**2.2 PACS cardiovascular symptoms**

CVS include a series of heterogeneous cardiovascular symptoms without objective evidence of cardiovascular disease using standard diagnostic tests. Exercise intolerance and tachycardia are the most common reported symptoms together to postural orthostatic tachycardia syndrome (POTS) post-exertional malaise and chronic fatigue syndrome. Chest pain and dyspnea with or without exercise intolerance including memory impairment and attention deficit with poor executive function (frequently described as brain fog) and sleep disturbance are other symptoms reported. There are not established timeline for diagnosing PACS-CVS but it should be considered when cardiovascular symptoms persist beyond a time frame typical for acute infection severity and expected recovery based on age and status of underlying health and without the evidence of cardiovascular impairment because of COVID-19 infection. Ten to 30% of patients seem to experience prolonged symptoms following SARS-CoV-2 infection related to cardiovascular system [140]. In a study one-third of patients with COVID-19 noted at least one symptom and nearly 15% experienced 3 or more symptoms lasting 12 weeks or longer [141]. Different mechanisms have been proposed for PACS-CVS: inflammation [142] immune activation [142, 143] viral persistence [144] triggering of latent viruses [145] endothelial dysfunction [146, 147] impaired exercise metabolism [148] and cardiac deconditioning following viral infection [149, 150].

*Perspective Chapter: Cardiovascular Post-Acute COVID-19 Syndrome – Definition, Clinical... DOI: http://dx.doi.org/10.5772/intechopen.109292*

#### **2.3 Post-COVID-19 Tachycardia, exercise intolerance with post-exertional malaise and chronic fatigue syndrome**

Inappropriate sinus tachycardia and exercise intolerance are often associated after COVID-19 infection. It is usually an inappropriate compensatory response that reflects dysautonomia, hyperadrenergic, and inflammatory post-infection state and the presence of metabolism alterations and immune dysfunction [151–153]. Deconditioning represents a final common pathway starting from these two conditions. There are reduced circulating volume and cardiac atrophy with a shift in the LV pressure-volume curve because of hypovolemia and reduced stroke volume with compensatory tachycardia [149–151]. Once symptoms develop, a downward spiral characterized by short periods of bedrest that produce exercise intolerance, postexertional malaise, and tachycardia leads to further inactivity and worsening of cardiovascular deconditioning with even more debilitating symptoms and chronic fatigue [35]. Patients with COVID-19 reported at home chronic fatigue and dyspnea by 30% and 15%, respectively, at 6 months [152].

Post-COVID-19 Postural Orthostatic Tachycardia Syndrome: Inappropriate tachycardia represents one of the most common cardiovascular sequelae of PACS as well as the most common cause of exercise intolerance in individuals without exertional desaturation. Symptoms often include both cardiac symptoms (palpitations, light-headedness, chest discomfort, dyspnea, or pre-syncope) and non-cardiac symptoms (brain fog, headache, nausea, tremulousness, blurred vision, and exercise intolerance or fatigue) [153]. The presence of inappropriate tachycardia may result in significant limitations on functional capacity as well as in daily living activities such as doing housework or bathing [154]. In the absence of orthostatic hypotension, postural orthostatic tachycardia syndrome (POTS) is defined by an increase in heart rate of >30 beats per minute in those aged >19 years or >40 beats per minute in those aged 120 beats per minute during the 10-minute active stand test. Orthostatic hypotension is defined by a drop in systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg within 3 min of standing [154]. Figure shows symptoms, diagnostic criteria, mechanisms, and therapy of post-COVID-19 POTS as well as a tachogram and autonomic function data of a case of post-COVID-19 male with symptomatic POTS due to hyper-adrenergic response to orthostatic position (**Figure 4**).

Under normal conditions, the assumption of upright posture affects an instantaneous shift of ≈500 mL of blood from the thorax to the lower abdomen and legs, a secondary shift of plasma volume (10–25%) out of the vasculature and into the interstitial tissue, which decreases venous return to the heart (preload), and further affects a decline in cardiac filling and BP [154]. In response of preload reduction, in order to maintain blood pressure homeostasis, the baroreceptors trigger a compensatory decrease in parasympathetic tone as well as an increase in sympathetic activation, that result in an increase in HR and systemic vasoconstriction [154]. The net hemodynamic effect of transition to upright posture is a 10- to 20-bpm increase in HR, a negligible change in systolic BP, and a ≈5-mmHg increase in diastolic BP [149]. Orthostatic dysregulation occurs when this gravitational regulatory mechanism does not respond properly. Patients can present with orthostatic hypotension (seen in autonomic nervous system failure) or with orthostatic tachycardia [154]. Patients with POTS typically maintain (or even increase) their BP on standing. The cardinal hemodynamic feature in POTS is that HR increases excessively and is associated with multiple symptoms on standing that improve with recumbence [154]. Of note,

#### **Figure 4.**

*Evaluation, diagnostic criteria, mechanisms, and therapy of post-COVID POTS.*

tachycardia should last for more than 30 to induce symptoms. It is also important that the patient stands quietly for the full 10 min, as an increase in heart rate may take time. Initial evaluation requires supine blood pressure, saturation, and heart rate measurements, followed by periodic re-assessment in standing position as well as during a 6-minute walking test. Exercise testing should also recommend in patients with exercise intolerance, especially in those with chest pain or discomfort; cardiopulmonary exercise testing (CPET) could be useful in order to evaluate patients with exercise intolerance and dyspnea, since it allows to differentiate between cardiac, pulmonary, or peripheral causes. Ambulatory rhythm monitoring should also be considered to exclude arrhythmia and define the pattern of heart rate elevation [61]. Whereas the latter can likely be done with a 24- to 48-hour Holter monitor, longerduration monitoring (e.g. extended Holter monitor and event monitor) should be considered in those with episodic palpitations, depending on their reported frequency [61]. Mobile health devices capable of heart rate and ECG monitoring can also help in evaluation and surveillance monitoring during recovery [61]. **Figure 5** shows proposed diagnostic workup for post-COVID-19 POTS.

The benefits of exercise training following bedrest deconditioning and that resulting from POTS [155–158] are well described. To achieve these effects, however, specific types of exercise training are recommended. For patients unable to tolerate upright exercise, recumbent or semi-recumbent exercise (e.g. rowing, swimming, or cycling) is recommended initially, with transition to upright exercise over time as orthostatic intolerance resolves [159, 160]. Exercise duration should be short initially and increased gradually as functional capacity increases, with submaximal level of intensity. In fact, since autonomic dysfunction represents the main cause of POTS, physical exercise represents the most powerful therapy able to positive modulate autonomic function, thereby improving functional capacity, even in the presence of cardiovascular disease [161]. Other non-pharmacological interventions should be also considered such as: salt and fluid loading (5–10 g or 1–2 teaspoons of table salt per day as well as 2–3 liters of water or an electrolyte-balanced fluid per day), support stockings, avoid factors that contribute to dehydration (alcohol and/or caffeine, excessive heat exposure [162]. Although no pharmacological therapies are currently approved

*Perspective Chapter: Cardiovascular Post-Acute COVID-19 Syndrome – Definition, Clinical... DOI: http://dx.doi.org/10.5772/intechopen.109292*

**Figure 5.** *Diagnostic work-up for post-COVID POTS.*

for POTS treatment in PAC, low-dose beta-blocker (e.g. bisoprolol, metoprolol, nebivolol, and propranolol) or a non-dihydropyridine calcium-channel blocker (e.g. diltiazem and verapamil) may be used empirically in order to slow heart rate. On the other hand, nonselective beta-blockers (e.g. propranolol) may help to control symptoms in POTS patients [163, 164], especially in those with coexisting anxiety or migraine. Moreover, ivabradine has also been used in those with severe fatigue exacerbated by beta-blockers and calcium-channel blockers. A trial of 22 patients with POTS an improvement in heart rate and quality of life was observed following treatment with ivabradine for 1 month [165]. Fludrocortisone (up to 0.2 mg taken at night) may also be used in conjunction with salt loading to increase blood volume and help with orthostatic intolerance (AHA). Finally, midodrine (2.5–10 mg) may help with orthostatic intolerance, with the first dose taken in the morning before getting out of bed and the last dose taken no later than 4 pm [162].

### **2.4 Post-COVID-19 angina or chest pain**

Chest pain represents one of the symptoms most frequently encountered in patients with previous Sars-Cov-2 infection. Ischemic chest pain (angina) can be related to coronary involvement by thrombotic or vasospasm mechanism or microvascular disease, instead non-ischemic chest pain can be found in the case of pericarditis or myocarditis. Sometimes, non-cardiac chest pain can be experienced by originating from the lungs or pulmonary circulation, aorta or mediastinum for lymphadenitis. A careful anamnesis on the characteristics of the symptom allows to address the diagnostic workup (see figure work-up). Troponin values together with the ECG and echocardiogram must be used to exclude the hypothesis of ischemic or non-ischemic myocardial injury. Stress test, better if cardiopulmonary exercise testing, allows to highlight inducible ischemia as well as to differentiate between cardiac, peripheral, or ventilatory causes of chest pain. Echocardiography or myocardial scintigraphy (SPECT) with pharmacological or physical stress in association with anatomical study of coronary artery with angio-TC or invasive coronary angiography allow the diagnosis of obstructive or microcirculatory coronary disease in specific cases. Particularly if microvascular dysfunction is suspected, Positron Emission Tomography (PET) for myocardial perfusion assessment may be particularly useful [166, 167]. Finally, invasive coronary vasomotor test helps in coronary vasospasm evaluation, but it must be performed in specialized centers [166, 167]. In the case of non-cardiac chest pain, anatomical study (chest X-ray, chest CT, and possible pulmonary angio-TC) associated with a functional study (arterial O2 saturation, resting spirometry, and cardiopulmonary exercise testing) together with the determination of the D-dimer can help to identify any thrombo-embolic or pulmonary parenchymal disease resulting from COVID-19 infection. Additional targeted diagnostics examination such as chest angio-TC or PET study must be reserved for patients with specific diagnostic suspicions such as aortic or mediastinal disease.

### **2.5 Post-COVID-19 dyspnea**

Since lung disease represents the major manifestation of SARS-COV2, a careful cardio-respiratory physical examination represents the first assessment to investigate causes of post-COVID-19 dyspnea, followed by arterial oxygen saturation (both at rest and during the 6-minute Walking Test). Subsequently, an anatomical study of the respiratory system with chest X-ray associated with a functional study with Spirometry at rest will be necessary. Chest computed tomography or computed tomography pulmonary angiogram should be reserved for patients with highly suspicious and/or suggestive findings of significant pulmonary, parenchymal, and/ or vascular involvement (history of moderate or severe COVID-19-related disease, elevated D-dimer levels during the acute phase, risk factors for venous thromboembolism). When pulmonary causes were excluded, the diagnostic process must include the study of the cardiovascular system (see figure work-up). ECG allows to exclude cardiac rhythm abnormalities (e.g., tachyarrhythmias such as atrial fibrillation), new conduction abnormalities that may underlie left or right ventricular dysfunction, or to observe anomalies indicative of myocardial necrosis-ischemia. Echocardiography allows the analysis of the left ventricle and can highlight a systolic dysfunction with global or segmental kinetics anomalies suggestive for myocardial injury, giving the clinical suspicion of myocarditis or ischemic event. Right ventricular dilatation and systolic dysfunction associated with pulmonary hypertension and dilated pulmonary circulation may be suggestive of pulmonary thromboembolism and/or moderate or severe pulmonary parenchymal disease. Pericardial effusion may be a suggestive finding for a pericardial event. Laboratory tests with blood gas analysis may help and must include the determination of the hemoglobin values, of BNP (in the suspicion of heart failure), of the troponin values (to highlight any chronic myocardial damage), of D-dimer (in the suspect of a thrombo-embolic event or of the oxygen saturation and partial pressure values and of the acid-base balance). The most informative test for patients with post-COVID-19 dyspnea is still the cardiopulmonary exercise Testing (CPET) [168]. CPET allows to assess the presence of myocardial ischemia (reduced values of VO2/WR slope, reduced oxygen pulse, and ST abnormalities), of ventilatory dysfunction (high VE/VCO2 slope values,

#### *Perspective Chapter: Cardiovascular Post-Acute COVID-19 Syndrome – Definition, Clinical... DOI: http://dx.doi.org/10.5772/intechopen.109292*

trend anomalies, and PET-O2 and PET-CO2 values), of muscle-metabolic inefficiency (altered anaerobic threshold and reduced oxygen uptake extraction slope values) or aortic stiffness [169]. Moreover, post-COVID-19 unexplained dyspnea without cardiopulmonary abnormalities is common with PACS and may relate to deconditioning with poor cardiovascular fitness. In a study, 59% of patients with COVID-19 had persistent dyspnea at 3 months [170]. On Cardiopulmonary exercise testing (CPET), patients with post-COVID-19 dyspnea had lower peak VO2, lower VO2 at anaerobic threshold, and data suggestive of muscular inefficiency such as lower oxygen uptake extraction slope (**Figure 6**).

Finally, third-level assessments can be reserved for those patients with a picture that is not yet perfectly clear but is suspected of specific pathologies. If inducible ischemia is highlighted, pharmacological or exercise eco stress or myocardial scintigraphy, coronary computed tomographic angiography (CCTA) or invasive coronary angiography can be performed. Instead, if myocarditis is suspected, it will be necessary to perform a contrast-enhanced cardiovascular magnetic resonance imaging to

#### **Figure 6.**

*Cardiopulmonary exercise testing evaluation in post-COVID patients.*

#### **Figure 7.**

*Diagnostic work-up for post COVID-19 dyspnea and chest pain.*

assess the possible presence of myocardial damage with myocardial fibrosis. Cardiac biopsy should be evaluated only in special cases. **Figure 7** shows proposed diagnostic workup for post-COVID-19 dyspnea and chest pain.
