Interview: Alexander E Berezin - European Medical Journal

Interview: Alexander E Berezin

EMJ Cardiol. ; DOI/10.33590/emjcardiol/10180879.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

Alexander E Berezin | Fellow of the European Society of Cardiology (ESC) and Senior Consultant, Lecturer, and Professor of Medicine, Zaporozhye State Medical University, Ukraine

EMJ had the pleasure of interviewing Alexander E Berezin, Fellow of the European Society of Cardiology (ESC) and Senior Consultant, Lecturer, and Professor of Medicine, Zaporozhye State Medical University, Ukraine, on his research in cardiology.

Please explain the research that led to you receiving the Award of the Cabinet of Ministers of Ukraine in 2002 and the Honor of the Ukrainian Cardiology Association in 2004.

I received both awards for developing a comprehensive strategy for biomarker-based stratification of patients at risk of heart failure (HF) and HF treatment with angiotensin II receptor antagonists as an add-on to β-blockers, prior to their routine use for this indication. I am especially proud of these achievements as they marked the completion of my long studies and the completion of my Doctor of Science degree.

Please describe the primary duties and key projects you have undertaken since becoming a member of the Ukrainian Heart Failure Association.

My main role in the Ukrainian Heart Failure Association is a co-ordination of the efforts with the aim of harmonising national clinical standards in HF management to international clinical recommendations, including the European Society of Cardiology (ESC) guidelines. I am also involved in the development and implementation of current national guidelines, initiatives, and algorithms in HF. Recently, along with my colleagues from the Working Group of the Ukrainian Association of Cardiology and Ukrainian Association of Heart Failure Specialists, I executed the national guidelines for the use of biomarkers in HF and the management of HF depending on comorbidities. The basic issues of these recommendations being harmonised with current ESC guidelines have been deeply adapted to the healthcare system in Ukraine. These documents have been incorporated into routine clinical practice in my country.

One of your principal research interests is the fundamental study of biological markers of cardiovascular diseases. Please could you summarise the established and emerging roles of biomarkers in HF.

Circulating cardiac biomarkers, mainly natriuretic peptides, high-sensitive cardiac troponins, rarely soluble suppression of tumorigenicity-2 (sST2), and galectin-3, are considered to be surrogate indicators of clinical outcomes, response to management, and undoubtedly a component of the diagnostic algorithm of HF. However, there is a large amount of evidence regarding the lack of a universal biomarker that is unique and approachable for every phenotype of HF. For instance, cascade genetic testing offers the opportunity for early intervention in dilated cardiomyopathy-related HF. On the other hand, comprehensive adipocytokine and myokine testing encompasses ever-increasing metabolic panels with the aim of improving predictive ability of natriuretic peptides in people with diabetes, obesity, or cardiac cachexia. So far, a signature of circulating biomarkers as well as epigenetic and genetic biomarkers can relate to coexisting conditions, age, gender, and ethnicity. Unfortunately, we do not know which of these biomarkers are best fitted to be monitored in the follow-up and which are considered to be singly measured. Scientific data from large clinical trials are quite optimistic to consider cardiac biomarkers as surrogate indicators of survival and death. However, multiple biomarker models appear to be an increasingly promising tool to diagnose HF and properly predict a clinical course, including expected response on pharmacological therapy, because there is a real potential to personally adjust it to the purpose and patient.

Could you provide an overview of your 2019 EMJ Cardiology article, entitled ‘Circulating Cardiac Biomarkers in Heart Failure: A Critical Link to Biomarker-Guided Therapy’?

Circulating cardiac biomarkers remain the most discussed topic in the field of risk stratification of patients with cardiovascular disease. Indeed, this approach seems to have shown several benefits in the personalised management of HF and prediction of short- and long-term outcomes, while biomarker-guided therapy for HF does not support the 2022 ESC guideline as it does not have strong enough evidence. The use of single and serial measures of cardiac biological markers, mainly N-terminal segment of brain natriuretic peptide (NT-proBNP) and sST2, as a surrogate endpoint to predict HF-related clinical events has been widely investigated in large clinical trials and numerous meta-analyses. Previously, it had been suggested that biomarker-guided therapy with serial biomarker measures could be a powerful means to appraise composite risk score and predict HF-related outcomes based on therapeutic adjustment. However, the results of the majority of these studies have yielded controversial issues that influenced the clinical implementation of these findings in routine practice. In fact, NT-proBNP and sST2 remained in a loop of scientific discussion around justification of an individualised strategy for HF management, whereas other biomarkers continue to be used in their combinations.

Could you highlight the principal findings and wider relevance of the recent EMJ Cardiology review you co-authored, entitled ‘Biomarker-Based Guideline-Directed Medical Therapy of Heart Failure: The Gap Between Guidelines and Clinical Practice’?

Although there is resoundingly clear proof of natriuretic peptides, which are a crucial point in the biomarker-based strategy for the stratification of patients with HF at risk of untoward outcomes and recognition of new HF/acute decompensated HF to rule out these conditions, the new definition of HF requires an updated biomarker concept. It depends on a high variability of both diagnostic and predictive values of natriuretic peptides in patients with different HF phenotypes: their age, gender, and signature of comorbidities. To improve the discriminative ability of natriuretic peptides, including NT-proBNP, several alternative biomarkers have been proposed. They reflect biomechanical stress (adrenomedullin), inflammation and fibrosis (growth differentiation factor-15, sST2, galectin-3, and high-sensitivity C-reactive protein), cardiac damage (cardiac troponins and heart-type fatty acid binding protein), extracellular matrix remodelling (matrix metalloproteinase-2, -6, -7, and -9), renal injury and dysfunction (cystatin C), liver fibrosis (YKL-40), neurohormonal regulators of mineral metabolism and calcification (fibroblast growth factor-23, osteonectin, and osteoprotegerin), intermediary metabolism and adipose tissue dysfunction (fatty-acid binding protein-4, apelin, irisin, and visfatin), and angiogenesis (angiopoietin-2). Please note, this is not a final list because a number of these promising molecules steadily increase. It is a big challenge to choose from it and make the biomarker strategy of HF management more predictable and personally relevant to routine clinical practice.

Another problematic issue, apart from variable discriminative ability of circulating biomarkers related to coexisting comorbidity profile, is identifying a reasonable number of biomarkers for patients with different HF phenotypes. In fact, patients with HF with reduced ejection fraction (HFrEF) and mildly reduced ejection fraction (HFmrEF) had higher median levels of growth differentiation factor-15, high-sensitivity cardiac troponins, heart-type fatty acid-binding protein, and NT-proBNP, but not sST2, galectin-3, high-sensitivity C-reactive protein, procollagen peptides, and other abundant biomarkers of extracellular turnover, relative to those with HF with preserved ejection fraction (HFpEF). In this connection, multiple biomarker panels seem to be a more promising tool in detecting patients at higher risk of death and HF hospitalisation. Current 2022 American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Failure Society of America (HFSA) and 2021 ESC guidelines recommend the use of natriuretic peptides as a prominent tool to screen, diagnose, and stratify patients with HF or at risk of HF. Furthermore, the 2022 AHA/ACC/HFSA guideline also proposes alternative biomarkers (sST2, galectin-3, and cardiac troponins) when needed. However, large clinical trials are required to elucidate the benefits of a personal adjusted biomarker strategy for the management of HF and prediction of HF-related outcomes.

Could you share the key conclusions drawn from your 2021 paper, ‘Shift of Conventional Paradigm of Heart Failure Treatment: From Angiotensin Receptor Neprilysin Inhibitor to Sodium-Glucose Co-transporter 2 Inhibitors?’

This narrative review article opens up the changes affecting the management of HFrEF, which have recently occurred, and mainly focuses on the combined use of angiotensin receptor-neprilysin inhibitors (ARNI) and sodium–glucose co-transporter 2 inhibitors (SGLT2i). It has been purported that the favourable molecular effects of ARNI and SGLT2i (e.g., attenuation of cardiac remodelling; suppression of oxidative stress, apoptosis, and inflammation; mediating repair activity; and improvement of energetic homeostasis) contribute to tissue protection and thereby dramatically decrease the risk of death and HF hospitalisation in HFrEF. The approach, which is widely known as neurohumoral modulation, results from the benefits observed in numerous large clinical trials such as PARADIGM-HF, DAPA-HF, EMPEROR-Reduced, and EMPEROR-Preserved. These studies have revealed the possibility to improve fatal and non-fatal HF events and renal outcomes among optimally treated individuals. Thus, a shift from the traditional approach of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and β-blockers to a more effective one composed of ARNI, β-blocker, SGLT2i, and optionally mineralocorticoid receptor antagonists appears to be much more effective in this matter. Nowadays, this treatment algorithm the so-called four-pillar strategy, is approved and generally recommended by the 2022 AHA/ACC/HFSA and 2021 ESC guidelines.

Please describe the key take-home messages from the two ePosters you presented during the 2022 ESC Preventative Cardiology congress: ‘Predictive Value of Both Irisin and Apelin for Health Failure with Preserved Ejection Fraction in Type 2 Diabetes Mellitus Patients’ and ‘Elevated Levels of Apelin Predict Favourable Clinical Course of Heart Failure in Type 2 Diabetes Mellitus Patients’.

The first ePoster, entitled ‘Predictive Value of Both Irisin and Apelin for Health Failure with Preserved Ejection Fraction in Type 2 Diabetes Mellitus Patients’, elucidated whether serum levels of both irisin and apelin could predict HFpEF in patients with Type 2 diabetes (T2D). Indeed, both peptides were found to play a central role in metabolic homeostasis, inflammation, immune reaction, tissue reparation, and adaptive cardiac remodeling. Irisin is skeletal muscle-derived peptide, which is produced by a proteolytic cleavage of fibronectin Type III domain-containing transmembrane protein 5, the expression of which is under close control of peroxisome proliferator-activated receptor-γ coactivator 1α. Apelin is considered to be a powerful regulatory peptide with positive inotrope ability, and acts as an autocrine regulator of cardiac and vascular reparation. One hundred and eight patients with HF and T2D had HFpEF (EF>50%; n=58), HFmrEF (EF<40%; n=22), HFrEF (EF<40%; n=28) aged 41–62 years. Twenty patients with T2D but without HF were enrolled in the study. We found that the levels of irisin were significantly higher in patients with HFpEF than in people with HFrEF, whereas healthy volunteers and patients with T2D but without HF demonstrated lower concentrations of these peptides. In contrast, apelin levels were significantly increased in patients mainly with HFrEF. Then, we divided all patients with HF having elevation of NT-proBNP >750 pmol/mL into three subgroups, depending on the level of the biomarkers. Patients from Subgroup A had both irisin and apelin levels higher than the cut-off points; individuals from Subgroup B had higher concentrations of one of the two biomarkers; and patients from Subgroup C demonstrated levels of both peptides lower than the cut-off points. Multivariate logistic regression analysis revealed that the discriminative value of irisin and apelin to predict HFpEF in Subgroup B (hazard ratio [HR]: 2.18; 95% confidence interval [CI]: 1.26–3.14; p=0.001) was substantially higher compared with Subgroups A and C (HR: 1.03; 95% CI: 1.00–1.05; p=0.64 and HR: 0.92; 95% CI: 0.89–1.01; p=0.62, respectively). Adding irisin and apelin to NT-proBNP as independent variables to the predictive model sufficiently improved discriminative ability of whole model for HFpEF.

The next ePoster illustrated the finding that add-on of apelin to the combined predictive model constructed from NT-proBNP (>785 ng/mL) improved the relative integrated discrimination indices by 10.5% and net-reclassification improvement of 11.5% for the combined endpoint. Moreover, the Kaplan–Meier curve showed that patients with levels of apelin >3.55 ng/mL demonstrated better clinical course of HF compared with those who had lower apelin levels (log-rank test: p=0.001). Thus, we found that apelin levels >3.55 ng/mL regardless of NT-proBNP had positive discriminative ability for clinical course of HF in patients with T2D.

You have authored more than 550 research articles. What do you believe to be the current knowledge gaps with respect to heart failure diagnosis and treatment?

Despite 2022 AHA/ACC/HFSA and 2021 ESC recommendations yielding novel strategies in HF management, we are not completely satisfied about the mortality rate in patients with HFrEF, HFmrEF, and HFpEF. I think that the new four-pillar approach to HF medical care composed of ARNI, mineralocorticoid receptor antagonist, β-blocker, and SGLT2i will allow us to make a breakthrough in it.

Conceptually, the prevention of asymptomatic HF occurrence and its turning from HFpEF to HFmrEF and finally to HFrEF seems to be more promising in this way. In addition, thorough care of comorbidities such as diabetes, chronic kidney disease, hypertension, valvular heart diseases, cardiomyopathies, arrhythmias, anaemia, etc., should be a focus in the prevention of HF manifestation and progression. In this way, biomarkers can play a pivotal role as low cost, personal, and practically useful predictive tools to identify patients at higher risk and detect a response on the treatment further.

Overall, I believe that personal adaptation of each direction of HF management; education of the patient, their family members, and caregivers; and extensive support of non-profit sectors and official institutions could reduce the total cost of management and make it more affordable for the patients at different stages of the natural evolution of HF. Last but not least, the prevention and management of acute, acutely decompensated, and advanced HF need to be justified according to the optimal algorithm of interplay between HF team members.

To date, what have been the proudest achievements of your career?

To be honest, I am most proud of being awarded Fellow of the ESC, which became a tipping point in my academic career last year. I am in an on-going communication with the European Union (EU) scientific community, especially with scientists from Austria, Germany, and Slovenia, but not only with them. I also have many friends from other countries, including the USA, Canada, Argentina, Brazil, and Japan, whose scientific interests overlap with my own activities. Thanks to the ESC congresses and working groups, we are able to discuss ideas together. However, it is true that nothing can replace close personal communication.

The next achievement that I especially value is my activities on the editorial boards of several highly reputed scientific journals. This gives me incredible scientific experience, which cannot be overvalued, because it allows me to be present during formation of new ideas and find out more prior to official publication. I have also had some of my proudest moments during the preparation and publication of both current national Ukrainian guidelines for biomarkers in HF and HF management, which have been successfully executed in close co-operation with my friends and colleagues from the Working Group of the Ukrainian Association of Cardiology and Ukrainian Association of Heart Failure Specialists.

Where can we expect to see your focus lie in the near future?

My most recent presentation was at the ESC’s 2022 Heart Failure Congress, which was held in Madrid on 21st–24th May. I spoke about new arguments in terms of potential mechanisms by which empagliflozin, a SGLT2i, mediates cardiac protection in patients with HF and T2D. Moreover, my new research article entitled ‘Serum Levels of Irisin Predict Cumulative Clinical Outcomes in Heart Failure Patients with Type 2 Diabetes Mellitus’ has been approved for production and accepted for publication.

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