Prevention of Acute Myocardial Injury by Trimetazidine in Patients Hospitalized for COVID-19
Prevention of Acute Myocardial Injury by Trimetazidine in Patients Hospitalized for COVID-19
Acute myocardial injury has been a finding of variable frequency among patients diagnosed
 with COVID-19. It is now recognized that cTnI levels are strongly associated with increased
 mortality. The mechanisms underlying the myocardial injury remain unknown, and it is not
 clear whether they reflect local/systemic inflammatory process and/or cellular ischemia.

 Both myocardial ischemia and ventricular dysfunction result in dramatic changes in
 mitochondrial oxidative metabolism. These changes involve an increase in the rate of
 cytoplasmic anaerobic glycolysis to compensate for the decrease in mitochondrial adenosine
 triphosphate (ATP) production. The rest of the mitochondrial oxidative metabolism originates
 mainly from the β-oxidation of free fatty acids, which occurs at the expense of glucose
 oxidation.

 Trimetazidine is a competitive inhibitor of the enzyme 3-ketoacyl coenzyme A (CoA) long-chain
 thiolase (3-KAT), the last enzyme involved in the oxidation of fatty acids. Stimulation of
 glucose oxidation by trimetazidine results in a better coupling between glycolysis and
 glucose oxidation, with a consequent decrease in lactate production and intracellular
 acidosis, present in situations of myocardial ischemia or heart failure.

 Thus, the PREMIER-COVID-19 study was designed to test the hypothesis that the use of
 trimetazidine associated with usual therapy in patients admitted with a diagnosis of moderate
 to severe acute respiratory syndrome by SARS-CoV2 infection reduces the extent of acute
 myocardial injury assessed by the peak release of ultra-sensitive troponin compared to usual
 therapy.
Acute myocardial injury, defined by increased levels of high-sensitivity cardiac troponin I
 (cTnI), has been a finding of variable frequency among patients diagnosed with COVID-19. This
 myocardial impairment can occur in the form of acute myocarditis or an injury secondary to
 the imbalance between oxygen supply and demand (type 2 myocardial infarction). It is now
 recognized that cTnI levels are strongly associated with increased mortality. The mechanisms
 underlying the myocardial injury remain unknown, and it is not clear whether they reflect
 local/systemic inflammatory process and/or cellular ischemia.

 Both myocardial ischemia and ventricular dysfunction result in dramatic changes in
 mitochondrial oxidative metabolism. These changes involve an increase in cytoplasmic
 anaerobic glycolysis rate to compensate for the decrease in mitochondrial ATP production.
 Unfortunately, the increase in glycolysis exceeds the subsequent mitochondrial oxidation
 capacity of pyruvate (glucose oxidation) derived from glycolysis, resulting in the
 intracellular accumulation of lactate and protons. The protons produced from this decoupling
 between glycolysis and glucose oxidation contribute to a rupture in ionic homeostasis and
 myocardial cells, resulting in lower cardiac efficiency. In both the ischemic heart and the
 insufficient heart, the rest of the mitochondrial oxidative metabolism originates mainly from
 the β-oxidation of free fatty acids, which occurs at the expense of glucose oxidation.

 Trimetazidine is a competitive inhibitor of the enzyme 3-ketoacyl CoA long-chain thiolase
 (3-KAT), the last enzyme involved in the oxidation of fatty acids. Stimulation of glucose
 oxidation by trimetazidine results in a better coupling between glycolysis and glucose
 oxidation, with a consequent decrease in lactate production and intracellular acidosis
 present in situations of myocardial ischemia or heart failure.

 Thus, the PREMIER-COVID-19 study (open and randomized) was designed to test the hypothesis
 that the use of trimetazidine associated with usual therapy in patients admitted with a
 diagnosis of moderate to severe acute respiratory syndrome by SARS-CoV2 infection reduces the
 extent of acute myocardial injury assessed by the peak release of ultra-sensitive troponin
 compared to usual therapy. Investigators will also assess, as secondary outcomes, the impact
 on clinical evolution to more severe forms (admission to the intensive care unit or the need
 for mechanical ventilatory support, length of stay in hospital and in-hospital mortality).
A. Inclusion Criteria:

 1. Clinical diagnosis of moderate to severe acute respiratory syndrome due to SARS-CoV2
 defined as:

 1.1. Tachypnea: > 24 breaths per minute 1.2. Hypoxemia: arterial oxygen saturation
 <94% in room air by pulse oximetry 1.3. Presumptive (or confirmed) diagnosis of
 SARS-Cov2 infection by at least one of the following criteria:

 1. Polymerase chain reaction assay (+) for SARS-CoV2

 2. Serology (+) for SARS-CoV2

 3. SARS-CoV2 antigen diagnostic tests (+)

 4. Chest CT with findings suggestive of the diagnosis of COVID-19 in the presence of
 medical history or clinical signs compatible with the diagnosis of COVID-19

 2. Signature of the Informed Consent Form

 B. Exclusion Criteria:

 1. Chronic renal dysfunction stage 4 (GFR <30mL / min / 1.73m2 calculated by the Chronic
 Kidney Disease Epidemiology Collaboration (CKD-EPI) equation

 2. Patient on renal replacement therapy by dialysis

 3. Pregnant and lactating women

 4. Previous use of trimetazidine less than two weeks before hospital admission

 5. Any clinical condition at the investigator´s discretion likely to be associated with
 elevation of baseline hs-troponin >99th percentile