New cholesterol drug shows promise

reposted from: http://www.nhs.uk/news/2013/10October/Pages/New-cholesterol-drug-show-promise.aspx

crabsallover highlights, key points, comments / links.

“Heart attack risk could be cut by new cholesterol lowering drug,” The Guardian reports.

This headline – and others like it – stretch the findings from an early safety trial of ALN-PCS, a new drug that targets LDL (or ‘bad’) cholesterol.

Such trials are not designed to see whether a drug is effective, and in this case, the trial had too few people involved to be able to tell.

ALN-PCS belongs to a class of molecules known as small interfering RNAs or siRNAs. The drug is designed to block the effects of a protein, called PCSK9, that is associated with cholesterol levels.

The trial included 32 healthy people and found that a single dose of the new drug was safe and well tolerated. Further trials are planned to assess the long-term safety and effectiveness of the drug in people with high cholesterol who need lipid-lowering medications such as statins.

As this was just a phase I trial the drug was not compared to other cholesterol-lowering drugs, and information on long-term outcomes, such as reduced risk of heart attacks, was not assessed. Also, the drug was tested in healthy volunteers and not among individuals with very high cholesterol levels who would normally need such treatment.

Further research, in the form of a phase II clinical trial is now required.

The 1, 2, 3 of clinical trials

There are three levels to clinical trials:

• phase I trials are small trials that enrol healthy people and are primarily designed to see if a drug is safe, and to determine the best dosage for future studies
• phase II trials are larger, longer-term trials designed to see if a drug is both safe and effective
• phase III trials are very large trials, usually lasting several years, to see how well the drug works in real patients

Where did the story come from?

The study was carried out by researchers from Alnylam Pharmaceuticals, the University of Texas South Western in the US, Guy’s Hospital in London, and Covance Clinical Research Unit, Leeds. The trial was funded by Alnylam Pharmaceuticals.

A number of the researchers involved in the study are employees of, and/or stock owners in Alnylam Pharmaceuticals, which represents a potential conflict of interest (which was declared in the study).

The study was published in the peer-reviewed medical journal, The Lancet.

Media coverage of the study was mixed, with most headlines focusing on the cholesterol lowering effects of the drug. This was despite the fact that this was not the main aim of the study, and that it was not large enough to detect such changes. The Daily Telegraph did go on to report that, “larger studies would now be needed to check long-term safety and tolerability of the drug on patients who take statins as well as those who cannot take the drugs”.

What kind of research was this?

This was a phase I clinical trial (a randomised controlled trial) that assessed the safety and tolerability of a newly developed cholesterol lowering drug called ALN-PCS.

ALN-PCS is a small interfering RNA (siRNA) molecule, which prevents the production of a protein called PCSK9. PCSK9 has been shown to bind to other proteins called LDL receptors, which are responsible for clearing ‘bad’ LDL cholesterol from the blood. When these receptors are blocked by PCSK9, LDL cholesterol builds up in the blood. There is substantial evidence that high LDL cholesterol levels increase the risk of coronary heart disease.

ALN-PCS works by interrupting the production of PCKS9. The process by which such siRNA molecules interrupt gene expression is called RNA interference (RNAi).

Based on previous research in animals, researchers expected that when participants received ALN-PCS, the levels of PCSK9 in their blood would drop, and a corresponding reduction in LDL cholesterol would be seen.

What did the research involve?

The researchers recruited 32 healthy volunteers with mild to moderately elevated LDL cholesterol. They were randomly assigned to receive either a placebo infusion of a salt solution or a single infusion of the drug, called ALN-PCS, into a vein.

The night and morning before the infusion, volunteers were given a pre-treatment including paracetamol, a corticosteroid and an antihistamine. This was in order to reduce the chances of an adverse reaction to the infusion of the drug.

As a phase I trial, the main aim of the study was to determine whether the drug was safe, and which doses were tolerable by people. As such, six different doses of ALN-PCS were tested, and the primary outcome of the study was the frequency and severity of adverse events (side effects).

As a secondary outcome, the researchers checked for changes in PCSK9 and LDL cholesterol levels in the blood, measured at the beginning of the study and seven days after the drug infusion.

What were the basic results?

Of the 32 healthy participants, 24 were randomly assigned to receive the drug (ALN-PCS) and eight to receive placebo.

Treatment with ALN-PCS was found to be both safe and well tolerated at all doses.

No one receiving the drug experienced any drug-related serious side effects. One patient receiving a low dose was diagnosed with a serious condition on the third day of the study. However, this was determined to be unrelated to the drug being trialled.

Overall, similar proportions of patients receiving ALN-PCS and placebo experienced mild to moderate side effects (79% in the treatment group and 88% in the placebo group).

The researchers also found that the single dose of ALN-PCS was found to significantly reduce concentrations of PCSK9 in the blood, with greater reductions seen at higher drug doses. This was associated with a reduction in LDL cholesterol levels, with higher drug doses causing greater and longer reductions in cholesterol concentrations. The highest drug dose resulted in an average reduction of 40%, compared to placebo.

How did the researchers interpret the results?

The researchers concluded that treatment with the RNAi drug ALN-PCS was safe and well tolerated, and that “future trials are needed to fully assess the benefit and long-term safety of ALN-PCS in various patient populations” including patients who are receiving statins as well as patients who cannot tolerate statins.

Conclusion

Media headlines reporting on this phase I trial concentrated on the secondary outcome (that ALN-PCS reduced LDL cholesterol levels). However, these results will need to be confirmed during phase II and phase III clinical trials, which will involve more participants who would normally receive cholesterol-lowering treatment.

While it is tempting to focus on the results of the cholesterol levels, phase I clinical trials are designed to test the safety of a new drug to make sure it is safe enough to test further. They also aim to determine what the highest tolerable dose is, so the appropriate one can be used in later studies. For those reasons, they involve testing the drug in a small group of healthy individuals.

The researchers note (although no media outlets seemed to report on this aspect of the study) that the study was too small to detect statistically significant changes in PCSK9 or LDL cholesterol levels compared with placebo group.

The results of this study will be used to design further phase II and phase III trials, which will further characterise the safety profile of the drug and determine its effectiveness at reducing LDL cholesterol among people who need cholesterol-lowering medications. Only then can we determine whether the drug offers an effective option for managing high LDL cholesterol.

While perhaps less immediately interesting from the general public’s perspective, one of the more exciting aspects of this research is that it is the first time an RNA interference drug has been shown – in humans – to lower a protein that is made in the liver. It is also the first time such a drug has shown a measurable health benefit, even though this was not the primary outcome of the study.

The process of RNA interference is a relatively new discovery (first described in 1998), and substantial research efforts have been directed towards the development of siRNA treatments for human disease. This field of research has hit several hurdles, so this study showing potential clinical benefit from siRNA treatment is exciting news for scientists.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on twitter.

Links to the headlines

Heart attack risk could be cut by new cholesterol lowering drug, study says. The Guardian, October 3 2013

New drug 'cuts cholesterol'. ITV News, October 3 2013

Could a single dose of this drug lower your cholesterol? Treatment may help those at risk of heart disease who can't take statins. Mail Online, October 3 2013

New cholesterol drug without the side-effects. The Daily Telegraph, October 3 2013

Tests of new cholesterol drug ALN-PCS suggest it can cut levels by more than half. Daily Mirror, October 3 2013

‘Smart’ cholesterol buster may help to stop heart attacks. The Times, October 3 2013

Links to the science

Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. The Lancet. Published online October 3 2013

Short bursts of exercise at home good for the heart

reposted from: http://www.nhs.uk/news/2013/February/Pages/Short%20bursts-of-exercise-good-for-heart.aspx

crabsallover highlights, key points, comments / links.

Short bursts of exercise, such as raking the lawn and climbing the stairs, are an excellent way of warding off health problems such as high blood pressure, high cholesterol and diabetes, the Daily Mirror and many global media outlets reported.

The news is based on the results of a cross-sectional study which suggested that even less than 10 minutes of moderate or vigorous activity, such as climbing stairs, ‘count’ and may be as beneficial as longer periods of exercise.

This useful and well-conducted study measured the physical activity of more than 6,000 adults, in addition to measuring various health markers such as blood fats, blood sugar and blood pressure, that are known to be risk factors for chronic conditions including diabetes and heart disease.

The study found that performing moderate or vigorous activity of any duration – either short bursts of less than 10 minutes or for longer – was associated with improved measurements of several cardiovascular risk factors.

The study suggests that even people who do not have time to go to the gym or an exercise class can get many of the health benefits of exercise from adopting an ‘active’ lifestyle.

While the study cannot directly prove cause and effect, it would suggest that any moderate or vigorous exercise you can fit in during the course of a day, benefits your health.

10-minute exercise programmes

NHS Choices has produced a series of 10-minute exercise programmes you can do in the comfort of your own home:

• 10-minute home cardio workout
• 10-minute legs, bums and tums home workout
• 10-minute home toning workout

Don’t forget to warm up before, and then cool down after, exercising.

Where did the story come from?

The study was carried out by researchers from Bellarmine University and Oregon State University. The source of funding for this study was not declared.

The study was published in the peer-reviewed American Journal of Health Promotion.

This study was covered by the Daily Mirror and the Mail Online. Although the gist of the story is correct, the researchers looked at short bursts of moderate and vigorous physical activity, rather than the ‘light exercise’ reported in the Mail Online.

How active should I be?

To stay healthy, adults aged 19-64 should try to be active daily and should do:

• at least 150 minutes (2 hours and 30 minutes) of moderate-intensity aerobic activity such as cycling or fast walking every week, and
• muscle-strengthening activities on two or more days a  week that work all major muscle groups (legs, hips, back, abdomen, chest, shoulders and arms)

Read more about physical activity guidelines for adults

What kind of research was this?

This cross-sectional study aimed to determine whether short bursts of physical activity were associated with a decreased risk of metabolic syndrome.

Metabolic syndrome is a term used to describe a combination of related risk factors for chronic conditions such as heart disease and type 2 diabetes – these factors include high waist circumference, blood fats, blood sugar and blood pressure.

The researchers also looked at some additional biological markers known to be risk factors for cardiovascular disease.

They looked at whether there were any differences in risk factors for short bursts of activity versus more prolonged bursts.

Cross-sectional studies have a inherent limitation as they cannot prove causation (a direct cause and effect), they can only highlight possible associations.

So in this case, the researchers cannot conclude that it is the short bursts of activity directly affecting the biological markers measured.

Also, because participants aren’t followed over time we don’t know what came first, so we don’t know:

• if people who exercise a certain way are healthier
• if people who are healthier exercise a certain way

What did the research involve?

The researchers used data collected as part of the US National Health and Nutrition Examination Survey, which collects annual health and nutrition data on a random sample of US citizens. For this study, data from 6,321 non-pregnant adults with data on physical activity from the 2003-2004 and 2005-2006 cycles was used.

A participant’s physical activity was determined by collecting data using an accelerometer. Accelerometers measure the participant’s change in velocity over time (acceleration) allowing the intensity of physical activity to be measured, as well as the duration.

Participants had data on physical activity for at least four days, and at least 10 hours each day. The researchers classified the intensity of physical activity into moderate or vigorous using cut-offs for accelerometry readings.

The researchers also classified activity levels by duration, into two main groups:

• less than 10 minutes duration (‘nonbout’)
• more than 10 minutes duration (‘bout’)

Each period of activity was terminated if accelerometry readings fell below the cut off for three minutes or more.

The researchers also calculated whether a participant met physical activity guidelines, defined as engaging in 150 minutes of moderate-intensity activity or 75 minutes of vigorous-intensity activity or some combination of the two per week, and whether a participant met the criteria by only performing short, less than 10 minute duration ‘nonbout’ periods of activity.

The US National Health and Nutrition Examination Survey also collected data on a participant’s cardiovascular risk factors, including:

• metabolic syndrome – defined as having three or more of the following symptoms: a high waist circumference, a high level of triglycerides (a type of fat), low levels of high-density (‘good’) cholesterol, elevated blood pressure, elevated fasting blood sugar
• systolic and diastolic blood pressure
• blood levels of C-reactive protein (an inflammatory marker), high-density cholesterol, low-density (‘bad’) cholesterol, total cholesterol and blood sugar
• anthropometric measurements including waist circumference, skinfold thickness and body mass index (BMI)

The researchers also collected data on age, gender, smoking status, race/ethnicity, current health status, and whether the participant was taking any medication.

The researchers analysed whether there was an association between short ‘nonbout’ periods of activity and longer ‘bout’ periods of activity and cardiovascular risk factors.

They also looked at whether there was any difference in risk factors when physical activity guidelines were only met by performing short ‘nonbout’ periods of activity.

In these analyses, the researchers controlled for age, gender, smoking status, race/ethnicity, and current health status.

What were the basic results?

The researchers found that on average, participants performed 23.6 minutes of moderate-to vigorous-intensity physical activity per day in short, ‘nonbout’ bursts, and 6.6 minutes in 10 minutes or longer bursts (this rather confusing figure is due to some people not doing any moderate to vigorous physical activity in bouts of 10 minutes or longer, during some days).

A total of 42.9% of participants met physical activity guidelines if nonbout physical activity was included, but only 9.7% met guidelines if only 10 minutes or longer periods only were included.

Both ‘nonbout’ and ‘bout’ physical activity were associated with a reduction in cardiovascular risk factors. The associations were strongest when enough activity was performed to meet physical activity guidelines.

The strengths of associations were generally similar for ‘bout’ and ‘nonbout’ physical activity for all risk factors measured, with the exception of BMI.

To make sure the results weren’t due to the fact that people who performed the longer periods of activity were also performing the shorter periods of activity, the researchers repeated the analyses controlling for 10 minutes or longer periods of activity.

Short ‘nonbout’ physical activity was still associated with a reduced risk of metabolic syndrome; favourable levels of C-reactive protein, high density lipoprotein cholesterol, triglycerides; and favourable sized waist circumference, skinfold thickness and BMI.

Again, the associations were strongest when enough ‘nonbout’ physical activity was performed to meet the physical activity guidelines.

Finally, the researchers compared the mean levels of biological markers in people meeting the physical activity guidelines solely through performing short ‘nonbout’ periods of physical activity and those meeting guidelines by performing longer periods of activity.

There was no statistical difference between the level of any marker except for BMI. Participants who met guidelines through longer periods of activity had significantly lower body mass indices (25.85) than those meeting guidelines through short periods of activity (27.49, p<0.0001).

How did the researchers interpret the results?

The researchers conclude that these results show that “with the exception of BMI, meeting physical activity guidelines using an ‘active lifestyle’ approach (nonbout activity) as opposed to a more structured exercise approach (bout activity) resulted in similar health outcomes.”

They suggest that “to reduce levels of adult adiposity (body fatness), adults are encouraged to engage in bouts of physical activity of at least 10 minutes in duration; however, for other health outcomes, an active lifestyle approach (for example, climbing a flight of stairs vs. taking the elevator), particularly of vigorous intensity, may be beneficial for initiating physical activity behaviour among inactive adults as well as being sufficient to elicit improvements in health parameters.”

Conclusion

The results of this study suggests that even short periods of physical activity ‘count’ and are associated with improved levels of several risk factors for cardiovascular disease. The study found that the strength of this association was generally as strong for short periods of activity as longer periods of activity.

This study has strengths and weaknesses. The strengths are that both physical activity and the levels of the biological markers were measured objectively, and did not rely on self-reporting, and that it was performed using a large sample of US adults.

However, it was a cross-sectional study, and cross-sectional studies have the limitation that they cannot show causation, in this case, the researchers cannot conclude whether it is the short bursts of activity that affect the biological markers measured.

Also, because participants aren’t followed over time we don’t know what came first, so we don’t know if people who exercise a certain way are healthier or if people who are healthier exercise a certain way.

However, overall this study supports the suggestion that any level of physical activity is better than no activity.

Even if you don’t feel ready to join your local gym, you can still begin making changes to your lifestyle today to improve your activity levels – read more about how you can get fitter without the gym.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter.

Links to the headlines

Well, I'll go to the foot of the stairs! Light exercise around the house is as good for your heart as workout. Daily Mirror, January 31 2013

Forget the gym and try the stairs! Short bursts of exercise are just as beneficial as a regular workout. Daily Mail, January 31 2013

Taking the Stairs, Raking Leaves May Have Same Health Benefits as a Trip to the Gym. Sciencedaily.com, published online January 28 2013

Links to the science

Loprinzi PD, Cardinal BJ. Association Between Biologic Outcomes and Objectively Measured Physical Activity Accumulated in >10-Minute Bouts and <10-Minute Bouts. American Journal of Health Promotion. Published online January 2013

High plasma HDL cholesterol is NOT associated with reduced risk of myocardial infarction

reposted from: http://www.lancet.com/journals/lancet/article/PIIS0140-6736(12)60312-2/fulltext?_eventId=login

crabsallover highlights, key points, comments / links.

Background

High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.

Methods

...

Findings

...

Interpretation

Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.

Discusssion

In summary, our results showed that polymorphisms related to plasma LDL cholesterol were consistently associated with risk of myocardial infarction, whereas this was not the case for variants related to plasma HDL cholesterol. A polymorphism in the endothelial lipase gene and a genetic score of 14 common SNPs that specifically raised HDL cholesterol were not associated with myocardial infarction, suggesting that some genetic mechanisms that raise HDL cholesterol do not lower risk of myocardial infarction. Hence, interventions (lifestyle or pharmacological) that raise plasma HDL cholesterol cannot be assumed ipso facto to lead to a corresponding benefit with respect to risk of myocardial infarction.

Cardiovascular Disease Risk Prediction Charts

reposted from: http://heartuk.org.uk/health-professionals/resources/risk-charts

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Risk charts

How to use the Cardiovascular Disease Risk Prediction Charts* for Primary Prevention

These charts are for estimating cardiovascular disease (CVD) risk (non-fatal myocardial infarction [MI] and stroke, coronary and stroke death and new angina pectoris) for individuals who have not already developed coronary heart disease (CHD) or other major atherosclerotic disease. They are an aid to making clinical decisions about how intensively to intervene on lifestyle and whether to use antihypertensive, lipid lowering medication and aspirin. The use of these charts is not appropriate for the following patients groups.

• Those with: CHD or other major atherosclerotic disease 
• Familial hypercholesterolaemia or other inherited dyslipidaemias 
• Chronic renal dysfunction 
• Type 1 and 2 diabetes mellitus

The charts should not be used to decide whether to introduce antihypertensive medication when blood pressure (BP) is persistently at or above 160/100 or when target organ damage (TOD) due to hypertension is present. In both cases antihypertensive medication is recommended regardless of CVD risk.

Similarly the charts should not be used to decide whether to introduce lipid-lowering medication when the ratio of serum total to high density lipoprotein (HDL) cholesterol exceeds 7. Such medication is generally then indicated regardless of estimated CVD risk.

To estimate an individual’s absolute 10 year risk of developing CVD choose the table for his or her gender, smoking status (smoker/non-smoker) and age. Within this square define the level of risk according to the point where the coordinates for systolic blood pressure (SBP) and the ratio of total cholesterol to HDL-cholesterol meet. If no HDL cholesterol result is available, then assume this is 1.00mmol/l and the lipid scale can be used for total serum cholesterol alone.

Higher risk individuals (red areas) are defined as those whose 10 year CVD risk exceeds 20%, which is approximately equivalent to the CHD risk of >15% over the same period indicated by the previous version of these charts. As a minimum those at highest CVD risk (greater than 30% shown by the line within the red area) should be targeted and treated now. When resources allow, others with a CVD risk of >20% should be progressively targeted.

The chart also assists in the identification of individuals whose 10 year CVD risk moderately increased in the range 10-20% (orange area) and those in whom risk is lower than 10% over 10 years (green area).

Smoking status should reflect lifetime exposure to tobacco and not simply tobacco use at the time of assessment. For example, those who have given up smoking within 5 years should be regarded as current smokers for the purposes of the charts.

The initial BP and the first random (non-fasting) total cholesterol and HDL cholesterol can be used to estimate an individual’s risk. However, the decision on using drug therapy should generally be based on repeat risk factor measurements over a period of time.

Men and women do not reach the level of risk predicted by the charts for the three age bands until they reach the ages 49, 59, and 69 years respectively. Everyone aged 70 years and over should be considered at higher risk. The charts will overestimate current risk most in the under forties. Clinical judgement must be exercised in deciding on treatment in younger patients. However, it should be recognised that BP and cholesterol tend to rise most and HDL cholesterol to decline most in younger people already possessing adverse levels. Thus untreated, their risk at the age 49 years is likely to be higher than the projected risk shown on the age-less-than 50 years chart.

These charts (and all other currently available methods of CVD risk prediction) are based on groups of people with untreated levels of BP, total cholesterol and HDL cholesterol. In patients already receiving antihypertensive therapy in whom the decision is to be made about whether to introduce lipid-lowering medication or vice versa the charts can act as a guide, but unless recent pre-treatment risk factor values are available it is generally safest to assume that CVD risk is higher than that predicted by current levels of BP or lipids on treatment.

CVD risk is also higher than indicated in the charts for:-

• Those with a family history of premature CVD or stroke (male first degree relatives aged <55 years and female first degree relatives aged <65 years) which increases the risk by a factor of approximately 1.5 
• Those with raised triglyceride levels 
• Women with premature menopause 
• Those who are not yet diabetic, but have impaired fasting glucose (6.1-6.9mmol/l) 
• In some ethnic minorities the risk charts underestimate CVD risk, because they have not been validated in these populations. For example, in people originating from the Indian subcontinent it is safest to assume that the CVD risk is higher than predicted from the charts (1.5 times). 
• The charts may be used to illustrate the direction of impact of risk factor intervention on estimated level of CVD risk. However, such estimates are crude and are not based on randomised trial evidence. Nevertheless, this approach maybe helpful in motivating appropriate intervention. 
• The charts are primarily to assist in directing intervention to those who typically stand to benefit most. 

*Cardiovascular Disease Risk Prediction Chart reproduced with permission from The University of Manchester Department of Medical Illustration, Manchester Infirmary.

ASSIGN number is the risk percent of cardiovascular disease over ten years

reposted from: http://www.assign-score.com/estimate-the-risk/visitors/

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ASSIGN score: 10

The ASSIGN number is the risk percent of cardiovascular disease over ten years, based on the recent SHHEC study. ASSIGN 20 means 20% risk. The actual risk is probably now less than that number. What matters more is what somebody's score is in relation to other ASSIGN scores, and therefore their priority or ranking for action to lower their risk.

ASSIGN score below 20 is not currently high risk, implying general preventive measures (nobody is free of risk) Repeat the scoring in 5 years or earlier, depending how high the current score is.

The higher the CRP, the greater likelihood of heart disease but CRP does not cause heart disease

reposted from: http://www.nytimes.com/2009/07/01/health/01heart.html

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Study Dismisses Protein’s Role in Heart Disease 

By GINA KOLATA Published: June 30, 2009

A blood protein that only a short time ago was thought by some to be more important than cholesterol in heart disease now appears to be little more than a bystander.


The substance, C-reactive protein, or CRP, a marker of inflammation in the body, is unquestionably associated with heart disease: the more CRP in a person’s blood, the greater the likelihood of heart disease.

But in a paper to be published Wednesday in The Journal of the American Medical Association, researchers analyzing genetic data from more than 100,000 people conclude that their study “argues against” the notion that the protein causes heart disease.

Dr. David Altshuler, a professor of genetics and medicine at Harvard Medical School, said the distinction was important. If CRP caused heart disease, lowering it would protect people. But if it was merely associated with the disease, lowering CRP would have no more effect on health than quelling a shrieking fire alarm would have on putting out a fire.

Many believed CRP caused heart disease, especially after a widely publicized study released last year suggested that people with low cholesterol but high CRP levels had fewer heart attacks if they took a statin, a cholesterol-lowering drug that also lowers CRP.

That could mean that lowering CRP could prevent heart disease. Of course, it also could have been the cholesterol lowering that was protective, but many researchers argued that it was the reduction in CRP.

“There certainly has been a very vocal constituency in the idea that CRP causes or contributes to the development of heart disease,” said Dr. Daniel Rader, a lipid expert at the University of Pennsylvania. He noted that some companies were trying to develop drugs to lower CRP.

But Dr. Michael S. Lauer, director of the division of prevention and epidemiology at the National Heart, Lung and Blood Institute, said it might now be smart to abandon that search.

“It is likely that drugs or agents that specifically target CRP are not going to work,” Dr,. Lauer said.

The findings will not change current treatment. And one leading CRP researcher, Dr. Paul M. Ridker of Brigham and Women’s Hospital in Boston, director of last year’s study, called Jupiter, and the researcher most closely associated with the excitement over CRP, said the new study did not change anything for him.

Dr. Ridker, an inventor of a laboratory test for CRP who profits from its use, said that while the new results did not support causality, he did not think they definitely excluded it either.

Now that is interesting!

Anyway, he said, it does not matter because the real issue is inflammation. CRP goes along with inflammation, and it is inflammation that is likely to be causing heart disease, Dr. Ridker said.

The thought is that white blood cells invade artery walls and release damaging chemicals, leading to plaque formation.

The new study, by Dr. Paul Elliott of Imperial College in London and 35 co-authors, used a recently developed technique that can get answers quickly about causality. Without it, the only method was what is seen as the gold standard in medicine: large clinical trials in which people are randomly assigned to take a drug, or not, and followed for years.

The new method, Mendelian randomization, “is changing the way we think about causality,” Dr. Lauer said. It only recently became feasible as researchers found genetic variants associated with proteins like CRP and developed tools to analyze data from what was, in this case, more than 100,000 people.

Different people produce different amounts of CRP, and the amount a person produces is determined by tiny inherited changes in the CRP gene. So in a population, there are people who just happen to produce more CRP throughout their lives and others who just happen to produce less. If CRP causes heart disease, those who make more would have more heart disease. That, however, is not what the study found.

“There was no association” between CRP genes and heart disease rates, Dr. Elliott said.

The association between CRP and heart disease must be reflecting something else. For example, if CRP levels go up when heart disease begins, because of inflammation in arteries, CRP levels would be higher in people with incipient heart disease. But CRP itself would be playing no role in heart disease risk; it was just marker of inflammation.

A smaller study of CRP, using the same method and published last October in The New England Journal of Medicine, came to the same conclusion.

But this second, larger, study was needed to convince heart experts, said Dr. Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital.

“It’s a very important question particularly in the context of the Jupiter trial,” Dr. Kathiresan said.

Dr. Rader, at Penn, said he still did CRP tests on selected patients and expected to continue. An elevated CRP level indicates increased risk, even if the protein does not cause the risk. Dr. Rader tests CRP to help decide whether to give a statin to patients with normal cholesterol but with a family history of heart disease. A high CRP, he said, could tip the balance, leading him to prescribe a statin.

Dr. Altshuler noted that part of the power of a Mendelian randomization study was that it could stop a hypothesis from prematurely becoming viewed as fact.

Ordinarily, science starts with an observation, like the one associating CRP with heart disease. That generates a hypothesis — that CRP causes heart disease. Then comes a trial, if there is a treatment, like a drug to specifically attack CRP, that people can be randomly chosen to take or not.

But it can be years or decades before the clinical trials are completed. In the meantime, Dr. Altshuler said, the hypothesis comes to be regarded as true.

And if the clinical trial contradicts the hypothesis, “some people are unwilling to question their beliefs, even if there was no evidence of causality to begin with,” Dr. Altshuler said.

reposted from: http://www.scfmresidency.com/SCFM_Curriculum/Journal_Club/9-19_Journal_Club/Journal_Club_9-19-05_CRP_Article.pdf

crabsallover highlights, key points, comments / links.

Background 

Statins lower the levels of low-density lipoprotein (LDL) cholesterol and C-reactive protein (CRP). Whether this latter property affects clinical outcomes is unknown.

Methods 

We evaluated relationships between the LDL cholesterol and CRP levels achieved after treatment with 80 mg of atorvastatin or 40 mg of pravastatin per day and the risk of recurrent myocardial infarction or death from coronary causes among 3745 patients with acute coronary syndromes.

Results 

Patients in whom statin therapy resulted in LDL cholesterol levels of less than 70 mg per deciliter (1.8 mmol per liter) had lower event rates than those with higher levels (2.7 vs. 4.0 events per 100 person-years, P=0.008). However, a virtually identical difference was observed between those who had CRP levels of less than 2 mg per liter after statin therapy and those who had higher levels (2.8 vs. 3.9 events per 100 person-years, P=0.006), an effect present at all levels of LDL cholesterol achieved. For patients with post-treatment LDL cholesterol levels of more than 70 mg per deciliter, the rates of recurrent events were 4.6 per 100 person-years among those with CRP levels of more than 2 mg per liter and 3.2 events per 100 person-years among those with CRP levels of less than 2 mg per liter; the respective rates among those with LDL cholesterol levels of less than 70 mg per deciliter were 3.1 and 2.4 events per 100 person-years (P<0.001). Although atorvastatin was more likely than pravastatin to result in low levels of LDL cholesterol and CRP, meeting these targets was more important in determining the outcomes than was the specific choice of therapy. Patients who had LDL cholesterol levels of less than 70 mg per deciliter and CRP levels of less than 1 mg per liter after statin therapy had the lowest rate of recurrent events (1.9 per 100 person-years).

Conclusions 

Patients who have low CRP levels after statin therapy have better clinical outcomes than those with higher CRP levels, regardless of the resultant level of LDL cholesterol. Strategies to lower cardiovascular risk with statins should include monitoring CRP as well as cholesterol.

Statins effective prevents of heart attacks in persons with low cholesterol but high C-reactive protein (CRP)

reposted from: http://www.westhertshospitals.nhs.uk/whc/archive/evidence/01%20prevention/AFCAPS%20CRP-NEJM%202001.pdf
Published: June 2001

crabsallover highlights, key points, comments / links.

As highlighted by David Agus in 'The end of Illness' (2012), the JUPITER study (wikipedia) suggested that high CRP may indicate risk of future heart attack up to 8 years in advance, even if cholesterol levels are low.

ABSTRACT 

Background Elevated levels of C-reactive protein, even in the absence of hyperlipidemia, are associated with an increased risk of coronary events. Statin therapy reduces the level of C-reactive protein independently of its effect on lipid levels. We hypothesized that statins might prevent coronary events in persons with elevated C-reactive protein levels who did not have overt hyperlipidemia.

Methods 

The level of C-reactive protein was measured at base line and after one year in 5742 participants in a five-year randomized trial of lovastatin for the primary prevention of acute coronary events.

Results 

The rates of coronary events increased significantly with increases in the base-line levels of C-reactive protein. Lovastatin therapy reduced the C-reactive protein level by 14.8 percent (P<0.001), an effect not explained by lovastatin-induced changes in the lipid profile. As expected, lovastatin was effective in preventing coronary events in participants whose base-line ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol was higher than the median ratio, regardless of the level of C-reactive protein (number needed to treat for five years to prevent 1 event, 47; P=0.005). However, lovastatin was also effective among those with a ratio of total to HDL cholesterol that was lower than the median and a C-reactive protein level higher than the median (number needed to treat, 43; P=0.02). In contrast, lovastatin was ineffective among participants with a ratio of total to HDL cholesterol and a C-reactive protein level that were both lower than the median (number needed to treat, 983; P=0.87).

Conclusions 

Statin therapy may be effective in the primary prevention of coronary events among persons with relatively low lipid levels but with elevated levels of C-reactive protein. (N Engl J Med 2001;344:1959-65.)

Egg Yolks study

reposted from: http://www.nhs.uk/news/2012/08august/Pages/Eating-egg-yolks-as-bad-as-smoking.aspx

crabsallover highlights, key points, comments / links.

"Eating egg yolks is as bad as smoking in speeding up coronary heart disease" the Daily Mail says, reporting that egg yolks contribute to the clogging up of arteries which, in turn, can increase the risk of heart disease.

The news is based on a Canadian study which used ultrasound to look at the fatty build-up in the arteries of around 1,200 adults who were attending a clinic because they had pre-existing risk factors for heart disease.

The adults were questioned on their smoking history, the number of egg yolks eaten per week and how long they had eaten this amount of egg yolks.

They found that a combination of smoking and egg yolk consumption was related to a fatty build-up in the arteries, which could increase the risk of heart disease as well as other conditions that can affect the heart and blood vessels (cardiovascular diseases or CVDs).

This study does contain some important limitations, such as:

• the accuracy of the participants’ recollections of their egg yolk consumption
• a lack of detailed information on how the eggs were cooked
• there may have been additional risk factors contributing to artery ‘clogging’, not assessed by the study, such as lack of exercise or alcohol consumption
• while it is reasonable to assume that fatty build-up in the neck arteries can increase the risk of heart disease, it is uncertain exactly what the increased level of risk would be

This study perhaps best supports the notion of “all things in moderation”. Eggs are a good source of protein. Without further study, there is no firm evidence that egg yolks are as bad for you as smoking.

Where did the story come from?

The study was carried out by researchers from the Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, and other research institutions in Canada and was funded by the Heart & Stroke Foundation of Ontario.

The study was published in the peer-reviewed medical journal: Atherosclerosis.

While the Mail reports that eating egg yolks is two-thirds as bad for you as smoking when it comes to artery build-up, this cannot be concluded when you consider the limitations of this single piece of research. Also, the headline does not make it clear that the researchers were only looking at people with pre-existing risk factors for heart disease and not the population at large.

What kind of research was this?

The authors report that although high cholesterol contributes to heart disease, there is a general lack of consensus on whether eggs actually raise blood cholesterol and contribute to heart disease.

This study aimed to examine whether egg yolk consumption was related to the fatty (plaque) build-up in the arteries of a consecutive series of adults attending a vascular clinic in Canada.

The design of this study includes several limitations:

• it recruited a small, selective sample of adults
• egg yolk consumption is being estimated through questionnaire responses which may contain inaccuracies
• other factors not studied by the researchers, such as less exercise or a diet higher in other saturated fats, may also contribute towards a build-up of plaque

What did the research involve?

The observational study included 1,231 consecutive patients (average age, 62) referred to a vascular prevention clinic at a hospital in Canada. The total plaque area of their carotid arteries (the main arteries in the neck supplying blood to the head) was measured by ultrasound scan. At the time of referral lifestyle information was also measured by questionnaire. This included smoking history and the frequency of egg yolk consumption. From these responses the researchers calculated:

• pack-years of smoking: the number of packs of cigarettes per day multiplied by the number of years of smoking
• egg-yolk years: the number of egg yolks per week multiplied by the number of years consumed

The researchers specifically say that they did not assess:

• alcohol intake
• exercise taken
• liquorice consumption (high intake of liquorice can increase blood pressure and cause problems in people with heart disease)

What were the basic results?

Overall the researchers found that, as would be expected, the extent of plaque build-up in the carotid arteries increased with age. They also found that both increased smoking and increased egg yolk consumption were associated with more plaque build-up.

Average plaque area in the carotid arteries of patients consuming less than two eggs per week (388 people) was 125mm2 compared to 132mm2 in those consuming three or more eggs per week (603 people). This was a statistically significant difference (not the result of chance).

The association was not affected by adjustment for age.

The researchers did additional analysis adjusting for other cardiovascular risk factors, such as:

• sex
• total blood cholesterol
• blood pressure
• diabetes
• body mass index (BMI)
• smoking

The researchers do not give figures for the build-up in the arteries associated with smoking, but say that the increase in total plaque area with increasing egg consumption followed a similar, linear pattern to that of cigarette smoking.

The highest consumption of eggs (eating more than 200 yolks per year) was said to be equivalent, in terms of plaque build-up, to two thirds of the effect of the highest amount of smoking – the figure quoted by the Mail.

How did the researchers interpret the results?

The researchers say that their findings suggest that regular consumption of egg yolk should be avoided by people at risk of cardiovascular disease. They do acknowledge though, that their theory should be tested in a prospective study that includes more detailed information about diet and other possible confounding factors, such as exercise and waist circumference.

Conclusion

This study found that egg yolk consumption was associated with increased fatty build-up in the arteries of the neck, though this was small when compared to the build-up expected with age. This study has important limitations which mean that it cannot be concluded that egg yolks are as bad for you as smoking:

• Average egg yolk consumption per week and duration was evaluated through a questionnaire response. These are only estimates and may include a considerable degree of inaccuracy. Consumption may vary over time. We also don’t know how these eggs were prepared (boiled, fried in oil, scrambled in butter, etc).
• This wasn’t a trial, and so people are choosing the number of egg yolks they eat. People who ate more egg yolks may differ in other health and lifestyle factors from people who ate less, and this may account for their different artery build-up. For example, as the researchers rightly acknowledge, they did not thoroughly assess other dietary factors, exercise or waist circumference. It is possible that higher egg yolk consumption could be associated with less exercise and higher overall saturated fat intake – both well known risk factors for heart disease. The small changes in fatty build-up in the arteries seen with higher egg yolk consumption could have been accounted for by these other factors.
• None of the participants in this study were reported to be suffering from heart disease and the heart arteries were not examined.
• We do not know how or whether the extent of fatty build-up in the neck arteries was associated with build-up in the heart arteries.
• This is a relatively small, select sample of people attending a vascular clinic in Canada, and further quality studies would be needed to better assess the question.

This study perhaps best supports the notion of all things in moderation. Eggs are a good source of protein in addition to other vitamins and minerals and most experts advise that they can form part of a healthy, balanced diet.

If you have been told you have pre-existing risk factors for heart disease, or other CVDs, your GP will be able to provide more detailed advice about a recommended diet. 

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on twitter.

Links to the headlines

'Eating egg yolks is as 'bad as smoking' in speeding up coronary heart disease'. Daily Mail, August 15 2012

Links to the science

Spence D, Jenkins DJA, Davignon J. Egg yolk consumption and carotid plaque. Atherosclerosis. Published online July 31 2012

LDL, HDL, Cholesterol test results

NHS UK

The government advises http://www.nhs.uk/Planners/NHSHealthCheck/Pages/Healthycholesterol.aspx

 that adults should have:

• Total cholesterol lower than 5mmol/L
• LDL cholesterol lower than 3mmol/L

LabtestOnline

What does the HDL test result mean?

reposted from: http://www.labtestsonline.org.uk/understanding/analytes/hdl/test.html

High levels of HDL cholesterol are better than low HDL cholesterol.  The higher your HDL cholesterol level, the lower risk of developing heart disease. There are two ways that HDL cholesterol values are interpreted—as a percent of total cholesterol or as a measured value.  

• Percent: If HDL is 20% of the total cholesterol, the risk of heart disease is average. If HDL is more than 20% of the total cholesterol, the risk of heart disease is less than average. This is usually expressed as a ratio of cholesterol to HDL. It is desirable for the cholesterol/HDL ratio to be less than 5.
• Measured Value: If HDL cholesterol is less than 1.0 mmol/L in men or less than 1.2 mmol/L in women, there is an increased risk of heart disease. A desirable level of HDL is greater than 1.0 mmol/L for men and greater than 1.2mmol/L for women and is associated with average risk of heart disease. A good level of HDL is 1.5 mmol/L or more and is associated with a less than average risk of heart disease.

HDL should be interpreted in the context of the overall findings from the lipid profile and in consultation with your doctor about other risk factors for heart disease.

What does the Cholesterol test result mean? 

http://www.labtestsonline.org.uk/understanding/analytes/cholesterol/test.html

The cholesterol level measured in your blood will be considered along with other risk factors for heart disease (high blood pressure, smoking etc.) when assessing your overall risk of developing heart disease. This overall assessment is what will be used to decide whether or not you require further treatment in the form of dietary changes or drugs to lower your cholesterol level.
If you are taking treatment to lower your cholesterol, the target is to lower your total cholesterol to a value less than 4 mmol/L, with a fall of around 20-25%.

What does the LDL test result mean?

http://www.labtestsonline.org.uk/understanding/analytes/ldl/test.html#what

Elevated levels of LDL indicate risk for heart disease. Treatment (with diet or drugs) for high LDL aims to lower LDL to a target value of less than 3 mmol/L.

This is especially important if you have other risk factors for heart disease. Risk factors include cigarette smoking, hypertension, low HDL (< 1 mmol/L), family history, age (male 55 or older; female 65 or older), being overweight, and failure to exercise regularly.