They say blood is thicker than water. When it comes to cardiovascular risk, the big question is, how much thicker?
Blood viscosity is an important, though overlooked risk factor for heart disease and stroke. Recent data show a strong connection between elevated blood thickness, heart disease and conditions like diabetes and lupus.
Emerging new technology will soon make it much easier for office-based physicians to measure and interpret blood viscosity, hopefully leading to earlier detection of risk especially in patients with normal lipid profiles. The really good news is that nattokinase, an enzyme derived from the Japanese fermented soy food called natto, appears to be able to reverse high blood viscosity.
According to Ralph Holsworth, Jr., DO, a family physician who has taken a deep interest in the impact of blood viscosity on heart health, many of the 300 or so other independent CVD risk factors all share a common denominator: an association with increased blood viscosity. In an interview with Holistic Primary Care, he pointed out that increased blood viscosity is a primary reason why metabolic syndrome and type 2 diabetes increase CVD risk.
"In metabolic syndrome, there's an increase in LDL and TGL, but you also have a marked increase in plasminogen activator inhibitor (PAI)-1. PAI is the principle inhibitor of tissue plasminogen activator. Elevated PAI results in increased viscosity and a greater propensity toward clotting. This is why diabetics have a lot of vessel disease." In short, metabolic syndrome and diabetes predispose toward having thicker, more clot-prone blood. This in turn, has detrimental effects on the vasculature (Suzuki Y, et al. Life Sciences. 2003; 73: 1289–1298).
Changes in blood viscosity also help explain the cardioprotective effects of the menstrual cycle in women. This is not some mysterious estrogen effect. "If you look at the Framingham study, not one menstruating female has evidence of CVD. Menstruating women are losing 1,000 to 1,500 cc of blood each month. Reproductive age women show consistently lower blood viscosity compared with men of the same age. After menopause, they lose this, and catch up with the males in terms of CVD rates, within 2 years," said Dr. Holsworth,
Blood Viscosity & Autoimmune Diseases
Recently, researchers at the University of Chicago completed a study showing that elevated blood viscosity may be a key driver of CVD associated with lupus. Tammy Utset, MD, MPH, at the University's rheumatology department, studied 80 patients with systemic lupus erythematosus. Some had no history of thrombotic events; others had histories of arterial thrombotic events (MI or stroke); still others had histories of venous thrombotic events (deep vein thrombosis or pulmonary embolism). They also included healthy controls matched for age, sex, BMI, tobacco usage history and race.
SLE patients with arterial events had significantly higher blood viscosity than any of the other groups, including patients with venous thrombotic events, reported Dr. Utset, who presented the findings at the 2006 meeting of the American College of Rheumatology. The data are slated for publication in a major journal later this year. Dr. Utset is continuing her exploration of blood viscosity in other rheumatologic and autoimmune diseases, including scleroderma.
Her research illuminates what has been a bit of a mystery for cardiologists and rheumatologists alike. Both have long recognized a connection between lupus and CVD, but the reasons have remained obscure. In 2003, Vanderbilt University researchers showed that lupus patients have 140 percent higher prevalence of atherosclerosis compared to non-lupus individuals with comparable CV risk and demographic profiles. The difference is even more dramatic for younger patients. Lupus patients aged 40 and under show a 480 percent increased prevalence of atherosclerosis. These findings are not attributable to differences in lipid profiles (Asanuma Y, et al. N Engl J Med. 2003; 349(25): 2407–2415).
Differences in blood viscosity may be the missing link to explain the observed connections.
Enter the Rheolog!
Recognition of blood viscosity as an important variable in human circulation is nothing new; it goes back to the days of William Harvey, Dr. Holsworth told Holistic Primary Care. But by and large, it has been forgotten in clinical practice, especially in recent decades where the focus has been on biochemical modulation of lipid metabolism and inflammation. Biophysical factors like blood viscosity somehow never captivated the medical imagination.
Cardiothoracic surgeons, he contends, have functioned largely as plumbers, taking a "roto-rooter" approach to heart disease: if there are occlusions, the goal is to clear out the vessels. But this is incomplete, because it ignores the fact that "the condition of the pipe is reflecting the condition of the fluid it carries. You need to look at the physical characteristics of the fluid, in this case the blood. "
Fortunately, that is becoming easier with the advent of the Rheolog, a blood viscometer designed for clinical use and soon to be marketed by Rheologics, Inc., a Pennsylvania medical technology company (www.rheologics.com). The device measures whole blood viscosity across a complete cardiac cycle. It just underwent successful beta-testing and is in use in several clinical research settings including Dr. Utset's lab at the University of Chicago.
Kenneth Kensey, MD, Rheologics' founder and chief scientific officer, believes blood viscosity measurement will vastly improve our understanding of various CV problems. Using Dr. Utset's study as an example, he pointed out that viscosity was markedly increased in the patients with histories of arterial thrombotic events, but not in those with venous thrombotic problems. Even though both are associated with harmful thrombus formations, the mechanisms differ greatly.
"Arterial and venous events follow different thrombosis pathways," explained Dr. Kensey in a printed statement following initial presentation of Dr. Utset's data. "The thrombotic cascade in the vein is based on the principle of stagnant blood flow, while arterial thrombosis is a result of plaque that is ruptured by injurious and abrasive blood flow. Elevated blood viscosity quantifies the increased injurious frictional force of pathological blood flow."
He and his colleagues at Rheologics hope that wider clinical use of blood viscosity measurement will result in earlier detection of CVD risk not only among patients with diseases like lupus, but in the general population as well.
According to Dr. Holsworth, elevated blood viscosity, which is entirely independent of lipid profiles, is not only a common risk factor, it is also very treatable using nattokinase, a naturally occurring protease found in natto, the gooey fermented soy "cheese" that has been a staple in Japanese households for centuries.
Nattokinase was first discovered by Prof. Hiroyuki Sumi, a physiologist at the Miyazake Medical College in 1987. This enzyme has a 4-fold increased fibrinolytic activity compared with plasmin. By inactivating PAI-1, nattokinase increases the natural clot-lysing activity of tissue plasminogen activator. But it has other effects as well; it can directly induce fibrinolysis even when PAI is removed (artificially) from fibrin clots.
Dr. Holsworth recently teamed up with researchers at Keck School of Medicine, University of Southern California, to assess the impact of nattokinase on blood viscosity and red cell aggregability. They incubated human blood samples with nattokinase at doses of 0, 15.6, 31.3, 62.5 and 125 units/ml, and found a significant, dose-dependent reduction in RBC aggregation and low-shear viscosity. At the highest doses, the nattokinase gave a 62% reduction in RBC aggregation (Pais E, et al. Clinical Hemorrheology & Microcirculation. 2006; 35(1–2): 139–142).
High fibrinogen levels, elevated RBC aggregation and high blood viscosity all correlate with onset and progression of CVD. Reducing any or all of them would, presumably, reduce the risk of future CV events, said Dr. Holsworth.
A True Blood Thinner
He believes nattokinase can do what current drug therapies cannot: modulate blood viscosity. "Pharmaceuticals affect lipid metabolism or they biochemically modulate the clotting process. But they do not alter blood viscosity," he said. "Even aspirin, which is promoted as a "blood thinner," does not actually change viscosity; it only inhibits clotting. If you measure viscosity using hemorheology, there's no difference with regular aspirin use." Neither, for that matter, is coumadin a true blood thinner. "Again, it is an anticoagulant, but it doesn't actually reduce viscosity."
Nattokinase increases endogenous production of tissue plasminogen activator. "It is a third-order fibrinolytic, and it does not bypass Mother Nature. In fact, it actually nurtures nature. As far as I know, nattokinase is the only thing we have that can actually reduce the thickness of the blood." Moreover, it does this without adversely affecting normal coagulation, so it does not increase risk of excessive bleeding or bruising.
Clinical studies of nattokinase for CVD treatment are just beginning. A preliminary trial in India showed the enzyme can reduce damage due to ischemic strokes, and eliminate neurological deficits associated with microvascular stroke.
The strongest evidence for nattokinase so far comes from the LONFLIT-FLITE study published in 2003 showing that in combination with pycnogenol, a natural anticoagulant derived from the bark of the French Maritime Pine tree, nattokinase could greatly reduce incidence of edema and deep vein thromboses during long plane flights (Cesarone MR, et al. Angiology. 2003; 54(5): 531–539). Some airlines now stock the nattokinase-pycnogenol combo on overseas flights. (For a review of LONFLIT, and related stories, visit www.holisticprimarycare.net and search "nattokinase".)
Dr. Holsworth has been using nattokinase in clinical practice for many years, and he founded a company called NZymeCeuticals to bring the nattokinase formula now widely used in Japan, to the US market (www.nzymeceuticals.com). His company supplied the nattokinase used in the LONFLIT study. "Nattokinase is as powerful as any pharmaceutical agent I know of. For all intents and purposes it acts like a drug. I took it to FDA to get it declared as a medical food, and we were granted that designation 4 years ago."
Dosing is standardized in terms of fibrin degradation units (FUs), an indicator of a substance's ability to break up fibrin clots. The therapeutic dose range for prevention of CVD risk is between 4,000 and 6,000 FUs divided into three doses. This translates into 300 mg per day, as three divided 100 mg doses. The half-life is between 6 and 8 hours. Because it is rapidly metabolized it is best to take it with food, which slows things down a bit.
Safe When Supervised
Although nattokinase is generally safe, it is not something patients should experiment with by themselves. It can reduce blood pressure—so much so that it can sometimes obviate the need for antihypertensive drugs, said Dr. Holsworth. For this reason alone, patients should only take it under physician supervision.
He has used nattokinase in patients taking warfarin, and so far has not seen any negative interactions. In fact, he considers it a valuable alternative to warfarin in those who cannot take warfarin, though the equivalence needs to be verified in controlled clinical studies. It does not, however, mix well with Plavix (clopidogrel). Both substances prevent platelets from aggregating. "By adding one to the other, you can easily over-do it."
One also needs to be careful with nattokinase in patients taking a lot of other supplements with potential anti-coagulant effects like fish oils, vitamin E, and Ginkgo biloba. Though serious adverse effects are rare, this can increase the incidence of nosebleeds and other relatively minor bleeding problems.
In addition to nattokinase, another way to reduce blood viscosity is to donate blood. The mechanism is not clear, but frequent blood donors show "a statistically significant decreased incidence of heart attacks and strokes and, coincidentally, lower blood viscosity," Dr. Holsworth said. Water is the other key element in reducing viscosity. "Staying well hydrated keeps everything running better."