Coronary disease

Is Omega-3 Pointless for Preventing Heart Disease?

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Meta-analysis showed no significant link to coronary disease, any major vascular events

Omega-3 fatty acids have gotten a heart-healthy reputation without good evidence that they actually prevent major cardiovascular disease events, according to a meta-analysis.

Across 10 large randomized trials lasting at least 1 year, taking the supplements was not associated with significantly reduced risk of:

  • Death from coronary heart disease: rate ratio 0.93 (99% CI 0.83-1.03)
  • Nonfatal myocardial infarction: RR 0.97 (99% CI 0.87-1.08)
  • Any coronary heart disease events: RR 0.96 (95% CI 0.90-1.01)
  • Major vascular events: RR 0.97 (95% CI 0.93-1.01)

Benefits also weren’t seen in subgroups with prior coronary heart disease, diabetes, elevated lipid levels, or statin use, Robert Clarke, MD, of the University of Oxford in England, and colleagues reported in JAMA Cardiology.

While the European Society of Cardiology has called a protective effect of omega-3s debatable at best, the American Heart Association has recommended use as “reasonable” for secondary prevention of coronary heart disease in patients with recent events and “might also be considered” in people with heart failure and reduced ejection fraction.

“However, the results of the present meta-analysis provide no support for the recommendations to use approximately 1 g/d of omega-3 FAs in individuals with a history of CHD for the prevention of fatal CHD, nonfatal MI, or any other vascular events,” Clarke’s group concluded. “The results of the ongoing trials are needed to assess if higher doses of omega-3 [fatty acids] (3-4 g/d) may have significant effects on risk of major vascular events.”

The study was supported by the British Heart Foundation, British Heart Foundation Centre for Research Excellence Oxford, and Medical Research Council Clinical Trial Service Unit.

Is Omega-3 Pointless for Preventing Heart Disease?

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Meta-analysis showed no significant link to coronary disease, any major vascular events

Omega-3 fatty acids have gotten a heart-healthy reputation without good evidence that they actually prevent major cardiovascular disease events, according to a meta-analysis.

Across 10 large randomized trials lasting at least 1 year, taking the supplements was not associated with significantly reduced risk of:

  • Death from coronary heart disease: rate ratio 0.93 (99% CI 0.83-1.03)
  • Nonfatal myocardial infarction: RR 0.97 (99% CI 0.87-1.08)
  • Any coronary heart disease events: RR 0.96 (95% CI 0.90-1.01)
  • Major vascular events: RR 0.97 (95% CI 0.93-1.01)

Benefits also weren’t seen in subgroups with prior coronary heart disease, diabetes, elevated lipid levels, or statin use, Robert Clarke, MD, of the University of Oxford in England, and colleagues reported in JAMA Cardiology.

While the European Society of Cardiology has called a protective effect of omega-3s debatable at best, the American Heart Association has recommended use as “reasonable” for secondary prevention of coronary heart disease in patients with recent events and “might also be considered” in people with heart failure and reduced ejection fraction.

“However, the results of the present meta-analysis provide no support for the recommendations to use approximately 1 g/d of omega-3 FAs in individuals with a history of CHD for the prevention of fatal CHD, nonfatal MI, or any other vascular events,” Clarke’s group concluded. “The results of the ongoing trials are needed to assess if higher doses of omega-3 [fatty acids] (3-4 g/d) may have significant effects on risk of major vascular events.”

Exercise Prevents Heart Disease as Effectively as Expensive Medications.

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·         After reviewing 305 randomized controlled trials, researchers found no statistically detectable differences between physical activity and medications for prediabetes and heart disease, including statins and beta blockers

·         Exercise was also found to be more effective than drugs after you’ve had a stroke. The only time drugs beat exercise was for the recovery from heart failure, in which case diuretic medicines produced a better outcome

·         Exercise is in fact so potent, the researchers suggested that drug companies ought to be required to include it for comparison when conducting clinical trials for new drugs

·         High-intensity interval training, which requires but a fraction of the time compared to conventional cardio, has been shown to be FAR more effective. It’s also the only exercise that really gives you an efficient cardiovascular workout

Did you know that exercise is one of the safest, most effective ways to prevent and treat chronic diseases such as heart disease?

This common-sense advice was again confirmed in a meta-review conducted by researchers at Harvard University and Stanford University,1 which compared the effectiveness of exercise versus drug interventions on mortality outcomes for four common conditions:

·         Diabetes

·         Coronary heart disease

·         Heart failure

·         Stroke

After reviewing 305 randomized controlled trials, which included nearly 339,300 people, they found “no statistically detectable differences” between physical activity and medications for prediabetes and heart disease.

Exercise was also found to be more effective than drugs after you’ve had a stroke. The only time drugs beat exercise was for the recovery from heart failure, in which case diuretic medicines produced a better outcome.

The drugs assessed in the studies included:

·         Statins and beta blockers for coronary heart disease

·         Diuretics and beta blockers for heart failure

·         Anticoagulants and antiplatelets for stroke

Exercise Should Be Included as Comparison in Drug Development Studies

The featured review is a potent reminder of the power of simple lifestyle changes, as well as the shortcomings of the drug paradigm. If you’re interested in living a longer, healthier life, nothing will beat proper diet and exercise.

Exercise is in fact so potent, the researchers suggested that drug companies ought to be required to include it for comparison when conducting clinical trials for new drugs! As reported by Bloomberg:2

“The analysis adds to evidence showing the benefit of non-medical approaches to disease through behavior and lifestyle changes.

Given the cost of drug treatment, regulators should consider requiring pharmaceutical companies to include exercise as a comparator in clinical trials of new medicines, according to authors Huseyin Naci of Harvard and John Ioannidis of Stanford.

‘In cases where drug options provide only modest benefit, patients deserve to understand the relative impact that physical activity might have on their condition,’ Naci and Ioannidis said in the published paper. In the meantime, ‘exercise interventions should therefore be considered as a viable alternative to, or, alongside, drug therapy.’”

There are glimmers of hope that change is possible, slow and begrudging as it may be. Dean Ornish, founder of the Preventive Medicine Research Institute, spent 16 years proving that a vegetarian diet along with exercise and stress management is more effective than conventional care for the treatment of heart disease.

And, as of January 2011, Medicare actually began covering the Ornish Spectrum—Reversing Heart Disease program,3 under the benefit category of “intensive cardiac rehabilitation.”

How Exercise Benefits Your Heart and Health

Heart disease and cancer are two of the top killers of Americans, and exercise can effectively help prevent the onset of both, primarily by normalizing your insulin and leptin levels.

Other beneficial biochemical changes also occur during exercise, including alterations in more than 20 different metabolites. Some of these compounds help you burn calories and fat, while others help stabilize your blood sugar, among other things.

In a nutshell, being a healthy weight and exercising regularly creates a healthy feedback loop that optimizes and helps maintain healthy glucose, insulin and leptin levels through optimization of insulin and leptin receptor sensitivity.

And, as I’ve mentioned before, insulin and leptin resistance—primarily driven by excessive consumption of refined sugars and grains along with lack of exercise—are the underlying factors of nearly all chronic disease that can take years off your life.

Previous research has shown that exercise alone can reduce your risk of cardiovascular disease by a factor of three.4However, endurance-type exercise, such as marathon running, can actually damage your heart and increase your cardiovascular risk by a factor of seven…

Research5 by Dr. Arthur Siegel, director of Internal Medicine at Harvard’s McLean Hospital found that long-distance running leads to high levels of inflammation that can trigger cardiac events. Another 2006 study6 found that non-elite marathon runners experienced decreased right ventricular systolic function, again caused by an increase in inflammation and a decrease in blood flow.

All in all, such findings are a powerful lesson that excessive cardio may actually be counterproductive. In the featured review, the types of exercise, frequency, intensity and duration varied widely across the included studies, which made it impossible to ascertain the specifics of what was most or least effective for the prevention and treatment of disease.

However, it was clear that exercise in general is comparable to many of the drugs used for heart disease, heart failure, and stroke. That said, other research has clearly demonstrated that short bursts of intense activity is safer and more effective than conventional cardio—for your heart, general health, weight loss, and overall fitness.  One of the easiest ways to exercise is simply by performing body weight exercises.

Are You Exercising Effectively and Efficiently?

The answer is to exercise correctly and appropriately, and making certain you have adequate recovery, which can be as important as the exercise itself. There is in fact overwhelming evidence indicating that conventional cardio or long-distance running is one of the worst forms of exercise there is. Not only have other studies confirmed the disturbing findings above, but they’ve also concluded it’s one of the least efficient forms of exercise. Research emerging over the past several years has given us a deeper understanding of what your body requires in terms of exercise. 

High-intensity interval training, which requires but a fraction of the time compared to conventional cardio, has been shown to be FAR more efficient, and more effective. This type of physical activity mimics the movements of our hunter-gatherer ancestors, which included short bursts of high-intensity activities, but not long-distance running. This, researchers say, is what your body is hard-wired for. Basically, by exercising in short bursts, followed by periods of recovery, you recreate exactly what your body needs for optimum health. Twice-weekly sessions, which require no more than 20 minutes from start to finish, can help you:

·         Lower your body fat

·         Improve your muscle tone

·         Boost your energy and libido

·         Improve athletic speed and performance

This type of exercise will also naturally increase your body’s production of human growth hormone (HGH)—a synergistic, foundational biochemical underpinning that promotes muscle and effectively burns excessive fat. It also plays an important part in promoting overall health and longevity. Conventional cardio will NOT boost your HGH level.

Interval Training—A Much Better Cardio Workout

Most people still think that in order to improve your cardiovascular fitness, endurance training is a must. But this is actually not true. Quite the contrary. According to fitness expert Phil Campbell, getting cardiovascular benefits actually requires working ALL your muscle fibers and their associated energy systems. Interestingly enough, this cannot be achieved with traditional cardio, and here’s why: Your body has three types of muscle fibers: slow, fast, and super-fast twitch muscles, and your heart has two different metabolic processes:

·         The aerobic, which requires oxygen for fuel

·         The anaerobic, which does not require any oxygen

Slow twitch muscles are the red muscles, which are activated by traditional strength training and cardio exercises. The fast and super-fast twitch muscles are white muscle fibers, which are only activated during high intensity interval exercises or sprints. Activating the fast and super-fast muscles is also what causes the production of therapeutic levels of growth hormone, as mentioned earlier. Many athletes spend $1,000 a month on HGH injections, which carry certain health risks, but there’s really no need for that. With Peak Fitness exercises and the use of the Power Plate, you can increase your levels of HGH to healthy young normal’s.

Now, traditional cardio exercises work primarily the aerobic process, associated with your red, slow-twitch muscles. High-intensity interval training, on the other hand, work both your aerobic AND your anaerobic processes, which is what you need for optimal cardiovascular benefit. Quite simply, if you don’t actively engage and strengthen all three muscle fiber types and energy systems, then you’re not going to work both processes of your heart muscle. Many mistakenly believe that cardio works out your heart muscle, but what you’re really working is your slow twitch muscle fibers, associated with the aerobic process only. You’re not effectively engaging the anaerobic process of your heart…

Demonstration of an Effective High Intensity Interval Session

In the case of high intensity exercises, less is more, as you can get all the benefits you need in just a 20-minute session performed twice to three times a week. It’s inadvisable to do them more than three times a week. If you do, you may actually do more harm than good—similar to running marathons. Because while your body needs regular amounts of stress like exercise to stay healthy, it also needs ample recuperation, and if you give it more than you can handle your health will actually begin to deteriorate. As a general rule, as you dial up the intensity, you can dial back on the frequency. While the entire workout is only 20 minutes, 75 percent of that time is warming up, recovering or cooling down. You’re really only working out intensely for four minutes:

·         Warm up for three minutes

·         Exercise as hard and fast as you can for 30 seconds. You should feel like you couldn’t possibly go on another few seconds

·         Recover at a slow to moderate pace for 90 seconds

·         Repeat the high intensity exercise and recovery 7 more times

For Optimal Health, Add Variety to Your Fitness Routine

While high intensity interval exercises accomplish greater benefits in a fraction of the time compared to slow, endurance-type exercises like jogging, I don’t recommend limiting yourself to that alone. Of equal, if not greater importance, is to avoid being too sedentary in general. Compelling research now tells us that prolonged sitting can have a tremendously detrimental impact on your health even if you exercise regularly. The reason for this is because your body needs to interact with gravity in order to function optimally. Therefore, make sure to get out of your chair every 10 minutes or so, as suggested below.

Ideally, to truly optimize all aspects of your health, you’d be wise to design a well-rounded fitness program that incorporates a variety of different exercises. Without variety, your body will quickly adapt, so as a general rule, as soon as an exercise becomes easy to complete, you’ll want to increase the intensity and/or try another exercise to keep it challenging. I recommend incorporating the following types of exercise into your program:

1.    Interval (Anaerobic) Training: This is when you alternate short bursts of high-intensity exercise with gentle recovery periods.

2.    Strength Training: Rounding out your exercise program with a 1-set strength training routine will ensure that you’re really optimizing the possible health benefits of a regular exercise program. You can also “up” the intensity by slowing it down. For more information about using super slow weight training as a form of high intensity interval exercise, please see my interview with Dr. Doug McGuff.

3.    Avoid Sitting for More Than 10 Minutes. This is not intuitively obvious but emerging evidence clearly shows that even highly fit people who exceed the expert exercise recommendations are headed for premature death if they sit for long periods of time. My interview with NASA scientist Dr. Joan Vernikos goes into great detail why this is so, and what you can do about it. Personally, I usually set my timer for 10 minutes while sitting, and then stand up and do one legged squats, jump squats or lunges when the timer goes off. The key is that you need to be moving all day long, even in non-exercise activities.

4.    Core Exercises: Your body has 29 core muscles located mostly in your back, abdomen and pelvis. This group of muscles provides the foundation for movement throughout your entire body, and strengthening them can help protect and support your back, make your spine and body less prone to injury and help you gain greater balance and stability.

Foundation Training, created by Dr. Eric Goodman, is an integral first step of a larger program he calls “Modern Moveology,” which consists of a catalog of exercises. Postural exercises such as those taught in Foundation Training are critical not just for properly supporting your frame during daily activities, they also retrain your body so you can safely perform high-intensity exercises without risking injury. Exercise programs like Pilates and yoga are also great for strengthening your core muscles, as are specific exercises you can learn from a personal trainer.

5.    Stretching: My favorite type of stretching is active isolated stretches developed by Aaron Mattes. With Active Isolated Stretching, you hold each stretch for only two seconds, which works with your body’s natural physiological makeup to improve circulation and increase the elasticity of muscle joints. This technique also allows your body to repair itself and prepare for daily activity. You can also use devices like the Power Plate to help you stretch.

Exercise Tips for Those with Chronic Health Problems

Remember that even if you’re chronically ill, exercise can be a potent ally. That said, if you have a chronic disease, you will of course need to tailor your exercise routine to your individual scenario, taking into account your stamina and current health. For example, you may at times need to exercise at a lower intensity, or for shorter durations, but do make a concerted effort to keep yourself moving. Just listen to your body and if you feel you need a break, take time to rest. But even exercising for just a few minutes a day is better than not exercising at all.

In the event you are suffering from a severely compromised immune system, you may want to exercise in your home instead of visiting a public gym. But remember that exercise will ultimately help to boost your immune system, so it’s very important to continue with your program, even if you suffer from chronic illness.

Exercise Is More Effective Than Potent Medicines

The take-home message here is that one of the best forms of exercise to protect your heart is short bursts of exertion, followed by periods of rest. By exercising in this way, you recreate exactly what your body needs for optimum health. Heart attacks, for example, don’t happen because your heart lacks endurance. They happen during times of stress, when your heart needs more energy and pumping capacity, but doesn’t have it. So rather than stressing your heart with excessively long periods of cardio, give interval training a try.

During any type of exercise, as long as you listen to your body, you shouldn’t run into the problem of exerting yourself excessively. And, with interval training, even if you are out of shape you simply will be unable to train very hard, as lactic acid will quickly build up in your muscles and prevent you from stressing your heart too much.

Most importantly, the featured review is a powerful message to anyone considering taking a medication to address risk factors and lower your risk of heart disease. There’s simply no evidence suggesting that statins or beta blockers are any more effective than exercise, which means you can forgo all the side effects and exorbitant expense associated with such drugs.  

Remember what these Harvard and Stanford University researchers concluded after reviewing 305 studies comparing exercise versus drug treatment: “[E]xercise interventions should… be considered as a viable alternative to, or, alongside, drug therapy.” What could possibly be more empowering than that?!

Aircraft Noise and CVD: Two New Studies Bolster Link.

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Aircraft noise from some of the world’s busiest airports is linked to an increased risk of hospital admissions for cardiovascular disease, according to two new papers. The studies broaden concerns about the impact of living close to airports; previously, aircraft noise, as well as other “sound pollutants,” has been linked to hypertension.

In the first of two studies published online October 8, 2013 in BMJ,Dr Anna L Hansell (Imperial College London, UK) and colleagues assessed hospital admissions for 3.6 million people living near Heathrow Airport. Their paper linked daytime and nighttime aircraft noise and hospital visits for stroke, coronary heart disease, and cardiovascular disease by comparing residents in the noisiest areas with those living farther from the airport.

They found that, after adjustment for confounders, high-noise areas (>63 dB) had significantly increased risks for all three diagnostic codes as compared with the quieter areas (<51 dB).

High vs Low Aircraft Noise Exposure

Admission diagnosis Relative risk 95% CI
Stroke 1.24 1.08–1.43
Coronary artery disease 1.21 1.12–1.31
Cardiovascular disease 1.14 1.08–1.20

In the second paper, Dr Andrew W Correia (NMR Group, Somerville, MA) and colleagues looked at hospitalization for cardiovascular disease among subjects 65 years or older according to “contours of aircraft noise levels” around 89 airports in the US[2].

They report that every 10-dB increase in noise exposure (by zip code) was associated with a 3.5% higher rate of hospital admissions for cardiovascular disease. The observation held up after they controlled for other covariates, including air pollution as well as ethnic and socioeconomic factors. Importantly, note the authors, the effects were particularly marked at the highest levels of aircraft noise (above the 90th percentile for noise exposure) suggesting a threshold effect above 55 dB.

In an accompanying editorial[3], Dr Stephen Stansfeld (Barts and the London School of Medicine, UK) asserts: “the link seems real.”

The findings also echo a somewhat larger body of work looking at traffic noise, including the large HYENAstudy. He notes that a link between aircraft noise and stroke, seen in the Hansell et al paper, “is new and fits with associations between aircraft noise and hypertension and between road traffic noise and death from stroke.”

Other factors that could not be controlled for in the current analyses include individual-level confounders, including smoking status and household income, he notes. “There is a need for prospective cohort studies of exposure to aircraft and road traffic noise . . . that might also take account of air pollution, social disadvantage, and migration in and out of study areas,” Stansfeld writes.

Still, he continues, the results have implications for the siting of airports, he concludes. “Planners need to take this into account when expanding airports in heavily populated areas or planning new airports.”

Hansell disclosed receiving consultancy fees from AECOM as part of a UK Department for Environment, Food and Rural Affairs report on health effects of environmental noise. Disclosures for the coauthors are listed in the paper. Stansfeld disclosed being a member of the Acoustic Review Group for High Speed 2. Correia et al had no conflicts of interest.

Perceived job insecurity as a risk factor for incident coronary heart disease: systematic review and meta-analysis.

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Abstract

Objective To determine the association between self reported job insecurity and incident coronary heart disease.

Design A meta-analysis combining individual level data from a collaborative consortium and published studies identified by a systematic review.

Data sources We obtained individual level data from 13 cohort studies participating in the Individual-Participant-Data Meta-analysis in Working Populations Consortium. Four published prospective cohort studies were identified by searches of Medline (to August 2012) and Embase databases (to October 2012), supplemented by manual searches.

Review methods Prospective cohort studies that reported risk estimates for clinically verified incident coronary heart disease by the level of self reported job insecurity. Two independent reviewers extracted published data. Summary estimates of association were obtained using random effects models.

Results The literature search yielded four cohort studies. Together with 13 cohort studies with individual participant data, the meta-analysis comprised up to 174 438 participants with a mean follow-up of 9.7 years and 1892 incident cases of coronary heart disease. Age adjusted relative risk of high versus low job insecurity was 1.32 (95% confidence interval 1.09 to 1.59). The relative risk of job insecurity adjusted for sociodemographic and risk factors was 1.19 (1.00 to 1.42). There was no evidence of significant differences in this association by sex, age (<50 v ≥50 years), national unemployment rate, welfare regime, or job insecurity measure.

Conclusions The modest association between perceived job insecurity and incident coronary heart disease is partly attributable to poorer socioeconomic circumstances and less favourable risk factor profiles among people with job insecurity.

Source: BMJ

Uric Acid Found to Be a Confounder, Not a Risk Factor, in CHD Risk.

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Hyperuricemia, although associated with higher risks for cardiovascular disease and hypertension, is likely not a causal factor, but a confounder associated with higher body mass index, according to aBMJ study.

Researchers examined uric acid levels and did genetic analyses in two large Danish cohorts. Subjects were assessed for hypertension at study entry and were followed for the development of ischemic heart disease.

Increases in uric acid were associated with increased risk for both coronary disease and hypertension, but the associations disappeared when taking into account the role of a common mutation in theSLC2A9 gene linked to high levels of uric acid. The presence or absence of the mutation had no association with coronary risk. In fact, higher BMI levels were independently associated with increased uric acid.

The authors write that their findings “suggest that uric acid is of limited clinical interest” in coronary disease or blood pressure.

Source: BMJ 

 

Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women.

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Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials.

Objective.—  To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease.

Design.—  Randomized, blinded, placebo-controlled secondary prevention trial.

Setting.—  Outpatient and community settings at 20 US clinical centers.

Participants.—  A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years.

Intervention.—  Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n=1380) or a placebo of identical appearance (n=1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years.

Main Outcome Measures.—  The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered.

Results.—  Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38).

Conclusions.—  During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue.

MANY OBSERVATIONAL studies have found lower rates of coronary heart disease (CHD) in women who take postmenopausal estrogen than in women not receiving this therapy.1– 5 This association has been reported to be especially strong for secondary prevention in women with CHD, with hormone users having 35% to 80% fewer recurrent events than nonusers.6– 12 If this association is causal, estrogen therapy could be an important method for preventing CHD in postmenopausal women. However, the observed association between estrogen therapy and reduced CHD risk might be attributable to selection bias if women who choose to take hormones are healthier and have a more favorable CHD profile than those who do not.13– 15 Observational studies cannot resolve this uncertainty.

Only a randomized trial can establish the efficacy and safety of postmenopausal hormone therapy for preventing CHD. The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized, double-blind, placebo-controlled trial of daily use of conjugated equine estrogens plus medroxyprogesterone acetate (progestin) on the combined rate of nonfatal myocardial infarction (MI) and CHD death among postmenopausal women with coronary disease. We enrolled women with established coronary disease because their high risk for CHD events and the strong reported association between hormone use and risk of these events make this an important and efficient study population in which to evaluate the effect of hormone therapy.

COMMENT

In this clinical trial, postmenopausal women younger than 80 years with established coronary disease who received estrogen plus progestin did not experience a reduction in overall risk of nonfatal MI and CHD death or of other cardiovascular outcomes. How can this finding be reconciled with the large body of evidence from observational and pathophysiologic studies suggesting that estrogen therapy reduces risk for CHD?

Contrast With Findings of Observational Studies

Observational studies may be misleading because women who take postmenopausal hormones tend to have a better CHD risk profile13,21– 22and to obtain more preventive care14 than nonusers. The consistency of the apparent benefit in the observational studies could simply be attributable to the consistency of this selection bias. The lower rate of CHD in hormone users compared with nonusers persists after statistical adjustment for differences in CHD risk factors,22 but differences in unmeasured factors remain a possible explanation.

The discrepancy between the findings of HERS and the observational studies may also reflect important differences between the study populations and treatments. Most of the observational studies of postmenopausal hormone therapy enrolled postmenopausal women who were relatively young and healthy and who took unopposed estrogen.1– 3,23 In contrast, participants in HERS were older, had coronary disease at the outset, and were treated with estrogen plus progestin. However, some observational studies did examine women with prior CHD, and all of these reported a beneficial association with postmenopausal hormone therapy.6– 12 Similarly, some observational studies did examine the effect of postmenopausal estrogen plus progestin therapy on CHD risk in women, and these generally report a lower rate of CHD events in hormone users that is similar to that reported for estrogen alone4– 5,22,24– 27; however, details in these studies about the specific progestin formulations and dosing regimens used are limited.

Possible Adverse Effects of Medroxyprogesterone Acetate

Several potential mechanisms whereby estrogen therapy might reduce risk for CHD have been proposed, including favorable effects on lipoproteins, coronary atherosclerosis, endothelial function, and arterial thrombosis.28– 29 Progestins down-regulate estrogen receptors and may also have direct, progestin receptor–mediated effects that oppose these actions of estrogen30; medroxyprogesterone acetate may do this to a greater extent than other progestins. In the Postmenopausal Estrogen-Progestin Interventions Trial, medroxyprogesterone acetate blunted the estrogen-associated increase in HDL cholesterol substantially more than did micronized progesterone.31 Oral medroxyprogesterone acetate appears to significantly attenuate the beneficial effects of estrogen on coronary atherosclerosis in nonhuman primates,32 while subcutaneous progesterone does not.33 Animal data also suggest that medroxyprogesterone acetate may inhibit the beneficial effects of estrogen on endothelial-dependent vasodilation,34 but this has not been documented in women.35 Despite these mechanistic data suggesting an adverse effect of medroxyprogesterone acetate, observational studies show a similar reduction in CHD risk in women using medroxyprogesterone acetate plus estrogen as in women taking unopposed estrogen.4

Possible Differences in the Effects of Therapy Over Time

When the results were examined by year since randomization, the estrogen plus progestin regimen appeared to increase risk for primary CHD events in the first year of therapy but to decrease risk in subsequent years. This time trend should be interpreted with caution. It could simply represent random variation, although the level of statistical significance makes this unlikely. More importantly, between-group contrasts that exclude the first several years are not true randomized comparisons, as the remaining study groups may no longer be comparable if, for example, treatment has caused high-risk individuals to have events early in the study.

On the other hand, the time trend is biologically plausible. The early increase in risk for CHD events might be attributable to an immediate prothrombotic, proarrhythmic, or proischemic effect of treatment that is gradually outweighed by a beneficial effect on the underlying progression of atherosclerosis, perhaps as a result of beneficial changes in lipoproteins. In trials of lipid interventions, the delay before CHD risk is reduced has ranged from 0 to 2 years.36– 41 After a lag period, the 11% net reduction in LDL cholesterol and 10% net increase in HDL cholesterol observed in the hormone group would be expected to reduce the risk of CHD events36,42 and may account for the trend toward a late benefit observed in HERS.

A pattern of early harm and later benefit could account for part of the discrepancy between the results of this trial and observational studies of estrogen and CHD. Attrition of susceptible individuals soon after starting estrogen replacement could increase the prevalence of survivors available for inclusion in observational studies; most observational studies are not designed to observe the onset of therapy or to detect an early adverse effect.

Previous Clinical Trial Evidence

The CHD data from previous hormone trials in women have been summarized43 but are of limited value because the studies were small, short term, and not designed to examine CHD as an outcome. The only large prior trial of estrogen therapy to prevent CHD events was the Coronary Drug Project, which studied very high doses of estrogen (5.0 mg or 2.5 mg of conjugated equine estrogen daily) in men with preexisting CHD. The estrogen arms of this trial were stopped early because of an excess of MIs, thromboembolic events, and estrogenic symptoms in the 5.0-mg/d group44 and the lack of benefit on the CHD end point and estrogenic symptoms in the 2.5-mg/d group.45 The relevance of this trial of high-dose estrogen in men to postmenopausal hormone therapy in women is uncertain.

Safety and Other Noncardiovascular Outcomes

Venous thromboembolic events were 3 times more common in the hormone group than in the placebo group. Recent observational studies have reported similar relative risks for idiopathic venous thromboembolism among users of both unopposed estrogen46– 49 and estrogen plus progestin therapy.47,49 The excess incidence of venous thrombotic events in HERS was 4.1 per 1000 woman-years of observation, an order of magnitude higher than the excess reported in the observational studies; the higher rate is probably a consequence of the facts that women enrolled in HERS were older and had multiple risk factors for venous thrombosis and that only idiopathic events were counted in the observational studies.

We found an increased risk of gallbladder disease in the hormone group that is likely attributable to the estrogen therapy. Metabolic studies indicate that estrogen enhances hepatic lipoprotein uptake and inhibits bile acid synthesis, resulting in increased biliary cholesterol and cholelithiasis.50

Observational studies have suggested that therapy with postmenopausal estrogen for 5 years or less is not associated with an increased risk of breast cancer but that longer duration of therapy might be associated with a small increase in risk.51 The HERS trial was not large enough and therapy did not continue for long enough to address this issue.

The incidence of fractures in the hormone group was only slightly lower than in the placebo group. Wide CIs around the fracture risk estimates reveal inadequate statistical power and do not exclude a reduction in risk of hip fracture of as much as 51% or a reduction in risk of other fracture of as much as 27%.

Strengths and Limitations of the Trial

The CHD risk factor profile of women enrolled in HERS is similar to that of a random sample of US women with probable heart disease, suggesting that the findings of HERS may be generalized to that population.52 However, HERS did not evaluate the effect of estrogen plus progestin therapy in women without CHD, and it is not known whether our findings apply to healthy women. It is also not known whether use of a different progestin or of estrogen alone would have been beneficial.

HERS exceeded the recruitment goal by 18%, carried out a successful randomization, collected objective, blindly adjudicated disease outcome data, and achieved 100% vital status ascertainment. Compliance with hormone treatment, while lower than projected, was sufficient to produce LDL and HDL cholesterol changes that compare favorably with previous studies.31 The 95% CIs for the effect of treatment assignment on primary CHD events (RH, 0.99; 95% CI, 0.80-1.22) make it unlikely that HERS missed a benefit of more than 20% for the overall 4.1-year period of observation. However, this statistic does not address the possible late benefit of treatment suggested by the time trend analysis, which is plausible based on the finding of a 1- to 2-year lag period observed in lipid trials36– 41; a longer study would be more definitive for investigating this possibility.

Future Directions

HERS is the first large trial of the effect of postmenopausal estrogen plus progestin therapy on risk for CHD events. The findings differ from those of observational studies and studies with surrogate outcomes, emphasizing the importance of basing treatment policies on randomized controlled trials.53 Other randomized trials of postmenopausal hormone therapy are likely to answer some of the questions raised by HERS. The Women’s Health Initiative Randomized Trial54 includes a group of women who have undergone hysterectomy and receive unopposed estrogen as well as women with intact uterus who receive the same estrogen plus progestin regimen used in HERS. Participants are not required to have CHD and are generally younger than the HERS cohort. The Women’s Health Initiative Randomized Trial plans to enroll 27500 women and to report the results in 2005 after 9 years of treatment. Further information will also emerge from HERS as we continue disease event surveillance.

Several interventions have been proven to reduce risk for CHD events in patients with coronary disease, including aspirin, β-blockers, lipid lowering, and smoking cessation.55 The need for encouraging these interventions for women with coronary disease is illustrated by the facts that 90% of the HERS cohort had LDL cholesterol exceeding 2.59 mmol/L (100 mg/dL) at baseline and that only 32% were receiving β-blockers.

Conclusions

First, in the population studied in HERS, ie, postmenopausal women with established coronary disease and an average age of 66.7 years, daily use of conjugated equine estrogens and medroxyprogesterone acetate did not reduce the overall risk for MI and CHD death or any other cardiovascular outcome during an average of 4.1 years of follow-up. This therapy did increase the risk of venous thromboembolic events and gallbladder disease.

Second, we did not evaluate the cardiovascular effect of treatment with unopposed estrogen, commonly used in women who have had a hysterectomy, or other estrogen plus progestin formulations. We also did not study women without coronary disease.

Third, based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving hormone treatment to continue. Extended follow-up of the HERS cohort and additional randomized trials are needed to clarify the cardiovascular effects of postmenopausal hormone therapy.

Source:JAMA

 

Association Between Duration of Overall and Abdominal Obesity Beginning in Young Adulthood and Coronary Artery Calcification in Middle Age.

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Importance  Younger individuals are experiencing a greater cumulative exposure to excess adiposity over their lifetime. However, few studies have determined the consequences of long-term obesity.

Objective  To examine whether the duration of overall and abdominal obesity was associated with the presence and 10-year progression of coronary artery calcification (CAC), a subclinical predictor of coronary heart disease.

Design, Setting, and Participants  Prospective study of 3275 white and black adults aged 18 to 30 years at baseline in 1985-1986 who did not initially have overall obesity (body mass index [BMI] ≥30) or abdominal obesity (men: waist circumference [WC] >102 cm; women: >88 cm) in the multicenter, community-based Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants completed computed tomography scanning for the presence of CAC during the 15-, 20-, or 25-year follow-up examinations. Duration of overall and abdominal obesity was calculated using repeat measurements of BMI and WC, respectively, performed 2, 5, 7, 10, 15, 20, and 25 years after baseline.

Main Outcomes and Measures  Presence of CAC was measured by computed tomography at the year 15 (2000-2001), year 20 (2005-2006), or year 25 (2010-2011) follow-up examinations. Ten-year progression of CAC (2000-2001 to 2010-2011) was defined as incident CAC in 2010-2011 or an increase in CAC score of 20 Agatston units or greater.

Results  During follow-up, 40.4% and 41.0% developed overall and abdominal obesity, respectively. Rates of CAC per 1000 person-years were higher for those who experienced more than 20 years vs 0 years of overall obesity (16.0 vs 11.0, respectively) and abdominal obesity (16.7 vs 11.0). Approximately 25.2% and 27.7% of those with more than 20 years of overall and abdominal obesity, respectively, experienced progression of CAC vs 20.2% and 19.5% of those with 0 years. After adjustment for BMI or WC and potential confounders, the hazard ratios for CAC for each additional year of overall or abdominal obesity were 1.02 (95% CI, 1.01-1.03) and 1.03 (95% CI, 1.02-1.05), respectively. The adjusted odds ratios for CAC progression were 1.04 (95% CI, 1.01-1.06) and 1.04 (95% CI, 1.01-1.07), respectively. Associations were attenuated but largely persisted following additional adjustment for potential intermediate metabolic factors during follow-up.

Conclusions and Relevance  Longer duration of overall and abdominal obesity was associated with subclinical coronary heart disease and its progression through midlife independent of the degree of adiposity. Preventing or at least delaying the onset of obesity in young adulthood may lower the risk of developing atherosclerosis through middle age.

Source: JAMA

 

Subclinical thyroid disease: where is the evidence?

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Subclinical thyroid disease is very common, particularly in elderly people. Recognition of this endocrine disorder is increasing, partly due to a large increase in thyroid function testing, especially in primary care. Many cross-sectional studies have investigated whether subclinical hyperthyroidism or subclinical hypothyroidism are associated with specific symptoms, signs, or comorbidities, and a smaller number of prospective studies have examined whether subclinical thyroid disease predicts specific adverse outcomes.1

What is the latest evidence driving the need, or otherwise, for therapeutic intervention in these common, and largely asymptomatic, biochemically defined disorders? A large and seemingly irrefutable body of evidence exists supporting the association of subclinical hyperthyroidism with atrial fibrillation risk, especially when thyroid-stimulating hormone (TSH) is at undetectable concentrations.2, 3 Subclinical hyperthyroidism is also associated with other adverse cardiac outcomes, such as coronary heart disease events and mortality, and heart failure. Evidence linking cardiovascular disorders with tests of thyroid function within the reference range, including higher circulating free thyroxine concentrations,4 suggests that the cardiovascular system is particularly sensitive to subtle changes in thyroid status. Thus, the cardiovascular system is the most important physiological system for which to consider risk, and, in turn, with the potential to benefit from treatment.

If the evidence for risk association with cardiovascular endpoints is strong, why is there controversy about intervention? Several crucial reasons exist. First, association does not prove causation, and many studies have not fully considered potential confounders for comorbidities in conditions such as coronary heart disease and heart failure. Second, nearly all studies have been based on one or two TSH measurements in individual subjects, but low TSH is often transient, especially when only slightly low, and frequently reflects non-thyroidal illnesses or drugs, rather than underlying thyroid disease such as mild Graves’ disease or toxic nodular hyperthyroidism. Third, intervention for subclinical hyperthyroidism means radioiodine therapy or antithyroid drugs, neither of which is trivial. Radioiodine is generally considered the treatment of choice for toxic nodular disease (the most common underlying thyroid diagnosis, in view of the typical age when subclinical hyperthyroidism is diagnosed). Radioiodine treatment often results in hypothyroidism and the need for permanent thyroxine replacement. Since up to half of patients taking thyroxine have subclinical hyperthyroidism or hypothyroidism biochemically, subclinical hyperthyroidism can be perpetuated or replaced with subclinical hypothyroidism. Finally, there have been no randomised controlled trials of treatment of subclinical hyperthyroidism with meaningful clinical endpoints. Two trials were stopped because of low recruitment and a third has recruitment that is lower than planned, although it is continuing. These issues were described in a recent article about the problems encountered with such trials.4 Despite this absence of evidence, expert groups recommend that treatment should be strongly considered, especially in elderly patients;5 surveys of practice show this is occurring. It seems extraordinary that evidence that the benefit of treatment outweighs the risk does not exist in the 21st century for such a common disorder. We can only hope that evidence will accrue in the next few years.

The situation regarding subclinical hypothyroidism is probably more complex and controversial than that for subclinical hyperthyroidism. The most relevant physiological system is again cardiovascular; the largest meta-analysis performed so far reports an association with cardiovascular mortality in more severe cases (ie, serum TSH >10 mIU/L).6 Again, raised TSH is frequently transient, although a persistent increase is a more specific indicator of underlying thyroid disease. However, the upper limit of the TSH reference range rises with age,7 leading to controversy about the definition of disease, especially if TSH is in the 5—10 mIU/L range in elderly people. Randomised controlled trials of treatment (thyroxine replacement) have been done, but these are largely small, heterogeneous, and underpowered, and their findings are unsurprisingly negative or conflicting. A Cochrane review indicated insufficient evidence to recommend for, or against, treatment, including in those with a TSH greater than 10 mIU/L and in very elderly patients.8 However, new evidence9 exists for improved outcomes of coronary heart disease in younger, but not older, patients treated with thyroxine, and there are new data10 showing that thyroxine treatment helps to preserve renal function in people with subclinical hypothyroidism and chronic kidney disease. Fortunately, several clinically relevant trials are underway—including one EU-funded multicentre study of patients older than 80 years that will examine cardiovascular and quality-of-life outcomes—so the evidence base for subclinical hypothyroidism should increase and better guide us in our therapeutic approach.

References

1 Cooper DS, Biondi B. Subclinical thyroid disease. Lancet 2012; 379: 1142-1154. Summary | Full Text | PDF(416KB) |CrossRef | PubMed

2 Collet TH, Gussekloo J, Bauer DC, et al. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality.Arch Intern Med 2012; 172: 799-809. CrossRef | PubMed

3 Gammage MD, Parle JV, Holder RL, et al. Association between serum free thyroxine concentration and atrial fibrillation.Arch Intern Med 2007; 167: 928-934. CrossRef | PubMed

4 Goichot B, Pearce SH. Subclinical thyroid disease: time to enter the age of evidence-based medicine. Thyroid 2012; 22:765-768. CrossRef | PubMed

5 Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocr Pract 2011; 17: 456-520.CrossRef | PubMed

6 Rodondi N, den Elzen WP, Bauer DC, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality.JAMA 2010; 304: 1365-1374. CrossRef | PubMed

7 Waring AC, Arnold AM, Newman AB, Buzkova P, Hirsch C, Cappola AR. Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study. J Clin Endocrinol Metab 2012; 97: 3944-3950.CrossRef | PubMed

8 Villar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev 2007; 3. CD003419

9 Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med 2012; 172: 811-817. CrossRef | PubMed

10 Shin DH, Lee MJ, Kim SJ, et al. Preservation of renal function by thyroid hormone replacement therapy in chronic kidney disease patients with subclinical hypothyroidism. J Clin Endocrinol Metab 2012; 97: 2732-2740. CrossRef | PubMed

Source: Lancet

What causes coronary heart disease?

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Coronary heart disease (CHD) is arguably the the UK’s biggest killer. CHD develops when the blood supply to the muscles and tissues of the heart becomes obstructed by the build-up of fatty materials inside the walls of the coronary arteries.

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What is coronary heart disease?

Your heart is a pump the size of a fist that sends oxygen-rich blood around your body. The blood travels to the organs of your body through blood vessels known as arteries, and returns to the heart through veins.

Your heart needs its own blood supply to keep working. Heart disease occurs when the arteries that carry this blood, known as coronary arteries, start to become blocked by a build-up of fatty deposits.

How common is CHD?

  • CHD causes round 74,000 deaths each year. That’s an average of 200 people every day
  • In the UK, there are an estimated 2.3 million people living with the condition
  • About one in six men and one in nine women die from the disease
  • Death rates are highest in Scotland and northern England
  • In the past couple of decades, deaths from CHD have nearly halved due to better treatments

Source: British Heart Foundation

The inner lining of the coronary arteries gradually becomes furred with a thick, porridge-like sludge of substances, known as plaques, and formed from cholesterol. This clogging-up process is known as atherosclerosis.

The plaques narrow the arteries and reduce the space through which blood can flow. They can also block nutrients being delivered to the artery walls, which means the arteries lose their elasticity. In turn, this can lead to high blood pressure, which also increases the risk of heart disease. This same process goes on in the arteries throughout the body, and can lead to high blood pressure which puts further strain on the heart.

If your arteries are partially blocked you can experience angina – severe chest pains that can spread across your upper body – as your heart struggles to keep beating on a restricted supply of oxygen. You are also at greater risk of a heart attack.

Some people have a higher risk of developing atherosclerosis due to genetic factors – one clue to this is a family history of heart disease in middle-age. Lifestyle factors that increase the risk include an unhealthy diet, lack of exercise, diabetes, high blood pressure and, most importantly, smoking.

However, in the past couple of decades deaths from coronary heart disease have nearly halved, thanks to better treatments.

What happens during a heart attack?

A heart attack happens when one of the coronary arteries becomes completely blocked. This usually happens when a plaque, which is already narrowing an artery, cracks or splits open. This triggers the formation of a blood clot around the plaque, and it is this blood clot that then completely blocks the artery.

With their supply of oxygen completely blocked, the heart muscle and tissue supplied by that artery start to die. Emergency medical intervention is needed to unblock the artery and restore blood flow. This may consist of treatment with drugs to dissolve the clot or thrombus, or a small operation done through the skin and blood vessels to open up the blocked artery.

The outcome of a heart attack hinges on the amount of the muscle that dies before it is corrected. The smaller the area affected, the greater the chance of survival and recovery.

While a heart attack will always cause some permanent damage, some areas may be able to recover if they are not deprived of blood for too long. The sooner a heart attack is diagnosed and treated, the greater the chance of recovery.

Other heart diseases

Other diseases that commonly affect the heart include:

  • Chronic heart failure – CHD is one of the main causes of heart failure. It affects around one million people in the UK, and many more have it but haven’t been formally diagnosed. Here, the heart doesn’t works effectively as a pump, and fluid gathers in the lower limbs and lungs. This causes a variety of symptoms and significantly reduces quality of life.
  • Infection – bacterial infections such as endocarditis are much rarer these days thanks to antibiotics, but can damage the valves of the heart as well as other tissues. Viral infections can damage the heart muscle leading to heart failure, or cause abnormal heart rhythms.
  • Congenital heart disease – a number of defects can develop in the heart as a baby grows in the womb. One example is a hole in the heart, also known as a septal defect. Congenital heart disease may cause abnormal blood flow and put excessive strain on the infant’s heart after it has been born.
  • Cardiomyopathy – a disease of the heart muscle that can occur for different reasons, including coronary heart disease, high blood pressure, viral infection, high alcohol intake and thyroid disease.

Source: BBC