que "burden," i.e., an indirect yardstick for coronary plaque. The greater the quantity of coronary calcium, the higher the heart scan "score," the greater the risk for heart attack and other unstable coronary syndromes that lead to stents, bypass, etc.
But can calcium also cause plaque to form or trigger processes that lead to plaque formation and/or instability?
Nadra et al show, in an in vitro preparation, that calcium phosphate crystals are actively incorporated into inflammatory macrophages, which then trigger a constellation of inflammatory cytokine release (tumor necrosis factor-alpha, interleukins), fundamental processes underlying atherosclerotic plaque formation and inflammation.
Here's the abstract of the study: Proinflammatory Activation of Macrophages by Basic Calcium Phosphate Crystals via Protein Kinase C and MAP Kinase Pathways:
A Vicious Cycle of Inflammation and Arterial Calcification?
Basic calcium phosphate (BCP) crystal deposition underlies thedevelopment of arterial calcification. Inflammatory macrophagescolocalize with BCP deposits in developing atherosclerotic lesionsand in vitro can promote calcification through the release of TNF alpha. Here we have investigated whether BCP crystals can elicit a proinflammatory response from monocyte-macrophages.BCP microcrystals were internalized into vacuoles of human monocyte-derived macrophages in vitro. This was associated with secretion of proinflammatory cytokines (TNF, IL-1ß and IL-8) capable of activating cultured endothelial cells and promoting capture of flowing leukocytes under shear flow. Critical roles for PKC, ERK1/2, JNK, but not p38 intracellular signaling pathways were identified in the secretion of TNF alpha, with activation of ERK1/2 but not JNK being dependent on upstream activation of PKC. Using confocal microscopy and adenoviral transfection approaches, we determined a specific role for the PKC-alpha isozyme.
The response of macrophages to BCP crystals suggests that pathological calcification is not merely a passive consequence of chronic inflammatory disease but may lead to a positive feed-back loop of calcification and inflammation driving disease progression.
This observation adds support to the notion that increasing coronary calcium scores, i.e., increasing accumulation of calcium within plaque, suggests active plaque. As I say in Track Your Plaque, "growing plaque is active plaque." Active plaque means plaque that is actively growing, inflamed and infiltrated by inflammatory cells like macrophages, eroding its structural components, and prone to "rupture," i.e., cause heart attack. Someone whose first heart scan score is, say, 100, followed by another heart scan score two years later of 200 is exposed to sharply increasing risk for cardiovascular events which may, in part, be due to the plaque-stimulating effects of calcium.
Conversely, reducing coronary calcium scores removes a component of plaque that would otherwise fuel its growth. So, people like our Freddie, who reduced his heart scan score by 75%, can be expected to enjoy a dramatic reduction of risk for cardiovascular events.
If you're having difficulty convincing a loved one or someone else that wheat should be eliminated from the human diet, here are some useful one-liners to use:
Wheat makes your boobs big. (This is true. Priceless for women to use on their husbands.)
Wheat causes dementia. (And confirmed on examination of brain tissue at autopsy. Yes, autopsy.)
Wheat makes you look pregnant. (The visceral fat of a wheat belly does a darn good imitation of a near-term infant.)
The first sign of wheat intolerance can be wetting your pants. (Cerebellar ataxia, i.e., destruction and atrophy of the cerebellum, caused by wheat leads to loss of coordination and bladder control. Average age of onset: 53 years old.)
White flour bad, whole grain better; just as Marlboros are bad, Salems are better. (The flawed syllogism that led to the "eat more healthy whole grain" colossal blunder.)
Wheat is the only food with its very own mortality rate. (Celiac disease, osteoporotic hip fractures, and the neurologic diseases triggered by wheat can be fatal.)
"Wheat" is no longer wheat; it's the dwarf mutant that came from genetics research in the 1960s. (Over 99% of all wheat today comes from the 18-inch tall dwarf mutant.)
Wheat increases blood sugar higher than nearly all other foods. (Higher than Milky Way bars, higher than Snickers bars, higher than table sugar.)
There you have it: A full arsenal of one-liners to shoot at your husband, wife, or friend when they roll their eyes at your refusal to consume this thing called "wheat."
If you were a "cold blooded" poikilotherm unable to regulate internal body temperature, you would have to sun yourself on rocks to raise your body temperature, just like turtles and snakes. When it got cold, your metabolic rate would slow and you might burrow into the mud to hide.
You and I, however, are homeotherms, terrestrial animals able to regulate our own internal body temperature. Principal responsibility for keeping your body temperature regulated falls with the thyroid gland, your very own thermoregulatory "thermostat."
But internal body temperature, even in a homeotherm, varies with circadian rhythm: Highest temperature occurs in the early evening around 8 p.m.; the low temperature nadir occurs at around 4 a.m.
The notion that normal human temperature is 98.6 degrees Fahrenheit is a widely-held fiction, a legacy of the extraordinary experience of 19th century German physician, Carl Reinhold August Wunderlich, who claims to have measured temperatures of one million people using his crude, uncalibrated thermometer to obtain axillary (armpit) body temperatures.
Dr. Broda Barnes was a 20th century American proponent of using the nadir body temperature to gauge thyroid function. Like Wunderlich, Barnes also used axillary temperatures.
Modern temperature assessments have employed radiotransmitting thermistors that are swallowed, with temperatures tracked as the thermistor travels through the stomach, duodenum, small intestine, large intestine, rectum, then peek-a-boos back out. Such internal "core temperature" assessments have shown that:
--Axillary temperatures do not track with internal core temperatures very well, often veering off course due to external factors. --Axillary temperatures are subject to ambient temperatures, such as room temperature, and are affected by clothing. --Axillary temperatures are more susceptible to physical activity, e.g., increased with exercise or physical work.
Even right vs. left axillary temperatures have been shown to vary up to 2 degrees Fahrenheit.
Studies such as this demonstrate that normal oral temperature upon arising is around 97.2-97.3 degrees Fahrenheit. While we lack data correlating thyroid function with circadian temperature variation, the a.m. nadir does indeed, as Dr. Barnes originally suggested, seem to track thyroid status quite well: lower with hypothyroidism, higher with normal or hyperthyroidism.
I have been using 97.3 degrees F orally as the cutoff for confirming or uncovering thyroid dysfunction, particularly when symptoms or blood tests (TSH, free T3, free T4) are equivocal, a value that has held up well in the majority of cases. I find it helpful when, for instance, someone complains of cold hands and feet and has normal TSH (1.5 mIU/L or less in my view) but low free T3. An a.m. oral temperature of, say, 95.7 degrees F, suggests that there will be a favorable response to T3 supplementation. And it nearly always plays out that way.
Wouldn't it be interesting to know if there was insight into thyroid status provided by also examining the circadian behavior of temperature (e.g., height or timing of the peak)?
Merck recently reported preliminary results with its drug-in-development, anacetrapib.
After six months of treatment, participants showed:
LDL cholesterol was reduced from 81 mg/dl to 45 mg/dl in those taking anacetrapib, and from 82 mg/dl to 77 mg/dl in the placebo group.
HDL increased from 41 mg/dl to 101 mg/dl in the drug group, from 40 mg/dl to 46 mg/dl in those on placebo.
As you'd expect, the usual line-up of my colleagues gushed over the prospects of the drug, salivating over new speaking opportunities, handsomely-paid clinical "research" trials, and plenty of nice trips to exotic locales.
Anacetrapib is a cholesteryl-ester transfer protein inhibitor, or CETP inhibitor, much like its scrapped predecessor, torcetrapib . . . you know, the one that went down in flames in 2006 after 60% excess mortality occurred in people taking the drug compared to placebo. The hopes of many investors and Pfizer executives were dashed with torcetrapib's demise. The data on torcetrapib's lipid effects were as impressive as Merck's anacetrapib.
These drugs block the effects of the CETP enzyme, an enzyme with complex effects. Among CETP's effects: mediating the "heteroexchange" of triglycerides from triglyceride-rich VLDL particles that first emerge from the liver for cholesterol from LDL particles. This CETP-mediated process enriches LDL particles with triglycerides, which then make LDL a target for action by another enzyme, hepatic lipase, that removes triglycerides. This yields a several nanometer smaller LDL particle, now the number one most common cause of heart disease in the U.S., thanks to conventional advice to cut fat intake and increase consumption of "healthy whole grains."
With effects like this, anacetrapib, should it hold up under the scrutiny of FDA-required trials and not show the same mortality-increasing effects of torcetrapib, will be a huge blockbuster for Merck if release goes as scheduled in 2015. It will likely match or exceed sales of any statin drug. Statin drugs have achieved $27 billion annual sales, some of it deserved. Anacetrapib will likely handily match or exceed Lipitor's $12 billion annual revenue.
More than increasing HDL, CETP inhibition is really a strategy to reduce small LDL particles.
As with many drugs, there are natural means to achieve similar effects with none of the side-effects. In this case, similar effects to CETP inhibition, though with no risk of heightened mortality, is . . . elimination of wheat, in addition to an overall limitation of carbohydrate consumption. Not just low-carb, mind you, but wheat elimination on the background of low-carb. For instance, eliminate wheat products and limit daily carbohydrate intake to 50-100 grams per day, depending on your individual carbohydrate sensitivity, and small LDL drops 50-75%. HDL, too, will increase over time, not as vigorously as with a CETP inhibitor, but a healthy 20-30% increase, more with restoration of vitamin D.
Eliminating wheat and adjusting diet to ratchet down carbs is, of course, cheap, non-prescription, and can be self-administerd, criteria that leave the medical world indifferent. But it's a form of "CETP inhibition" that you can employ today with none of the worries of a new drug, especially one that might share effects with an agent with a dangerous track record.
, IL-1ß and IL-8) capable of activating cultured endothelial cells and promoting capture of flowing leukocytes under shear flow. Critical roles for PKC, ERK1/2, JNK, but not p38 intracellular signaling pathways were identified in the secretion of TNF alpha, with activation of ERK1/2 but not JNK being dependent on upstream activation of PKC. Using confocal microscopy and adenoviral transfection approaches, we determined a specific role for the PKC-alpha isozyme.