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STUDY PROTOCOL
Year : 2016  |  Volume : 1  |  Issue : 4  |  Page : 160-165

Clinical and morphological characteristics of chronic inflammation in the myocardium in patients with decompensated chronic heart failure accompanied by ischemic systolic dysfunction: study protocol for an open-label nonrandomized trial


1 Cardiology Research Institute, Tomsk National Research Medical Center, 111a Kievskya Street, 634012 Tomsk; National Research Tomsk State University, 36 Lenin Avenue, 634050 Tomsk; Siberian State Medical University, 2 Moscovskytrakt, 634050 Tomsk, Russian Federation
2 Cardiology Research Institute, Tomsk National Research Medical Center, 111a Kievskya Street, 634012 Tomsk; National Research Tomsk State University, 36 Lenin Avenue, 634050 Tomsk, Russian Federation
3 Cardiology Research Institute, Tomsk National Research Medical Center, 111a Kievskya Street, 634012 Tomsk, Russian Federation

Date of Web Publication30-Dec-2016

Correspondence Address:
Ekaterina V Kruchinkina
Cardiology Research Institute, Tomsk National Research Medical Center, 111a Kievskya Street, 634012 Tomsk; National Research Tomsk State University, 36 Lenin Avenue, 634050 Tomsk
Russian Federation
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2468-5658.196980

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  Abstract 

Background: Heart failure is one of the leading causes of morbidity and mortality in the world. Mortality remains high (50%), despite optimal treatment according to the recommendations of the European Society of Cardiology (ESC) and Russian Society of Cardiology (RSC). Tremendous evidence has emerged over the past decades that heart failure is associated with inflammation. However, anti-inflammatory therapy widely lacks positive outcomes. Currently, there are no clinical studies investigating the molecular and cellular phenotypes of inflammation in myocardial tissue (viral, viral and autoimmune, and autoimmune types of inflammation) in patients with decompensated chronic heart failure (CHF). Therefore this study aims to develop a new medicinal drugs and approaches to treatment of decompensated CHF.
Methods/Design: This open-label, nonrandomized, single-center, prospective trial includes decompensated CHF patients with ischemic systolic dysfunction (left ventricular ejection fraction < 40%) undergoing percutaneous coronary intervention (PCI)/coronary artery bypass graft (CABG) not earlier than 6 months before hospitalization. This group of patients will receive standard treatment of acute decompensated CHF according to RSC national guidelines and ESC guidelines. All patients will undergo coronary angiography to exclude ischemic etiology of decompensated CHF and endomyocardial biopsy to determine type of inflammation in the myocardium by immunohistochemistry. The following parameters are assessed during hospitalization and at 12-month follow-up: inflammatory infiltrate in the myocardial tissue, incidence of acute myocardial infarction, incidence of cardiac rhythm and conduction disturbances, left ventricular ejection fraction, end-diastolic and end-systolic volumes, mortality rate, incidence of stroke, and the rates of hospital admission due to the progression of CHF.
Discussion: Elucidation of inflammatory infiltrate types in the myocardium and determination of frequency of their occurrences in patients with decompensated CHF and ischemic systolic dysfunction will contribute to the development of new pharmacological approaches to CHF treatment.
Trial registration: ClinicalTrials.gov Identifier: NCT02649517; registered on January 5, 2016.
Ethics: The study protocol follows the Declaration of Helsinki and has been approved by the Ethics Committee of the authors' institution on April 20, 2015. The study complies with the National Standard of Good Clinical Practice (RF GOST P52379-2005 form April 1, 2006) and with the international guidelines for Good Clinical Practice.
Informed consent: Investigators or investigator-authorized officers will be responsible for explaining the objective, content, study procedures, benefits, and risks of participating in the clinical trial to each patient or the patient's legal representative. Written informed consent will be obtained from all patients before the start of the trial.

Keywords: clinical trial; decompensated heart failure; ischemic heart disease; inflammatory cardiomyopathy; endomyocardial biopsy; immunohistochemistry


How to cite this article:
Ryabov VV, Kruchinkina EV, Rogovskaya YV, Ryabova TR, Batalov RE, Rebenkova MS, Popov SV, Karpov RS. Clinical and morphological characteristics of chronic inflammation in the myocardium in patients with decompensated chronic heart failure accompanied by ischemic systolic dysfunction: study protocol for an open-label nonrandomized trial. Clin Trials Degener Dis 2016;1:160-5

How to cite this URL:
Ryabov VV, Kruchinkina EV, Rogovskaya YV, Ryabova TR, Batalov RE, Rebenkova MS, Popov SV, Karpov RS. Clinical and morphological characteristics of chronic inflammation in the myocardium in patients with decompensated chronic heart failure accompanied by ischemic systolic dysfunction: study protocol for an open-label nonrandomized trial. Clin Trials Degener Dis [serial online] 2016 [cited 2019 Apr 21];1:160-5. Available from: http://www.clinicaltdd.com/text.asp?2016/1/4/160/196980


  Introduction Top


Decompensated chronic heart failure (CHF) is a challenging medical and social problem of the modern society. The CHF prevalence rates are 7.9 million in Russia (Ageev and Ovchinnikov, 2013), 15 million in European countries, and 5.7 million people in the USA (Miró et al., 2016). Almost 80% of health care budget accrues to the treatment of heart failure (Teerlink et al., 2015).

During the period from 1979 to 2000, studies have shown that treatment strategies, based on administration of angiotensin-converting enzyme inhibitors, beta-blockers, mineralocorticoid receptor antagonists, myocardial revascularization, and device therapy improve survival of patients with CHF (Batalov et al., 2014; Mozaffarian et al., 2016). In spite of that, the mortality rate remains high and nearly 50% of people with heart failure die within 5 years (Hobbs et al., 2007; Roger, 2013). Immune system plays an important role in the etiology and the course of CHF (Kharchenko, 2012). Acute decompensated CHF presents with increase in the cytokines which can lead to the left ventricular dysfunction, negative inotropic effect, cardiac metabolism alteration, myocardial remodeling, and progression of CHF (Briasoulis et al., 2016). Earlier, correlation relationship between the levels of pro-inflammatory biomarkers and high risk of mortality and readmission for acute decompensated CHF has been shown (Cowie et al., 2000). Unfortunately, the results of the experimental and exploratory clinical studies have not produced the effective anti-inflammatory strategy in CHF syndrome yet.

Probably, conservative and invasive treatments of patients with decompensated CHF are not effective because of a combination of ischemic and inflammatory cardiomyopathy. Now the cardiomyopathy is a common cause of acute decompensated CHF (Pauly, 2014). Similarly to dilated cardiomyopathy (DCM), inflammatory cardiomyopathy (ICM), often leading to an unfavorable outcome, is difficult to treat so it has received increased attention recently (Gombozhapova et al., 2015). Virus-positive inflammation is a common reason for ICM. However, the autoimmune response also plays an important role in this pathology (Caforio et al., 2013). The most common viruses in the myocardium are enterovirus (Coxsackie virus), human herpes virus types 1 and 2, human herpes virus type 6, adenovirus, parvovirus B19, and Epstein-Barr virus (Noutsias et al., 2010; Rogovskaya et al., 2015). 60% of DCM cases present with ICM confirmed by using the polymerase chain reaction (Hofmann and Frantz, 2013). The Euroheart Failure Survey II showed that DCM is diagnosed in 11% of patients with CHF (Alaeva et al., 2012), and the five-year survival rate of these patients is 36%, which implies a poor prognosis in the significant proportion of patients with DCM, though medical treatment of CHF is given (Noutsias et al., 2010). Until now, there is no commonly accepted concept underlying diagnostics and treatment of ICM. In the available literature, there are no reports on exploration of the molecular and cellular phenotypes of myocardial inflammation (viral, viral and autoimmune, and autoimmune types of inflammation) in patients with decompensated CHF and ischemic cardiomyopathy. Based on these considerations, this study aims to develop a new treatment strategy for decompensated CHF.


  Methods/Design Top


Design

This study is an open-label, nonrandomized, single-center, prospective trial implemented at the Cardiology Research Institute, Tomsk NRMC, Russia.

The study comprises decompensated CHF patients with ischemic cardiomyopathy (LVEF < 40%) who underwent PCI/CABG not earlier than 6 months before hospitalization. These patients receive standard treatment for acute decompensated CHF according to the national guidelines from the Russian Society of Cardiology as well as the guidelines from the European Society of Cardiology. All patients undergo endomyocardial biopsy and coronary angiography to rule out ischemic etiology of decompensated CHF and are randomly divided into virus-positive and virus-negative groups according to the results of immunohistochemistry. After that, they are further divided into four subgroups: virus-negative patients with or without myocardial inflammation; virus-positive patients with or without myocardial inflammation ([Figure 1]).
Figure 1: Flowchart of the trial.
Note: LVEF: Left ventricular ejection fraction; PCI: percutaneous coronary intervention; CABG: coronary artery bypass graft; RSC: Russian
Society of Cardiology; ESC: European Society of Cardiology


Click here to view


Inclusion criteria

Patients that meet all the following criteria are included in the study:

  • Older than 18 years and body weight below 130 kg
  • Clinical symptoms of decompensated heart failure in medical history
  • Heart failure decompensation requiring hospitalization because of at least three of the following symptoms: shortness of breath, or position orthopnea, rales, peripheral edema, jugular venous pulsations, signs of pulmonary congestion according to chest X-ray
  • Confirmed coronary artery disease with diastolic dysfunction (LVEF < 40%) in medical history and at time of admission
  • At least 6 months after percutaneous coronary intervention (PCI)/coronary artery bypass graft (CABG)
  • Medical treatment according to the national guidelines of the Russian Society of Cardiology and the guidelines of the European Society of Cardiology with individually tailored doses of drugs


Exclusion criteria

Patients presenting with one of the following criteria will be excluded:

  • Refusal to conduct the necessary studies
  • Poor ultrasound visualization of the heart
  • Hemodynamically significasnt valvular heart disease
  • Acute coronary syndrome
  • Thrombosis of the right atrium and right ventricle
  • Condition after the operation, impeding access to the right ventricle (vena cava filters, vena cava plication, the Mustard and Senning procedure for dextro-transposition of the great arteries, and mechanical prosthetic tricuspid valve)
  • Severe comorbidities


Sample size

No sample size calculation was performed because this is a pilot study. A sample size of 60 patients seems sufficient.

Baseline and follow-up evaluation

The following parameters are determined during hospitalization: rate of inflammatory infiltrate in the myocardial tissue; rate of virus-positive inflammatory infiltrate in the myocardial tissue; left ventricular ejection fraction; end-diastolic volume of the left ventricle; and end-systolic volume of the left ventricle according to echocardiography.

The following parameters are determined at 12-month follow-up: rate of a certain type of inflammatory infiltrate in the myocardium; rate of virus-positive inflammatory infiltrate in the myocardial tissue; left ventricular ejection fraction; left ventricular end-diastolic volume; left ventricular end-systolic volume according to echocardiography; viruses present in the myocardial tissue; rate of acute myocardial infarction, rate of cardiac rhythm and conduction disturbances.

Determinations

The endomyocardial biopsy is usually performed through the femoral vein under fluoroscopic guidance using local anesthesia. During the procedure, three myocardial samples are harvested for immunohistochemistry analysis (Fiorelli et al., 2011). Immunohistochemistry of myocardial biopsies with mono- and polyclonal antibodies will allow for quantitative and qualitative characterization of the infiltrates in the presence/absence of viral antigens. Chronic myocardial inflammation is classified into the autoimmune, viral, and autoimmune-viral types. The criterion of viral inflammation consists in the presence of viral antigens in the myocardium (Rebenkova et al., 2015). Criterion for the autoimmune inflammation consists in the absence of viral antigens with/without serum antimyocardial autoantibodies. Autoimmune-viral inflammation requires the presence of viral antigens in the myocardium and the presence of serum antimyocardial autoantibodies (Caforio et al., 2013). Left ventricular ejection fraction, end-diastolic volume, and end-systolic volume will be assessed using echocardiography during hospitalization and at 12-month follow-up.

Study parameters

Study parameters will be assessed during hospitalization and at 12-month follow-up.

Primary parameters

  • Rate of inflammatory infiltrates in the myocardial tissue


Secondary parameters

  • Rate of the virus-positive inflammatory infiltrates in myocardial tissue
  • The most common viral agents in myocardial tissue in this geographic area
  • Incidence of acute myocardial infarction
  • Incidence of cardiac rhythm and conduction disturbances
  • Left ventricular ejection fraction by echocardiography
  • Left ventricular end-diastolic and end-systolic volumes
  • Mortality rate
  • Incidence of stroke
  • The rates of hospital admission due to the progression of CHF


Outcome assessment is shown in [Table 1].
Table 1: Measures and design

Click here to view


Statistical analysis

All data will be statistically analyzed using Statistica 10.0 software (Stat Soft Inc., Tulsa OK, USA). Data that are normally distributed are expressed as mean, standard deviation, minimum value, and maximum value. Data that are non-normally distributed are expressed as the lower (q1), median, and upper quartile (q3). Rates and frequencies of occurrence are expressed as percentages (%). Data are compared between groups using Student's t-test; nonparametric variables are compared between groups using the Friedman test, Kruskal-Wallis analysis of variance and Median Test. A value of P < 0.05 is considered statistically significant.


  Discussion Top


Serum markers of inflammation in patients with decompensated CHF have been determined in previous studies (Kostenko et al., 2014; Goonewardena et al., 2016). Inflammatory serum markers were demonstrated to be increased in patients with ischemic heart disease (Naumov et al., 2013; Ryabov et al., 2013). An increasing number of studies have investigated the clinical efficacy of etanercept and infliximab, but no encouraging results regarding the outcomes in patients with CHF are obtained (Sychev and Mareev, 2009; Kovalev, 2011; Hofmann and Frantz, 2013). Discouraging results have raised important questions on the significance of the inflammatory activation in CHF. Meanwhile, basic and translational clinical studies accumulated a lot of novel mechanistic information suggesting that inflammatory cells may represent new promising targets for therapy (Hofmann and Frantz, 2013). However, until now, an effective anti-inflammatory therapy has not been established for patients with CHF. This study is unique as it elucidates types of inflammation and frequencies of their occurrences in the myocardium in association with clinical-morphological course of CHF. New data generated in this study may be helpful for the development of new drugs and approaches to treatment of CHF.


  Trial Status Top


Recruitment is ongoing at the time of submission.[25]

 
  References Top

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Declaration of patient consent
The authors certify that they will obtain all appropriate patient consent forms. In the form the patient(s) will give his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
None declared.
Author contributions
VVR and EVK conceived and designed the study, acquired data, and drafted the manuscript. All other authors acquired data and made substantial contributions and revisions to the manuscript.TRR performed echocardiography examinations. REB, YVR, and MSR identified cell-morphological composition of infiltration in the myocardium. SVP and RSK participated in critical review of the manuscript. All authors have read and approved the final manuscript.
Plagiarism check
This paper was screened twice using CrossCheck to verify originality before publication.
Peer review
This paper was double-blinded and stringently reviewed by international expert reviewers.


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