ΔESVI = postoperative ESVI /preoperative ESVI x 100 – 100 ( )

To evaluate changes of LV ESVI 20% interval in comparison with preoperative values was used: changes > 20% into positive or negative side were considered sufficient to take these changes as true. The patients in which LV ESVI was <80% from preoperative values were assigned to group I. In these patients the process of LV remodeling was stopped and reversed by surgical intervention i.e. reverse (regressive) remodeling type. The calculated value of ∆ESVI was < minus 20%.

The patients in which ESVI was > 80% from preoperative values were assigned to group II of the study. In these patients the course of HF remained unchanged due to the complex surgical treatment of ICMP: remodeling process was either resistant to the exposure or went on progressing after surgical treatment, i.e. had progressing remodeling type. The calculated value of ∆ESVI was > minus 20%.

The distribution of the patients between the groups basing on the ∆ESVI value was the following: the 1st group consisted of 97 patients (63.4%) with the reverse remodeling type (i.e. with positive dynamics of the late postoperative period); the 2nd group consisted of 56 patients (36.6%) with progressing remodeling type (i.e. with negative dynamics of the late postoperative period).

Analysis of the control EchoCG data showed that in the early postoperative period in all the patients end-diastolic and end-systolic heart volumes decreased: LV EDVI from (114.9±28.4) ml/m2 to (98.0±25.3) ml/m2, LV ESVI from (83.9 ±21.6) ml/m2 to (64.3±21.0) ml/m2; and LV EF significantly increased from (32.1±5.5) % to (36.7±8.9) %.The values of echocardiography study performed during control follow-up period are shown in Table 3.

Performed comparison of EchoCG data in the group of the patients with reverse LV remodeling showed that LV EF was significantly higher and the values of LVESVI and LVEDVI – significantly lower.

It should be noted that the great majority of the patients continued medical treatment recommended at the time of their dismissal from the hospital after the surgery. The groups with reverse and progressing types of remodeling were comparable in respect to the frequency of taking of different drug groups and their mean dosages.

Morphological Predictors and Molecular Markers of Progressing

correlation relationship with ∆ESVI shown in Table 5.

cases – moderate.

confluent.

Postoperative Remodeling of Left Ventricle in Patients with Ischemic Cardiomyopathy 123

Analysis of preoperative EchoCG data and the values calculated on their basis revealed

Mixed lymphocytic-macrophage infiltrate in LV myocardium of the IInd group patients was found in 42 out of 48 ICMP patients (87.5%) and in only 24 out of 90 patients (26.7 %) with reverse remodeling (p<0.01). In LV myocardium, as a rule, fibrosis was moderate (degree II according to Marburg classification) in the Ist group of patients; in the IInd group of patients with ICM in the most cases it was severe (unfavorable, or the IIId degree fibrosis) and in rare

In 8 out of 24 patients from group I (33.3%) and in 33 out of 42 patients from group II (78.6) infiltration had diffuse nature (p<0.01), in the rest of the cases – focal and even less often –

Besides, in 18 patients (37.5%) with repeated LV dilatation and in 13 patients (14.4%) with favorable late outcomes of surgical treatment the infiltrate of a similar nature was found in myocardium of RA auricle (p<0.01). As a rule, fibrosis in RA auricle myocardium was I-II

Mitral regurgitation (degree) 2 4 0 –0.149 NS Tricuspid regurgitation (degree) 0 3 0 –0.120 NS Mean pressure in RV(mm Hg) 40 60 30 –0.025 NS LV ESV (ml) 142 266 65 0.294 S LV EDV(ml) 245.5 395.0 104.0 0.199 NS LV ESVI (ml/m2) 75.5 133.6 45.6 0.843 S LV EDVI (ml/m2) 111.1 190.0 71.2 –0.215 NS LV EF M-mode (%) 34 40 20 –0.131 NS LV EF B-mode (%) 32 38 19 –0.213 NS Cardiac index (l/min/m2) 2.2 5.0 1.6 –0.099 NS Thickness of ventricular septum (mm) 10.5 15.0 6.0 –0.055 NS Index of relative LV wall thickness 0.307 0.222 0.410 –0.026 NS

Table 5. Correlation relationships of EchoCG parameters with the degree of LV dilatation in

It should be mentioned that there was no a case of cellular inflammatory infiltrate found in myocardial stroma in the autopsy material of the similar sites of LV myocardium and RA

Statistical analysis of the obtained morphometrical data did not reveal any significant differences of the values of specific volume of edema and vessels among the patients with progressive and regressive remodeling. The specific volume of parenchyma was significantly higher and stroma specific volume – lower in both LV myocardium and in myocardium of RA auricle of the Ist group patients. Morphometrical parameters of mean value of capillary diameter and diameter of LV and RA auricle myocardial cardiomyocytes did not differ significantly among the patients with different late outcomes of surgical treatment. Specific volume of capillaries in the aforementioned heart parts was significantly higher in the patients with reverse remodeling (group I). All the morphometrical parameters mentioned above differed statistically significantly from those of the control study group.

auricle myocardium taken from 25 cadavers which were the relative control group.

Parameters Values R value р<0.05 ME max min

degrees lower by Marburg classification than that in LV myocardium.

*Note*: NS – statistically insignificant difference; S – statistically significant difference.

the patients with ICMP after combined surgical treatment.


*Note* \* – significance of the differences between the groups of the patients before surgical intervention and in a year after the surgery; \*\* – significance of the differences between the groups of the patients with reverse and progressive LV remodeling (p < 0.05).

Table 3. The values of HF functional class and the data of EchoCG study in the patients with ICMP in the control follow-up period

Among 153 patients included into the study and examined in a year after surgical treatment mean value of ΔESVI was minus 24.0: maximum value – 36.8, minimum – minus 64.7.

It is obvious that SVR results in higher values of ΔESVI in comparison with isolated CABG providing more significant decrease of LVESVI in a year after the surgery. To avoid statistical and methodological mistakes in the analysis of correlation relationships, the patients with maximum and minimum values of ΔESVI and the patients with hypercorrection associated with diastolic LV dysfunction with postoperative EDVI less than 60ml/m2 were excluded from the further study. One hundred and thirty eight patients out from 153 were included into the further analysis: 90 patients with reverse remodeling (group I) and 48 patients with progressive remodeling (group II).

Screening analysis of correlation relationships between clinical data and ∆ESVI with the use of Spearman test showed moderate reverse correlation relationship with the age of a patient (Table 4). This correlation relationship was also proved during detailed analysis; an absolute p value was 0.0001. Thus, taking into account that the smallest (negative) values of ∆ESVI are optimal for a favorable clinical course, older patients with ICMP are prone to the development of progressive remodeling in postoperative period.

Initial clinical data characterizing the degree of coronary artery disease and heart failure did not demonstrate any correlation with the values of ∆ESVI after surgical treatment.


*Note*: NS – statistically insignificant difference; S – statistically significant difference.

Table 4. Correlation relationships of clinical signs with the degree of LVESVI changes after surgical treatment of the patients with ICMP.

All the pts (n=153)

FC NYHA 2.6±0.5\* 2.3±0.3\* 2.1±0.2\*\* 3.0±0.2\*\* LV EDVI (ml/m2) 114.9±28.4\* 98.0±25.3\* 84.4±13.7\*\* 102.6±14.6\*\* LV ESVI (ml/m2) 83.9±21.6\* 64.3±21.0\* 50.4±11.6\*\* 71.9±17.3\*\* LV EF (%) 32.1±5.5\* 36.7±8.9\* 43.0±3.7\*\* 33.0±5.1\*\* *Note* \* – significance of the differences between the groups of the patients before surgical intervention and in a year after the surgery; \*\* – significance of the differences between the groups of the patients

Table 3. The values of HF functional class and the data of EchoCG study in the patients with

Among 153 patients included into the study and examined in a year after surgical treatment mean value of ΔESVI was minus 24.0: maximum value – 36.8, minimum – minus 64.7. It is obvious that SVR results in higher values of ΔESVI in comparison with isolated CABG providing more significant decrease of LVESVI in a year after the surgery. To avoid statistical and methodological mistakes in the analysis of correlation relationships, the patients with maximum and minimum values of ΔESVI and the patients with hypercorrection associated with diastolic LV dysfunction with postoperative EDVI less than 60ml/m2 were excluded from the further study. One hundred and thirty eight patients out from 153 were included into the further analysis: 90 patients with reverse remodeling

Screening analysis of correlation relationships between clinical data and ∆ESVI with the use of Spearman test showed moderate reverse correlation relationship with the age of a patient (Table 4). This correlation relationship was also proved during detailed analysis; an absolute p value was 0.0001. Thus, taking into account that the smallest (negative) values of ∆ESVI are optimal for a favorable clinical course, older patients with ICMP are prone to the

Initial clinical data characterizing the degree of coronary artery disease and heart failure did

Parameters Value R value р<0.05 M<sup>Е</sup> max min

not demonstrate any correlation with the values of ∆ESVI after surgical treatment.

*Note*: NS – statistically insignificant difference; S – statistically significant difference.

surgical treatment of the patients with ICMP.

Age 54.3 43 68 0.600 S Number of MI 1 1 4 –0.097 NS Hypertonic disease 3 0 3 –0.060 NS Angina FC III I IV –0.244 NS NYHA FC 3 2 4 0.127 NS Men –0.166 NS Women –0.166 NS Diabetes mellitus –0.088 NS Obesity –0.147 NS

Table 4. Correlation relationships of clinical signs with the degree of LVESVI changes after

In a year after surgical intervention

Group I (n=97)

Group II (n=56)

Value Before the

with reverse and progressive LV remodeling (p < 0.05).

ICMP in the control follow-up period

surgery (n=153)

(group I) and 48 patients with progressive remodeling (group II).

development of progressive remodeling in postoperative period.

Analysis of preoperative EchoCG data and the values calculated on their basis revealed correlation relationship with ∆ESVI shown in Table 5.

Mixed lymphocytic-macrophage infiltrate in LV myocardium of the IInd group patients was found in 42 out of 48 ICMP patients (87.5%) and in only 24 out of 90 patients (26.7 %) with reverse remodeling (p<0.01). In LV myocardium, as a rule, fibrosis was moderate (degree II according to Marburg classification) in the Ist group of patients; in the IInd group of patients with ICM in the most cases it was severe (unfavorable, or the IIId degree fibrosis) and in rare cases – moderate.

In 8 out of 24 patients from group I (33.3%) and in 33 out of 42 patients from group II (78.6) infiltration had diffuse nature (p<0.01), in the rest of the cases – focal and even less often – confluent.

Besides, in 18 patients (37.5%) with repeated LV dilatation and in 13 patients (14.4%) with favorable late outcomes of surgical treatment the infiltrate of a similar nature was found in myocardium of RA auricle (p<0.01). As a rule, fibrosis in RA auricle myocardium was I-II degrees lower by Marburg classification than that in LV myocardium.


*Note*: NS – statistically insignificant difference; S – statistically significant difference.

Table 5. Correlation relationships of EchoCG parameters with the degree of LV dilatation in the patients with ICMP after combined surgical treatment.

It should be mentioned that there was no a case of cellular inflammatory infiltrate found in myocardial stroma in the autopsy material of the similar sites of LV myocardium and RA auricle myocardium taken from 25 cadavers which were the relative control group.

Statistical analysis of the obtained morphometrical data did not reveal any significant differences of the values of specific volume of edema and vessels among the patients with progressive and regressive remodeling. The specific volume of parenchyma was significantly higher and stroma specific volume – lower in both LV myocardium and in myocardium of RA auricle of the Ist group patients. Morphometrical parameters of mean value of capillary diameter and diameter of LV and RA auricle myocardial cardiomyocytes did not differ significantly among the patients with different late outcomes of surgical treatment. Specific volume of capillaries in the aforementioned heart parts was significantly higher in the patients with reverse remodeling (group I). All the morphometrical parameters mentioned above differed statistically significantly from those of the control study group.

Morphological Predictors and Molecular Markers of Progressing

CAD history – 5 years. **Preoperative examination** 

regurgitation.

years old.

histological study.

classification of myocarditis).

Stained with hematoxylin and eosin. X 300.

**Hospitalization in a year after the surgery.** 

associated with unfavorable late outcomes of surgical treatment.

regurgitation. Pre- and postoperative EchoCG images are shown in Figure 9.

Postoperative Remodeling of Left Ventricle in Patients with Ischemic Cardiomyopathy 125

EchoCG: LV EDVI – 102.4 ml/m2; LV ESVI – 68.2 ml/m2; LV EF – 34 %. Mild mitral

**Surgery**: SVR by Menicanti, CABG. Intraoperative biopsy of LV myocardium taken for

During histological study of intraoperative samples of LV myocardium pathomorphological signs of myocarditis were found: presence of diffuse-macrophage inflammatory infiltration of myocardial stroma, the 3d degree fibrosis (severe or unfavorable by Marburg

Picture 8 shows a microimage of a histological preparation of LV from the patient N of 56

Fig. 8. Intraoperative biopsy sample of LV myocardium. Patient N, 56 year old. Diffusemacrophage inflammatory infiltration of myocardial stroma. Severe (unfavorable) fibrosis.

Morphometrical values of LV myocardium: parenchyma-stromal ratio – 1.04; trophic index – 0.0097; pericapillar diffusion zone – 1375.0 mcm; Kernogan index – 1.74; diameter of cardiomyocytes – 20.6 mcm. Thus, the morphological study revealed prognostic criteria

CHF II FC. LV EDVI – 96.6 ml/m2; LV ESVI – 62.2 ml/m2, LV EF – 36%. Mild mitral

Parenchymo-stromal ratio reflecting quantitative relationships between parenchyma and stroma of cardiac muscular tissue was significantly lower in LV myocardium and in myocardium of RA auricle in 48 ICMP patients with unfavorable late outcomes of surgical treatment (Table 6).


*Note*: \*, \*\* – significance of morphometrical values differences between the patient groups with positive and negative dynamics of late postoperative follow-up period for RA auricle and LV myocardium respectively (p<0.05).

Table 6. Morphometrical parameters of LV and RA auricle myocardium in ICMP patients with different late outcomes of surgical treatment, Van-der-Waerden test (M±m)

Trophic index of these parts of myocardium which better reflects the condition of cardiac muscular tissue and is assessed as a ratio between capillary specific volume and specific volume of cardiomyocytes, was statistically lower in patients with progressive remodeling; according to the data of intraoperative biopsies of LV myocardium the condition of myocardial trophy in these patients was 8-12 times lower in comparison with that of the control study group.

Pericapillar diffusion zone (the value reflecting load on capillary bed) and Kernogan index (the value showing carrying capacity of microvasculature – the bigger index is the less is carrying capacity of arterioles and the worse are the values of tissue trophy) of LV and RA auricle myocardium were statistically higher in the patients of group II. Values of PcDZ in ICMP patients with unfavorable late outcomes of surgical treatment assessed as a ratio of capillary diameter to their specific volume, 15-20 times exceeded those of the IInd group patients.

There was no significant difference between the groups concerning cardiomyocytes diameter in both LV and RA auricle myocardium found.

As a result of the complex clinical-morphological study we were granted the patent "The prognostic method for postoperative heart remodeling in patients with ischemic cardiomyopathy" #2310372 of 20.11.2007 by the Federal Intellectual Property, Patent and Trademark Service. The method was based on the evaluation of morphofunctional condition of LV myocardial samples on histological preparations stained with hematoxylin-eosin and by Mallory with the help of light microscopy. With simultaneous presence of pathomorphological picture of myocarditis and values of parenchyma-stromal ratio < 1.7, trophic index < 0.010, pericapillar diffusion zone > 1000 mcm and Kernogan index > 1.6 postoperative heart remodeling and progressive chronic heart failure can be predicted.

The offered prediction method of postoperative heart remodeling based on complex evaluation of myocardial morphology in preoperative period or during surgical intervention allows to avoid unfavorable late outcomes of surgical treatment. Clinical cases are the best proof of reliability of the patented prognostic method:

#### **Clinical case 1. Patient N., 56 years old**

**Diagnosis: CAD.** *Obliterating atherosclerotic stenosis of coronary arteries. Postinfarction cardiac sclerosis. LV aneurism. HF of III functional class by NYHA.*

CAD history – 5 years.

124 Front Lines of Thoracic Surgery

Parenchymo-stromal ratio reflecting quantitative relationships between parenchyma and stroma of cardiac muscular tissue was significantly lower in LV myocardium and in myocardium of RA auricle in 48 ICMP patients with unfavorable late outcomes of surgical

Patients Myocardium PSR TI PcDZ (mcm) KI

*Note*: \*, \*\* – significance of morphometrical values differences between the patient groups with positive and negative dynamics of late postoperative follow-up period for RA auricle and LV myocardium

Table 6. Morphometrical parameters of LV and RA auricle myocardium in ICMP patients

Trophic index of these parts of myocardium which better reflects the condition of cardiac muscular tissue and is assessed as a ratio between capillary specific volume and specific volume of cardiomyocytes, was statistically lower in patients with progressive remodeling; according to the data of intraoperative biopsies of LV myocardium the condition of myocardial trophy in these patients was 8-12 times lower in comparison with that of the

Pericapillar diffusion zone (the value reflecting load on capillary bed) and Kernogan index (the value showing carrying capacity of microvasculature – the bigger index is the less is carrying capacity of arterioles and the worse are the values of tissue trophy) of LV and RA auricle myocardium were statistically higher in the patients of group II. Values of PcDZ in ICMP patients with unfavorable late outcomes of surgical treatment assessed as a ratio of capillary

There was no significant difference between the groups concerning cardiomyocytes

As a result of the complex clinical-morphological study we were granted the patent "The prognostic method for postoperative heart remodeling in patients with ischemic cardiomyopathy" #2310372 of 20.11.2007 by the Federal Intellectual Property, Patent and Trademark Service. The method was based on the evaluation of morphofunctional condition of LV myocardial samples on histological preparations stained with hematoxylin-eosin and by Mallory with the help of light microscopy. With simultaneous presence of pathomorphological picture of myocarditis and values of parenchyma-stromal ratio < 1.7, trophic index < 0.010, pericapillar diffusion zone > 1000 mcm and Kernogan index > 1.6 postoperative heart remodeling and progressive chronic heart failure can be predicted. The offered prediction method of postoperative heart remodeling based on complex evaluation of myocardial morphology in preoperative period or during surgical intervention allows to avoid unfavorable late outcomes of surgical treatment. Clinical cases

**Diagnosis: CAD.** *Obliterating atherosclerotic stenosis of coronary arteries. Postinfarction cardiac* 

diameter to their specific volume, 15-20 times exceeded those of the IInd group patients.

diameter in both LV and RA auricle myocardium found.

are the best proof of reliability of the patented prognostic method:

*sclerosis. LV aneurism. HF of III functional class by NYHA.*

**Clinical case 1. Patient N., 56 years old** 

with different late outcomes of surgical treatment, Van-der-Waerden test (M±m)

RA 2.17±0.31\* 0.042±0.016\* 245.6±27.9\* 1.61±0.37\* LV 2.18±0.27\*\* 0.027±0.011\*\* 385.5±51.3\*\* 1.55±0.32\*\*

RA 1.85±0.38\* 0.024±0.008\* 481.2±61.7\* 1.84±0.30\* LV 1.65±0.31\*\* 0.008±0.003\*\* 1315.7±88.2\*\* 1.85±0.21\*\*

RA 5.96±0.14 0.086±0.006 81.0±1.7 1.13±0.10 LV 9.48±0.20 0.087±0.003 66.1±2.6 1.15±0.08

treatment (Table 6).

Group I (n=90)

Group II (n=48)

Control group(n=25)

respectively (p<0.05).

control study group.

#### **Preoperative examination**

EchoCG: LV EDVI – 102.4 ml/m2; LV ESVI – 68.2 ml/m2; LV EF – 34 %. Mild mitral regurgitation.

**Surgery**: SVR by Menicanti, CABG. Intraoperative biopsy of LV myocardium taken for histological study.

During histological study of intraoperative samples of LV myocardium pathomorphological signs of myocarditis were found: presence of diffuse-macrophage inflammatory infiltration of myocardial stroma, the 3d degree fibrosis (severe or unfavorable by Marburg classification of myocarditis).

Picture 8 shows a microimage of a histological preparation of LV from the patient N of 56 years old.

Fig. 8. Intraoperative biopsy sample of LV myocardium. Patient N, 56 year old. Diffusemacrophage inflammatory infiltration of myocardial stroma. Severe (unfavorable) fibrosis. Stained with hematoxylin and eosin. X 300.

Morphometrical values of LV myocardium: parenchyma-stromal ratio – 1.04; trophic index – 0.0097; pericapillar diffusion zone – 1375.0 mcm; Kernogan index – 1.74; diameter of cardiomyocytes – 20.6 mcm. Thus, the morphological study revealed prognostic criteria associated with unfavorable late outcomes of surgical treatment.

#### **Hospitalization in a year after the surgery.**

CHF II FC. LV EDVI – 96.6 ml/m2; LV ESVI – 62.2 ml/m2, LV EF – 36%. Mild mitral regurgitation. Pre- and postoperative EchoCG images are shown in Figure 9.

Morphological Predictors and Molecular Markers of Progressing

eosin. X 350.

**Hospitalization in a year after the surgery.** 

mitochondrial-myofibrillar ratio increases.

progressing. Nuclear SV does not change significantly.

Postoperative Remodeling of Left Ventricle in Patients with Ischemic Cardiomyopathy 127

Fig. 10. A microimage of the histological sample of LV myocardium from the 53 year old patient B. No stromal inflammatory infiltration and fibrosis. Stained with hematoxylin and

CHF I FC. LV EDVI – 62.5 ml/m2; LV ESVI – 33.8 ml/m2, LV EF – 46%. Mild mitral

Clinical examples support our conclusions about improper use of a mean value of LV myocardial cells diameter as a predictor of postoperative heart remodeling for ICMP patients: in a patient with the LV cardiomyocytes diameter > 28mcm signs of progressive HF were not found, however with the diameter of cardiac muscular cells <21mcm repeated heart remodeling was registered in the late postoperative follow-up period (as it was

Out from 58 ICMP patients whose myocardium was studied by electron-microscopy, 47 were included into the further analysis (43 men and 4 women): 34 with the reverse

Morphometrical analysis of the specific volumes of LV and RA auricle myocardial cardiomyocytes ultrastructures confirmed our hypothesis about reduction of myocardial cells contractile apparatus as HF progressing as a result of exhaustion of compensatory adaptation processes: myofibrillar SV of cardiomyocytes significantly decreases. As myofibrillar SV decreases in cardiomyocytes, specific rate of mitochondrias grows,

SV of natriuretic peptide of RA auricle cardiomyocytes insignificantly grows as chronic HF

regurgitation. Pre- and postoperative EchoCG images are shown in Figure 11.

described by Moreira et al for the patients with dilated CMP (2001)).

remodeling (group Ia) and 13 with the progressive remodeling (group IIa).

Fig. 9. Pre- and postoperative EchoCG images of the 56 year old patient N. Notice repeated postoperative LV remodeling and progression of chronic HF.

#### **Clinical case 2. Patient B. 53 year old.**

**Diagnosis: CAD.** *Obliterating atherosclerotic stenosis of coronary arteries. Postinfarction cardiosclerosis. LV aneurism. HF FC III by NYHA.*

```
Six year CAD history.
```
#### **Preoperative examination**

EchoCG: LV EDVI – 98.7 ml/m2; LV ESVI – 61.3 ml/m2; LV EF – 37 %. Mild mitral regurgitation.

**Surgery:** SVR by Menicanti, CABG. Intraoperative biopsy of myocardium taken for histological study.

Histological study of intraoperative samples of LV and RA auricle myocardium did not reveal any signs of inflammatory infiltration of myocardium. In Figure 10 one can see a microimage of the histological sample of LV myocardium from the 53 year old patient B.

*Morphometrical values of LV myocardium*: parenchyma-stromal ratio – 2.83; trophic index – 0.0417; pericapillar diffusion zone – 311.2 mcm; Kernogan index – 1.21; diameter of cardiomyocytes – 28.7 mcm. Thus, combination of the prognostic criteria for the progression of heart failure was not found, postoperative heart remodeling in the late follow-up period is not predicted.

Fig. 9. Pre- and postoperative EchoCG images of the 56 year old patient N. Notice repeated

**Diagnosis: CAD.** *Obliterating atherosclerotic stenosis of coronary arteries. Postinfarction* 

EchoCG: LV EDVI – 98.7 ml/m2; LV ESVI – 61.3 ml/m2; LV EF – 37 %. Mild mitral

**Surgery:** SVR by Menicanti, CABG. Intraoperative biopsy of myocardium taken for

Histological study of intraoperative samples of LV and RA auricle myocardium did not reveal any signs of inflammatory infiltration of myocardium. In Figure 10 one can see a microimage of the histological sample of LV myocardium from the 53 year old patient B. *Morphometrical values of LV myocardium*: parenchyma-stromal ratio – 2.83; trophic index – 0.0417; pericapillar diffusion zone – 311.2 mcm; Kernogan index – 1.21; diameter of cardiomyocytes – 28.7 mcm. Thus, combination of the prognostic criteria for the progression of heart failure was not found, postoperative heart remodeling in the late follow-up period

postoperative LV remodeling and progression of chronic HF.

**Clinical case 2. Patient B. 53 year old.** 

Six year CAD history. **Preoperative examination** 

regurgitation.

histological study.

is not predicted.

*cardiosclerosis. LV aneurism. HF FC III by NYHA.*

Fig. 10. A microimage of the histological sample of LV myocardium from the 53 year old patient B. No stromal inflammatory infiltration and fibrosis. Stained with hematoxylin and eosin. X 350.

#### **Hospitalization in a year after the surgery.**

CHF I FC. LV EDVI – 62.5 ml/m2; LV ESVI – 33.8 ml/m2, LV EF – 46%. Mild mitral regurgitation. Pre- and postoperative EchoCG images are shown in Figure 11.

Clinical examples support our conclusions about improper use of a mean value of LV myocardial cells diameter as a predictor of postoperative heart remodeling for ICMP patients: in a patient with the LV cardiomyocytes diameter > 28mcm signs of progressive HF were not found, however with the diameter of cardiac muscular cells <21mcm repeated heart remodeling was registered in the late postoperative follow-up period (as it was described by Moreira et al for the patients with dilated CMP (2001)).

Out from 58 ICMP patients whose myocardium was studied by electron-microscopy, 47 were included into the further analysis (43 men and 4 women): 34 with the reverse remodeling (group Ia) and 13 with the progressive remodeling (group IIa).

Morphometrical analysis of the specific volumes of LV and RA auricle myocardial cardiomyocytes ultrastructures confirmed our hypothesis about reduction of myocardial cells contractile apparatus as HF progressing as a result of exhaustion of compensatory adaptation processes: myofibrillar SV of cardiomyocytes significantly decreases. As myofibrillar SV decreases in cardiomyocytes, specific rate of mitochondrias grows, mitochondrial-myofibrillar ratio increases.

SV of natriuretic peptide of RA auricle cardiomyocytes insignificantly grows as chronic HF progressing. Nuclear SV does not change significantly.

Morphological Predictors and Molecular Markers of Progressing

Open capillary Rate (%)

and negative dynamics in the late follow-up period (p<0.05).

patients from group II.

Patients Myocardium

Van-der-Waerden test (М±m)

autoantibodies were not detected.

Group Ib (n=33)

Group IIb (n=6)

Postoperative Remodeling of Left Ventricle in Patients with Ischemic Cardiomyopathy 129

0.0678 mcm3/mcm3 in the group of ICMP patients with progressing chronic HF in the late follow-up period. All in all morphofunctional condition of microvasculature in ICMP patients with the reverse type of heart remodeling looks favorable in comparison with ICMP

> Luminal area of open capillaries (mcm2)

*Note*: \* – significance of morphological values differences between the groups of patients with positive

myocardial microvasulature of ICMP patients with different outcomes of surgical treatment,

To make sure of diagnostic reliability of intraoperative myocardial biopsies we studied LV and RA autopsy material of 9 ICMP patients (7 men and 2 women) died at different periods after surgical intervention whose intraoperative myocardial samples we had taken during surgical intervention. We have not found any false-positive or false-negative results of diagnostics of pathomorphological myocarditis signs according to intraoperative biopsy samples (with the control on the autopsies material). Morphometric values of autopsy and biopsy samples were also comparable. Intraoperative biopsy of myocardium should not be considered as an absolute true, but on the whole, without any doubt, it reflects functional morphology of cardiac muscular tissue. First of all it depends on the volume of the material obtained for morphological studies and on the possibility of a targeted harvesting of a necessary LV area.

Table 7. Morphometrical values of functional morphology of the LV and RA auricle

**3.2 Molecular markers of postoperative LV remodeling in patients with ICMP** 

intervention. The control group consisted of 17 healthy volunteers.

Samples of peripheral blood from 53 ICMP patients were taken 1-2 days prior to the surgical

Analysis of the obtained data revealed that in ICMP patients the content of pro-ANP and NT-proBNP in blood plasma was significantly higher than that in the group of healthy volunteers (p<0.001). The study of the content of matrix metalloproteinase in blood serum showed that between the groups of ICMP patients and healthy volunteers there were no differences in the content of matrix metalloproteinases of types 1, 3, 9 and tissue inhibitor ММР-1 (ТIMP-1). But only MMP-9 content in blood serum obeyed normal distribution law. During evaluation of the detection rate of antimyocardial antibodies of difference specificity in the healthy volunteers group in 53% of the cases there were no found autoantibodies to the cardiac tissue; in 47% of the cases antibodies to fibrillar structures were detected, but in only 6% of them these antibodies were present in a titre exceeding acceptable values. In the group of patients with ICMP the distribution of antibodies titres to fibrillar structures was the following: in 46 % of the patients the antibodies were detected in titre 20, in 24.3 % – in titre 40, in 21.6 % – in titre 80, in 2.7 % the titre reached 160 and in only 5.4 % of the patients

In determining antibodies to sarcolemmic structures it was found that in 53% of the cases these antibodies in healthy donors were absent. Antibodies to sarcolemmic structures were

RA 82.0 10.5±1.9 0.0547±0.0079 5.7±0.6 LV 73.0\* 10.5±1.4 0.0796±0.0113\* 6.8±0.7

RA 82.8 10.4±2.1 0.0539±0.0092 5.5±0.8 LV 56.4\* 10.5±1.8 0.0678±0.0127\* 6.3±0.9

Density of free pinocytic vesicles in endotheliocytes (mcm3/mcm3)

Number of pinocytic vesicles per 1 mcm2

Fig. 11. Pre- and postoperative EchoCG images of the 53 year old patient B. Repeated postoperative LV remodeling and progressing chronic HF were not noticed.

Out from 47 ICMP patients whose myocardium was taken for the investigation of functional morphology of microcirculatory link of the LV and RA auricle vascular bed at an ultrasonic level, 39 patients were included into the further analysis (37 men and 2 women): 33 with the reverse remodeling (group Ib) and 6 with the progressive remodeling (group IIb).

Morphometrical values of functional morphology of microvasculature of the LV and RA auricle myocardium of ICMP patients are presented in Table 7.

The rate of open capillaries in myocardium of LV and RA auricle myocardium in ICMP patients with reverse remodeling type was significantly higher than that in the patients of Group II (73.0% vs 56.4% respectively). A similar value for RA auricle myocardium did not differ significantly among the patients with different late outcomes of surgical treatment. Luminal area of the open capillaries in ICMP patients with the reverse and progressive remodeling types as well as the number of pinocytic vesicles connected with a luminal contour of endotheliocytes per a unit of capillary luminal area were identical for both LV myocardium and myocardium of RA auricle.

Density of free pinocytic vesicles in capillary endotheliocytes of LV myocardium has become another value of functional morphology of microvasculature which differed significantly in ICMP patients with different late outcomes of surgical treatment: 0.0796 mcm3/mcm3 in the group of patients with positive postoperative dynamics versus

Fig. 11. Pre- and postoperative EchoCG images of the 53 year old patient B. Repeated

reverse remodeling (group Ib) and 6 with the progressive remodeling (group IIb).

Out from 47 ICMP patients whose myocardium was taken for the investigation of functional morphology of microcirculatory link of the LV and RA auricle vascular bed at an ultrasonic level, 39 patients were included into the further analysis (37 men and 2 women): 33 with the

Morphometrical values of functional morphology of microvasculature of the LV and RA

The rate of open capillaries in myocardium of LV and RA auricle myocardium in ICMP patients with reverse remodeling type was significantly higher than that in the patients of Group II (73.0% vs 56.4% respectively). A similar value for RA auricle myocardium did not differ significantly among the patients with different late outcomes of surgical treatment. Luminal area of the open capillaries in ICMP patients with the reverse and progressive remodeling types as well as the number of pinocytic vesicles connected with a luminal contour of endotheliocytes per a unit of capillary luminal area were identical for both LV

Density of free pinocytic vesicles in capillary endotheliocytes of LV myocardium has become another value of functional morphology of microvasculature which differed significantly in ICMP patients with different late outcomes of surgical treatment: 0.0796 mcm3/mcm3 in the group of patients with positive postoperative dynamics versus

postoperative LV remodeling and progressing chronic HF were not noticed.

auricle myocardium of ICMP patients are presented in Table 7.

myocardium and myocardium of RA auricle.

0.0678 mcm3/mcm3 in the group of ICMP patients with progressing chronic HF in the late follow-up period. All in all morphofunctional condition of microvasculature in ICMP patients with the reverse type of heart remodeling looks favorable in comparison with ICMP patients from group II.


*Note*: \* – significance of morphological values differences between the groups of patients with positive and negative dynamics in the late follow-up period (p<0.05).

Table 7. Morphometrical values of functional morphology of the LV and RA auricle myocardial microvasulature of ICMP patients with different outcomes of surgical treatment, Van-der-Waerden test (М±m)

To make sure of diagnostic reliability of intraoperative myocardial biopsies we studied LV and RA autopsy material of 9 ICMP patients (7 men and 2 women) died at different periods after surgical intervention whose intraoperative myocardial samples we had taken during surgical intervention. We have not found any false-positive or false-negative results of diagnostics of pathomorphological myocarditis signs according to intraoperative biopsy samples (with the control on the autopsies material). Morphometric values of autopsy and biopsy samples were also comparable. Intraoperative biopsy of myocardium should not be considered as an absolute true, but on the whole, without any doubt, it reflects functional morphology of cardiac muscular tissue. First of all it depends on the volume of the material obtained for morphological studies and on the possibility of a targeted harvesting of a necessary LV area.

#### **3.2 Molecular markers of postoperative LV remodeling in patients with ICMP**

Samples of peripheral blood from 53 ICMP patients were taken 1-2 days prior to the surgical intervention. The control group consisted of 17 healthy volunteers.

Analysis of the obtained data revealed that in ICMP patients the content of pro-ANP and NT-proBNP in blood plasma was significantly higher than that in the group of healthy volunteers (p<0.001). The study of the content of matrix metalloproteinase in blood serum showed that between the groups of ICMP patients and healthy volunteers there were no differences in the content of matrix metalloproteinases of types 1, 3, 9 and tissue inhibitor ММР-1 (ТIMP-1). But only MMP-9 content in blood serum obeyed normal distribution law.

During evaluation of the detection rate of antimyocardial antibodies of difference specificity in the healthy volunteers group in 53% of the cases there were no found autoantibodies to the cardiac tissue; in 47% of the cases antibodies to fibrillar structures were detected, but in only 6% of them these antibodies were present in a titre exceeding acceptable values. In the group of patients with ICMP the distribution of antibodies titres to fibrillar structures was the following: in 46 % of the patients the antibodies were detected in titre 20, in 24.3 % – in titre 40, in 21.6 % – in titre 80, in 2.7 % the titre reached 160 and in only 5.4 % of the patients autoantibodies were not detected.

In determining antibodies to sarcolemmic structures it was found that in 53% of the cases these antibodies in healthy donors were absent. Antibodies to sarcolemmic structures were

Morphological Predictors and Molecular Markers of Progressing

Se=p(P/D). Calculation is performed as follows:

**4. Conclusion** 

been considered as risk factors of such interventions.

postoperative heart remodeling basing on the obtained material.

Postoperative Remodeling of Left Ventricle in Patients with Ischemic Cardiomyopathy 131

an attempt to calculate sensitivity and specificity of molecular prognostic criteria of

Test sensitivity (Se) may be identified as a probability of a positive outcome in the patients:

Se=(the number of positive outcomes in the group of patients P / number of the patients D) × 100 %. Specificity (Sp) – is the probability of negative results of the test in healthy volunteers: Sp=p(N/H). Calculated as follows: Sp=(the number of negative results among the healthy N / number of the healthy H) × 100 %. A test with high specificity, as a rule, does not refer healthy people to the category of patients. **For MMP-3**  Cut-off value = 7.7 ng/ml. Se = (11/13) × 100 % = 84.6 %. Sp = (40/40)× 100 % = 100.0 %. **For MMP-9**  Cut-off value = 102.4 ng/ml. Se = (7/13) × 100 % = 53.8 %. Sp = (40/40)× 100 % = 100.0 %. As for antibodies to myocardial structures, their titre is much higher in ICMP patients. This fact proves our hypothesis about the presence of inflammatory infiltrate in myocardial stroma as the key factor for unfavorable outcome of surgical treatment. Nowadays it is obvious that taking blood of the patients with massive postinfarction cardiac sclerosis at the preoperative stage for the evaluation of MMPs content and antibodies titre to myocardial structures in order to make prognosis for the late postoperative period is not only perspective but reasonable. Identification of the antimyocardial antibodies titre in blood serum preoperatively as well as in the dynamics of early and mid-term postoperative period will indirectly allow for monitoring of inflammatory process in myocardium and evaluation of the efficacy of a complex medical treatment avoiding repeated biopsies of myocardium.

Our clinical observations demonstrate progress of chronic HF in the late postoperative period and inefficiency of SVR in ICMP patients in 35% of the cases. These patients should be refused from the standard procedure of surgical restoration of normal left ventricular geometry in favor of alternative methods of surgical treatment – isolated bypass grafting for the patients with symptomatic CAD, cardiac resynchronization therapy for patients with QRS >120 msec and left bundle branch block, primary heart transplantation and implant of the devices preventing ventricular dilatation. Attempts to find clinical, instrumental or other markers of chronic HF progression have been made many times but the results are very modest. The age older than 55 years and high values of LV ESVI in preoperative period have

In our opinion the reason of unfavorable outcomes of surgical treatment lies in peculiarities of myocardial functional morphology of an each and every patient and depends on irreversibility of the far gone pathological changes in cardiac muscular tissue. Assessment of an initial morphofunctional condition of myocardium (at the moment of surgical treatment)

not found in 10.8 % of ICMP patients, in 24.3 % – they were detected in titre 20, in 43.3 % – in titre 40, in 16.2 % – in titre 80, in 5.4 % – in titre 160.

Maximal detection rate of antibodies to nuclear structures in titre 80 in the control group was 11.8%, in 88.2% of the patients did not have these antibodies. The highest titre in ICMP patients where nuclear antibodies were found was equal to 80 (2.7%); in 5.4% of the cases antibodies to nuclear structures were detected in titre 40, in 32.4% - in titre 20, in 59.5% autoantibodies of this specificity were absent.

In a year after the surgical treatment all the patients included into the study were examined (n=53, 100%). In accordance with the aforementioned algorithm for the evaluation of late postoperative period 40 patients were assigned into group I (with positive dynamics of the late postoperative period), 13 patients – into group II (with negative dynamics of the late postoperative period). The levels of pro-ANP, NT-proBNP and pro-ММР-1, MMP-3, MMP-9, TIMP-1 in blood plasma and serum In the ICMP patients with different dynamics of the late postoperative period are shown in Table 8.


*Note*: \* – statistically significant data.

Table 8. The content of natriuretic peptides and matrix meatlloproteinases in blood plasma and serum in ICMP patients with different dynamics of the late postoperative treatment

We managed to follow the late postoperative period of 32 (86.5%) out from 37 patients whose blood was tested for antimyocardial antibodies. Postoperative LV remodeling took place in only 5 patients which does not allow to reliably associate the activity of inflammatory response in myocardium with postoperative heart function.

Thus, evaluation of the content of MMP-3 and MMP-9 in blood serum at the preoperative stage let us "foresee" the outcome of possible surgical treatment since their content is significantly higher in the group of patients with postoperative heart remodeling. We made an attempt to calculate sensitivity and specificity of molecular prognostic criteria of postoperative heart remodeling basing on the obtained material.

Test sensitivity (Se) may be identified as a probability of a positive outcome in the patients: Se=p(P/D). Calculation is performed as follows:

Se=(the number of positive outcomes in the group of patients P / number of the patients D) × 100 %.

Specificity (Sp) – is the probability of negative results of the test in healthy volunteers: Sp=p(N/H). Calculated as follows:

Sp=(the number of negative results among the healthy N / number of the healthy H) × 100 %.

A test with high specificity, as a rule, does not refer healthy people to the category of

patients. **For MMP-3**  Cut-off value = 7.7 ng/ml. Se = (11/13) × 100 % = 84.6 %. Sp = (40/40)× 100 % = 100.0 %. **For MMP-9**  Cut-off value = 102.4 ng/ml. Se = (7/13) × 100 % = 53.8 %. Sp = (40/40)× 100 % = 100.0 %.

As for antibodies to myocardial structures, their titre is much higher in ICMP patients. This fact proves our hypothesis about the presence of inflammatory infiltrate in myocardial stroma as the key factor for unfavorable outcome of surgical treatment. Nowadays it is obvious that taking blood of the patients with massive postinfarction cardiac sclerosis at the preoperative stage for the evaluation of MMPs content and antibodies titre to myocardial structures in order to make prognosis for the late postoperative period is not only perspective but reasonable. Identification of the antimyocardial antibodies titre in blood serum preoperatively as well as in the dynamics of early and mid-term postoperative period will indirectly allow for monitoring of inflammatory process in myocardium and evaluation of the efficacy of a complex medical treatment avoiding repeated biopsies of myocardium.
