TOWNSEND LETTER – JUNE 2009
by Chris D. Meletis, ND and Nieske Zabriskie, ND
Fortunately, there are many clinical markers that can be used to quantify risk and to measure successful therapeutic intervention when applied in the patient model. The following discussion offers a select review of well-known and more obscure clinical indices along with proactive considerations for mitigating risk that, when combined with sensible dietary and lifestyle modification, can help prevent premature death and associated disease processes.
Factors Associated with CVD and Hypertension
Hypertension is defined as an untreated blood pressure of 140/90 mm Hg or higher, a patient’s taking antihypertensive medication, or at least two elevated blood pressure readings recorded by a health-care professional. Prehypertension is considered an untreated systolic blood pressure of 120–139 mm Hg or an untreated diastolic blood pressure of 80-89 mm Hg. The latest data suggest that 29.3% of adults in the US have hypertension,3 and approximately 25%–37% of the population age 20 and older has prehypertension.1
Hypertension can lead to stroke, heart attack, heart failure, or kidney failure. According to the Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, the risks of stroke and heart attack begin to increase at a blood pressure of 115/75.4 In addition, the Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis (CAMELOT) trial showed that subjects with coronary artery disease (CAD) who had a starting blood pressure in the normal range of 129/78 and had their blood pressure further reduced to 124/76 with medication, resulted in modest but significant reduction in future risk of heart attack and stroke over two years.5 Thus, the once-held standard recommendation of acceptable blood pressure below 140/90 mm Hg is no longer ideal, and further reduction in blood pressure may be required to reduce the risk of disease.
It is well established that elevated cholesterol is one of the major risk factors for coronary heart disease, heart attack, and stroke. Other important factors include elevated plasma concentrations of triglycerides, low-density lipoprotein (LDL) cholesterol, and intermediate-density lipoprotein (IDL) and very low-density lipoprotein (VLDL) cholesterol, and decreased levels of high-density lipoprotein (HDL) cholesterol. Research is finding, however, that contributors other than total LDL, HDL, and total cholesterol are important risk factors, such as having increased small, dense LDL particles or oxidized LDL. Evidence indicates that small, dense LDL subfractions are more atherogenic than larger subfractions, and these particles are associated with carotid atherosclerosis.6 In fact, researchers have shown that small LDL particle size is the best risk predictor for the presence of coronary heart disease.7 Although treatment guidelines recommend reducing LDL to 100 mg/dL in high-risk individuals, studies have shown that when LDL was lowered to 70 mg/dL or less, carotid plaque was more effectively reduced.8
IDL are also triglyceride-rich lipoproteins, and elevated levels are strongly and independently predictive of progression of carotid artery intimal-medial thickness, a measure of early atherosclerosis that is associated with coronary disease risk.9 Studies have also shown that elevated IDL increases lipid deposition in plaques after eating a fatty meal.10 A low level of HDL cholesterol also has been shown to be an important determinant of coronary risk. HDL plays a significant role, as it removes cholesterol from the circulation and transports it to the liver.
Other measurable lipid-related cardiovascular risk factors include lipoprotein(a), apolipoprotein A-I (apo A-I), and apolipoprotein B (apo B). Apo A-I is the major protein constituent of HDL cholesterol and is a cofactor for the enzyme lecithin-cholesterol acyltransferase, which is important in the formation of HDL. Apo A-I also acts by transporting cholesterol released from cells to the liver for excretion from the body. Apo B is the primary protein found in LDL cholesterol and acts as a ligand for LDL receptors in various cells. Research suggests that apo B is important for targeting the selective uptake of LDL by the liver. Evidence also indicates that apo B levels are a better indicator of heart disease risk than total cholesterol or LDL.
In one study, individuals with angiographic evidence of CAD and healthy patients were evaluated for lipids, lipoproteins, and apolipoproteins. The results indicated that the strongest association with CAD was the ratio of apo B to apo A-I.11 In another study investigating the risk associated with CAD, lipids were evaluated in subjects in a lower-risk population with and without coronary artery stenosis. The results showed that in men, total cholesterol and apo B:apo A-I ratio were significantly different between the groups with and without CAD. In the women studied, triglyceride, HDL, and apo B:apo A-I ratio were significantly different between the two groups with and without CAD. The study showed that in both men and women, in the group with the lowest levels of total cholesterol, triglycerides and LDL, and the highest HDL levels, only the apo B:apo A-I ratio was associated with CAD. Thus, this ratio was the only variable showing a significant difference between subjects with and without CAD.12
Lipoprotein(a) is a complex of LDL and apo A, with a sulfide bond linked to apolipoprotein B-100. Lipoprotein(a) is proatherogenic and antifibrinolytic. Elevated plasma levels of lipoprotein(a) are associated with an increased risk for atherosclerosis, ischemic heart disease, cerebrovascular disease, and peripheral vascular disease.13,14 Lipoprotein(a) is similar to LDL, as it is localized in the blood vessel walls, and can become oxidized and forms foam cells associated with atherosclerotic plaques. Additionally, the subunit apo A is highly homologous to the fibrinolytic proenzyme plasminogen, and lipoprotein(a) can inhibit plasminogen activation along with its ability to stimulate secretion of plasminogen activator inhibitor-1 (PAI-1). In fact, researchers have elucidated that the concentration of lipoprotein(a) particles containing small apo A isoforms, which have the highest affinity for fibrin, is one of the leading risks in advanced stenotic atherosclerosis.15
Clinically, the question must be asked: why isn’t the standard for Western health care a more comprehensive look at these multiple lipid components, as more aptly captured by a VAP and other testing methodology, as opposed to the currently limited yet broadly accepted total cholesterol, LDL, and HDL?
C-reactive protein (CRP) is an inflammatory marker and is useful to predict future cardiovascular risk. Clinically, measuring high-sensitivity CRP (hsCRP) is useful as a potential warning sign for future disease. Researchers have shown that elevated inflammatory markers increase years in advance of first-ever myocardial infarction (MI) or thrombotic stroke, and are highly predictive of recurrent MI, recurrent stroke, diabetes, and cardiovascular death.16 Additional studies show that in patients with CAD, CRP is a significant risk factor for the progression of atherosclerosis.17 This association supports the concept that cardiovascular disease is not simply a lipid accumulation disease but an inflammatory disorder. CRP is a nonspecific acute phase reactant protein that amplifies the inflammatory cascade, and concentrations increase in the serum in response to inflammatory stimuli. Studies correlate increased hsCRP with hypertension, diabetes mellitus, and CAD. Additionally, in subjects without disease, plasma hsCRP showed independent correlations with white blood cell count, body mass index, age, and smoking. Plasma hsCRP also positively correlated with male gender, systolic blood pressure, blood hemoglobin, fasting blood glucose, serum gamma-GTP, uric acid, and triglycerides, and inversely correlated with serum albumin and HDL-cholesterol.18 Researchers have also found that individuals with lower CRP levels after statin therapy had better clinical outcomes than subjects with higher CRP levels, regardless of the resultant level of LDL cholesterol.19
Fibrinogen is an acute phase protein involved in the inflammatory process. Similarly to CRP, fibrinogen can be measured to evaluate inflammation and is strongly associated with CVD risk.20 In the cardiovascular system, fibrinogen plays several roles, including being converted to fibrin by thrombin in the final step of the coagulation cascade, modulating endothelial function, promoting smooth muscle cell proliferation and migration, being essential for platelet aggregation, and interacting with the binding of plasmin with its receptor.21 Researchers have shown that plasma fibrinogen is an independent risk indicator for CHD, and individuals with high serum LDL cholesterol who also showed high plasma fibrinogen concentrations have a 6.1-fold increase in coronary risk. Additionally, individuals with low plasma fibrinogen had a low incidence of coronary events even when serum LDL cholesterol was high.22
Increased serum levels of the amino acid homocysteine are an independent predictor for atherosclerosis and thromboembolism and are correlated with significant risk of CAD, MI, peripheral and cerebral vascular occlusive disease, and retinal vascular disease.23 Research has shown that elevated homocysteine is associated with a significant increased risk of cardiovascular disease, particularly when combined with other risk factors such as smoking, hypertension, and hypercholesterolemia. One study showed that elevated homocysteine increased the risk of CVD associated with all cholesterol subfraction levels, and low plasma cholesterol did not protect against the risk associated with a raised plasma homocysteine.24 Desirable plasma levels of homocysteine are below 10 μmol/L. Research has also shown that homocysteine levels from 9 to 14.9 µmol/L almost doubled the risk of cardiovascular-related mortality, and levels over 20 µmol/L increased the risk of cardiovascular-related mortality by more than 4-fold compared with levels below 9 umol/L.25 Deficiencies of folic acid, vitamin B6, or vitamin B12 can lead to high homocysteine levels.
A less well-known cardiovascular risk factor is the enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2). Lp-PLA2 is a pro-inflammatory enzyme secreted by macrophages that hydrolyzes oxidized phospholipids to yield potentially proatherogenic particles and appears to be a specific marker of plaque inflammation. Research suggests that it plays a direct role in the formation of rupture-prone plaque. Numerous studies indicate that Lp-PLA2 is useful as a biomarker for cardiovascular disease, showing consistent correlations between elevated Lp-PLA2 levels and the increased risk for cardiovascular events, even after adjustment for traditional risk factors.26 In fact, the highest quintile of Lp-PLA2 is associated with approximately double the risk of cardiovascular events. Additionally, using Lp-PLA2 a predictor of cardiovascular risk has been shown to be independent and complementary to hsCRP measurements.27 Lp-PLA2 may provide clinically relevant information indicating patients with a high level of atherosclerotic disease activity as manifested by vascular inflammation, endothelial dysfunction, and increased risk for progression toward rupture-prone plaque.28 Also, unlike LDL and other lipid parameters, Lp-PLA2 consistently predicts stroke risk, thus making it a useful to identify misclassified persons who are actually at high risk of stroke.29 Also clinically useful, Lp-PLA2 levels correlate with an increased risk of recurrent ischemic events in patients presenting with acute coronary syndromes or MI.30
The Lp-PLA2 blood test was approved in 2005 by the US Food and Drug Administration (FDA) for assessing the risk of ischemic stroke and CAD. One study showed that after correcting for lipid variables, elevated Lp-PLA2 levels were associated with increased plaque volume and percent plaque volume.31 Increased levels of Lp-PLA2 in symptomatic carotid artery plaques also correlate with markers of tissue oxidative stress, inflammation, and instability.32 Evidence indicates that Lp-PLA2 levels positively correlate with age, body mass index, LDL, triglycerides, and CRP, and negatively correlate with HDL.33 The PLAC test is available for measuring Lp-PLA2.
Natural TreatmentsThere is a great deal of research on natural therapies and various aspects of cardiovascular disease. Due to the breadth of this topic, there are numerous other treatments deserving mention, but they will not be discussed because of space limitations. We have selected a few, less well-known nutrients to discuss at length.
Various proteolytic enzymes have been studied as potential therapies for cardiovascular disease. Proteolytic enzymes are used by both alternative and conventional physicians. Pharmaceuticals such as the clot-buster urokinase are protease inhibitors used clinically as a thrombolytic agent for conditions including deep venous thrombosis, pulmonary embolism, myocardial infarction, and occluded intravenous or dialysis cannulas.
Nattokinase is a fibrinolytic enzyme derived from a fermented soybean product known as natto. Nattokinase provides physiological activity by inactivating plasminogen activator inhibitor 1 (PAI-1),34 and enhances tissue-type plasminogen activator-induced fibrin clot lysis. Nattokinase has fibrinolytic activity four times more potent than plasmin.35 Studies indicate that nattokinase supplementation inhibits the thickening of the intimal wall after endothelial injury and enhanced thrombolytic activity.36 In one study, endothelial injury was induced in the femoral artery in rats followed by supplementation with nattokinase. The thrombi near the vessel wall showed lysis, and most of them detached from the surface of vessel walls in the rats receiving nattokinase, whereas the control group had mural thrombi attached on the surface of vessel walls.37 Other research also shows that nattokinase causes a significant, dose-dependent decrease of red blood cell aggregation in vitro38 and may be beneficial for thrombosis prevention.39
In a randomized, double-blind, placebo-controlled trial, subjects with prehypertension or stage 1 hypertension were supplemented with 2,000 fibrinolytic units of nattokinase or placebo for 8 weeks. The group receiving nattokinase showed a decrease in systolic blood pressure by 5.5 mm Hg and diastolic blood pressure by 2.84 mm Hg.40 Another study investigated the effects of nattokinase in subjects with increased risk of edema and deep vein thrombosis undergoing a long plane flight. In the control group, 5.4% developed deep vein thrombosis, 7.6% developed superficial thromboses, and 12% developed edema. In total, the control group showed 19.6 % of subjects experiencing a thrombotic event. In the subjects who received nattokinase, only 7% experienced a thrombotic event (all superficial thromboses), and no deep vein thromboses occurred. Edema was also decreased by 15% in the nattokinase group.41
Serrapeptase is another proteolytic enzyme that was originally isolated from the silkworm. It has anti-inflammatory, fibrinolytic, and antiedemic activity. Studies indicate that serrapeptase is effective for treating postoperative swelling and pain.42 Research also has shown it to be useful for treating various inflammatory conditions such as acute or chronic ear, nose or throat disorders,43 carpal tunnel syndrome,44 and musculoskeletal injury.45 Although currently there is no research on serrapeptase and cardiovascular diseases, it is reasonable to assume that it may provide benefit for decreasing inflammation associated with CVD.
Another proteolytic enzyme, bromelain, is derived from the fruit and stem of pineapple (Ananas comosus). Bromelain exhibits fibrinolytic activity, as well as reducing pain, edema, and inflammation. Evidence suggests that the fibrinolytic activity of bromelain is due to stimulating the conversion of plasminogen to plasmin, thereby limiting the coagulation cascade by degrading fibrin.46,47 Additionally, bromelain produces dose-dependent decrease in serum fibrinogen, and can prolong prothrombin and activated partial thromboplastin time at higher concentrations.48 Several studies have shown that bromelain decreases aggregation of blood platelets,49-51 prevents thrombin-induced platelet aggregation, reduces the adhesion of thrombin-stimulated platelets to endothelial cells, and inhibits thrombus formation in vivo and vitro.52,53 Previous studies have reported that bromelain may reduce angina,54 exhibits antihypertensive activity,55 and significantly reduces the incidence of coronary infarct when supplemented with potassium and magnesium orotate.56 Animal models have demonstrated that bromelain can reduce blood viscosity and improve ischemia-reperfusion injury in a skeletal muscle model.57,58 During ischemia-reperfusion, bromelain supplementation also improved left ventricular functional recovery during reperfusion, decreased the infarct size, decreased the amount of apoptosis, and increased aortic blood flow compared with the controls.59
The anti-inflammatory activity of bromelain may be due to several mechanisms. Bromelain has been shown to inhibit the generation of bradykinin at the inflammatory site by depletion of the plasma kallikrein system.60 Other studies show that bromelain significantly reduces neutrophil migration by 50% to 85% to inflamed tissue in vivo,61 and selectively modulates the synthesis of thromboxanes and prostacyclins.62
Vitamin K2 (menaquinone) plays an important role in vascular calcification and the development of atherosclerosis. Vitamin K1 (phylloquinone) is found in green leafy vegetables, while vitamin K2 is found primarily in animal products. Although some ingested K1 is converted to K2 in the body, significant benefits occur when vitamin K2 is supplemented.63 Vitamin K2, unlike vitamin K1, promotes arterial elasticity; and atherosclerosis has been associated with low serum levels of vitamin K. In the arteries, vitamin K is required to activate matrix Gla-protein. which is found in blood vessel walls. Matrix Gla-protein inhibits calcification of blood vessels, and some researchers believe that vitamin K deficiency causes an increase in nonfunctional matrix Gla-protein, leading to increased vascular calcification and atherosclerosis.64
According to the Rotterdam Study, subjects who ingested the greatest quantities of vitamin K2 in their diet experienced a 57% reduction in death from heart disease compared with people who ingested the least, as well as a decrease in all-cause mortality. Higher intakes of vitamin K2 also correlated with decreased aortic calcification, compared with subjects who ingested less vitamin K2. Vitamin K1 intake did not correlate to any of these findings. 65 In another study, rats fed a diet rich in vitamin K showed a 50% reduction in the arterial calcium content, arterial distensibility was restored, and localized vitamin K deficiency was demonstrated at sites of calcification.66
Grape Seed Extract
Grape seeds are high in proanthocyanidins, which are believed to provide cardiovascular-protective properties. Grape seed extract (GSE) causes an endothelium-dependent relaxation of blood vessels by the induction of nitric oxide synthase67 and may also act as a calcium channel blocker.68 Research indicates that grape seed procyanidin extract (GSPE) significantly decreased plasma levels of triglycerides and apo B in normolipidemic rats, and it downregulated several lipogenic genes in the livers of mice.69 Proanthocyanidin GSE significantly inhibited experimentally induced thrombus formation in the mouse carotid artery, and inhibited in vitro platelet reactivity to shear stress, suggesting that the in vivo antithrombotic effect of proanthocyanidins may be due to a direct inhibitory effect on platelets.70 GSE has also been shown to decrease plasma cholesterol an average of 11% in cholesterol-fed hamsters, prevent the development of aortic atherosclerosis by 34% to 68%, and induce endothelium-dependent relaxation by 72% to 84%.71 Further, GSE has been shown to significantly decrease plasma oxidized LDL and intercellular adhesion molecule-1 while increasing the levels of nitric oxide.72
Evidence indicates that GSE supplementation improves cardiac functional assessment including postischemic left ventricular function, reduces myocardial infarct size, reduces ventricular fibrillation and tachycardia, decreases the amount of reactive oxygen species (ROS), reduces malondialdehyde formation in the heart perfusate, and reduces foam cells.73 Animal models indicate that procyanidins from grape seeds decrease plasma CRP, decrease the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in the white adipose tissue, and increase the anti-inflammatory cytokine adiponectin, thus suggesting a mechanism in which GSE reduces cardiovascular and metabolic risk factors.74 In rats with experimentally induced insulin resistance, GSE prevented insulin resistance, hypertriglyceridemia, and overproduction of ROS.75 GSE reduced ischemia-reperfusion-induced organ injury through its ability to balance the oxidant-antioxidant status, inhibit neutrophil infiltration, and regulate the release of inflammatory mediators.76 GSE has also been shown to inhibit the pro-inflammatory enzyme 5-lipoxygenase (5-LOX).77
In one clinical trial, subjects with systolic blood pressure between 120 and 139 mm Hg and/or a diastolic pressure between 80 and 89 mm Hg were given 300 mg/day GSE or placebo for 8 weeks. The results showed that the group receiving GSE had a reduction in systolic blood pressure of 8.3 mm Hg and in diastolic blood pressure by 5.7 mm Hg.78 Another study supplemented 150 mg/day, 300 mg/day, or placebo for 4 weeks in hypertensive subjects with metabolic syndrome. The subjects receiving GSE significantly lowered their blood pressure compared with the placebo group. The group receiving the 150 mg dose of GSE experienced a 13mm Hg drop in systolic blood pressure and a 6 mm Hg drop in diastolic measurements, and the group receiving the 300 mg per day experienced a 12 mm Hg reduction in systolic blood pressure and an 8 mm Hg reduction in diastolic blood pressure.79
In another interesting study, estrogen-depleted female spontaneously hypertensive rats were fed a diet supplemented with GSE and either low or high levels of sodium chloride. The results showed that grape proanthocyanidin supplementation significantly reduced arterial pressure in the rats fed the low and high sodium chloride diet, compared with the nonsupplemented controls. Additionally, superoxide production was significantly reduced by 23% by the grape seed polyphenols.80
In another study, hyperlipidemic rabbits were fed a casein-based semisynthetic diet or semisynthetic diet plus GSE for 15 weeks. The semisynthetic diet was associated with increased hypercholesterolemia. The group receiving GSE had significantly lower plasma cholesterol at week 7, and developed hypercholesterolemia more slowly compared to the controls. Also, aortic atherosclerosis was reduced in the male rabbits.81 This research was conducted on a specific GSE called Meganatural BP and has been combined with vitamin K2 and wild blueberry extract.
Intravenous and oral ethylenediamine tetraacetic acid (EDTA) chelation therapy has been used for decades for the treatment of vascular disease. Research suggests that EDTA removes calcium from coronary arteries, reduces oxidized LDL, increases the effectiveness of hydroxyl radical scavengers, reduces reperfusion injury, and reduces platelet adhesiveness.82 Although there is a great deal of controversy surrounding the efficacy of chelation, evidence suggests it may benefit some patients.
In a small study, patients with CAD received 10 EDTA infusions of 1.5 g over 6 weeks, with and without B vitamin supplementation. The results showed that EDTA plus B vitamins showed a selective increase in the vasodilator response to acetylcholine, indicating that nitric-oxide related endothelial function was improved. Additionally, this group had a decrease in plasma homocysteine, which may be important, as the EDTA group without B vitamins did not show this improvement.83
In another small study, subjects with peripheral vascular disease received EDTA plus magnesium, B complex, and vitamin C, or a placebo of magnesium, B complex, and vitamin C in Ringer’s lactate solution. The EDTA group showed significant improvement compared with the placebo group in clinical and laboratory evaluation.84 Evidence also suggests that EDTA chelation therapy might prevent hypercoagulability resulting from the placement of stents, as well as a lower the rate of subsequent cardiac events, including MI and death compared with patients treated with conventional therapies.85 According to a retrospective analysis, EDTA chelation therapy resulted in “marked” improvement in 76.89% and “good” improvement in 16.56% of patients with ischemic heart disease, “marked” improvement in 91% and “good” improvement in 7.6% of patients with peripheral vascular disease and intermittent claudication, and “marked” improvement in 24% and “good” improvement in 30% of patients with cerebrovascular and other degenerative cerebral diseases.86 Despite concerns that EDTA causes renal damage, research has shown that infusions of EDTA with vitamins and minerals and oral supplements in patients with renal damage improved creatinine clearance significantly.87
In an interesting animal study, rabbits were fed a 1% cholesterol-supplemented diet for 45 days with subcutaneous injections of 300 mg EDTA plus 500 mg magnesium sulfate or saline. The chelation treatment prevented the rise of serum cholesterol and serum triglyceride concentrations, lowered serum calcium concentrations, and reduced aortic atheroma. Next, rabbits initially on a high-cholesterol diet were then put on a standard diet, and received the chelation injections or saline for 121 days. The serum calcium concentration and the percentage of the area of aorta occupied by atheroma were significantly lower in the chelation treated rabbits as compared with the control group. The authors concluded that “chelation injections have a definite prophylactic effect on atherogenesis in the cholesterol-fed rabbit, and may have some therapeutic value in the regression phase.”88
Due to the astounding prevalence of cardiovascular diseases in the US, it is more important than ever to understand the various risk factors and treatments for these conditions. Natural therapies provide treatments with numerous beneficial mechanisms, addressing various aspects of cardiovascular disease risk. The choice we must make as a both consumers and health-care providers is whether we passively wait to reach a predetermined number indicative of the need for therapeutic intervention, or do we treat proactively and begin to shift the trend towards maintaining true wellness?
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