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REVIEW ARTICLES

Calcific aortic valve stenosis and COVID-19: clinical management, valvular damage, and pathophysiological mechanisms

Bäck, Magnus1,2,3,∗; Hashem, Mohammed1,2; Giani, Anna1,2,4; Pawelzik, Sven-Christian1,2,3; Franco-Cereceda, Anders5,6

Author Information
doi: 10.1097/CP9.0000000000000001
  • Open

Abstract

Introduction

Corona virus disease (COVID)-19 could cause damages to myocardium and vasculature, either due to direct viral infection or as consequences of systemic inflammation, hypoxia, cytokine storm, endothelial dysfunction, and immune responses[1–4]. Myocardial injury occurs with a similar frequency in infection with influenza virus and Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) (65.5% and 47.8%, respectively), but the mortality is almost 4-fold higher in COVID-19 compared with influenza[5]. Cardiac valves are also potential targets for the SARS-CoV-2 virus[6] besides myocardial and pericardial complications[7]. In addition to direct exposure to viremia, cardiac valves are sensitive to local and systemic inflammatory stimuli. The endothelial cell layer that covers cardiac valves is a target for SARS-CoV-2[4]. Despite very few reported cases of valvular involvement in COVID-19, increasing evidence points toward COVID-19 having serious consequences for the clinical management of valvular heart disease (VHD) with prognostic implications. The causal relation of SARS-CoV-2 infection and valvular damage for long-term VHD remains to be established.

Calcific aortic valve stenosis (CAVS) is the most common VHD and shares several risk factors with severe COVID-19. In particular, CAVS is more common in men than in women, with the highest prevalence in older adults. In addition, CAVS is associated with cardiovascular co-morbidities[8], obesity[9], hypertension[10], diabetes[11], and chronic kidney disease[12], which also represent major risk factors for poor prognosis in COVID-19.

The prevailing pathophysiological processes underlying CAVS are inflammation, fibrosis, leaflet thrombosis, and calcification of the aortic valve[13]. The resulting thickening and reduced opening of the aortic valve causes a left ventricular outflow obstruction. If untreated, severe and symptomatic CAVS is a cause of heart failure and increased mortality. The mainstay of CAVS treatment is valve prothesis, by means of either surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI).

This review summarizes the evidence that suggests CAVS is an overlooked cardiovascular implication in COVID-19. We also review several strategies in managing CAVS patients in the COVID-19 era. Specifically, the impact of the COVID-19 pandemic on CAVS management is reviewed along with the proposed changes in diagnostic, interventional, and follow-up clinical processes for patients with VHD in general and CAVS in particular. Prognostic implications for concomitant CAVS and SARS-CoV-2 infection are also addressed. Putative SARS-CoV-2-induced direct and systemic indirect effects on the aortic valve and possible mechanisms linking COVID-19 to CAVS pathophysiology are presented. Finally, specific changes in the management of CAVS, clinical considerations, and future therapeutic options will be outlined.

Clinical management of CAVS during the COVID-19 pandemic

Consequences of COVID-19 for the management of CAVS

Observational studies in the initial phases of the COVID-19 pandemic reported increased waiting times for patients with severe CAVS to undergo TAVI and SAVR. In a single-center cohort from the United States, the rate of cardiovascular events in patients receiving TAVI was 35% over 3-month versus 10% with 1-month delay[14]. A two-site center study in the UK reported an initial reduction by more than one third of all aortic valve surgery with more than two thirds reduction in elective cases balanced by a substantial increase in urgent SAVR[15]. The reported periprocedural risk was higher, whereas 30-day survival and complication rates were unchanged. The recent prospective cohort study Deferred versus Expedited Aortic Valve Replacement in Patients with Symptomatic Severe Aortic Stenosis During the SARS-CoV-2 Pandemic (AS DEFER) from the initial pandemic period, when elective interventions were banned in Switzerland, showed that deferred AVR was associated with an increased risk of all-cause mortality, stroke, and hospitalization for heart failure due to an increased waiting time[16]. These reports illustrate changes in the clinical management of prevalent VHD during the pandemic may be one of the factors behind the prognostic implications.

Concomitant CAVS and COVID-19

In addition to delays of SAVR and TAVI, subjects with concomitant CAVS and COVID-19 have poorer CAVS prognosis. The COVID-19 Valve Disease (CVD) Registry is an international multicenter collaboration including 74 severe CAVS patients positive for SARS-CoV-2[17]. The 20% who underwent either TAVI or SAVR had a >40% 1-month mortality. The worst outcome was observed in COVID-19 patients >80 years of age without interventional treatment, reaching a 1-month mortality of almost 60%. The mortality was lower in patients undergoing valve intervention, but still as high as 17% in treated older patients[17].

Approaches to optimize CAVS management during the COVID-19 pandemic

Table 1 summarizes reports that made recommendations for the clinical management of VHD during the COVID-19 pandemic. These recommendations included: prioritization of urgent SAVR and TAVI, preference of early hospital discharge, and limitation of pre- and post-procedural outpatient contact. Telemedicine has also been proposed to reduce physician-to-patient contact[18], but requirement of repeated cardiac imaging for CAVS diagnosis and follow-up remain a challenge. A recent report on Creating a better journey of care for patients with heart valve disease[19] concluded that ensuring access to appropriate diagnosis and care without delay is imperative for rebuilding health systems after the COVID-19 pandemic.

Table 1 - Summary of reports on Clinical management of VHD during COVID-19
Authors Main topic Recommendations for Management
Radke et al. [80] Valvular disease is part of the high-risk factors in ACHD with COVID-19. Low to moderate risk ACHD patients without signs of deterioration should be subject remote follow-up.High-risk patients with signs of respiratory or cardiovascular impairment should be admitted to a tertiary ACHD centre.
Chung et al. [81] How structural heart disease practice was altered in a cardiac clinic during COVID-19 pandemic. Ensure timely treatment of structural heart disease patients.Minimise risk of COVID-19 exposure.Limit resource utilisation under conditions of constraint.
Khan et al. [82] Impact of the COVID-19 pandemic on the management of severe CAVS Preparation phase for increased capacity and cancellation of elective procedures. Surge phase with treatment limited to urgent patients. Recovery and restoration phase with procedures postponed until after pandemic peak.
Shah et al. [83] Outpatient management of VHD following the COVID-19 pandemic Highest clinical priority is for those with symptomatic followed by asymptomatic VHD.Severe low-flow low-gradient aortic stenosis should receive face-to-face visits.Aortic valve replacements should be considered on an individual basis.Guidance on the identification of stable VHD that could have follow-up deferred.Virtual clinics should be further developed and evaluated.
George et al. [84] Cardiac surgical priority during the pandemic Prioritize VHD procedures with shorter stay (e.g., TAVI).Asymptomatic CAVS surgery should be postponed due to low risk.
Tay et al. [85] The impact of COVID-19 on TAVI procedures in Asia assessed with a survey. Pre-TAVI workup with minimized testing, teleconsultation, and COVID19 testing. COVID-adjusted TAVI timings (critical, semi-urgent, elective TAVI), TAVI procedure (negative cath lab pressure, minimize periprocedural personnel, local anaesthesia when possible). [18] Post procedure measure (early discharge, teleconsultation follow-up).
Khialani and MacCarthy [86] TAVI in CAVS during the COVID-19 pandemic Cancel elective procedures.Prioritise urgent inpatients.Triage new patients and patients on TAVI/SAVR waiting lists.Maintain capacity by rapid discharge.
Fudulu et al. [87] Mini-sternotomy aortic valve replacement during COVID-19 pandemic. Triaged weighing up mortality risks of COVID against VHD.Intraoperatively, robot-assisted surgery could reduce transmission of COVID-19.Consider patients as COVID-19 positive even with a negative test.Postoperative patients should have rapid discharge.
Shafi and Awad [88] TAVI versus SAVR during COVID-19 pandemic. Further data on long-term mortality, morbidity, and costs are needed for TAVI as an alternative to SAVR due to pandemic.
ACHD: adults with congenital heart disease; CAVS: calcific aortic valve stenosis; COVID-19: corona virus disease-19; SAVR: surgical aortic valve replacement; TAVI: transcatheter aortic valve implantation; VHD: valvular heart disease.

Clinical observations of valvular damage in COVID-19

Endocarditis

A recent review identified 15 case reports of infective endocarditis concurrent with COVID-19, of which 73% developed infectious endocarditis of native heart valves and 27% on bioprosthetic valves[20]. Mortality was 38%, and the most common infective agents were Enterococcus faecalis, and methicillin-resistant (MRSA) or -susceptible (MSSA) Staphylococcus aureus. Since these pathogens are bacterial, it is postulated that widespread inflammation due to COVID-19 infection could cause damage to the endocardium, which allows for subsequent bacterial adhesion and colonization. However, one need to consider that case studies alone cannot be used to demonstrate either association or causation.

Valve thrombosis

One case of bioprosthetic valve thrombosis associated with COVID-19 has been reported. In this case, increased transaortic velocity on transthoracic echocardiography and hypoattenuated leaflet thickening (HALT) on computed tomography angiography were apparent[21].

Valvular calcification

A higher prevalence of cardiovascular comorbidities in male COVID-19 patients has been reported[22]. Vascular calcification is generally higher in men than in women, but the same burden of coronary calcification has been found in men and women with poor COVID-19 outcomes. Coronary artery calcification has been proposed as a marker for worse COVID-19 outcomes[23]. Given that calcification is the prevailing pathophysiology in CAVS[13], the observed link between COVID-19 and coronary calcification may have implications for CAVS. Importantly, the cardiovascular calcification process develops over a large time span and is regulated by pro- and anti-calcifying factors[24]. The relation between an acute infection and chronic valvular calcification remains to be established.

Rheumatic heart disease

Rheumatic heart disease (RHD) manifests as stenotic affection of mainly the mitral but also the aortic valve. A diagnosis of uncomplicated RHD can progress to cardiovascular complications[25] and population-based screening for subclinical RHD has been studied for early detection[26]. Importantly, direct and indirect risks of COVID-19 occur in people living with RHD[27]. Since RHD develops as a sequel of acute rheumatic fever caused by group A beta-haemolytic streptococci[27], this illustrates a prototype for a possible relation between an acute infection and chronic VHD. The parallels of rheumatic fever and RHD with COVID-19 and valvular complications can at the moment only be speculated. However, RHD brings attention to acute irreversible valve injury and persistent immunological modifications as possible risk of long-term valvular affection after an acute SARS-CoV-2 infection.

Putative mechanisms for CAVS consequences of COVID-19

ACE2 and viral entry

The renin-angiotensin-aldosterone-system (RAAS) is a key cardiovascular regulatory pathway. Angiotensin converting enzyme (ACE) catalyzes the generation of angiotensin II (Ang II). The Ang II-induced effects on blood pressure, vasoconstriction, and vascular inflammation are prevented by ACE inhibitors and Ang II type 1 receptor (AR1-R) antagonists. ACE2 has both transport and enzymatic functions to facilitate cellular amino acid transport and to degrade Ang II and thus negatively regulate the RAAS system[28]. The wide distribution of ACE2 in cardiovascular tissues and the fact that ACE2 is the receptor for the SARS-CoV-2 receptor S protein, may explain the high rate of cardiovascular complications in COVID-19[4].

ACE2 and valve remodeling

The RAAS system is activated in CAVS as evidenced by elevated Ang II in the circulation as well as in calcified versus healthy aortic valves. In both in vivo and in vitro experiments, Ang II induces profibrotic responses, indicating a causal role in the fibrocalcific transition in CAVS. Increased Ang II as well as the use of ACE inhibitors and AR1-R antagonists have been associated with a systemic increase in ACE2. In contrast, compensatory ACE2 increase is not observed locally in calcified aortic valve tissue[29]. Nevertheless, valvular ACE2 expression throughout the CAVS disease continuum provides a rationale for possible local viral uptake in the aortic valve[4]. Furthermore, SARS-CoV-2 binding ACE2 for valvular uptake and lysosomal ACE2 degradation may decrease the enzymatic degradation of Ang II into the Ang (1–7) peptide, and by doing so, limit the ligand binding and block the profibrotic response though AT1-R (Figure 1). In addition, Ang (1–7) is an agonist for the MAS-receptor (mitochondrial assembly 1 (MAS1) proto-oncogene) transducing potential beneficial effects in aortic valves, including antifibrotic and anti-inflammatory effects and enhanced NO-mediated responses in endothelial cells[29].

F1
Figure 1:
The role of ACE 2 in SARS-CoV-2 infection and calcific aortic valve disease.ACE: angiotensin converting enzyme; AT1R: angiotensin type 1 receptor; MAS: mitochondrial assembly; SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus-2.

ACE2 in CAVS

A recent report highlighted a link between ACE2 activity and the degree of aortic valve calcification but failed to establish an association with hemodynamic disease severity[30]. Furthermore, older adults awaiting TAVI for severe CAVS had 4- and 6-fold higher circulating ACE2 levels than young hypertensive and healthy subjects, respectively. The observed difference in ACE2 levels between CAVS and hypertension was also evident in an age-matched subgroup, and ACE2 levels were not altered by angiotensin modifying drug use[31]. Although ACE2 sex-differences were not observed in the latter CAVS cohort, male sex has been established as the strongest predictor of ACE2 levels in heart failure and believed to explain the higher incidence and mortality for COVID-19 in men[32]. In view of the pronounced sex-differences in CAVS prevalence, management, and prognosis[33] as well as sex-differential disease mechanisms through a prevailing valve fibrosis in women[34], ACE2 has increasingly been viewed as a regulator of valve fibrocalcific morphology and a link to COVID-19 cardiovascular implications and severity.

Systemic and cardiac ACE2

The soluble form of ACE2 may exert competitive viral binding with the membrane-attached form[28], leading to a hypothesis of a possible protective role of soluble ACE2[35]. Initial circulating ACE2 correlates, however, with COVID-19 severity and predicts mortality[36]. Importantly, serum ACE2 levels in patients undergoing heart transplantation reflect cardiac ACE2 expression[37]. The results of the latter study suggested that increased soluble ACE2 is a risk marker for COVID-19-related cardiac injury, with possible extrapolation for valvular implications. These findings warrant further exploration of a causative relation of SARS-CoV-2 and ACE2 interaction with aortic valve structural and functional alterations, as well as of ACE2 as a contributing factor to CAVS risk for COVID-19 severity.

Endothelial function

ACE2 is implicated as the starting point for a SARS-CoV-2-induced endothelitis in the vasculature, which in turn enhances the immune cell recruitment, cytokine production, and prothrombotic effects[4]. Importantly, the aortic valve is covered by an endothelial layer, which regulates the homeostasis of the aortic valve[38]. Valvular endothelial dysfunction has been identified as one of underlying causes of CAVS initiation and progression. Damaged valvular endothelial layer increases the valvular stiffness[39]. In addition, reduced nitric oxide (NO) is hallmark for endothelial dysfunction[40]. Finally, valvular endothelium is key for the recruitment and activation of immune cells locally in the aortic valve. In total, disruption of a functional valvular endothelial may move aortic valve processes over a “tipping point” toward severe CAVS[38].

Flow-mediated dilation has revealed chronic vascular endothelial dysfunction in convalescent COVID-19 patients[41]. Given the shared stimulators, a concomitant vascular and valvular endothelial dysfunction may occur as long-term consequences of a previous acute SARS-CoV-2 infection. Furthermore, artery flow mediated dilation (FMD) is altered with aortic valve morphology[42], supporting a role of endothelial dysfunction in valvular consequences in the COVID-19 continuum.

Acute and chronic inflammation

The mediators of the hyperinflammation in acute COVID-19 have the potential to directly exert effects on the aortic valve. A large spectrum of cytokines, chemokines, and proinflammatory lipid mediatore of the eicosanoid family are increased in COVID-19 (Figure 2) and have been evaluated as specific therapeutic targets to dampen the hyperinflammation stage[43–45]. The efficacy of glucocorticoids in COVID-19[46] confirmed the benefit of immunosuppression, albeit with important caveats[47].

F2
Figure 2:
The inflammatory response during acute and convalescent COVID-19, and its implications for the aortic valve.[44]COVID-19: corona virus disease-19.

A large proportion of the identified components of the COVID-19 hyperinflammation have been previously studied for their contribution to local effects in aortic valves. Inflammatory valvular damage in response to acute infection is hence probable. However, it is unknown if immune-mediated effects on the aortic valve during the acute phase of COVID-19 may lead to irreversible changes. Cardiac imaging has implicated persistent myocardial inflammation post COVID-19[48]. Long-term follow up of patients with convalescent COVID-19 are needed to provide information on whether COVID-19 leads to persistent valvular inflammatory activity.

One of the characteristics for the immune response to SARS-CoV-2 infection with potential cardiovascular relevance is a high neutrophil to lymphocyte ratio (NLR). Increased NLR has been associated with poor prognosis in COVID-19[49], as well as adverse cardiovascular outcomes[50], CAVS severity[51], and post AVR mortality[52]. The cardiovascular outcomes rather reflect chronic NLR status, and it is unknown if COVID-19-induced acute changes in NLR are directly linked to long-term cardiovascular outcomes. High NLR in CAVS patients undergoing surgical AVR is however also associated with short-term postoperative mortality[52], raising the notion that NLR should be considered in COVID-19 patients with severe CAVS for the disease outcome and timing of aortic valve intervention. The lymphopenia component of high NLR is more severe and persists for a longer period after COVID-19 compared with other respiratory virus infections[53]. SARS-CoV-2-specific T lymphocytes in convalescent patients reflect immunological memory, but long-term immunological aberration and its implications for chronic aortic valve inflammation remain unknown.

Mast cells are implicated in the immune response of long-haul COVID syndrome (LHCS), which is characterized by persistent malaise, myalgias, and neuropsychiatric symptoms[54]. LHCS has been associated with chronic mast cell activation syndrome[55]. Mast cell activation in addition plays a key role in the chronic inflammation leading to CAVS[56]. In particular, mast cell-derived lipid eicosanoid mediators have been implicated in the pathophysiological pathways leading to CAVS[57].

Prolonged inflammatory stimulation in COVID-19 also illustrates a dysfunctional resolution of inflammation, resulting in either a chronic non-resolving inflammation or a slow-resolving inflammatory response, hence prolonging the exposure of the aortic valve to inflammatory stimulation (Figure 2). Macrophage polarization is a key feature of the resolution of inflammation[58], which in part is regulated through epigenetic reprogramming[59]. The latter suggests that the COVID-19 microenvironment may result in persistent epigenetic alterations of macrophages phenotypes. Furthermore, specialized proresolving mediators (SPM)[60] are decreased in COVID-19[61] and CAVS[62], suggesting a common regulatory pathway. Stimulating the resolution of inflammation through supplementation with omega-3 fatty acids as substrate for increased SPM biosynthesis has been proposed a therapeutic option for both COVID-19[44] and CAVS[63].

Toll-like receptors (TLRs) are part of the first immune defence against SARS-CoV-2, but with both beneficial and harmful consequences in COVID-19[64]. The rare genetic TLR7 deficiency leads to more severe COVID-19 in young men without other risk factors[65], pointing to important regulatory mechanisms of this pathway. Calcified aortic valve tissue contains decreased levels of TLR-7-expressing macrophages, which are characterized by a proresolving response to the TLR-7 ligand imiquimod[66]. These findings reinforce the notion that a failure in the resolution of inflammation predicts more severe disease in both COVID-19 and CAVS.

Taken together, cardiac valve damage in response to acute COVID-19 hyperinflammation, dysfunctional resolution of inflammation, and long-term persistent valvular immunological aberrations all contribute to CAVS but require further studies (Figure 2).

Oxidative stress

Production of reactive oxygen species (ROS) by neutrophils has also been implicated in COVID-19 (Figure 2)[67]. CAVS is characterized by a reduction of antioxidant activity[68], indicating a susceptibility to excess valvular oxidative stress in COVID-19 with concomitant CAVS compared with infection in subjects with healthy aortic valves.

The local valvular ROS generation may contribute to lipid and lipoprotein oxidation, which is one of the key initiating stages of CAVS[69]. ROS serve as a stimulator of osteogenic activation of valvular interstitial cells and valve calcification[69,70]. Oxidative stress also regulates macrophage polarization and impedes the resolution of inflammation[71]. In addition, ROS may trigger responses that persist after viral clearance. Tissue damage caused by increased ROS may in some cases be irreversible (Figure 2). Furthermore, excess ROS generation in response to SARS-CoV-2 infection may also induce DNA damage and trigger dysfunctional DNA-repair[69], leading to permanent alterations, including local telomere shortening[72], which, when appearing locally in aortic valves, may participate in the development of CAVS[73].

Prothrombotic effects

Increased thrombosis due to SARS-CoV-2 infection was first described in lung tissue of patients who died of COVID-19 compared to influenza[74]. In addition to severe endothelial injury, intracellular virus particles, and disrupted cell membranes, COVID-19 patients displayed widespread thrombosis and microangiopathy in pulmonary vessels[74]. The reported case of valve thrombosis[21] indicates that local valvular microthrombi may be triggered by SARS-CoV-2 infection. The increased immuno-thrombosis, endothelial dysfunction, and ROS-induced valve damage can potentially represent an augmented exposure of cardiac valves to a prothrombotic milieu during active COVID-19, with a potentially persistent pro-thrombotic state post COVID-19 (Figure 2).

The formation of thrombi on prosthetic aortic valves is the underlying cause of HALT and may participate in prosthesis degeneration and thromboembolic complications. In addition, microthrombi have been described on native aortic valves[75] and shown to stimulate calcification of aortic valve interstitial cells[76]. Localized valvular thrombosis at the sites of endothelial damage[76] suggests that valve damage in COVID-19 may expose trigger sites for valvular platelet aggregation. Continuing augmented valvular thrombus formation post COVID-19 may be stimulated by irreversible valvular damage as well as a persistent endothelial dysfunction and pro-thrombotic state (Figure 2). If the resolution of inflammation is dysfunctional in COVID-19, the resulting chronic inflammation may serve as a stimulator of continued active immune-thrombosis.

The estimated incidence of thrombotic complications is 1 per 100,000 COVID-19 vaccinated people irrespective of age versus 1 in 50,000 in older people (above 50 years of age) vaccinated with ChAdOx1 nCoV-19[77]. This phenomenon is referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT) and is associated with increased levels of anti-PF4 antibodies[77]. Cases of valvular thrombosis have been reported in subjects with anti-PF4-positive heparin-induced thrombocytopenia (HIT)[78–79], providing a possible link to direct valve thrombosis.

Summary and conclusions

Cardiac valves are potential additional cardiac targets for SARS-CoV-2. First, main risk factors for CAVS (male sex, older age, cardiovascular co-morbidities, obesity, hypertension, diabetes, and chronic kidney disease) are associated with poorer prognosis in COVID-19 and may represent either confounders for the observed associations or common vulnerability for the two diseases. Second, the presence of CAVS has prognostic implications for SARS-CoV-2 infection presentation and how COVID-19 affects CAVS prognosis. Third, the clinical management of CAVS, in terms of diagnostic, interventional, and follow-up processes, needs to be optimized. Fourth, direct valve damage has been documented in case reports of COVID-19 patients. Fifth, potential mechanisms include valve fibrosis affection through the SARS-CoV-2 interaction with ACE2, a failure in the resolution of COVID-19-induced hyperinflammation, endothelial dysfunction, oxidative stress, and thrombosis. Importantly, the acute phase of COVID-19 may cause irreversible valve damage favoring future CAVS. In addition, persistent prothrombotic state and endothelial dysfunction, in combination with a non-resolving or slow-resolving immune response under some circumstances, may represent chronic stimulation of pathophysiological pathways toward CAVS.

Funding

The authors are supported by the Swedish Research Council (grant number 2019-01486), the Swedish Heart and Lung Foundation (grant number 20180571), the King Gustaf V and Queen Victoria Freemason Foundation, Stiftelsen Professor Nanna Svartz fond, and a donation from Mr. Fredrik Lundberg.

Author contributions

MB and MH wrote original draft preparation; MB, AG, and SCP prepared the revised manuscript; MB and AFC conceptualized the manuscript and supervised the project. All authors reviewed, edited, and approved the manuscript.

Conflict of interest statement

The authors declare that they have no financial conflict of interest with regard to the content of this manuscript.

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Keywords:

Aortic stenosis; Inflammation; Resolution of inflammation; Omega-3 fatty acids; Valve thrombosis

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