamine, this second medication works by causing the stomach to secret more mucous to coat and protect itself against excess acid.)

After 24 weeks, Dr. Kitakaze and his colleagues discovered that as hypothesized those patients receiving 30 mg doses of famotidine each day were displaying less-severe symptoms of chronic heart failure. All patients were examined by three independent cardiologists who were unaware of the treatment protocols to ensure unbiased results.

Ilk gene underlies heart failure

Sat, 19 Aug 2006 21:34:37 PST

( from http://www.rxpgnews.com ) Two independent papers in the September 1 issue of G&D reveal a critical role for the ILK protein in regulating cardiac contractility identifying a new genetic component of heart disease.

Congestive heart failure affects 2-3 million people in the United States annually. A large portion of congestive heart failure cases is caused by a condition known as cardiomyopathy. Cardiomyopathy is a mostly genetic disease of the heart muscle that causes the heart to become enlarged, and to pump less efficiently.

Independent research groups from the labs of Drs. William J. Muller (McGill University) and Wolfgang Rottbauer (University of Heidelberg) demonstrate that the ILK protein is integral to the heart's ability to adapt its force of contraction to meet the body's changing needs for oxygenated blood.

Dr. Rottbauer explains that, "The work reported here suggests for the first time that ILK and some of its binding partners are essential components of the cardiac mechanical stretch sensor, dysfunction of which is suspected to be responsible for a significant proportion of human heart failure."

ILK, or integrin-linked protein kinase, is a component of the integrin signaling pathway, which recognizes changes in the extracellular environment and sends signals within the cell to affect an appropriate cellular response. In particular, integrins direct the assembly of actin-based adhesion structures to propagate cellular forces, and are thus essential for cell migration, growth, and survival.

Using two different animal model systems, Drs. Muller and Rottbauer show that loss of ILK in heart cells results in cardiomyopathy and heart failure. Lead author Donald White, a post-doctoral fellow in Dr. Muller's lab emphasizes that, "The fact that ILK plays such a critical role in cardiac physiology in such different organisms is undoubtedly exciting. It reinforces the central importance of this molecule in such a vital physiological process."

Dr. Muller adds: "Our collaborators at the Montreal Heart Institute, Montreal's Shriners' Hospital and the BC Cancer Agency have really played a critical role in helping us understand the role of ILK in cardiac physiology. We hope that our work will provide an ideal model for testing therapeutic strategies for heart disease, including exciting new approaches involving the use of stem cells to repair damaged heart tissue."

Nocturnal Hypertension Increase Congestive Heart Failure Risk

Thu, 29 Jun 2006 02:51:37 PST

( from http://www.rxpgnews.com ) Having a relatively high blood pressure level at night may increase the risk for congestive heart failure, according to a study in the June 28 issue of JAMA.

Congestive heart failure (CHF) is one of the most common, costly, disabling, and deadly diseases. Once diagnosed as having CHF, patients have a 1 in 3 chance of dying within 1 year and a 2 in 3 chance of dying within 5 years, according to background information in the article. The death rate associated with CHF exceeds that of most cancers, although recent reports suggest an improving prognosis. The predominant causes of CHF are hypertension and coronary heart disease, and high blood pressure (BP) is suggested to be the most important risk factor for CHF. Previous studies have established that 24-hour BP measurements, which provide information that is not obtained from conventional office-based BP measurement, such as average BP over a 24-hour period and night-day patterns, are powerful predictors of cardiovascular illness and death. However, no previous studies have examined 24-hour ambulatory (as opposed to office-measured) BP as a predictor of CHF in persons free of CHF at baseline.

Erik Ingelsson, M.D., Ph.D., of Uppsala University, Uppsala, Sweden, and colleagues analyzed BP characteristics of 951 elderly men, free of CHF, valvular disease, and left ventricular hypertrophy at baseline between 1990 and 1995. They followed the participants until the end of 2002. Twenty-four-hour ambulatory blood pressure monitoring was performed at baseline, and the blood pressure variables were analyzed as predictors of subsequent CHF.

Seventy men developed heart failure during follow-up. In analysis adjusted for antihypertensive treatment and established risk factors for CHF (heart attack, diabetes, smoking, body mass index, and serum cholesterol level), a 9mm Hg increase in nighttime ambulatory diastolic blood pressure and the presence of nondipping blood pressure (BP that is at least as high at night as during the day) were associated with an increased risk of CHF. Nighttime ambulatory diastolic blood pressure and nondipping blood pressure were also significant predictors of CHF after excluding all participants who had a heart attack before baseline or during follow-up.

Furthermore, a nondipping nighttime BP pattern increased the risk of CHF even after adjusting for conventional office BP measurement. This indicates that nighttime BP patterns may be important in development of CHF and that a traditional office BP measurement does not capture all of the increased risk that an increased nighttime BP conveys, the authors write.

Nighttime BP appears to convey additive risk information about CHF, but its clinical value remains to be established in future studies.

Gender-based differences seen in predictive value of exercise test results of heart failure patients

Sat, 03 Jun 2006 09:11:37 PST

( from http://www.rxpgnews.com ) Peak oxygen consumption during an exercise test is one of the key criteria used to determine when a heart failure patient may need a heart transplant, but the standard values currently used may not accurately predict outcomes for female patients, according to a new study in the June 6, 2006, issue of the Journal of the American College of Cardiology.

"There is some fundamental difference between the genders and we have to be sensitive to that," said Andrew Kao, M.D., F.A.C.C. Dr. Kao was at the University of Pennsylvania School of Medicine in Philadelphia at the time of this study. He is now with Cardiovascular Consultants, PA, which manages the Mid-America Heart Institute in Kansas City, Missouri.

Peak oxygen consumption (VO2) is a powerful and reliable predictor of survival in patients with advanced heart failure. If a patient who is working hard on the treadmill is consuming less than about 12 milliliters of oxygen per kilogram of body weight per minute (ml/kg/min), then the odds of long-term survival may be poor and it is generally thought to be appropriate to consider heart transplantation, Dr. Kao said.

However, the VO2 standards are based on the experiences of patients who were almost all men.

"Most of us in tertiary referral centers end up seeing mostly men, and so the reports that come out are mostly on men. We took this opportunity to go back and look at all of our heart failure patients, both men and women." Dr. Kao said. The researchers, including first author Sammy Elmariah, M.D., from the University of Pennsylvania School of Medicine, reviewed the records of 594 heart failure patients who took treadmill exercise tests at the University of Pennsylvania's Heart Failure and Transplant Ambulatory Care Center between July 2000 and December 2003. They found that on average women had significantly lower peak VO2 compared to men, despite adjusting for their body size. However, women had better survival rates than men. The researchers correlated the peak VO2 results from those tests with the survival and heart transplant data for the patients up until June 30, 2004. They wanted to determine what VO2 test results predicted an 85 percent chance of surviving at least one year without needing a heart transplant. This survival rate would be equivalent to the expected one-year survival after heart transplantation.

"When we did that, we found that for men, the VO2 result was 11.5, which is really very close to the 12 that has been reported in the literature recently; but surprisingly, in women, because they do have both lower exercise capacity as well as better survival, we found that they would not have benefited from transplant until their VO2 level was less than 10," he said.

To put it another way, the women in this study had better one-year survival rates than men for any given VO2 level, so over-reliance on VO2 test results might lead clinicians to think their female heart failure patients are sicker than they really are, perhaps leading them to consider heart transplantation earlier than necessary.

Dr. Kao noted that women are smaller and have less muscle mass on average than men, but that difference did not fully explain why the relationship between exercise test results and one-year survival is different for female and male heart failure patients.

"At this time we don't have a really good answer. What we do want people to be aware of is that they shouldn't just use the same criteria for everyone, because you may end up transplanting women too early," he said.

Dr. Kao stressed that the results of this initial study need to be confirmed in a larger study. Also, he pointed out that physicians look at many factors other than VO2 test results before deciding whether a patient would benefit from a heart transplant.

He cautioned physicians against changing their clinical practice based on this single report.

"We're not trying to do that. We're just trying to raise awareness that men and women heart failure patients may have different outcomes. If physicians see someone who has a low VO2 value, but the clinical judgment is that they are stable clinically, they should perhaps use this new information to help them say that maybe their initial impression was right," Dr. Kao said.

David Feldman, M.D., Ph.D., F.A.C.C. from Ohio State University in Columbus, Ohio, wrote an editorial in the journal that said this study brings forward "a provocative and potentially contentious idea--that men and women are not the same and should be treated differently." He cautioned that the characteristics of this study and the lack of an explanation for such gender differences make the results "an observation, not an irrefutable fact."

"I would make the following points: one, for any level of functional capacity, women with heart failure may survive longer then men and, two, this study is not definitive and until confirmatory evidence is available, women and men should be treated the same," Dr. Feldman said.

Training program may reverse underlying abnormalities in heart failure more effectively than drug treatment

Fri, 28 Apr 2006 01:30:37 PST

( from http://www.rxpgnews.com ) Aerobic training is associated with a reversal of abnormal hormonal patterns that underlie many of the debilitating symptoms of heart failure, according to a new study in the May 2, 2006, issue of the Journal of the American College of Cardiology.

"A feasible home-based and progressively adjusted aerobic training strategy is able to overcome the limitation of pharmacological treatment in antagonizing neurohormonal activation in heart failure patients, likely contributing to a significant improvement in quality of life, and possibly to the positive prognostic effects," said Claudio Passino, M.D. from the CNR Institute of Clinical Physiology in Pisa, Italy.

It is well-known that exercise training helps many heart failure patients feel better and improves their ability to function more normally. This study indicates that aerobic training may produce these benefits by reversing the abnormal production of certain neurohormones that result in many of the severe symptoms of heart failure.

After a heart attack or other cardiac event, the body responds by increasing the production of B-type natriuretic peptide (BNP). This neurohormonal activation, as it is called, helps the heart continue to pump blood in the short run by constricting blood vessel and retaining sodium in cardiac cells.

"This neurohormonal imbalance becomes detrimental on the long-term, promoting left ventricular fibrosis, dilatation, arrhythmias, peripheral tissue hypoperfusion, edemas, and thus leading to a symptomatic disease with dyspnea and fatigue," Dr. Passino said.

Previous studies indicated that patients with higher levels of B-type natriuretic peptide have poorer prognoses. Drug treatments are often unable to adequately reverse the neurohormonal activation.

Since physical activity often helps heart failure patients, the researchers wanted to find out what effect aerobic training has on the neurohormonal imbalance. They randomized heart failure patients into two groups. The treatment group consisted of 47 patients who entered a nine-month aerobic training program that progressively increased the amount of work the patients were able to perform. The control group of 48 patients received standard heart failure treatments, but no physical training.

The 44 patients who completed the training program improved their fitness and said their quality of life was better than the 41 patients who completed the control group arm of the study. But in addition, the patients who worked out had decreased levels of three key hormones, B-type natriuretic peptide (BNP), amino-terminal pro-brain natriuretic peptide (NT-proBNP), and norepinephrine.

Dr. Passino said the results indicate that aerobic training may be able to restore neurohormonal balance in a way that may improve on current drug therapies.

"Reversing neurohormonal activation by physical training adds to the current clinical practice a novel non-pharmacological aid. Out of 85 patients who completed the protocol, only the 44 randomized to the training program improved functional capacity, systolic function, and quality of life, in contrast to the controls. These beneficial effects were associated with a decrease in plasma level of BNP, NT-proBNP, and norepinephrine, only in the training group," he said.

In addition, he said that the measurements of neurohormonal activation used in this study may be a useful way for physicians to assess the effect of training in their patients.

John Floras, M.D., D.Phil., F.R.C.P.C. from the University of Toronto in Canada, who was not connected with this study, said the results provide additional evidence of the benefits of exercise for selected heart failure patients, while offering fresh insight into how training works to provide those benefits.

"While an acute bout of exercise will lead to increases in both norepinephrine and BNP, with chronic training plasma concentrations of these factors diminish, suggesting that exercise training modulates beneficially activation of several neurohumoral pathways that reflect the severity of heart failure, and that following BNP concentrations may be one way of assuring that long term exercise training programs are having beneficial effects in individual patients. Pending is evidence from large randomized clinical trials that such short term changes will translate, over time, into mortality benefits for patients with chronic heart failure," Dr. Floras said.

Acetazolamide improves sleep apnea associated with heart failure

Wed, 18 Jan 2006 23:32:37 PST

( from http://www.rxpgnews.com ) Since sleep apnea is associated with heart failure, patients who take a single dose of acetazolamide--a mild diuretic and respiratory stimulant--before going to bed exhibit less sleep apnea, improved blood oxygen levels and fewer daytime symptoms of sleepiness.

The results of the double-blind, placebo-controlled study appear in the second issue for January 2006 of the American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.

Shahrokh Javaheri, M.D., of the Pulmonary Service in the Department of Veterans Affairs Medical Center and Department of Medicine at the University of Cincinnati College of Medicine in Cincinnati, Ohio, studied 12 male patients with stable heart failure who had more than 15 episodes per hour each night of sleep apnea (breathing pauses during sleep lasting 10 seconds or more.)

In heart failure, the quantity of blood pumped each minute by the heart is insufficient to meet the body's requirements for oxygen and nutrients.

In the past, acetazolamide's principal use has been to help treat breathing irregularities and sleep apneas occurring at high altitude.

According to the authors, the 12 patients with stable heart failure were randomized to a double-blind cross-over protocol with either acetazolamide or placebo, taken one hour before bedtime over the course of six nights. There was a two-week washout period between the two study segments--acetazolamide and placebo.

"An important finding of the double-blind study was the significant improvement in patient perception of improved sleep quality, waking up more refreshed, with less daytime fatigue and sleepiness while taking acetazolamide, compared with placebo," said Dr. Javaheri.

The average age of the patients was 66. There were no significant patient differences in body mass index levels, blood pressure or heart rate during the two phases of the study.

Each patient underwent a sleep test, an analysis of blood gases as well as a pH study (a test of acidity or alkalinity), a measurement of serum electrolytes, a pulmonary function test, plus other measurements at the start of the study and at the completion of each arm (acetazolamide and placebo).

"We hypothesize that with long-term drug therapy, as sleep-related breathing disorders improve, it may be reflected in an improvement in cardiac function that will further improve periodic breathing, resulting in a positive feedback cycle," said Dr. Javaheri. "Improvement in sleep apnea may assist cardiac function by a variety of mechanisms such as improved oxygenation."

The author points out that since the short-term efficacy of the drug has been documented, more long-term studies are needed to measure patient cardiac function, quality of life and the levels of norepinephrine in the plasma and urine. (Norepinephrine is a hormone used to maintain blood pressure and to treat cardiac arrest.)

NT-proBNP test results comparable to those of BNP blood test in patients with kidney disease

Thu, 15 Dec 2005 16:27:38 PST

( from http://www.rxpgnews.com ) A large-scale analysis has shown that a blood test previously found useful in diagnosing or ruling out heart failure in emergency room patients remains effective in patients with chronic kidney disease. The study also demonstrates that the test for a marker called NT-proBNP can identify patients at a higher risk for death, independent of kidney dysfunction. The report from investigators at the Massachusetts General Hospital (MGH) will appear in the January 3, 2006 Journal of the American College of Cardiology and is receiving early online release.

"It is well understood that kidney disease reduces the usefulness of testing for both NT-proBNP and a related biomarker called BNP, and the conventional understanding was that NT-proBNP was the more affected of the two," says James Januzzi Jr., MD, of the MGH Cardiology Division, the paper's senior author. "However, while kidney disease did lead to higher values of NT-proBNP in our study, what really matters is clinical performance; and at optimal cut-points, no matter how hard we looked, we found the relationship between chronic kidney disease and the diagnostic accuracy of NT-proBNP was no different than that of BNP. Our findings thus directly contradict observations based on smaller, less characterized patient populations."

Congestive heart failure, which occurs when an impaired heart muscle cannot pump blood efficiently, is a growing health problem and major cause of cardiac death. The diagnosis of heart failure may be challenging because its symptoms can overlap those of other conditions. Missing a heart failure diagnosis can put patients at high risk of serious problems, including death, but overdiagnosis may lead patients to receive unnecessary treatment.

Published earlier this year, the PRIDE study showed NT-proBNP to be highly sensitive and specific for the diagnosis of acute heart failure in patients with shortness of breath and to strongly predict patient deaths. A major concern about the widespread use of the marker had been previous assertions that kidney disease very common in patients with heart failure might confound the results of NT-proBNP testing, since levels of the marker were higher among those with reduced renal function.

Some researchers in the field argued that BNP was less affected by chronic kidney disease than was NT-proBNP. "We found no difference in our results when you examine them side-by-side with those for BNP," says Januzzi. "When you consider the data in totality, there just does not seem to be much difference between these two markers with respect to their diagnostic usefulness in patients with kidney disease. While kidney disease modestly reduces the diagnostic accuracy of both markers, when used in the appropriate manner, both tests appear to return identical information."

Besides the diagnostic value of NT-proBNP, the analysis evaluated the prospective value of NT-proBNP testing for predicting death within 60 days. "In fact, NT-proBNP measurement was an even stronger predictor of death in breathless patients with significant renal insufficiency, emphasizing the fact that the marker is likely detecting a true signal of cardiac disease in these patients," said Januzzi, an assistant professor of Medicine at Harvard Medical School. "This is a big step forward in the understanding of the optimal application of NT-proBNP measurement, as it removes one of the biggest obstacles that remained for the marker."

Moderate exercise may delay congestive heart failure

Sun, 11 Dec 2005 15:25:38 PST

( from http://www.rxpgnews.com ) A new University of Colorado at Boulder study involving laboratory rats that indicates low-intensity exercise may significantly delay the onset of congestive heart failure appears to have some promising implications for humans.

According to Professor Russell Moore of CU-Boulder's integrative physiology department who led the study, lab rats carrying the genetic characteristics for spontaneously developing heart failure were shown to live significantly longer if they exercised moderately on a treadmill. The exercise protocol, the equivalent of daily, leisurely strolls in humans, extended the life expectancy of the rat study group by at least 10 percent to 15 percent, according to the study.

"Assuming the results are applicable to humans, low-intensity exercise is likely to have benefits to humans in early stages of congestive heart failure," he said.

The study was published in the November 2005 issue of the American Journal of Physiology -- Heart and Circulatory Physiology. The study was co-authored by CU-Boulder doctoral student Craig Emter, Associate Professor Sylvia McCune, Research Associate Genevieve Sparagna and Ohio State University Professor Judith Radin.

"Our study, coupled with several human studies conducted elsewhere, shows a definite trend indicating that moderate intensity exercise has a potential role in stemming the downward spiral in heart failure," he said.

Moore said a unique feature of the CU-Boulder study was that the delay in the onset of CHF in the rats through moderate exercise was accomplished without reducing hypertension, or high blood pressure, in the animals. Most people in the early stages of development of heart failure also have hypertension, which is regularly treated to help improve the prognosis of CHF sufferers, said Moore.

Although several human studies in the last 10 to 20 years have shown that moderate exercise does not appear to harm CHF sufferers, the positive benefits of such exercise have not been found to be statistically significant, he said. Such studies are difficult to evaluate because participants often are taking a number of different medications, he said.

The intensity of exercise in the study was a crucial factor affecting longevity in the rats used in the study, said Moore. Early in the study, several of the rats that began exercising at nine months of age died after the locomotion speed was increased from 10 meters per minute to 17.5 meters per minute, he said. The speed was subsequently reduced to 14 meters per minute for the duration of the study, and no additional rat deaths occurred, he said.

"The bottom line is if the animals are exercised too hard, they will die," he said. "But when exercised moderately, in this case at barely more than a walk, the results were striking."

According to the American Heart Association, about 65 million Americans are afflicted with hypertension and nearly five million suffer from CHF. In addition, about 75 percent of patients diagnosed with CHF die within eight years. "This is the most costly health problem in the United States to manage and treat," Moore said.

Low-intensity exercise for patients diagnosed early with CHF could preclude the use of expensive drug therapies and their side effects until later in life, he said.

The rats used in the study were bred over generations to carry a genetic blueprint causing spontaneously hypertensive heart failure, or SHHF. Rats and humans share a large number of common genes and proteins, including many thought to be involved in heart disease, he said.

"The biggest issue still looming out there is which molecular switches govern healthy growth of hearts at the cellular level," said Moore. "The question is whether there are therapeutic ways to positive, as opposed to pathological, growth of the heart."

The study involved the work of four undergraduates, three of whom were participating in CU-Boulder's Undergraduate Research Opportunities Program, which has provided more than $5 million to almost 6,000 students since 1986.

Pulmonary artery catheter in critically ill has neutral effect

Thu, 06 Oct 2005 21:43:38 PST

( from http://www.rxpgnews.com ) A meta-analysis of previous studies indicates that use of a pulmonary artery catheter in critically ill patients neither increases risk of death or hospital stay or adds benefit, according to another article in this issue of JAMA.

The PAC is used to diagnose various diseases and physiological states, monitor the progress of critically ill patients, and guide the selection and adjustment of medical therapy, according to background information in the article. The PAC is often considered a cornerstone of critical care and a hallmark of the intensive care unit (ICU). Approximately 1 million PACs are used annually in the United States. However, despite widespread use of these devices, there is conflicting data about their effectiveness, and whether they increase risk of illness and death. Since the mid-1980s, randomized clinical trials (RCTs) have been conducted to evaluate the efficacy of the PAC. However, none of these trials have been persuasive individually, because they are limited by small sample sizes in heterogeneous populations. Despite the overwhelmingly negative outcomes of the literature, clinicians continue to use the PAC in ICUs based on personal experience and the belief that careful monitoring will improve decision making and clinical outcomes.

Monica R. Shah, M.D., M.H.S., of Columbia University Medical Center, New York, and colleagues performed a meta-analysis of recently published clinical trials testing the safety and efficacy of the PAC. The researchers located the RCTs, in which patients were randomly assigned to PAC or no PAC, from several databases. Eligible studies included patients who were undergoing surgery, in the ICU, admitted with advanced heart failure, or diagnosed with acute respiratory distress syndrome and/or sepsis; and studies that reported death and the number of days hospitalized or the number of days in the ICU as outcome measures. The researchers found 13 RCTs that included 5,051 patients.

"Our meta-analysis of 13 RCTs evaluating the safety and efficacy of the PAC demonstrates that use of the catheter neither improves outcomes in critically ill patients nor increases mortality or days in hospital. This provides a broader confirmation of the recent results of the ESCAPE trial, which showed that the routine use of the PAC in patients with advanced heart failure did not reduce or increase death or days in hospital," the authors write.

"During the past 60 years, the PAC has evolved from a simple diagnostic tool to a device that is used for monitoring and determining goal-directed therapy. Our meta-analysis shows that despite the widespread acceptance of the PAC, use of this device across a variety of clinical circumstances in critically ill patients does not improve survival or decrease the number of days hospitalized. ... These results suggest that the PAC should not be used for the routine treatment of patients in the ICU, patients with decompensated heart failure, or patients undergoing surgery until or unless effective therapies can be found that improve outcomes when coupled with this diagnostic tool," the authors conclude.

In an accompanying editorial, Jesse B. Hall, M.D., of the University of Chicago, comments on the articles in this week's JAMA on PAC.

"What is the evidence for the broader issue of PAC use in the ICU and perioperative setting? The data collected to date certainly do not support routine use of the catheter in any patient group, and the currently available information could be viewed as justifying 'pulling the pulmonary artery catheter' from routine use, a suggestion made almost 10 years ago. One important additional trial is nearing completion and evaluates the use of PAC in patients with adult respiratory distress syndrome."

"Should there be a positive result attributable to PAC in this trial, a specific niche for this technology may remain in critical care. If the results of this soon-to-be-completed trial show no benefit of PAC monitoring, it is likely that the available data will indicate that it is time to remove the catheter from widespread use, or at the very least relegate this former common monitoring tool to salvage therapy of an extremely small and select number of patients. The need to question the routine use of this monitoring modality was quite real and the results of the last 5 years of study most valuable. Once again the community of critical care physicians has been edified by the approach of 'Don't just do something, stand there! And then think about it. ...'" Dr. Hall concludes.

ESCAPE Trial - No Benefit From Pulmonary Artery Catheterization In Severe Heart Failure

Thu, 06 Oct 2005 21:39:38 PST

( from http://www.rxpgnews.com ) Hospitalized patients with severe congestive heart failure did not experience a benefit from use of pulmonary artery catheterization, but had more adverse events, according to a study in the October 5 issue of JAMA.

Advances in medical therapy have improved outcomes for many ambulatory patients with heart failure and low ejection fraction (EF; a measure of how much blood the left ventricle of the heart pumps out with each contraction), according to background information in the article. However, each year an estimated 250,000 to 300,000 patients are hospitalized for heart failure with low EF, and the 1-year survival rate after hospitalization may be as low as 50 percent, even with recommended medical therapies. Recent studies have indicated that pulmonary artery catheters (PAC), a device used to monitor hemodynamic status and guide therapy, may increase the risk of death for hospitalized patients.

Lynne W. Stevenson, M.D., of Brigham and Women's Hospital, Boston, and colleagues with the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial, tested the hypothesis that for patients with severe heart failure, therapy guided by PAC monitoring and clinical assessment would lead to more days alive and fewer days hospitalized during 6 months compared with therapy guided by clinical assessment alone. The randomized controlled trial included 433 patients at 26 sites and was conducted from January 18, 2000, to November 17, 2003. Patients were assigned to receive clinical assessment and a PAC or clinical assessment alone. The primary goal in both groups was resolution of clinical congestion, with other targets based on levels of pulmonary artery and right atrial pressures.

The researchers found that therapy in both groups led to substantial reduction in symptoms, jugular venous pressure, and edema (swelling from fluid buildup). Use of the PAC did not significantly affect the primary end point of days alive and out of the hospital during the first 6 months (133 days vs. 135 days), death (43 patients [10 percent] vs. 38 patients [9 percent]), or the number of days hospitalized (8.7 vs. 8.3). In-hospital adverse events were more common among patients in the PAC group (47 [21.9 percent] vs. 25 [11.5 percent]). There were no deaths related to PAC use, and no difference for in-hospital plus 30-day mortality (10 [4.7 percent] vs. 11 [5.0 percent]). Exercise and quality of life end points improved in both groups with a trend toward greater improvement with the PAC, which reached significance for the time trade-off at all time points after randomization.

"Based on ESCAPE, there is no indication for routine use of PACs to adjust therapy during hospitalization for decompensation of long-term heart failure. It seems probable that there are some patients and some therapies that yield improved outcome with PAC monitoring and others with counterbalancing deleterious effects," the authors write. "For patients in whom signs and symptoms of congestion do not resolve with initial therapy, consideration of PAC monitoring at experienced sites appears reasonable if the information may guide further choices of therapy.

"The ESCAPE trial defined the most compromised patient population to be studied in an National Heart Lung Blood Institute heart failure trial with medical therapy, with 19 percent (83 patients) mortality at 6 months. No diagnostic test by itself will improve outcomes. New strategies should be developed to test both the interventions and the targets to which they should be tailored. Although most trials in a high-event population have focused on reducing mortality, patients with advanced heart failure express willingness to trade survival time for better health during the time remaining. How patients value their daily lives should help guide both the design and evaluation of new therapies," the authors conclude.

Ryanodine receptors (RyRs) malfunction in the failing heart

Tue, 20 Sep 2005 20:31:38 PST

( from http://www.rxpgnews.com ) A new study has identified a molecular defect in cardiac cells that may be a fundamental cause of heart failure, a progressive weakening of the heart that leaves the organ unable to pump blood through the body.

The findings, by researchers at the Ohio State University Dorothy M. Davis Heart and Lung Research Institute, show that specialized proteins called ryanodine receptors (RyRs) malfunction in the failing heart. The RyRs form channels that become leaky, leading to calcium imbalances that prevent the heart from contracting effectively and relaxing adequately. The condition worsens until the heart can no longer work as a pump.

The root causes of heart failure are not known.

We found some drastic changes in the way muscle cells in the failing heart handle calcium, says principal investigator Sandor Gyorke, professor of physiology and cell biology at the OSU Davis Heart and Lung Research Institute. Currently, the only way to correct heart failure is by heart transplantation.

From 1992 to 2002, deaths from heart failure rose 35 percent and the incidence is expected to keep rising.

Calcium plays a fundamental role in muscle contraction, particularly in heart muscle. A heart contraction begins when the heart's pacemaker sends an electrical signal to heart-muscle cells. The electrical signal triggers the release of calcium from a large storage site within each muscle cell. The released calcium activates the muscle cell's contractile machinery, which causes the cell, and the heart as a whole, to contract.

The delicate, membrane-bound walls of the SR are penetrated with thousands of RyR channels. The amount of calcium stored in the SR determines the strength of the heart beat and how much blood the heart ejects when it contracts.

Molecular pumps, also located in the walls of the SR, then suck the released calcium back into the SR to prepare for the next contraction.

For this study, the OSU investigators used microscopic fluorescence imaging techniques to monitor changes in calcium ion concentrations in the SR and other regions of individual isolated heart cells.

They found that in heart failure, the channels cannot close tightly after a contraction. This leaves too little calcium in the SR, so strong contrations are not possible, and too much calcium outside SR, so the muscle cells remain slightly contracted and the heart cannot fully relax.

As the condition worsens, the heart grows weaker as a pump.

GRK2 or beta-adrenergic kinase (ßARK1) is a Potential Biomarker for Heart Failure

Sat, 20 Aug 2005 16:54:38 PST

( from http://www.rxpgnews.com ) Signs of heart failure may be in the blood. Cardiac researchers at Jefferson Medical College have found an enzyme in the blood that could be a potential marker for heart failure.

A team of scientists led by Walter Koch, Ph.D., director of the Center for Translational Medicine in the Department of Medicine in Jefferson Medical College of Thomas Jefferson University in Philadelphia, previously showed that an enzyme called GRK2 or beta-adrenergic kinase (ßARK1) is critically important in heart function. It is increased in failing human hearts and contributes to the loss of the hearts contractile strength during the development of heart failure. Decreasing or inhibiting the enzyme reversed heart failure in laboratory tests.

Now, Dr. Koch, who is W.W. Smith Professor of Medicine at Jefferson Medical College, and his co-workers have shown, using tissue samples from heart failure patients, that they could track heart levels of GRK2 in the blood.

We can track levels of this kinase with a simple blood test, he says. It appears that consistent with the numerous animal studies we have done. When GRK2 is elevated in the blood, patients have more severe heart failure.

Its a potential biomarker for heart failure, he says.

The researchers reported their findings July 29 in an online article in advance of print in the European Heart Journal.

In the study, Dr. Kochs team compared tissue samples from a group of 24 patients in heart failure who needed transplants to 58 patients who were not as sick, though had various stages of left ventricular malfunction. They found that the sicker patients had higher levels of GRK2 in the heart and in the blood.

Dr. Koch would like to eventually perform large human trials to specifically look at levels of GRK2 to see if they can predict responses to drugs such as beta-blockers or other treatments for heart failure. We want to see in our proposed clinical trial if GRK2 can be a biomarker that can predict response to various therapies, he says. In animal models, weve shown that when we lower GRK2 levels, the animal does better. We think that if a drug lowers GRK2 levels, the patient should benefit.

According to Dr. Koch, researchers have known from animal studies that the expression of GRK2 appears to be regulated by hormones called catecholamines, which include norepinephrine and epinephrine, message-carrying neurotransmitters in the sympathetic nervous system.

In heart failure, the sympathetic nervous system is in overdrive, and levels of these hormones are high. Dr. Koch says that they probably are responsible for increasing GRK2 levels in the heart in heart failure. Circulating white blood cells and cardiac cells bathed in blood are both exposed to levels of these hormones, he explains.

In congestive heart failure, the beta-adrenergic receptor system fails to work properly. Such receptors drive the heart both by rate and force of contraction, Dr. Koch says.

One of the functions of GRK2 or beta-adrenergic kinase (ßARK1) is to turn off beta-adrenergic receptors. In heart failure, beta adrenergic receptor density is decreased, ßARK is increased and both together cause dysfunctional beta receptor signaling, Dr. Koch says. A failing heart then has little capacity to respond to exercise or stress because there are fewer receptors, and remaining receptors are more or less turned off.
Congestive heart failure affects nearly 5 million Americans, many of whom have poor long-term prognoses, despite recent therapeutic advances.

Cardiovascular problems interfere with exercise

Sat, 20 Aug 2005 16:44:38 PST

( from http://www.rxpgnews.com ) A UCLA imaging study revealed significant tissue loss in the regions of heart-failure patients' brains that regulate the autonomic nervous system, interfering with the cardiovascular system's ability to swiftly adapt to changes in blood pressure and heart rate.

The damage lies in the same brain areas showing changes in people suffering major depression, which may explain why many heart-failure patients are often depressed.

The brain damage could dramatically affect heart-failure patients' ability to exercise and lowers their overall quality of life. Clinically, the findings emphasize the need for:

(1) cardiologists to recognize that heart-failure patients suffer from a brain injury, as well as a heart injury, and

(2) that drugs or other therapies must be developed to cross the blood-brain barrier, prevent brain injury and boost brain function.

New Heart Failure Guidelines Support the Use of BiDil(R)

Thu, 18 Aug 2005 11:34:38 PST

( from http://www.rxpgnews.com ) Updated heart failure guidelines released on Tuesday by the of Cardiology (ACC) and the American Heart Association (AHA) support the combined use of isosorbide dinitrate and hydralazine, now available as a proprietary fixed-dose formulation known as BiDil(R) (isosorbide dinitrate/hydralazine hydrochloride), as an adjunct to current standard heart failure therapy for black patients. BiDil was recently approved by the U.S. Food and Drug Administration (FDA) and launched by NitroMed, Inc. in July 2005.

"NitroMed is pleased that these most prestigious groups in the heart failure community -- the ACC and the AHA -- have recognized the important role that BiDil therapy can play in treating heart failure in self-identified black patients," said Manuel Worcel, M.D., Chief Medical Officer of NitroMed. "We hope that the use of BiDil according to the new heart failure guidelines will contribute to improved outcomes for black heart failure patients, who face a disproportionate burden from this serious disease."

According to the 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult, the addition of the combination to standard medical therapy for heart failure, including ACE inhibitors and beta- blockers, is "reasonable and can be effective in blacks with New York Heart Association (NYHA) functional class III or IV heart failure."

Although not mandatory, these heart failure practice guidelines are made available to help physicians and health care professionals make clinical decisions by providing a range of generally accepted approaches for the prevention, diagnosis and management of the disease. According to ACC and AHA, the guidelines focus on defining practices that meet the needs of most heart failure patients, in most cases.

In citing the results of the African American Heart Failure Trial (A- HeFT), the new guidelines further validate the landmark trial conducted by NitroMed in conjunction with the Association of Black Cardiologists, Inc. In A-HeFT, BiDil, a proprietary fixed-dose combination of isosorbide dinitrate and hydralazine, was shown to decrease the risk of mortality by 43 percent, reduce the risk of first hospitalization for heart failure by 39 percent and improve patient-reported functional status for self-identified black patients when taken as adjunctive therapy with current standard heart failure therapies. The trial was halted early by the study's safety review board due to the significant survival benefit seen with the drug.

Although the mechanism underlying the beneficial effects of BiDil in the treatment of heart failure is not known, the guidelines noted that the benefits seen with this treatment may be related to an improvement in nitric oxide bioavailability.

The issuance of these important guidelines for the management of heart failure comes within months of BiDil's approval by the FDA. NitroMed officially launched BiDil on July 1 and commercial product is now available in pharmacies.

About the ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult

The newly updated set of practice guidelines were developed by an expert panel of the ACC and AHA to reflect the most recent scientific findings on heart failure and guide physicians in its evaluation and management. The guidelines were developed in collaboration with the of Chest Physicians and the International Society for Heart and Lung Transplantation.

About BiDil

BiDil is indicated for the treatment of heart failure as an adjunct to current standard therapy in self-identified black patients, to improve survival, prolong time to hospitalization for heart failure and improve patient-reported functional status. There is little experience in patients with New York Heart Association (NYHA) class IV heart failure. Most patients in the clinical trial supporting effectiveness, referred to as A-HeFT, received, in addition to BiDil or placebo, a loop diuretic, an angiotensin converting enzyme inhibitor or an angiotensin II receptor blocker, and a beta blocker, and many also received a cardiac glycoside or an aldosterone antagonist. BiDil is a fixed-dose combination of isosorbide dinitrate and hydralazine hydrochloride. While the exact mechanism of action underlying the beneficial effects of BiDil in the treatment of heart failure is unknown, it is known that isosorbide dinitrate is a vasodilator with effects on both arteries and veins. The dilator properties of nitrates result from the release of nitric oxide that leads to the relaxation of vascular smooth muscle. Hydralazine is an arterial vasodilator.

In A-HeFT, self-identified black patients taking BiDil in addition to current standard heart failure therapies experienced a significant 43 percent decrease in the risk of mortality (P=.012) (absolute mortality rate: BiDil, 6.2% vs. placebo, 10.2%), a 39 percent reduction in the risk of first hospitalization for heart failure (P less than .001) (absolute first hospitalization rate: BiDil, 16.4% vs. placebo, 24.4%) and a statistically significant improvement at most time points in response to the Minnesota Living with Heart Failure Questionnaire, which is a self-report of the patient's functional status, versus patients taking placebo in addition to current standard therapies.

BiDil treatment is orally-administered and is initiated at a dose of one tablet, three times per day, and may be increased to a maximum of two tablets, three times per day, based on patient tolerance. Adjustments to maximum dosage may occur in three to five days; however, adverse side effects, which may include headaches and dizziness, may require that some patients take more time to reach their highest tolerated dose.

Heart Failure Burden in Black Patients

Heart failure, or end-stage cardiovascular disease, affects approximately five million Americans, including an estimated 750,000 African Americans. Each year, over 550,000 people are diagnosed with heart failure for the first time, and there is no cure for this disease -- with more than 50 percent of patients dying within five years of diagnosis. With respect to heart failure, blacks are affected at a rate greater than that of the corresponding non-black population, presenting with the disease earlier and dying sooner. According to the Centers for Disease Control and Prevention (CDC), African Americans between the ages of 45 and 64 are 2.5 times more likely to die from heart failure than Caucasians in the same age range.

Important Safety Information

BiDil is contraindicated in patients who are allergic to organic nitrates. Augmentation of the vasodilatory effects of isosorbide dinitrate by phosphodiesterase inhibitors (e.g., Viagra(R)/RevatioTM, Levitra(R), Cialis(R)) could result in severe hypotension. Treatment with hydralazine may produce a clinical picture simulating systemic lupus erythematosus (SLE) including glomerulonephritis. If SLE-like symptoms occur, discontinuation of BiDil should be considered. Residua have been detected many years after discontinuation of hydralazine. Symptomatic hypotension may occur with even small doses of BiDil. BiDil should be used with caution in volume depleted or hypotensive patients. Hydralazine can cause tachycardia potentially leading to myocardial ischemia and anginal attacks. Hydralazine hydrochloride has been associated with peripheral neuritis, evidenced by paresthesia, numbness and tingling, which may be related to an antipyridoxine effect. Caution should be exercised if BiDil is used with MAO inhibitors, alcohol, sildenafil, vardenafil or tadalafil.

Headache (50%) and dizziness (32%) were the two most frequent adverse events and were more than twice as frequent in the BiDil group.

Viagra is a registered trademark and Revatio is a trademark of Pfizer, Inc.; Levitra is a registered trademark of Bayer HealthCare, GlaxoSmithKline, and Schering-Plough; Cialis is a registered trademark of Lilly ICOS LLC.

Low hemoglobin levels are a predictor of increased risk of death in heart failure

Thu, 18 Aug 2005 02:04:38 PST

( from http://www.rxpgnews.com ) Low hemoglobin levels are a predictor of increased risk of death and complications among heart failure patients, according to a report in Circulation: Journal of the American Heart Association.

Hemoglobin (Hgb) is the major substance in red blood cells, and its level indicates the blood's ability to carry oxygen throughout the body. Studies have shown that low hemoglobin, which may result in anemia, is more common among patients with heart failure than it is among people in the general population. As many as 25 percent to 60 percent of heart failure patients have anemia, defined as hemoglobin less than 12 grams/deciliter in women and 13g/dL in men. "Studies have shown that if you have anemia and heart failure, your risk of death and complications are increased appreciably -- with as much as 30 percent to 60 percent additional risk of death and hospitalization from heart failure," said Inder S. Anand, M.D., FRCP, D. Phil. (Oxon.), the study's lead author, and professor of medicine at University of Minnesota Medical School and director of the Heart Failure Program, VA Medical Center, Minneapolis, Minn.

To study the association between anemia and mortality risk, the researchers used a database on 5,002 patients enrolled in the Valsartan Heart Failure Trial, a study evaluating the high blood pressure drug valsartan.

At the beginning of the study, researchers took a complete blood cell count, and repeated these measurements at regular intervals up to 24 months. Of the patients enrolled in the heart failure study, 23 percent were anemic. Anemic patients tended to be older, have diabetes and to have worse heart failure.

The researchers found that the quartile of patients with the largest average decreases in Hgb over 12 months (defined as an average decrease of 1.6 g/dL, from 14.2 to 12.6 g/dL) experienced 47 percent more hospitalizations and 60 percent more deaths, compared to those in the quartile that exhibited an insignificant (0.10 g/dL) change in hemoglobin during 12 months.

The researchers report that an increase in Hgb was associated with a 22 percent lower death rate in patients with anemia, compared to 21 percent without anemia, at the start of the study.

Patients who had anemia at the start of the study or whose Hgb decreased during the study had worse heart failure and an associated elevation of several other risk factors for heart disease, including neurohormones and C-reactive protein.

"If you are a heart failure patient and your hemoglobin drops, then you are at a greater risk of having problems. What remains unclear, however, is the ideal level of hemoglobin to be achieved in patients with heart failure," he said.

Researchers said one of the causes of anemia may be related to iron deficiency in heart failure patients because of malabsorption, nutritional deficiencies and impaired metabolism. Hemodilution (excess fluid retention) may also contribute to anemia in heart failure patients.

Researchers don't know if anemia worsens heart failure or if it is a marker of heart failure severity, or what effect raising hemoglobin will have on the heart's function.

"It is important to pursue hemoglobin's role in the risk of death and complications in heart failure patients," Anand said.

"The lifetime risk for developing heart failure for men and women at age 40 is one in five. If 30 percent to 60 percent of these people are at higher risk for death and complications because of low hemoglobin, we might have an opportunity to treat these patients," he said. "Treatment for anemia is relatively simple, with iron supplements, multivitamins or drugs. However, we do not yet know if treatment is the best strategy and what the goals of treatment should be."

New knowledge to shape new heart failure therapies

Fri, 22 Jul 2005 00:51:38 PST

( from http://www.rxpgnews.com ) Researchers have determined how metabolic pathways differ between healthy and failing hearts. Normally, a heart derives its energy from a balance of fatty acids and carbohydrates, specifically glucose.

But Dr. Gary Lopaschuk, a pharmacologist and professor in the University of Alberta Department of Pediatrics, and his colleagues in the U.S. and Italy have found that during the early stages of heart failure, the heart uses too much fatty acid and not enough carbohydrate; and then, later on, the heart doesn't use enough fat.

Lopaschuk thinks that better treatments for heart failure patients may be available now that they have discovered that the type of "fuel" that the heart uses can contribute to the severity of heart failures. There are existing drugs that can make the heart more productive, but they don't remedy the fact that the heart is still inefficient because a lot of oxygen is necessary for it to drive the same amount of contractile activity.

"Many forms of heart diseases have many pharmacological therapeutic approaches to treat it. But heart failure is a difficult one. If you're diagnosed with heart failure, your five-year prognosis isn't that good. There's a high likelihood of mortality. So there's a major push to find new approaches to treat heart failure," Lopaschuk said.

"Heart failure is not a situation where the heart completely fails, it is a condition in which the heart fails to provide even itself with enough blood under certain conditions," Lopaschuk added.

Heart failure can be brought on by heart attack, congenital heart defects, viral infections, hypertension and more. Because of this, Lopaschuk, an expert in regulatory pathways involved in energy metabolism in the heart, worked with his colleagues to find out how metabolic pathways differ between healthy and failing hearts.

"The heart has a huge need for energy. Everyone talks about the brain having a high energy demand, which it does, but the main energy user is the heart itself. Even though it pumps blood and oxygen around the rest of the body, the heart itself also consumes a huge amount of the oxygen that it takes in. And it's not unreasonable--it beats 24 hours a day," Lopaschuk said.

Extended Phase II Results of Furosemide GR(TM) in Congestive Heart Failure

Sat, 04 Jun 2005 11:44:38 PST

( from http://www.rxpgnews.com ) Depomed, Inc. (Nasdaq:DEPO) today announced results from its extended Phase II trial of Furosemide GR(TM), a controlled release formulation of the leading diuretic furosemide, which is used to treat edema in congestive heart failure (CHF) patients. Additional data from ten patients who underwent additional treatment indicated that Furosemide GR continued to produce comparable diuresis to immediate release furosemide, however with variable urinary urgency and frequency between the two treatment groups.

"While Furosemide GR tablets resulted in comparable total fluid output compared to immediate release furosemide, we are disappointed that the data didn't show a consistent improvement in urinary urgency and frequency as was observed in our Phase I trial in healthy volunteers," said John W. Fara, Ph.D., chairman, president and chief executive officer of Depomed. "Even though the extended study involved follow up in only ten patients from the initial Phase II trial, we believe the data warrant a re-evaluation of our pursuing a diuretic program in this patient population."

The company indicated that while it is re-evaluating the program, resources that were dedicated to Furosemide GR development will be reallocated to grow its pipeline with new programs as well as support its other late stage programs, including two products, Glumetza(TM) and Proquin(TM) XR, both under review at the FDA, and another product, Gabapentin GR(TM), currently in Phase II clinical testing. The company may choose to conduct additional development of Furosemide GR in a different patient population at a later time.

In September 2004, the company reported results from a Phase II clinical trial which involved 30 CHF patients to compare Furosemide GR to immediate release furosemide. The data showed comparable diuresis between the two treatment groups, but inconsistent results related to urinary urgency and frequency. The extended Phase II program was designed to evaluate potential differentiation of Depomed's controlled release product compared to the immediate release product, particularly related to urinary frequency and urgency.

Furosemide is a diuretic used to treat edema, a swelling due to excess fluid that is often associated with congestive heart failure, kidney diseases and liver diseases. Immediate release formulations of furosemide often result in an intense peak removal of fluid from the body, which Depomed has characterized as the "Niagara effect," that may lead to poor patient compliance. Depomed's Furosemide GR is a once daily, controlled release formulation of furosemide intended to achieve a moderated and gradual diuretic effect.

FDA approval for MOMENTUM trial of percutaneous CHF therapy

Thu, 28 Apr 2005 00:06:38 PST

( from http://www.rxpgnews.com ) Orqis Medical Corporation, developer of the novel and proprietary catheter-based Cancion® cardiac recovery system (CRSTM) to treat congestive heart failure (CHF), today announced U.S. Food and Drug Administration (FDA) unconditional approval for researchers to treat up to 200 CHF patients at 40 centers participating in the company's MOMENTUM pivotal clinical trial.

The Company previously announced conditional FDA approval in January to expand the MOMENTUM clinical investigation from 8 to 40 research centers nationwide.

"The Cancion CRS offers the promise of an exciting new percutaneous therapeutic modality to treat patients suffering from CHF," said Ken Charhut, Orqis Medical's president and CEO. "Unconditional FDA approval to advance the MOMENTUM clinical investigation will allow us to discover its therapeutic potential."

The Cancion CRS is the first therapy for congestive heart failure based on continuous aortic blood flow augmentation to the descending aorta. The MOMENTUM (Multicenter Trial of the Orqis Medical CRS for the Enhanced Treatment of CHF, Unresponsive to Medical Therapy) trial will determine efficacy of the Cancion CRS Therapy to treat patients with acute decompensation resulting from CHF.

Traditional therapies to treat acute CHF include drugs that pull off fluid (diuretics) or cause the heart to pump more strongly (inotropes). In contrast, the Cancion CRS is designed to create an environment that allows the heart to rest while it recovers from an acute decompensation event.

Congestive heart failure is a chronic disease that affects an estimated 5 million people in the U.S. with a projected cost of $27.9 billion in 2005.