Palpitations and chest pain remain one of the most frequent complaints seen in Long COVID patients. As previously mentioned, acute cardiac damage was frequently described during COVID-19 pneumonia, being associated with a poor prognosis ^[1][2][85,86]; however, its relation to residual symptoms is still argued. Several reports have emphasized a high incidence of orthostatic intolerance (OI), including orthostatic hypotension (OH), defined as a reduction in blood pressure of at least 20 mm Hg of systolic blood pressure or 10 mm Hg of diastolic blood pressure within 3 min of standing, and postural orthostatic tachycardia syndrome (POTS), an increase in heart rate of more than 30 bpm within 10 min of standing or during a tilt test in Long COVID patients, probably due to hypovolemia or deconditioning after prolonged bed rest ^[3][4][87,88]. Abnormal autonomic nervous system response to orthostatism, in addition to exaggerated levels of epinephrine and norepinephrine, contributes to the pathophysiological spectrum of mechanisms in OI that may be further accentuated by multiple factors such as excessive venous pooling in the lower extremities, volume dysregulations, autoimmunity and hyperadrenergic status ^[5][89]. Earlier reports emphasized a downregulation of renin activity and abnormal levels of angiotensin II in POTS patients ^[6][7][8][9][90,91,92,93]. This is further intensified in COVID-19 infection, as previous studies reported ^[10][11][94,95]. The renin angiotensin aldosterone system (RAAS) imbalance triggered by SARS-CoV-2 infection may have a fundamental role in Long-COVID-related POTS ^{[7][11][12][13]}[91,95,96,97]. Moreover, SARS-CoV-2 may damage the extracardiac postganglionic sympathetic nervous system, promoting dysautonomia and leading to POTS ^[7][8][14][91,92,98]. Other mechanisms such as autoimmunity or chronic inflammation have also been attributed to COVID-19 long-term sequelae including OI onset ^[15][99]. The true prevalence of OI in Long COVID patients is difficult to determine, considering it still remains an underdiagnosed syndrome. Yet, several reports described symptoms consistent with OI in up to 41% of recovered COVID-19 patients ^[16][17][100,101]. Potential limitations of these reports are represented by the retrospective design, with missing data prior to COVID-19 infection and a limited number of patients ^[18][102]. However, most of these reports are based on symptoms evaluation after COVID-19, implying newly diagnosed conditions. One report described a prevalence of 38% of OI in Long COVID patients ^[19][103]. These data are being supported by previous research on Long COVID and OI, suggesting autonomic dysfunction, which is known as a common finding during patients’ recovery after bacterial or viral infections ^[3][20][87,104]. Although several standard factors such as deconditioning, presence of venous insufficiency or hypovolemia may aggravate the symptomatology, the presence of OI was also observed in COVID-19 patients that did not require prolonged hospitalization and were apparently healthy before COVID-19 pneumonia ^[21][22][105,106].

As there is no specific treatment for POTS, current lifestyle measurements include: adequate hydration, specific exercise training and various pharmacotherapies, depending on POTS subtypes such as ivabradine or β-blockers, in combination with compression stockings when tachycardia is the dominant symptom to midodrine for persistent OH due to venous polling or fludrocortisone if hypovolemia and orthostatic intolerance are associated ^[3][23][87,107].

During the acute phase of COVID-19 pneumonia, acute cardiac injury was commonly described, especially in critically ill patients. Several clinical scenarios have been outlined from acute onset of arrhythmia, especially atrial fibrillation, to myocardial infarction or myopericarditis ^[24][25][18,47]. The majority of these reports defined acute cardiac injury based on the values of a biomarkers assessment, predominantly upon admission and cardiovascular imaging assessment, especially echocardiography or CMR, during cardiovascular complications. Considering the abnormalities in the coagulation and inflammation processes triggered by the viral action as the background for the high diversity of complications observed during an acute episode and also the conglomeration of symptoms reported during post-COVID-19, it is no surprise that different degrees of myocardial strain imaging deformation abnormalities may be identified in COVID-19 patients ^[26][108]. COVID-19 patients with persistent dyspnoea and exercise intolerance after an acute episode had impaired left atrium (LA) strain functions, particularly LA reservoir strain and LA stiffness suggesting LA myopathy, as indirect signs of diastolic dysfunction ^[26][27][72,108]. These changes in LA function are consistent with the onset and the severity of atrial fibrillation (AF) and the subsequent atrial fibrosis ^{[26][28][29][30][31]}[108,109,110,111,112]. However, the spectrum of cardiac arrhythmias is characterized by a high diversity and complexity, from supraventricular arrhythmias, especially atrial fibrillation, to ventricular tachyarrhythmias, bradyarrhythmias (BAs) and conduction defects ^[32][113].

During the acute phase, more than 10% of COVID-19 patients developed AF during hospitalization ^[33][114]. A similar number of patients developed ventricular arrhythmias ^[34][115]. The electrocardiogram (ECG) presentations seen in COVID-19 patients were predominantly represented by sinus tachycardia, followed by supraventricular tachycardia atrial fibrillation/flutter, ventricular tachycardia, QT prolongation and BA ^[35][116]. BA and atrioventricular blocks (AVBs) were less frequently observed in COVID-19 patients when compared to the prevalence of sinus tachycardia or supraventricular arrythmias ^[35][116]. BAs reported during the acute phase of the disease were mainly due to myocardial inflammation and endothelial injury in the context of a cytokine storm, hypoxia and electrolytes imbalance, all processes leading to the aggravation of pre-existing conduction abnormalities or the onset of new ECG changes ^[35][36][116,117]. Importantly, approximately 7.5% of myocardial cells express ACE 2 receptors ^[35][116]; therefore, direct virus action on myocardial cells leading to cardiac injury and consequently to the onset of arrythmias may represent one key element of the underlying pathophysiology. Moreover, several medications used during the first waves of the COVID-19 pandemic such as chloroquine, hydroxychloroquine and azithromycin may induce QT interval prolongation, leading to torsade de pointes ^[35][37][116,118]. The term viral channelopathy has recently emerged, explaining this subset of arrythmias occurring during viral diseases. Viruses are able to encode their own ion channels called viroporins in the host cell ^[38][119]. Consequently, some ion-channel-blocking drugs may demonstrate antiviral activity ^[38][119]. By understanding this new virus mechanistic concept, the medication used to treat viral diseases my contribute not only to virus annihilation but also to bypassing virus-induced channelopathies ^[38][119]. The host ion channels, especially the K⁺ and Ca²⁺ channels, participate at different stages of virus cycle; therefore, some dormant channelopathies may be exacerbated by viral infections ^[37][118]. Moreover, viral-modulated channel action may impact the cell contractility, inducing arrythmias, further enhanced by indirect factors, e.g., cytokine actions, endothelial hypoxia-induced injury or due to the treatment performed ^[37][118]. In this perspective, ongoing inflammation may act as the dominant substrate for long-term consequences of COVID-19 infection, where one key element of the chronic low-grade inflammation hypothesis is represented by the transforming growth factor beta (TGF-β) activity ^[39][120]. Activation of TGF-β is linked to inflammation, apoptosis and fibrosis, hence playing a crucial role in the acute and long-term effects of COVID-19 ^[39][120]. By modulating the cascade of signaling of TGF-β pathways, the deleterious effects may be circumvented. Irrespective of COVID-19 severity, the plasma levels of TGF-β, especially TGF-β1, were heightened in hospitalized COVID-19 patients, with an abnormal and uncontrolled immune response induced by the SARS-CoV-2 infection ^[40][121]. TGF-β1 dysregulation is associated with cardiac myofibroblast arrhythmogenicity ^[38][40][119,121] as a substrate for high-degree AVB in COVID-19 survivors ^[41][122]. Additionally, the presence of fibrosis facilitates re-entry circuits, which further triggers arrythmia genesis ^[32][113]. Nevertheless, data on arrhythmic events after the COVID-19 pandemic remain limited and divergent. Most reports on the prevalence of arrhythmic events are during acute infection, when the medical management may be encountering difficulties due to acute decompensation of other pathologies. During an acute episode of COVID-19 pneumonia, arrhythmic events were reported in approximately 5% to 10% of the patients ^[42][123]. In post-acute COVID-19 syndrome, the prevalence is difficult to establish due to limitations regarding study designs, including population characteristics, duration of the follow-up and patients lost to follow-up. In a Swedish cohort including more than 3000 patients with a history of severe COVID-19 infection, the incidence rates per 1000 persons-years of ventricular tachycardia, atrial fibrillation, other tachyarrhythmias and bradycardia/pacemaker implantation were 15.4, 78.4, 99.3 and 8.5, respectively, when compared to the general population, at 9 months follow-up ^[43][124]. A larger report including more than 600,000 COVID-19 survivors, without previous cardiovascular diseases prior to COVID-19 infection, showed a higher 12-month risk of arrythmias, especially atrial fibrillation and flutter (HR = 2.407 [2.296–2.523]), followed by tachycardia (HR = 1.682 [1.626–1.740]), ventricular arrhythmias (HR = 1.600 [1.535–1.668]) and bradycardia (HR = 1.599 [1.521–1.681]) when compared to the matched control group without a history of SARS-CoV-2 infection ^[44][125]. Although a trend in overestimation, the severity of cardiovascular outcomes in COVID-19 survivors was observed in smaller cohort studies; when compared to a population without documented COVID-19 infection, COVID-19 survivors have a higher risk of cardiovascular complications including mortality, irrespective of the severity of the acute episode ^[45][46][126,127]. Therefore, individualized medical management including referral to specific departments (electrophysiology, POTS clinics, heart failure clinics), especially in patients with persistent symptomatology following COVID-19 pneumonia, should be implemented.

Relative bradycardia (RB) is another phenomenon different from BA, being characterized by an abnormal response to high body temperature observed in various infectious diseases, including COVID-19 ^[47][128]. Several definitions have been proposed to characterize RB. In general, RB is defined by a less than 10 beats/minute rise in body temperature ^[47][48][128,129]. The prevalence of RB in the COVID-19 population is between 36% and 76% ^[47][128], depending on various factors from age, associated comorbidities like diabetes or use of antipyretic drugs to the release of inflammatory cytokines, increased vagal tone, direct virus effect on the myocardium and electrolyte disturbances, which are frequently described in COVID-19 pneumonia ^[48][129].

As the central mechanisms for COVID-19 and cardiovascular involvement are represented by inflammation, heart failure (HF) and COVID-19 during the acute and post-acute phase may coexist.

Common risk factors for poor prognosis in both pathologies remain older age, obesity and diabetes ^[49][50][51][130,131,132]. Importantly, the absence of systematic HF follow-up during the COVID-19 pandemic due to restrictions and the fear of patients contracting COVID-19 pneumonia contributed to the severity of both conditions, acute cardiac injury induced by COVID-19 and HF ^[51][52][132,133]. Consequently, during the COVID-19 pandemic, the post-discharge mortality among HF patients was especially augmented due to insufficient access to specialized care ^[53][134]. In one study analyzing the incidence of new HF onset or HF worsening before and after lockdown during the first COVID-19 pandemic wave, the investigators showed a significant decrease in the number of new HF diagnoses or HF worsening when compared to the pre-pandemic period, raising concerns about HF undertreatment and potential long-term consequences following COVID-19 ^[54][135].

Considering all those factors, several reports outlined a 2% HF incidence in COVID-19 survivors ^[52][55][133,136]. A meta-analysis comprising a large population showed an additional risk of 90% developing HF after COVID-19 infection that rises with age and the presence of arterial hypertension ^[55][136].

Endothelial dysfunction, microvascular damage, ongoing inflammation and prothrombotic state following acute COVID-19 pneumonia may play a significant role in multiorgan dysfunction, including new-onset or aggravating a pre-existing HF ^[56][57][137,138]. Several cardiac abnormalities have been reported in post-acute follow-up COVID-19 studies, highlighting the importance of continuous evaluation. The presence of subclinical cardiac dysfunction was a common finding in those studies, focusing on COVID-19 survivors. Nevertheless, a current limitation encountered in numerous studies focusing on discharged COVID-19 patients was represented by insufficient data on cardiac function prior to or even during COVID-19, due to a lack of systematically transthoracic echocardiography evaluations or incomplete diagnosis work-up in order to reduce cross-infection of the healthcare professional or transmission to other patients. During acute setting of the disease, studies have shown a significant correlation between the presence of right ventricle (RV) dysfunction and the onset of major cardiovascular events and in-hospital mortality ^[58][139]. At follow-up, CMR studies showed the persistence of abnormalities with lower RV and LV ejection fractions and higher ventricle volumes when compared to healthy controls, suggesting potential cardiac dysfunction associated with Long COVID ^[59][50]. Although the majority of discharged patients presented normal LV function at 3 to 6 months, abnormal echocardiographic findings such as RV adverse remodeling with RV dilatation or biventricular dysfunction were predominantly observed in patients with acute cardiac events (e.g., pulmonary embolism) during hospitalization ^[60][140], suggesting a correlation between the severity of the acute infection and the mid- and long-term consequences.

In one study of 367 participants, 53% of discharged COVID-19 patients without known cardiovascular diseases or other significant comorbidities prior to COVID-19 and mild episodes of COVID-19 pneumonia, followed-up at 109 days and 329 days with echocardiography and CMR, developed cardiac symptoms after COVID-19, whereas 23% remained asymptomatic during the entire follow-up, and only 20% converted from symptomatic to asymptomatic status ^[61][67]. The echocardiographic evaluation showed preserved LV and RV systolic functions and low values of LV global longitudinal strain, though still in the normal range irrespective of the presence of residual symptoms ^[61][67]. Compared to asymptomatic patients, patients with Long COVID and cardiac symptoms showed higher myocardial native mapping values, suggestive of inflammation and pericardial enhancement, suggesting pericardial inflammatory involvement ^[61][67]. Although mapping values improved by the end of the follow-up, they showed a trend toward higher values when compared to asymptomatic patients or the ones who became asymptomatic during the follow-up, emphasizing persistent low-grade inflammation without the presence of ischemic or structural cardiac disease ^[61][67]. Although more than half of the study population had traceable levels of cardiac troponin, its presence did not correlate with the ongoing cardiac symptoms ^[61][67]. Additionally, structural heart disease, e.g., reduced LVEF or reduced RV ejection fraction or dilated cardiomyopathy, was rarely reported in this study ^[61][67]. In the same direction, a 10-week follow-up study of 139 healthcare workers with confirmed past SARS-CoV-2 infection showed 75% CMR abnormalities incidence in asymptomatic patients ^[62][141]. Moreover, the same report showed evidence of pericarditis or myocarditis patterns in up to 40% of cases following an acute episode of SARS-CoV-2 ^[62][141]. Although the presented study is limited by the small sample size, the value of the research comes from the exhaustive examinations of the patients, including CMR, ECG and laboratory exams. Nevertheless, some of the findings reported by those follow-up studies may be incidental, due to a lack of previous imaging data before COVID-19 infection.

Contrastingly, earlier reports focusing on myocardial injury defined by increased plasma levels of cardiac biomarkers, e.g., cardiac troponin, showed no significant echocardiographic differences between discharged COVID-19 patients with cardiac injury during hospitalization and patients with normal values of cardiac biomarkers ^[63][142]. Moreover, they suggested a full recovery of cardiac function and no evidence of cardiac dysfunction. Hence, data on cardiac dysfunction attributed to COVID-19 are conflicting. Small cohort studies tend to overestimate or to underestimate the actual cardiovascular impact of COVID-19. For example, in a large cohort of more than 1500 participants, CMR screening for myocardial abnormalities after COVID-19 showed an incidence of 2.3% clinical and subclinical myocarditis, with reduced left ventricular systolic function, pericardial inflammation and effusion, out of which 1.8% were asymptomatic during the follow-up ^[64][143]. The incomplete recovery with residual dysfunction and negative remodeling after COVID-19 may represent the framework for HF onset. The lack of prospective studies with a sufficient sample size makes it difficult to assess the true impact of COVID-19 on heart function. HF was a constant finding in patients with acute COVID-19, irrespective of the presence of other comorbidities ^[52][65][133,144]. One report consisting of 100 patients hospitalized with COVID-19 showed a normal echocardiogram only in 32% of the patients, whereas 16% presented LV diastolic dysfunction, 39% RV dilatation or dysfunction and 10% LV systolic dysfunction ^[66][145]. Subsequently, patients with COVID-19 are at a higher risk of HF exacerbations. New onset of HF was also reported in almost a quarter of COVID-19 patients, and it was heightened in patients with severe forms of COVID-19 admitted to intensive care units ^[65][144]. Acute cardiovascular events during COVID-19, e.g., pulmonary embolism leading to RV dysfunction, stress cardiomyopathy or acute myocarditis, may represent the framework for HF development, having a significant impact on survival and promoting long-lasting cardiac dysfunction attributed to partial recovery of COVID-19 survivors ^[65][144].

Several reports focusing on lung parenchyma abnormalities following an acute episode of SARS-CoV-2 infection emphasized increased lung density and glycolytic metabolic activity, advocating for increased inflammation and endothelial activation, leading to a procoagulability status ^[67][146]. Detected levels of D-dimer were reported in COVID-19 survivors even at 4 months after the acute episode ^[68][147]. In hospitalized patients, circulation of hyperreactive platelets may contribute to the hypercoagulability state that may persist even after the resolution of the acute episode ^[68][147]. Additionally, COVID-19 survivors presented high plasma viscosity and fibrin amyloids ^[67][68][146,147]. Those microthrombi express α2-antiplasmin, an enzyme that blocks proteolytic activity of plasmin and subsequently their degradation ^[67][68][146,147]. The morphofunctional abnormalities described in Long COVID patients on chest computed tomography follow-up studies coupled with functional respiratory tests included: fibrotic-like and non-fibrotic abnormalities, perfusion defects or areas of increased perfusion ^[69][148].

It is difficult to estimate the true prevalence of thrombotic events in Long COVID, as the majority of information is obtained from sporadic events or series of case reports. In the post-acute phase of COVID-19 pneumonia, the incidence of venous thromboembolic events was considered to be below 5% ^[70][149]. Other post-discharge reports described an incidence of combined thrombotic events (venous thromboembolism, stroke, pulmonary embolism, intracardiac thrombi) in up to 2.5%, whereas for venous thrombotic events it was 0.6% ^[71][150]. It remains high in the first 45 days after discharge and diminishes progressively ^[72][151]. In addition to the intrinsic factors, the susceptibility to developing thrombotic events is influenced by the standard risk factors from the severity of the disease, intensive care unit admission or duration of hospitalization to the comorbidities of the patients ^[70][149].

An important aspect to be considered is represented by the coagulation abnormalities attributed to COVID-19 and their impact on RV function. RV dysfunction is associated with a worse outcome in COVID-19 patients ^[73][152]. Moreover, RV dysfunction may appear as a continuous phenomenon in recovered patients with a history of COVID-19-related pulmonary embolism, alveolar and endothelial injury and thrombotic microangiopathy ^[74][153]. Up to 42% of recovered COVID-19 patients may present abnormal RV free wall strain, without the presence of other RV structural modifications or in the absence of criteria for pulmonary hypertension, being linked to ongoing inflammation, ischemic lesions due to hypoxia or consequently RV injury post-mechanical ventilation ^[74][153]. Yet, it remains difficult to understand their clinical significance in the context of Long COVID.