Long Covid-19 INOCA is an investigator-initiated, prospective, randomized, sham-controlled, single center study. Its objective is to investigate the benefits of tailored medical therapy according to the results of the coronary functional testing (CFT) against the routine standard of care and the prevalence and endotypes of ischemia with non-obstructive coronary arteries (INOCA) in patients with long covid-19 syndrome (LCS) and new onset chest pain. All LCS patient with new onset of chest pain will be enrolled. Invasive coronary angiogram and epicardial physiological assessment will be performed to exclude significant epicardial coronary artery disease. Patients without significant epicardial coronary artery disease will undergo CFT which include Acetylcholine test and Coronary microvascular function test. Patients will be randomized into 2 groups: 1) tailored treatment group guided by the results of CFT (intervention) and 2) the routine standard of care group (sham). All patients will undergo the angina symptom and the quality-of-life (QoL) assessment at baseline, 3, and 12 months using the Seattle Angina Questionnaire (SAQ). In the sham group, patients and physicians will be blinded to the results of coronary functional testing for 3 months. Treatment of INOCA will be provided in both groups. The main hypothesis of the Long-Covid INOCA study states that, in LCS patients with chest pain, treatment guided by CFT will demonstrate better angina symptom control and improvement in quality of life (QoL) comparing to the routine standard of care.

Long Covid-19 INOCA is an investigator-initiated, prospective, randomized, sham-controlled, single center study intended to compare the benefits in angina symptom and Quality of Life assessed by the Seattle Angina Questionnaire (SAQ) between tailored medical therapy guided by the results of the coronary functional testing (CFT) and the routine standard of care in patient with LCS and new onset of chest pain. Secondary objective is to investigate the prevalence and endotypes of INOCA in LCS patients with chest pain. This study will be conducted at Hospital Clínico San Carlos, Madrid, Spain.

All patients with the history of SARS-CoV-2 infection, either with acute infection confirmed by PCR or antigen testing, or with past infection demonstrated by serological testing, with symptoms suggestive of LCS such as post exertional malaise, persistent fatigue, difficulty concentrating or shortness of breath who present with typical angina or angina equivalent chest pain starting after SARS-CoV2 infection will be enrolled in this study.

After obtaining patient's informed consent. patients will be randomized by simple randomization in a 1:1 ratio using a central online module to 1) tailored treatment guided by the results of CFT (intervention) or 2) the routine standard of care treatment (sham). All patients will undergo an invasive coronary angiogram as a first step. Patients with severe epicardial coronary artery stenosis define by stenosis ≥ 90% by angiogram will be excluded for further testing. Patients with intermediate coronary artery stenosis will undergo a wire-based physiological assessment of epicardial stenosis. If there is a significant epicardial coronary artery disease defined by fractional flow reserve (FFR) ≤ 0.80 or non-hyperemic pressure ratio (NPHR) ≤ 0.89, the patients will be excluded for further testing. In patients without significant epicardial coronary artery disease, coronary functional testing which include coronary microvascular dysfunction test and Acetylcholine test will be performed. Both tests will be performed in a standard fashion according to the protocol from the guidelines. The results of the CFT will be reported as follow: 1) normal coronary functional testing 2) vasomotor disorder (including both epicardial and microvascular) 3) coronary microvascular dysfunction (including both structural and functional) and 4) combined vasomotor disorder and coronary microvascular dysfunction.

All patients will receive the medications for treatment of INOCA at an out-patient clinic. In intervention group, patient and physician will receive the CFT's results and medications will be prescribed according to patient's type of INOCA and follow with the recommendations in the EAPCI Consensus Document on INOCA and ESC Guidelines. In sham group, patient and physician will be blinded from the CFT's results for 3 months and medications will be prescribed according to physician's decision during this period. After 3 months, the CFT's result will be given to all patients and the treatment will follow with the recommendations from the guideline. Angina symptom and Quality of life in both groups will be assessed by the Seattle Questionnaire of Angina (SAQ), Duke Activity Status Index (DASI) and Euro-Quality of life 5D (EQ-5D) at baseline and each follow up which will occur at 3, and 12 months.

Inclusion Criteria:

- All patients with the history of SARS-CoV-2 infection, either with acute infection confirmed by PCR or antigen testing, or with past infection demonstrated by serological testing, with symptoms suggestive of LCS such as post exertional malaise, persistent fatigue, difficulty concentrating or shortness of breath who present with typical angina or angina equivalent chest pain starting after SARS-CoV2 infection

Exclusion Criteria:

• Previously been diagnosed with coronary artery disease
• Severe left ventricular systolic dysfunction (LVEF) < 30%
• Any moderate to severe concomitant structural heart disease (e.g. moderate to severe valvular heart abnormalities, severe left ventricular hypertrophy)
• Severely reduced renal function (glomerular filtration rate < 30 ml/min/1.73m2)
• Contraindications to the administration of Adenosine or Acetylcholine
• A life expectancy of less than 2 years