Ketogenic Diets: Possible Hidden Cardiovascular Risks?

A rhyme originating in the 1600s later appeared in the Mother Goose collection about the dietary habits of the Sprat household. The modern version reads, "Jack Sprat could eat no fat, his wife could eat no lean; and so, between the both, you see, they licked the platter clean."


Obviously not desirable dinner guests, the Sprats are fine examples of two extremes in dieting that have dominated the American weight loss and healthy eating mania. Low-fat diets have long held the accepted position of being the politically correct and clinically accepted diet. The low-fat approach was originally developed to treat and prevent atherosclerotic cardiovascular disease (ASCVD), commonly visualized by cholesterol-laden plaques within the walls of large and small arteries (blood vessels).1 The assumption was that by reducing the dietary exposure to fat and cholesterol by discouraging the consumption of meat, eggs, and dairy, serum (blood) cholesterol and triglycerides (fat) would decrease and along with it, the risk of heart attack and stroke.

Unfortunately, low-fat diets do not offer much benefit beyond what would be gained from weight loss by any method. Limiting dietary cholesterol does not address the de novo cholesterol produced by the body, which is the cause of high cholesterol in most people. Along came the Atkins revolution, an antithetical approach that claims to promote weight loss by restricting carbohydrates rather than fat. Low-fat diets use the approach of reducing the caloric density of the diet to reduce calorie intake; low-carbohydrate diets make it easier for the body to break down and use stored fat for energy by reducing insulin release. Though many assumed the opposite, no evidence of unhealthy changes in cardiovascular markers has been noted. In fact, some components of the lipid profile (fats and cholesterol) improve on low-carbohydrate diets, suggesting they are at least as safe, and possibly safer diets for people at risk for heart attacks and stroke to follow.The Atkins diet has phases, including the induction phase, which severely restricts carbohydrate consumption. When carbohydrate intake is below 20-30 grams per day, the body enters a state called ketosis.2 Weight loss is dramatic and rapid when ketogenic dieting is followed; much of the early weight lost is water, as carbohydrate stores are depleted. Over the long term, weight loss is slower, particularly as people migrate to the more moderate parts of the diet. In time, there appears to be little difference between the various types of diets relative to the number of people who stay on the diet and the amount of weight they lose and keep off.3-5 Many people get discouraged by slow weight loss, while some people find the mental state associated with ketosis comforting, as a sign of ongoing fat reduction. The brain is highly dependent upon blood sugar and during ketosis, some people experience irritability and difficulty performing mental tasks. However, over time, some people claim they are sharper. Regardless, there is a definite subjective component to ketosis— some people become so committed (obsessive?) that they test their urine for ketones several times a day. Ketogenic dieting can be followed long term. Many people do so voluntarily; others are directed to do so by their physicians for specific conditions, such as epilepsy.6 Some have suggested that ketogenic dieting may not only be as effective as low-fat dieting for weight loss, but more effective and safer. This belief is certainly premature, as very few side-by-side studies have been done and none have followed the subjects long enough to state so definitely.

Bodybuilders and Cardiovascular Health
Cardiovascular health is important for bodybuilders and anabolic steroid-using athletes to consider, as certain anabolic-androgenic steroids (AAS) are associated with adverse changes in cholesterol, and heart attacks and heart failure are some of the most common causes of sudden death or serious injury in this group. Elite bodybuilders and many other AAS users have suffered heart problems. While it is not possible to directly assign AAS as a contributing cause to these cases, there is a strong base building due to several reasons:


• Use patterns of AAS— dose and duration of cycles— have changed.
• Polypharmacy (the use of multiple medications and/or the administration of more medications than are clinically indicated, representing unnecessary drug use) includes many other anabolic biologics (growth hormones and cytokines) and potent lipolytics (fat-reducers).
• The demographics of AAS users are aging.

'Cardiovascular' refers to the heart and the blood vessels. Heart damage is most commonly caused by ischemia (oxygen deprivation) but can also be electrical in nature, as the heartbeat is generated by an internal conduction system that accelerates and decelerates to meet the circulatory demand of the body. When the electrical signal is disrupted, the heart does not beat efficiently or if the disruption is severe enough, may not beat at all. Ischemic damage of the heart (and brain, as well as other tissues) is often due to a buildup of plaque in the arteries, but may also be due to inappropriate vasoconstriction (the blood vessel squeezing shut, as seen in the skin when exposed to cold) or not dilating (opening wider) when oxygen demand requires greater blood flow. Many abusers of cocaine suffered heart attacks due to coronary vasoconstriction, even though their arteries were perfectly healthy.7 When ischemia is mild-to-moderate and long-term, the body grows new blood vessels to shorten the distance between active cells and nearby capillaries (the smallest blood vessels and the site where oxygen and factors are diffuse back-and-forth to cells of the body).8 A person who lives in the mountains likely has a higher capillary density (a measure of how branched the circulation is to provide oxygen) than a person who lives on the beach at sea level. Many endurance athletes sleep in special chambers that mimic living in the mountains. This increases their red blood cell supply (the cells that carry oxygen) by stimulating the hormone erythropoietin, and likely stimulates new blood vessel growth. Many cancer drugs kill tumors by shutting down blood vessel growth, starving the malignant tumors of oxygen and nutrients.9One final mechanism that affects the buildup of plaque in artery walls is the ability of the blood vessel to maintain an intact lining. Major blood vessels are designed not to leak, and do so by having a lining that prevents red and white blood cells from escaping into the surrounding tissue. With the constant flow of blood rushing through the vessels, the lining wears away but is constantly replaced by new lining cells. If these replacement cells were not available, plaque can more easily build up under the lining in the artery walls. Picture a pickup truck bed with a spray-on liner. If the liner gets gouged, rust can develop in the underlying metal— unless a new layer of spray-on lining covers the damage. If neglected, the rust spreads, potentially causing significant damage.

Low-Carb Mice and Ketogenic Diets
This background is provided to put into context the relevance of a newly-published study that unveils some heretofore-unrealized concerns about ketogenic diets. A group of researchers at Beth Israel Hospital and other facilities, all part of the Harvard Medical System, compared the cardiovascular effect of three types of diets— all containing the same amount of cholesterol— in mice bred to be capable of developing atherosclerosis (plaque buildup).10 The standard chow was low in fat and protein, being 65 percent carbohydrate. The second group received a diet that mimics what most people in the United States consume, (43/15/42— carbohydrate/protein/fat); and the last group was provided with a low-carbohydrate diet of 12/45/43 (carbohydrate/protein/fat).
Mice do not develop atherosclerosis naturally, and the mice fed the standard 'mouse chow' had clean arteries after 12 weeks. Mice fed the Western diet had a significant amount of atherosclerosis and the low-carb mice had even more, nearly twice as much.
In looking at the typical lab markers to explain these findings, researchers discovered that there was no real difference in cholesterol, bad cholesterol, or oxidized cholesterol between mice fed the Western and low-carbohydrate diets. Both had a four-fold increase in serum (blood) cholesterol compared to the standard diet. The low-carbohydrate diet was not associated with any increase in oxidative damage (the molecular damage that is protected against by antioxidants). Oxidative damage is proposed to make blood vessels more susceptible to atherosclerosis.11


Another factor involved in atherosclerosis is inflammation. The study looked at two measures of inflammation and found the exact opposite of what would be expected. The low-carbohydrate diet resulted in lower measures of a specific marker for inflammation in the bloodstream— no different from measurements taken from mice fed the standard diet who had essentially no atherosclerosis.10 The mice fed the low-carbohydrate diet experienced a dramatic decrease in the healing 'replacement cells' that normally repair the blood vessel lining. The degree of decrease was greater than 80 percent and also affected precursor cells in the bone marrow.10 Ironically, one hormone that stimulates the production of the replacement cells, VEGF, actually increased in low-carbohydrate fed mice.10,12 Failing to directly measure the replacement cells (called endothelial progenitor cells, or EPC) and measuring VEGF instead would misled a clinician to believe that low-carbohydrate dieting was safer for cardiovascular health. The increase in VEGF may be a sign of the body reacting to the EPC-lowering effect of the low-carbohydrate diet in the mice.

EPC plays a role in new blood vessel growth, and corresponding to the decrease seen with EPC, low-carbohydrate fed mice were unable to respond to ischemia (oxygen deprivation).10,13 One of the factors known to stimulate EPC growth (pAkt) is a 'downstream' molecule in the insulin-signaling cascade. 'Downstream' means insulin turns on one molecule, which turns on another, which turns on pAkt. Statin drugs (Lipitor, for example), exercise, and estrogen have been shown to counteract impaired EPC production.13 Low-carbohydrate fed mice had significantly lowered insulin concentrations compared to other diets, as would be expected. Type 2 diabetics who are insulin-resistant also demonstrated impaired EPC production.14 Though this is not the entire reason EPC growth is impaired in low-carbohydrate diets, it likely plays a role. Thus far, low-carbohydrate diets have been shown to markedly increase atherosclerosis, even compared to high-fat diets. This is in a setting that would not raise suspicion. In fact, many measures suggest that cardiovascular health is improved with low-carbohydrate dieting. Also, the ability of the circulatory system (blood vessels) to respond to oxygen deprivation is seriously impaired. This study did not look at ketogenic dieting, as the carbohydrate content was high enough to prevent ketosis. Thus, it is difficult to determine whether the same concerns would be present during ketogenic dieting. However, another concerning observation has been noted during ketogenic dieting that adds another level of risk. One study published last year showed that people on a ketogenic diet had impaired dilation, whereas those on a low-fat diet actually demonstrated improved flow-mediated dilation and response to a dilating drug. Similar impairment is again seen in people with insulin resistance.15,16 This adverse effect may be exaggerated when saturated fat is high, but the balance of research appears to suggest that if mono- and polyunsaturated fats are consumed in sufficient quantities and saturated fats are moderated, blood vessels should respond more appropriately to dilating signals.17 Research looking at non-ketogenic, low-carbohydrate diets do not demonstrate the same defect, suggesting there may be different risks present during ketosis.18-20

Moderation Is Sound Advice
This body of research is quite significant, even though it is from a mouse study and has not been duplicated in humans, let alone in a second mouse study. Many people follow a low-carbohydrate diet to reduce their bodyweight, improve conditions associated with the Metabolic Syndrome (high cholesterol, high blood pressure, insulin resistance, etc.) and decrease cardiovascular risk. Further, some who are already at risk for cardiovascular disease or even those in rehab after a cardiovascular event may be following a low-carbohydrate diet, in the belief that it is more effective for weight loss and poses no more (or even less) of a risk to one's cardiovascular health. Indeed, the blood work performed during studies evaluating the various diets (including Atkins-like, low-carbohydrate diets) suggest that these diets are as safe or safer than the traditional low-fat diet.21 Yet, reports of individuals developing cardiovascular disease while following an Atkins-type plan have been published.22
Given the findings in this study, it is impossible to recommend low-carbohydrate or ketogenic diets to those with a significant personal or family history of cardiovascular disease. In fact, this data supports the recommendation for moderate carbohydrate intake sufficient to maintain a baseline insulin presence. The exact recommendation for carbohydrates remains fuzzy at this time, but it appears that at least 60-100 grams per day of low-glycemic carbohydrates, along with an intake of mono- and polyunsaturated fats to counterbalance saturated fat intake, is the optimal diet plan. Excessive carbohydrate intake should be avoided as well, suggesting that the age-old adage of moderation in all things remains sound advice.
AAS-using bodybuilders and athletes should take note, as hidden damage to the cardiovascular system may make the AAS-using individual more susceptible to heart or brain damage, even sudden death. Certainly, the inability of the circulatory system to develop new blood vessels to feed working and growing muscle would be a detriment to the anabolic effects of training.
There are many approaches to fat loss. Science, the media, and policymakers have so long focused on the dangers of various weight-loss drugs that the hidden dangers of (physiologically) extreme diets may have been ignored.

References:
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