Complications Associated with Catheter Ablation of Atrial Fibrillation in Current Practice: Insights from a Large, Real-World Collaboration

Background: Catheter ablation is a cornerstone treatment for symptomatic atrial fibrillation (AF) with major improvements in safety over time. However, rates of adverse events with use of current techniques in a contemporary quality-focused network remain undefined. Objective(s): Across a large, real-world sample, we sought to describe (1) rates of major, adverse events associated with catheter ablation of AF and (2) patient-level factors associated with complications. Method(s): Utilizing the REAL-AF collaboration, a registry of contemporary AF ablation procedures with granular patient, procedural and follow-up data comprised of cases from over 50 operators across academic and non-academic sites, we evaluated all patients undergoing their first ablation procedure from January 2018 - June 2022. Risk-adjusted analyses were conducted to evaluate the relationship between patient factors and complications. Result(s): Among 3144 patients (age 66.1 +/- 11.0 years, 42% female, 67.1% paroxysmal, 32.9% persistent) who underwent AF ablation, procedure-related complications (n =77) were identified in 65 patients (2.1%) with multiple complications occurring in 9 patients (0.2%). Most complications (n=70, 93.5%) occurred in the peri-procedural (within 30 days) period and 6.5% (n=5) after 30 days, the latter of which all represented vascular injuries (Figure). Major complications (18 of 72 peri-procedural complications, 25.0%) are defined, detailed, and associated data reported in the Figure. Unadjusted (16.0% without CHF vs. 33.3% with CHF, p = 0.045) and risk-adjusted (OR 2.8, 95% CI 1.03-7.60, p=0.045) analyses indicated history of CHF was associated with a composite outcome of major complications. Analyses of independent complications showed those who suffered from peri-procedural stroke (n=3) were of significantly greater age (77.3 +/- 5.5 years vs. 66.1 +/- 10.9 years, p=0.035). Risk-adjusted analyses showed history of vascular disease (OR 2.9, 95% CI 1.02-8.20, p=0.045) was associated with vascular injury (n=18). From 0-695 days post-procedure, 31 deaths occurred (unknown cause: 17, COVID-19 related: 4, heart failure: 2, cardiac arrest: 2). Conclusion(s): Major complications represent rare events among those undergoing AF ablation in current practice. Risk-adjusted analyses suggest a history of CHF is associated with major complications. Similarly, older age and a history of vascular disease are associated with stroke and vascular complications, respectively. [Formula presented]Copyright © 2023

Mechanisms of impaired gas exchange following hospitalisation for severe COVID-19

Introduction/Aim: Reduced carbon monoxide diffusing capacity (DL CO) is common after recovery from severe COVID-19 and cohort studies have found it to be more abnormal than either VC or TLC. There is no specific evidence that this relates to membrane disfunction or vascular injury. Concurrent measurement of nitric oxide diffusing capacity (DL NO) and DL CO can be used to partition gas diffusion into its two components - membrane conductance (D m CO) and capillary blood volume (V C). In this study, we sought to evaluate D m CO and V C in the early and later recovery periods after severe COVID-19. Method(s): Patients attended for post-COVID outpatient clinical review and complex lung function testing including DL NO /DL CO (Hyp'Air;Medisoft, Leeds). Further appointments and repeat testing occurred when indicated. Lung function comparisons were made using t-tests. Result(s): 46 (8 female) subjects (mean+/-SD age 58+/-13, BMI 34+/-8), who had severe COVID pneumonitis, WHO ordinal severity classification of 6+/-1 and prolonged (19+/-22 days) length of hospital stay, were assessed 51+/-29 days post discharge. Mean TLC [z-score -1.64+/-1.31] and D L CO [z-score -1.60+/-1.48] were both reduced. V C and D m CO were reduced to a similar extent (Z-score -1.36+/-1.19 and -1.14+/-1.06, p=0.4). 14 (1 female) patients returned for testing 70+/-35 days later. In this subgroup, D L CO improved but remained below LLN (Z-score -2.98+/-0.73 [Visit 1] Vs -2.17+/-0.69 [Visit 2], p=0.01). D m CO improved (Z-score -1.99+/-0.91 Vs -1.25+/-1.17, p=0.01) but V C was unchanged (Z-score -2.33+/-0.53 Vs -2.03+/-0.76, p=0.17). Conclusion(s): Gas exchange is persistently abnormal after severe COVID. Membrane conductance is abnormal in the earlier recovery phase but improves to a significant extent. In contrast, reduced capillary blood volume persists. Repeat testing at longer intervals after recovery from acute illness is still required but these data raise the possibility that persisting effects of acute vascular injury will contribute to physiological impairment long after severe COVID pneumonitis.

Multi-scale Mechanisms of Maxing Shigantang in Treating Pneumonia Based on Transcriptomic Data.

Objective: Pneumonia is an infectious inflammation of the alveoli,distal airway,and interstitium caused by bacterial,viral,and other pathogens. Maxing Shigantang,originated from Treatise On Cold Damage Diseases,is a classic prescription for treating pneumonia,with significant clinical efficacy. However,its treatment mechanism is still elusive. Method(s): In that paper,the transcriptome-based multi-scale network pharmacology was used to reveal the overall pharmacological mechanism of Maxing Shigantang in treating pneumonia from six scales of tissue,cell,pathological process,biological process,signaling pathway, and target. Result(s):At the tissue level,Maxing Shigantang mainly acted on the focal tissue of pneumonia-lung and the main inflammatory immune tissues-blood and spleen. Analysis of cell,pathological process and biological process suggested that Maxing Shigantang could treat pneumonia by reversing inflammatory and immune functions and improving cardiopulmonary and vascular injury caused by pneumonia. Analysis of signaling pathway and target showed that Maxing Shigantang regulated inflammatory immune response pathways such as "coronavirus disease-COVID-19" and "Toll-like receptor signaling pathway",and related targets such as "MAPKAPK3" and "NRG1". Conclusion(s):This paper,from molecular to tissue levels,indicated Maxing Shigantang treated pneumonia mainly by regulating inflammatory immune response and improving cardiopulmonary and vascular injury.Copyright © 2023, China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica. All rights reserved.

Mechanisms of impaired gas exchange following hospitalisation for COVID-19

Introduction/Aim: Reduced carbon monoxide diffusing capacity (DL CO) is the most prevalent lung function abnormality post COVID-19 infection. Two studies suggested this relates to alveolar unit loss with preserved capillary blood volume. The measurement of nitric oxide diffusing capacity (D L NO) concurrently with D L CO allows for the quantitation of the membrane component of gas diffusion (D m CO) and capillary blood volume (V C). We sought to monitor D m CO and V C in the recovery period of patients hospitalised for severe COVID-19. Method(s): Patients attended outpatient clinical review and lung function testing including DL NO /DL CO (Hyp'Air;Medisoft, Leeds), with further appointment if indicated. Lung function comparisons were made using t-tests and clinical associations using Pearson correlation. Result(s): 46 (8 female) patients (mean+/-SD) (age 58+/-13, BMI 34+/-8), were assessed 51+/-29 days post discharge. WHO ordinal severity classification was 6+/-1, suggesting severe disease, with prolonged (19+/-22 days) length of admission. V C and D m CO were similarly reduced (Z-score -1.36+/-1.19 Vs -1.14+/-1.06, p = 0.4). V C was negatively correlated with length of stay (r=-0.42, p < 0.01). TLC (Z-score -1.64+/-1.31) and D L CO (-1.60+/-1.48) were significantly reduced and negatively correlated with length of stay (r>-0.41, p<=0.02). WHO severity negatively correlated with TLC only (r=-0.45, p < 0.01). Demographic and biochemical data did not correlate with lung function.14 (1 female) patients returned for repeat testing 70+/-35 days later. D m CO improved (Z-score -1.99+/-0.91 Vs -1.25+/-1.17, p = 0.01). V C was unchanged (Z-score -2.33+/-0.53 Vs -2.03+/-0.76, p = 0.17). D L CO improved but remained below LLN (Z-score -2.98+/-0.73 Vs -2.17+/-0.69, p = 0.01). Conclusion(s): Similar reductions in D m CO and V C following hospitalisation for COVID-19 were identified. In those who returned for repeat testing, D m CO values normalised, but V C did not improve. Abnormal lung function related to increasing severity and length of stay. These findings suggests vascular injury may play a more important role rather than alveolar unit loss as the primary contributor to gas exchange impairment following COVID-19.

Ventilatory support in Covid-19 pneumonia.

The Covid-19 pandemic led to a major influx of patients suffering from acute hypoxemic respiratory failure, which conducted intensivists to adapt ICU structures and question respiratory support strategies. Available data suggest that pathophysiology of Covid-19 associated - acute respiratory distress syndrome (ARDS) is substantially similar to the pathophysiology of ARDS unrelated to Covid-19. Specific vascular injuries may however be more frequent during Covid-19 and some patients may present a major alteration in hypoxic pulmonary vasoconstriction. To date, ventilatory support strategies of patients with Covid-19 should be in line with guidelines for ARDS unrelated to Covid-19, including in particular a cautious evaluation of positive end-expiratory pressure effects.Copyright © SRLF 2021.

COVID-19 and cardiovascular system: Not only heart but also vascular. The effects of the infection on arterial stiffness

Background: SARS-CoV-2 determines a framework of multi-organ dysfunction that can involve the cardiovascular system creating damages of different nature. Among these, endothelial damage could play a key role in increasing arterial stiffness and thus the cardiovascular risk of infected patients. The aim of this study is to evaluate the Pulse Wave Velocity (PWV) of a population of patients after recovery from infection and to compare them with those of a group affected by arterial hypertension. Method(s): This prospective observational monocentric study involved 143 patients with previous diagnosis of Covid-19 who undergone PWV measurement during the follow-up at a median time of 3.8 months after the infection. These patients were compared to a population of 143 patients with hypertension matched by age, sex, Systolic Blood Pressure values and Body Mass Index. Result(s): PWV values were higher in Covid-19 group comparing to hypertension group (10.5+/-3.0 m/s VS 8.9+/-2.5 m/s). Furthermore, there is a correlation between higher PWV values and lower values of SpO2% at time of admission at the Emergency Department. (R=-0.302;p<0.001). Conclusion(s): SARS-CoV-2 infection seems related to increased PWV values. Moreover, higher arterial stiffness seems correlated to a worse oxygen saturation in Emergency Department. More studies with longer follow-up time are necessary to establish whether the vascular damage is reversible and whether it correlates with an increase of long-term cardiovascular risk.

Persistence of inflammatory and vascular damage mediators 5 months after acute COVID-19

Background: In the acute phase, patients with severe COVID-19 exhibit pulmonary inflammation and vascular injury, as well as an exaggerated cytokine response. Aim(s): To describe the inflammatory cytokine and vascular injury mediator profiles in patients previously hospitalised with COVID-19, and to compare these profiles with those in healthy controls and in patients recovering from severe sepsis of other aetiology. Method(s): Plasma levels of 28 different cytokine, chemokine, angiogenic and vascular injury markers were measured by MSD V-PLEX multiplex assays in 49 post-COVID patients 5.0+/-1.9 (mean+/-SD) months after hospitalisation with COVID-19 pneumonia, 11 post-sepsis patients (5.4+/-2.9 months after hospitalised non-COVID sepsis) and 18 healthy controls. Kruskal-Wallis or ANOVA were used to compare groups;false discovery rate correction (Benjamini Hochberg) allowed for multiple testing. Result(s): In the post-COVID group, IL-6, TNFalpha, SAA, MCP1, Tie-2, Flt1, PIGF and CRP were significantly elevated, whereas IL-7 and bFGF were significantly depressed. The differences in TNFalpha, SAA, MCP1, Tie-2, Flt1, IL-7 and bFGF appeared unique to the post-COVID group, but increased IL-6, PIGF and CRP levels were also seen in postsepsis patients compared with controls. In post-COVID patients we found strong negative spearman correlations between each of IL-6 (r=-0.51) and CRP (r=-0.57) with TLCO %predicted (p<0.001) and positive correlations with post-recovery CT abnormality scores: IL-6 (r=0.28) and CRP (r=0.46), p<0.05. Conclusion(s): A unique signature of inflammatory and vascular damage markers is seen months after acute COVID19 infection. Further research is needed to determine their pathophysiological significance.

Ayurvedic Herbs and Spices: A Promising Approach for the Treatment of COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus accountable for the coronavirus disease 2019 (COVID-19) that has led to many fatal cases worldwide. It causes a severe acute respiratory syndrome, a hyperinflammatory response, vascular damage, mi-croangiopathy, and widespread thrombosis. Vaccines, interferon therapies, and small-molecule drugs may be among the various alternatives for managing or preventing emerging SARS-CoV-2 infections. New interventions, on the other hand, are likely to take months to years to develop. Furthermore, existing antiviral agents commonly develop viral resistance along with certain side effects. Therefore, effective prevention and treatment medications without side effects against human coronavirus are urgently needed. Indian and Chinese traditional medicine have suggested some natural products for the prevention, treatment, and rehabilitation of the diseases, including COVID-19 and various herbs and mushrooms that have been reported to possess potential antiviral and anti-inflammatory activities. Therefore, in this pandemic, traditional medicines pose a ray of hope for human health. The Ministry of Ayush, India, has also recommended a number of therapies to increase immunity in addition to ayurvedic treatments. Thus, the probability of naturally occurring substances as successful treatments against COVID-19 may seem hopeful due to their diverse biological and therapeutic properties. This review focuses on the latest updates of Ayurvedic herbs and spices as promising approaches for treatment during this devastating pandemic situation.Copyright © 2023 Bentham Science Publishers.

Finding an Answer for an Adolescent with Back Pain

Case report - Introduction: This is the case of an adolescent referred to rheumatology following 5 years of back pain. After years of trying a number of treatments without much success, the cause was found to be a previously undiagnosed urological pathology. The case highlights awareness of non-rheumatological causes and incidental findings which can redirect a patient towards more appropriate treatment and reduce the potential for long-term adverse health issues and anxiety. Case report - Case description: B was referred age 16 to rheumatology with a 5-year history of lower back pain. She had previously seen paediatricians with symptoms initially attributed to constipation due to intermittent straining and hard stool. However, constipation remedies had not relieved the pain which progressed gradually to a more persistent dull ache with impact on daily activities. Various analgesics (including paracetamol and non-steroidal anti-inflammatories), exercises and acupuncture had not helped. There was no history of recurrent urinary tract infections or symptom correlation with fluid intake, menstruation or bowel habit. No inflammatory features or connective tissue disease symptoms were noted and family history was unremarkable Clinical examination was normal apart from mild tenderness in the lumbar region. Rheumatoid factor was borderline positive (15 iu/mL) with the rest of blood tests normal including renal function, inflammatory markers (CRP, ESR), anti CCP and ANA. She had minimal microscopic haematuria without proteinuria. MRI spine in 2015 was normal. In view of her young age and symptoms affecting daily activities, STIR sequence spinal MRI was requested. This excluded any new or old inflammatory changes but incidentally identified a dilated left pelvi-calyceal system. Renal ultrasound confirmed a grossly hydronephrotic left kidney with hydroureter and minimal renal tissue suggesting longstanding obstruction. No calculi were seen. The patient was referred to urologists. Further investigations (including MRI abdomen) confirmed similar findings and a distal ureteric stricture. A MAG 3 renogram showed a normal right kidney but only 12% functioning of the left kidney. Urologists have advised surgery (removal of left kidney and ureter) which may relieve symptoms or a conservative non-surgical approach (continue analgesia, physiotherapy and monitoring). The patient and her family are relieved to have a possible cause identified and are considering the surgical option due to ongoing flank discomfort. Case report - Discussion: This was an interesting finding of hydroureter and hydronephrosis causing longstanding back pain presenting to rheumatologists. Until completion of the spondyloarthropathy protocol MRI (STIR images), aetiology had been unclear. Hydronephrosis and hydroureter has no specific age or racial predilection. Signs and symptoms may depend on whether obstruction is acute/chronic. Chronic cases may be asymptomatic or present as a dull discomfort (like this case). Some cases may only present in adulthood with pain precipitated by fluid intake. Blood tests may show impaired kidney function. Post-mortem studies suggest 50% of people have at least one renal abnormality (e.g., renal cysts, duplex ureters) with autopsy series incidence of hydronephrosis reported as 3.1%. Causes include anatomical abnormalities such as vesico-ureteric reflux, urethral strictures (usually present in childhood), calculi, benign prostatic hyperplasia, or intrapelvic neoplasms, pregnancy and infections (e.g., TB). Sudden onset unilateral renomegaly was reported in one case of primary Sjogren's with lymphocytic interstitial nephritis and positive Sjogren's autoantibodies. Our patient has no clinical or serological evidence of connective tissue disease. Minor pelvi-calyceal distension can occur as a normal finding in wellhydrated patients and pregnancy. However, significant hydronephrosis requires assessment to determine cause as it may affect long term renal function. Imaging via computed tomography, ultrasound and urograms can help guide further management. In this case the preceding cause and duration of pathology is unknown. Sterile, giant hydronephrosis treatment options include observation and ureteric stent or nephrostomy in patients unfit for surgery. Nephrectomy is advised for pain and recurrent infection in a non-functioning kidney. Complications may include bowel perforation, vascular injury and urine leakage. Both open and minimally invasive procedures have good reported outcomes. The COVID-19 pandemic and exams have affected timing of any elective procedures and the patient understands surgery may or may not offer complete symptom resolution. Case report - Key learning points: . Non-inflammatory causes of back pain should always be considered in cases of persistent back pain, particularly in young people to ascertain if there is a treatable cause . Hydronephrosis cases can be asymptomatic or present with vague, intermittent, non-specific abdominal symptoms with normal physical examination with or without haematuria. This can cause diagnostic uncertainty and delay referral to urology and appropriate renal investigations . Assessment of renal function (including MAG 3 renogram) is important to guide further management . Surgical interventions (pyeloplasty/nephrectomy) may ease symptoms long term but there is no guarantee of a successful outcome and operative risks need to be considered too . Left undiagnosed, potentially this patient could have had further disruption to daily activities and both physical and mental well being.

Finding an Answer for an Adolescent with Back Pain

Case report - Introduction: This is the case of an adolescent referred to rheumatology following 5 years of back pain. After years of trying a number of treatments without much success, the cause was found to be a previously undiagnosed urological pathology. The case highlights awareness of non-rheumatological causes and incidental findings which can redirect a patient towards more appropriate treatment and reduce the potential for long-term adverse health issues and anxiety. Case report - Case description: B was referred age 16 to rheumatology with a 5-year history of lower back pain. She had previously seen paediatricians with symptoms initially attributed to constipation due to intermittent straining and hard stool. However, constipation remedies had not relieved the pain which progressed gradually to a more persistent dull ache with impact on daily activities. Various analgesics (including paracetamol and non-steroidal anti-inflammatories), exercises and acupuncture had not helped. There was no history of recurrent urinary tract infections or symptom correlation with fluid intake, menstruation or bowel habit. No inflammatory features or connective tissue disease symptoms were noted and family history was unremarkable Clinical examination was normal apart from mild tenderness in the lumbar region. Rheumatoid factor was borderline positive (15 iu/mL) with the rest of blood tests normal including renal function, inflammatory markers (CRP, ESR), anti CCP and ANA. She had minimal microscopic haematuria without proteinuria. MRI spine in 2015 was normal. In view of her young age and symptoms affecting daily activities, STIR sequence spinal MRI was requested. This excluded any new or old inflammatory changes but incidentally identified a dilated left pelvi-calyceal system. Renal ultrasound confirmed a grossly hydronephrotic left kidney with hydroureter and minimal renal tissue suggesting longstanding obstruction. No calculi were seen. The patient was referred to urologists. Further investigations (including MRI abdomen) confirmed similar findings and a distal ureteric stricture. A MAG 3 renogram showed a normal right kidney but only 12% functioning of the left kidney. Urologists have advised surgery (removal of left kidney and ureter) which may relieve symptoms or a conservative non-surgical approach (continue analgesia, physiotherapy and monitoring). The patient and her family are relieved to have a possible cause identified and are considering the surgical option due to ongoing flank discomfort. Case report - Discussion: This was an interesting finding of hydroureter and hydronephrosis causing longstanding back pain presenting to rheumatologists. Until completion of the spondyloarthropathy protocol MRI (STIR images), aetiology had been unclear. Hydronephrosis and hydroureter has no specific age or racial predilection. Signs and symptoms may depend on whether obstruction is acute/chronic. Chronic cases may be asymptomatic or present as a dull discomfort (like this case). Some cases may only present in adulthood with pain precipitated by fluid intake. Blood tests may show impaired kidney function. Post-mortem studies suggest 50% of people have at least one renal abnormality (e.g., renal cysts, duplex ureters) with autopsy series incidence of hydronephrosis reported as 3.1%. Causes include anatomical abnormalities such as vesico-ureteric reflux, urethral strictures (usually present in childhood), calculi, benign prostatic hyperplasia, or intrapelvic neoplasms, pregnancy and infections (e.g., TB). Sudden onset unilateral renomegaly was reported in one case of primary Sjogren's with lymphocytic interstitial nephritis and positive Sjogren's autoantibodies. Our patient has no clinical or serological evidence of connective tissue disease. Minor pelvi-calyceal distension can occur as a normal finding in wellhydrated patients and pregnancy. However, significant hydronephrosis requires assessment to determine cause as it may affect long term renal function. Imaging via computed tomography, ultrasound and urograms can help guide further management. In this case the preceding cause and duration of pathology is unknown. Sterile, giant hydronephrosis treatment options include observation and ureteric stent or nephrostomy in patients unfit for surgery. Nephrectomy is advised for pain and recurrent infection in a non-functioning kidney. Complications may include bowel perforation, vascular injury and urine leakage. Both open and minimally invasive procedures have good reported outcomes. The COVID-19 pandemic and exams have affected timing of any elective procedures and the patient understands surgery may or may not offer complete symptom resolution. Case report - Key learning points: . Non-inflammatory causes of back pain should always be considered in cases of persistent back pain, particularly in young people to ascertain if there is a treatable cause . Hydronephrosis cases can be asymptomatic or present with vague, intermittent, non-specific abdominal symptoms with normal physical examination with or without haematuria. This can cause diagnostic uncertainty and delay referral to urology and appropriate renal investigations . Assessment of renal function (including MAG 3 renogram) is important to guide further management . Surgical interventions (pyeloplasty/nephrectomy) may ease symptoms long term but there is no guarantee of a successful outcome and operative risks need to be considered too . Left undiagnosed, potentially this patient could have had further disruption to daily activities and both physical and mental well being.

The "footprints" of COVID-19 in the tissues: Only in the lungs?

COVID-19 was identified in late 2019 and spread rapidly to become a pandemic. The causative agent is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-virus, which affects mainly the respiratory tract. SARS-CoV-2 enters the host's alveolar lung cells through the angiotensin converting enzyme (ACE2) receptor. During infection, in addition to abnormal activation of the immune system, an acute decrease in the ACE2 expression level occurs, result-ing in acute respiratory distress syndrome (ARDS) and acute lung damage. Histopathologically, diffuse alveolar damage is observed, and vascular injury appears to be very important, as the pulmonary vessels demonstrate extensive thrombosis with microangiopathy and endothelitis. The virus has also been shown to affect heart tissue, and some patients develop acute cardiovascular syndrome. Endothelitis has also been found in the heart, kidney, spleen, liver and small intestine, and thrombogenic angiopathy is observed in the skin. Vascular injury also affects the brain. In placentas from COVID-19 positive mothers, inflammation and infarcts have been observed. The aim of this literature review is to summarize emerging data on the pathophysiology of SARS-CoV-2 disease in the lungs and other target organs, with an emphasis on microscopic findings in the tissues. Progress in understanding the pathophysiology of COVID-19 is of great importance for comprehension of clinical condition and administration of optimal treatment. Copyright © Athens Medical Society.

S P O N Ta N Eous R E S O Lut I O N O F Large Pericardial Effusion after Cardiopulmonary Resuscitation in a Chronic Kidney Disease Patient on Maintenance Haemodialysis

BACKGROUND: Here we discuss a chronic kidney disease (CKD) patient with large pericardial effusion who arrested secondary to tamponade and had an unintentional pericardial decompression secondary to cardiopulmonary resuscitation (CPR) that subsequently saved his life. AIM OF THE STUDY: To bring to light management difficulties in chronic kidney disease patients undergoing maintenance hemodialysis with large pericardial effusion METHODS: 67-year-old male a case of CKD on maintenance hemodialysis (for last two years) but inadequately dialyzed over last two months after recent Covid pneumonia was detected to have large pericardial effusion on echocardiography. He was planned for intensive heparin-free dialysis in view of absence of frank clinical and echocardiographic findings of tamponade with close surveillance for pericardial effusion. 60 minutes into hemodialysis patient developed dyspnea hypotension and cardiac arrest. Return of spontaneous circulation was achieved after three cycles of cardiopulmonary resuscitation. Echocardiography (echo) guided pericardiocentesis was planned based on clinical suspicion of tamponade. But echocardiography revealed only mild pericardial effusion. Chest X-ray showed new left pleural effusion. Pleurocentesis revealed hemorrhagic fluid. Subsequently done CT thorax showed multiple rib fractures. Patient was discharged on day eleven in stable condition with repeat chest X ray and echocardiography showing no further collection. RESULT(S): Though cardiac tamponade is largely a clinical diagnosis, various other features like echocardiography aid in its diagnosis. Diagnosis of tamponade in CKD patient with pericardial effusion is difficult because of several reasons. All classical clinical features of tamponade like hypotension or elevated systemic pressures may not be manifested all the time in cases of tamponade. Our patient developed clinical signs of tamponade 60 minutes into dialysis session indicating that precipitation of tamponade was likely due to reduction in preload due to ultrafiltration (UF) during hemodialysis. Though, daily dialysis is the initial preferred treatment of choice for uremic pericardial effusions in CKD patients without clinical or echocardiographic signs of tamponade, there are case reports which support early pericardiocentesis as treatment of choice in all large pericardial effusions in CKD patients on maintenance hemodialysis (MHD). In our case of large pericardial effusion, due to absence of frank clinical/ echocardiographic evidence of tamponade, we were prompted to go for aggressive dialysis treatment plan, but had tamponade during dialysis. CPR can cause inadvertent injury to surrounding structures, ribs, abdominal organs, and vascular injury. In our case, CPR-associated injury leads to unintentional pericardial decompression probably due to rib injury or due to high force generated during CPR coupled with high pericardial pressures which overcame the tensile strength of pericardium resulting in pericardial decompression. Findings of fractured ribs on CT scan post-resuscitation in our case supports that high force and pressure were generated during CPR. CONCLUSION(S): This case report supports early pericardiocentesis as treatment of choice for large pericardial effusion in CKD patients on MHD. Also, care should be taken while dialyzing these patient as rapid UF can precipitate tamponade.

Er-Resident S1pr1 in Lung Endothelium Regulates Innate Immune Function and Mediates Inflammatory Lung Injury

Endothelial-cell surface localized sphingosine 1 phosphate receptor 1 (S1PR1) is known to promote anti-inflammatory and barrier enhancing niche upon ligating S1P. Recently we showed that S1P and TNFalpha, later being a well-known inflammatory agonist, phosphorylate S1PR1 at tyrosine143 (Y143 ) which functions as an endoplasmic reticulum (ER) import signal (Anwar et al, 2021). ER-retained S1PR1 instructs barrier disruptive signaling but the mechanism remains unclear. Here, we generated S1PR1 knock-in mice using CRISPR-Cas9 strategy to edit endogenous S1PR1 into Y143D-S1PR1 (phospho mimicking) or Y143F-S1PR1 (phosphodefective) to test the hypothesis that ER-localized S1PR1 subverts EC from anti-inflammatory to pro-inflammatory EC leading to vascular injury. Because EC constitutes about 50% of cells in the lungs, we assessed if knock-in of Y143 DS1PR1 impaired lung homeostasis. We show that editing of S1PR1 into Y143D- or Y143F-S1PR1 did not alter total S1PR1 expression. Interestingly, Y143D-S1PR1 knock-in mice showed marked vascular leak at homeostasis along with increased neutrophil influx and inflammatory cytokine generation including TNFalpha, IL1beta and MiP2 as compared to Y143F-S1PR1 or WT mice. We next challenge these mice with intratracheal LPS. LPS-induced non-resolvable vascular inflammatory injury in Y143D-S1PR1 mice. Surprisingly, Y143F-S1PR1 knock-in mice did not develop vascular inflammatory injury. Furthermore, NFkappaB activity, a predominant transcription factor inducing inflammatory EC phenotype, was increased in EC transducing Y143D-S1PR1 mutant as compared to WT. However, TNFalpha failed to induce NFkB activity in EC transducing Y143F-S1PR1 mutant. Together, these results show that ER-resident S1PR1 program endothelial niche into immune-active niche by activating NFkB pathway leading to irreparable lung injury. Further experiments are being done to assess epigenetic changes (ATACseq and ChIP-Seq) in EC to address the concept the ER- resident S1PR1 controls the fate of immune cells in the lungs. We believe that understanding how ER-resident S1PR1 programs EC into inflammatory phenotype would allow development of new targets for treating the inflammatory vascular diseases including lung injury, ARDS, and COVID-19 .

Covid Sepsis Gene Expression Subphenotypes Manifest Differential Plasma Protein Signatures

INTRODUCTION: Transcriptome-derived sepsis subphenotypes, termed 'adaptive', 'inflammopathic' and 'coagulopathic', have been reliably identified in sepsis cohorts, however plasma proteomics in these groups have not been well characterized. We hypothesized that inflammatory and vascular injury markers would be elevated in the inflammopathic and coagulopathic groups compared to the adaptive group. METHOD(S): We prospectively enrolled and obtained blood from 130 inpatients with COVID19-related sepsis. Severity was classified by NIH ordinal scale. Gene expression analysis was performed by Nanostring nCounter (Inflammatix). Inflammatory proteins interleukin (IL)-6, IL8, IL10, IL1RA, IL1RL1, and IFNg and vascular markers ANGPT2, sICAM, vWF, ADAMTS13, and protein C were measured with OLINK proximity extension assay. Clinical variables were compared by chi-square and protein levels were compared using ANOVA with Bonferroni adjustment. RESULT(S): The transcriptomic classifier identified 32% (41) inflammopathic, 50% (65) adaptive and 18% (24) coagulopathic subjects. The inflammopathic group had more patients requiring mechanical ventilation (39% vs 9% vs 21%;p < 0.001) and higher 90-day mortality (32% vs 8% vs 13%, p = 0.016). Inflammatory cytokines IL8 and IL10 were significantly higher in inflammopathic compared to adaptive (p=0.038 and p=0.017 respectively), but not compared to coagulopathic (p>0.99 and p=0.24, respectively). Both the inflammopathic and coagulopathic groups expressed higher IL1RL1 and interferon-gamma compared to adaptive (IL1RL1;p< 0.001, p=0.002, IFNg;p=0.007, p=0.001). Plasma IL6 and IL1RA did not differ between groups, nor did many vascular proteins. The inflammopathic group expressed higher sICAM (p=0.049 vs adaptive) and lower ADAMTS13 compared to the adaptive group, and the coagulopathic group did not differ in its vascular protein expression. CONCLUSION(S): Transcriptomic subphenotypes are present in COVID-19 sepsis at similar proportions to non-COVID-19 sepsis. Inflammopathic subjects manifested higher severity of illness at admission, higher expression of inflammatory proteins and higher mortality. Markers of vascular injury did not distinguish the coagulopathic group. Integrating RNA and protein expression may offer new insights to host immune dysregulation during COVID sepsis.

Particular Misdiagnosed Acs-Nstemi in a Young Adult with History of Hodgkin's Lymphoma in the Era of Frequent Sars-Cov2 Related Myocarditis: Nothing Should Ever Be Left to Chance

Background: Radiotherapy plays a key role in the multimodality treatment of thoracic tumors. Radiotherapy-induced heart disease (RIHD) has become an increasingly recognized adverse reaction contributing to major radiation-associated toxicities, including nonmalignant death. Especially patients with diseases with excellent prognosis, such as breast cancer or Hodgkin's lymphoma, may suffer from delayed side effects 2-6 including RIHD in a dose-dependent manner. The pathological spectrum of RIHD includes conduction abnormalities, valvular disease, coronary artery disease, pericarditis and pericardial constriction or effusion, cardiomyopathy, and myocardial fibrosis. Here we describe the case of a young man cured of Hodgkin's lymphoma who presented to our laboratory with the diagnosis of suspected myocarditis in the Sars-COV 2 era, but the presenting clinical picture confused the clinicians and complex coronary artery disease was behind it. Method-Clinical Case: A young 33-years-old man presented to the emergency room with typical exertional chest pain. Clinical history: smoker patient who denied familiarity for cardiovascular diseases, dyslipidemic, 10 years previously underwent chemotherapy and radiotherapy for Hodgkin's Lymphoma in complete remission. A nasopharyngeal molecular swab for Sars-COV 2 was performed, which was negative. The presentation electrocardiogram (EKG) documented nonspecific repolarization abnormalities;the myocardionecrosis enzyme curve performed at three times was frankly positive with elevated PCR values (102 pg/ml). Color Doppler echocardiography documented a left ventricular ejection fraction at the lower limits of normal, hypokinesia of the midbasal segments of the infer-posterolateral wall with moderate mitral valve regurgitation. On suspicion of acute myocarditis, the patient was transferred to the Coronary Care Unit and, during admission, underwent MRI, which showed a slightly enlarged left ventricle (DTD 58 mm, EDV 147 ml), slightly depressed systolic function (LVEF 46%), akinesia of the proximal lateral and mid-proximal wall. In delayed enhancement sequences late persistence of gadolinium in the endomesocardium (60%), proximal lateral and mid-proximal wall with involvement of areas adjacent to the base of implantation of both papillary muscles. In light of the instrumental picture, the patient underwent coronarography, which showed an unexpected nightmare picture, given his young age. Circumflex branch (lcx-lesion culprit) suboccluded to the middle segment with TIMI I downstream flow at the bifurcation with a prominent obtuse marginal branch (OM) with a delayed reperfusion (Medina 1,1,1);diffusely atheromatous left anterior descending artery (LAD), showing 70% complex critical disease in the proximal segment at the bifurcation with a first diagonal branch of good caliber and good distribution area (Medina 1,1,1). Clinical resolution/Results: Therefore, in a patient with misdiagnosed ACS-NSTEMI, two complex coronary bifurcation angioplasties according to TAP technique (Fig 3-4) were performed through left radial access with Slender 7 in 6 introducer at one time. The following drugs were administered in the cathlab: Cangrelor bolus/kg followed by continuous infusion for 2 hours and Prasugrel 60 mg, initially UFH 5000 IU and anticoagulation control according to ACT during the procedure. The procedure ended with complete revascularization and asymptomatic patient. During the following days of hospitalization, no late electrical or mechanical complications occurred. Conclusion(s): The one just described represents a complex and unexpected scenario for a young adult. The literature available has analyzed the pathophysiology of myocardial damage resulting from exposure to high amounts of radiation in patients undergoing curative radiotherapy for Hodgkin's lymphoma. It is now generally accepted that the most common clinical syndromes after irradiation are pericarditis in acute and chronic forms,. However, coronary vessel lesions have been considered exceptionally rare, so the true pathophysi logical triggering mechanism is still poorly understood. The most widely accepted hypothesis on the onset of RICHD is a dual pathway of vascular damage ("two-hit combined hypothesis"). The most important preventive measure regarding RICHD is doseminimization. Few data are available in the literature on outcomes according to the revascularization strategy adopted in patients with RICHD (PCI vs. CABG). Morbidity andmortality from post-radiotherapy cardiovascular complications in patients with Hodgkin's lymphoma must be reduced through close cardiological surveillance in primary prevention and a close collaboration between oncologists and cardiologists in order to minimize any deleterious complications, especially in the young. Further research is needed to elucidate profibrotic mechanisms, identify promising therapies that can be implemented early during the course of treatment and to compare revascularization strategies with longer-term mortality in such patients, in order to guide the physicians in the decision-making.

COVID-19 and cardiovascular system: Not only heart but also vascular. The effects of the infection on arterial stiffness

Background and Aims : SARS-CoV-2 determines a framework of multi-organ dysfunction that can involve the cardiovascular system creating damages of different nature. Among these, endothelial damage could play a key role in increasing arterial stiffness and thus the cardiovascular risk of infected patients. The aim of this study is to evaluate the Pulse Wave Velocity (PWV) of a population of patients after recovery from infection and to compare them with those of a group affected by arterial hypertension. Method(s): This prospective observational monocentric study involved 143 patients with previous diagnosis of Covid-19 who undergone PWV measurement during the follow-up at a median time of 3.8 months after the infection. These patients were compared to a population of 143 patients with hypertension matched by age, sex, Systolic Blood Pressure values and Body Mass Index. Result(s): PWV values were higher in Covid-19 group comparing to hypertension group (10.5 +/- 3.0 m/s VS 8.9 +/- 2.5 m/s). Furthermore, there is a correlation between higher PWV values and lower values of SpO2% at time of admission at the Emergency Department. (R= -0.302;p<0.001). Conclusion(s): SARS-CoV-2 infection seems related to increased PWV values. Moreover, higher arterial stiffness seems correlated to a worse oxygen saturation in Emergency Department. More studies with longer follow-up time are necessary to establish whether the vascular damage is reversible and whether it correlates with an increase of long-term cardiovascular risk. Copyright © 2022

Circulating Extracellular Vesicles Carrying Thromboinflammatory Proteins Promote Pulmonary Vascular Injury in Covid-19 Patients

It is increasingly recognized that moderate/severe coronavirus disease 2019 (COVID-19) disease is in part due to a dysregulated immune response in conjunction with increased thromboinflammation, coagulopathy, and vascular injury. In this study, we analyzed the cargo of extracellular vesicles (EVs) isolated from the plasma of patients with COVID-19 for the identification of potential biomarkers of disease severity and to explore their role in disease pathogenesis. Severe acute respiratory syndrome coronavirus 2-infected patients hospitalized at the University of Kansas Health System were enrolled in the COVID-19 In-patient Biorepository and blood samples were collected for the isolation of plasmaderived EVs. The patients were grouped based on the WHO Clinical Progression Scale score during hospitalization. Our results revealed enrichment of proinflammatory, procoagulation, and tissue-remodeling markers in circulating EVs, distinguishing symptomatic COVID-19 patients from uninfected controls and delineating patients with moderate disease from the critically ill. Among all proteins analyzed, the levels of proinflammatory DAMP: EN-RAGE (aka calgranulin C or S100A12) showed the strongest correlation with length of hospitalization and disease severity. In addition, tissue factor levels/activity linked to EVs appeared to distinguish patients with severe disease from those with a moderate disease but on supplemental oxygen. Alterations in EV cargo corresponded to enhanced apoptosis of primary human pulmonary microvascular endothelial cells and smooth muscle hyperplasia on exposure to EVs from COVID-19 patients. In conclusion, our findings suggest a pivotal role of EVs in the pathogenesis of acute COVID-19 disease. Whether these EV-mediated alterations continue leading to long-haul COVID including cardiopulmonary vascular complications is the focus of our ongoing studies.

Role of the Complement System and Vascular Endothelium in COVID-19 Pathogenesis

Background: Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2 infection has become a global pandemic, presenting with varying degrees of severity from respiratory distress to multi-organ damage. Kidneys are of several organs affected in COVID-19, with acute kidney injury (AKI) being a common consequence, occurring in more than 30% of patients with severe COVID-19. While the underlying mechanisms of COVID-19 pathogenesis remain poorly understood, there is evidence linking complement system overactivation and endothelial injury to organ damage that increases the risk of mortality in COVID-19. Evidence from previous coronavirus epidemics also suggest direct involvement of inflammation, complement dysregulation, and endothelial cell dysfunction. Thus, we hypothesize that vascular endothelial injury resulting from complement overactivation contributes to COVID-19-associated organ injury. Method(s): Clinical information and sera from SARS-CoV-2+ patients with mild (n=7) and severe COVID-19 (n=7) diseases were obtained from the Canadian COVID-19 Prospective Cohort Study (CANCOV). Complement activation on ECs was evaluated via immunofluorescence assays, measuring the deposition of complement products C3b and C5b-9 on Human Umbilical Vein Endothelial Cells exposed to control or patient sera. In addition, a permeability assay using a transwell model was used to measure the integrity of the endothelial monolayer exposed to patient sera. Result(s): Complement was found to be overactivated on ECs treated with SARSCoV-2+ patient sera compared to those treated with normal human serum as evidenced by significantly increased C3b and C5b-9 deposition. While ECs treated with sera from patients with mild COVID-19 seemed to have higher C3b deposition, ECs treated with sera from patients with severe COVID-19 disease were associated with higher C5b-9 deposition. In addition, increased permeability of the monolayer incubated with SARSCoV-2+ patient sera was seen over time regardless of disease severity. However, ECs tretaed with severe COVID-19 patient sera had signficiantly increased vascular leakiness as evidenced by increased permeability of the treated monolayer. Conclusion(s): Thus, we conclude that complement is overactivated in SARS-CoV-2+ patients and use of anti-complement therapies may be an effective strategy in treating COVID-19 associated vascular injury, hyperinflammation, and organ damage.

COVID-19 Infection Is a Risk Factor for CKD and Glomerulonephritis

Background: The ongoing COVID19 pandemic continues to challenge healthcare systems. While COVID19 disease is associated with Acute Kidney Injury and collapsing glomerulonephritis, little is known about the potential kidney manifestations of PASC (Post-Acute Sequelae of COVID19). In this study we used TrinetX, a large health research network that aggregates data from multiple centers in the United States to analyze the effects of COVID19 on chronic kidney disease (CKD) manifestations of PASC. Method(s): We searched TrinetX for patients > 18 years old with a documented SARSCOV-2 PCR test and classified them into 2 cohorts: C19+ve (with a [+] molecular test for SARS-COV-2 or a clinical diagnosis of COVID19 disease) and C19-ve (absence of such findings). We excluded patients who had received any COVID19 vaccine. We collected demographics, comorbidities, diagnoses for up to two years after any COVID19 PCR test (index event). A 1:1 propensity score matching (PSM) using the nearest neighbor method was used to balance the 2 cohorts on age, gender, Hispanic ethnicity, black race, hypertension, diabetes, heart failure and atherosclerosis. Patients with a kidney specific diagnosis prior to their COVID19 PCR test were excluded. Result(s): We identified 2,780,780 C19+ve and 6,757,849 C19-ve patients. After PSM each group contained 2,775,418 subjects. Mean age was 40.2+/-23.1, females were 54.7%, blacks were 15.8% & 12.3% were Hispanic or Latinos. COVID19 diagnosis was a strong risk factor for CKD (Relative Risk, RR 2.474, p<0.001), nephritic, nephrotic syndrome and glomerular disorders. Conclusion(s): COVID19 disease is a major risk factor for incident CKD, nephrotic and nephritic syndrome. These findings should be confirmed in prospective studies. Whether these sequalae represent persistence of the kidney tropic SARS-COV-2 virus, vascular damage from the acute infection or a manifestation of autoimmunity can only be established through targeted mechanistic studies.

An Unusual Case of ANCA Associated Vasculitis (AAV) After a COVID-19 Vaccine

Introduction: COVID-19 vaccines have been related to immune mediated adverse events and recently some case reports of AAV precipitated after either RNA or viral vector vaccines have been reported. Case Description: A 83 year old woman with past records of polymyalgia rheumatica (2017) treated with low dose prednisone, was admitted to our hospital because of malaise, hyporexia and weight loss in the context of urinary symptoms. These started since the second COVID-19 Pfizer- BioNTech vaccine dose administred 3 months ago. Initial blood test revealed anemia, acute kidney injury (serum creatinine 1.7mg/dl), leucocytosis and elevated CRP. Urinalysis showed microhematuria and mild proteinuria in the context of a positive urine culture. She had normal kidneys on ultrasonography. Diuretics and antibiotics were started, but few days after renal function continued worsening (sCr 4,3 mg/dl) with an active sediment. For this reason, immunology tests were ordered with positive high MPO-ANCA antibodies. Hence, a kidney biopsy was performed showing 11 normal glomeruli but severe arteritis in two small-middle sized arterioles with fibrinoid necrosis. Steroids and Rituximab were given as induction therapy with good renal response. Discussion(s): AAV after COVID-19 vaccine administration has been reported previously, and it could be related to its molecular mimicry and immune crossreaction. Most of them were typical forms of pauci-immune crescentic glomerulonephritis, but none with isolated vascular damage. Although cases reported appeared shorter time after vaccine administration, our patient was on low dose prednisone which may explain a subacute onset of the disease. Moreover, she clearly presented constitutional sypmtoms ever since the second vaccine dose was administred. Finally, although the efficacy and safety of the COVID-19 vaccines have been demonstrated, particular attention should be paid to patients with known or suspected autoimmune diseases.