Wood Street Clinic Blog

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Interim results support the clinical utility of the Corus CAD test in the assessment of obstructive coronary artery disease

CardioDx, Inc., a molecular diagnostics company specializing in cardiovascular genomics, has announced results from a multi-center, community-based patient registry called the PRESET Registry which found that patients with symptoms of obstructive coronary artery disease (CAD)* and who had low Corus® CAD test scores had an 82% decreased odds of referral for further cardiac evaluation versus patients with elevated Corus CAD test scores.[1]

The Corus CAD test is a blood-based test that integrates age, sex, and gene expression levels into a single score indicating the current likelihood of a significant narrowing or blockage of the coronary arteries. The data was presented at American Heart Association Scientific Sessions 2015 in Orlando, Fl. on November 7-11, 2015.

"Challenges associated with diagnosing obstructive CAD in symptomatic patients can lead to repeat and unnecessary tests and procedures," said Joseph A. Ladapo, M.D., Ph.D., Assistant Professor of Medicine, Department of Population Health and Medicine, NYU School of Medicine and lead author of the study. "The PRESET Registry analysis reinforces the benefits of implementing the age/sex/gene expression score (ASGES) test in the primary care setting for patients and clinicians. With the ASGES test, clinicians are able to safely and efficiently rule-out low-risk patients suspected of having CAD."

The registry study, "Primary Endpoint Results from a Community-Based Registry Evaluating the Use of a Blood-Based Age/Sex/Gene Expression Test in Patients Presenting with Symptoms Suggestive of Obstructive Coronary Artery Disease: the PRESET Registry (A Registry to Evaluate Patterns of Care Associated with the Use of Corus CAD in Real World Clinical Care Settings)," evaluated 718 stable, non-acute and non-diabetic adult patients without a history of obstructive CAD from 21 primary care practices from September 2012 to August 2014.

The interim results of the primary efficacy endpoint demonstrated that the use of the Corus CAD test in the primary care setting was associated with a clinically relevant and statistically significant impact on medical decision making in patients presenting with typical or atypical symptoms suggestive of obstructive CAD. The median test score was 18 (range: 1-40), and 310 of the 718 (43%) patients had low scores ( ≤ 15). In a 30-day follow up, 27 of 310 (9%) patients with low Corus CAD scores were referred for further cardiac evaluation (OR 0.18, p

"With approximately $5.9 billion spent annually on non-invasive and invasive cardiac testing among non-diabetic patients in the U.S. we are faced with the challenge to better and more confidently diagnose patients presenting with symptoms suggestive of obstructive CAD," said Mark Monane, M.D., FACP, Chief Medical Officer of CardioDx. "The large number of community-based office practices included in the PRESET registry helps to address the generalizability of the study findings. The results of the primary endpoint showing a low rate of further cardiac referral reinforce results from previous studies showing the clinical utility of Corus CAD on clinical decision making."

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Sanofi and Regeneron announce new Praluent (alirocumab) injection analyses

Sanofi and Regeneron Pharmaceuticals, Inc. have announced a new post-hoc analysis of six Phase 3 clinical trials showing that approximately three quarters (74 percent) of patients reached their pre-specified LDL cholesterol targets within 8 weeks of adding Praluent® (alirocumab) Injection 75 mg to their standard-of-care, which included statins. In the 26 percent of patients whose dose was increased to 150 mg, most were able to achieve their pre-specified LDL cholesterol target, with an average additional 14 percent reduction in LDL cholesterol. The results from this and other analyses, which evaluated Praluent every two weeks, were presented at the American Heart Association (AHA) Scientific Sessions in Orlando, FL.

"In this analysis of patients who required further improvement of their LDL cholesterol levels, adding Praluent 75 mg to their standard-of-care allowed the majority of patients to achieve their LDL cholesterol goals. For those who required further LDL cholesterol lowering, increasing Praluent to 150 mg provided additional efficacy," said Harold Bays, M.D., from the Louisville Metabolic & Atherosclerosis Research Center, Kentucky, U.S. "Data such as these provide clinicians practical insight as to how the two Praluent doses may better allow patients to achieve their LDL cholesterol goals."

These results are based on a pooled post-hoc analysis of 1,291 patients with high cardiovascular (CV) risk or an inherited form of high cholesterol (heterozygous familial hypercholesterolemia, or HeFH) which found 74 percent of patients who added Praluent 75 mg achieved their LDL cholesterol-lowering goals at week 8, and the remaining 26 percent had their dose adjusted to 150 mg at week 12. In other results:

By week 24, 61 percent of patients who switched to 150 mg achieved their goal, with a mean additional LDL cholesterol reduction of 14 percent. Comparable adverse event (AE) rates were observed in patients whose Praluent dose was increased, versus those whose dose was not (66 percent in both arms in placebo-controlled trials; and 55 percent versus 56 percent respectively in ezetimibe-controlled trials). About the data: The pooled analysis included results from six Phase 3 ODYSSEY trials where patients added Praluent 75 mg to standard-of-care, and had their dose adjusted at week 12 to 150 mg if they did not reach their LDL cholesterol goals by week 8. Cholesterol goals were either less than 70 mg/dL or less than 100 mg/dL, dependent on CV risk. All patients across the six trials received background statin therapy. In three trials Praluent was compared to placebo (ODYSSEY FH I, FH II, COMBO I), and in three it was compared to ezetimibe (ODYSSEY COMBO II, OPTIONS I, OPTIONS II).

In a separate pooled post-hoc analysis of 3,499 patients, individuals with diabetes (n=1,051) who initially received Praluent 75 mg or 150 mg every two weeks had a mean percent difference in LDL cholesterol of 44 percent and 58 percent, respectively, versus placebo at week 24 (p

Praluent was generally well tolerated, with the most common adverse events among people with diabetes being nasopharyngitis (11 percent Praluent, 10 percent placebo) and upper respiratory tract infection (8 percent Praluent, 9 percent placebo). About the data: The pooled analysis included results from five placebo-controlled trials of individuals with diabetes (1,051), and without diabetes (2,448) with inadequately controlled hypercholesterolemia receiving standard-of-care, which included maximally-tolerated statins. In two of the trials, patients initially received Praluent 150 mg (ODYSSEY LONG TERM, HIGH FH). In three of the trials, patients initially received Praluent 75 mg and had their dose adjusted to 150 mg at week 12 if they required additional lipid-lowering to meet their LDL cholesterol goals (ODYSSEY COMBO I, FH I, FH II).

A third post-hoc analysis of 4,974 patients did not find an increased risk of diabetes-related AEs among those who didn't have diabetes when they entered the trials, regardless of whether they were taking Praluent or were in a control group (placebo or ezetimibe). There was also no evidence that Praluent affected the incidence of new-onset diabetes or pre-diabetes. The ongoing ODYSSEY OUTCOMES trial will provide further data on the impact of Praluent on glycemic measures.

About the data: The pooled analysis included results from 10 Phase 3 ODYSSEY trials of patients with inadequately controlled hypercholesterolemia, ranging from 24 to 78 weeks (ODYSSEY LONG TERM, FH I, FH II, HIGH FH, COMBO I, COMBO II, OPTIONS I, OPTIONS II, MONO, ALTERNATIVE). In total, 1,526 (31 percent) had a medical history of diabetes upon entering the trials, 1,969 (40 percent) were identified as having pre-diabetes, and 1,479 (30 percent) did not have diabetes (e.g., had a normal concentration of glucose in the blood).
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New vaccine could offer 'cheaper, more effective' treatment for high cholesterol

Around 73.5 million adults in the US have high levels of "bad" cholesterol, but only 1 in 3 have the condition under control. In a new study, researchers reveal the development of a vaccine they say could offer a cheaper and more effective alternative to current cholesterol-lowering treatments.
[Vaccination]
The new vaccine was found to dramatically reduce cholesterol in mice and monkeys, suggesting it could do the same for humans.

In the journal Vaccine, study coauthor Dr. Bryce Chackerian - of the Department of Molecular Genetics and Microbiology at the University of New Mexico - and colleagues reveal how the new vaccine significantly reduced low-density lipoprotein (LDL) cholesterol in both mice and rhesus macaque monkeys.

LDL cholesterol is commonly referred to as "bad" cholesterol; high levels of LDL cholesterol can cause a build-up of plaque in the arteries, increasing the risk of heart attack, stroke and heart disease - the leading cause of death in the US.

According to the Centers for Disease Control and Prevention (CDC), people with high LDL cholesterol are twice as likely to develop heart disease than those with normal levels.

While lifestyle changes, such as adopting a healthy diet and increasing physical activity, are key for maintaining normal cholesterol levels, many people take statins to lower LDL cholesterol. Statins work by blocking an enzyme needed by the liver to produce cholesterol.

Though statins can be effective, Dr. Chackerian and colleagues note that they do not work for everyone and may cause severe side effects, including muscle pain, liver damage, digestive problems and increased diabetes risk.

But the team says their vaccine - which works by inhibiting a cholesterol-regulating protein in the blood called PCSK9 (proprotein convertase subtilisin/kexin type 9) - may provide a more effective alternative to statins.

For their study, the researchers created a bacteriophage virus-like particle (VLP) vaccine that produces strong antibody responses against PCSK9.

PCSK9 works by binding to the LDL cholesterol receptor in the blood. In the liver, the LDL receptor effectively removes LDL cholesterol from the blood, but when PCSK9 binds to it, it no longer has this ability. By blocking PCSK9 - which the new vaccine does - the LDL receptor can do its job.

Fast facts about cholesterol

Less than half of adults in the US with high LDL cholesterol are receiving treatment for it However, the percentage of Americans receiving treatment for high LDL cholesterol has increased, from only 28.4% in 1999-2002 to 48.1% in 2005-08 All adults should have their cholesterol levels checked every 5 years.

Learn more about cholesterol

On testing a single dose of the vaccine in 4-6-week-old mice, the team found it significantly reduced LDL cholesterol levels. When combined with statins, the team found the vaccine produced an even greater reduction in LDL cholesterol among 9-17-year-old rhesus macaques. The findings suggest the vaccine may also lower cholesterol in humans, according to the researchers.

"One of the most exciting things about this new vaccine is it seems to be much more effective than statins alone," notes Dr. Chackerian.

The new vaccine is the not the first cholesterol-lowering treatment to be developed that targets PCSK9. In August, the US Food and Drug Administration (FDA) approved a drug called evolocumab (brand name Repatha) that uses monoclonal antibodies to block PCSK9 and lower LDL cholesterol.

The FDA approved the drug to be used alongside a healthy diet and maximally-tolerated statin therapy for adults with a genetic predisposition for high cholesterol, as well as heart attack and heart disease patients who require further lowering of LDL cholesterol.

However, Dr. Chackerian and colleagues believe their vaccine may not only be more effective than such treatments, but it may also be a much cheaper alternative, noting that monoclonal antibody-based therapies can cost a patient more than $10,000 annually.

"While the developed world may be able to sustain these costs, expense is likely to be a major impediment to the use of such drugs in the developing world," say the authors. "In contrast, vaccination for a wide variety of mostly infectious communicable diseases has been proven to be compatible with the health care infrastructure in the developed and developing world."

Commenting on their overall findings, the researchers say:

"The data reported here, in both mice and macaques, provides proof-of-principle evidence that a vaccine targeting PCSK9 can effectively lower lipid levels and work synergistically with statins.

Thus, the use of VLP-based vaccines targeting PCSK9 peptide could serve as a cost-effective alternative to other therapies and could lead to a widely applicable vaccine-based approach for controlling hypercholesteremia [high cholesterol] and cardiovascular disease. If successful, this approach could obviously have a major impact on human health worldwide."

The researchers plan to conduct further testing of the vaccine in macaques, and they hope to move forward with vaccine development by teaming up with commercial partners.

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Low-income, elderly, women less likely to complete cardiac rehab after bypass

Bypass patients who are older, female and/or from lower-income neighbourhoods are more likely to face delays in beginning cardiac rehabilitation (CR), making them less likely to complete CR, which can lead to a higher mortality risk, suggests a new study.

The study, led by Dr. Susan Marzolini, exercise physiologist, Toronto Rehabilitation Institute (TR), UHN, examined nearly 6,500 coronary artery bypass graft surgery patients enrolled in the Cardiovascular Prevention and Rehabilitation program at Toronto Rehab over the course of 16 years.

Published in the November issue of Circulation: Cardiovascular Quality and Outcomes, the study found that bypass patients who waited longer than 60 days after their surgery to start CR were more likely to drop out of the program, attended fewer classes, and saw less improvement in their fat percentage and fitness, the Toronto study suggests.

"We know cardiac rehabilitation saves lives," says Dr. Paul Oh, Medical Director of the Cardiovascular Prevention and Rehabilitation Program at TR and co-author of the study. "Our past research has found that those who participate in cardiac rehabilitation after experiencing a major heart event cut the risk of dying from a subsequent heart event in half."

The study found that bypass patients are more likely to experience longer wait times, and subsequently poorer participation, if they are women, older, from a lower socioeconomic neighbourhood, employed, or had less social support. Any one of these factors is associated with longer wait times.

"We have now pinpointed a specific profile of bypass surgery patients most vulnerable to these delays and this study offers evidence that these wait times are problematic for the health of bypass patients," Dr. Marzolini notes.

In Ontario, cardiac rehabilitation services are reimbursed by the province's Ministry of Health. However, socioeconomic barriers exist that prevent some from accessing cardiac rehabilitation soon after bypass, she says.

"Women tend to experience heart events when they're older, and are more likely to be single," Dr. Marzolini explains. "With a lack of social support in place, they may have less access to transportation or be unable to overcome the cost associated with travel to the CR program, limiting their participation.

"Now that we've identified a gap with socially vulnerable bypass patients, this is a group we - as CR programs - can focus on and be equipped to reach out and help them."

Dr. Marzolini suggests the system could increase timely CR participation by ensuring surgical teams inform and refer patients to CR before hospital discharge. CR patients should be informed of the program options available in CR programs such as home program (off-site) models, evening classes, classes specifically for women; social support services; and help identifying transportation alternatives.

This study is specific to Toronto, ON, and similar research across Ontario and in the United States has also shown wait times to start CR after a heart event tend to exceed the suggested 60 days.

"While we cannot generalize the findings of this study yet, it gives us a great starting point to explore the impact of CR delays on a larger scale, find methods to integrate the socially vulnerable earlier, and continue to examine CR wait times for other cardiac patient populations," says Dr. Oh.

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Highly sensitive sensors successfully map electrical patterns of embryonic heart

Highly sensitive sensors have been successfully used to map the electrical activity of the developing heart in embryos, in a University of Sussex study published today (10 November 2015).

Zebrafish Embryo
This is an example of the electrocardiogram mapped from the embryonic zebrafish heart three days after fertilization.
Credit: Dr. Elizabeth Rendon-Morales

The study could lead to new insight into how heart rhythm abnormalities develop, the researchers say.

The team fine-tuned patented Electric Potential Sensing (EPS) technology, developed at the University, to detect the electrical signals of zebrafish embryos from just three days after fertilization. The findings have been published in the scientific journal Applied Physics Letters.

This is the first time that scientists have been able to see the full picture of the electrical activity in the developing heart of such a small organism, given that currently electrocardiography (ECGs) methods only measure the heartbeat.

Zebrafish hearts are remarkably similar to those of humans, making them a good model organism for scientific research. These latest results "push the frontiers" of the EPS sensor technology and could help scientists better understand how the heart develops - particularly during the early stages of life - and how defects originate.

Professor Robert Prance, head of the Sensor Technology Research Centre at the University of Sussex, said: "The EPS is a sensor technology that measures changes in an electric field in a similar way to a 'perfect voltmeter', drawing no current into the sample, making it non-invasive and safe to use. The sensor has already been used to carry out human ECG heart scans -- or their cranial equivalent, electroencephalographs -- saving patients from uncomfortable electrodes.

"Zebrafish embryo hearts are 2,500 times smaller than the human heart, so we needed to enhance the EPS design to make possible the detection of such cardiac activity.

"This could provide the biomedical research community with a novel instrumentation tool for performing cardio-electrophysiological studies at early developmental stages."

Dr Elizabeth Rendon-Morales, a Research Fellow at the University of Sussex and lead author of the study, said: "With this research we wanted to push the frontiers of the EPS sensor design towards its performance limits.

"Currently heart-related diseases such as congenital cardiac arrhythmias and long/short QT syndrome cost the EU economy almost 196 million euros a year. It is vital for us to develop tools that help our professionals understand as much as possible. This research could potentially generate new insights into the origins of such heart abnormalities.

"Using our technique based on electric field detection, we were able to obtain electrophysiological signals from living zebrafish embryos starting at three days post-fertilization. This is an excellent demonstration of the high sensitivity provided by the EPS sensor, which is also non-invasive and completely biocompatible."

Although the technique has not yet been tested on human embryos, the study nevertheless provides a solid 'proof of principle' to underpin further research.

The team is now designing a multiplatform based on EPS arrays for the recording of electrophysiological signals simultaneously, which could potentially be used for applications in drug screening studies and neuroscience.

The EPS sensor was developed out of research led by Professor Prance, in collaboration with the University's business incubation network Sussex Innovation. A licensing agreement was signed in 2010 with Plessey Semiconductors to bring new applications to market and it was shortlisted in the 2011 Times Higher Educations Awards for technological innovation of the year.

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'Post-hospital syndrome' found to be a risk factor for elective surgery

A condition known as "post hospital syndrome" (PHS) is a significant risk factor for patients who undergo elective outpatient surgery, a Loyola study has found.

PHS is defined as having been hospitalized during the previous 90 days. The first-of-its-kind study found that among patients with PHS, 7.6 percent had to be readmitted to the hospital within 30 days of undergoing elective outpatient hernia surgery. By comparison, only 1.6 percent of non-PHS patients had to be readmitted following hernia surgery.

Also, 8.3 percent of PHS patients were admitted to the emergency department within 30 days of hernia surgery, compared with 4.3 percent of non-PHS hernia surgery patients.

The study by senior author Paul Kuo, MD, first author Anai Kothari, MD, and colleagues was presented at the annual meeting of the Western Surgical Association in Napa Valley, Ca. Dr. Kuo is chair of the Department of Surgery of Loyola University Medical Center and Loyola University Chicago Stritch School of Medicine. Dr. Kothari is a resident in the Department of Surgery.

"Surgeons must consider all recent inpatient admissions when risk-stratifying patients for ambulatory, elective surgery," researchers concluded.

PHS was first identified in an article in the New England Journal of Medicine by Harlan Krumholz, MD of Yale University School of Medicine. Dr. Krumholz defined PHS as "an acquired condition of vulnerability."

During hospitalization, patients often are sleep deprived and in pain or discomfort. They receive medications that can alter their mental and physical abilities. They become deconditioned (loss of muscle mass, reduced cardiac output, etc.). And patients may not get sufficient nutrition if, for example, they are on a ventilator or have to fast before surgery or tests. These problems can impair their recovery and make them more prone to disease and mental errors, Dr. Krumholz wrote.

The Loyola researchers analyzed records of 57,988 California patients who underwent hernia repair in 2011, including 1,332 patients who had PHS. Data sets came from the U.S. Agency for Healthcare Research and Quality. Researchers focused on hernia repair because it is a common surgery performed at ambulatory surgery centers, community hospitals and academic medical centers.

Among the PHS patients, the most common reason for their previous hospitalization was gastrointestinal problems (25.1 percent), followed by cardiovascular problems (12.3 percent), hip fractures and other injuries (8.2 percent) and pregnancy-related complications (7.1 percent). The average length of time between their previous hospitalization and their elective hernia surgery was 48.7 days.

The study is titled "Impact of the Post-Hospital Syndrome on Outcomes Following Elective Outpatient Surgery". In addition to Drs. Kuo and Kothari, co-authors are Robert Blackwell, MD; Ryan Yau; Matthew Zapf; Matthew Arffa; and Gerard Abood, MD.

Loyola researchers are doing a follow-up study to determine what measures hospitals could take to reduce the negative impact of PHS.

The PHS study was conducted by Loyola's predictive analytics program, which mines large data sets to predict health outcomes. In addition to the PHS study, researchers are studying, for example, how hospitals can reduce the negative effects of having surgery on the weekend and whether having a trauma department confers a beneficial "halo effect" on patient outcomes across the board.

Large new databases, electronic medical records and more powerful computing capabilities are enabling researchers to conduct such studies. "We're now able to ask and answer a broad range of questions that could significantly help improve patient care and reduce costs," Dr. Kuo said. Dr. Kuo heads Loyola's analytics group, One to Map Analytics. (One-to-map is a common computer command in analytics research.)

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Obese 8-year-olds found with signs of heart disease

The obesity epidemic is never far from the news desk, and for good reason. Today, around 1 in 3 American kids and teens are overweight, which is three times the rate it was in 1963.
[Overweight baby with stethoscope]
Researchers found significant heart defects in MRI scans of obese children.

This relatively new plague of juvenile obesity is, of course, a huge concern.

Science has already uncovered a barrage of negative health implications tied to obesity. Even more worrying, perhaps, are the things we are yet to find out about obesity.

This range of unknowns is particularly obvious in children, because, since the birth of humanity, children have not been witnessed at such large sizes and in such high numbers.

Children who are overweight already display similar reactions to excess weight as adults. Issues such as high blood pressure, type 2 diabetes and elevated blood cholesterol levels, once the reserve of adults, are now known to strike at any age.

Added to the worrying barrage of physical woes, overweight kids and teens face additional psychological issues such as depression and low self-esteem - both epidemics in their own right.

New research presented at the American Heart Association's Scientific Sessions 2015 by lead study author Linyuan Jing, PhD, adds another worrying finding to the tsunami of weight-related health news.

Jing and colleagues took MRI scans of 20 overweight children and compared the function and dimensions of their hearts with 20 children within the normal weight range. The results make somber reading.

MRI scans produce sobering results

The overweight children did display negative health impacts due to their size and weight, such as asthma and depression, but none directly attributed to heart malfunction.

The scans, however, told a different story:

The team found that the obese youths had 27% more muscle mass in the left ventricle of their hearts and 12% thicker heart muscles, which are both signs of heart disease.

The study also considered 40% of the children to be "high-risk" because the type of thickening seen in their heart wall is associated with a reduced ability to pump blood.

Of the 20 obese children, seven were teenagers, but the younger participants yielded the most shocking results. The researchers were particularly surprised to see signs of heart disease in children as young as 8 years old: "This was alarming to us."

Jing hopes this study might spur parents on to spend a little more time and thought on their child's diet:

"Ultimately we hope that the effects we see in the hearts of these children are reversible; however, it is possible that there could be permanent damage. This should be further motivation for parents to help children lead a healthy lifestyle."

Childhood obesity

As mentioned above, 1 in 3 children in America are overweight. Even worse, perhaps, is that 70-80% of those children are likely to remain overweight for their entire lives.

In adulthood, 7 out of 10 Americans are overweight or obese. In other words, they outnumber people who are in a healthy weight range.

Surgeon General Richard Carmona spoke of the epidemic in chilling terms:

"Because of the increasing rates of obesity, unhealthy eating habits and physical inactivity, we may see the first generation that will be less healthy and have a shorter life expectancy than their parents."

The effects of childhood obesity can be complex, but in most cases, the causes are much less so. The bottom line is that children are taking on more calories than they are burning off.

Underlying this simple equation are a multitude of personal and societal causes. Factors include increased portion sizes, hours spent staring at screens rather than playing outdoors, eating the wrong kinds of foods and eating out more regularly.

A second sting in the tail

Jing and his team chose their candidates by measuring the children's height and weight. If they were in the 95th percentile - heavier than 95% of other children at that age and sex - they could be included.

During the process of selecting candidates, however, children with existing diabetes or who were too large to fit in the MRI scanner were rejected. Worryingly, if these children had been included, the overall picture might have been substantially worse.

Medical News Today recently covered news of the discovery of an obesity gene.

Written by Tim Newman

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Alcohol abuse may predict congestive heart failure; even among younger adults

Alcohol abuse was associated with a 70 percent increased risk of congestive heart failure in adults and the link was especially strong among younger adults (60 years or younger) and those without high blood pressure, according to a study presented at the American Heart Association's Scientific Sessions 2015.

Researchers analyzed 858,187 patients randomly selected from a California database of all emergency department, ambulatory procedural and inpatient healthcare encounters between 2005 and 2009. Patient ages ranged from 30s to 70s; and more than a third were men and almost half were white.

During study follow-up, 4 percent, or 33,046 patients, were diagnosed with alcohol abuse and 12 percent, or 106,655, developed congestive heart failure.

Alcohol abuse emerged as a strong predictor of congestive heart failure after adjustment for age, gender, race, high blood pressure, diabetes, coronary artery disease, chronic kidney disease, valvular heart disease, dyslipidemia, smoking, obesity, obstructive sleep apnea, and income.

Researchers said their study suggests younger adults and those without high blood pressure might be disproportionately prone to the toxic heart effects from alcohol.

Isaac R. Whitman, M.D.; University of California, San Francisco, San Francisco, California

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