Procoagulant phenotype of virus-infected pericytes is associated with portal thrombosis and intrapulmonary vascular dilations in fatal COVID-19.

BACKGROUND & AIMS: The underlying mechanisms and clinical impact of portal microthrombosis in severe COVID-19 are unknown. Intrapulmonary vascular dilation (IPVD)-related hypoxia has been described in severe liver diseases. We hypothesised that portal microthrombosis is associated with IPVD and fatal respiratory failure in COVID-19. METHODS: Ninety-three patients who died from COVID-19 were analysed for portal microvascular damage (histology), IPVD (histology and chest-computed tomography, CT), and hypoxemia (arterial blood gas). Seventeen patients who died from COVID-19-unrelated pneumonia served as controls. Vascular lesions and microthrombi were phenotyped for endothelial (vWF) and pericyte (αSMA/PDGFR-ß) markers, tissue factor (TF), viral spike protein and nucleoprotein (SP, NP), fibrinogen, and platelets (CD41a). Viral particles in vascular cells were assessed by transmission electron microscopy. Cultured pericytes were infected with SARS-CoV-2 to measure TF expression and tubulisation of human pulmonary microvascular endothelial cells was assessed upon vWF treatment. RESULTS: IPVD was present in 16/66 patients with COVID-19, with available liver and lung histology, and was associated with younger age (62 vs. 78 years-old), longer illness (25 vs. 14 days), worsening hypoxemia (PaO2/FiO2 from 209 to 89), and an increased requirement for ventilatory support (63% vs. 22%) compared to COVID-19/Non-IPVD. IPVD, absent in controls, was confirmed by chest CT. COVID-19/IPVD liver histology showed portal microthrombosis in >82.5% of portal areas, with a thicker wall of αSMA/PDGFR-ß+/SP+/NP+ pericytes compared with COVID-19/Non-IPVD. Thrombosed portal venules correlated with αSMA+ area, whereas infected SP+/NP+ pericytes expressed TF. SARS-CoV-2 viral particles were observed in portal pericytes. In vitro SARS-CoV-2 infection of pericytes upregulated TF and induced endothelial cells to overexpress vWF, which expanded human pulmonary microvascular endothelial cell tubules. CONCLUSIONS: SARS-CoV-2 infection of liver pericytes elicits a local procoagulant response associated with extensive portal microthrombosis, IPVD and worsening respiratory failure in fatal COVID-19. IMPACT AND IMPLICATIONS: Vascular involvement of the liver represents a serious complication of COVID-19 infection that must be considered in the work-up of patients with long-lasting and progressively worsening respiratory failure, as it may associate with the development of intrapulmonary vascular dilations. This clinical picture is associated with a procoagulant phenotype of portal venule pericytes, which is induced by SARS-CoV-2 infection of pericytes. Both observations provide a model that may apply, at least in part, to other vascular disorders of the liver, featuring obliterative portal venopathy, similarly characterised at the clinical level by development of hypoxemia and at the histological level by phlebosclerosis and reduced calibre of the portal vein branches in the absence of cirrhosis. Moreover, our findings shed light on an overlooked player in the pathophysiology of thrombosis, i.e. pericytes, which may present a novel therapeutic target.

Effect of late gadolinium enhancement on left atrial impairment in myocarditis patients.

OBJECTIVE: The aims of our study were to investigate the effect of the extent and location of late gadolinium enhancement (LGE) on the left atrium (LA) function in patients with acute myocarditis (AM) using cardiovascular magnetic resonance (CMR). METHOD: This retrospective study performed CMR scans in 113 consecutive patients (89 males, 24 females; mean age 45.8 ± 17.3 years) with AM that met the updated Lake Louise criteria. Reservoir, conduit, and booster LA functions were analyzed by CMR feature tracking using dedicated software. Besides LA strain measurements, myocardial scar location and extent were assigned and quantified by LGE imaging. RESULTS: AM patients with septal LGE had impaired reservoir, conduit, and conduit strain rate function in comparison with AM patients with non-septal LGE (p = 0.001, for all). In fully adjusted multivariable linear regression, reservoir and conduit were significantly associated with left ventricle (LV) LGE location (ß coefficient = 8.205, p = 0.007; ß coefficient = 5.185, p = 0.026; respectively). In addition, LA parameters decreased according to the increase in the extent of LV fibrosis (LGE ≤ 10%; LGE 11-19%; LGE ≥ 20%). After adjustment in multivariable linear regression, the association with LV LGE extent was no longer statistically significant. CONCLUSION: In patients with acute myocarditis, LA function abnormalities are significantly associated with LV LGE location, but not with LGE extent. Septal LGE is paralleled by a deterioration of LA reservoir and conduit function. CLINICAL RELEVANCE STATEMENT: Left atrium dysfunction is associated with the presence of late gadolinium enhancement in the left ventricle septum and can be useful in the clinical prognostication of patients with acute myocarditis, allowing individually tailored treatment. KEY POINTS: • Myocardial fibrosis is related to atrial impairment. • The location of myocardial fibrosis is the main determinant of atrial dysfunction in myocarditis patients. • The quantification of atrial mechanisms may provide more in-depth insight into myocarditis pathophysiology.

Atrial and ventricular strain using cardiovascular magnetic resonance in the prediction of outcomes of pericarditis patients: a pilot study.

OBJECTIVE: Our study aimed to explore with cardiovascular magnetic resonance (CMR) the impact of left atrial (LA) and left ventricular (LV) myocardial strain in patients with acute pericarditis and to investigate their possible prognostic significance in adverse outcomes. METHOD: This retrospective study performed CMR scans in 36 consecutive patients with acute pericarditis (24 males, age 52 [23-52]). The primary endpoint was the combination of recurrent pericarditis, constrictive pericarditis, and surgery for pericardial diseases defined as pericardial events. Atrial and ventricular strain function were performed on conventional cine SSFP sequences. RESULTS: After a median follow-up time of 16 months (interquartile range [13-24]), 12 patients with acute pericarditis reached the primary endpoint. In multivariable Cox regression analysis, LA reservoir and LA conduit strain parameters were all independent determinants of adverse pericardial diseases. Conversely, LV myocardial strain parameters did not remain an independent predictor of outcome. With receiving operating characteristics curve analysis, LA conduit and reservoir strain showed excellent predictive performance (area under the curve of 0.914 and 0.895, respectively) for outcome prediction at 12 months. CONCLUSION: LA reservoir and conduit mechanisms on CMR are independently associated with a higher risk of adverse pericardial events. Including atrial strain parameters in the management of acute pericarditis may improve risk stratification. CLINICAL RELEVANCE STATEMENT: Atrial strain could be a suitable non-invasive and non-contrast cardiovascular magnetic resonance parameter for predicting adverse pericardial complications in patients with acute pericarditis. KEY POINTS: • Myocardial strain is a well-validated CMR parameter for risk stratification in cardiovascular diseases. • LA reservoir and conduit functions are significantly associated with adverse pericardial events. • Atrial strain may serve as an additional non-contrast CMR parameter for stratifying patients with acute pericarditis.

Percutaneous recanalization of non-cirrhotic extrahepatic portal vein obstruction in children: technical considerations in a preliminary cohort.

OBJECTIVES: Portal hypertension resulting from non-cirrhotic extrahepatic portal vein obstruction (EHPVO) in children has been primarily managed with the Meso-Rex bypass, but only a few patients have a viable Rex recessus, required by surgery. This study reports a preliminary series of patients who underwent interventional radiology attempts at portal vein recanalization (PVR), with a focus on technical aspects and safety. METHODS: A retrospective review of consecutive patients with severe portal hypertension due to non-cirrhotic EHPVO at a single institution from 2022, who underwent percutaneous attempts at PVR, was performed. Technical and clinical data including fluoroscopy time, radiation exposure, technical and clinical success, complications and follow-up were recorded. RESULTS: Eleven patients (6 males and 5 females; median age 7 years, range 1-14) underwent 15 percutaneous transhepatic (n = 1), transplenic (n = 11), or simultaneous transhepatic/transplenic (n = 3) procedures. Rex recessus was patent in 4/11 (36%). Fluoroscopy resulted in a high median total dose area product (DAP) of 123 Gycm2 (range 17-788 Gycm2) per procedure. PVR was achieved in 5/11 patients (45%), 3/5 with obliterated Rex recessus. Two adverse events of grade 2 and grade 3 occurred without sequelae. After angioplasty, 4/5 patients required stenting to obtain sustained patency, as demonstrated by colour-Doppler ultrasound in all PVR after a median follow-up of 6 months (range 6-14). CONCLUSION: Our preliminary experience suggests that 45% of children with non-cirrhotic EHPVO can restore portal flow even with obliterated Rex recessus. In non-cirrhotic EHPVO, PVR may be an option, if a Meso-Rex bypass is not feasible, although the radiation exposure deserves attention. CLINICAL RELEVANCE STATEMENT: Innovative percutaneous procedures may have the potential to be an alternative option to the traditional surgical approach in the management of non-cirrhotic EHPVO and its complications in children not eligible for Meso-Rex bypass surgery. KEY POINTS: Non-cirrhotic portal hypertension in children has been traditionally managed by surgery with Meso-Rex bypass creation. Percutaneous PVR may restore the patency of the native portal system even when the Rex recessus is obliterated and surgery has been excluded. Interventional radiological techniques may offer a minimally invasive solution in complex cases of EHPVO in children when Meso-Rex bypass is not feasible.

An MRI assessment of prostate cancer local recurrence using the PI-RR system: diagnostic accuracy, inter-observer reliability among readers with variable experience, and correlation with PSA values.

OBJECTIVES: The Prostate Imaging for Recurrence Reporting (PI-RR) system has been recently proposed to promote standardisation in the MR assessment of prostate cancer (PCa) local recurrence after radical prostatectomy (RP) and radiation therapy (RT). This study aims to evaluate PI-RR's diagnostic accuracy, assess the inter-observer reliability among readers with variable experience, and correlate imaging results with anatomopathological and laboratory parameters. METHODS: Patients who underwent a pelvic MRI for suspicion of PCa local recurrence after RP or RT were retrospectively enrolled (October 2017-February 2020). PI-RR scores were independently assessed for each patient by five readers with variable experience in prostate MRI (two senior and three junior radiologists). Biochemical data and histopathological features were collected. The reference standard was determined through biochemical, imaging, or histopathological follow-up data. Reader's diagnostic performance was assessed using contingency tables. Cohen's kappa coefficient (κ) and intraclass correlation coefficient (ICC) were calculated to measure inter-observer reliability. RESULTS: The final cohort included 120 patients (median age, 72 years [IQR, 62-82]). Recurrence was confirmed in 106 (88.3%) patients. Considering a PI-RR score ≥ 3 as positive for recurrence, minimum and maximum diagnostic values among the readers were as follows: sensitivity 79-86%; specificity 64-86%; positive predictive value 95-98%; negative predictive value 33-46%; accuracy 79-87%. Regardless of reader's level of experience, the inter-observer reliability resulted good or excellent (κ ranges across all readers: 0.52-0.77), and ICC was 0.8. Prostate-specific antigen (PSA) velocity, baseline-PSA, and trigger-PSA resulted predictive of local recurrence at imaging. CONCLUSIONS: The PI-RR system is an effective tool for MRI evaluation of PCa local recurrence and facilitates uniformity among radiologists. CLINICAL RELEVANCE STATEMENT: This study confirmed the PI-RR system's good diagnostic accuracy for the MRI evaluation of PCa local recurrences. It showed high reproducibility among readers with variable experience levels, validating it as a promising standardisation tool for assessing patients with biochemical recurrence. KEY POINTS: • In this retrospective study, the PI-RR system revealed promising diagnostic performances among five readers with different experience (sensitivity 79-86%; specificity 64-86%; accuracy 79-87%). • The inter-observer reliability among the five readers resulted good or excellent (κ ranges: 0.52-0.77) with an intraclass correlation coefficient of 0.8. • The PI-RR assessment score may facilitate standardisation and generalizability in the evaluation of prostate cancer local recurrence among radiologists.

Diffusion magnetic resonance imaging for kidney cyst volume quantification and non-cystic tissue characterisation in ADPKD.

OBJECTIVES: Beyond total kidney and cyst volume (TCV), non-cystic tissue plays an important role in autosomal dominant polycystic kidney disease (ADPKD) progression. This study aims at presenting and preliminarily validating a diffusion MRI (DWI)-based TCV quantification method and providing evidence of DWI potential in characterising non-cystic tissue microstructure. METHODS: T2-weighted MRI and DWI scans (b = 0, 15, 50, 100, 200, 350, 500, 700, 1000; 3 directions) were acquired from 35 ADPKD patients with CKD stage 1 to 3a and 15 healthy volunteers on a 1.5 T scanner. ADPKD classification was performed using the Mayo model. DWI scans were processed by mono- and segmented bi-exponential models. TCV was quantified on T2-weighted MRI by the reference semi-automatic method and automatically computed by thresholding the pure diffusivity (D) histogram. The agreement between reference and DWI-based TCV values and the differences in DWI-based parameters between healthy and ADPKD tissue components were assessed. RESULTS: There was strong correlation between DWI-based and reference TCV (rho = 0.994, p < 0.001). Non-cystic ADPKD tissue had significantly higher D, and lower pseudo-diffusion and flowing fraction than healthy tissue (p < 0.001). Moreover, apparent diffusion coefficient and D values significantly differed by Mayo imaging class, both in the whole kidney (Wilcoxon p = 0.007 and p = 0.004) and non-cystic tissue (p = 0.024 and p = 0.007). CONCLUSIONS: DWI shows potential in ADPKD to quantify TCV and characterise non-cystic kidney tissue microstructure, indicating the presence of microcysts and peritubular interstitial fibrosis. DWI could complement existing biomarkers for non-invasively staging, monitoring, and predicting ADPKD progression and evaluating the impact of novel therapies, possibly targeting damaged non-cystic tissue besides cyst expansion. CLINICAL RELEVANCE STATEMENT: This study shows diffusion-weighted MRI (DWI) potential to quantify total cyst volume and characterise non-cystic kidney tissue microstructure in ADPKD. DWI could complement existing biomarkers for non-invasively staging, monitoring, and predicting ADPKD progression and evaluating the impact of novel therapies, possibly targeting damaged non-cystic tissue besides cyst expansion. KEY POINTS: • Diffusion magnetic resonance imaging shows potential to quantify total cyst volume in ADPKD. • Diffusion magnetic resonance imaging might allow to non-invasively characterise non-cystic kidney tissue microstructure. • Diffusion magnetic resonance imaging-based biomarkers significantly differ by Mayo imaging class, suggesting their possible prognostic value.

Chest CT opportunistic biomarkers for phenotyping high-risk COVID-19 patients: a retrospective multicentre study.

OBJECTIVE: To assess the value of opportunistic biomarkers derived from chest CT performed at hospital admission of COVID-19 patients for the phenotypization of high-risk patients. METHODS: In this multicentre retrospective study, 1845 consecutive COVID-19 patients with chest CT performed within 72 h from hospital admission were analysed. Clinical and outcome data were collected by each center 30 and 80 days after hospital admission. Patients with unknown outcomes were excluded. Chest CT was analysed in a single core lab and behind pneumonia CT scores were extracted opportunistic data about atherosclerotic profile (calcium score according to Agatston method), liver steatosis (≤ 40 HU), myosteatosis (paraspinal muscle F < 31.3 HU, M < 37.5 HU), and osteoporosis (D12 bone attenuation < 134 HU). Differences according to treatment and outcome were assessed with ANOVA. Prediction models were obtained using multivariate binary logistic regression and their AUCs were compared with the DeLong test. RESULTS: The final cohort included 1669 patients (age 67.5 [58.5-77.4] yo) mainly men 1105/1669, 66.2%) and with reduced oxygen saturation (92% [88-95%]). Pneumonia severity, high Agatston score, myosteatosis, liver steatosis, and osteoporosis derived from CT were more prevalent in patients with more aggressive treatment, access to ICU, and in-hospital death (always p < 0.05). A multivariable model including clinical and CT variables improved the capability to predict non-critical pneumonia compared to a model including only clinical variables (AUC 0.801 vs 0.789; p = 0.0198) to predict patient death (AUC 0.815 vs 0.800; p = 0.001). CONCLUSION: Opportunistic biomarkers derived from chest CT can improve the characterization of COVID-19 high-risk patients. CLINICAL RELEVANCE STATEMENT: In COVID-19 patients, opportunistic biomarkers of cardiometabolic risk extracted from chest CT improve patient risk stratification. KEY POINTS: • In COVID-19 patients, several information about patient comorbidities can be quantitatively extracted from chest CT, resulting associated with the severity of oxygen treatment, access to ICU, and death. • A prediction model based on multiparametric opportunistic biomarkers derived from chest CT resulted superior to a model including only clinical variables in a large cohort of 1669 patients suffering from SARS- CoV2 infection. • Opportunistic biomarkers of cardiometabolic comorbidities derived from chest CT may improve COVID-19 patients' risk stratification also in absence of detailed clinical data and laboratory tests identifying subclinical and previously unknown conditions.

Venous outflow obstruction in pediatric left lateral segment split liver transplantation.

BACKGROUND: Venous outflow obstruction (VOO) is a known cause of graft and patient loss after pediatric liver transplantation (LT). We analyzed the incidence, risk factors, diagnosis, management, and outcome of VOO in a large, consecutive series of left lateral segment (LLS) split LT with end-to-side triangular venous anastomosis. METHODS: We evaluated data collected in our prospective databases relative to all consecutive pediatric liver transplants performed from January 2006 to December 2021. We included in this study children undergoing LLS split liver transplant with end-to-side triangular anastomosis. Diagnosis of VOO was based on clinical suspicion and radiological confirmation. RESULTS: VOO occurred in 24/279 transplants (8.6%), and it was associated with lower graft weight (p = .04), re-transplantation (p = .008), and presence of two hepatic veins (p < .0001). In presence of two segmental veins' orifices, the type of reconstruction (single anastomosis after venoplasty or double anastomosis) was not significantly related to VOO (p = .87). Multivariable analysis indicated VOO as a risk factor for graft lost (hazard ratio 3.21, 95% confidence interval 1.22-8.46; p = .01). Percutaneous Transluminal Angioplasty (PTA) was effective in 17/22 (77%) transplants. Surgical anastomosis was redone in one case. Overall six grafts (25%) were lost. CONCLUSION: VOO after LLS split LT with end-to-side triangular anastomosis is an unusual but critical complication leading to graft loss in a quarter of cases. The occurrence of VOO was associated with lower graft weight, re-transplantation, and presence of two hepatic veins. PTA was safe and effective to restore proper venous outflow in most cases.

CT renal arteriography as a novel imaging guidance for the percutaneous ablation of small renal tumors.

PURPOSE: To report procedural data and outcomes of a novel image guidance technique, CT renal arteriography (CTRA), performed to target and ablate small intraparenchymal renal tumors. MATERIALS AND METHODS: We retrospectively analyzed data of 2 patients undergoing CTRA-guided ablation for 3 renal intraparenchymal tumors, from February to March 2023. We previously evaluated tumor visibility with US/CEUS, and in all cases conspicuity was poor, whereas contrast-enhanced CT (CECT) clearly depicted all hypervascular nodules. Our primary endpoint was CTRA-guidance feasibility for renal ablation, defined as the precise probe deployment inside the target tumor. The secondary endpoint was CTRA-guided ablation technical success, intended as the inclusion of the whole tumor inside the necrotic volume, with 5 mm safety margins. RENAL scores, complications, procedural time, dose length product (DLP), serum creatinine variation and hospital stay length were also recorded. RESULTS: A confident deployment of the probe tip inside the nodule was accomplished in all 3 cases, with a 100% of correct targeting. We observed immediate technical success after all 3 ablations. The 3 nodules had a RENAL score <7 points, and we encountered no complications due to line placement or ablation. The average time from preablative to postablative CTRA was 54 min (50-58min), with a DLP of 3632mGy*cm (2807-4458mGy*cm). Serum creatinine didn't show a significant variation after the procedures; both patients were hospitalized for 2 days. CONCLUSION: Preliminary data showed that CTRA-guidance might provide unique advantages over conventional CECT-guidance to assist the ablation of small renal intraparenchymal tumor not visualized on US/CEUS.

US-guided percutaneous thrombin injection to treat non-femoral artery pseudoaneurysms: preliminary experience and review of the literature.

PURPOSE: To evaluate the clinical outcome of US-guided percutaneous thrombin injection in the treatment of non-femoral artery pseudoaneurysms (NFAP). MATERIALS AND METHODS: Among all pseudoaneurysms treated in our institution, we retrospectively collected NFAP embolized with percutaneous thrombin injections from January 1, 2015, to December 31, 2021. The embolization was prompted for an ongoing antiaggregating/anticoagulation therapy, NFAP optimal US visibility, or high surgery-related risks. Causes, location, size and neck of NFAP, complications, number of repeated treatments, clinical success and patients clinical conditions at discharge were annotated. The endpoint for clinical success was the resolution of NFAP at postprocedural imaging, with no resort to surgery. RESULTS: Eight consecutive patients (5 females, median age 73 years, range 46-84) underwent 16 procedures. Arterial damage was due to catheterization (3), CVC mispositioning (2), trauma, hemorrhagic diathesis and endoprosthesis endoleak. We treated humeral (2), subclavian (2), thyrocervical, anterior tibial, radial and pancreaticoduodenal arteries. Median pseudoaneurysm size was 530 mm2 (range 32-2400 mm2), with a thin (7/8) or non-visible (1/8) neck. No complications occurred. Clinical success was obtained in 7/8 patients (88%), with a single treatment in 4, multiple in 3 cases (4 embolizations, 3 and 2, respectively). One patient underwent surgical suture after the second failed attempt of percutaneous embolization. Seven patients were discharged in good clinical conditions; one died during hospitalization, due to the worsening of the underlying cardiac disease. CONCLUSIONS: Percutaneous US-guided thrombin injection to treat NFAP is feasible in selected cases, with rare complications. Clinical success is often reached, also by repeated injections.