[Heart Failure With Low and Preserved Left Ventricular Ejection Fraction - are These Two Different Independent Diseases or One Disease, but at Different Stages of its Progression? How Does This Affect the Choice of Therapy and Its Effectiveness?]

The article discusses the question of whether it is possible to conclude that any heart failure (HF), throughout the entire range of left ventricular ejection fractions (LVEF), is a single holistic disease, based on the "external" similarity of treatments for reduced (HFrEF) and preserved (HFpEF) LVEF, and that positioning HFpEF and HFrEF as separate independent diseases is not valid.

[What is "normal left ventricular ejection fraction" and its relationship with the pathogenesis and effectiveness of the treatment of heart failure].

The article focuses on modern views on the role and place of left ventricular ejection fraction (LV EF) in determining the status of cardiovascular patients (primarily patients with heart failure) in the algorithm for their diagnosis, treatment, and prediction of the outcome. Conclusions and recommendations on the use of LV EF in patients with chronic heart failure (CHF) are the following: 1) LV EF remains a familiar and convenient instrumental indicator not so much of myocardial contractility as of hemodynamics in general. Assessment of LV EF is useful for selection and ranking of CHF patients whereas the LV EF dynamics is useful for assessing the quality of their management. 2) In the entire population of cardiovascular patients, the "normal" LV EF (mortality nadir) is in the range of 60-65%. 3) LV EF demonstrates a U-shaped relationship with prognosis: in cardiovascular patients with LV EF below the mortality nadir, the relationship is inversely proportional, and above the mortality nadir, it is directly proportional. The question of the boundary between "normal" and "reduced" LV EF in terms of CHF syndrome remains open, but obviously, this boundary is most likely within the range of 50 to 60%. 4) LV EF determines the effectiveness of CHF treatment, but this rule is not applicable to all LV EF ranges and not to all classes of drugs.

[Diastolic heart failure: 20 years later. Сurrent issues of pathoge-nesis, diagnosis and treatment of heart failure with preserved LVEF].

Relevant aspects of the pathogenesis, diagnosis, And treatment of heart failure with preserved LV EFThis review analyzes results of studies of the recent decade that focus on epidemiology, mechanisms of development, diagnostic methods, and treatments of heart failure with preserved ejection fraction (HFpEF). As expected, the prevalence of HFpEF continues to increase due to the growing contribution of comorbidities to the structure of causes for chronic heart failure (CHF), such as arterial hypertension with left ventricular hypertrophy, obesity, chronic kidney disease, as well as due to ageing of the population and decreased contributions of ischemic heart disease and myocardial infarction. Concomitant diseases are a source of low-intensity microvascular inflammation, which is currently assigned a role of a trigger mechanism eventually provoking energy deficiency, disorders of cardiomyocyte relaxation, and diffuse myocardial fibrosis. Both these processes lead to increased heart muscle rigidity and abnormally high left ventricular filling pressure (LVFP). High LVFP is associated with the development of pulmonary venous congestion and impairment of alveolar blood oxygenation, which form the clinical picture of HFpEF. Detecting high LVEF with tissue Doppler echocardiography by the E / e' value became the instrumental basis for the HFpEF diagnostics. Recognition of inflammation and fibrosis as the key pathogenetic factors marked the main vector of modern therapy for HFpEF (anti-inflammatory and antifibrotic). The best implementation of this vector became possible with the advent of drugs from the class of angiotensin receptor and neprilysin inhibitors (ARNI), sodium-glucose cotransporter type 2 (SGLT2) inhibitors, and aldosterone antagonists. However, the efficacy of such treatments is evident only with the LV EF <60-65% while at higher values, the efficacy substantially decreases. This limitation may result from the heterogenous nature of the disease and requires more advanced methods for verification of HFpEF clinical phenotypes. Among such methods, transcriptomic, metabolomic, and proteomic approaches are considered. With the use of capabilities of the "machine learning" and the artificial intelligence, these approaches can become a new frontier in research to represent an important step towards personalized medicine for patients with HFpEF.

[Treatment of patients with heart failure and preserved ejection fraction: reliance on clinical phenotypes].

The article discusses the problem of improving the effectiveness of treatment of heart failure with preserved left ventricular ejection fraction (HFpEF). The relative "failure" of early studies with renin-angiotensin-aldosterone system inhibitors was largely due to the lack of understanding that patients with HFpEF represent a heterogeneous group with various etiological factors and pathogenetic mechanisms of the disease. Therefore, the so-called personalized approach should be used in the treatment of these patients. This approach is based on the identification of clearly defined disease phenotypes, each characterized by a set of demographic, pathogenetic, and clinical characteristics. Based on the literature and own experience, the authors consider four main phenotypes of HFpEF: 1) phenotype with brain natriuretic peptide "deficiency" syndrome associated with moderate/severe left ventricular hypertrophy; 2) cardiometabolic phenotype; 3) phenotype with mixed pulmonary hypertension and right ventricular failure; and 4) cardiac amyloidosis phenotype. In the treatment of patients with phenotype 1, it seems preferable to use the valsartan + sacubitril (possibly in combination with spironolactone) combination treatment; with phenotype 2, the empagliflozin treatment is the best; with phenotype 3, the phosphodiesterase type 5 inhibitor sildenafil; and with phenotype 4, transthyretin stabilizers. Certain features of different phenotypes overlap and may change as the disease progresses. Nevertheless, the isolation of these phenotypes is advisable to prioritize the choice of drug therapy. Thus, the diuretic treatment (preferably torasemide) should be considered in the presence of congestion, regardless of the HFpEF phenotype; the valsartan + sacubitril and spironolactone treatment is appropriate not only in the shortage of brain natriuretic peptide but also in the presence of concentric left ventricular hypertrophy (except for the amyloidosis phenotype); and the treatment with empagliflozin and statins may be considered in all situations where pro-inflammatory mechanisms are involved.

[Ð ossibility of using European (HFA-PEFF) and American (H2FPEF) algorithms for diagnosing heart failure with preserved ejection fraction in Russian clinical practice].

This article focuses on the significance of a unified approach to diagnosing heart failure with preserved left ventricular ejection fraction (HFpEF). The key hemodynamic index of HFpEF is increased left ventricular filling pressure (LVFP) and its noninvasive marker, the E / e' value obtained by tissue Doppler echocardiography (EchoCG). The modern verified algorithms for HFpEF diagnosis, HFA-PEFF and Н2FPEF, mandatorily take into account the E / e' value. However, the routing use of these algorithms in the Russian practice may be complicated since even among "advanced" specialists who are interested in heart failure, 38% of the interviewed do not use or do not know how to use tissue Doppler EchoCG or the algorithm for diagnosing HFpEF with E / e'. In addition to the obvious way of overcoming this problem by equipping respective medical facilities with ultrasonic apparatuses with tissue Doppler EchoCG software and educating physicians, a possibility of using simplified HFA algorithm without the E / e' value is being considered. However, such approach will inevitably lead to erroneous estimation of the probability of HFpEF and, at the best, to underestimation of this probability with ensuing mistakes in diagnosis and treatment. Simplifying the HFA-PEFF and H2FPEF algorithms by omitting one or more parameters is possible but this requires a special investigation to develop a new rating scale and actually a new algorithm, which, in turn, will require a new validation.

[Focus ultrasound for cardiology practice. Russian consensus document].

This document is a consensus document of Russian Specialists in Heart Failure, Russian Society of Cardiology, Russian Association of Specialists in Ultrasound Diagnostics in Medicine and Russian Society for the Prevention of Noncommunicable Diseases. In the document a definition of focus ultrasound is stated and discussed when it can be used in cardiology practice in Russian Federation.

[The use of diuretics in chronic heart failure. Position paper of the Russian Heart Failure Society].

The document focuses on key issues of diuretic therapy in CHF from the standpoint of current views on the pathogenesis of edema syndrome, its diagnosis, and characteristics of using diuretics in various clinical situations.

[The role of diastolic transthoracic stress echocardiography with incremental workload in the evaluation of heart failure with preserved ejection fraction: indications, methodology, interpretation. Expert consensus developed under the auspices of the National Medical Research Center of Cardiology, Society of Experts in Heart Failure (SEHF), and Russian Association of Experts in Ultrasound Diagnosis in Medicine (REUDM)].

Diagnosis of heart failure with preserved ejection fraction (HFpEF) is associated with certain difficulties since many patients with HFpEF have a slight left ventricular diastolic dysfunction and normal filling pressure at rest. Diagnosis of HFpEF is improved by using diastolic transthoracic stress-echocardiography with dosed exercise (or diastolic stress test), which allows detection of increased filling pressure during the exercise. The present expert consensus explains the requirement for using the diastolic stress test in diagnosing HFpEF from clinical and pathophysiological standpoints; defines indications for the test with a description of its methodological aspects; and addresses issues of using the test in special patient groups.

The Molecular and Cellular Mechanisms Associated with a Microvascular Inflammation in the Pathogenesis of Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a severe disease with an often unfavorable outcome. The prevalence of HFpEF continues to increase, while effective treatment options remain elusive. All the medical strategies used to improve the outcome in a heart failure with reduced ejection fraction proved ineffective in HFpEF, which was probably due to the different mechanisms of development of these two types of heart failure and the diversity of the HFpEF phenotypes. According to the current paradigm of HFpEF development, a chronic mild pro-inflammatory state causes a coronary microvascular endothelial inflammation, with further myocardial fibrosis and diastolic dysfunction progression. This inflammatory paradigm of HFpEF has been confirmed with some evidence, and suppressing the inflammation may become a novel strategy for treating and managing HFpEF. This review summarizes current concepts about a microvascular inflammation in hypertrophied myocardium and provides a translational perspective of the anti-inflammatory and immunomodulatory approaches in HFpEF.

The Role of Neprilysin Inhibitors in the Treatment of Heart Failure with Preserved Ejection Fraction.

Clinical and hemodynamic aggravation of heart failure with preserved ejection fraction (HFpEF) is largely due to progression of left ventricular (LV) diastolic dysfunction. The key role in the normal maintenance of diastolic function is played by a high level of activity of the intracellular signaling axis, cyclic guanosine-monophosphate-protein kinase G, the activity of which is significantly reduced in HFpEF. The activity of this axis can be increased by increasing the bioavailability of natriuretic peptides by blocking the enzyme neutral endopeptidase (neprilisin), which is responsible for the destruction of natriuretic peptides.This review presents experimental and clinical data on the use of neprilysin inhibitors in HFpEF and addresses prospects of this treatment.

[Mechanisms of exercise intolerance in patients with heart failure and preserved ejection fraction. Part II: The role of right heart chambers, vascular system and skeletal muscles].

The main clinical manifestation of heart failure with preserved ejection fraction is poor exercise tolerance. In addi-tion to the dysfunction of the left heart chambers, which were presented in the first part of this review, many other disorders are involved in poor exercise tolerance in such patients: impairments of the right heart, vascular system and skeletal muscle. The second part of this review presents the mechanisms for the development of these disorders, as well as possible ways to correct them.

[Mechanisms of exercise intolerance in patients with heart failure and preserved ejection fraction. Part I: The role of impairments in the left heart chambers].

During exercise an increase in oxygen delivery to working muscles is achieved through well­coordinated interaction of many organs and systems: the heart, lungs, blood vessels, skeletal muscles, and the autonomic nervous system. In heart failure with preserved left ventricular ejection fraction, all mechanisms involved in the normal exercise tolerance are impaired. In the first part of this review, the impairments of the left heart chambers are considered ­ left ventricular diastolic dysfunction, the weakening of the contractile and chronotropic reserves, left atrium dysfunction; the possible ways of their medical correction are also presented.

Heart failure with mid-range ejection fraction: are there clinical reasons in introduction of this new group as a distinct entity?

The article discusses the clinical expedience of isolating into a separate classification subgroup of patients with heart failure and a mid­range ejection fraction (EF) of 40-49 %. Analysis of studies 2017-2018 focusing on the issue of patients with mid­range LV EF showed that this subgroup is highly heterogenous and by some clinical and demographic parameters takes an intermediate position between heart failure (HF) patients with reduced (<40 %) and preserved (>50 %) LV EF. However, patients with mid­range LV EF positively respond to beta­blocker and RAAS inhibitor therapy, and their response is close to that of patients with reduced LV EF. This is a principal difference between patients with mid­range and preserved LV EF who generally do not display any beneficial effect of such therapy. One of the major causes for such difference is a dissimilarity of HF etiology and, hence, pathogenesis in patients with reduced and mid­range LV EF: primarily IHD (so­called "ischemic" phenotype) in patients with reduced and mid­range LV EF and non­cardiac causes ("non­ischemic" phenotype) in patients with preserved LV EF. Since the nonischemic phenotype is also rather common among patients with mid­range LV EF a new HF classification should definitely indicate, in addition to LV EF, the clinical phenotype of disease, which is particularly important for patients with mid­range LV EF of 40-49 %. Further studies should focus on variants of HF clinical phenotypes.

[Left ventricular dysfunction in hypertensive heart: Current view of the pathogenesis and treatment].

The article shows major mechanisms for development of left ventricular dysfunction in patients with hypertensive heart and provides major trends in the treatment of heart failure with preserved ejection fraction in the light of state-of-the art in its pathogenesis.

[Cardiotoxicity of trastuzumab: mechanisms of development, diagnosis, treatment].

The review discusses mechanisms of trastuzumab cardio- toxicity. There are presented risk factors of development of the left ventricular dysfunction in treatment of a drug, among which the most important are the simultaneous administration of anthracycline antibiotics and the presence of associated cardiovascular diseases. There are discussed the features of cardiac management of patients receiving trastuzumab therapy that focuses on early detection of abnormalities of left ven- tricular function from the normality as well as measures aim- ing at preventing the occurrence of cardiac dysfunction and its treatment.

[Clinical, hemodynamic and neurohumoral effects of switching patients with chronic heart failure from not recommended -adrenoblockers to bisoprolol in ambulatory practice].

At present only bisoprolol, metoprolol succinate, nebivolol, and carvedilol are considered to be beta adrenoblockers with proven efficacy relative to course and prognosis of chronic heart failure (CHF). However in real clinical practice most patients continue to receive preparations which are not recommended for application. Therefore we have conducted this study in order to assess efficacy of switching ambulatory patients from therapy with "not recommended" beta adrenoblockers to bisoprolol which is recommended for the treatment of CHF. We recruited 35 patients with stable class II-III CHF on standard therapy which included beta adrenoblockers not recommended for the treatment of CHF. In all patients at baseline and after 6 months of therapy we assessed clinical status, quality of life with the Minnesota questionnaire and visual analog scale, performed 6 min walk test and echocardiography for evaluation of left ventricular (LV) ejection fraction (EF) and measured level of N terminal fragment of pro brain natriuretic peptide in blood serum. Switching patients from "not recommended" beta adrenoblockers to bisoprolol was associated with significant improvement of clinical status with increase of 6 min walk distance, betterment of parameters of quality of life, and significant rise of LV EF combined with lowering of mean CHF functional class (all <0.01 compared with baseline). There was no significant dynamics of NT proBNP level in the whole group but in the subgroup with NT proBNP values above median significant lowering we noted its significant lowering (<0,05). No significant association between dynamics of main clinico-laboratory parameters and decrease of heart rate was observed. Switch of patients with moderate CHF to bisoprolol from therapy with beta adrenoblockers not recommended for application in this disease was associated with improvement of quality of life, clinical status, and LV systolic function. This was combined with lowering of initially elevated NT proBNP level irrespective of changes of heart rate.

[ATR1 gene polymorphism in patients with hypertrophic cardiomyopathy and hypertensive heart].

Aim of the study was analysis of dependence of clinical picture and degree of severity of left ventricular hypertrophy (LVH) on polymorphism A/C of ATR1 gene in patients with hypertrophic cardiomyopathy (HCMP) and hypertensive disease (HD). With the method of polymerase chain reaction genotyping for polymorphic markers of A/C of ATR1 gene was carried out in 35 patients with HCMP and 33 patients with LVH developed at the background of long lasting HB. In the work we used clinico-instrumental methods of investigation (electrocardiography - ECG, echocardiography). It was revealed as result of the study that in HCMP type AA in comparison with type AC of ATR1 gene was associated with addition of arterial hypertension, presence of left ventricular outflow tract obstruction, greater severity of heart failure. In case of combination of HD with LVH type AA in comparison with types AC and CC of ATR1 gene is associated with more pronounced LVH.

[Effects of renin-angiotensin system blockers on left ventricular hypertrophy and biochemical markers of collagen balance in patients with hypertensive hypertrophy].

AIM: To evaluate the effect of ACE inhibitor enalapril, AR blocker candesartan and their combination on left ventricular hypertrophy (LVH) and content of biochemical markers of collagen balance in patients with hypertensive LV hypertrophy. MATERIAL AND METHODS. A total of 66 patients with arterial hypertension with LV hypertrophy were divided into two groups. Group 1 (n = 33) received candesartan (8-16 mg/day), group 2 (n = 33) received enalapril (10-20 mg/day). In effective hypotensive response to the initial treatment, it was continued for 6 months. If in two months of monotherapy the effect was unsatisfactory, the other drug was added. At baseline and upon 6 months of treatment all the patients were examined for myocardial mass index (MMI), matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of matrix metalloproteinase-1 (THMP-1) in the blood. RESULTS: In effective initial treatment with candesartan 6-month treatment lowered LV MMI by 13.9%, while in enalapril group--only by 1.5%. In addition of the second drug in ineffective initial therapy the reduction was 5.1%. THMP-1 did not change during the trial. CONCLUSION: In patients with hypertensive LVH candesartan more effectively treated LVH. The addition of the second RAS blocker in insufficient efficacy of the initial one significantly reduces LV MMI. A significant antifibrotic effect was achieved only in case of simultaneous use of two RAS blockers.