Research finds new target in search for why statin drugs may cause problems for some patients

10th February, 2016
Research by the University of Warwick, the University Hospital Coventry and Warwickshire NHS Trust (UHCW), and Tangent Reprofiling Limited, has discovered that statin drugs interact with a gap junction protein called GJC3 that releases ATP, a major signaling molecule for inflammation in the body.  This discovery provides a significant new target in the search for why statin drugs can sometimes cause harmful effects such as muscle toxicity in some patients.

GJC3 gap junction proteins

Speaking on behalf of the team in the Department of Chemistry at the University of Warwick, Dr Andrew Marsh said:

“Statins are powerful cholesterol-lowering medicines that are widely prescribed to reduce the burden of cardiovascular disease. Gap junction proteins are important in forming communication channels between cells and organs in the body. In this new research, two clinically used statin therapeutics have been found to interact with an important part of GJC3, a gap junction protein which acts to release ATP, a signaling molecule that is key to the body’s response to injury and inflammation.

“Many people know ATP as the cell’s main energy transfer molecule, but when released outside cells, ATP coordinates how tissues including our liver and muscles deal with recovery from injury. These results may give us better understanding of how some of the harmful effects of statins in some patients, such as muscle toxicity, might come about”.

The new research paper entitled “Simvastatin sodium salt and fluvastatin interact with human gap junction gamma-3 protein” http://dx.plos.org/10.1371/journal.pone.pone.0148266 is published on Wednesday 10th February 2016 in the open access journal PLOS ONE. The study was a collaboration between scientists and clinicians at the University of Warwick, the University Hospital Coventry and Warwickshire NHS Trust (UHCW) and Tangent Reprofiling Limited.

The researchers found that the statins simvastatin sodium salt and fluvastatin were found to interact with a peptide from the gap junction protein GJC3. In work which confirmed the observed interaction, the researchers also found that certain pharmacological probes of other gap junction proteins are also bound to the peptide sequence they had identified. The orange colour in the Figure highlights the important portions of GJC3 gap junction proteins.

University of Warwick research chemist Dr Andrew Marsh also said that

“GJC3 is present in many tissues in the body, but its role in cell signaling is poorly understood. Our work opens doors to its investigation”.

Professor Donald Singer, President of the Fellowship of Postgraduate Medicine and who was the lead investigator of the teams working on this study in Warwick Medical School and UHCW commented

“Finding additional ways in which statins act at the cellular and molecular level is important for giving clues to potential new medical applications for these drugs. 

"These results may also give us better understanding of how some of the harmful effects of statins in some patients might come about”.

Notes for editors:

The research refers to the open access journal PLOS ONE paper http://dx.plos.org/10.1371/journal.pone.pone.0148266, 10 Feb 2016 and the paper was entitled Simvastatin sodium salt and fluvastatin interact with human gap junction gamma-3 protein”. PLOS ONE publishes work from science and medicine and “facilitates the discovery of connections between research whether within or between disciplines”.

The work was funded by the Engineering and Physical Sciences Research Council (EPSRC, UK), the University of Warwick and Tangent Reprofiling Limited. EPSRC’s vision is “for the UK to be the most dynamic and stimulating environment in which to engage in research and innovation.”

https://www.epsrc.ac.uk/about/facts/mission/

Equipment used in this research was obtained through Birmingham Science City: Innovative Uses for Advanced Materials in the Modern World with support from Advantage West Midlands (AWM) and part funded by the European Regional Development Fund (ERDF).

For further information please contact:

Dr Andrew Marsh,

Department of Chemistry, University of Warwick, Coventry CV4 7AL. Tel. +44 24 7652 4565

a.marsh@warwick.ac.uk

 or

 Peter Dunn, Director of Press and Policy,

 University of Warwick, Tel UK: 024 76523708 office 07767 655860 mobile

 Tel Overseas: +44 (0)24 76523708 office +44 (0)7767 655860 mobile/cell

 Email: p.j.dunn@warwick.ac.uk

PR31 PJD 9^th February 2016

NICE and wider use of statins?

In the UK it is currently recommended that a statin should be prescribed to lower cholesterol for a
patient in whom the risk of developing cardiovascular disease in the next 10 years is 20% ie 1 in 5.

NICE - the National Institute for Health and Care Excellence - is now consulting on its proposal to reduce the threshold for prescribing a statin to a 10% ie 1 in 10 risk of cardiovascular disease in the next 10 years.

Here are my comments within the 12th February 2014 Science  Media Centre briefing on this new draft guidance from NICE:

"Heart disease, strokes and other serious disorders of the circulation are a major cause of premature ill health and death. 

Statins can help to prevent and reduce the severity of these serious medical problems. 

This initiative from NICE is important in extending to many more people protection from serious cardiovascular risk. 

Clear information will need to be made available on two key points: the need to combine statin use with a healthy lifestyle and addressing the other risk factors commonly present in people with high cholesterol, and information on the balance of risk versus benefit for these powerful medicines."

More comments from the SMC briefing.

The NICE draft proposal on statins.

A good time to get weight in trim

New Year is a familiar time for people to make resolutions and aims to improve lifestyle.

Why bother about overweight?
Excess weight increases the burden of cardiovascular risk (high blood pressure, raised cholesterol and diabetes mellitus); causes premature ageing of arteries, leading to heart attacks, strokes and other serious disorders of the heart, brain and circulation; contributes to risk of sleep dusturbance and sleep apnoea syndrome; causes premature joint ageing with arthritis; non-alcholic fatty liver disease is the commonest cause worldwide of liver damage; and increased risk of cancers - weight gain and overweight estimated to be linked to 1 in 5 cancers.
People who have no difficulty in maintaining normal weight may find it difficult to understand the challenges. For those who are currently overweight, the challenges in regaining a more healthy weight include beating the psychological, physical and social addiction to causes of overweight, and resisting peer pressure.

Getting started
Importants steps on the path to reducing excess weight include being ready to think about action, to think about taking action and to prepare to take action. That might mean telling friends and family you are serious about losing weight, and to seek whatever help may work - e.g.  family doctor or nurse or other health professional, and support groups for the overweight.

What works? 
Smaller portion size, cutting down on processed foods and increasing exercise are the big 3 factors that help. Keep a weight chart and if possible find a friend with whom to lose overweight. Wear a belt. Pace your eating and drink water with your food. Eat regular small meals. Avoid snacking, Research evidence suggests that successful measures include recording weight regularly, knowing the approximate energy intake of what you eat, and regular activity.
It is also clear that insight into the personal health risks of overweight provide extra incentive to lose weight. Better of course to reduce excess weight before serious clinical effects of overweight occur.
There are many support groups and diet plans available to order, often at high cost.

Research evidence suggests that success in maintaining weight loss is associated with clear strategies for coping with life stresses and with 'continued adherence to diet and exercise strategies, low levels of depression and disinhibition, and medical triggers for weight loss'. In contrast, unsuccessful weight maintainers are erratic or inconsistent in recording their weight and being vigilant in keeping to healthy types and amounts of food and in continuing regular activity.
Once overweight people have maintained a weight loss for 2-5 years, the chances of longer-term success in maintaining a healthy weight are much greater.
 
Apps
 There an increasing variety of 'apps' for smartphones and PCs, that reinforce the combined impact of healthier dietary intake and maximising exercise. Many are free, with myfitnesspal an excellent example. These and other free lifestyle apps are like your personal health bank. The more active you are, the more energy balance you have towards losing weight, the more you eat, the less reserves in your health bank.

© DRJ Singer
@HealthMed 

Companion diagnostics - a new concept for safer medicines?

@HealthMed Diagnostics can be used in several ways: to establish the nature, subtype and severity of disease; to monitor wanted response to treatment with lifestyle, drugs and/or devices; to monitor for disease progression and for adverse effects of treatment. The term 'companion diagnostics' describes coupling diagnostic imaging or laboratory investigations with selection and monitoring of treatment. Although a logical idea, its use in the medical setting appears surprisingly recent.

In the late and 1980s and 1990s, reports of the use of combination diagnostics appear largely applying to veterinary and dental practice.

The partner term 'companion therapeutics' was used in a 2003 commentary on the FDA  "Draft Guidance for Industry: Pharmacogenomic Data Submission" issued on November 3, 2003, which noted that the [pharmaceutical and biotech] 'industry is now expected to accelerate its development of diagnostics and companion therapeutics towards the goal of personalized medicine'. Implicit in this evolution of a personalised approached to medicines is the recognition that diagnostics will not necessarily identify that a given patient may have a safe or effective treatment flagged as the result of testing.

An early example of a pharmacogenetic companion diagnostic is the UGT1A1 molecular assay for in vitro diagnostic use. This pharmacogenetic test was approved in 2005 by the FDA for use as a companion diagnostic to a specific drug therapy. The test was to be used to identify mutations in this gene in patients who may as a result be at increased risk of adverse reaction to the anti-cancer drug irinotecan. 

2006 and 2007 discussion of companion diagnostics pointed both to more efficient patient selection for clinical trials and a more profitable approach for drug developers. 

Current descriptions use narrower definitions of companion diagnostics as referring to tests to 'identify and detect genetic, protein, or gene expression markers to predict whether a drug works or causes adverse effect in patients'. However there is a long history of coupling tests with treatment choice and refinement, in every therapeutic area from cardiovascular disorders such as hypertension and raised cholesterol, to anaemia and treatment of lung, gastro-intestinal, renal and neurological disease.

To date there are only 75 publications in the PubMed research database with companion diagnostics as a key term, with a typical recent example from August 2011 in Nature Reviews on Clinical Oncology by La Thangue and Kerr applied to cancer chemotherapy: Predictive biomarkers: a paradigm shift towards personalized cancer medicine.

© DRJ Singer 

New ideas on diet and cardiovascular health?

What foods may actively help to promote the health of the heart, brain and circulation? And for people who have cardiovascular risk factors, heart disease or stroke syndromes, are there dietary factors that can reduce disease severity or prevent recurrent disease?

To address these and related questions outlined below, the CVRT organised an afternoon symposium on the 'Cardiovascular effects of ‘Healthy’ foods in London on Thursday 8th December, at the Medical Society of London rooms - 11 Chandos Street - 5 minutes walk from Oxford Circus. The symposium considered evidence and mechanisms for cardiovascular benefits (or not) of ‘healthy’ foods. A key message from KT Khaw was that healthy lifestyle actions are cumulative in protecting against serious disorders of the heart and circulation.

See weblink for the programme.

Too many calories, and high intake of saturated and transfats, are well recognised to increase risk of obesity, diabetes mellitus and accelerated vascular disease (atheroma) and low salt (sodium chloride) and potassium rich foods to confer cardiovascular protection.

Outstanding questions include whether particular types of macro-nutrient (protein, carbohydrate and fats) or micronutrients (vitamins, flavenoids, trace minerals) are protective. An association between dietary factor(s) and apparent cardiovascular benefit may be causative, due to 'reverse causation' [e.g. because healthier people believe in the link or are more likely to be able to afford particular dietary constituents]; or may be a coincidental association.

Speakers at the Symposium included Professor Roger Corder from the William Harvey Institute in London, Professor KT Khaw from the University of Cambridge and Associate Professor Naila Rabbani from the University of Warwick. KT Khaw  discussed current controversies, Naila Rabbani  bioactives in fruit and vegetables, and Roger Corder dietary polyphenols and potential vascular benefits of red wine and chocolate. And Jinit Masania outlined a new EU research programme, applying nutrigenomics to assess health claims made for foods.

This Symposium followed the July 2011 event on Exercise and Cardiovascular Health, also organized by the Cardiovascular Research Trust.

Further Symposia planned by the Cardiovascular Research Trust:
- 2nd Symposia on Cardiovascular Health, Diet and Exercise: Thursday 6th December 2012 

- 3rd Symposia on Cardiovascular Health, Diet and Exercise: Thursday 5th December 2013 

 

See blog on the French healthy heart 'paradox' 20 years on.

See also Dr Carolyn Staton’s excellent blog on 'Food and microcirculation' on the British Microcirculation Society site. 


© DRJ Singer

Exercise and cardiovascular health on Everest

Jesuit priest Father Jose Acosta, wrote of his crossing the Andes in the late 16th century problems with sickness and vomiting which he attributed to the "thinne air", so "delicate as it is not proportionable wth the breathing of man". In 1865 the first man to climb the Matterhorn, Edward Whymper, recently commemorated in London by a blue plaque, was an early student of sickess at altitude. In recent modern times, climber Charles Houston made a major contribution to research into mountain sickness, his interest inspired by his episode in August 1953 of unconsciousness high on K2. He crystallised key ideas on mechanisms in his 1980 book "Going Higher: Oxygen, Man and Mountains".  Speaking about his talk at the 14th July Symposium on 'Exercise and Cardiovascular Health’ organized by the Cardiovascular Research Trust, Professor Chris Imray commented: "increasing numbers of people travel to altitude for both leisure and work purposes. On ascent to altitude, there is a reduction in atmospheric pressure, and there is consequently a reduction in the inspired levels of oxygen. The resulting physiological challenge stresses the body both at rest and further during exercise.

The cardio-respiratory challenges and the subsequent responses of ascending to high altitude will be discussed in detail, as will the role of ‘altitude training’."

Professor Imray will present "unique data from the Caudwell Xtreme Everest expedition, including arterial blood gases and the response to exercise at extreme altitude ...".

These studies provide important messages for health and risk for climbers at high altitude. They raise interesting questions about impact on brain and heart function of working at high altitude for border guards who are not acclimatised to low oxygen levels. They also provide insight into the physiological challenges and pressure for emergence of survival genetic variants for populations historically living at altitude.

See the symposium website for the programme.

Exercise and cardiovascular health

The good news is that even mild activity can be helpful in keeping healthy and in reducing risk of joining the pandemic of cardiovascular disease in the 'developed' world and emerging epidemic of heart attacks and strokes in less developed countries.

At the elite end of the exercise spectrum, internationally competitive athletes benefit from positive feedback effects of exercise on the heart and circulation. 

And for patients with established clinical heart problems, exercise under medical supervision is now well recognised to help to complement medical and surgical treatments to aid recovery and reduce the risk of future heart disease.
Not a good idea though for the out-of-condition to go from none to extreme exercise. What advice should the health or sports professional consider ?
These themes form the programme for a symposium on 'Exercise and cardiovascular health' in London on the afternoon of Thursday 14th July 2011. 

Of interest to a diverse audience - sports professionals and health professionals and students looking for an update on benefits and risks of exercise, from prospective to the elite athletes interested in benefits of exercise for their health and performance, to people with heart conditions wanting to find out more about exercise and the heart. And as an interesting case study on extreme athletes, surgeon and Everest researcher and mountaineer Professor Chris Imray will be discussing exercise at extreme altitude. 

See the symposium website for the programme.