Malattia di coronavirus 2019 (COVID-19) e malattia cardiovascolare: Un circolo vizioso

Francesco Vetta1*, Giampaolo Vetta1 and Leonardo Marinaccio2

Astratto
Negli ultimi due decenni, abbiamo assistito a gravi epidemie di gravi infezioni respiratorie acute che rappresentano una grave minaccia per la salute globale, con alti tassi di morbilità e mortalità. La mobilità umana più diffusa e più veloce dai trasporti moderni, permettendo rapidi collegamenti internazionali, ha contribuito alla rapida diffusione delle epidemie, principale, come nel caso della malattia di Coronavirus 2019 (COVID-19), in uno stato di pandemia in breve tempo. I primi dati della letteratura mostrano un'elevata infettività di COVID-19, con un marcato tropismo respiratorio, and a mortality rate ranging between 2 e 8% in different countries, in relation to people affected different mean age and comorbidity. In fact, in COVID-19 patients a close association between mortality, age and comorbidity have been demonstrated. Pre-existing cardiovascular diseases are widely represented in these patients and are associated with a poorer prognosis. inoltre, this virus has also shown a specific tropism towards the cardiovascular system, showing itself responsible for a series of severe acute and chronic diseases. Because of the frequent association with cardiovascular diseases, it is important to keep in mind the principal pharmacological interactions between cardiovascular drugs and those commonly used for the treatment of COVID-19 patients. Finalmente, given the complexity of these patients and their comorbidities, it seems essential to propose the establishment of a multi-specialist COVID-Team.

parole
COVID-19; Myocardial Injury; Cardiovascular Complications; Cardiovascular Therapy; Pandemic.

introduzione
Over the past two decades, le epidemie di infezioni respiratorie acute da coronavirus hanno rappresentato una grave minaccia per la salute globale, con significativi tassi di morbilità e mortalità. Sei specie di coronavirus sono note per causare malattie nell'uomo: quattro virus (229E, OC43, NL63, e HKU1) sono prevalenti e in genere causano sintomi di raffreddore comuni in soggetti immunocompetenti [1,2]. Le altre due varietà, la grave sindrome respiratoria acuta coronavirus (SARS) e la sindrome respiratoria del Medio Oriente coronavirus (MERS) are of zoonotic origin and have been linked to sometimes fatal diseases [3,4]. Given the ubiquitous distribution and high prevalence of coronaviruses, the frequent recombination of their genomes, as well as the increased human-animal interface, new coronaviruses are likely to emerge periodically in humans due to frequent cross-infection and occasional relapse events [1,6,7].In December 2019, some cases of pneumonia caused by a new coronavirus, called Coronavirus Disease 2019 (COVID-19) or Wuhan coronavirus, based on the name of the city where the first viral outbreak occurred, have started to be reported [2,5,8]. The COVID-19 causes a subclinical or mild degree disease in 85% of cases but compared to common influenza viruses it promotes more frequent respiratory complications such as severe interstitial pneumonia, evident in 10-15% of cases. About 5% of infected patients require hospitalization in intensive care and the mortality rate is estimated at 2-3%. Compared to previous coronavirus outbreaks, the contagiousness is higher, but the mortality rate is much lower compared to the severe acute respiratory syndrome (SARS) di 2002 and the Middle East respiratory syndrome (MERS) di 2012, which showed a mortality rate of 10% e 37%, rispettivamente [9-11]. Since January 2020, COVID-19 has gradually spread to Europe and then America and the World Health Organization (OMS) has declared a pandemic status. In Europa, the number of cases and the mortality rate is progressively and rapidly exceeding the data recorded in China [12-14]. In Italy, the main country involved in Europe, the mortality rate was higher than in other countries, with values that in mid-March reached about 8% of infected patients. The main reason for this high prevalence is that Italy is the second oldest nation in the world. In fact, likewise to other pathological conditions common in elderly patients, the mortality rate of COVID-19 is directly related to patientsage, frailty and comorbidities [15,16] (Figures 1 e 2).

figura 1: Age-related mortality rate in COVID-19 patients.

figura 2: Role of comorbidities in influencing COVID-19 patient’s outcome.

The COVID-19 infection is not only of pneumatological and internists interest but must also see cardiologists in the front row. Indeed the cardiac implications of COVID-19 are far from marginal and provide an opportunity for draw the cardiologist’s attention to the relevant interactions between respiratory virus infections and cardiovascular risk. The correlation between influenza virus infection and myocardial infarction has long been known, as well as the incidence of myocarditis, often undiagnosed, and the association with the onset of left ventricular dysfunction [17,18] Similarly, it is worth remembering the protective role of flu vaccination against acute coronary syndrome and heart failure. Despite this evidence, little attention has unfortunately been paid so far to the cardiovascular burden of influenza pandemics and other respiratory viruses [19]. In patients with pneumonia from COVID-19 a first report of 99 patients admitted to Jinyntan Hospital in Wuhan, China in January 2020, showed that 40% of the cases had a pre-existing cardiovascular or cerebrovascular disease [20]. Subsequent reports of COVID-19 patients with pneumonia showed a significantly higher prevalence of comorbid dities such as diabetes, cardiovascular and cerebrovascular disease (Figura. 3) highlighting that 15-25% of patients needed treatment in intensive care [21,22].

Inoltre, a higher incidence of cardiovascular disease was noted among these patients, con 16.7% developing arrhythmic complications and 7% acute myocardial injury [21,22]. A subsequent larger report of 1099 patients with COVID-19 infection confirmed these data [23], underlining that the presence of concomitant diseases, come l'ipertensione, diabete, ischemic heart disease and cerebrovascular disease, was more common in the subgroup of patients with a more severe form of the disease (38.7% vs 21.0%).

figura 3: Prevalence of cardiovascular comorbidities in COVID-19 patients.

Inoltre, the presence of comorbidity has been shown to be associated with significantly different mortality rates: in fact, data provided by the Chinese Center for Disease Control and Prevention for 72314 cases showed that, compared to an overall mortality of 2.3%, this was 10.5% in patients with pre-existing cardiovascular disease and 7.3% in those with diabetes. Similar results, unfortunately on larger samples, are being highlighted in Europe and chiefly in Italy, the most affected country[22,24]

Cardiovascular complications in COVID-19 patients
Beyond the acquired association between pre-existing cardiovascular diseases and the severity of respiratory infections with negative outcome for patients, attention should be focused on cardiovascular complications directly associated with COVID-19 [figura: 4].

Very often in COVID-19 patients, especially in severe forms evolving into ARDS, cardiac injury appears with increased troponin values [25,26], not necessarily associated with an acute coronary syndrome, since it can also be related to non-ischemic forms such as myocarditis [26,27].A meta-analysis of 4 studi, involving 341 COVID-19 patients, showed that cardiac troponin I values were significantly higher in patients with more severe expression of the disease [26], acquiring a negative prognostic significance even more evident when associated with electrocardiographic and echocardiographic alterations. Cohort studies of hospitalized patients in China estimate that cardiac injury occurs in 7-17% of patients hospitalized with the disease [5,21,28] and is significantly more common in patients admitted to intensive care (22,2% vs. 2,0%, p < 0,001) and among those who died (59% vs. 1%, p < 0,0001) [28,29].The association between viral pathologies and acute coronary syndromes has been known in the literature for years now [28]. figura 4: Cardiovascular diseases promoted by COVID-19. The instabilization of a pre-existing coronary plaque, mediated by the systemic inflammatory process with consequent rupture of the fibrous cap, exposure of thrombogenic material and thrombotic occlusion of the vessel, rappresenta l'ipotesi patogenetica più probabile. Lo stato infiammatorio contribuisce a questa sequenza di eventi attraverso diversi determinanti, come il rilascio di citochine infiammatorie, iperattivazione simpatica, aumento dei radicali liberi e stress delle pareti, tachicardia, ipossia e infine uno stato di aumento della trombofilia [30]. A questo proposito, uno studio recente ha dimostrato che i pazienti con infezioni respiratorie acute hanno un rischio più elevato di sviluppare un infarto miocardico acuto sia dopo l'influenza (HR = 6.1) and after not influenza viral diseases, including the other species of coronavirus previously mentioned (HR 2.8) [31]. Initial literature data from COVID-19 patients with STEMI suggest that this clinical scenario is highly likely [32]. The role of myocarditis in COVID-19 patients should not be underestimated. Previous studies on other coronavirus species (MERS) have demonstrated a high prevalence of acute myocarditis using cardiac MRI [33]. In a recent study of 150 patients with COVID-19, myocarditis was shown to be the direct cause of death in 7% of cases, representing a contributing cause in 33% of cases [34]. Several reports described cases of fulminant myocarditis with histological evidence of high inflammatory mononuclear infiltration into myocardial tissue [35-37]. Pericardial involvement has not yet been reported, but further studies are needed. Virus induced cardiac injury can promote a scenario of heart failure in these patients. In fact, a recent study showed a 23.0% incidence of heart failure in COVID-19 patients [28], which was frankly higher in patients with a worse prognosis (51.9% vs. 11.7%). It is unclear whether heart failure is more commonly due to exacerbation of a pre-existing left ventricular dysfunction than a new cardiomyopathy due to myocarditis or stress cardiomyopathy [38]. Right heart failure and subsequent pulmonary hypertension should always be considered, particularly in the context of severe parenchymal lung disease and ARDS. In fact, it is essential to determine whether or not a concomitant cardiogenic component is present when considering the appropriateness of using mechanical respiratory and circulatory support with extracorporeal membrane oxygenation (ECMO) or other techniques, as this may result in changes in device selection, although the limited literature data demonstrate the poor efficacy of these devices in such patients, given that about 83% of COVID-19 patients, although treated with ECMO, fail to survive [39]. Cardiac arrhythmias are another common cardiovascular manifestation described in COVID-19 patients, related to hypoxia, neuro-hormonal stress, cytokine release and metabolic disorders.In patients hospitalized with COVID-19, cardiac arrhythmia was observed in 16.7% and was more common in intensive care patients (44.4% vs. 6.9%) [21]. A new onset of malignant tachyarrhythmias associated with an elevation of troponin values should raise suspicion for underlying myocarditis [40]. In these patients, moreover, we should not forget that changes in inflammatory parameters expose them to a presumably increased risk of systemic and venous thromboembolism (VTE). Although at present there are no extensive scientific data on this subject, an alteration of coagulation parameters has been noted in hospitalized patients with severe COVID-19 disease [41,42].In a retrospective multicenter cohort study from China, high levels of D-dimer (>1g/L) were strongly associated with hospital death (OR 18.4; p=0.003) (28).In un altro studio che confronta i sopravvissuti COVID-19 con i non sopravvissuti, quest'ultimo ha mostrato livelli significativamente più alti di D-dimero e prodotti di degradazione della fibrina (FDP) e 71.4% di questi hanno soddisfatto i criteri clinici per la coagulazione intravascolare disseminata (DIC) durante la loro malattia [42].Oltre a DIC, i pazienti gravemente malati con immobilizzazione prolungata sono ad alto rischio di TEV. Il regime tromboprofilattico ottimale per i pazienti con malattia correlata a COVID-19 non è noto. Perciò, le strategie attuali approvate dalle linee guida dovrebbero essere osservate [43]. Le interazioni farmacologiche tra alcuni trattamenti antivirali e anticoagulanti orali diretti indicano che è probabile che in questi pazienti siano preferite eparine a basso peso molecolare o eparina non frazionata.

Interazioni farmacologiche in pazienti COVID-19
Dato l'uso, in parte sperimentale, dei farmaci usati nei pazienti COVID-19, è consigliabile disporre di uno strumento unico in cui visualizzare rapidamente le principali interazioni note [tavolo 1], le cui specifiche possono essere confermate o meno nei prossimi mesi, alla luce dei dati che emergeranno durante questo periodo [44-53]. ACE-I (Inibitori dell'enzima di conversione dell'angiotensina) e ARB (Bloccanti dei recettori dell'angiotensina) meritare una valutazione separata. I recettori dell'enzima di conversione dell'angiotensina 2 (ACE2) sono il punto di ingresso nelle cellule umane per il virus COVID-19 [17,54,55]. In alcuni studi sperimentali con modelli animali, entrambi gli enzimi di conversione dell'angiotensina (ASSO) inibitori e bloccanti del recettore dell'angiotensina (ARB) hanno dimostrato di sovraregolare l'espressione di ACE2 nel cuore [56,57], portando a speculazioni su un potenziale aumento del rischio di grave infezione da COVID-19 in pazienti trattati con questi farmaci. È importante notare che questi dati non sono mai stati dimostrati nell'uomo [58]. Anzi, altri studi sembrano mostrare, in pazienti con polmonite virale, un'azione protettiva polmonare di entrambi gli ACEi e gli ARB [59-61], portando a speculazioni su un'azione protettiva anche nei pazienti COVID-19. Perciò, in assenza di chiaro, dati non speculativi, le Società Scientifiche Cardiologiche Internazionali hanno concordato sul fatto che la terapia con ACEI o ARB dovrebbe essere continuata, anche nei pazienti COVID-19 [62,63].

tavolo 1: Farmaci usati in pazienti COVID-19: potenziali interazioni cardiovascolari ed effetti avversi

conclusioni
In anni recenti, lo sviluppo e la maggiore velocità e diffusione dei viaggi internazionali hanno promosso una nuova situazione per la trasmissione di malattie infettive in tutto il mondo, rendendo le pandemie globali più facili, come nel caso di COVID-19. Anche se questo virus, come i coronavirus precedenti, ha un tropismo più pronunciato per il sistema respiratorio, le manifestazioni extrapolmonari associate e le loro conseguenze a lungo termine sono spesso ignorate. Certamente, le malattie cardiovascolari preesistenti influiscono in modo significativo sull'esito di questi pazienti, ma è sempre necessario tenere presente le malattie cardiache che possono derivare direttamente da COVID-19, nonché le interazioni farmacologiche e gli effetti avversi. Perciò, è più appropriato che mai promuovere la gestione interdisciplinare dei pazienti COVID-19, specialmente in pazienti con malattie cardiovascolari preesistenti con un team COVID multi-specialista.

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