Prophylaxis of atherosclerosis in patients with metabolic syndrome: A phytotherapeutic approach

In westernized societies, the epidemic atherosclerosis and its clinical sequelae heart disease and stroke are the underlying cause of about 50% of all deaths. Thus, the prevention or deceleration of atherogenesis is one of the most significant clinical objectives since this is a matter of avoidance of myocardial and cerebral infarction. Epidemiological studies have revealed several important environmental and genetic risk factors associated with atherosclerosis. For example, oxidized LDL particles are highly atherogenic. To approach the aim of cardiovascular protection, phytochemical medication counteracting peroxidation of blood lipids based on their scavenger qualities for reactive oxygen species (ROS) could be of benefit.

In a pilot study, we had reported on the beneficial effects of Ginkgo biloba special extract (EGb 761) on atherosclerotic nanoplaque formation and size in cardiovascular high-risk patients who had undergone an aortocoronary bypass operation. Briefly, nanoplaque formation and size, the ratio oxLDL/LDL and the highly atherothrombotic lipoprotein(a) concentration were substantially reduced, while superoxide dismutase (SOD) activity and the blood concentration of the vasodilating substances cAMP and cGMP were upregulated (Atherosclerosis 2007; 192: 438–444). Methodically, the very earliest stages of atherosclerotic plaque development were measured by applying a novel nanotechnologic biosensor utilizing ellipsometric techniques (patent EP 0 946 876). This so-called nanoplaque formation is represented by the ternary aggregational complex of the HS-PG receptor, lipoprotein particles, and calcium ions. The model was validated in several clinical studies on cardiovascular high-risk patients introducing their native blood lipoprotein fractions. Since the atherosclerosis prophylactic and well-aging promotive impact of Ginkgo extract has been undoubtedly proven in this pilot study of cardiovascular high-risk patients, we wanted to confirm these beneficial effects through a second observational clinical trial. The measurable variables formerly used were additionally supplemented by a wide, novel biomarker spectrum, through which the latest parameters and markers of plaque stability and progression, oxidative stress, and inflammation were available.

In 11 patients with metabolic syndrome in the initial stage, the reduction of atherosclerotic nanoplaque formation amounted to 14.7±3.3% (p<0.0039) and of nanoplaque size to 21.5±4.4% (p<0.0039), respectively, after a 2-month treatment with Ginkgo biloba extract (EGb 761, 2×120mg daily, Rökan®novo, Spitzner Arzneimittel, Ettlingen, Germany). Additionally, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were upregulated by 19.6±10.0% (p<0.0785) and 11.6±2.3% (p<0.001), respectively, the quotient oxLDL/LDL lowered by 21.0±4.3% (p<0.002), and lipoprotein(a) concentration decreased by 26.3±4.8% (p<0.001) in the patients' blood. The decrease in Lp(a) was linearly correlated to a decrease in IL-6 by 12.9±7.0% (p<0.0407) and an increase in TGFβ1 by 38.4±11.8% (p<0.0068). The concentration of the vasodilating substances cAMP and cGMP was augmented by 41.4±12.0% (p<0.001) and 32.9±10.4% (p<0.001), respectively.

Surprisingly, we found a lowering of the serum Ca²⁺ concentration by 5.4±1.6% (p<0.0076) from 2.37±0.03 to 2.24±0.03 mmol/L (p<0.0069) as well as an enhancement of the mean corpuscular haemoglobin (MCH) by 3.2±0.6% (p<0.0044) and of the mean corpuscular haemoglobin concentration (MCHC) by 4.8±0.6% (p<0.001) together with a simultaneous decrease in mean corpuscular volume by 1.6±0.3% (p<0.002) and of the hematocrit (Hct) by 12.0±1.4% (p<0.001). Apart from an additional vasodilatory effect, the lowered extracellular Ca²⁺ concentration affects nanoplaque formation restrictively, since this is a Ca²⁺ driven process. In conjunction with the vasodilation, the augmented MCH and MCHC signify an improved oxygen supply combined with an improved perfusion of the organs. Furthermore, we could show a favourable development of the biomarkers 8-iso-PGF2α, oxLDL/LDL, SOD, GPx (oxidative stress), hs-CRP, MPO, TNF-α, TGFβ1 (inflammatory status) and MMP-9 (plaque stability) which will be discussed here in detail. The markers selected are suited to provide a comprehensive risk profile for the prevention of atherosclerosis (Atherosclerosis, doi:10.1016/j.atherosclerosis.2007.05.011).

A multiple regression analysis between the oxLDL/LDL ratio, the Lp(a) concentration and the cGMP concentration on the one hand and changes in nanoplaque formation on the other hand yielded a mechanistic explanation of nanoplaque reduction under Ginkgo treatment. The atherosclerosis inhibiting effect can be attributed to a stimulation of radical scavenging enzymes in the body, a restriction of the risk factors oxLDL/LDL and Lp(a) as well as an increase in NO/cGMP release.