COVID-19 and cardiovascular diseases: from epidemiology to rehabilitation и сердечно-сосудистые заболевания: от эпидемиологии реабилитации

The article is devoted to a review of data on the prevalence and impact of cardiovascular diseases on the course and outcomes of the new coronavirus infection COVID-19. The review examines the relationship between COVID-19 and the functioning of the renin-angiotensin-aldosterone system, the pathophysiological mechanisms of their mutual influence. The analysis of the latest literature data on the safety of taking angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers is presented. The causes and pathophysiological mechanisms of the development of acute myocardial damage in COVID-19 are discussed. The issue of organizing rehabilitation assistance for patients who have undergone COVID-19 is being considered. The main components and features of the COVID-19 rehabilitation program are presented. words: Conflict of interests. The authors declare the absence of conflict of interests.

A retrospective analysis of clinical and demographic parameters of 1,007 COVID-19 patients hospitalised to in-patient clinics (resuscitation and intensive care unit, ICU) in the Russian Federation with acute respiratory distress syndrome (ARDS) demonstrated that 61.4% of patients had CVD [7]. Most common were AH (56.3% of patients) and IHD (16.3%), followed by a history of stroke (7.1%) and atrial fibrillation (9.3%). Obesity and type 2 diabetes were recorded in 26.1% and 25% of patients, respectively. The incidence of CVD was age-dependant, reaching 80% in the group of patients > 60 years old.
A viral infection can de-stabilise the heart condition, significantly increasing the risk of comorbid CVD. In the trial [12] the risk of death with CVD was 2.4-fold higher (р = 0.019). An analysis of 44,672 cases with confirmed COVID-19 from the Chinese Centre for Disease Control and Prevention showed high mortality in patients with CVD (10.5%), AH (6.0%), and DM (7.3%), whereas the overall mortality was 2.3% [13].
Thus, very often concomitant CVDs are associated with severe COVID-19 with patient hospitalisation to ICU and worse prognosis. Therefore, all patients, even with moderate and even mild COVID-19 should be subject to a cardiac examination and follow-up.

COVID-19, arterial hypertension and renin-angiotensin-aldosterone system
According to various studies, AH is recorded in 15 -40% of COVID-19 patients [15,16]. AH is prevailing in patients with severe COVID-19; e.g. in the study by W.J. Guan et al. 23.7% of patients had AH (vs 13.4% with mild disease) [17]. It is reported that COVID-19 mortality in patients with AH is 2.6 times higher [10]. Possible mechanisms of AH correlation with poorer COVID-19 outcome can relate to the role of type 2 angiotensin converting enzyme (ACE2) [18].
ACE2 is an essential component of the renin-angiotensin-aldosterone system (RAAS) participating in pathogenesis of AH and other CVDs. It is known that ACE2 is a type I transmembrane protein expressed in lungs (high ACE2 expression is seen on the surface of type II alveolar cells), heart, kidneys, vascular endothelium, liver, testicles, and intestine [19]. ACE2 can be present in a free form as well (in blood).
The physiological role of ACE2 is primarily related to angiotensin I (ATI) cleavage to inactive AT 1 -9 peptide, which then turns into AT 1 -7 with the help of ACE or other peptidases, and to ATII degradation to AT 1 -7 binding to Mas receptors ( Figure 1). AT 1 -7 ensures vaso-and cardioprotection, antiproliferative, antiinflammatory and natriuretic effect. When cleaving ATII, ACE2 mitigates negative effect of the latter (vasoconstriction, cytokine-like activity, sodium retention and development of fibrosis).
SARS-CoV-2 virus binds to ACE2 receptors on target cell surfaces with the help of glycoprotein (peplomer), known as a spike protein (S-protein) [20]. S-protein of SARS-CoV-2 virus mimics ACE2. Then the virus and ACE2 transmembrane domain penetrate cells (endocytosis). SARS-CoV-2 virus causes imbalance in the ACE2 system associated with reduction in AT 1 -7 levels together with increase in АТII and ACE-ATII-AT 1 -receptor path activation. As a result, acute damages to lungs, myocardium, vessels and other organs initially caused by SARS-CoV-2 can worsen.
Another possible mechanism of AH association with severe COVID-19 is related to synergistic immune response [16]. Poor blood pressure (BP) control promotes overactivation of the immune system causing chronic inflammation in the vessel walls and tissues of kidneys. In a study with "mendelian randomization", patients with AH had a correlation between AH and circulating lymphocytes and monocytes [21]. Experimental, prospective and intervention studies demonstrated interaction of some cytokines with AH regulating systems (RAAS, sympathic nervous system) and AH develop-  ment. For instance, interleukin-6, a predictor of poor COVID-19 outcome, is one of the key cytokines in initiation of inflammatory immune response in AH [18]. In another study on animal models, the relation between AH and circulating CD8 + T-cells was identified [22]. In SARS-CoV-2 infection, a high rate of circulating cytotoxic CD8 + T-cells facilitates hyperproduction of proinflammatory cytokines [18]. It can be believed that, while ensuring better AH control, RAAS inhibitors can mitigate immune system imbalance in AH [16]. During a virus infection, patients with AH should have their AH and cardiovascular risk monitored.

COVID-19 and RAAS inhibitors
The main activity of ACE inhibitors (ACEi) is related to reduction in ATII formation, while ATII receptor inhibitors (ARI) inhibit the interaction between АТII and type 1 angiotensin receptors (АТ 1 receptors). ACE2 is not the target for RAAS inhibitors, despite the fact that an experiment on animals demonstrated that administration of RAAS inhibitors can increase ACE2 expression on cell surface [23,24]. Therefore, there appeared a hypothesis: administration of RAAS inhibitors will promote SARS-CoV-2 internalization to lungs, heart, etc., thus increasing the risk of COVID-19 infection and severity [25]. It provoked a hot discussion.
Unlike experimental studies, COVID-19 patients did not demonstrate sound evidence of increase in ACE2 expression on target cell surface, therefore no increase in the viral load with ACEi/ARI administration [26]. It is obvious that increase in ACE2 activity with RAAS inhibitor therapy does not necessarily cause an increase in patient's susceptibility to infection [18,27]. To penetrate the host cell, SARS-CoV-2 uses other receptors as well, e.g. transmembrane glycoprotein CD147, transmembrane protease serine 2 (TMPRSS2), acting as a co-factor of S-protein activation for efficient cell invasion by the virus [28]. After virus internalization in the cell and virus RNA release in the cell cytoplasm, ACE2 expression on the cell surface reduces (including alveolar cells). Loss of functional ACE2 (and reduced АТ 1 -7) associated with excessive АТII accumulation promotes lung damage [29]. Studies demonstrated a direct correlation between АТII blood level, viral load and lung damage severity [30]. The protective action of ACE2 in acute lung and myocardium damages has been proven on animal models [31].
It can be assumed that increase in ACE2 expression together with inhibition of proinflammatory ACE2 activ-The article is licensed by CC BY-NC-ND 4.0 International Licensee https://creativecommons.org/licenses/by-nc-nd/4.0/ ity and "ACE2/АТ1 -7-Mas-receptor" signalling associated with administration of RAAS inhibitors will have a protective effect in SARS-CoV-2 infection [32].
In their study of 1,178 patients hospitalised with COVID-19 in China, J.Li et al. demonstrated the lack of correlation between ACEi/ ARI administration and severe infection and mortality [33]. G.Mancia et al., who conducted a case-control analysis on an Italian cohort of COVID-19 patients (n = 6,272, mean age: 68 ± 13 years), did not find any negative impact of ACEi/ARI on the risk of complications, including severe cases [34].
Currently, global communities are unanimous: withdrawal from ACE inhibitors or ARI in COVID-19 patients can increase the risk of cardiovascular complications, especially in patients with AH, chronic cardiac failure (CF) and/or a history of myocardial infraction (MI) [37,38]. Further studies will allow clarifying some mechanisms of RAAS activation and inhibition in COVID-19.
Cardiac manifestations can be a primary phenomenon in COVID-19 (according to some researchers, this is a "cardiac phenotype" of the disease); however, they can be secondary to pulmonary damages (mixed pulmonary and cardiac phenotype) [41]. Of note, symptoms of CVD can be diagnosed at any stage of patient hospitalisation, but usually the risk increases from day 15 after fever initiation (or manifestation of other symptoms of a viral infection). Cardiovascular complications often appear after stabilisation and/or improvements in patient's respiratory status [41].
There are no clear explanations of the variability of cardiological manifestations of COVID-19 and it is unknown why some patients have their cardiovascular system affected. Possible mechanisms of SARS-CoV-2induced myocardium damages are associated with increased ACE2 expression in heart and vascular endothelium ( Figure 2) [20]. Various pathophysiologic mechanisms of cardiovascular complications in COVID-19 [8,39] have been discussed: • direct noci-influence of SARS-CoV-2 virus on pericapillary cells (high ACE2 expression on their surface), cardiomyocytes and fibroblasts [42]; • indirect influence of SARS-CoV-2 virus on myocardium during a "cytokine storm" (release of excessive inflammatory mediators and cytokins/chemokines) [42,43]; • direct noci-influence of SARS-CoV-2 virus on vascular endothelium causing its dysfunction [44,45]; • hypercoagulation resulting from endothelial dysfunction, increased activity of platelets and von Willebrand factor, increased expression of type 1 antioxidant tissue-type plasminogen activator inhibitor, and reduced tissue-type plasminogen activator production which causes thrombolysis, blood flow disturbances and micro-and macrothrombosis [44]; • marked hypoxaemia resulting in anaerobic processes activation, intracellular acidosis and oxidative stress (direct influence of virus on hematoglobulin causing reduction in blood oxygen capacity) [44]; • imbalance between myocardium oxygen demand and oxygen supply caused by virus-induced inflammation, hypoxia, oxidative stress, endothelial involvement and hypercoagulation, resulting in acute myocardium damage, atheroma instability and rupture associated with coronary artery thrombosis [16]; • sympathic nervous system activation and stress-induced release of catecholamines into the blood flow, causing vasospasm, myocardium hypoperfusion/ischemia and life-threatening arrythmias [46]; • electrolyte imbalance (in severe COVID-19) promoting tachyarrythmia; hypokalaemia is a result of SARS-CoV-2 impact for RAAS [44]. However the exact mechanism of acute myocardium damage in COVID-19 needs further elaboration. Therefore, COVID-19 can provoke acute myocardium damage with poor prognosis for the patient. Prompt myocardium damage identification upon patient admission into hospital and inpatient management is of great importance. Autopsy results demonstrated that cardiotropic viruses, like SARS-CoV-1, can remain in myocardium tissue for several weeks and even months [47]. The information on previous infection caused by SARS-CoV-1 virus makes it possible to assume that COVID-19 survivors may have more cardiovascular complications in future.
COVID-19 and myocardial/cardial damages. Acute myocardial damage in COVID-19 can be associated with a non-ischemic cause (myocarditis, cytokine-or stress-induced cardiomyopathy, etc.) or with myocardial ischemia resulting from coronary artery atherothrombosis [40]. Manifestations of acute myocardial damage are increase in specific cardiobiomarkers, typical abnormal ECG changes or instrumental test results. Т-and I-troponins are known risk factors of poor outcomes in acute cardiovascular pathology. Highly-specific cardiac troponin I levels of over 99 th percentile of the upper reference limit are an evidence of acute myocardium damage in COVID-19 [8,40].
In a study of 187 COVID-19 patients by T.Guo et al., 35% had concomitant CVD (AH, IHD or cardiomyopa-thy), 28% were diagnosed with acute miocardial damage (troponin Т > 99 th percentile of the upper limit) after contact with the virus [51]. Hospital mortality with normal troponin T in patients without CVD was 7,62%, while where patients had concomitant CVD, hospital mortality was 13.33%; with increased troponin Т, the value was 37.50% and 69.44%, respectively (the highest value in this group).
In a series of studies of COVID-19 patients, acute myocardial damage was associated with high levels of  D-dimer, N-thermal pro-B-type natriuretic peptide (NTpro-BNP), С-reactive protein and interleukin-6 [42,48,51,52]. It proves the association between acute myocardial injury in COVID-19 and marked inflammation and cardiac dysfunction.
COVID-19 and cardiac failure. Viral infection can provoke decompensation of chronic CF, if the patient has comorbidies, and a shock. The incidence of CF in patients who died of COVID-19 was 52%, while in survivors this value was 12% (p < 0.0001) [10]. The incidence of new CF cases in COVID-19 patients was aprox. 23% [10].
Acute CF associated with viral infection seems to be a consequence of a prior systolic dysfunction, ARDS and cardiovascular pathology de novo (acute myocardial ischemia, MI, tachyarrythmia, myocarditis or cardiomyopathy). First COVID-19 cases in the USA described cardiomyopathy in 33% cases [49]. E. Argulian et al. found that right ventricle dilatation seen at echocardiography is associated with a high risk of hospital mortality in COVID-19 patients [53]. COVID-19-associated pulmonary hypertension caused by lung damage and hypoxia or PATE leads to increased right ventricle load and cardiomyocyte damage.
Daily diuresis monitoring, reasonable water schedule, continued scheduled base therapy, including ACEi and ARI, are all very important for COVID-19 patients with chronic CF decompensation [8].
In pathogenic terms, ACS in SARS-CoV-2 is associated with marked microvascular inflammation, endothelial dysfunction, thrombothic disorders, and haemodynamic changes [39]. It is known that circulating interleukin-6, a biomarker of high COVID-19 mortality, is one of the key inflammatory factors of atherothrombosis [16]. ACS can be promoted by inadequate control of associated cardiovascular risk factors. To verify the diagnosis of ACS in COVID-19 patients, a thorough examination is required [8].
In patients with chronic IHD, SARS-CoV-2 aggravates the disease because of atheroma destabilisation and high risk of atheroma rupture [8,39,51]. COVID-19 patients who underwent invasive cardiovascular procedures or surgery are at higher risk of stent or bypass thrombosis.
In pandemic settings, an exact routing and transportation of patients with suspected ACS should be strictly followed. In general, a widely accepted strategy for management of such patients should be adhered to [8]. In severe COVID-19 and lung damage, when the patient is hospitalised to with respiratory support, conservative strategy is preferable, including in MI1 cases (if an invasive procedure is contraindicated).
Prognosis depends on the type of heart rhythm disorder and COVID-19 severity (more favourable prognosis with mild or moderate infection) [8]. There have been reports of arrythmia in COVID-19 patients resulting from proarrhythmic effect of medications (prolonged QT interval and a higher risk of torsade de pointes) [8].
Therefore, standard 12-lead ECG, transthoracic echocardiography, and blood potassium level measurement are mandatory.
ECG monitoring should be started next day after antiviral therapy initiation. In initially congenital or acquired long QT-syndrome, brachycardia (< 50 bpm), ECG monitoring is required 4 hours after first antiviral medication administration. Prior to antiviral medication prescription, plasma potassium should not be < 3.5 mmol/L. In patients with atrial fibrillation, heart rhythm and ventricular contraction rate should be monitored and thromboembolic disorders should be prevented with anticoagulants, taking into account possible interaction of oral anticoagulants with antiviral therapy.

Cardiopulmonary rehabilitation in COVID-19 patients
COVID-19 survivors with cardiovascular complications, especially in moderate and severe cases, need medical rehabilitation. Currently rehabilitation programs are being prepared for such patients. Then these programs will be tested in randomised clinical trials. As COVID-19 is a multi-system disease, rehabilitation programs should be based on syndromic-pathogenetic approach. It will ensure that an adequate number of rehabilitation methods/ techniques will be used to correct pathological changes in a specific patient.
Rehabilitation of COVID-19 survivors aims at recovery of functions of external respiration, oxygen transport and utilization by functioning tissues/organs; reduction in dyspnea; cardiovascular system support and minimisation of the risk of cardiovascular complications; improved quality of life; psychological status normalisation; daily activities recovery, and active life.
Key principles of medical rehabilitation of COVID-19 patients: staggered and personalised approach, early initiation (when acute COVID-19 is over and after patient's clinical condition has stabilised), multidisciplinarity, continuous monitoring of patient's condition during rehabilitation (first of all, respiratory and cardiovascular parameters), comprehensive approach to the rehabilitation program.
Any rehabilitation intervention should take into account disease severity, rate of cardiorespiratory decompensation and other organs involvement (kidneys, neurocognitive, psychiatric, musculoskeletal systems), fatigue, asthenia, risk of thromboembolic disorders, and comorbidities. For patients who had severe COVID-19, rehabilitation should consider nutrition status, total body weight and muscle mass. Most promising for pulmonary rehabilitation are first two months after acute coronavirus infection; this is a therapeutic window [57]. During physical rehabilitation COVID-19 patients should have access to oxygen therapy (as required), especially patients with clinical indications or those patients who did not have any respiratory support.
In the novel coronavirus infection, rehabilitation starts in and continues in a specialised inpatient unitthis is stage 1 of early rehabilitation. This is an important stage because it allows preventing or minimising com-plications of a viral disease and detrimental effect from immobilisation; ensuring prevention of critical conditions, joint stiffness and contractions, thrombotic complications; and, if possible, recovery of physical and psychological state of the patient. For patients with severe COVID-19 early rehabilitation is not recommended; it can be considered only after the acute stage, vital functions stabilisation, with positive dynamics evidenced by computer-aided tomography or ultrasound examination [58].
Attention should be paid to exercises of weakest and most important muscles involved in verticalization and locomotion of the patient. Methods of physical rehabilitation comprise: patient positioning ("positioning" rehabilitation, also with the help of the prone position), early mobilisation (passive, partially passive and active motions in all joints with more and more physical activity), verticalization, respiratory manoeuvres, neuromuscular electrical stimulation of lower limbs (for certain groups of patients), dynamic physical activities with low-intensity, low amplitude and slow pace (a bedside stationary bike can be used), moderate resistance exercises (to reduce muscle mass losses and to strengthen the muscles), physical exercises for imbalance correction (if any) [59].
In one therapeutic exercise session (either passive, or passive-active mode) should last for 5 to 15 minutes 3 and more times daily (with the overall duration of at least 30 minutes a day). Once the patient is moved to inpatient setting, therapeutic exercises should last for 10 -15 minutes 2 -3 times daily.
Stage 2 of rehabilitation (early inpatient rehabilitation in a specialised inpatient rehabilitation unit) should be arranged in accordance with the antiepidemic provisions. It includes in-ward patient isolation, no group therapy, minimum staff involved into rehabilitation, remote communication between the patient and multidisciplinary team members, use of video, booklets and other telerehabilitation techniques for patient education [60]. At stage II, rehabilitation procedures should last for at least 3 hours 5 times a week.
Physical rehabilitation at stage II means early activation of patient's physical activity, use of various methods of pulmonary and cardiological rehabilitation: diaphragm breathing, exercises for inhale muscles (inspiratory training devices can be used), vibration and compression therapy and acoustic exercises together with drain-activating exercises (where indicated), exercises for general strength, dynamic physical exercises with low intensity (including aerobic exercises on a statutory bike), low-intensity resistance loads (to train main groups of muscles).
Physical exercises in COVID-19 patients with CVD has some features: • they start with low-intensity loads (exercise stress intensity ≤ 3 points on modified Borg Dyspnoea Scale or laboured breathing ≤ 3 on Borg Dyspnoea Scale); • intensity increases gradually, initially at the account of exposition (duration), then at the account of more intensive exercises (with adequate response to exercises); • strict state monitoring during exercises.
• power loads in COVID-19 should be based on MRC, UK Medical Research Council. Special attention should be paid when prescribing physical exercises to patients, whose coronavirus infection was complicated with acute myocarditis, cardiomyopathy, postinfectious cardiac failure [61]. In such cases, rehabilitation should be started after acute period (taking into account contraindications), when the clinical condition is stable and CT, ECG and ultrasonic cardiography results demonstrate positive dynamics.
Stage 3 of rehabilitation is late outpatient rehabilitation (in outpatient settings). Physical rehabilitation of COVID-19 survivors with CVD involves continuation of exercise therapy in order to recover respiratory and cardiovascular system, and transition to more lengthy exercises (statutory bike and/or step exercises). Physical exercises are supervised by medical professionals (also via telerehabilitation). Then patients are recommended to do exercises at home. At home, patients can walk on a flat surface, step up, etc. At this stage it is very important to teach the patient to self-control the condition and ensure safe exercises.
A significant aspect of rehabilitation of COVID-19 patients at all three stages is awareness of the healthy life style (no bad habits, anti-atherosclerotic diet and stress tolerance), explanation why it is important to follow doctor's recommendations, take medications and participate in rehabilitation. Psychological support should be offered almost to all patients with coronavirus infection [62]. Anxiodepressive disorders are managed as required.
Three-stage cardiorehabilitation of COVID-19 patients complicated with ACS (myocardial infraction) or coronary artery bypass grafting should be based on the recommendations of the Russian Society of Cardiosomatic Rehabilitation and Secondary Prevention [63,64].

Conclusion
The impact from SARS-CoV-2 and other pathogens with toxic, proinflammatory and procoagulation effects can cause decompensation of concomitant CVD and increase hospital mortality rates. The new role of ACE2 as a receptor for SARS-CoV-2 can partially explain the pathophysiological association between the viral infection, immune system and CVD. The novel coronavirus infection can provoke acute myocardial damage and other cardiological complications. As some medications used to treat COVID-19 have cardiotoxic effect, continuous haemodynamic monitoring, ECG and ultrasonic cardiography (as indicated) are mandatory.
As the association between administration of RAAS inhibitors (ACEi and ARI) and a higher risk of infection with more severe COVID-19 has not been yet proven, patients with CVD should keep on taking these medications. COVID-19 survivors should take part in rehabilitation programs for faster and better recovery of their functions (first of all, of respiratory and cardiovascular systems), better quality of life and lower risk of disability.