Arginine Cardio: Evidence-based reduction of blood pressure (1) L-Arginine is the precursor of Nitric Oxide L-Citrulline potentiates the bioavailability of L-arginine Arginine Cardio is the L-Arginine supplement that has the highest L-citrulline Content Nitric Oxide causes vasodilation and thereby reduces blood pressure. The first part of this presentation deals with the ability of L-arginine to lower blood pressure in people with hypertension.

Arginine Cardio: Evidence-based reduction of blood pressure (2) L-Arginine is not being marketed by pharmaceutical industry with a multi million dollar budget for promotion. Clinical trials with L-arginine to lower blood pressure have been performed by independent academic research institutions, with small research budgets. Therefore, patient numbers in clinical trials with L-arginine are comparatively small. However, there is a recent meta-analysis summarizing clinical trials with L-arginine. Like with other therapeutic approaches that are not supported by marketing interests of the pharmaceutical industry, budgets and possibilities are comüaratively small for performing controlled clinical trials. Therefore, state-of-the-art meta-analysis is a highly regarded statistical approach to overcome these shortcomings caused by insufficient public funding.

Arginine Cardio: Evidence-based reduction of blood pressure (3) 11 randomized, double-blind, placebo-controlled trials involving 387 participants with oral L-arginine intervention ranging from 4 to 24 g/d […] Compared with placebo, L-arginine intervention significantly lowered systolic blood pressure by 5.39 mm Hg (95% CI −8.54 to −2.25, P = .001) and diastolic BP by 2.66 mm Hg (95% CI −3.77 to −1.54, P = .001). A meta-analysis of eleven placebo-controlled clinical trials with L-arginine supplements to lower systemic blood pressure was published in the American Heart Journal in 2011. By using state-of-the-art statistical methodology identical to that used for evaluating the therapeutic effects of pharmaceutical drugs, the authors came to the conclusion that L-arginine significantly lowers both systolic and diastolic blood pressure in humans. Despite the wide range of doses used in these different studies, ranging from 4 to 24 g per day, the magnitude of this blood pressure-lowering effect turned out to be comparable to the anti-hypertensive effect of medium-dose diuretics. Dong et al.; American Heart Journal 2011

This graph shows the effects of L-arginine versus placebo on systolic blood pressure in each of the trials included in the analysis. With the exception of one trial, all showed a favourable effect of L-arginine on systolic blood pressure. Due to small patient numbers, the blood pressure-lowering effect was not statistically significant in most studies; however, the summarized effect revealed in this meta-analysis was a highly significant, clear reduction of systolic blood pressure. L-Arginine better Placebo better Dong et al.; American Heart Journal 2011

This graph shows the effects of L-arginine versus placebo on diastolic blood pressure in each of the trials included in the analysis. With the exception of two trials, all showed a favourable effect of L-arginine on systolic blood pressure. Due to small patient numbers, the blood pressure-lowering effect was not statistically significant in most studies; however, the summarized effect revealed in this meta-analysis was a highly significant, clear reduction of diaastolic blood pressure. L-Arginine better Placebo better Dong et al.; American Heart Journal 2011

This is a very important finding of the meta-analysis for this dietary supplement. First, we must say that no treatment goes without any side effects. For blood pressure-lowering medicines, one of the most frequently seen side effects is overly blood pressure reduction. This can go along with dizziness, falls, and hip fracture, specifically in the elderly who are often affected by high blood pressure. Being a dietary supplement that corrects a deficit in one essential nutrient, but has no direct, immetiate pharmacological effect, L-arginine all but normalizes the physiological regulation of blood pressure. This graphic shows that the anti-hypertensive effect of L-arginine strictly depends on baseline blood pressure before start of treatment: As an example, a person with a baseline systolic blood pressure of 160 mm Hg (red lines) can, according to the results of this meta-analysis, expect to experience a reduction of systolic blood pressure by some 12 mm Hg. By contrast, an individual with a baseline blood pressure as low as 110 mm Hg (i.e., someone who would need no anti-hypertensive agent, but who may need L-arginine for other reasons) will experience almost no blood pressure reduction at all (green lines). Because a dietary supplement is not supervised by doctors as closely as presciption medicines are, this is an extremely important safety feature of L-arginine. Dong et al.; American Heart Journal 2011

Arginine Cardio: Evidence-based reversal of atherosclerosis (1) Nitric Oxide has been known to protect from atherosclerosis ever since the Nobel Prize for Medicine was awarded for this finding in 1998. L-Arginine is the precursor of Nitric Oxide. Animal experiments have unequivocally proven in different models and in various laboratories around the world that L-arginine can reverse atheroslcerosis. Whilst no big, multinational studies could be performed with L-arginine due to lack of funding from public sources, multiple studies have shown reversal of endothelial dysfunction, the early clinical sign of atherosclerosis, by L-arginine. We have a collection of case reports that show reversal of atherosclerotic plaque in humans during a few months of L-arginine intake. The second part of this presentation deals with the ability of L-arginine to reverse atherosclerosis.

* Study A: Prevention of Plaque Build-Up Design: A. carotis Results: # Cholesterol + L-Arginine Cholesterol Control 8 weeks CONTROL CHOLESTEROL 5 10 15 20 25 30 35 40 45 50 55 60 Carotid intimal plaque area [% of total intima] * CHOL. + L-ARGININE # (0) A. carotis Results: This slide shows the results of an animal experiment that was performed in the laboratory of Professor Böger, the inventor of the Arginine Cardio formula. L-arginine was given to cholesterol-fed rabbits for eight weeks in a study design that mirrored a preventive approach, i.e. L-arginine was given from the first day of cholesterol feeding. As a result, plaque build-up in the carotid arteries of the rabbits was reduced by more than 80%. Cholesterol Cholesterol; treated with L-arginine Böger et al., Atherosclerosis 1995; 117: 273 – 284

Study B: Stopping the Progression of Plaque Build-Up Cholesterol + L-Arginine Design: Cholesterol Cholesterol Cholesterol + Lovastatin Control Control 4 10 16 weeks Results: 50 This is another animal study by Professor Böger. In this study, a therapeutic approach was used, in order to more closely resemble the acutal situation in humans. Rabbits were fed a high cholesterol diet for four weeks. This induced plaque buid-up, which covered some 20% of the carotid arteries‘ intimal surface. From then on, L-arginine was administered to one group, and another group of rabbits was treated with the cholesterol-lowering drug, lovastatin. As a result, plaque build-up, which progressed to a level of 45% of the carotid arterial intima in the cholesterol-fed group of animals in the course of 12 more wqeeks on the diet (orange column), was completely stopped by L-arginine (blue column). By contrast, lovastatin was able to slow down the build-up of plaque, but it did not stop it completely (green column). 40 „Dietary L-arginine completely suppressed the aggravation of intimal plaque formation during the second part of the study Lovastatin treatment significantly reduced the progression of plaque formation but did not completely block it.“ 30 Intimal plaque area (carotid artery) [%] -92% 20 10 4 16 weeks Böger et al., Circulation 1997; 96: 1282-1290

Study C: Reversal of Pre-Existing Plaque Design: Cholesterol Cholesterol Cholesterol + L-Arginine Cholesterol 10 18 23 weeks Results: 75 This slide shows the result of a third animal study which was performed in the laboratory of Professor Cooke, at Stanford University, California. These investigators used a slightly different protocol. After 10 weeks of cholesterol fedding, plaque build-up in this study amounted to about 30% of the carotid artery in the rabbits. At 14, 18, and 23 weeks, there was a continued progressio nof plaque (orange columns). However, in a group of animals who had received L-arginine starting after week 10, plaque continuously declined over time, to below 10% at 23 weeks (blue columns). AS an important side finding of this study, when L-arginine treatment was ended at 18 weeks in some rabbits, their plaque progressed again, reaching almost the same magnitude like in the animals that had never been treated with L-arginine. Thus, this study supports the notion that L-arginine reverses atherosclerotic plaque when it is used continuously. When intake is interrupted, the disease process progresses again as before. 60 „This is the first demonstration that restoration of NO activity can induce regression of preexisting intimal lesions and provides evidence that L-arginine therapy may be of potential clinical benefit “ 45 Intimal plaque area (carotid artery) [%] 30 15 10 14 18 23 weeks Candipan et al., Arterioscler. Thromb. Vasc. Biol. 1996; 16: 44-50

This is a controlled clinical study with L-arginine in apparently healthy subjects above the age of 70. The primary end point was endothelial function, i.e. the ability of the endothelium to produce enough nitric oxide to relax the arteries under stress.

12 elderly subjects received, in a randomized order, 8 g of L-arginine b.i.d or placebo for 2 weeks. These subjects had high blood levels of ADMA, an endogenous blocker of NO production in the endothelium. It had been shown before that there is an increase in ADMA with increasing age, an observation explaining the aggravating lack of nitric oxide in old age and the concomitant stiffening of arteries and hypertension. Supplementation with L-arginine caused the L-arginine / ADMA ratio, which was very low at 15, to double. From today‘s perspective, this increase in L-arginine / ADMA ratio was significant, but not yet clinically sufficient, as large controlled prospective studies have suggected that an L-arginine/ADMA ratio above 160 should be considered as optimal.

Despite the limited increase in L-arginine blood levels, there was a significant improvement in endothelium-dependent vasodilation in this study. This feature of NO-mediated vascular function, which is measured as flow-mediated vasodilation in the brachial artery after subtotal transient occlusion with a blood pressure cuff, was pathologically low at baseline, indicating early atherosclerosis. Whilst placebo had no effect on endothelium-dependent vasocilation, L-arginine significantly increased this feature by more than 120%. Interesting, baseline flow-mediated, NO-dependent vasodilation was highly significantly and inversely associated with ADMA levels in blood. This latter finding sugegsts that ADMA is an ideal biomarker to identify subjects who have a high need for L-arginine and who are at risk of heart disease and atherosclerosis.