Cardiology




The ARISTOTLE trial



 



Results have been released from the large-scale ARISTOTLE trial which shows that the new oral drug Apixaban is superior to the standard Warfarin in patients with atrial fibrillation for preventing stroke, reducing bleeding, and saving lives. Middle East Health reports.

The large-scale randomised, double-blind clinical trial known as Reduction In Stroke and Other ThromboemboLic Events – ARISTOTLE – randomised 18,201 patients at 1034 clinical sites in 39 countries to apixaban (5mg twice daily) or to warfarin for an average of 1.8 years. The trial shows that apixaban, a new type of oral anticoagulant known as a factor Xa inhibitor, is superior to the standard drug warfarin for preventing stroke and systemic embolism in patients with atrial fibrillation. Moreover, apixaban results in substantially less bleeding, and also results in lower mortality.

“These are important findings because they show when compared to warfarin, itself a very effective treatment to prevent stroke, apixaban resulted in an additional 21% relative reduction in stroke and systemic embolism. It also resulted in a 31% relative reduction in major bleeding, as well as an 11% relative reduction in overall mortality,” says Christopher Granger, Professor of Medicine, Director of the Cardiac Care Unit at Duke University School of Medicine in Durham, North Carolina, US.

The better prevention of stroke was statistically significant with P=0.011, the lower rate of major bleeding at P<0.001, and the lower mortality at p=0.047. Haemorrhagic stroke was reduced by about 50%.

The results were presented by the cochairs of the ARISTOTLE trial in two sessions at the European Society of Cardiology in Paris, France, last year and the main trial results were published simultaneously online in the New England Journal of Medicine. The time in therapeutic range analysis was presented by Lars Wallentin, professor of cardiology and director of the Uppsala Clinical Research Center in Sweden. The main trial results were presented by Professor Granger.

Prof Wallentin noted that these benefits are with a drug that has major practical advantages over warfarin: it does not require monitoring and has few interactions with other medications or food. Apixaban was better tolerated than warfarin, with fewer discontinuations. And he stated that “the benefits of reducing stroke and lower rates of bleeding were consistent across all major subgroups and despite the heterogeneity that exists in the quality of warfarin use across the world”.

Speaking at the at the Canadian Cardiovascular Congress last year, Dr Justin Ezekowitz, from the University of Alberta, Canada, explained that the majority of patients with atrial fibrillation need an anticoagulant. However he pointed out that the current anticoagulant [warfarin] can be a burden for physicians and patients due to its side effects and narrow therapeutic range.

“It is associated with a risk of bleeding and needs very close monitoring, whereas this new drug [apixaban] is taken twice a day and does not require monitoring,” he said.

He noted that warfarin can also interact with a variety of foods and drugs that patients might also be taking.

He said that the ARISTOTLE trial shows that Apixaban resulted in fewer strokes (ischemic or haemorrhagic) and fewer systemic embolisms, caused less bleeding and resulted in fewer deaths in patients with atrial fibrillation.

“We have a drug that can increase reductions in death and stroke and it is safer in terms of bleeding,” said Dr Ezekowitz. “It is also easier to use.”

Discussing ARISTOTLE, John Alexander, MD, a study co-author and Duke University cardiologist, noted that the number of events prevented per 1000 people, which indicate absolute risk reduction, were also impressive.

“Apixaban prevented 6 patients from having a stroke, 15 patients from having major bleeding, and 8 patients from dying. The predominant effect on stroke prevention was on haemorrhagic stroke. Apixaban prevented 4 patients from having haemorrhagic stroke and 2 patients from having an ischemic or uncertain type of stroke,” he said.

Prof Granger said: “There is an enormous unmet need in terms of treatment of patients at risk for stroke associated with atrial fibrillation. Only about half of patients who should be treated are being treated. The disparity exists because warfarin treatment has several limitations.”

Warfarin is a vitamin K antagonist that is well documented for its ability to prevent blood clots. Previous studies indicate longterm use of warfarin in patients with atrial fibrillation and other stroke risk factors can reduce stroke by up to 70%. However, only about half of patients who could benefit from warfarin actually do.

Because of these limitations, doctors and patients have been eagerly awaiting alternative therapies, one of which is currently available, and several others are currently under investigation in large clinical trials.



Coronary calcium test proves to be key indicator of heart attack risk

If your doctor says you have a negative stress test, or that your cholesterol or blood pressure are normal, how assured can you be that you’re not likely to have a heart attack in the next seven to 10 years? Assessing traditional risk factors, such as age, high blood pressure, cholesterol, smoking and family history can estimate a person’s risk, but the picture is not always clear-cut. Some newer tests can be offered to provide reassurance or guidance about the need for medications or further testing.

Michael Blaha, MD, MPH, from the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease in the United States, has developed a simple mathematical formula to help doctors calculate their patients’ risks based on a variety of tests, such as a blood test for Creactive protein, carotid ultrasound and coronary calcium scoring, which are not part of the usual menu of risk factors. The goal was to determine which test, if results were normal, would provide the most reassurance for patients.

The study shows that by far, a test that looks for coronary calcium is the best indicator of low risk compared with other tests. Dr Blaha presented the results of the study, “Comparing Zero Coronary Artery Calcium with Other Negative Risk Factors for Coronary Heart Disease,” at the American Heart Association Scientific Sessions, on 15 November last year.

Dr Blaha and his colleagues used data from the Multi-Ethnic Study of Atherosclerosis (MESA), a longitudinal study of more than 6,800 people without cardiovascular disease at enrolment who have been followed for an average of seven years. They compared heart attack rates in the study population with results of tests the individuals had been given to assess their risk. In that way, the researchers could calculate which tests predicted the lowest heart attack risk. They found that a coronary calcium score of zero, meaning no coronary calcium could be seen in heart arteries, was, by far, the most reassuring indicator.

“None of the other tests, such as C-reactive protein, are sensitive enough to reassure patients that they have a very low risk of a heart attack over the next seven years,” says Dr Blaha. “The findings related to coronary artery calcium are important from a public health perspective because they mean we can identify people who do not need further testing or medical interventions for the immediate future.”

Coronary calcium scoring is a CT test that uses about the same amount of radiation as a mammogram to show evidence of calcium build-up in arteries feeding the heart. C-reactive protein is a marker of inflammation somewhere in the body that is assessed by a blood test. Carotid ultrasound looks at fatty deposits in arteries or thickening of the artery walls in the neck.

According to Dr Blaha’s new model, if a patient is thought to have a 10% risk of a heart attack, according to the widely regarded Framingham risk scale, and the patient’s calcium scoring test shows zero coronary calcium, his projected risk could be reduced to 3%.

“That’s a meaningful change in the estimated risk that will influence patient treatment,” Dr Blaha says. Half of the people in MESA between age 45 and 84 had zero levels of coronary calcium.

In contrast, for the same group of people whose risk of a heart attack over the next decade was thought to be 10% because of traditional risk factors, a low C-reactive protein level only reduced their true risk to 9%, according to Dr Blaha’s model. “Therefore,” says Dr Blaha, “finding no coronary calcium is a much more robust predictor of low risk compared with having low levels of C-reactive protein.”

Along the same lines, those with a 10% risk of a heart attack based on traditional risk factors, whose carotid artery test is normal, would see a drop in their risk to 7%, based on Dr Blaha’s model.

“This ingenious mathematical model may provide a useful tool to help physicians assess their patients’ risk,” says Roger S. Blumenthal, MD, professor of medicine and director, Johns Hopkins Ciccarone Center for the Prevention of Heart Disease. “It may also have public health significance in terms of guiding the proper allocation of healthcare resources, including medications.”

Dr Blumenthal says coronary calcium scoring to assess heart disease risk is analogous to a bone density test to assess the risk of bone fracture. “If a 60-year-old woman has a family history of osteoporosis and is thin,” he explains, “she may be presumed to be at high risk for bone fractures. A bone density scan would provide a key piece of information about her actual risk and need for medication to lower her risk of fractures.”

He adds: “We don’t prescribe medicine to prevent fractures to all postmenopausal women – only to those who have osteoporosis on the basis of a bone density scan. In the same way, coronary calcium scoring can tell us whether or not there is evidence of hardening in the walls of the heart arteries and therefore, more accurately determine a person’s risk of a heart attack or other cardiac event.”



Study offers clues as to why some patients get infections from cardiac implants

By Emily Caldwell

New research suggests that some patients develop a potentially deadly blood infection from their implanted cardiac devices because bacterial cells in their bodies have gene mutations that allow them to stick to the devices.

Patients with implants can develop infections because of a biofilm of persistent bacterial bugs on the surfaces of their devices. Researchers found that some strains of the bacteria, Staphylococcus aureus, have just a few genetic variants in the proteins on their surfaces that make them more likely to form these biofilms.

The research seeks to get to the heart of a medical paradox: Devices such as pacemakers, defibrillators and prosthetic cardiac valves save lives, but they cause infections. In the United States about 4% of the estimated 1 million patients receiving implants are infected. Because biofilms resist antibiotics, the only treatment is surgery to remove the contaminated device and implant a new one. In the US this adds up to thousands of surgeries and more than $1 billion in healthcare costs every year.

A team led by scientists at Ohio State University and Duke University Medical Center used atomic-force microscopy and powerful computer simulations to determine how Staph bacteria bond to the devices in the process of forming these biofilms. The findings offer clues about potential techniques that could be employed to prevent infections in patients who need these devices to stay alive.

“We’re probing the initial step to that biofilm formation. Can you shut that down somehow? If that bacterium never sticks, there’s no biofilm. It’s that simple. But it’s not quite that simple in practice,” said Steven Lower, associate professor in the School of Earth Sciences at Ohio State University in the US and co-lead author of the study.

The research is published in the Proceedings of the National Academy of Sciences.

Using Staph cells collected from patients – some with cardiac devicerelated infections – the researchers examined how these bacteria adhere to implants to create a biofilm. The bond forms when a protein on the bacterial cell surface connects with a common human blood protein coating an implanted device.

But an estimated half of all Americans have Staph bacteria living in their noses, and not every cardiac implant patient develops an infection. So why do some strains of these bacteria cause infection while others remain dormant?

The researchers discovered that Staph surface proteins containing three genetic variants, or single-nucleotide polymorphisms, formed stronger bonds with the human proteins than did Staph proteins without those variants. The presence of these genetic variants was associated with the strains of bacteria that had infected implanted cardiac devices. First step

The finding is a first step toward preventing the bacteria from bonding to the devices. Though many scientists are trying to develop materials that repel bacteria, these researchers wonder if there might be another way to work around the bacteria’s manipulative behaviour.

“It will be useful to explore this in more detail and see if we can understand the basic science behind how these bonds form, and why they form. Perhaps then we can exploit some fundamental force law,” said Prof Lower.

Prof Lower, a scientist with a background in geology, physics and biology, has collaborated for a decade with Vance Fowler, an associate professor of medicine at Duke University Medical Center and the study’s co-lead author. Prof Fowler, who specialises in infectious diseases, has assembled a rare library of hundreds of Staphylococcus aureus isolates collected from patients. Prof Lower specialises in atomic-force microscopy and molecular dynamics simulations to explore molecular- level relationships between inanimate surfaces and living microorganisms.

Prof Fowler hopes his samples might help answer a broader question related to varied patient responses to the blood infection bacteremia.

“Staphylococcus aureus infections of prosthetic devices are devastating to patients and expensive to healthcare systems. For this reason, the best way to treat these infections is to prevent them in the first place. I believe that our research is a critical first step towards understanding, and eventually preventing, cardiac device infections caused by Staphylococcus aureus,” Prof Fowler said.

Study

For this study, the researchers used 80 Staph isolates from three different groups: patients with a blood infection and a confirmed cardiac device infection, patients with a blood infection and an uninfected cardiac device, and Staph from the noses of healthy people living in the same area.

Single-cell studies of bacteria are complicated by their tiny size, one millionth of a meter, so an atomic-force microscope is required to visualise their behaviour. Co-author and Ohio State postdoctoral researcher Nadia Casillas- Ituarte performed these experiments, connecting single Staph bacteria to a protein-coated probe to allow bonds to form, and then rupturing the bonds to measure the strength of each connection.

Casillas-Ituarte simulated the human heartbeat, allowing bonds to form over the course of a second and then pulling the probe away. By doing this at least 100 times on each cell and verifying the work on hundreds of additional cells, she generated over a quarter-million force curve measurements for the analysis.

“The first step in all of this is to determine how a bacterium feels a surface,” she said. “You can’t stop that process until you first understand how it happens.”

The researchers coated the probe with fibronectin, a common human blood protein found on the surface of implanted devices. Staph bacteria can create a biofilm by forming bonds with this protein through a protein on their own surface called fibronectin-binding protein A. To learn more about the bacterial protein, the scientists then sequenced the amino acids that make up fibronectin-binding protein A in each isolate they studied.

And this is where they found the singlenucleotide polymorphisms (or SNPs), which were more common in the isolates collected from patients with infections related to their heart implants.

To further test the effects of these SNPs, the team used a supercomputer to simulate the formation of the bond between the bacterial and human proteins. When they plugged standard amino acid sequences from each protein into the supercomputer, the molecules maintained a distance from each other. When they altered the sequence of three amino acids in the bacterial surface protein and entered that data, hydrogen bonds formed between the bacterial and human proteins.

“We changed the amino acids to resemble the SNPs found in the Staph that came from cardiac device-infected patients,” Prof Lower explained. “So the SNPs seem to have a relationship to whether a bond forms or not.”

Fibronectin-binding protein A is just one of about 10 of these types of molecules on the Staph surface that can form bonds with proteins on host cells, Prof Lower noted. And it’s also possible that fibronectin, the human protein on the other side of the bond studied so far, might contain genetic variants that contribute to the problem as well.

What the scientists do know is that bacteria will do all they can to survive, so it won’t be easy to outsmart them. “

Bacteria obey Charles Darwin’s law of natural selection and can evolve genetic capabilities to allow them to live in the presence of antibiotics,” Prof Lower said. “Most physicists would tell you there are certain laws of physics that dictate what happens and when it happens, and you can’t evade or evolve ways around those. If you understand the basic physics of it, can you exploit a fundamental force law that bacteria can’t evade or evolve a mechanism around?”



Researchers find new pathway critical to heart arrhythmia

University of Maryland School of Medicine researchers have uncovered a previously unknown molecular pathway that is critical to understanding cardiac arrhythmia and other heart muscle problems. Understanding the basic science of heart and muscle function could open the door to new treatments. The study, published recently in the journal Cell, examined the electrical impulses that coordinate contraction in heart and skeletal muscles, controlling heart rate, for example. Unravelling how the body regulates these impulses is key to understanding serious health conditions such as paralysis, muscle relaxation and heart arrhythmia.

Researchers in the Cell study examined ion channels – membrane proteins that allow the electrical charges to flow into and out of the cell. The number and location of channels on the cell's surface are critical to the heart's rhythm. The scientists found a new, previously unknown intracellular trafficking pathway that controls the number and location of the ion channels on the cell surface, affecting the passage of electrical charges and controlling the beat of the heart and other muscle activity.

Ion channels are proteins that form pores at the cell's surface. The pores open with careful regulation, allowing the passage of ions like potassium, sodium or chloride. These ions carry distinct electrical charges, and their regulated passage into and out of the cell stimulate and coordinate contractions such as the heart's rhythm.

"This study illuminates a new pathway for therapeutic intervention," says Paul Welling, MD, professor of physiology at the University of Maryland School of Medicine. "Drugs that interfere with or augment this signal may be used to control the number and location of ion channels in such a way to fight arrhythmia and other muscle disorders, potentially saving lives."

Until recently, scientists have focused on the regulatory mechanisms that control the way that these ion channels open and close and how that action affects muscle contraction and heart rate. Years of research have shown that it is not simply the action of these ion channels that affects heart arrhythmia. Scientists have found that the location and number of channels on the cell's surface are just as important to the heart's rhythm. The study in Cell describes a new intracellular trafficking pathway that controls the number and location of these ion channels on the cell surface.

“Previously, we were unsure how the ion channels get out to the surface of the cell,” says Dr Welling. "We found a new mechanism that operates like a molecular zip code, ensuring that the appropriate numbers of ion channels are sent to the correct cellular location, the cell surface. It also functions as a type of proofreading mechanism, making sure that only correctly made ion channels make it to the cell surface."

Dr Welling and his colleagues examined the molecular pathology of the genetic condition Andersen-Tawil Syndrome, characterised by uncoordinated muscle contractions, paralysis and disruptions in the normal heart rhythm. The syndrome is caused by mutations in the gene known as KCNJ2, which encodes a potassium channel in the heart and skeletal muscle known as Kir2.1.

The scientists examined how mutations in the potassium channel affects its passage through a key intracellular sorting station called the Golgi apparatus. The Golgi apparatus modifies, sorts and packages molecules for the cell's use. Dr. Welling's lab found that the Golgi apparatus selects the Kir2.1 channel to travel to the surface of the cell in an unusual, signal-dependent manner. The signal determines where the Golgi apparatus sends the potassium channel and how many it sends and verifies that the channels are of quality. In patients with Andersen-Tawil Syndrome, the signal is faulty and fails to properly regulate the ion channels and their path to the cell surface.

“Elucidating the mechanisms behind this rare disease provides insight into more prevalent forms of arrhythmia such as heart failure,” says Dr Welling. “There is great interest in understanding the mechanisms by which cardiac ion channels are regulated. This new pathway may be an excellent target for therapeutic intervention for both Andersen-Tawil syndrome and the far more common condition, like arrhythmias associated with heart failure.”

The study has implications beyond the science of the heart, he added. The class of ion channels the researchers examined includes about 12 other ion channels that control various body processes from cognition to the salt balance in the kidneys. The next step for his lab, Dr Welling says, is to study this pathway in relation to the kidneys. It is possible the same pathway affects the entire class of channels and helps regulate all the body processes associated with them.



Stem cells show promise in healing damaged hearts



Efforts to use stem cells to help revitalise hearts damaged by heart attack got a boost from three studies presented at the annual meeting of the American Heart Association, recently.

Cardiologists attending the conference heard how infusing bone marrow stem cells into the heart soon after a heart attack might improve survival, and how cardiac stem cells might also come to the aid of patients battling heart failure.

Doctors have recently been using bone marrow-sourced stem cells to repair the damage done to cardiac tissue by heart attack. And two new studies presented at the meeting may help define the “window of opportunity” during which this therapy is likely to save lives.

Infusing these cells into the heart several days after a heart attack is safe and provides benefits that last up to five years, one study found. However, waiting 10 to 20 days after a heart attack to inject the cells back into the heart is too long, the second trial concluded.

In the first study, German researchers led by Dr David Leistner of the University Hospital of Frankfurt found fewer deaths, fewer subsequent heart attacks and fewer procedures needed to open blocked arteries in people who received bone marrow stem cells within a few days of a heart attack. Earlier studies had shown that this experimental treatment improved heart muscle function for up to four months after a heart attack, but the new study, involving 62 patients, showed that these benefits last for up to 5 years.

“This is a big deal,” said Dr Joshua M. Hare, the director of the Interdisciplinary Stem Cell Institute at the University of Miami Miller School of Medicine. “There is a lot of controversy in the field about how much heart function actually improves after this treatment,” he said. “Many experts argue that although published results were statistically significant, that they might not have been clinically meaningful. The thing that matters the most is whether or not there was a reduction in [death], and this study shows that there might be.”

However, another study presented at the meeting found that waiting 10 to 20 days after a heart attack to infuse bone marrow stem cells may be too long. The findings also appeared in the 14 November 2011 online edition of the Journal of the American Medical Association.

The study involved 87 patients who had undergone angioplasty and/or placement of an artery-opening stent after heart attack. The researchers injected stem cells into the patients’ hearts about two to three weeks after a heart attack – only to find that therapy did not improve heart function after six months.

“When you have such a brand new treatment, negative data can be just as helpful as positive data,” said Dr Hare. The take-home message, according to Dr Hare: “This is too late to give the cells to the heart.”

Study co-author Dr Robert Simari, a cardiologist at the Mayo Clinic in Rochester, Minnesota, agreed.

“We are modifying our prior enthusiasm for bone marrow stem cells and developing some framework for their use,” he explained.

Stem cells sourced from bone marrow are not the only type being studied in this way, however. A third study looked at the use of stem cells originating from the patient’s own heart.

The results of a phase 1 clinical trial presented at the AHA meeting, published simultaneously in The Lancet, found real benefit from cardiac stem cell infusions for heart failure patients who had suffered a heart attack. This is the first time this approach has been tested in humans, the team said.

In the Stem Cell Infusion in Patients with Ischemic Cardiomyopathy (SCIPIO) study, researchers retrieved cardiac cells from individuals who were undergoing bypass surgery to re-open blocked arteries. The cells were taken from undamaged areas of the heart, purified, harvested and then injected back into the patients’ hearts four months later.

And it worked. Dr Roberto Bolli of the University of Louisville and colleagues report that the therapy improved heart function for 16 people with heart failure who received an infusion of their own cardiac stem cells. What’s more, the scars on their hearts are healing, the study showed.

“This is more promising in terms of the magnitude of the effect than what we are seeing with bone marrow stem cells,” said one expert, Dr Kenneth B. Margulies, a professor of medicine at the Hospital of the University of Pennsylvania in Philadelphia.

Still, he cautioned that the research is in its infancy, and more studies are needed. Right now, this procedure is for patients who are in the throes of a heart attack, he noted. “We are getting more bang for the effort when this is not done in the middle of crisis,” he said.

While more study is needed to understand the best ways to use the different types of stem cells after a heart attack, they will both likely have a big role in preventing or reversing damage after a heart attack in the future, Dr Simari said.

“In the next 10 to 15 years, these stem cells will be an off-the-shelf sell. We won’t need to harvest them and can take them off the shelf and deliver them at that time or soon thereafter,” he said. He conjectured that one healthy donor could provide thousands of doses.

 Date of upload: 21st Jan 2012

 

                                  
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