Post-Acute Sequelae of Coronavirus-19 (COVID-19) With Dyspnea on Exertion And Associated TaChycardia TrEatment Study

Most patients with acute COVID-19 (Coronavirus 19) recover within weeks, however a significant number of individuals will develop the post-acute COVID 19 syndrome (PASC). As of July 2021, the post COVID syndrome qualifies as a disability under the Americans with Disabilities Act. The symptoms which comprise this condition are highly variable and often extraordinarily debilitating. They may be distinct from the initial presentation or may mimic those which defined the initial infection. The post COVID syndrome can be diagnosed when symptoms persist longer than 3 months and may extend to beyond one year. There are risks for permanent levels of disability. Patients who seemingly did not have active COVID-19 symptoms in the days following infectious exposure may also develop post Covid syndromes. These syndromes are considered to constitute a distinct clinical entity which has of yet no clearly defined pathogenic mechanism or validated treatment algorithms.

International investigative efforts are now underway to determine who might develop the post COVID syndrome, it's long term consequences and how best to treat its many problematic symptoms.

Although the long Covid syndrome or PASC is a well recognized syndrome, its pathogenesis is poorly understood. Hypotheses have included persistent viral remnants with consequent provocation of the generalized symptoms characteristic of systemic inflammation. The virus may continue to infect heart, lung or neurologic tissue rendering various organs dysfunctional. Alternatively there could be persistently infected or damaged endothelial cells which line blood vessels and thereby create perturbations of blood flow.

The altered blood flow might then explain the many reported symptoms. However the pathogenesis can be distinguished and studied independently from the physiological disturbance. Existing and accepted therapies for tachycardia and shortness of breath, although they might not reverse the virus caused injury, could be used to reduce the resultant physiologic abnormalities which in turn produce the symptoms of the long Covid syndrome. Beta blockers are standard therapies in sinus tachycardias, (1,2) and postural orthostatic tachycardia syndrome (POTS) (3,4) which are often characterized by high levels of sympathetic drive which beta blockers are designed to modulate.

Thus it is reasonable to hypothesize that that treatment with beta blockers may be an effective intervention as Covid-19 directly infects the nerve and vascular tissues which regulate sympathetic excess which in turn may produce the cardiovascular symptoms of PASC. Moreover it is important to specifically study beta blockers in PASC because they are currently actively in use for this indication. Yet the possibility remains that although the symptoms are similar to those in which beta blockers have been effective, the pathologic processes in PASC will not be responsive to beta blocker therapy. If this were to be true, beta blockers would prove ineffective and might carry a risk of harm. Equally as important is to properly determine the effective dose as the therapeutic window for these agents is wide.

Metoprolol which is a widely used agent in cardiovascular disease is approved in doses ranging from 25 to 400 mg per day. The proposed study will compare 6 minute walk distances (pre and post the treatment), the echocardiographic measurement of the impact of sympathetic excess on the heart's ability to empty effectively and a quality of life survey. Each of these study elements will be measured before and after progressively increased doses of beta blocker.

Our study is thus designed to study two issues:

1. Whether beta blockers which have been utilized to treat tachycardias, POTS (postural orthostatic tachycardia syndrome), and hypertension will have similar effectiveness in PASC
2. To determine appropriate dosing which may be different than those used on non PASC conditions.

Eligibility Criteria:
Inclusion Criteria:

1. Subject should be between the ages of 18 and 40 with DOE (dyspnea on exertion) for 3 - 12 months
2. Subjects recovered from acute, polymerase chain reaction (PCR) positive, COVID-19 infection
3. Recovery from COVID-19 will be defined as substantial improvement in or essential resolution of initial clinical symptoms
4. Demonstration of tachycardia and/or dyspnea with minimal activity (subjectively different than pre-COVID 19 infection state)
5. Abnormal HUTT (heads up tilt test)
6. Normal chest x-ray
7. Left ventricular ejection fraction (LVEF) \>50% by transthoracic echocardiography
8. Zva \>3.5 as calculated from TTE (transthoracic echocardiogram).
9. Hemoglobin/Hematocrit within normal laboratory standards
10. Thyroid-stimulating hormone (TSH) within normal laboratory standards

Exclusion Criteria:

1. Active pregnancy (negative pregnancy test is the standard of care prior to HUTT)
2. Demonstrate a primary cause of appropriate DOE and sinus tachycardia

   1. Fevers/infection
   2. Hypovolemia
   3. Anemia
   4. Hyperthyroidism
   5. Alcohol/drug/medication withdrawal
3. Currently taking beta blocker medications
4. Currently being treated for pre-existing neurally mediated hypotension/syncope or known dysautonomia.
5. Medical history of chronic lung disease or reactive airway syndrome.