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CINCINNATI—Researchers at UC have confirmed that fat surrounding the outside of arteries in humans—particularly the left coronary artery—may influence the onset of coronary artery disease, or atherosclerosis, which is the leading cause of death in the U.S.

These findings, being presented at the American Heart Association’s Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) 2012 Scientific Sessions in Chicago April 20, 2012, may help in identifying the molecular culprit, with the goal of creating targeted therapies for atherosclerosis before the disease forms.

Coronary artery disease is a narrowing of the small blood vessels that supply blood and oxygen to the heart.

Tapan Chatterjee, PhD, and researchers in the division of cardiovascular diseases at UC found through global gene expression analysis (measurement of the activity of thousands of genes at once) that this outer fat tissue—known as perivascular fat tissue—is different from subcutaneous (beneath the skin) fat tissues in other parts of the body.

Research has previously shown that perivascular fat tissue in humans with coronary artery diseases is highly inflamed, leading to the belief that dysfunctional perivascular fat is the real culprit in the formation of coronary artery diseases.

Chatterjee’s team was able to replicate this inflammation in animal models.

“The proximity of the perivascular fat to the artery easily influences the function of the coronary blood vessel wall,” Chatterjee says. “The perivascular fat is very sensitive to high-fat diet induced inflammatory changes in mice. We found that by transplanting perivascular fat from high-fat diet fed obese mice to the carotid artery of lean mice, the tissue was detrimental to the blood vessel wall and promptly caused disease to form there.

“Our next steps will be to identify various secreted factors, or signals, from perivascular fat tissue of obese mice that could negatively influence the functions of the blood vessel wall,” he continues. “We believe this cross-talk between perivascular fat and the coronary artery is very important in triggering coronary artery diseases. We hope this knowledge helps in targeting the molecules before the onset of coronary artery diseases and treating patients before they ever experience the disease.”

This study was funded by the National Heart Lung and Blood Institute.

Source: Eurekalert: 4/21/2012

Sophia Antipolis, France: Tuesday 14 June : The European Society of Cardiology (ESC) Working Group of Atherosclerosis and Vascular Biology has published a position paper to raise the profile of vulnerable plaques and the need for greater use of therapies to promote plaque stabilisation. The position paper, published online today in Thrombosis and Haemostasis, is also calling for more research into the causes of plaque rupture, and for the development of better diagnostics and treatments.

“We want more medical professionals to understand the concept that stabilising vulnerable plaques offers a fundamental approach to preventing cardiovascular events,” said Seppo Ylä-Herttuala, chairman of the position paper task force. Indeed, he added, several statin trials for secondary prevention have reported a reduction in cardiovascular events, and furthermore anti platelet therapies have been shown to have a beneficial effect.

“Introducing stabilisation of vulnerable plaques as part of secondary prevention would offer the opportunity to wipe out half of coronary events,” said Ylä-Herttuala, from University of Eastern Finland (Kuopio, Finland).

“Wide spread stabilization of vulnerable plaques would also have important socio economic implications dramatically reducing the need for invasive treatments,” said Christian Weber, also a member of the working group.

The idea of vulnerable plaques is that not all plaques (the fatty deposits in arterial walls) are equal and that some are particularly prone to rupture and causing cardiovascular events . These plaques are not necessarily the same as those that cause symptoms such as angina. Explaining the concept of vulnerable plaques, Weber, from Ludwig-Maximilians-University (Munich, Germany) said that it is thought that inflammatory cells resulting from ongoing inflammation destabilise the structure of the plaque. “It is believed that they degrade the fibres that make the plaque stable, leading to a greater potential for the plaque to rupture,” he said.

The concept of plaque stabilisation was introduced to explain how acute coronary events could be reduced by lipid lowering therapy without accompanying regression of coronary atherosclerosis seen on angiography.

Part of the motivation for producing the working paper, said Ylä-Herttuala, was to provide general clinicians with greater guidance. “The whole field can be really confusing. After patients have been treated with statins for two or three years family doctors can be really concerned that they see no changes on angiograms. In such cases there’s a danger that they may decide to stop life saving treatment.”

The position paper reviewed the current state of knowledge around unstable plaques exploring the role of inflammation, chemokines, growth factors, platelets, angiogenesis and smoking. Evidence for therapies such as statins, antiplatelet therapies, and antihypertensive treatments were outlined, in addition to reviewing new approaches ,such as the development of drugs targeting the fibrous cap. Detection of unstable plaques through genetic testing, biomarkers and imaging was also explored.

“The single most important advance that would help us to tackle vulnerable plaques would be to have a non invasive imaging tool that would allow us to identify at risk patients before they suffer an event,” said Ylä-Herttuala.

The position paper is also calling for more translational research into imaging, biomarkers and the development of new treatments. “There is a real need to develop treatments specifically for the purpose of stabilising vulnerable plaques. At the moment we only have treatments that were discovered to have a beneficial effect through serendipity,” said Weber.

Dr. Brian Denton
A new study from North Carolina State University shows that the vast majority of patients at high risk for heart disease or stroke do a poor job of taking statins as prescribed. That’s especially unfortunate, because the same study shows that taking statins can significantly increase the quality and length of those patients’ lives.

“We found that only 48 percent of patients who have been prescribed statins are taking their prescribed dose on a regular basis after one year – and that number dips to approximately 27 percent after 10 years,” says Jennifer Mason, a Ph.D. student at NC State and lead author of a paper describing the study. Statins are a component of many current cardiovascular medical treatment guidelines. They lower cholesterol levels and may significantly reduce the risk of heart attack and stroke, particularly in patients that are considered to be at high risk.

The researchers also found that, for high-risk patients, high adherence to a prescribed statin regimen may increase quality-adjusted life years (QALYs) by as much as 1.5 years compared to low adherence – and up to two years compared to not taking statins at all. Low adherence means a patient is taking the statins irregularly or at less than the prescribed dosage. QALYs are established metrics for measuring the effect of health conditions, such as heart disease and stroke, on quality of life.

The study used operations research models to look specifically at patients who have type 2 diabetes, because they are at particularly high risk for heart disease, heart attack and stroke.

“These findings suggest that adherence-improving interventions – such as patient education or electronic reminders to take medications – can significantly improve the quality and length of life, particularly for high-risk patients,” says Dr. Brian Denton, co-author of the paper and an associate professor in the Edward P. Fitts Department of Industrial & Systems Engineering at NC State.

The paper, “Optimizing Statin Treatment Decisions for Diabetes Patients in the Presence of Uncertain Future Adherence,” is forthcoming from the journal Medical Decision Making. The research was funded by the Agency for Healthcare Research and Quality (AHRQ) and the National Science Foundation (NSF). The paper was co-authored by Dr. Darin England; Drs. Steven Smith and Nilay Shah of the Mayo Clinic College of Medicine; and Mr. Murat Kurt of the University of Pittsburgh.

“Optimizing Statin Treatment Decisions for Diabetes Patients in the Presence of Uncertain Future Adherence”

Authors: Jennifer E. Mason and Brian T. Denton, North Carolina State University; Darin A. England; Steven A. Smith and Nilay D. Shah, Mayo Clinic College of Medicine; Murat Kurt, University of Pittsburgh

Published: forthcoming, Medical Decision Making

Abstract: Background: Statins are an important part of the treatment plan for patients with type 2 diabetes. However, patients who are prescribed statins often take less than the prescribed amount or stop taking the drug altogether. This suboptimal adherence may decrease the benefit of statin initiation.

Objective: To estimate the influence of adherence on the optimal timing of statin initiation for patients with type 2 diabetes.

Method: The authors use a Markov decision process (MDP) model to optimize the treatment decision for patients with type 2 diabetes. Their model incorporates a Markov model linking adherence to treatment effectiveness and long-term health outcomes. They determine the optimal time of statin initiation that minimizes expected costs and maximizes expected quality-adjusted life years (QALYs).

Results: In the long run, approximately 25% of patients remain highly adherent to statins. Based on the MDP model, generic statins lower costs in men and result in a small increase in costs in women relative to no treatment. Patients are able to noticeably increase their expected QALYs by 0.5 to 2 years depending on the level of adherence.

Conclusions: Adherence-improving interventions can increase expected QALYs by as much as 1.5 years. Given suboptimal adherence to statins, it is optimal to delay the start time for statins; however, changing the start time alone does not lead to significant changes in costs or QALYs.

WINSTON-SALEM, N.C. – Monday, March 21, 2011 – For a patient at high risk of cardiovascular disease (CVD), keeping up with what pills to take at different times of the day can be tedious. Window sills lined with prescription bottles – a pill for cholesterol, another for blood pressure, and an aspirin to keep blood thin and flowing – the list can get quite long and, as a result, many people, especially the elderly, often forget doses or take the wrong pill at the wrong time.

But what if there was a single pill that had all the benefits of multiple medications in one dose? Would people take it? Would doctors prescribe it? And would it be effective?

A new study done by researchers at Wake Forest Baptist Medical Center provides evidence that, in fact, such a pill may be a viable option for developing countries, where CVD is strongly emerging and the demand for cost-effective, low maintenance treatment is high.

“The idea behind the polypill is that it offers a simpler way to give medications to people so that they will have better adherence to their pills,” said Elsayed Z. Soliman, M.D., M.Sc., M.S., director of the Epidemiological Cardiology Research Center (EPICARE) at Wake Forest Baptist and lead author on the study. “It’s not always easy for people to consistently take multiple pills, even if they are needed to treat a serious condition, like CVD. This is especially true in developing countries, where cost of CVD medications is another major challenge. This one pill has the potential to improve adherence while being less costly to the population in developing countries.”

To adopt the polypill approach in developing countries, a large scale clinical trial is needed, Soliman added. However, before conducting such a trial, research was needed to see if it was even possible to conduct a clinical trial in a developing country.

Going into this study, there were many perceived barriers to doing research in a developing country, Soliman said. Among them, would the country have investigators capable and willing to participate in a study and the necessary follow-up? Would patients sign up to participate? And if the pill was proven to work, would doctors even feel comfortable prescribing it?

So Soliman and colleagues brought the study to Sri Lanka, where they enrolled 216 participants without diagnosed CVD, in the hope of answering some of these questions. Half of the participants received “standard’ treatment for CVD risk prevention, and the other half received the polypill. Patients were recruited as planned. Two hundred three patients (94.0%) completed the treatment program and returned for their follow-up visits. No safety concerns were reported.

These findings suggest a high rate of patient acceptability, a finding that is bolstered by the fact that the majority of patients who completed the trial – 90 percent – indicated that they would take the polypill “for life” if proven to be effective in reducing CVD risk. Approximately 86 percent of the physicians surveyed agreed with and supported use of the polypill for primary prevention and 93 percent for secondary prevention of CVD. In terms of reduction in CVD risk, both the polypill and “standard treatment” resulted in marked reductions in systolic blood pressure, total cholesterol and 10-year estimated risk of CVD.

“Our trial has fulfilled its purposes,” Soliman said. “We wanted to check the feasibility of doing a large-scale clinical trial with a polypill in a developing country and to examine the acceptability of the polypill by patients and physicians, and we now know that it’s feasible and acceptable.”

He added that the “standard” treatment in this trial was administered by highly specialized physicians in tertiary-care centers, making it a tough competitor, yet the simple polypill held its own.

Although feasibility has been demonstrated, Soliman explained that there are other important questions about the polypill that still need answers, such as: Which patient population should a polypill target: those who have not yet been diagnosed with CVD (primary prevention) or those who have a CVD diagnosis in their medical history (secondary prevention)? Also, what components should make up the pill and in what doses will they be most effective?

“There are many questions, but a single trial will never answer all of them,” Soliman said. “At least now we know that it is possible to begin looking for the answers.”

The study, published recently in Trials, was funded by World Health Organization (WHO) headquarters in Geneva. Co-authors include Curt D. Furberg, M.D., Ph.D., of Wake Forest Baptist; Shanthi Mendis, M.D., of the WHO, Geneva; Wasantha P. Dissanayake, M.D., Noel P. Somasundaram, M.D., Padma S. Gunarantne, M.D., and I. Kumundini Jayasingne, M.D., of the Ministry of Health, Sri Lanka.

Author Interview: Dr. Kami Banks

Clinical characteristics, vascular function, and inflammation in women with angina in the absence of coronary atherosclerosis the dallas heart study.

What are the main findings of the study?

Our study has several major findings.  First, we found the clinical syndrome of angina is not related to coronary atherosclerosis in women.  Second, African-American ethnicity, increased waist circumference and premature family history of myocardial infarction are independently associated with angina in women without coronary atherosclerosis.   Finally, measures of poor vascular health, including reduced aortic compliance and increased serum levels of cell adhesion molecules, were also related to angina in this population.

Clinical characteristics, vascular function, and inflammation in women with angina in the absence of coronary atherosclerosis the dallas heart study.

JACC Cardiovasc Imaging. 2011 Jan;4(1):65-73.
Banks K, Puttagunta D, Murphy S, Lo M, McGuire DK, de Lemos JA, Chang AY, Grundy SM, Khera A.

Read the rest of the Interview with Dr. Kami Bank as well as the abstract on Angina.com