How Inducible Nitric Oxide Causes Rheumatic Heart
The free radical theories of disease gives a clearer explanation of rheumatic heart
Starts with rheumatic fever
Rheumatic fever is “inflammatory disease of the heart, joints, central nervous system, and subcutaneous tissues that develops after a throat infection with group A beta-hemolytic Streptococcus bacteria, (Streptococcus pyogenes) including untreated scarlet fever or strep throat... Rheumatic fever is particularly important because of the heart disease, which includes vascular damage, that may ensue” (Encyclopedia Britannica 2009, parenthetical mine).
Rheumatic heart develops from “inflammation of the endocardium (heart lining), myocardium (heart muscle), and pericardium (the sac that surrounds the heart) that occurs during acute rheumatic fever...The disease includes those later developments that persist after the acute process has subsided and that may result in damage to a valve....” (Encyclopedia Britannica 2009).
“Rheumatic heart disease occurs years after acute rheumatic fever, and although it usually affects the mitral and aortic valves, it can also result in damage to the tricuspid valve.” Once the acute phase of rheumatic fever had set in, penicillin turns less effective against it. It looks like an allergic reaction to the bacterium (DeBakey,M., M.D. and A. Gotto, M.D. 1977. The Living Heart).
The bacterium of the type beta streptococcus (spherical), Streptococcus pyogenes, enters through the skin and attacks heart muscles then triggers inflammation. Scar develops in the valve resulting in stenosis (narrowing) or valve insufficiency. Not properly closed, the valve allows backflow of blood. About 65% of those who suffered from rheumatic fever had inflammation of the heart (the saclike covering, heart muscles, and valves). Mitral valve prolapse involves floppy valves: one or both the valve cusps “balloon upward into the atrium” (Clayman, C. B., M.D. ed. Your Heart. 1989:90).
Valves of the heart are two types: the bicuspid valve consists of two flaps, technically called cusps; the tricuspid valve consists of three cusps. In rheumatic heart, the cusps had grown callus or it had sustained a narrowing called stenosis. The stenosis disables the valve to close sufficiently after the passage of blood such that it allows backflow. This blood may reach the lungs through the pulmonary circulatory system that is why a person suffering from rheumatic heart may spit blood.
The immune system reacts to the attack by the bacteria during rheumatic fever. The macrophage, a component of the immune system, “eats” asbestos, virus, and bacteria that form the pus in infection. It also shoots the bacteria in the inflamed cells with free radicals used as bullets (Cranton, E. MD and A. Brecher. Bypassing Bypass. 1984).
Cranton used a layman's language to describe the development of rheumatic heart. Let's get into something more technical, nay, molecular.
Nitric oxide (NO) is synthesized by nitric oxide synthase (NOS) from L-arginine, an amino acid. (L means left). NO is a free radical gas with a life span of few seconds (Spieker, L.S. et al. “The Vascular Endothelium in Hypertension.” The Vascular Endothelium II.2006:249-269). Earlier, NO was given the loose name endothelium relaxation factor (EDRF) by Robert Furchgott. It is produced and released by the endothelium, the inner wall of arteries to dilate the artery.
Ferid Murad found that nitroglycerin (Isordil, Imdur) used as vasodilators to alleviate angina or chest pain in one suffering from heart disease produces nitric oxide. Louis Ignarro found out that ERDF and nitric oxide are the same. The findings of the three combined to explain how nitroglycerin works; nitroglycerin had been used a long time ago but its mechanism had not been well understood. It was like that of vaccination that provided protection but its mechanism was discovered only after several years. It is also like aspirin. How does it alleviate heart attack? Lately, it was found that aspirin inhibits the production of prostaglandins, especially thromboxaneA2 that promotes platelet aggregation (Sears, B. The Zone. 1995). Platelet aggregation results in clotting that forms thrombos that blocks bloodflow to the heart, thus heart attack. In short, no thromboxaneA2, no thrombos, no heart attack.
Furchgott, Murad and Ignarro shared the Nobel Prize for Medicine in 1998. Their work has spurred medical research on nitric oxide and its role in treatment of heart disease.
There are three kinds of nitric oxide synthase, one is endothelial NOS, another is neuronal NOS. The third is the inducible form (iNOS) that is an “important inflammatory mediator expressed in macrophages, vascular smooth muscle and other cells in response to immunological stimuli (Palmer et al. 1992)....” (Spieker, L.S. et al.). That stimulus can be a bacterial attack.
NO, being a free radical, has one free electron that is unstable. The macrophage shoots the infected cells with NO accelerated by the enzyme iNOS. However, some NO also strike healthy cells in the vicinity of the inflamed ones, most importantly those in the bicuspid or tricuspid valves. NO (indicated as NO-, the negative sign showing one free unpaired electron) scatters the capsule of the bacterium or degrades its particles by grabbing electrons from them. The healthy cells get injured and sustain scars or dents on the valve resulting in stenosis.
This stenosis will not go away or reverse itself. The main reason is that muscles of the vascular system (like brain and nerves) do not replace themselves. They are not subject to apoptosis or programmed cell death. Blood cells are replaced every 120 days; even bones are turned over periodically. The kidney or liver can repair themselves by means of apoptosis.
Apoptosis is different from cell death that involve inflammation. The nucleus of a cell that apoptose shrinks. The apoptosed cell is engulfed by neighboring healthy cells and are disposed of from the body.
Stenosis results in rheumatic heart.
This clearer, molecular view of rheumatic heart materialized through the framework of free radical theories of disease. When Dr. DeBakey said that rheumatic heart is probably an allergic reaction to the bacterium, he was using the germ theory of disease inaugurated by Pasteur in 1881-84. But the germ theory misses the mark; it can explain the fever or infection but not the scar or stenosis.
A free radical is any atom, or molecule or fragment of a molecule with at least one unpaired electron. For example, molecular oxygen that consists of two atoms of oxygen joined together. Each oxygen atom has one unpaired electron, but now the two unpaired electron spin around the whole molecule. Each unpaired electron is unstable that seeks to stabilize itself by grabbing an electron from another molecule or tissue that sustains an injury. That injury results in a tumor or cancer. (I have a Hub “Free Radicals With Unpaired Electrons in Alternative Medicine”).
In heart disease (occlusion of arteries around the heart that supply it with blood) the grabbing of an electron from the inside wall of the artery results in a non-malignant tumor called atheroma. To repair this injury, the body patches it with collagen, elastin, fibrin, cholesterol and other debris. Calcium comes in later which serves as a cementing agent (Cranton, E. MD and A. Brecher. Bypassing Bypass. 1984). Their combination grows into a mound then into a plaque. In other words, the attempt at repair goes awry – now graduates into heart disease.
In the case of rheumatic heart, the body attempts to kill the bacterium with NO facilitated by iNOS but shoots the healthy cells in the vicinity as well resulting in stenosis. NO and iNOS belong in the free radical theories of disease.
Prevention and control
One gets well from rheumatic fever, but the matter of concern is the scar that develops long after the occurrence of fever. The scar in the valve would not go away, or it is very hard to treat. The scarred valve can be replaced with the Starr-Edwards caged-ball valve or the Bjork-Shiley tilting valve (same source as above, page 88). A valve from the heart of a pig can be used as a replacement. However, this is rarely used because the pig’s valve might be infected with virus, the pig being a host of virus. Of course, the cost, risk and trauma in valve replacement must be factored in. A friend whose doctoral dissertation on statistical modelling of rice yields I had just edited opted to go through heart valve operation. I met his wife after the scheduled operation; she could not hide her tears from me.
Rheumatic heart can be prevented by controlling the bacterium in rheumatic fever. At this stage, penicillin is still effective against Streptococcus pyogenes or a host of bacteria that causes strep throat, according to Dr. DeBakey.
By controlling bacteria, the avalanche of NO and iNOS produced by macrophages to shoot inflamed cells and the bacterium is avoided. Production of macrophage by the immune system is induced by stimuli; millions of them can be produced in a short time to deal with infection. The less infection, the less macrophages, the less NO and iNOS.
NO works like a chemotherapy drug, Adriamycin for example, that is used as treatment against cancer. Adriamycin produces a lot of free radicals to kill cancerous cells. However, these free radicals also kill healthy cells in the vicinity of cancer cells (Sharma, H. Freedom from Disease. 1993). That is why an overdose of Adriamycin causes new cancer. To mitigate the avalanche of free radicals, a dose of suppressant is administered.
Similarly, the proliferation of NO can be mitigated with antioxidants, some of them are built-in in the body, others are supplemented. A built-in antioxidant like superoxide dismutase converts superoxide, a free radical, into hydrogen peroxide, a reactive oxygen species that acts like a free radical. Glutathione peroxidase, a built-in antioxidant, dismantles hydrogen peroxide into safe water. Supplementary antioxidants are vitamin C, E, B-complex, beta carotene (carrot) and vitamin A. Antioxidants donate the electron of the hydrogen atom in their molecules to the unstable unpaired electron of free radicals or reactive oxygen species. For example, vitamin C has 8 hydrogen atoms, vitamin E has 37 hydrogen atoms, that give 8 and 37 electrons respectively. Glutathione synthase produces glutathione from food (glutamate, cysteine, cystine and cofactors B2, selenium, zinc and lipoic acid which the body makes). Supplementary antioxidants are available in nutrition.
Stenosis can be remedied by stem cell therapy and chelation therapy (oral or infusion) as alternatives to valve replacement which is invasive. Gene therapy is being developed.
Prolapse that occurs in adult life can be reversed by chelation therapy, according to Dr. Arturo V. Estuita, MD, a cardiologist-chelationist in Pasay City, Philippines, who is administering my infusion chelation therapy.
A stem cell can be grown to replace a bicuspid or tricuspid valve. Stem cell can be grown to replace a sheared ear. Another example, a stem cell from the cord blood obtained from the umbilical cord or placenta and cryopreserved can be grown to replace cancerous blood in leukemia (Bellomo, M. The Stem Cell Divide. 2006). Stem cell therapy recognizes free radicals as causes of disease. That is why a stem cell for use in therapy must be purged of free radicals or must be free of free radical damage.
The dread of rheumatic heart comes from uncertainty on its nature, prevention and control. In the germ theory of disease, its nature and development are matters of speculation. In the free radical theories of disease, a high degree of certainty on its nature and development has emerged that leads to more effective means of prevention and control.