Coronary artery disease (CAD) is the commonest form of cardiovascular disease and the leading cause of morbidity and mortality in many parts of the world including North America. Current therapy for myocardial ischemia relies on drugs that reduce myocardial oxygen demand, mechanical endovascular revascularization procedures (angioplasty) or bypass Surgery. However recent advances in the management of coronary artery disease include what is known as therapeutic angiogenesis. Although Folkman had identified the therapeutic and pathologic implications of neovascularisation due to angiogenic growth factors almost 30 years ago, it is not until recent that therapeutic angiogenesis emerged as a clinically feasible modality in the management of cardiovascular disease and has generated considerable interest as such.

Angiogenesis, the process of new blood vessel formation from pre-existing fully differentiated endothelial cells is comprised of several discrete steps. These include dissolution of matrix, endothelial cell migration, proliferation and organization into a network structure, followed by lumen formation. In therapeutic angiogenesis, erogenous angiogenic growth factors or genes encoding these growth factors are used to stimulate the growth of collateral vessels to ischemic tissues. In all the above-mentioned processes, endothelium derived nitric oxide (NO) has been implicated. NO is an endothelial survival factor, inhibiting apoptosis and enhancing endothelial cell proliferation. NO is generated from a reaction catalyzed by enzyme nitric oxide synthase (NOS). It is also noted that vascular endothelial growth factor (VEGF) which is considered to be the most important angiogenic growth factor, stimulates the release of NO and up regulates the expression of nitric oxide synthase (NOS). It binds to receptors on endothelial cells, resulting in their growth, proliferation and migration.

Other factors that are known to regulate angiogenesis are Transforming Growth Factor-beta (TGF-beta) and Tumour Necrosis Factor-alpha (TNF-alpha). Both TGF-beta and TNF-Alpha are angiogenic in vivo. It has been demonstrated on that these cytokines induce angiogenesis indirectly by stimulating the production of direct-acting positive regulators from stromal and chemo-attracted cells. In this context then, TGF-beta and TNF-alpha are considered to be indirect positive regulators.

Apart from the mentioned angiogenic growth factors, a few others have been identified. Among them are fibroblast growth factor, platelet derived growth factor and interleukin 8. It is also imperative to know that expression of the growth factors and the receptors is unregulated by hypoxia and ischemia, allowing a targeted therapeutic response and also limiting the potential for pathologic angiogenesis.

A large body of evidence shows that administration of angiogenic growth factors can augment nutrient perfusion through neovascularisation. Theoretically, angiogenesis can be achieved either by the use of growth factor proteins or by the introduction of genes encoding these proteins (protein versus gene therapy). Hence trials have been carried out to determine the efficacy of such of methods in the treatment of ischemic heart disease. Proof of concept in humans was initially established in severely symptomatic patients with critical limb ischemia. Shortly thereafter, clinical investigations were extended to severely symptomatic patients with coronary artery disease.

Within the same framework, we explore other frontiers that may share the same premise of scientific ingenuity. Could therapeutic angiogenesis be triggered by other mechanisms than protein or gene therapy?

Researchers at the Second University of Naples conducted a study to evaluate the effect of oxygen-ozone therapy upon haemorheological parameters and haemoglobin-oxygen affinity in patients with peripheral occlusive arterial disease. They concluded that ozonized autotranfusion improved the viscosity of blood and its ability to deliver oxygen to tissues in patients suffering from occlusive arterial disease.

Ozone therapy has also been shown to reduce scavenger enzyme activity in patients with cardiovascular disease, which seems to be a critical fact, in the pathogenesis of the disease. It is also reported that ozone can reduce the blood cholesterol level. Anecdotal evidence showed marked improvement clinically and new collaterals angiographically in patients treated with ozone. Could there be a scientific explanation to this phenomenon?

Research carried out at the Institute of General Physiology, University of Siena have shown that the treatment of human endothelial cells with ozonated serum yielded a significant and steady increase of nitric oxide (NO). This observation is extremely important in view that as we had mentioned earlier, NO plays a crucial role in every steps of angiogenesis. We hypothesized that this then could be the link to the observed angiogenic phenomenon. It should also be noted that ozone therapy would also result in increase in levels of a few biological factors namely transforming growth factor beta, tumour necrosis factor alpha, interleukin 8 and platelet derived growth factor. All of these factors as mentioned earlier are angiogenic growth factors. Furthermore ozone has also been shown to increase nitric oxide syntase (NOS) activity, the enzyme catalyzing the production of NO.

The only thing at this moment in time we cannot say is whether ozonated serum is able to increase gene expression of VEGF. However Chua et al. have clearly shown that VEGF mRNA was expressed in a dose and time dependent manner when rat endothelial cells were exposed to 0.5-1 mM H₂0₂. It is a known fact that human serum exposed to biologically active ozone concentration incubated with human endothelial cells will induce H₂0₂ production. Therefore there seem to be an apparent correlation in term of gene expression of VEGF mediated by a known active compound triggered by ozone in human blood.

In a superbly written article entitled " Complementary Medicine: from quackery to scientific?" Prof. Edzard Ernst has pointed out that time has come "to submit to scientific scrutiny treatments that appear potentially useful. The obvious way to do this is to conduct randomized controlled trials taking into account the peculiarities of the remedies that are being tested". That is exactly what we have done and are doing in our hospitals and clinics.

                                                                                 

RHP® (Recuirculatory Haemoperfusion) is born as a remedy to many cardiological problems, without undergoing the threatening high risk, painful, expensive and complicated procedures of surgery.

Specialized ozone therapy centres, on administrating the non-invasive wonder therapy RHP® to severe coronary heart disease patients, have found amazing results which have put even the strongest of critics and specialists in the field of cardiology to silence and all they could respond on the observations made was 'unbelievable, but true'.

Through years of extensive research, Ozone Research Group Inc. (The Centre for Specialized Ozone Therapy) has developed a therapy called RHP® that manages to treat 3-4 litres of blood with medical ozone in extracorporeal circulation for a period of 60 to 90 minutes on patients with coronary heart disease. RHP® has proven second to none, in delivery and efficacy. To achieve satisfactory results one has to undergo 15 to 35 hours of therapy depending on the state of the disease and patient.

Similar to haemodialysis, RHP® is performed by withdrawing venous blood and the same blood is infused into an oxygen-ozone gas exchange filter in an upward direction, using a specialized bloodline with a computerized peristaltic pump controlling the rate of withdrawal. Medical ozone is introduced into this hydrophobic and ozone resistant gas exchange filter in the opposite direction from top going downwards and ozonation of blood begins. To avoid blood coagulation during the process of RHP® treatment, thinning of the blood is done, just before the blood is infused into the filter. After passing through the oxygen-ozone gas exchange filter, treated blood is reinfused to the patient. Upon establishment of extracorporeal circuit, the withdrawal rate will be increased to a range of 60 to 80 ml per minute, depending on the condition of the patient.

Results

It has been established by various scientific researchers that reinfusion of oxygenated and ozonated blood enhances the release of Nitric Oxide and Interleukin-8 in the human endothelial cells (the layer of cell lining on the artery wall)

Achieved results of the therapy in general from varied condition of patients' shows:-

1. Improved Vasodilatation (stretching of a vessel/arteriole beyond its normal dimension leading to increased blood flow) in ischemic areas.
2. Reduced Hypoxia ( reduction of oxygen carrying capacity of blood )
3. Induced Neoanglogenesis ( formation of new blood vessels )

As an example, one gentleman had already undergone RHP® treatment for 2 hours per week to complete 35-hour regimen for Triple Vessel Disease (3VD) with Left Main Stem (Involvement) and Impaired Left Ventricular Function.

Conclusion

After completion of 35 hours of RHP® therapy, Ozone Research Group Inc. recommends to repeat the angiogram to reveal the success of the therapy, hereby proving what seemed unbelievable as a theoretical mystery true.

May God Bless You And Keep You Well

 

Peter (Professor Ozone) Jovanovic

www.ozoneuniversity.com

www.ozonehospital.com

www.oxygentherapyexperts.com

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http://www.youtube.com/user/ozoneresearch

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"The only way to discover the limits of the possible is to venture a little way past them into the impossible."

Arthur C. Clarke

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