Uloga inhibitora renin-angiotenzin-aldosteronskog sustava u patogenezi koronavirusne bolesti (COVID-19)

Marijana Knežević Praveček, Blaženka Kljaić Bukvić, Blaženka Miškić

Koronavirusna bolest (COVID-19) zarazna je bolest koju uzrokuje novi koronavirus odnosno virus teškoga respiratornog sindroma (engl. Severe acute respiratory syndrome coronavirus 2 – SARS-CoV-2). U većeg broja zaraženih bolest obilježavaju opći simptomi infekcije koji su praćeni upalnim promjenama donjih dišnih putova. U osoba starije dobi s komorbiditetima, osobito s kardiovaskularnim bolestima, koronavirusna bolest češće napreduje prema akutnomu respiratornom distresu, akutnoj ozljedi miokarda, višestrukom zatajenju organa i mogućemu smrtnom ishodu. Bolest se prvi put pojavila u prosincu 2019. u kineskom gradu Vuhanu i do danas je poprimila razmjere pandemije, s više od 70 milijuna oboljelih i 1,6 milijuna umrlih. Koronavirus SARS-CoV-2 inficira stanice domaćina preko receptora enzima koji konvertira angiotenzin tipa 2 (engl. Angiotensin converting enzyme 2 – ACE2) i važna je komponenta renin-angiotenzin-aldosteronskog sustava (engl. Renin-angiotensin- aldosterone system – RAAS). Kao membranski protein, ACE2 je prisutan u plućima, srcu, bubrezima i crijevima. Patologija koronavirusne bolesti pokazuje povezanost s raspodjelom ACE2 po tkivima. RAAS je presudan u homeostazi kardiovaskularnog sustava. Inhibitori RAAS-a (inhibitori enzima koji konvertira angiotenzin, blokatori receptora angiotenzina II tipa 1) primjenjuju se u liječenju kardiovaskularnih bolesti, hipertenzije i šećerne bolesti. Iz pretkliničkih radova poznato je da inhibitori RAAS-a mogu povećati ekspresiju ACE2. U vrijeme pandemije koronavirusne bolesti javila se zabrinutost o sigurnosti njihove primjene. Razmatra se kako povećana ekspresija ACE2 može utjecati na tijek te bolesti: povećanjem infektivnosti koronavirusa (SARS-CoV-2) ili zaštitnim, organoprotektivnim učincima koji vode do smanjene smrtnosti. Znanstvenici su postulirali potencijalno štetne učinke inhibitora RAAS-a u patogenezi koronavirusne bolesti (COVID-19), kao i njihove moguće korisne učinke, međutim, rezultate eksperimentalnih i pretkliničkih radova ne možemo potpuno primijeniti na ljudsku fiziologiju. Stručna društva preporučila su nastavak primjene inhibitora RASS-a za vrijedeće kardiovaskularne indikacije. Potrebna su klinička ispitivanja o sigurnosti i učinkovitosti rekombinantnoga humanog ACE2 i drugih inhibitora RAAS-a u koronavirusnoj bolesti. Dotad inhibitore RAAS-a treba i dalje primjenjivati u liječenju stabilnih pacijenata bez obzira na rizik ili koronavirusnu bolest.

COVID-19 is a contagious disease caused by a new coronavirus, called the severe acute respiratory syndrome Coronavirus-2, SARS-CoV-2. In many infected people the disease is characterized by general symptoms of infection, which are accompanied by inflammatory changes in the lower respiratory tract. In the elderly persons with comorbidities, especially cardiovascular disease, the disease progresses more frequently to acute respiratory distress, acute myocardial injury, multiple organ failure, and possible fatal outcome. The disease first appeared in December 2019 in the city of Wuhan, China, and has received pandemic proportions to date, with over 70 milions patients and 1.6 milions patients deaths. SARS-CoV-2 infects host cells via the angiotensin converting enzyme 2 (ACE2) receptor, which is an important component of the renin-angiotensin-aldosterone system (RAAS). ACE2 is a membrane protein, present in the lungs, heart, kidneys and intestines. The pathology of COVID-19 diseas  shows an association with tissue distribution of ACE2. RAAS is crucial in the homeostasis of the cardiovascular system. RAAS inhibitors (angiotensin converting enzyme inhibitors, angiotensin II type 1 receptor blockers) are used in the treatment of cardiovascular disease, hypertension and diabetes. It is known from preclinical work that RAAS inhibitors can increase ACE2 expression. Concerns have been raised about the safety of their application during the COVID-19 pandemic. It is discussed how increased ACE2 expression may affect the course of COVID-19
through increased infectivity of SARS-CoV-2 or through protective, organoprotective effects leading to reduced mortality. Scientists have postulated the potentially harmful and potentially beneficial effects of RAAS inhibitors in the pathogenesis of COVID-19, however, the results of experimental and preclinical studies cannot be fully applied to human physiology. Expert societies have recommended the continued use of RAAS inhibitors for valid cardiovascular indications. Clinical trials on the safety and efficacy of recombinant human ACE2 and other RAAS inhibitors in COVID-19 are required. Until then, RAAS inhibitors should continue to be used in the treatment of stable patients regardless of the risk or disease of COVID-19.