Is TMAO the New LDL CHOLESTEROL?

Prevention of heart disease has centered on smoking cessation, controlling blood pressure, achieving an appropriate weight, regular exercise, control of blood sugar and control of your cholesterol.  Despite addressing and controlling these items individuals still have heart attacks and strokes and vascular events. Researchers are now directing their attention to a dietary metabolite of red meat called trimethlamine N-oxide or TMAO.

Recent peer reviewed and published studies have shown an association between high blood levels of TMAO and increased risk of all-cause mortality and cardiovascular disease.  A 2017 study published in the Journal of the American Heart Association found a 60% increased risk of a major cardiovascular event and death from all causes in individuals with elevated TMAO.  Other research has linked high TMAO levels to heart failure and chronic kidney disease.

Our bodies make TMAO when choline and L-carnitine are metabolized by our gut bacteria in the microbiome. Red meat is particularly high in L-carnitine.  A study group at the Cleveland Clinic found that red meat raised the TMAO levels more than white meats or non-meat protein. They also discovered that red meat allowed more bacteria in the gut microbiome to be switched to producing TMAO. Of interest was the fact that the amount of fat in the food, particularly saturated fat, made no difference on the TMAO levels obtained.   Stanley Hazen, M.D. PhD, section head of preventive cardiology at the Cleveland Clinic, feels the TMAO pathway is “independent of the saturated fat story.”  The important issue to Dr Hazen is the presence of the gut bacteria to produce the TMAO from foods eaten.

Not all scientists buy into the TMAO theory of cardiovascular disease because of the relatively high level of TMAO found in many fish.  Some experts believe the beneficial effects of omega 3 fatty acids in fish offset the negative effects of TMAO. The leading researcher on TMAO says it is an evolving study and he is supported by experts who believe TMAO is “atherogenic, prothrombotic and inflammatory” per Kim Williams, M.D., chief of cardiology at Rush University Medical Center in Chicago.

There is even a blood test to measure TMAO levels developed by the Cleveland Clinic and available through Quest Labs.  Do not get too excited about asking your physician to order it on your blood because it requires eliminating meat, poultry and fish plus other food items for several days in advance of the test.

For many years researchers at the Cleveland Clinic and Emory University recognized that 50% or more of heart attacks occurred in men who followed all the risk reduction guidelines including stopping smoking, controlling blood pressure and lipids, losing weight and getting active. Perhaps the answer as to why will be in the TMAO research and the solution will be changing the gut bacteria or their ability to convert L-carnitine to TMAO.

Advertisements

Keep Moving for Cardiovascular Benefits

We keep extolling the benefits and virtues of regular exercise and fitness. Some research studies have documented the intensity and duration of exercise programs with cardiovascular events and mortality. Those who do more and are fitter apparently do much better which surprises few of us.

It comes down to the “which came first the chicken or egg “question?  Are people genetically able to exercise at a high level living longer and healthier because they exercise at a high intensity and duration or vice versa?

It is quite comforting to read the recent study in JAMA by Andrea LaCroix, PhD, MPH and colleagues from the University of California, San Diego that shows the benefits of even modest movement and exercise.  The study was conducted under the umbrella of the Women’s Health Initiative and put pedometers and accelerometers on women to measure activity during waking hours.  Light physical activity was defined as less than 3 metabolic equivalents (Walking one mile in about 22 minutes expends about 3 Metabolic Equivalents of Activity).  They noted that for each hour per day increment in light activity there was a 14% lower risk of Coronary Heart Disease and 8% lower risk of cardiovascular disease.

The researchers evaluated 5,861 women with a mean age of 78.5 years. Average follow-up spanned 3.5 years with study members having 570 cardiovascular disease events and 143 coronary heart disease events. The study group was diverse with there being 48.8% Caucasian women, 33.5 % Black women and 17.6% Hispanic women.

The study’s results and message was clear. Keep moving. Even modest exercise is beneficial in reducing heart attack and stroke risk.

Scientific Reports, Media Reports and Ambiguity

Last week I read an article in a peer reviewed journal citing the benefits of a few eggs per week as part of a low carbohydrate dietary intervention for Type II Diabetes.  The information was so meaningful about a controversial food source of protein that I decided to write about it in my blog and pass it along to my patients.  Three days later the American Heart Association and American College of Cardiology discussed the increased risk of cardiovascular events and mortality in individuals consuming three or more eggs regularly. They talked about the detrimental cholesterol being concentrated in the yolk making egg white omelets look healthier than traditional omelets.

In the early 1970’s a VA study was published showing that veterans over 45 years of age who took an aspirin a day had fewer heart attacks and strokes and survived them better than those who don’t.  Fast forward almost 50 years and we have different recommendations for people who have never had an MI or CVA or evidence of cardiovascular disease compared to secondary prevention in individuals who have known coronary artery disease, cerebrovascular disease or diabetes. Throw in the controversial discussions of aspirin preventing colorectal adenomas from developing, aspirin preventing certain types of skin cancers and today’s report that suggests it may prevent liver cancer. Now three studies suggest that in older individuals (70 or greater) the risk of bleeding negates the benefits of cardio and cerebrovascular protection and aspirin may not actually prevent heart attacks and strokes in that age group.

We then turn to statins and prevention of heart attacks and numerous articles about not prescribing them to older Americans.  I saw articles on this topic covered by CNN, the Wall Street Journal, ARP Journal, AAA magazine and in several newsletters published by major national medical centers.  In each piece they caution you to talk to your doctor before stopping that medicine.

I am that seventy year old patient they all talk about.  I have never smoked. I exercise modestly on a regular basis, getting my 10,000 or more steps five or more days a week.  I battle to keep my weight down and find it difficult to give up sweets and bread when so many other of life’s pleasures are no longer available due to age and health related suggestions.

There are clearly no studies that look at patients who took a statin for 15 years and aspirins for over 20 years, stopped them and then were followed for the remainder of their lives.   How will they fare compared to patients who never took them?

I have this discussion every day with my patient’s pointing out the current guidelines and trying to individualize the suggestions to their unique lifestyle and issues. On a personal level, I still have no idea what the correct thing is to do even after discussing it with my doctors.  How can I expect my patients to feel any differently?

Sleep and Cardiovascular Health

Several recent publications and presentations of data on the relationship between sleep patterns and vascular disease occurred at the recent meeting of the European Society of Cardiology. The PESA (Progression of Early Subclinical Atherosclerosis) study performed by Dr Fernando Dominguez, MD, of the Spanish National Center for Cardiovascular Research in Madrid talked about the dangers of too little or too much sleep.

The principal researcher, Valentin Fuster, MD PhD, looked at 3,974 middle-aged bank employees known to be free of heart disease and stroke. They wore a monitor to measure sleep and activity. Interestingly, while only about 11% reported sleeping six or fewer hours per night, the monitor showed the true figure was closer to 27%. They found those who slept less than six hours per night had more plaque in their arteries than those people who slept six to eight hours. They additionally looked at people who slept an average of greater than eight hours.

Sleeping longer had little effect on men’s progression of atherosclerosis but had a marked effect of increasing atherosclerosis in women. Researchers then adjusted the data for family history, smoking, hypertension, hyperlipidemia, diabetes and other known cardiovascular risk factors. They found that there was an 11% increase in the risk of diagnosis of fatal or non-fatal cardiovascular disease in people who slept less than six hours per night compared to people who slept 6-8 hours per night. For people who slept an average of greater than eight hours per night they bore a 32% increased risk as compared to persons who slept 6-8 hours on average. Their conclusion was distilled down into this belief: “Sleep well, not too long, nor too short and be active.”

In a related study, Moa Bengtsson, an MD PhD student at the University of Gothenburg in Sweden presented data on 798 men who were 50 years old in 1993 when they were given a physical exam and a lifestyle questionnaire including sleep habits. Twenty one years later 759 of those men were still alive and they were examined and questioned. Those reporting sleeping five hours or less per night were 93% more likely to have suffered an MI by age 71 or had a stroke, cardiac surgery, and admission to a hospital for heart failure or died than those who averaged 7-8 hours per night.

While neither study proved a direct cause and effect between length of sleep and development of vascular disease, there was enough evidence to begin to believe that altering sleep habits may be a way to reduce future cardiovascular disease.

Inflammation and Increased Risk of Cardiovascular Disease

For years, experts have noted that up to 50% of men who have a heart attack do not have diabetes, high blood pressure, high cholesterol, do not smoke and are active. This has led to an exploration of other causes and risk factors of cardiac and cerebrovascular disease.

In recent years, studies have shown an increased risk of cardiovascular disease in patients with rheumatoid arthritis, in untreated psoriatic arthritis and in severe psoriasis. We can also add atopic eczema to the list of cardiovascular risk factors.

In a publication in the British Medical Journal, investigators noted that patients with severe atopic eczema had a 20% increase risk in stroke, 40 – 50% increase risk of a heart attack, unstable angina, atrial fibrillation and cardiovascular death. There was a 70% increased risk of heart failure. The longer the skin condition remained active the higher their risks.

The study looked at almost 380,000 patients over at least a 5 year period and their outcomes were compared to almost 1.5 million controls without the skin conditions. Data came from a review of medical records and insurance information in the United Kingdom.

It’s clear that severe inflammatory conditions including skin conditions put patients at increased risk. It remains to be seen whether aggressive treatment of the skin conditions with immune modulators and medications to reduce inflammation will reduce the risks?

It will be additionally interesting to see what modalities cardiologists on each side of the Atlantic suggest we should employ for detection and with what frequency? Will it be exercise stress testing or checking coronary artery calcification or even CT coronary artery angiograms? Statins have been used to reduce inflammation by some cardiologists even in patients with reasonable lipid levels? Should we be prescribing statins in men and women with these inflammatory skin and joint conditions but normal lipid patterns?

The correlation of inflammatory situations with increased risk of vascular disease currently raises more questions with few answers at the present time.

More Good News for Coffee Drinkers

When I first started practicing, fresh out of my internal medicine residency and board certification, we were taught that consuming more than five cups of coffee per day increased your chances of developing pancreatic cancer. Thankfully that theory has been proven to be false.

Last week I reviewed a publication in a peer reviewed journal which showed that if you infused the equivalent of four cups of coffee into the energy producing heart cell mitochondria of older rodents, those mitochondria behaved like the mitochondria found in very young healthy rats. The authors of that article made the great leap of faith by suggesting that four cups of caffeinated coffee per day was heart healthy.

This week’s Journal of the American Medical Association Internal Medicine published a study which said if you drank eight cups of coffee per day your mortality from all causes diminished inversely. Their study included individuals who were found to be fast and slow metabolizers of caffeine. It additionally made no distinction between ground coffee, instant coffee or decaffeinated coffee.

The research study investigated 498,134 adults who participated in the UK Biobank study. The mean age of the group was 57 years with 54% women and 78% coffee drinkers. The study participants filled out questionnaires detailing how much coffee they drank and what kind. During a 10 year follow-up there were 14,225 deaths with 58% due to cancer and 20% due to cardiovascular disease. As coffee consumption increased, the risk of death from all causes decreased. While instant coffee and decaffeinated coffee showed this trend, ground coffee showed the strongest trend of lowering the mortality risk.

This is an observational study and, by design, observational studies do not prove cause and effect. It is comforting to know however that having an extra cup or two seems to be protective rather than harmful. At some point a blinded study with true controls will need to be done to prove their point. If the caffeine doesn’t keep you up or make you too jittery, and the coffee itself dehydrate you or give you frequent stools, then drink away if you enjoy coffee in large volume.

Coffee and the Healthy Heart

Two German biologists are stating there is sufficient data to claim that four cups of caffeinated coffee is the optimal daily dosage to maintain a healthy heart. Their findings were published in Plos Biology and summarized in Inverse Magazine. The scientists cite past warnings by public health officials of the danger of caffeine when given to people with heart conditions. Quite the contrary. They believe that up to four cups of coffee per day are actually therapeutic for the heart.

In their research they noted caffeine helps a protein called “p27” enter the energy producing mitochondria of heart cells making them function more efficiently. They experimented with rats comparing the mitochondrial function of old rats and young rats. When they injected the older rats with the caffeine equivalent of four cups of coffee, their aging mitochondria performed at the level of young rats’ mitochondria. They then experimentally caused the older rats to have a heart attack or myocardial infarction. Half of these heart damaged rats were injected with the equivalent of four cups of coffee and their heart cells repaired themselves at a far more rapid rate than those not exposed to that dose of coffee and caffeine.

The researchers conclude that four cups of coffee is probably the optimal daily dosage of coffee for a healthy heart. They caution that certain patients, especially those with malignant tumors, should probably avoid that much coffee because it may promote growth of blood vessels to the tumors. They additionally caution against using caffeine pills or energy drinks because their research was done with coffee.

Coffee in moderation is probably not harmful for any human adult.

Keep in mind, this biologic evidence was obtained in rats not human beings. Fortunately, I have not seen rats breaking into my local Dunkin Donuts and Starbucks craving a lifesaving nutrient.

Coffee has been associated with preventing cognitive dysfunction, preventing diabetes and now keeping your heart healthy. If you enjoy coffee, drinking it in moderation makes sense to me.