Cardiovascular Diseases

From FETAL PRECURSOR CELL TRANSPLANTATION (FPCT)
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Conductive system of heart:


Heart contains muscle cells which create and conduct electric impulses as well as those that respond to electric impulse by muscle contraction. In distinction to peripheral muscle, creation of the impulse takes place inside of the organ, i.e. heart has enormous autonomy. Myocardial fibers of atria and ventricles are united into a functional syncytium, i.e. cells are not isolated from each other, on the contrary they are interconnected through gap junctions. Impulse created anywhere in ventricles or atria always leads to a complete contraction of both ventricles and atria in accordance with ‘all or nothing law’. Impulse is normally created in sinoatrial node, and this structure is called cardiac pacemaker. Impulse is spread from it onto both atria toward atrioventricular node and then passes through His bundle and both its (Towar) branches to Purkinje fibers that transmit impulse to myocardium of the ventricles. There impulse spreads from endocard to epicard and from apex to the base of heart. During action potential Ca2+ enters myocardial cell from extracellular space through voltage controlled channels. Important prerequisites for normal activation of conductive system but also of working myocardium of atria and ventricles are:

- normal deep and stable resting potential (-80 to –90 mV),

- quick depolarization (dV/dt=200 – 1000 V/s) at the beginning of action potential and

- sufficiently long duration of action potential.


Any change of impulse creation or conduction that leads to different sequence of electric activation of atria or ventricles, or to disturbance of their mutual interconnection, causes arrhythmia.


In two adult X-linked muscular dystrophy dogs, lacking an expression of dystrophin in both cardiac and skeletal muscles, fetal canine atrial cardiomyocytes, including also sinus nodal cells, were injected into the left ventricle. Four weeks later a catheter ablation of AV-node was carried out. Immediately thereafter a ventricular escape rhythm emerged, that originated from a new pacemaker within the labeled cell transplantation site. This was the first in vivo evidence of electrical and mechanical coupling between allogeneic donor cardiomyocytes and host myocardium. [209]


Fetal cell transplants of cardiomyoblasts, hypothalamus, placenta, were used for treatment of 10 patients with intractable arrhythmia at the Research Center of Cardiology of Russian Academy of Medical Sciences in Novossibirsk In all 10 patients cell transplantation reversed the lack of therapeutic response so that patients were converted to sinus rhythm.

All our patients with incurable/untreatable arrhythmias treated since then were restored to a normal cardiac rhythm. BCRO created a special fetal precursor cell transplants: ‘Conductive system of heart’.


Myocardium:


An interesting feature not seen in voluntary muscle is that the heart has a number of different receptors located a t its sarcolemma, that respond to adrenaline (epinephrine), such as alpha- and beta-adrenergic receptors. Adrenaline released into the blood stream will increase heart rate by interaction with alpha-adrenergic receptors and cardiac output. Myocardium is responsive to adrenaline, noradrenaline and acetylcholine, while voluntary skeletal muscle is responsive only to acetylcholine.


The response of smooth muscle to alpha-adrenergic stimulation is a muscle relaxation.


Hypertension has incidence of 20% in industrial countries. Primary hypertension in the first labile stage can be succesfully treated by fetal precursor cell transplantation of placenta, hypothalamus, artery, liver. Treatment by anti-hypertensives continues as necessary until the benefit of cell transplantation is known 8 weeks later.


secondary hypertension is found in 5 - 15% of all hypertensive patients, and is divided into two main types according to the pathogenesis:

- renal hypertension: Every renal ischemia leads to a release of rennin, that separates a peptide angiotensin I from plasma angiotensinogen. By splitting off additional two amino acids from angiotensin I by peptidase, present mostly in lungs, angiotensin II develops, that is a strong vasoconstrictor. It releases aldosterone as well.

- endocrine hypertension:

- adrenogenital syndrome: production of cortisol in adrenal cortex is inhibited and thereby secretion of ACTH is unblocked, and that leads to a massive production and release of precursors of cortisol and aldosteron in adrenal cortex with mostly mineralocorticoid and androgenic activity;

- primary hyperaldosteronism, or Conn syndrome: tumor of adrenal cortex produces high quantity of aldosteron without any regulatory limits, with Na+ retention in kidneys and increase of ECT volume;

- Cushing syndrome: very high secretion of ACTH by pituitary tumor, or due to neurogenous factors, or autonomous adrenal cortex tumor increases glucocorticoid level in plasma;

- pheochromocytoma: tumor of adrenal medulla produces catecholamines with uncontrolled rise of level of adrenaline and noradrenaline and thereby hypertension.


Every chronic hypertension will cause sooner or later secondary renal disfunctions, hypertrophy of vessel wall, atherosclerosis, that makes hypertension permanent despite successful treatment of primary cause. Kidneys play leading role in idiopathic hypertension, hypertension in adrenogenital syndrome, Cushing syndrome.


Hypotension goes usually hand in hand with autonomous nervous system dysfunction, and if cell transplantation is necessary, then fetal cell transplants of hypothalamus, placenta, adrenal medulla, adrenal cortex, cardiomyoblasts, are advised.


Ischemic heart disease: Characteristic feature is a lowered coronary reserve whereby available oxygen cannot cover the needs. Myocard gets its energy from free fatty acids, glucose and lactate, which substances are used up for production of ATP, all of them dependent on oxygen.


Main reason is narrowing of major coronary arteries by atherosclerosis. Fetal cell transplantation of placenta, heart myoblasts, liver, and artery, has been used for years for such patients.


For treatment of unstable angina the cell transplantation is the same as for myocardial infarction.


Myocardial infarction: If myocardial ischemia continues for a longer time, then approximately after one hour tissue necrosis will take place, i.e. infarct. In 85% of cases the fault lies with acutely developing thrombus at the point of atherosclerotic coronary stenosis.


It is not a common medical knowledge that the myocardial muscle cells & fibers lose their ability to proliferate after birth and their power to regenerate disappears as well. For that reason myocardial injury, as after heart attack, heals by replacement of contractile heart muscle fibers by fibrotic tissue scar, which not only cannot participate in pumping of blood, it does not contribute to passive mechanical function of the heart either.

Massive loss of cardiomyocytes after heart attack is a common cause of congestive heart failure.  

Every patient after a recent heart attack with extensive (more than 70%) damage of myocardium, as determined by gallium scan upon admission to the hospital, cannot survive unless a certain substantial quantity of damaged muscle fibers (at least 50%) recovers back to normal  by direct stimulation of regeneration by fetal precursor cell transplantation prepared by BCRO method so that the transplants are available immediately upon the admission to the hospital for intracoronary implantation to be carried out right after emergency stent placement into the blocked branch of coronary artery.

When the size of myocardial scar is diminished from 70% to 35% of the total myocardial mass the patient can function in life quite well and survive the second myocardial infarction with a high probability - in the rare case of survival of the massive first myocardial infarction.

Additional fetal precursor cell transplants must stimulate angiogenesis, formation of new blood vessels from the existing ones.

During the last fifteen years many patients with recent extensive myocardial infarction have been treated by fetal precursorcell transplantation in various western European countries with remarkably good results. 


The purpose is to regenerate as many damaged heart muscle fibers as possible, and thereby decrease the size of myocardial scar, as well as stimulate angiogenesis, i.e. forming new blood vessels from the pre-existing ones. 


For patients with massive heart attacks it is a matter of life or death, or a matter of debilitating disability versus ability to live reasonably well.


For such specific indication fetal precursor cell transplants have to be implanted into heart, either into a re-opened obstructed branch of coronary artery via angiography, or into infarcted heart muscle via heart catheterization.


According to U.S. statistics 1.1 million people gets heart attack every year,  and then there is 4.8. million of patients with congestive heart failure, over one half of which dies within 5 years. All patients with extensive myocardial infarction and decompensated congestive heart failure are candidates for fetal precursor cell transplantation treatment.


Experimental data collected over the years about the ability of implanted myoblastic cells to restore function of damaged cardiomyocytes encouraged cardiologists in Paris, France, and Dusseldorf, Germany, to treat patients with extensive myocardial infarction by cell transplantation. Due to paucity of suitable donors for orthotopic heart transplantation, and severity and risk of such undertaking, success of fetal precursor cell transplantation in prevention of massive damage of heart muscle after MI is of enormous significance. [279] It is reported i.a. in "Handbook of Cardiovascular Cell Transplantation", published in 2004 by Martin Dunitz, a U.K. publisher, in a chapter by the author.


Cell transplants used in the above two clinical trials were autologous: skeletal myoblasts in Paris [203], mononuclear bone marrow cells in Duesseldorf [204].


The Duesseldorf group reported clinical data of 10 patients after MI treated with their method of cell transplantation along with their standard therapy, compared with parameters of 10 patients receiving standard therapy only. After 3 months’ follow-up the post-MI scar, measured by left ventriculography, was decreased significantly within the fetal cell transplantation group, and was significantly smaller than in standard therapy group. Infarction wall movement velocity increased significantly in fetal precursor cell transplantation group only. Dobutamine stress echocardiography, radionuclide ventriculography, catheterization of the right heart, all showed a significant improvement in stroke volume index, left ventricular end-systolic volume, contractility, and myocardial perfusion of the infarct region. [205]


Due to limited availability of human fetal cardiomyocytes alternative sources of suitable cell transplants for treatment of myocardial infarction, congestive heart failure, dilated cardiomyopathy, and other heart diseases, have been searched. Here are reports about some laboratory studies. Interestingly, in cardiology experimental data seem to bear a close relationship to clinical data.


A single fiber of skeletal muscle retains skeletal myoblasts beneath basal lamina throughout lifetime. From these myoblasts skeletal muscle regenerates in case of injury. In two rat models of heart failure allogeneic skeletal myoblasts were injected into four myocardial sites. Within 3 days donor single skeletal fibers disappeared, while their myoblasts began to differentiate into multinucleated myotubes. This process took 4 weeks, and caused a significant improvement of cardiac function.[206]


Clonal stem cell line WB-F344 from a male adult rat liver was injected as cell xenogeneic transplant into the left ventricle of adult female nude mice. Male WB-F344 cells with the same genotype were identified within the implantation site 6 weeks later. Phenotype of these new ‘stem cell derived cells’ was that of cardiomyocytes. So adult liver-derived stem cells responded in vivo to the tissue environment of adult heart and differentiated into mature cardiomyocytes. [207]


Autologous skeletal myoblasts have been favored in clinical practice to-date because of easy availability. In reality due to lack of connexin43, a gap junction protein, skeletal myoblast transplants should not be as effective as cardiomyocytes to treat MI. Only connexin43 containing cardiomyocyte transplants build intercellular connections with host myocardial fibers, such as gap junctions and desmosomes, and thereby act synchronously with the host heart.


Neonatal cardiomyocytes of 3 days’ old rats were injected into the border zone of infarct 10 days after injury. Subsequently, from 4 to 14 days later, treated hearts were studied by immunohistochemistry. Antibodies against connexin43, desmoplakin, and cadherin, identifying gap junctions, desmosomes, and adherens junctions, respectively, were found between grafted cardiomyocytes, as well as between grafted and host cardiomyocytes. Grafted cardiomyocytes were seen aligning parallel to, and establishing electrical pathways with, the host cardiomyocytes. [208]


How soon after MI should cell transplantation be done? Following two studies are not in full agreement but indicate that CT should be carried out no later than 6 days after MI. When carried out by selective coronary catheterization and infusion of myoblasts, rather than injection into infarcted myocardium, CT can take place at the time of initial balloon angioplasty, stenting or other invasive procedure.


In a rat model of MI fetal cardiomyocytes were transplanted immediately, 2 weeks and 4 weeks, after myocardial injury. At 8 weeks, studies of heart function, planimetry, and histology were carried out. Inflammatory reaction was greatest during the first week and subsided during the second week after MI. Scar size increased up to 8 weeks after MI. Cardiomyocytes transplanted immediately after MI were absent at 8 weeks and the scar size and heart function were as in untreated group. Cardiomyocyte transplantation should be carried out immediately after the inflammatory reaction is over, but before the scar expansion. [210]


Previous studies with bone marrow stromal cells engrafted into xenogeneic fetal recipients were repeated: the recipients were fully immunocompetent adults, and no immunosuppression was used. Bone marrow stromal cells were taken from C57B1/6 mice and injected into adult Lewis rats. One week later the recipients underwent coronary artery ligation and were sacrificed 1 to 12 weeks thereafter. Labeled mice cells were engrafted into bone marrow cavities for the duration of experiment. Circulating mice cells were found only in rats with 1-day old MI. Mice cells were found in the damaged myocardium by immunohistochemistry. This study proved that adult stem cells engraft into a xenogeneic live being, without immunosuppression, without difficulty. Simultaneously, they can home to injured myocardium, differentiate into cardiomyocytes, and create a stable chimera in the heart. [211]


Human mesenchymal xenogeneic fetal precuror cells were injected into the left ventricle of CB17 SCID beige adult mice without immunosuppression. After 7 days, de novo expression of desmin, beta-myosin heavy chains, alpha actinin, cardiac troponin T, and phospholamban, all typical of cardiomyocytes, could be detected. Human adult xenogeneic mesenchymal fetal precursor cells engrafted in the myocardium and differentiated into cardiomyocytes. [212]


Embryonic cardiac cells were cultured for 3 days, and then implanted 7 days after extensive MI into myocardium in a rat model, without immunosuppression. Engrafment of cell xenotransplants was observed 1, 4 and 7 weeks after CT. Differentiation of embryonic cells into cardiomyocytes was proven by antibodies against a-SMA, connexin43, and fast and slow myosin heavy chain. Serial echocardiography revealed that cell transplantation prevented scar thinning, left ventricular dilatation and dysfunction as compared with controls. [213]


Of 5 described studies dealing with cell xenotransplantation no immunosuppression was used, and in 9 of 12 included papers about allogeneic cell transplantation the authors did not utilize immunosuppresssion as well.


Autologous cell transplantation, of skeletal myoblasts, or mononuclear bone marrow stem cells, directly into damaged myocardium, is a reliable treatment for patients with serious myocardial infarction, or heart failure, that do not need cell transplantation immediately to save their life, and are hospitalized in a top hospital, with qualified invasive cardiologists, and excellent tissue culture laboratory.


If this therapeutic method should become important for the health care system worldwide, fetal precursor cell xeno-transplantation have to be utilized. Fetal precursor cell xeno-transplants can be delivered to any hospital without delay, at all times, and transplanted indirectly into liver if interventional cardiologist is not at hand, without immunosuppression. Subsequently such patient can be transferred to the high level hospital for the specialist’s care.

There are numerous German publications starting in 1950’s about the non-invasive fetal precursor cell transplantation treatment of hundreds of patients with extensive myocardial infarctions, with ~72 % success rate.

Reports from Germany on treatment of over 1000 patients with decompensated congestive heart failure by fetal precursor cell transplantation show success rate from 67 to 73%. 

A report about treatment of 251 chronic cardiac patients with cell transplantation is remarkable, because only one of 251 patients got worse, the rest were improved or unchanged. In 35 patients 3 - 6 months post-MI the success rate was 51%, in 76 patients with various other types of myocardial damage success rate was 53%, in 41 patients with ‘myodegeneratio cordis’success rate was 72%, in 9 patients with conduction block of Adams-Stokes type success rate was 55%. [218] This was before the era of routine heart catheterization and interventional cardiology, and other modern technologies: none of the above patients received cell transplants via injection into damaged myocardium or via balloon catheter in the branch of coronary artery. Fetal cell xenotransplants of myocardium, placenta, liver, were implanted deeply subcutaneously, counting on homing of these fetal progenitor cells into injured tissue, and their differentiation into cardiomyocytes and vascular cells. The concept of homing was proven in 50-ies in Germany by isotope and intravital dye studies [216, 217, 219, 95], and since 1993 also in other western countries. [19, 20, 21]


In 1993 the author gained first clinical experience with cell transplantation in cardiology. In a cooperative study of International Institute of Biological Medicine in Moscow and Russian Research Institute of Pediatrics of Russian Academy of Medical Sciences 7 terminal patients with dilated cardiomyopathy, often with relative insufficiency of 1 - 2 valves, aged 4 to 14 years, were treated by human fetal cell transplantation. Cell transplants of myocardium, liver, and placenta, were implanted under the aponeurosis of rectus abdominis muscle above the umbilicus.


One 10 years’ old female died four days after cell transplantation and at autopsy it was learned that dilated cardiomyopathy was secondary to anomalous origin of coronary arteries.


One 14 years’ old female, discharged in improved condition, with liver decreased by 2.5 cm, lesser crural edema, diminished scleral icterus, normal auscultation of lungs, was brought back to ICU 6 weeks later in her home town and died two weeks later.


One 14 years old male died 9 months later at home.


Remaining patients survived for the duration of follow-up, and were in good condition: 4 years old female for 14 months, 13 years old male for 17 months, 5 years old female for 15 months, 10 years old male for 17 months. No repeated cell transplantations were carried out.


Only small children in early stages of their illness are treated by one cell transplant only. The usual chronically ill patient requires transplantation of cells of all those organs or tissues which are involved in the pathophysiology of patient’s disease(s). The more exact is the pathophysiological diagnosis the more accurate will be the choice of cell transplants for treatment. Cardiac patients have usually received besides transplant of cardiomyoblasts also cells of liver and placenta, and lungs in cases of decompensated left heart with pulmonary congestion and hypertension, unless additional malfunctions are discovered which could be corrected by transplants of cells with necessary compensatory functions.


Congestive heart failure:

Cardiac insufficiency is a decreased ability of myocardium to carry out its function, mostly applicable to the left ventricle. The most common causes are ischemic heart disease, hypertension, cardiomyopathies. The body uses compensatory mechanisms to rise the circulating blood volume and blood pressure, mainly the increased tonus of sympathetic nervous system that by the release of additional catecholamines triggers an activation of cardiac alphalpha1-adrenergic receptors, whereby fS rises, along with tachycardia, and there is a positive inotropic effect as well.


Besides that alpha1-adrenergic vasoconstriction limits blood flow through skeletal musculature (tiredness), skin (paleness), and kidneys, since priority is given to the maintenance of blood flow through coronary and cerebral arteries. Decreased flow of blood through kidneys leads to activation of rennin-angiotensin-aldosteron system, rise of filtration fraction and reflexive rise of ADH secretion, and all that is triggered in the atrium of decompensated heart. The final outcome is rising reabsorption of water and salts with peripheral edemas.


Reports by Kleinsorge, Kuhn, Oetzman, Rietschel, on treatment of over 1, 000 their own patients with chronic heart failure proved the success of cell transplantation of placenta, heart, liver. Besides the general revitalization, placenta stimulates the internal breathing of myocardial cells. Transplants of cardiomyoblasts regenerate contraction ability of damaged heart. Transplanted hepatocytes restore variety of disturbed metabolic functions. Cell transplantation reverses digitalis resistance. Usually 10 - 14 days after cell transplantation a massive diuresis sets in, lung and liver congestion diminishes, all parameters of cardiovascular and respiratiry function improve, as well as subjective status of the patient. The success rate in 150 patients of Oetzmann was 73.2%, in 700 patients of Kuhn 67%, in 93 patients of Rietschel 72.1%, and duration of success was 12 - 15 months. Repeated cell transplantation was equally succesful. [239]


Cardiac decompensation at rest requires implantation of fetal precursor cell transplants via heart catheterization.


Peripheral arterial disease


While treating peripheral arterial disease with implantation of cell transplants of placenta, every physician observed how livid and cold feet and lower legs turned warm and pink within 3 – 10 minutes after the implantation. This was due to vasoactive substances in the placenta or hormones; such an immediate effect was only temporary, and was replaced by a permanent positive effect upon peripheral circulation 3 - 4 weeks later.


While developing his surgical method of transplantation of cornea, Prof.Dr. Filatov tried to find a way to avoid post-operative clouding of corneal transplants. Once during such operation he implanted tissue fragments of placenta subcutaneously. After many failures the corneal clouding finally did not occur, and implantation of placental cells became a major topic of Soviet research institutes, and soon spread to the West as ‘Filatov treatment’.


Experimental controlled study on treatment of arteriosclerotic vascular disease by cell transplantation of placenta showed remarkable improvement in fresh weight of aortas, significantly lowered calcium content in aortas and kidneys, and positive changes during macro- and micro-scopic examination of arteries of experimental rabbits. The report describes also studies on clinical application of the same treatment and its success rate in terms of improvement of coronary and peripheral circulation, mental efficiency, degenerative myocardial diseases, and various dyslipoproteinemias. [214] Similar conclusions reached Kleinsorge again using rabbits, and Wietek and Taupitz in their study of experimental arteriosclerosis of rats treated by cell transplantation of placenta.


For years cell transplantation of placenta played a major role in therapy of arteriosclerotic vascular disease, because placenta cells cause generalized vasodilatation, overall circulatory improvement, and increased budding of capillary collaterals.


Success rate of fetal precursor cell transplantation treatment of 150 patients with peripheral arterial disease in Germany in 1965 was 70%. The level of lipoproteins and cholesterol lowered significantly in all 64 patients with arteriosclerosis within 4 – 6 weeks after cell transplantation of placenta. There were no changes in 100 patients that served as controls. [280]


Objective and subjective improvement was found in 8 of 15 patients with advanced peripheral arteriosclerotic vascular disease after an implantation of cell transplants of placenta. Improvements persisted 8 months, and were recorded ergometrically, oscillometrically and rheographically. In 5 out of 15 patients cholesterol decreased. Of 3 patients suffering from Raynaud’s disease there was an improvement in two. In another study the walking distance doubled within 4 - 12 weeks in 8 and tripled in 3 from a total of 21 patients, and 3 patients became completely asymtomatic. Such results persisted for 13 - 16 weeks in 14 out of 21 patients, and for a shorter period in remaining 7 patients. [281] Similar findings were obtained by Rietschel and Kleinsorge. [329]


In a study by Oetzman 72 patients with peripheral arterial disease were treated by fetal cell transplantation of placenta, liver and gonads, and 58 patients improved; warming of of skin, lowering of cholesterol, increased walking distances, were recorded. In other studies Kuhn reports 67% success in 700 patients, Rietschel 72.1% success rate in 93 patients, and Oetzman 73.2% success rate in 150 patients. [95]


Scientific explanation why placenta cells have been the most widely used cell transplants to-date is limited.


Overall, cell transplantation of placenta, hypothalamus, liver, spleen, has been recommended for treatment of peripheral arterial disease caused by arteriosclerosis. Treatment of peripheral arterial disease as a complcation of diabetes mellitus is covered under ‘Diabetes mellitus’.


Vasculitis


Migraine, or hemicrania, is a well known disease of blood vessel regulation, that many famous people suffered from, such as Julius Caesar, von Bismarck, von Beethoven, etc., that has remained incurable. The acute attacks can be treated, but the disease cannot be cured. Cell transplantation has worked wonders in this respect. Intractable migraine when all other treatment has failed was treated by BCRO fetal precursor cell transplantation with success in nearly every patient. Cell transplantation of hypothalamus is of cardinal importance, as a controlling organ of autonomous nervous system and endocrine system, accompanied by cell transplants of blood circulation regulating adrenal cortex, liver, kidney, placenta, and pregnant ovaries, i.e. corpus lutem cells, for female patients since it is a known fact that migraine disappears during pregnancy, and testis with placenta for male patients. [297]

57 years old female suffered from migraines since childhood. In 23 years she had tried so many treatment that she could no longer count them. One son committed suicide, and the second one was a drug addict, in and out of jail. Six years before this report she underwent cell transplantation of placenta, frontal lobe of brain, temporal lobe of brain, adrenal cortex, liver. She has not had any migraines since. [308]


Several conditions are triggered by deposition of immune complexes or by cell-mediated immunity, and are treatable by fetal precursor cell transplantation as any other autoimmune disease.

- Polyarteritis nodosa, involving small and medium arteries, the resulting ischemia damages kidneys, heart, liver.

- Temporal or arteritis magnocellularis, involves larger arteries of head, causing headaches or facial pain, claudication of masticatory muscles, blindness.

- Thromangiitis obliterans, known also as Burger’s disease, involves medium and small arteries of extremities, and is present mostly in male smokers.

- Raynaud disease, painful vascular spasms caused by cold, with anesthesia of fingers or toes, at first white, then cyanotic, and finally red (reactive hyperemia). Fetal precursor cell transplantation of placenta, cardiomyoblasts, artery, is advised.