Watch how long you sit!

I recently blogged about the relationship between lack of sleep and disease. Now it looks like a group of investigators in Canada has found some evidence linking sitting time and various chronic diseases. The paper was published recently in the Medicine and Science in Sports and Exercise journal.

Katzmarzyk and his co-workers from the Pennington Biomedical Research Centre in Ontario noted that although moderate-to-vigorous physical activity is related to premature death, the relationship between sedentary behaviors and mortality has not been fully explored and may represent a different paradigm than that associated with lack of exercise. They prospectively examined sitting time and mortality in a representative sample of 17,013 Canadians 18-90 yr of age. Information such as the daily sitting time (almost none of the time, one fourth of the time, half of the time, three fourths of the time, almost all of the time), leisure time physical activity, smoking status, and alcohol consumption were captured at commencement of the study.

The volunteers were then followed prospectively for an average of 12.0 yr. Of the 17.013 volunteers, there were 1832 deaths (759 of cardiovascular disease (CVD) and 547 of cancer). After adjustment for potential confounders, there was a progressively higher risk of mortality across higher levels of sitting time from all causes and CVD but not cancer. Similar results were obtained when stratified by sex, age, smoking status, and body mass index.

Katzmarzyk and his co-workers concluded from their study that their data demonstrate a dose-response association between sitting time and mortality from all causes and CVD, independent of leisure time physical activity. In addition to the promotion of moderate-to-vigorous physical activity and a healthy weight, physicians should discourage sitting for extended periods.

Pharmacogenetics Blog

My colleague here in NUS, Professor Edmund Lee, has started a cool blog on pharmacogenetics.

Go on and have look!

More genomic markers identified for heart attack and coronary artery disease. Surprised?

Time really flies by so quickly!

I have just noted that my last posting was done more than two months ago! There have been several interesting developments in the field of cardiiology, such as the prasugrel episode and identification of new genetic markers. Given my research interest, my attention naturally turns toward the reports related to the genetic studies.

After the publication of a series of papers reporting the association of chromosome 9 with the risk of myocardial infarction (heart attack) and coronary artery disease (artery blockage) last year, the 8 Feb 2009 issue of Nature Genetics published not one, not two, not three, but FIVE papers describing the association of various regions of the genome with MI and CAD. These studies had all used the genome-wide approach (called genome-wide association studies or GWAS), meaning that the entire human genome (23 pairs of chromosomes) were screened instead of looking at certain specific regions only. Though significant, all the reported effects are small, as measured in terms of odds ratios in the range of 1.1 to 1.2.

In the first paper by lead author Dr Jeanette Erdmann (University of Lubeck, Germany) and her team, a new susceptibility locus for CAD on chromosome 3q22.3 was reported following a three-stage analysis of genomewide data in 1222 German individuals with MI and 1298 controls. It appears that when the initial genome-wide scans were done, only the low-hanging fruits, ie chromosomal regions that emitted very strong signals, were picked up. Now, these authors are paying attention to the signals that are of moderate significance, believing that some of them are certainly genuine. They concluded that with their large-scale replication that they have identified 3Q22.3 as a new susceptibility locus for CAD. In addition, they also found suggestive evidence for a second locus on 12q24.31.


In the second study, Dr David-Alexandre Tregouet (University Pierre and Marie Curie, Paris, France) and colleagues reported a new gene cluster—SLC22A3-LPAL2-LPA—as a strong susceptibility locus for CAD. Unlike most genome-wide studies, the novelty of this paper lies in the use of haplotypes – groups of SNPs that are inherited together, rather than analyzing individual differences in DNA sequence called single nucleotide polymorphisms (SNPs). One of the authors for three of the five papers, Dr Nilesh Samani, said in an interview with heartWire that "Tregouet has slowly walked across the chromosomes identifying these haplotypes to see whether the signal was better when looking at the haplotype rather than individual SNPs . . . and one region showed very strong evidence, which was apparent in the individual SNP analysis but wasn't strong enough to be definite. By analyzing it in this way [by haplotype], we found evidence that this locus is strongly associated with CAD. So the findings are twofold: first, we identified a new locus; and second, it shows we can extract more information out of GWAS by doing a slightly more sophisticated analysis."

The third study was conducted by the international Myocardial Infarction Genetics Consortium research and involved using GWAS to test SNPs and copy number variants (CNVs) for association with early-onset MI in 2967 cases and 3075 controls and replicated in an independent sample of 19 492. According to the corresponding author of the paper, Dr Sekar Kathiresan (Massachusetts General Hospital, Boston, MA), this study is the largest GWAS for MI conducted to date and the first to comprehensively test whether CNVs are associated with MI.

CNVs are large chunks of DNA that are either deleted or duplicated, and it has been hypothesized that they might be responsible for some of the inherited component of common diseases. They found no evidence in this new study, however, that any CNVs were associated with MI. However, they did find that SNPs at nine loci reached significance, three of which were new: 21q22, 6p24, and 2q33. The remaining six had previously been observed, including one at 9p21, which is recognized to be the strongest genetic predictor of early MI discovered to date. The nine variants in aggregate identify 20% of the population at 2.25-fold increased risk for MI.

Probably the most surprising of these is the report from Dr David F Gudbjartsson (deCODE Genetics, Reykjavik, Iceland) and his team. They found a link between a high-eosinophil-count gene and MI in 9392 Icelanders and, using the most significant SNPs identified, they studied them further in 12 118 Europeans and 5212 East Asians . Some of the SNPs were associated with asthma but one of them, which is a nonsynonymous SNP at 12q24, was significantly associated with MI in six different populations (6650 cases and 40 621 controls). This raises the question of whether a certain pathway might be common between asthma and MI. With CAD and MI increasingly shown to be of inflammatory nature in their disease origin, such a seemingly remote association might just turn out to be genuine upon further verification.

Japanese researchers Dr Kouichi Ozaki (Center for Genomic Medicine, RIKEN, Yokohama, Japan) and his team have previously reported an association of variants in LGALS2, encoding galectin-2, with MI susceptibility in the Japanese. In the fifth study, they now identify BRCA-1 associated protein (BRAP) as a galectin-2 binding protein and report an association of SNPs in BRAP with MI risk in a large Japanese cohort (OR 1.48, 2475 cases and 2778 controls), with replication in additional Japanese and Taiwanese cohorts [5].

I supposed Dr Eric Topol MD, from the Scripps School of Medicine best sums it up by saying that "there are several pathways that set up a genomic susceptibility to MI. Some are ancestry-specific (such as galectin2-BRAP) and some are unanticipated (eg, eosinophilia). While we see the common phenotype of MI, [it appears] there are many ways to get there at the molecular level."

Sleep And Your Heart

Here is a question for all of us during this Christmas season: Have we been sleeping enough? Should we be making a resolution for the new year to have sufficient sleep (and for those who sleep too much - not to sleep more than 9 hours)?

Who would have thought that how we sleep would turn out to be a coronary artery risk factor every bit as important as smoking or high blood pressure? But that's how it is shaping up. Getting a good night’s sleep prevents coronary artery calcification - the accumulation of calcified plaques in the coronary arteries, a predictor of future heart disease.

A recent study in the Journal of the American Medical Association is making the sleep-heart connection impossible to ignore. Although this is not a brand new discovery, they have demonstrated, with stronger evidence, that as hours of sleep drop toward five or fewer from the eight hours most humans seem to need, the chance of developing coronary disease in young middle-aged men and women grows in close proportion. The JAMA study used a relatively new low-dose CT scanning technique to detect calcium buildup in arteries long before patients have the slightest inkling any plaque is there. Recent studies have found that sleep duration is related with risk factors for coronary artery calcification including glucose regulation, blood pressure, sex, age, education, and body mass index.


To determine whether sleep duration and quality are associated with incidence of calcification, researchers from the University of Chicago followed 495 healthy individuals, aged between 35 and 47 years, for 5 years. The participants completed sleep questionnaires regularly.

Accelerating hardening of the arteries in those skimping on sleep is consistent with many prior observations. For example, people afflicted with chronic loud snoring, a sleep disrupter known particularly to men, experience more heart attacks and higher blood pressure than those who sleep like a baby. And a 10-year study involving 72 thousand middle-aged femal nurses found that those who slept for five or fewer hours a night had a greater chance of suffering heart attacks than similar women who managed a good eight hours of sleep. (Prudence in all things: Getting too much sleep wasn't the best either—with those exceeding nine hours bumping up their heart risk.)

Sure, these studies do not prove causality, but they do offer rather hefty circumstantial evidence of sleep's powers. And for ages, lay instincts have held that sleep is a health potion, with lore ranging from the belief that slumber heals weary bones, to early to bed making one healthy and wise, to sleep being the best face-lift.

The rather novel and surprising strong correlation between sleep deprivation and early coronary artery calcification is compelling enough to change behavior now. After all, the medical intervention is a prescription for more sleep, a therapy that's a pleasure to behold, costs nothing, and comes without side effects. Maybe it's time also to make a seven-to-eight-hour sleep night a serious public-health goal for all in 2009.

More details from the study:

• Ihe incidence of calcification in the heart arteries ranged from 6 percent among the participants who slept more than 7 hours per night, to 11 percent among those who slept between 5 and 7 hours nightly, and 27 percent in those who slept less than 5 hours.


• After adjusting for other factors that might influence the results, such as age, sex, race, education and smoking, one hour more of sleep per night decreased the estimated odds of calcification by 33 percent.

Pfizer to drop development of drugs for hyperlipidemia, atherosclerosis, and heart failure

This comes as a shocker to me since Pfizer is the main powerhouse of CV drug development. Their drug, Lipitor, is almost a household name, especially for families with members being treated for high cholesterol. It is a pity that all the experts in their team will have to go separate ways. However, I believe that it will not be long before this vacuum is quickly filled by companies waiting in the sidelines to make their forray into this market segment.

Pfizer to drop development of drugs for hyperlipidemia, atherosclerosis, and heart failure
October 2, 2008
New York, NY - Pfizer is getting out of the cholesterol-lowering game to focus on what it perceives to be more lucrative diseases, according to an internal memo obtained by Forbes [1]. And for the most part, the chosen "disease areas" don't include the heart.
In the memo, Martin Mackay, president of Pfizer Global Research & Development (R&D), informed his staff that the company plans to "exit" the fields of atherosclerosis/hyperlipidemia, heart failure, obesity, and peripheral arterial disease.
Instead, the company, whose cholesterol-lowering drug atorvastatin (Lipitor) is the world's top-selling drug, says it is turning its attention and R&D dollars to cancer, diabetes, Alzheimer's, pain remedies, and mental health as its "higher-priority areas."
The news comes in the wake of the flop of Pfizer's hoped-for new flagship, torcetrapib, a CETP inhibitor that was widely predicted to be the company's next blockbuster drug. While CV drugs have been the major moneymakers for Pfizer in recent years, those days are drawing to a close. In addition to Lipitor, which will lose patent protection in 2011, Pfizer's other major player in the CV drug arena is Norvasc (amlodipine), which came off patent in 2007.
Among the lower-priority "disease areas" where the company says it will continue working are thrombosis and transplant, the memo notes.
Contacted by heartwire, a handful of leaders for some of the major Pfizer-sponsored trials in cardiovascular disease over the past decade declined to comment on the company's announcement or speculate on what it might mean to the field of CV drug development—with one exception. Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands), who was an investigator in the Pfizer-sponsored ASAP, TNT, and IDEAL trials, called Pfizer "a real powerhouse" in the CV drug arena.
"I kind of knew this was coming, but when you see it in print, it still hits hard," he told heartwire. "I think this is very, very significant both for the company itself and for the whole field of CV drug development. Pfizer had truly excellent people in the development arm of their company for CV and metabolic drugs, and they've contributed to this whole notion that you need more robust LDL lowering and that that's better than mild LDL lowering, which has become one of the axioms of CV prevention. And if they're stepping out now, that not only signifies their own problems, but it also signifies the problems in CV drug development, and how incredibly difficult and costly it has become to bring new drugs forward. And that's not good for patients."
Kastelein predicts that drug companies, having "lost faith" somewhat in HDL-raising therapies, will need to look more closely at anti-inflammatory drugs in the setting of coronary artery disease. "But there, the problem is, if you have no biomarkers whatsoever to do even dose-finding studies, you need to move from relatively small phase 2 trials to incredibly large, hard-outcome studies, which is taking quite a risk," he said. And that, at least for Pfizer, is too much risk.
"Everyone, not just Pfizer, is realizing that the days of the really big blockbuster drugs are over. And what is going to replace that are drugs in a class that are 10 times or 100 times more difficult to develop, so the risks are much higher. And these days, after Avandia and ezetimibe, everything is about safety. This means the FDA is forced, by public and colleague pressure, to demand even larger databases before drugs are going to market, which is of course making it more expensive. It's a cycle that's very hard to break."
Calls to Pfizer were not returned before this story was published.

Advantages of using sunflower oil, corn oil, canola oil, soybean oil, and olive oil

In the latest issue of the American Journal of Clinical Nutrition, it is reported that the consumption of partially hydrogenated vegetable oils (PHVO) [click to see what is meant by this], which contain high levels of trans-fat, has raised the level of inflammation in middle-eastern women. Inflammation leads to formation of artery blockages, which in turn, leads to heart disease and stroke.

So the take home point is: use non-hydrogenated vegetable oils! Examples of which are sunflower oil, corn oil, canola oil, soybean oil, and olive oil.

The abstract of the full-text article is given below. I have explained some terms in [brackets] for the sake of lay persons reading this.

American Journal of Clinical Nutrition, Vol. 88, No. 4, 913-921, October 2008

ORIGINAL RESEARCH COMMUNICATION
Home use of vegetable oils, markers of systemic inflammation, and endothelial dysfunction among women
Ahmad Esmaillzadeh and Leila Azadbakht

Department of Nutrition, School of Public Health, and the Food Security and Nutrition Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

Background: Most knowledge about adverse health effects of trans fats was mainly derived from studies done in Western populations of European or American origins; few data are available in the understudied region of the Middle East.

Objective: We assessed the association between consumption of partially hydrogenated vegetable oils (PHVOs) [containing trans fat] and non-HVOs and circulating concentrations of inflammatory markers among Tehrani women aged 40–60 y.

Design: Usual dietary intakes were assessed with a food-frequency questionnaire among 486 apparently healthy women. PHVOs (commonly used for cooking in Iran) were considered as PHVOs category. Sunflower oil, corn oil, canola oil, soybean oil, and olive oil were defined as non-HVOs. Anthropometric measurements [eg body weight, height, blood pressure] were done, and fasting blood samples were taken to measure inflammatory markers [molecules in the blood that indicate the level of inflammation, eg CRP, TNF etc as listed by authors below].

Results: The energy-adjusted daily intakes (mean ± SD) of PHVOs and non-HVOs were 23 ± 11 and 22 ± 10 g/d, respectively. After control for potential confounders, women in the highest quintile of PHVO intake had higher plasma concentrations of C-reactive protein (CRP; percentage difference from lowest quintile: 45%; P for trend: <0.01), tumor necrosis factor- (TNF-; 66%; P for trend: <0.01), interleukin-6 (72%; P for trend: <0.05), and soluble intercellular adhesion molecule-1 (sICAM-1; 22%; P for trend: <0.01) than did women in the lowest quintile. In contrast, higher consumption of non-HVOs was associated with lower circulating concentrations of CRP (percentage difference between top and bottom quintiles: –23%; P for trend: 0.05), TNF- (–29%; P for trend: <0.01), serum amyloid A (–24%; P for trend: <0.01), and sICAM-1 (–19%; P for trend:<0.05). Adjustment for body mass index, fasting plasma glucose, and lipid profiles slightly attenuated the associations in some cases.

Conclusions: Higher intakes of PHVOs are associated with elevated concentrations of inflammatory biomarkers, whereas higher intakes of non-HVOs are associated with lower plasma concentrations of these biomarkers.

Take a genetic test first before you take your weight-loss drugs?

ScienceDaily (Oct. 2, 2008) — Obese patients with a specific genetic make-up lose more weight when taking the weight loss drug sibutramine and undergoing behavioral therapy compared to those without this genetic make-up, reports a new study in Gastroenterology, the official journal of the American Gastroenterological Association (AGA) Institute.

The obesity epidemic continues to be an increasingly global problem: an estimated 1.6 billion adults worldwide are overweight (body mass index [BMI]>25) and 400 million are obese (BMI>30). In addition, the incidences of diabetes and other debilitating diseases attributable to obesity continue to rise.


Genes Influence Effectiveness Of Weight-loss Drug
While there are numerous options for the treatment of obesity, this study examined sibutramine, a medication approved for the long-term treatment of obesity. The drug creates a feeling of fullness, prevents decline in metabolic rate associated with low calorie diets and causes weight loss, especially when combined with behavioral therapy. However, weight loss with the drug is highly variable. Therefore, a research team at the Mayo Clinic assessed the influence of specific markers of candidate genes controlling serotonergic and adrenergic mechanisms (α2A-receptor, 5-HTTLPR and GNβ3) on weight loss/body composition in response to sibutramine or placebo.

"We found significantly lower values for weight, BMI and proportion of body fat in patients taking sibutramine. The candidate gene variations provided useful markers of enhanced response to the drug," said Michael Camilleri, MD, AGAF, of the Mayo Clinic and lead author of the study. "Gene variations may help select obese patients who are more likely to experience improved outcome with this treatment. Since the different markers were present in almost 50 percent of patients, inclusion of screening for these genetic markers before prescribing the medication may even be cost-effective from a public health perspective."

In this randomized, double-blind, pharmacogenetic study, Dr. Camilleri and colleagues evaluated behavioral therapy and sibutramine (10 or 15 mg daily) or placebo for 12 weeks in 181 overweight or obese participants. They measured body weight, BMI, body composition, gastric emptying and genetic variation.

Study results showed that sibutramine at both doses, given in combination with behavioral therapy, caused significant weight loss (p = 0.009). The drug resulted in lower values for weight, BMI and proportion of body fat compared to placebo (p<0.01, p<0.001 and p=0.05, respectively). Weight loss at four weeks was a predictor of weight loss achieved at 12 weeks.
There was a statistically significant gene-by-dose interaction for GNβ3 genotype. This gene determines the function of G proteins, which are involved in translating the message from surface receptors that bind the transmitters serotonin and norepinephrine (e.g. of cells controlling appetite). Those surface receptors are indirectly influenced by sibutramine, which blocks the reuptake of the two transmitters. For each candidate gene, treatment effects were observed at 12 weeks (p<0.017) for all specific genotype variants. The research showed gene pairs (e.g. for GNβ3and α2A-receptor) resulted in greater sibutramine treatment effects on weight (both p<0.002). However, there was no evidence of synergism between combinations of two genotypes on the response to sibutramine therapy compared to the effect on weight loss associated with individual genotypes.
"Our results suggest the genetic make-up of patients could predispose their responsiveness to a drug. This could have important implications for the future of personalized molecular-based or individualized medicine," added Dr. Camilleri. As new and exciting research like this study continues into the causes, prevention and treatments for obesity, the role played by the GI tract is becoming more defined. This understanding has the potential to lead to novel endoscopic, pharmacological and nutritional therapies for obesity as well as changes in policies and societal practices related to obesity.