key: cord-1011260-q275egr2 authors: Ramandi, Alireza; Akbarzadeh, Mohammad Ali; Khaheshi, Isa; Khalilian, Mohammad Reza title: Aortic dissection and Covid-19; a comprehensive systematic review date: 2022-02-06 journal: Curr Probl Cardiol DOI: 10.1016/j.cpcardiol.2022.101129 sha: 48e1057de593b1c6a98a42c8210db14e0c234ae7 doc_id: 1011260 cord_uid: q275egr2 Coronavirus disease 19 (Covid-19) has been declared as a pandemic disease since March 2020; causing wide array of signs and symptoms, many of which result in increased mortality rates worldwide. Although it was initially known as an acute respiratory disease, Covid-19 is accompanied with several extrapulmonary manifestations, of which the cardiovascular ones are of major importance. Among other cardiovascular complications of Covid-19, aortic dissection has been a significant yet underrated problem. The pathophysiology of aortic dissection consists of various inflammatory pathways, that could be influenced by Covid-19 infection. We herein have reviewed articles inclusive of aortic dissection concurrent with Covid-19 infection in a systematic manner, along with the probable similarities in pathophysiology of aortic dissection with Covid-19 infection. Since 11th March 2020, the outbreak of severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) has been declared as a pandemic disease, causing numerous morbidities and mortalities worldwide. (1, 2) Although Coronavirus disease had been Initially known as an acute respiratory distress syndrome, more recently it appeared to affect various organs and organ systems, including cardiovascular, gastrointestinal, renal, coagulation, and skin disorders; Most of which related to the hyper-inflammatory state in Covid-19. (3, 4) Multiple findings imply that the inflammatory state in Covid-19 patients is similar to strong inflammatory syndrome; both of which showing abnormal platelet count, increase in D-dimer, increase in Von Willebrand Factor (VWF), endothelialitis, and pro-inflammatory cytokines activation. (3) The Covid-19 is known to cause increased risk of several cardiovascular complications; including acute myocardial injury, arrhythmias, cardiogenic shock, acute coronary syndrome, and venous thromboembolism. (4) Among the cardiac complications, aortic dissection is an important yet underrated problem in Covid-19 patients. Even though few articles indicate that the rate of aortic dissection has been increased during the course of pandemic, no comprehensive studies have been conducted about the molecular basis and coincidence rate of Covid-19 and aortic dissection. (5) We herein report a comprehensive systematic review of literature to cognize the patients with aortic dissection and concurrent or previous Covid-19. We have also discussed the similarities between the pathologic pathway of Covid-19 and aortic dissection. Aortic dissection is the blood passage into the aortic media as a result of the rupture in intimal layer of the aortic wall. (6) Consequently, separation of the intimal layer from the outer layers occurs, and hence a false lumen appears in juxtaposition with the main aortic lumen. The ascending aorta is reported to be the most common site of aortic dissection, as 65% of the dissections originate in this region. (7) Numerous major risk factors contribute to increased risk of aortic dissection, including hypertension and smoking, and genetic factors such as Marfan Syndrome (MFS) and Ehlers Danlos. (6) Vasculitis is also a notable factor that increases the risk of aortic dissection, as in Takayasu arteritis, Behcet's disease, and syphilis infection. (7) Figure 1 ] The major factors include Transforming growth factor beta (TGF-β), total plasma homocysteine Y (tHCy), and Matrix metalloproteinases (MMPs). (11) (12) (13) Several reports illustrated that excessive activation of TGF-β in MFS patients is correlated with aortic root dilation and predisposition to aortic dissection. (12) Ghazavi et al. indicated that in a study of 63 Covid-19 patients and their matched controls, the level of TGF-β increased in Covid-19 patients. Furthermore, TGF-β in this study was significantly higher in patients with severe form of Covid-19 compared to the patients with mild form. With these findings, one may assume that the Covid-19 can possibly increase the probability of aortic root dilation and henceforth aortic dissection. It is worthy to mention that in MFS patients, treatment with β-blockers decreases the TGF-β levels. According to the literature, the tHCy is described as a marker of the level of aortic atherosclerosis. Moreover, in a study of one hundred and seven patients, Giusti et al. concluded that higher levels of tHCy in MFS patients is correlated with the incidence rate of aortic dissection and other cardiovascular complications. (12, 14) In case of Covid-19, it has been shown that tHCy can be used as a predictive value for the severity of the disease, as the higher levels of tHCy corresponds to more severe pneumonia in imaging evaluations. One of the major similarities between MFS patients with aortic dissection and Covid-19 patients, is the imbalance between MMP and Tissue inhibitor of metalloproteinase (TIMP). Prior studies have demonstrated that macrophage infiltration in the media layer of aorta may result in excessive production of MMPs, specifically MMP-1, MMP-9 and MMP-12. As a result, collagen and elastin degeneration leads to aortic aneurysms and aortic dissections. (2) One of the molecular characteristics of MFS is known to be increased expression of MMPs, that ensues an imbalance between MMP and TIMP levels. For the LOX and FBN1 gene pathways, as two other factors that predispose MFS patients to aortic dissection, there is not enough evidence that Covid-19 has a similar pathway and hence is correlated. However, this idea may lead to further investigations in future publications. A comprehensive search was conducted on PubMed, Embase, Scopus, and Google scholar for the articles that have been published until January 2, 2022. Proper Boolean operators have been used for the subject headings "Covid-19" and "dissection" and any synonyms observed in literature. Multiple combinations of words have been used to ensure a comprehensive search. Indexing methods (e.g., Mesh terms, Emtree, etc.) were also utilized if available. The search was conducted by one reviewer and crosschecked by another. From the initial articles in the primary search, the duplicates and unrelated articles were excluded. After primary screening, suitable quality appraisal tool was utilized to assess the article before data extraction. (18, 19) The exclusion criteria were 1) article written in languages other than English, 2) reviews and commentaries without any patients studied, 3) lack of demographic, clinical, imaging or laboratory evidences of Covid-19 infection, 4) insufficient details of the type of acute aortic syndrome (i.e., articles which did not differentiate dissection from aneurysm or other manifestations of acute aortic syndrome in the patients discussed). Due to unavailability of reverse transcription polymerase chain reaction test (RT-PCR) early in the course of the pandemic, we did not exclude patients who were diagnosed with Covid-19 based on clinical or imaging methods. Statistical analysis was conducted by using SPSS software (SPSS Inc, Chicago, Illinois, USA). Initially, 246 articles were obtained from the primary search. After comprehensive analysis of the articles according to figure 2, 19 articles met the criteria for data extraction and qualitative synthesis. [ Aortic dissection is a form of acute aortic syndrome that is more prevalent in men (2:1) and has a peak incidence in the sixth and seventh decades of life. It is known that the incidence of aortic dissection increases in cold seasons and places with lower climate temperature. Notably, in one study held in the United Kingdom in April 2020, the number of patients with Stanford type A acute aortic dissection was significantly higher than the same month in the last decade. (5) Although no signs of aortitis were found in evaluation of these patients, there should be a mutual factor between these patients that has increased this relatively rare manifestation. Similar studies have also demonstrated increase in the incidence of aortic dissection, along with other cardiovascular manifestations such as myocardial infarction and aortic aneurysms in the first wave of Covid-19. (39) Among the risk factors, hypertension is one of the most prevalent causes of increased risk of aortic dissection. Some studies suggested that Covid-19 infection down-regulates angiotensinconverting enzyme 2 and activates renin-angiotensin-aldosterone system, causing the hypertensive state which may lead further towards aortic dissection. (40) these findings, along with other molecular findings discussed earlier, intensify the role of Covid-19 in predisposing patients to aortic dissection. For diagnostic aspects of aortic dissection, several imaging modalities have been proposed; including plain chest radiography, CT, CTA, TEE, and TTE. (7) While TEE has overcome many of the constraints in other methods, the majority of patients in this study were diagnosed using CT. This may probably due to non-invasiveness and speed of CT while reducing the Covid-19 exposure for the medical staff compared to the TEE procedure. It is worthy to mention that high level protection is suggested for surgical procedures in patients with Covid-19, which further complicate any method of diagnosis other than noninvasive methods. (29) In conclusion, aortic dissection may be a relatively rare but important complication in Covid-19 patients. Henceforth further research and investigation is necessary for diagnosis, prevention, and treatment of this major problem. AR and IK contributed to methodology, searching and screening. AR, MK, and MA extracted the data. AR and MA helped with data analysis. AR and IK drafted the manuscript. AR, and MA revised the manuscript SARS-CoV-2: A comprehensive review from pathogenicity of the virus to clinical consequences SARS-CoV-2, Cardiovascular Diseases, and Noncoding RNAs: A Connected Triad Thromboembolic involvement and its possible pathogenesis in COVID-19 mortality: lesson from post-mortem reports Frequency of Cardiovascular Complications and Its Association with Prognosis of COVID-19 Patients The COVID-19 Pandemic and Acute Aortic Dissection: an unintended consequence? Authorea Preprints Thoracic aortic aneurysms Acute aortic dissection Correlation analysis between disease severity and clinical and biochemical characteristics of 143 cases of COVID-19 in Wuhan, China: a descriptive study COVID-19 and peripheral artery thrombosis: A mini review Coronary microvascular dysfunction pathophysiology in COVID-19 Cytokine profile and disease severity in patients with COVID-19 Biomarkers of aortopathy in Marfan syndrome Biomarkers associated with COVID-19 disease progression Phenotypic variability of cardiovascular manifestations in Marfan Syndrome: Possible role of hyperhomocysteinemia and C677T MTHFR gene polymorphism Matrix metalloproteinase 3 as a valuable marker for patients with COVID-19 Neutrophil more than platelet activation associates with thrombotic complications in COVID-19 patients. The Journal of Infectious Diseases An immune-based biomarker signature is associated with mortality in COVID-19 patients Methodological quality (risk of bias) assessment tools for primary and secondary medical studies: what are they and which is better? Joanna Briggs Institute Reviewer's Manual. The Joanna Briggs Institute Acute aortic dissection in the Marfan syndrome during the COVID-19 epidemic Type 1 Acute Aortic Dissection in the Early Period After COVID-19 Infection Successful surgery in acute type a dissection in a patient with covid-19 Acute Type A Aortic Dissection During the COVID-19 Outbreak A fatal association of COVID-19 and acute complicated Type-B aortic dissection: Interventional management in a difficult situation Acute Type A Aortic Dissection Complicated by COVID-19 Infection Surgical management of thoracic aortic emergency with pre-and postoperative COVID-19 disease Acute type A aortic dissection in a patient with COVID-19 Acute pulmonary embolism following acute type A aortic dissection in a patient with COVID-19 Successful Anesthesia Management in a Patient With Type A Aortic Dissection Complicated by Renal Failure and Suspected Coronavirus Disease Acute Aortic Dissection Surgery in a Patient With COVID-19 Ultrastructural Evidence for Direct Renal Infection with SARS-CoV-2 Acute aortic dissection in a patient with Williams syndrome infected by COVID-19. Cardiology in the Young Cardiovascular patients in COVID-19 era, a case series Isolation protocol for a COVID-2019 patient requiring emergent surgical intervention: Case presentation Covid-19 positivity affects outcome of cardiac surgical patients Type A aortic syndromes in COVID-19 positive patients: Case series from a UK multicentre study Anesthetic Management of Patients Undergoing Aortic Dissection Repair With Suspected Severe Acute Respiratory Syndrome COVID-19 Infection Turn down of acute aortic syndrome cases during COVID-19: Results from UK multicentre studies Hospitalizations for emergency-sensitive conditions in Germany during the Covid-19 pandemic-Insights from the German-wide Helios hospital network. medRxiv Impact of COVID-19 on aortic operations. Seminars in Vascular Surgery The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.