RU2250772C1 - Method for treating the cases of non-operable cardiologic patients - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method involves using mononuclear autologic marrow fraction containing 6-9x10⁴ mesenchyma cells per 1 ml or autologic mesenchyma trunk cells. The cells are separated from brain bioptate in the amount of 10⁶ cells/kg of patient body mass. The preparations are intracoronarily introduced in fractions at a rate of 3-5 ml/min into the right coronary artery. The introduction is also carried out in intra-arterial mode in jets or in drops.

EFFECT: higher survival rate and life quality of cardiologic patients.

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Description

The invention relates to medicine, more specifically to cardiology and cardiovascular surgery, and may find application in the treatment of cardiac patients.

The proposed method relates to the treatment of inoperable patients with coronary heart disease and idiopathic dilated cardiomyopathy, which belong to one of the most difficult groups of cardiological patients and for which there is currently no specific treatment.

Coronary heart disease (CHD) is one of the leading causes of disability and death. The treatment of ischemic heart disease is carried out mainly through drug therapy. Surgical (surgical) treatment of coronary artery disease is performed in the case of ineffective drug therapy or in cases where the nature of the coronary artery lesion determines a high risk of cardiac death of the patient (Recommendations from the American Heart Association and the American Cardiology College “Coronary Artery Bypass Surgery” JACC, Vol. 34, No. 4, October 1999: 1262-1347). Inoperable patients are patients with coronary artery disease, in whom the risk of surgical intervention exceeds the expected benefit of surgical treatment in the form of eliminating symptoms that limit life activity. These patients make up the most difficult category of patients with coronary heart disease, since drug treatment is already ineffective, and the severity of the condition or the nature of the damage to the heart vessels makes surgical treatment practically impossible. Nevertheless, surgical treatment remains the only way to save life in this category of patients.

Idiopathic dilated cardiomyopathy (IDKMP) - an incurable, genetically determined myocardial damage inherited according to the autosomal dominant or autosomal recessive principle (Towbin J, Bowie S K, Ortiz-Lopez R, Wang Q. Genetic basis of dilated cardiomyopathy 1999 56i Cardiomy; -65.). IDCMP is one of the common causes of the development of severe heart failure, which is not amenable to drug therapy. Failures in the medical treatment of IDKMP require resolving the issue of heart transplantation (Olson T, Michels V., et al. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure // Sciense 1998; 280) or implantation of mechanical devices (Gronda F., Vitali E. Left ventricle assist systems: a possible alternative to heart transplantation for heart failure patients? Patient selection, techniques and benefit. Eur J. Heart Failure, Dec 1999; 1: 320-5.)

There is currently no specific treatment for IDCMP.

A known method for the surgical treatment of patients with coronary artery disease, which consists in restoring blood flow and metabolism of affected areas of the myocardium by applying an aortocoronary anastomosis or performing endovascular angioplasty and stenting. However, for most patients, due to the severity of their condition, such surgery is not feasible.

A known method of medical treatment of IDKMP, which consists in the use of angiotensin-converting enzyme inhibitors (ACE inhibitors), diuretics, drugs with positive inotropic effects, etc. However, this method is symptomatic and ineffective.

Thus, the only specific treatment for inoperable cardiological patients of both coronary artery disease and cardiopulmonary bypass surgery is a heart transplant, inaccessible to the vast majority of patients, since the number of such patients is many times greater than the number of donors.

Closest to the proposed one is a medication method for treating this category of patients (Treatment of heart failure. Recommendations of the working group for the study of heart failure of the European Society of Cardiology. Rus. Medical journal. Appendix. 1999.), taken as a prototype.

Since drug therapy, the purpose of which is to reduce the clinical manifestations of heart failure - complications of the underlying disease, is not aimed at restoring the function of the heart muscle, the quality of life of such patients is unsatisfactory, and mortality remains high (more than 50% of patients die during the first year when severe heart failure occurs) ) There is currently no specific drug therapy for this category of patients.

The technical result of the present invention is to increase the survival of patients and improve their quality of life.

This result is achieved by the fact that in the treatment regimen for inoperable patients with coronary artery disease and IDCMP, an autologous mononuclear fraction of bone marrow containing 6-9 × 10 ⁴ mesenchymal cells in 1 ml or autologous mesenchymal stem cells (AMSC) in the amount of 10 ⁶ cells / kg of patient weight is used which are injected intracoronary fractionally in a volume of up to 50 ml with a speed of no higher than 5-10 ml / min into the left and up to 30 ml fractionally with a speed of no higher than 3-5 ml / min into the right coronary artery, and if the patient’s condition does not allow intracoronary introduction, carry out apelnoe intravenous or intraarterial administration jetting.

Previously, experimental and clinical studies have shown (Zhang S et / al. Transplantation of bone marrow cells upregulated vascular endothelial growth factor and its receptor and improved ischemic myocardial function. Beijing Da Xue Xue Bao. 2003; 35 (4): 429-433 ) that the use of a bone marrow mononuclear fraction or stem cell culture in acute tissue damage is accompanied by activation of repair (reparative) processes of functioning tissue and a decrease in the formation of replacement scar (fibrous) tissue (Assmus B. Et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002; 1 06 (24): 3009-3017). However, the reverse development of already formed fibrous tissue of the heart and the acquisition of metabolic traits characteristic of a functioning myocardium are considered impossible (Kipshidze N., Serruys P. Handbook of Cardiovascular Cell Transplantation // Martin Dunits, UK, 2004: P425). This is because the most likely stimulus for the differentiation of stem cells into a specific tissue is the products of the acute death of the corresponding tissue.

It is known to use bone marrow stem cells (both hematopoietic, mesenchymal cell cultures and as part of mononuclear suspension) for heart surgery, treatment of acute myocardial infarction, aimed at activating the recovery processes of functioning tissue and reducing the formation of fibrous tissue as a result of acute coronary insufficiency (Stamm C. et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003; 361; 9351: 45-46; Tse HF et al. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003; 361; 9351: 47-49; Assmus B et al. Transplantation o f progenitor cells and regeneration enchancment in acute myocardial infarction. Circulation Circulation 2002; 106: 3009-3017; Strauer BE et al. Repair ofinfarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002; 106). However, the reverse development of already formed fibrous tissue of the heart and the acquisition of metabolic features characteristic of a functioning myocardium, as mentioned above, is considered impossible. Fibrous tissue is non-functional, that is, it is not capable of contracting and is characterized by low (in relation to muscle tissue) glucose consumption. With positron emission tomography (PET) of the heart using fluorodeoxyglucose labeled with radioactive fluorine [18F], fibrous tissue is detected as a focal point of decreased fluorodeoxyglucose metabolism.

The use of stem cells in patients with no acute focal changes seemed to be meaningless also because these patients lacked incentives for differentiation of stem cells into specific tissue (there is no acute tissue necrosis). And if attempts were made to use stem cells in patients with chronic coronary heart disease, then intracoronary injection of cells was accompanied by modeling of ischemia by inflating the balloon in the lumen of the coronary vessel, and intramyocardial injection was always accompanied by surgical trauma.

A mononuclear suspension is obtained by sedimentation of bone marrow punctate according to a density gradient with hexaethyl starch and centrifugation of the supernatant.

AMSC is a fraction of highly purified own mesenchymal stem cells. To obtain AMSC, a patient needs to take 20-35 ml of bone marrow (the procedure is performed under local short-term anesthesia and lasts for 10-15 minutes). Subsequently, AMSCs are secreted from the bone marrow, which are typed and grown in a special medium. After 10-12 days from the start of cultivation, the amount of AMSK reaches 80-100 million, which is ten times higher than their content in the bone marrow.

We tried to introduce mesenchymal stem cells to a patient who was refused surgical (surgical) treatment due to the severity of damage to the heart vessels, and the reserves of drug therapy were already exhausted. As the results of this study showed, the patient's condition improved significantly, exercise tolerance increased, indicating an improvement in heart function. The results of ultrasound and PET studies confirmed the positive nature of changes in the heart. This fact is the basis of the present invention.

The essence of the method is illustrated by examples.

Example 1. Patient M. born in 1948, and / b No. 3323 was admitted to the hospital on 12/16/2003 with a diagnosis of IHD. Angina pectoris III-IV tension and rest. Atherosclerotic and post-infarction cardiosclerosis (myocardial infarction in 1999, 2003).

Ventricular fibrillation 03/14/2003. NK - III (NYHA)

On admission, pain was disturbed with minimal physical exertion, nocturnal pain at rest, shortness of breath with minimal physical activity.

With an echocardiographic study, there are akinesia zones in the anterior apical segment and hypokinesia in the posterior-lower segments of the left ventricle. Left ventricular contractility reduced (EF = 44%).

Coronary angiography No. 974 dated December 18 was performed. 2003:

Local Anesthesia Sol. Novocaini 0.25% -30.0. Puncture and catheterization a.femoralis dextra. Selective coronary angiography of LCA and RCA (contrast “Ultravist”).

Type of blood supply: mixed

Selective Coronary Angiography LCA:

Trunk LCA: no stenotic changes. Left descending artery (LAD): Diffusely altered. Occlusion after discharge of a large diagonal branch. There is no collateral filling. Envelope Artery (LCX): Diffusely changed from the mouth throughout, with a maximum stenosis of 80% in the proximal segment. Right Coronary Artery (RCA). Occlusion in the proximal segment. Retrograde filling from the LCA system.

Given the nature of the coronary lesion and the patient’s condition, surgical revascularization was refused.

After signing the informed consent, the patient underwent puncture of the iliac crest, ~ 180 ml of bone marrow was obtained, from which a mononuclear fraction containing 6.0 × 10 ⁴ mesenchymal cells in 1 ml was isolated, and fractionally intracoronary was introduced in a volume of 40 ml at a rate of 10 ml / min. left and 30 ml fractionally with a speed of 3-5 ml / min into the right coronary artery. When trying to increase the rate of introduction into the left coronary artery, an almost instant increase in ischemic changes according to ECG data (there was no pain).

The patient received satisfactory mononuclear suspension and was discharged from the clinic on December 22, 2003.

With a follow-up examination after 3 months (drawing, B) after the introduction of mononuclear suspension - the disappearance of pain at rest. A repeated PET study showed normalization of metabolism in the scar zone after myocardial infarction (in segments with initial glucose hypometabolism (Figure A), an increase in radiopharmaceutical uptake by 46-127% is noted). Exercise bicycle ergometry test revealed a significant increase in exercise tolerance (110 W). The contractility of the heart increased during the observation period from 44% to 53%, including regional contractility in areas with initial hypo-akinesia.

Subsequent follow-up in April 2004 and July 2004 confirmed the positive effect of the treatment.

Example 2. Patient B. born in 1950, and / b 949, was admitted to the clinic 03/26/2004. disabled person of group I. Diagnosis: ischemic heart disease. Angina pectoris III-IV functional class and rest. Atherosclerotic and post-infarction cardiosclerosis (repeated myocardial infarction in 2001, 2002). Chronic heart failure IV Art.

On admission: coronary angiographic examination (BMA clinic named after Kirov - small diameter of coronary vessels, three-vascular lesion). Consulted in cardiac surgery departments of the Kirov Medical Academy, Cardiology Research Institute of the Ministry of Health of the Russian Federation. Surgical revascularization is denied. In an ultrasound examination, the presence of pericardial effusion, ejection fraction 22%, mitral and tricuspid insufficiency. Objectively, the condition is serious, heart rate 120 in 1 min, NPV 26 in 1 min. Inductive edema of the lower extremities to the level of the lower third of the thigh, refractory to diuretic therapy. Cachexia.

Daily attacks of cardiac asthma. Given the serious condition of the patient and the high risk of death, a decision was made on the intravenous administration of AMSK.

Similarly to example No. 1, the bone marrow was punctured, a biopsy was obtained, from which AMSC were isolated, then typed and grown in a special medium. After 10-12 days from the start of cultivation, the number of AMSKs reached 70 million. AMSKs were administered intravenously. The administration procedure was transferred to the patient satisfactorily and the patient was discharged from the clinic. 1 month after the introduction - a gradual improvement in well-being, a decrease in signs of heart failure.

3 months after the introduction of the culture of mesenchymal cells, a clear clinical improvement is the disappearance of refractoriness to the ongoing diuretic therapy. Reduction of edema of the lower extremities to pasty of the legs. The disappearance of attacks of cardiac asthma. The emergence of night sleep. Increased motor activity. Exile Faction - 28%. A repeat PET study showed a clear improvement in the metabolism in the scar zone after myocardial infarction (in segments with initial glucose hypometabolism, an increase in radiopharmaceutical uptake is noted). Subsequent follow-up in July 2004 confirmed the positive effect of the treatment.

Example 3. Patient M., born in 1956, a patient with severe right-left ventricular failure (Chronic heart failure (CHF) IV functional class), due to idiopathic DCMP.

From the anamnesis: I found out about my disease after the appearance of the first clinical manifestations of heart failure and subsequent examination. Symptomatic therapy is ineffective.

An increase in liver failure.

At admission: Moderate severity. Shortness of breath while talking. Heart rate - 110 in 1 min. Icterus sclera. Swelling of the lower extremities. Cardiac cirrhosis of the liver. The contractility of the heart is sharply reduced (EF = 32%). Mitral, tricuspid regurgitation.

After signing the informed consent, the patient underwent puncture of the iliac crest and received ~ 180 ml of bone marrow, from which a mononuclear fraction containing 9.0 × 10 ⁴ mesenchymal cells in 1 ml was isolated. The estimated scope of the examination included coronary angiography and intracoronary injection of mononuclear suspension.

However, for a technical reason, intracoronary administration of a mononuclear suspension was not possible; the suspension was injected intra-arterially jet (descending aorta).

3 days after the introduction of mononuclear suspension, the patient was discharged.

After 3 months at the control examination - a change in the functional class of heart failure to II-III (st). Increased contractility up to 39%. In a repeat PET study: a decrease in the size of the site of glucose hypometabolism in the apical segment of the lower wall of the left ventricle, the disappearance of the site of hypometabolism in the middle segment of the interventricular septum.

Subsequent dynamic observation after 6 months, 9 months. and 1 year confirmed the achieved clinical effect.

Example 4. Patient B. 54 years old, a patient with idiopathic DCMP.

Chronic heart failure IV functional class (NYHA classification).

At admission: Moderate severity. Sleeps half-sitting. Sinus tachycardia with heart rate - 96 beats. in 1 min. Hepatomegaly. Swelling of the lower extremities. The contractility of the heart is sharply reduced (EF = 37%). Mitral, tricuspid regurgitation.

Similarly to example No. 1, the bone marrow was punctured, a biopsy was obtained, from which AMSC were isolated, then typed and grown in a special medium. Two weeks after the start of cultivation, the number of MMSCs reached 80 million. MMSCs were administered intravenously. The administration procedure was transferred to the patient satisfactorily and the patient was discharged from the clinic.

3 months after intravenous administration of a culture of mesenchymal stem cells, a change in the functional class of heart failure to II-III (st). With a repeat PET study, an increase in radiopharmaceutical uptake is observed in segments with initial glucose hypometabolism. The contractility of the heart increased to 45%.

Subsequent observation for 9 months confirmed the achieved positive effect of the treatment.

To date, the proposed method has treated more than 30 inoperable patients who have been injected with mesenchymal stem cells in the form of a mononuclear suspension or tissue culture. None of the patients have died to date. The proposed method in comparison with the prototype has several advantages:

1. Provides higher survival in the most severe group of cardiological patients. With drug therapy, as indicated above, more than 50% of patients die during the first year with the appearance of severe heart failure. Heart transplantation is not available for the vast majority of patients, since the number of such patients is many times greater than the number of donors.

2. The quality of life of disabled patients who were treated with the above method was significantly higher. All patients increased exercise tolerance. This allowed not only to serve themselves in everyday life, but also to increase the level of social adaptation (easy work).

The method was developed at the TsNIRRI clinic of the Ministry of Health of the Russian Federation (St. Petersburg), together with the staff of the city multidisciplinary hospital No. 2, Academician I.P. Pavlov St. Petersburg State Medical University and underwent clinical testing in 30 patients with a positive result.

Claims (1)

A method of treating inoperable cardiological patients by administering a therapeutic agent to a patient, characterized in that an autologous mononuclear fraction of bone marrow containing 6-9 × 10 ⁴ mesenchymal cells in 1 ml or autologous mesenchymal stem cells in an amount of 10 ⁶ cells / kg of the patient’s weight, which is administered either intracoronary fractionally in a volume of up to 50 ml at a rate of no higher than 5-10 ml / min into the left and up to 30 ml fractionally with a speed of no higher than 3-5 ml / min into the right coronary artery, or intraarterially ruinously, or intravenously drip.