**Morphological Predictors and Molecular Markers of Progressing Postoperative Remodeling of Left Ventricle in Patients with Ischemic Cardiomyopathy**

Vladimir Shipulin1, Vitaly Kazakov1,2, Alexander Lezhnev1, Boris Kozlov1, Vadim Babokin1, Sergey Gutor2 and Irina Suhodolo2 *1Tomsk Institute of Cardiology, Tomsk, 2Siberian State Medical University, Tomsk, Russia* 

#### **1. Introduction**

106 Front Lines of Thoracic Surgery

[53] Menicanti L, Castelvecchio S, Ranucci M, Frigiola A, Santambrogio C, de Vincentiis C,

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#### **1.1 Background**

Coronary artery disease takes a leading role in the etiology of chronic heart insufficiency in 60% of the cases (Belenkov et al., 2002; Kalon et al., 1993; Oganov & Maslennikova, 2000; Simonsen, 2003). According to the data of different authors patients with coronary artery disease experience development of ischemic cariomyopathy preconditioned by diffuse, significantly pronounced atherosclerosis of coronary arteries manifesting as cardiomegaly termed as "heart remodeling" and symptoms of congestive heart failure in 10-35% of the cases (Belenkov et al., 2002; Mareev, 2002).

Postinfarction left ventricular remodeling is one of the most urgent challenges of modern cardiology and cardiac surgery. The heart remodeling process is a combination of changes in cavities' form and volume and in mass of postinfarction heart myocardium in response to significant inadequate hemodynamic conditions of its functioning not connected with sarcomeres elongation caused by their prior overstretching (Jackson, 2002; Maisch, 1996; Rosenberg & Nepomnyashchih, 2003). Among the patients with different cardiomyopathies these are the ones with ischemic cardiomyopathy who have the most unfavorable prognosis, which makes the problem of ischemic heart failure much more significant (Bellenger, 2000; Buckberg, 2005; Frazier, 2000).

Quite frequently the surgical intervention becomes the only treatment method for the patients with chronic heart insufficiency basing on deep changes of functional myocardium morphology. Different approaches to surgical ventricular reconstruction aimed at mechanical changes of the heart cavities sizes in combination with coronary artery bypass grafting (CABG) take the leading place in the complex treatment of this pathology. Nevertheless their outcomes show that in the late postoperative period repeated heart remodeling and CHF progressing i.e. return to the initial preoperative values of the heart cavities sizes and functional capacity of the heart takes place in a part of the operated patients (Batista, 1996; Dickstein, 1997; Dor, 1985; Gradinac, 1998; Menicanti & Di Donato,

Morphological Predictors and Molecular Markers of Progressing

dilatation, cardioresynchronizing therapy, etc.

1997; Sabbah, 2001).

**2. Materials and methods 2.1 Design of the study. Object** 

imaging of the heart with dye.

Postoperative Remodeling of Left Ventricle in Patients with Ischemic Cardiomyopathy 109

Until today, there have not been performed any complex fundamental scientific works devoted to the identification of tissue, cellular and molecular predictors of postoperative LV remodeling basing directly on real patients cases. The contemporary concept of CHF surgical treatment must be based on peculiarities of functional morphology of each individual patient's myocardium. Thorough patient selection basing on a complex clinicalmorphological and biochemical analysis of the prognosis for surgical treatment outcome may improve the efficacy of a standard SVR procedure making a surgeon refuse from it in predeterminedly prospectless patients in favor of alternative methods of surgical treatment such as primary heart transplantation, implant of the devices preventing heart chambers

The latter area has better perspective for the problem of organ transplantation is a very topical issue in modern medicine since the number of recipients exceeds significantly the number of donors. Cardiac support device (CSD) is a special device for suppression of heart chambers dilatation. Multi-centers randomized clinical trial for this device is being carried out at present and according to preliminary data its application is quite efficient for ischemic and dilated cardiomyopathies (Acorn cardiovascular, inc.™ Selected abstracts, 2000; Patel,

**Objective of the study**: The development of a diagnostic algorithm and justification of a modern concept of CHF surgical treatment basing on identification of morphological and

One hundred and ninety five patients with ICMP and with previous myocardial infarctions have become the object of the study. All the patients were admitted to the cardiovascular surgery department at Tomsk Institute of Cardiology during the period from 2002 to 2009. Preoperative diagnostics included transthoracic EchoCG, Halter ECG monitoring, coronaroventriculography with manometry, SPECT imaging with 99mTc-technetril, MRI

The clinical inclusion criteria for the patients enrolled into the study were the following parameters: LV end-diastolic volume index (LVEDVI) > 90 ml/m2, LVESVI > 70 ml/m2 , LV end-diastolic pressure (LVEDP) > 30 mmHg, EF LV < 40%, akinetic and dyskinetic areas of LV, angina II-IV CCS FC, heart failure (HF) II-IV NYHA, coronary artery disease from 1 - 10 years, lesions of coronary arteries – stenosis of more than 75% of LAD or of the trunk, or not less than 75% stenosis in at least two coronary arteries. The age of the patients included into the study was between 37 and 68 years (53.6±8.3), mean number of affected coronary arteries was 2.7±0.4. Lack of organic lesions of heart valves apart from ischemic mitral valve

The reason for the development of ICMP in all the patients was an extensive transmural myocardial infarction. In 135 patients (69.2%) heart insufficiency appeared after their first myocardial infarction. All the patients in conditions of bypass and cardioplegia underwent surgical reconstruction of LV by V.Dor and L.Menicanti methods in different combinations with myocardial revascularization, reduction and reconstruction of LV volume and shape due to exclusion of its scarred septal, anterior and basal parts by endoventriculoplasty and

regurgitation was also a clinical criterion for patients' selection.

by restoration of the mitral valve (MV) function.

blood markers of progressive postoperative LV remodeling in patients with ICMP.

2002; Menicanti & Di Donato, 2004; Moreira et al., 2001; Popovic et al., 1998; Popovic et al., 2001; Ratcliffe, 1998; Shah, 2003; Soo, 2005; Stolf, 1998).

The efforts to find clinical and instrumental prognostic criteria of unfavorable late outcomes of surgical treatment in patients with ICMP have not resulted in anything. According to publications, the following preoperative values have been associated with higher postoperative mortality and morbidity of the patients with ICMP: size of left ventricle (LV) (Yamaguchi, 2005), LV end-systolic volume index (LVESVI) (especially > 80 ml/m2 (Athanasuleas, 2004) and > 100 ml/m2 (Yamaguchi, 2000)), LV ejection fraction (EF) (< 20% (Di Donato, 2001; Yamaguchi, 2005) or < 30%(Yamaguchi, 2000; Athanasuleas, 2004)), mitral regurgitation (Sartipy et al., 2006; Schroder, 2005), number of segments affected by dyssynergia (Di Donato, 1997), pulmonary hypertension >33mmHg (Di Donato, 1997), QRS>130ms (Yamaguchi, 2005), preoperative renal failure (Yamaguchi, 2005), time after previous myocardial infarction (Yamaguchi, 2005), age older than 75 years old (Athanasuleas, 2004). Nevertheless, there have not been any definite preoperative clinical predictors of postoperative LV remodeling offered.

Myocardium is a unique tissue consisting of highly differentiated cells – cardiomyocites which possess a number of morphological features in norm responding by a set of nonspecific structural changes to pathomorphism of cardiovascular diseases. In our opinion, the degree of revensability/irreversibility of advanced pathological processes in myocardium plays a key role in the success of reconstructive cardiac surgical interventions.

It has been 10-12 years since researchers started their first search for morphological predictors of postoperative heart remodeling in patients with cardiomyopathies, carrying out the analysis of the postoperative period course and evaluating morphofunctional condition of LV myocardium by the data of intraoperative biopsies (Gradinac, 1998; Moreira et al., 2001; Popovic et al., 2001; Stolf, 1998). However, the results of these solitary studies have been quite controversial (Moreira et al., 2001; Popovic et al., 2001). We have not found data about any attempts to search for morphological predictors of progressive postoperative LV remodeling in patients with ICMP. In the available Russian publications there are separate articles devoted to studies of morphofunctional condition of LV myocardium and myocardium of RA auricle in patients with coronary artery disease of different functional classes (Kuznetsov, 2003; Salikova et al., 2002). These works can hardly boast wide analysis of morphological parameters (Kuznetsov, 2003) and some authors only provide descriptive morphology without deep investigation of the mechanisms of possible pathogenesis of heart remodeling (Salikova et al., 2002).

At the same time, identification of morphological predictors of postoperative LV remodeling will not solve all the problems which cardiac surgeons face when choose the tactics for surgical intervention and think of the prognosis for each individual patient since pre- and postoperative morphological diagnostics of the pathological processes reversibility degree in ischemic myocardium in reality is limited very much by a definite degree of a risk associated with harvesting biopsies from heart walls which very often becomes a reason to refuse from this diagnostics. In the light of this, one of the perspective directions of scientific research is the finding of molecular predictors of postoperative heart remodeling in peripheral blood of patients together with tissue and cellular aspects of this phenomenon for the blood is always available for laboratory testing and monitoring of its content.

Until today, there have not been performed any complex fundamental scientific works devoted to the identification of tissue, cellular and molecular predictors of postoperative LV remodeling basing directly on real patients cases. The contemporary concept of CHF surgical treatment must be based on peculiarities of functional morphology of each individual patient's myocardium. Thorough patient selection basing on a complex clinicalmorphological and biochemical analysis of the prognosis for surgical treatment outcome may improve the efficacy of a standard SVR procedure making a surgeon refuse from it in predeterminedly prospectless patients in favor of alternative methods of surgical treatment such as primary heart transplantation, implant of the devices preventing heart chambers dilatation, cardioresynchronizing therapy, etc.

The latter area has better perspective for the problem of organ transplantation is a very topical issue in modern medicine since the number of recipients exceeds significantly the number of donors. Cardiac support device (CSD) is a special device for suppression of heart chambers dilatation. Multi-centers randomized clinical trial for this device is being carried out at present and according to preliminary data its application is quite efficient for ischemic and dilated cardiomyopathies (Acorn cardiovascular, inc.™ Selected abstracts, 2000; Patel, 1997; Sabbah, 2001).

**Objective of the study**: The development of a diagnostic algorithm and justification of a modern concept of CHF surgical treatment basing on identification of morphological and blood markers of progressive postoperative LV remodeling in patients with ICMP.
