RU2568166C1 - Method for chemical ablation of hypertrophied myocardium section - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: in course of experiment femoral artery is exposed with further installation of catheter-introducer, guide. Sclerosing preparation, namely amyl or isobutyl alcohol or mixture of said alcohol with ethyl alcohol in ratio 1:1 is introduced through injection X-ray-contrast microcatheter. Injection of sclerosing preparation is realised into predetermined section of hypertrophy to the depth not less than 1/2 of myocardium thickness in volume 0.3-0.4 ml. After that microcatheter with guide is removed and gradient of arterial pressure on heart valve in output part of ventricle is registered.

EFFECT: increased efficiency of ablation of hypertrophied section of myocardium, which can contribute to reduction of risk of development of disease recurrence in remote period.

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Description

The invention relates to medicine, namely to cardiology, and is intended for endovascular treatment of patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCMP) is a genetically determined pathology inherited by an autosomal dominant type. HCMP is one of the most common causes of sudden cardiac death in people under 30 years old. The incidence of pathology is 1 in 500 people. According to various studies, HCMP in both sexes occurs equally often. The disease has the property of periodic manifestations, manifested by three main symptoms: shortness of breath, heart pain and rhythm disturbances. The pathological substrate of HCMP is asymmetric left ventricular myocardial hypertrophy, interventricular septum, less often the right ventricle. In the absence of adequate therapy, almost 100% of patients die due to sudden cardiac death.

The main methods of treating HCMP at the moment are: open heart surgery, the purpose of which is to radically remove the pathological substrate (Morrow myectomy with hypertrophic obstructive cardiomyopathy); myocardial alcohol ablation (combining toxic effects on the target area and mechanical disconnection from blood supply); and radiofrequency ablation (RFA), which is a physical effect on the pathological focus. In turn, each method has its advantages and disadvantages.

The most effective and informative is the surgical method of radical correction, but an open heart intervention is associated with a high risk of complications, not all patients can do it due to their advanced age, concomitant pathology or previous heart surgery, as well as a long difficult rehabilitation period (Hypertrophie cardiomyopathy: a systematic review / BJ Marón // JAMA. 2002. Vol. 287. P. 1308-20).

A known method of radiofrequency ablation of the transition zone of the anterior, lateral, posterior and interventricular walls of the left ventricle between a healthy myocardium and scar tissue by a radiofrequency destructor of the conduction pathways of the heart in the treatment of patients with coronary heart disease (patent RU 2391922 C1, publ. 20.06.2010).

The disadvantage of this method is the low efficiency of ablation.

Chemical ablation of hypertrophied myocardium with sparingly soluble substances using an endovascular injection delivery system may be a new step in the treatment of HCM. Chemical methods of myocardial ablation provide ample opportunities for choosing a sclerosing drug and its delivery method in comparison with existing methods for reducing myocardial volumes.

A known method of chemical ablation of the myocardium by subendocardial injection of ethanol (Weismüller P et. Al. Chemical ablation by subendocardial injection of ethanol via catheter-preliminary results in the pig heart // Eur Heart J. 1991. Vol. 12 (11). P. 1234. -9).

The disadvantages of this method are the impact only on the subendocardial zone of the myocardium, the inability to inject the entire thickness of the myocardium, the limited use of the method only for the treatment of arrhythmia.

The closest to the claimed method, the prototype is a method of chemical ablation of a hypertrophied portion of the interventricular septum, including the allocation of the femoral artery, the placement of an arterial catheter introducer, a guide, the introduction through the injection microcatheter of 1.0-1.5 ml of a 96% aqueous solution of ethyl alcohol into the septal branch anterior descending coronary artery using a coronary conductor and a 2-lumen balloon for angioplasty followed by removal of the microcatheter with conductor and register tion of blood pressure gradient on the heart valve into the ventricle pin section (Sigwart U. Non-surgical myocardial reduction for hypertrophic obstructive myocardial infarction. Lancet. 1995. Vol. 346. P. 211-214). The introduction of alcohol causes local myocardial necrosis, limited by the zone of blood supply to the septal branch, resulting in hypo- and akinesis of part of the interventricular septum, its subsequent sclerosis, thinning, resulting in a decrease in myocardial volume, restoration of normal hemodynamics in the phase of the expulsion of blood from the ventricle, and a decrease in the gradient blood pressure in the outlet of the left ventricle.

The disadvantages of this method are the increased risk of disease recurrence in the long term, increased risk of sudden cardiac death, unpredictability of the size of the myocardial ablation zone in patients, due to the different anatomical structure of the coronary bed. Excellent water solubility and a high rate of ethanol metabolism also reduces its sclerosing effect upon intracoronary administration.

The objective of the invention is to increase the effectiveness of chemical ablation of a hypertrophic myocardial site in the treatment of patients with HCMP.

The technical result is to increase the efficiency of chemical ablation of a hypertrophic myocardial site and to reduce the risk of developing a relapse of the disease in the long term.

The method is as follows.

Access to the hypertrophied portion of the myocardium of the left ventricle, interventricular septum or the right ventricle of the heart is carried out by puncture of an artery with the placement of an arterial introducer catheter and conductor. According to preoperative ultrasound, the zone of hypertrophy and the maximum thickness of the myocardium in it are determined. Then, a sclerosing chemical is administered through an injection X-ray contrast microcatheter. Adjust the magnitude of the exit of the needle from the microcatheter so as to be able to inject at least 1/2 of the thickness of the myocardium. Under X-ray control, the microcatheter is inserted into the ventricle of the heart through the conductor, the end of the microcatheter is positioned perpendicular to the surface of the myocardium, the needle is extended, an injection is made and one injection of a sclerosing preparation with a volume of 0.3-0.4 ml is made. Then the needle is pushed back into the microcatheter. If necessary, inject other zones of hypertrophy, the procedure is repeated. Then the microcatheter and conductor are removed, while recording the gradient of blood pressure on the heart valve in the output section of the ventricle. Aliphatic alcohols, or acetals, or their aqueous solutions or their mixtures with ethyl alcohol, taken in a 1: 1 ratio, can be used as a sclerosing drug, while the aliphatic alcohol is selected from the group: amyl alcohol, isobutyl alcohol, and acetals are selected from the group : methylal, 1,1-diethoxyethane.

The defining hallmarks of the proposed method, compared with the prototype, are:

- injection of a sclerosing drug is carried out using an injection X-ray contrast microcatheter into a predetermined section of hypertrophy to a depth of not less than 1/2 of the myocardial thickness in a volume of 0.3-0.4 ml, which allows, without damaging the coronary vascular bed, to administer a scerosizing drug directly in a hypertrophic area of the myocardium, which causes obstruction of the outlet of the ventricle or is an arrhythmogenic source, which, in turn, improves the efficiency of myocardial ablation;

- aliphatic alcohols, or acetals, or their aqueous solutions, or mixtures thereof with ethyl alcohol, taken in a 1: 1 ratio, are used as a sclerosing preparation, while the aliphatic alcohol is selected from the group: amyl alcohol, isobutyl alcohol; acetals are selected from the group: methylal, 1,1-diethoxyethane, which allows to increase the volume of sclerosed tissue, maintain the microvasculature of the vascular bed, which will lead to stabilization of the sclerosis zone, preservation of the mechanical properties of the myocardium and a decrease in the risk of postoperative aneurysms.

The invention is illustrated by the following examples.

Example 1. Biological testing of chemicals for ablation.

All experimental studies were carried out in accordance with the rules of Good Laboratory Practice, in accordance with the legal and ethical standards for the treatment of animals, with the approval of the local ethics committee.

Evaluation of the effectiveness of the use of drugs was performed in comparison with a 96% aqueous solution of ethyl alcohol. For each experiment, two groups of experimental animals of 10 Wistar rats each were used. According to ether anesthesia, animals of each group were injected intramuscularly into the right thigh once with a sclerotherapy drug or 96% aqueous solution of ethyl alcohol in a volume of 0.2 ml.

During the entire observation period, the behavior of animals of different groups did not differ. After 2 weeks, the results were compared by macroscopic and histological analysis of autopsy material.

The following chemicals were used as a sclerosing drug:

No. 1 Amyl alcohol

No. 2 Isobutyl alcohol

No. 3 Methalal

No. 4 Amyl + ethyl alcohol (mixture 1: 1 by volume)

No. 5 Isobutyl + Ethyl Alcohol (1: 1 mixture by volume)

No. 6 Methal + ethyl alcohol (mixture 1: 1 by volume)

The result of the study: visually and by palpation, the volume of sclerotic masses differed between groups, while it was most pronounced for preparations No. 2 and No. 1, less pronounced for preparations No. 3 and No. 4, in the remaining groups it did not differ from the control.

Morphological analysis showed an excess of sclerotic tissue in comparison with the control for preparation No. 2 by 7.2 times, for preparation No. 1 by 5.8 times, for preparation No. 4 by 4.3 times, for preparation No. 3 by 4 times, for preparations No. 5 and No. 6 2 times. Thus, all the studied drugs had a more pronounced sclerosing effect in comparison with the control ablation with ethyl alcohol.

Histologically, in all observation groups and in the control, the phenomena of muscle necrosis and sclerosis were observed. Injections of preparations No. 3 and No. 6 caused stronger necrotic changes, which upon macroscopic analysis were manifested by the release of caseous masses and a pale liquid with a characteristic chemical odor from the injection area, which could be due to the high chemical activity of acetals, low metabolic rate and a low degree of penetration of others tissues.

Example 2. Chemical ablation of the myocardium of the left ventricle minisign.

Isobutyl alcohol (preparation No. 2) was used as a sclerosing preparation, and a 96% aqueous solution of ethyl alcohol was used as a comparison preparation.

The test was carried out on a group of 3 minisibs of the Minisibs breed obtained from the vivarium of the Institute of Cytology and Genetics SB RAS. Under conditions of general anesthesia and mechanical ventilation, the femoral artery was isolated, taken to the holders, an arterial catheter introducer and a guide were installed. Under x-ray control, the injection microcatheter was drawn through a conductor into the left ventricle, oriented to its apex. Two animals received 3 injections to the depth of the XA of the myocardium, preparation No. 2 with a volume of 0.3 ml, in one animal from the comparison group 3 injections of 96% aqueous solution of ethyl alcohol with a volume of 0.3 ml were made. The catheter is removed, the wound in the access area is sutured in layers and drained. The picture of clinical and biochemical markers of myocardial damage returned to normal values 6-7 days after surgery. Animals were under dynamic observation for 2 months, after which material was collected for morphological and histological studies.

Macroscopically, the injection zones differed from the surrounding tissue, had a pale color, dense structure. The average surface area of tissues altered by sclerosis after injection of drug No. 2 exceeded the area of sclerosed myocardium in the comparison group by more than 4 times. The thickness of the tissues of the sclerotic zone directly depended on the depth of injection, determined by the settings of the injection microcatheter.

The histological microstructure of the myocardium in the injection zone was characterized by generalized foci of sclerosis with individual necrotic islands. Edema of myofibrils was observed, with single sites of myomalacia and intermuscular sclerosis phenomena. Based on the studies, it was concluded that transendocardial injection of the drug No. 2 has a better ability to sclerotic myocardium, in comparison with ethyl alcohol. The safety of the chemical ablation procedure for hypertrophied left ventricular myocardium on a working heart has been proven.

Example 3. Chemical ablation of the myocardium of the interventricular septum of the heart in minipigs.

The tests were carried out analogously to example 2 on a group of 3 minisibs of the breed "Minisibs". Under conditions of general anesthesia and mechanical ventilation, the femoral artery was isolated, taken to the holders, an arterial catheter introducer and a guide were installed. Under X-ray control, the injection microcatheter was inserted through the conductor into the left ventricle, oriented to the apical part of the interventricular septum, one injection was made deep into the entire thickness of the myocardium, preparation No. 1 with a volume of 0.4 ml, one injection of 96% aqueous solution was made in one animal from the comparison group ethyl alcohol with a volume of 0.4 ml. The catheter is removed, the wound in the access area is sutured in layers and drained. The picture of clinical and biochemical markers of myocardial damage returned to normal values on the 5th day after the operation. Animals were under dynamic observation for 2 months, after which material was collected for morphological and histological studies.

The average surface area of tissues altered by sclerosis after injection of drug No. 1 exceeded the myocardial area in the comparison group by more than 3 times. Macroscopically, the injection zones differed from the surrounding tissue, had a regular round shape, whitish color, and dense structure. The area of sclerotic tissue after injection of drug No. 1 extended to the entire depth of the myocardium. The area of sclerosis after the introduction of ethyl alcohol was limited by the subendocardial and medial layer on the injection side.

The histological microstructure of the myocardium in the injection zone was characterized by marked foci of sclerosis with small foci of resolving necrosis. Mild edema and swelling of myofibrils were also observed; foci of intermuscular sclerosis were determined in the peripheral zones. Based on the studies, it was concluded that transendocardial injection of the drug No. 1 has a better ability to sclerotize myocardium in comparison with ethanol.

Example 4

Chemical ablation of the myocardium of the interventricular septum of the heart in minipigs was carried out analogously to example 2 in two groups (experience and control), consisting of 3 minis pigs, breed Minisibs. The animals of the experimental group under X-ray control using an injection microcatheter, made one injection of the drug No. 4 (a mixture of amyl and ethyl alcohol in a 1: 1 ratio), 0.4 ml deep into the entire thickness of the myocardium of the interventricular septum, and the animals from the control group produced a similar single injection of a 96% aqueous solution of ethyl alcohol with a volume of 0.4 ml. Animals were under dynamic observation for 2 months, after which material was collected for morphological and histological studies.

The average surface area of tissues altered by sclerosis after injection of drug No. 4 exceeded the myocardial area in the comparison group by 4.3 times. Macroscopically, the injection zones differed from the surrounding tissue, had a regular round shape, whitish color, and dense structure. The area of sclerotic tissue after injection of drug No. 4 extended to the entire depth of the myocardium. The area of sclerosis after the introduction of ethyl alcohol was limited by the subendocardial and medial layer on the injection side.

Example 5

Chemical ablation of the myocardium of the interventricular septum of the heart in minipigs was carried out analogously to example 2 in two groups (experience and control), consisting of 3 minisibs of the breed Minisibs. Animals of the experimental group under X-ray control using an injection microcatheter made one injection of the preparation No. 5 (a mixture of isobutyl and ethyl alcohol in a 1: 1 ratio) with a volume of 0.4 ml, 1/2 depth of the interventricular myocardium thickness, and the animals from the control group produced a similar single injection of a 96% aqueous solution of ethyl alcohol with a volume of 0.4 ml Animals were under dynamic observation for 1.5 months, after which material was collected for morphological and histological studies.

The average surface area of tissues altered by sclerosis after injection of drug No. 5 exceeded the myocardial area in the comparison group by 2 times. Macroscopically, the injection zones differed from the surrounding tissue, had a regular round shape, whitish color, and dense structure. The area of sclerotic tissue after injection of drug No. 5 extended to the entire depth of the myocardium. The area of sclerosis after the introduction of ethyl alcohol was limited by the subendocardial and medial layer on the side

Using the proposed method will improve the efficiency of chemical ablation of a hypertrophic myocardial site and reduce the risk of developing a relapse of the disease in the long term, as well as reduce treatment costs.

Claims (3)

1. The method of chemical ablation of a hypertrophied myocardial region in an experiment, including the isolation of the femoral artery, placement of an arterial catheter, introducer, guide, injection of a sclerosing drug through an injection microcatheter, followed by removal of the microcatheter with a guide and registration of the blood pressure gradient on the heart valve in the ventricular, the fact that with the help of an injection X-ray contrast microcatheter, an injection of a sclerosing drug is carried out in advance An appropriately defined section of hypertrophy to a depth of not less than 1/2 the thickness of the myocardium in a volume of 0.3-0.4 ml, while amyl or isobutyl alcohol or a mixture of this alcohol with ethyl alcohol in a ratio of 1: 1 is used as a sclerosing drug. 2. The method according to p. 1, characterized in that the zone of hypertrophy and the maximum thickness of the myocardium in it is determined using ultrasound. 3. The method according to p. 1, characterized in that the injection of sclerosing drug is carried out under x-ray control.