Advanced heart failure

The authors of the article have analyzed the problem of advanced heart failure (AHF). Despite significant and, without exaggeration, revolutionary achievements in clinical pharmacology, cardiac surgery, and implantation arrhythmology, the number of patients with chronic heart failure (CHF) in many countries is not decreasing, and in some states, for example, in Russia, it is increasing. At the same time, unfortunately, immediate and long-term results of the so-called optimal therapy of CHF are often disappointing for both the patient and the doctor. In 2007, experts from The Heart Failure Association of the European Society of Cardiology proposed the term advanced heart failure (AHF) to refer to CHF in which optimal drug therapy, as well as cardiac resynchronization therapy, are not effective, which causes repeated hospitalizations and justifies the need for advanced treatment methods such as heart transplantation and mechanical circulatory support, and/or transition to palliative care. The opinions of experts from the established cardiological communities in the Old and New Worlds on the definition, diagnostic criteria, and treatment of AHF have been changing over time. Unfortunately, this evolution has not yet arrived at a consensus. The lecture consistently addresses the issues of terminology, diagnosis, prognostic stratification, and routing of patients with AHF, as well as short- and long-term strategies for treating these patients. therapy; ICD − implantable cardioverter-defibrillator; LVEF − left ventricular ejection fraction; NYHA − New York Heart Association; RAS – renin- angiotensin system; SBP− systolic blood pressure; SCr − serum creatinine.


INTRODUCTION
Chronic heart failure (CHF) is a notorious medical and social problem that belongs to the priorities of national health systems in almost all developed and developing countries [1,2]. This is explained by the fact that despite the significant and even revolutionary achievements in clinical pharmacology, cardiac surgery, and implantation arrhythmology, the number of patients (especially those with heart failure with preserved left ventricular (LV) ejection fraction (EF)) with this disabling, costly, and often deadly condition does not decrease in many countries. In some countries, for example in Russia, it increases [3−6]. At the same time, immediate and long-term results of the so-called optimal therapy of heart failure are, unfortunately, often disappointing for both the patient and the doctor [7,8].
The aim of this lecture was to consider contemporary views on the problem of advanced heart failure (AHF), the prevalence of which in the population of patients with CHF ranges from 1 to 10% [9,10].

TERMINOLOGY
In 2007, experts from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) proposed the term AHF to refer to heart failure, in which optimal drug therapy, including diuretics, renin-angiotensin-aldosterone system rest. All of the above is the reason for repeated hospitalizations (≥ 1 case over the past six months) and justifies the need of using such advanced treatment methods as heart transplantation and mechanical circulatory support, and/or the transition to palliative care [11]. Both, Nnot yet fatal cases of patients with refractory heart failure requiring consideration of the use of circulatory assist device and/or heart transplantation and patients with end-stage heart failure in which irreversible changes in the end-organs cause contraindications to surgery and palliative care is the only possible option (for example, inotropic drug infusions, ultrafiltration or peritoneal dialysis and end-of-life care) were in question.  Siberian Medicine» among other sources [12−14]. This subjectivity naturally leads to low reproducibility of the results of the assessment of FC CHF in the same patient by different doctors.

AHF
CHF affects mainly the elderly people. Taking into account the polymorbidity, the informativity of the exercise test performed to objectify FC (a 6-minute walk test, for instance) is often unacceptably low in these patients, since the distance traveled by the patient can be affected not only by myocardial, but also by coronary or respiratory failure and other factors [14].
At the same time, some doctors and researchers give a rather subjective interpretation of the (RAAS) inhibitors, beta-blockers (unless these drugs are not contraindicated and are well tolerated), and cardiac resynchronization therapy (if there are appropriate indications) are not effective. It is considered not effective if the following persist: objective signs of severe cardiac dysfunction, such as severe systolic and/or diastolic LV dysfunction, high ventricular filling pressure and increased natriuretic peptide blood levels, which are associated with heart failure corresponding to III-IV functional class (FC) according to NYHA (New York Heart Association), dyspnoea and/or fatigue at rest or with minimal exertion, as well as episodes of fluid retention and/or peripheral hypoperfusion at rest. All of the above is the reason for repeated hospitalizations (≥ 1 case over the past six months) and justifies the need for using such advanced treatment methods as heart transplantation and mechanical circulatory support, and/or the transition to palliative care [11]. The studied cases included not yet fatal patients with refractory heart failure requiring consideration of the use of a circulatory assist device and/or heart transplantation and patients with end-stage heart failure in which irreversible changes in the end-organs cause contraindications to surgery and palliative care is the only possible option (for example, inotropic drug infusions, ultrafiltration or peritoneal dialysis and end-of-life care) were in question.
Well-known difficulties of precise CHF functional class (FC) diagnosis, associated with the subjectivity of a patient and a doctor in determining what limitation to physical activity is slight or significant and what exertion is habitual for the patient, were described many times in the «Bulletin of Siberian Medicine» among other sources [12−14]. This subjectivity naturally leads to low reproducibility of the results of assessing CHF FC in the same patient by different doctors. CHF affects mainly elderly people. Taking into account polymorbidity, the infor- Heart Association; ** Classification by the American Heart Association and the American College of Cardiology mativity of the exercise test performed to objectify FC (a 6-minute walk test, for instance) is often unacceptably low in these patients, since the distance traveled by the patient can be affected not only by myocardial, but also by coronary or respiratory failure and other factors [14]. At the same time, some doctors and researchers give a rather subjective interpretation of the NYHA classification. They identify intermediate FC values (for example, III-IV) and attempt to introduce additional gradations into the classification. One of these is IIIb class which is not categorically identified as "advanced". This class is vaguely characterized as a more serious disturbance of the functional status than in FC III, on the one hand, but not as severe as in CHF corresponding to FC IV, on the other hand [14,15]. Medicine does not belong to exact sciences, but such an argument cannot be understood, as if you are being convinced that more than two results are possible after flipping a coin -not only "heads" or "tails", but also the coin's hanging in the air.
As for repeated hospitalizations, this is a controversial criterion, since some patients with AHF may often seek unplanned medical care and receive it in an outpatient setting (for example, in the United States in the emergency department), and some patients are hospitalized for reasons not directly related to CHF (for example, exacerbation of the underlying disease or comorbid pathology, or disturbances of heart rhythm and conduction). Most often, unplanned hospitalizations in these patients are caused by acute heart failure (including socalled acute decompensated heart failure) [8] and circumstances related to refractory CHF [11].
It is important not to allow for confusion of concepts. AHF is a form of CHF, which even in rapidly developing decompensation is fundamentally different from acute heart failure [1]. D.V. Preobrazhenskiy et al. [12] rightly consider the concepts of "heart failure" and "chronic heart failure" as synonyms, since speaking of acute heart failure, it is customary to indicate its specific form, such as pulmonary edema, cardiogenic shock, or acute pulmonary heart (it does not matter whether this preceded CHF or not). Nevertheless, in the special medical literature, there is also an opposite point of view, according to which acute heart failure includes episodes of acute cardiac decompensation in patients with CHF in the absence of the clinical presentation of pulmonary edema and cardiogenic shock. We quote what we cannot understand: "Acute decompensated heart failure (first-time, decompensation of CHF) -poorly expressed symptoms of acute heart failure that do not meet the criteria for cardiogenic shock, pulmonary edema ..." [16]. Apparently, all clinicians have encountered primary and secondary refractory disease in patients with CHF (it is important to recall pseudo-refractoriness that can be associated with the patient's non-compliance) with the treat-ment. There are no generally accepted criteria for verifying this condition (similar to those for resistant hypertension [17]). This is probably why repeated attempts to introduce the refractory phase (stage) of CHF in its classification are met with reasonable resistance from the leading cardiologists of Russia. Yu. N. Belenkov at the "Classification of chronic heart failure" round table at the annual (14.12.2001) conference of the Society of Specialists in Heart Failure, objected to such a pro-posal as follows: "You cannot introduce a refractory phase. Refractory to what? We do not make a classification for ourselves, but a classification for everyone. Your refractory patient and my refractory patient are different patients because we have plasmapheresis, ultrafiltration, and artificial LV" [18].
Finally, the final (terminal) stage of CHF should be distinguished from AHF. According to ESC experts [11], the main difference between them is the presence of a certain degree of reversibility in the severity of CHF manifestations when applying cutting-edge treatment methods. The ambiguous phrase "a certain degree of reversibility" dictates the need to search for informative discriminant signs. Doctors in the absence of the latter should not rush to pronounce a sentence on a patient with CHF.
Such indistinct criteria were the subject of deserved criticism and the reason for revising the definition of AHF for it to take into account the evaluation of the effectiveness of new classes of drugs (such as sinus node If-channel inhibitors and angiotensin receptor and neprilysin inhibitors), characteristics of comorbid pathology, the condition of the end-organs, and other variables neglected by the ESC experts in 2007. The opinions of experts of reputed cardiological communities in the Old and New Worlds regarding the definition and criteria for diagnosis and treatment of AHF have changed over time, but, unfortunately, their evolution has not yet ended in full consensus, and none of the proposed interpretations are indisputable [9,19]. In this regard, it is worth quoting the titles of the works of well-known cardiologists, who vividly designated the problem: "Advanced heart failure and end-stage heart failure: does a difference exist?" [20], "A changing trend toward destination therapy: are we treating the same patients different-Бюллетень сибирской медицины. 2021; 20 (1): 129-146 ly?" [21], "Rise of the machines? Left ventricular assist devices for treatment of severe heart failure" [22], "Mechanical ventricular assistance as destination therapy for end-stage heart failure: has it become a first-line therapy?" [23].

DIAGNOSTIC CRITERIA
Obviously, in order to speak about AHF with confidence, it is necessary to justify the presence of heart failure itself in the patient first. The principles of CHF diagnosis are well developed and described in numerous recommendations [3,5,24]. Modern criteria for the diagnosis of AHF, as a rule, include signs first formulated in 1998 by K.F. Adams Jr. and F. Zannad [25]: LV EF value determined at rest is less than 30%, CHF corresponds to FC III-IV, or maximum oxygen consumption is less than 14 ml / kg / min. However, even among patients hospitalized with acute heart failure, at least half have normal LV FV values. The absence of LV global contractile dysfunction should not contradict the diagnostic conclusion about AHF in the presence of other symptoms and signs of this condition [9].
Detailed criteria for the diagnosis of AHF, formulated in current memorandums of the HFA ESC [9], the American Heart Association (AHA) and the American College of Cardiology (ACC) [26], as well as the Heart Failure Society of America (HFSA) [27], are presented in Table 1.
After reviewing the criteria presented in Table  1, many clinicians are likely to have questions. The greatest list of questions, perhaps, is caused by AHF criteria presented in AHA/ACC recommendation, since they do not specify whether all criteria are obligatory for verification of AHF, they contain inaccurate wording (e.g., "frequent", "usually") and do not include any characteristics of a state of cardiac contractile and lusitropic functions. It should be noted that the North American experts focused strictly on CHF and discussed AHF briefly in the context of CHF [26]. However, in the absence of information about the presence and severity of global (segmental) systolic and diastolic ventricular dysfunction, as well as their remodeling, detection of CHF is not always infallible, and the diagnosis itself is not irreproachable [14,[28][29][30][31][32].
In this regard, the recommendations of the HFA ESC 2018 look more reasonable [9]. They em-phasize a thorny path at differential diagnosis, since the symptoms and signs indicated in paragraphs 1 and 4 (Table 1) can be the result of not only cardiac dysfunction, but other conditions (for example, severe lung disease, non-cardiac cirrhosis of the liver, or, most often, renal failure of mixed etiology). However, these patients have a low quality of life and a bad prognosis and require the same attention as someone in whom heart failure is the only existing illness. All the following criteria must be present despite optimal guideline-directed treatment:

PROGNOSTIC STRATIFICATION
Accurate and timely prognosis is important for any disease, but in such a severe pathology as AHF, the results of predictive stratification are of particular importance. In order to justify referring the patient with chronic heart failure in a specialized center (e.g., heart failure clinic), it is enough to detect pronounced decompensation. However, to select patients requiring the use of advanced treatment methods, such as heart transplantation and artificial left ventricle, and to determine the optimal time for this therapy, it is necessary at first to have a substantiated assumption on unacceptably high risks of death in the absence of aid from an organ transplant surgeon or specialists in mechanical circulatory support [9].
A fairly extensive list of indicators of adverse prognosis in AHF is presented in Table 2 [9]. It is logically grouped by ESC experts according to the method of obtaining information (markers obtained in a clinical study and by performing simple instrumental tests; biomarkers evaluated in the laboratory; results of heart and vascular imaging; and exercise testing) and the presence of comorbid pathology.
As you can see, the prognosis in AHF patients is associated with a large number of factors with an obvious linear relationship (from weak to almost functional) between many of them. For example, the quality of life in a patient with CHF is related to gender, parameters of LV remodeling (geometric and electrophysiological) and its functional state, the level of asthenia and the severity of depression, as well as the presence of metabolic syndrome (obesity and indicators reflecting the severity of systemic inflammation and oxidative stress), iron deficiency, and coronary insufficiency [33][34][35][36][37][38][39]. Depression of heart rate variability in these patients is directly related to age, heart remodeling, the degree of systolic and diastolic LV dysfunction, the presence of diabetes mellitus and diabetic autonomic neuropathy, as well as the clinical severity of heart failure, and, conversely, the effectiveness of CHF treatment [40][41][42][43]. Hyperuricemia can be one of the manifestations of metabolic syndrome or chronic kidney disease [44][45][46]. The number of cardiac and extracardiac factors affecting the level of the so-called cardiac biomarkers is generally difficult to calculate [47][48][49][50][51][52][53].
Due to the multicollinearity between risk factors, the partial prognostic value of each of them is difficult to determine and, therefore, it is not easy to distinguish significant independent predictors from    randomly detected and not carrying any additional information ones. The way out of the problematic situation in clinical practice can be the use of multi-factor models of prognosis, which, for obvious reasons, have their advantages over monofactor models [9,54,55].
Out of more than 100 multi-factor predictive models proposed for patients with CHF, the most well-validated are SHFM (Seattle Heart Failure Model), HFSS (Heart Failure Survival Score), MECKI (Metabolic Exercise test data combined with Cardiac and Kidney Indexes), INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support), MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure), BIO-STAT-CHF (A Systems Biology Study to Tailored Treatment in Chronic Heart Failure), BCN Bio-HF (Barcelona Bio-Heart Failure), and UCLA score (University of California, Los Angeles) [9]. An unacceptably low survival rate during the year in most cases is indicated by an assessment of the prognosis at a level not exceeding 80% (for example, on the SHFM or MAGGIC model) [9].
ESC experts emphasize the prognostic value of the treatment-related factor [9]. Non-compliance by a doctor or patient with the provisions of modern recommendations for treatment of CHF (particularly refusal to use a β-blocker) is associated with a worsening prognosis. However, it should be understood that the term AHF is applicable only to describe the phenotype of treated CHF. If the patient for one reason or another did not receive optimal therapy, then regardless of the clinical severity of decompensation, it is too early to talk about this form of heart failure.

PATIENT ROUTING
All patients with CHF should undergo regular checkups for timely detection of progression of symptoms and signs. The described mnemonic "I need help" is useful for identifying patients with AHF who need a timely referral to a specialized center which uses advanced methods of heart failure treatment that are not available in an ordinary clinic. It stands for the following: I (Inotropes), N (NYHA class), E (End-organ dysfunction), E (Ejection fraction), D (Defibrillator shocks), H (Hospitalizations), E (Edema/escalating diuretics), L (Low blood pressure), P (Prognostic medication) [56].
Unfortunately, patients with AHF are often referred to advanced heart failure centers too late. The routing scheme developed within the framework of the active screening concept, the goal of which is timely referral of these patients to the ap-propriate specialized medical centers, is presented in general form in Figure 2 [9]. The concept of active screening justifies referral (if there are appropriate indications) to a local heart failure clinic of patients with CHF symptoms corresponding to NYHA FC II.
When planning the timing of specialized medical care for patients with AHF, you can use the classification of heart failure severity phenotypes provided in the INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory Support) [9,57] (Table 3).
In general, only the 2 nd , 3 rd , and 4 th phenotypes are unconditionally related to AHF, since the 1 st type corresponds to acute heart failure and the 5 th -7 th types -to non-severe CHF.

SHORT-TERM TREATMENT STRATEGY
Since a reasonable conclusion about AHF leaves little hope for the success of pharmacotherapy aimed at hemodynamic, neurohumoral, volumetric, myocardial, and immune unloading of the heart, according to the figurative expression of V. Pernias et al. [58], the solution to the problem lies outside the heart (heart transplantation or implantation of a circulatory assist device). However, in a situation where the patient's clinical condition is rapidly deteriorating or there is a reason for assuming reversible dysfunction of end-organs, active pharmacotherapy or temporary mechanical circulatory support may be required. Such a short-term strategy can be lifesaving for a patient who is on the waiting list for a transplant or implantation of a circulatory assist device [9].
The use of non-glycosidic inotropes and vasoconstrictors should be limited to cases of acute decompensated heart failure, low cardiac output syndrome, and cardiogenic shock [9,[59][60][61][62]. Allowed medicines include vasoconstrictors (for example, norepinephrine and vasopressin), inotropes with vasoconstrictor properties (for example, dopamine and adrenaline), as well as inodilators, among which, according to some experts, the most promising is levosimendan (its use is permissible in the absence of a pronounced decrease in systolic blood pressure − >85 mmHg) [9,60].
The cornerstone of congestion correction in these patients is loop diuretics. For the purpose of the so-called decongestion (not to be confused with Бюллетень сибирской медицины. 2021; 20 (1): 129-146 anticongestant therapy in the otorhinolaryngologic practice) in case of refractory edema syndrome, including the one associated with the "braking phenomenon", they should be used (after or against the background of systemic arterial hypotension correction) intravenously at a high dose, in combination with one another, with neurohumoral modulators, and drugs improving renal filtration (for example, aminophylline or a "renal" dose of dopamine) and increasing oncotic blood pressure (albumin, blood plasma) [5,9,63,64].
In patients with normal or elevated systemic blood pressure, a combination of diuretics with vasodilators may be effective, the most promising of which are serelaxin (a recombinant analog of human relaxin-2), low doses of nesiritide (a recombinant form of human brain natriuretic peptide), and the vasopressin antagonist tolvaptan (especially in case of hyponatremia of dilution) [63,65,66]. Finally, the use of drugs from the group of the sodium-dependent glucose co-transporter type 2 inhibitors (such as dapagliflozin or empagliflozin) in combination therapy can help to shift the process from the "dead point" and achieve the coveted euvolemia in refractory edema syndrome [63,67,68].
If other methods of dehydration are ineffective, it is possible to use extracorporeal ultrafiltration (gentle regimes using a minimum volume of extracorporeal blood and an ultrafiltration rate of no more than 250 ml / hour are preferable) and peritoneal dialysis [5,9,69,70].
Temporary (usually from several days to several weeks) mechanical circulatory support (mono-and biventricular) can be indicated in the development of cardiogenic shock, as well as in a situation where it is necessary to gain time deciding on a heart transplant or implantation of an artificial ventricle (ventricles). For this, percutaneous transluminal methods are currently available, including intra-aortic balloon counterpulsation and Impella® ventricular support systems, as well as paracorporal devices (for example, the so-called tandem heart), including combining mechanical circulatory support with blood oxygenation (venoarterial extracorporeal membrane oxygenation) [9, 71−76].
The following terms are used to describe various technologies for temporary mechanical circulatory support in discrete clinical situations [24]: 1. "Bridge to decision" / "Bridge to bridge" − is used in patients with cardiogenic shock existing until haemodynamics and end-organ perfusion are stabilized to exclude contraindications for long-term mechanical circulatory support (for example, brain damage after resuscitation) and consider additional therapeutic options, including long-term ventricular assist device therapy or heart transplantation.
2. "Bridge to candidacy" − the use of temporary mechanical circulatory support can lead to improved function of the end-organs and give the right to heart transplantation to those patients for whom it was previously contraindicated; 3. "Bridge to transplantation" − mono-and biventricular mechanical circulatory support to keep alive patients at high risk of death waiting for a heart transplant (application may take several months or even years since only 10% of these patients will receive a donor heart within a year); 4. "Bridge to recovery" − mechanical circulatory support to keep patients alive until their cardiac function is restored to a level sufficient to remove the circulatory assist device (usually we are talking about a partially reversible cause of CHF, such as acute myocarditis or peripartum cardiomyopathy).

LONG-TERM TREATMENT STRATEGY
Conventional surgical treatment is aimed at correcting etiological factors, as well as the leading mechanisms underlying CHF. We are talking, for example, about revascularization of ischemic but viable myocardium in patients with LV EF < 35%, prosthetics of the aortic valve in severe symptomatic aortic valve stenosis with an average pressure gradient > 40 mm Hg. or in severe aortic regurgitation in all patients with symptoms and asymptomatic patients with LV EF ≤ 50%, as about surgery to correct mitral regurgitation (endovascular placement of the mitral valve clip theoretically looks more justified in a situation of high perioperative risk), including secondary (due to LV dilation) severe mitral insufficiency (especially in patients with LV EF < 30%), which cannot be corrected with the help of pharmacotherapy and electrophysiological methods of treatment [9].
Long-term mechanical circulatory support in the framework of "definitive treatment" technology can be considered as an alternative to heart transplantation in patients with end-stage CHF, in which  for objective or subjective reasons, transplantation is not feasible (see below). Naturally, such devices must be implanted and administered only in centers with professionally educated doctors to reduce the risk of complications (secondary infection, pump thrombosis, bleeding, thromboembolism, and dysfunction of the device itself), which, despite continuous improvement in technology, remains a serious problem [9,24,77].
The results (patient survival and quality of life) of implantation of circulatory assist devices largely depend on the correct selection of patients for this intervention and the type of device chosen. High survival rates are usually observed among people under 70 years of age, without diabetes, renal failure or cardiogenic shock. In carefully selected groups of patients, implantation of second-or third-generation continuous axial or centrifugal flow devices (that are more effective than devices that use pulsatile pumps) generally provides better results than optimal drug therapy in patients dependent on inotropes.
T a b l e 3

Phenotype
Time frame for intervention

INTERMACS 1: Critical cardiogenic shock
Patients with life-threatening hypotension despite rapidly escalating inotropic support, critical organ hypoperfusion, often confirmed by worsening acidosis and/or lactate levels.

«Crash and burn»
Definitive intervention needed within hours: ECLS, ECMO, percutaneous support devices

INTERMACS 2: Progressive decline
Patients with a declining function despite intravenous inotropic support, (may be manifested through worsening renal function, nutritional depletion, and inability to restore volume balance). Also describes declining status in patients unable to tolerate inotropic therapy. «Sliding on inotropes» Definitive intervention needed within few days: ECLS, ECMO, LVAD

INTERMACS 3: Stable but inotrope-dependent
Patients with stable blood pressure, organ function, nutrition, and symptoms with continuous intravenous inotropic support (or a temporary circulatory support device or both), but demonstrating repeated failure to wean from support due to recurrent symptomatic hypotension or renal dysfunction. «Dependent stability» Definitive intervention elective over a period of weeks to few months: LVAD

INTERMACS 4: Resting symptoms
Patients can be stabilized close to normal volume status but experience daily symptoms of congestion at rest or during ADL. Doses of diuretics generally fluctuate at very high levels.
More intensive management and surveillance strategies should be considered, which may in some cases reveal poor compliance that would compromise outcomes with any therapy. Some patients may shuttle between 4 and 5. «Frequent flyer» Definitive intervention elective over a period of weeks to few months: LVAD

INTERMACS 5: Exertion intolerant
Patients feel comfortable at rest and with ADL, but are unable to engage in any other activity, living predominantly within the house. Patients are comfortable at rest without congestive symptoms, but may have underlying refractory elevated volume status, often with renal dysfunction. If underlying nutritional status and organ function are marginal, patients may be more at risk than INTERMACS 4 and require definitive intervention. «Housebound» Variable urgency, depends upon maintenance of nutrition, organ function, and activity: LVAD

INTERMACS 6: Exertion limited
Patients without evidence of fluid overload feel comfortable at rest, with ADL and minor activities outside the home but fatigue after the first few minutes of any meaningful activity. Attribution to cardiac limitation requires careful measurement of peak oxygen consumption, in some cases with haemodynamic monitoring to confirm the severity of cardiac impairment. «Walking wounded» Variable, depends upon maintenance of nutrition, organ function, and activity level: LVAD / Discuss LVAD as option The survival rate after this operation is comparable to the early survival rate after heart transplantation (2-year survival at the level of 76−85%) [9,24,77,78].
The main pros and cons of long-term mechanical circulatory support, formulated by EACTS (European Association for Cardio-Thoracic Surgery) experts [79], are presented in Table 4.
Severe right ventricular dysfunction (for example, in the presence of significant tricuspid regurgitation) is usually considered as one of the main contraindications to implantation of a LV assist de-vice, but it is not an obstacle to heart transplantation [24]. If it is predicted that severe right ventricular dysfunction will be potentially reversible, then temporary (from days to several weeks) extracorporeal devices for mechanical support of the right ventricle can be used in addition to an implanted LV assist device [24]. In patients with irreversible right ventricular dysfunction secondary to left ventricular heart failure, the use of long-term biventricular mechanical circulatory support (using two implantable / extracorporeal pumps or a so-called total artificial heart) should be considered [79−81].
Despite the lack of well-organized controlled studies, the cardiological community is dominated by the view that heart transplantation at the final stage of CHF improves survival (1-year survival rate of about 90% and a median survival rate of 12.2 years), physical performance, and the quality of life to a much greater extent compared to conventional treatment, provided that the appropriate selection criteria are carefully met (the gold standard of treatment for refractory CHF) [9,82].
Indications for heart transplantation largely coincide with those for long-term mechanical circulatory support, and the list of contraindications is longer and includes additional points, such as high pulmonary vascular resistance or transpulmonary pressure gradient and recently treated cancer [9] (Table 5).
T a b l e 5

Indications and contraindications to heart transplantation [9]
Patients to consider 1. End-stage HF with severe symptoms, a poor prognosis, and no remaining alternative treatment options 2. Motivated, well-informed, and emotionally stable 3. Capable of complying with the intensive treatment required postoperatively Contraindications 1. Active infection 2. Severe peripheral arterial or cerebrovascular disease 3. Pharmacologic irreversible pulmonary hypertension (LVAD should be considered with a subsequent re-evaluation to establish candidacy) 4. Cancer (a collaboration with oncology specialists should occur to stratify each patient as to their risk of tumour recurrence) 5. Irreversible renal dysfunction (e.g. creatinine clearance <30 mL/min) 6. Systemic disease with multiorgan involvement 7. Another serious comorbidity with a poor prognosis 8. Pre-transplant BMI >35 kg/m 2 (weight loss is recommended to achieve a BMI <35 kg/m 2 ) 9. Current alcohol or drug abuse 10. Any patient for whom social supports are deemed insufficient to achieve compliant care in the outpatient setting N o t e . LVAD − left ventricular assist device; BMI − body mass index; HF − heart failure.
If we recall shortage of donor hearts, the problem of graft rejection, and lack of effective treatment for coronary artery disease of the transplanted heart, it becomes clear why the number of patients receiving permanent mechanical circulatory support is constantly increasing (for example, in Germany alone in 2016, 1,000 implantations of LV mechanical support devices were performed). At the same time, the number of heart transplants in the world has braked at the level of 1994 (about 5,000 per year) [5,9,83].

CONCLUSION
AHF is a form of CHF, progression of which has reached a stage where traditional evidence-based therapy becomes ineffective. Patients at this stage persist with symptoms and signs of severe heart failure, often accompanied by episodes of acute decompensation that are associated with an adverse prognosis. It is important to raise awareness of this form of heart failure, since its prevalence in the multilion population of patients with CHF can reach 10%, and it requires timely application of advanced treatment methods, such as heart trans-plantation and mechanical circulatory support and/or transition to palliative care.