Ischemic Infarction Research Articles

Effectiveness of buffered acetylsalicylic acid compared to other drugs in diseases patients in clinical practice: results of the CARDINAL observational retrospective study

Aim. To evaluate the effectiveness of acetylsalicylic acid (ASA) drugs for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in clinical practice and compare the effectiveness of the Cardiomagnyl with other ASA drugs.Material and methods. This observational, non-interventional, retrospective study included data from electronic medical records of 18199 patients with ASCVD who were divided into 2 following groups: patients who received ASA 75-100 mg (n=9784) and patients who did not receive ASA (n=8325). The prescription rate of ASA, the choice of the first drug, the duration of ASA therapy, the frequency of switching ASA during treatment, and the choice of the second ASA drug when changing therapy were assessed. Due to the heterogeneity of patients in the above groups, to assess the clinical outcomes, propensity score matching was performed and comparable groups were selected to evaluate the effectiveness of ASA drugs 75-100 mg in patients with ASCVD (n= 427) in comparison with patients not receiving ASA (n=427) and to assess the effectiveness of Cardiomagnyl 75 mg (n=1308) in comparison with enterosoluble ASA 100 mg (CRA) (n=1308) taking into account 24 parameters.Results. The average proportion of patients with ASCVD taking ASA drugs was 58%. During treatment, 54% of patients underwent a change in drug therapy from one ASA drug to another. The prescription rate of Cardiomagnyl as a first-choice drug was 33%, and as a second drug when changing therapy — 21%. The duration of Cardiomagnyl therapy was the longest compared to other ASA drugs and amounted to 16,3 months. The incidence of ischemic stroke, myocardial infarction and major adverse cardiovascular events in the group of patients who received ACS 75-100 mg was significantly lower than in patients who did not take ASA drugs and amounted to 4,7% vs 8,7%, 0,9% vs 3,3%, 5,6% vs 11,9%, respectively. Significantly lower incidence of unstable angina (0,8% vs 2,0%), myocardial infarction (1,5% vs 3,9%) and major adverse cardiovascular events (5,4% vs 7,8%) in group of patients who received Cardiomagnyl 75 mg as opposed to enterosoluble ASA.Conclusion. Significant advantages of buffered ASA (Cardiomagnyl) were revealed in comparison with enterosoluble ASA in clinical practice.

Cardiovascular and mortality outcomes with GLP-1 receptor agonists vs other glucose-lowering drugs in individuals with NAFLD and type 2 diabetes: a large population-based matched cohort study.

We aimed to determine whether the use of glucagon-like peptide-1 receptor agonists (GLP-1RA) in individuals with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus decreases the risk of new-onset adverse cardiovascular events (CVEs) and mortality rate compared with other glucose-lowering drugs in a real setting at a population level. We conducted a population-based propensity-matched retrospective cohort study using TriNetX. The cohort comprised patients over 20 years old who were newly treated with glucose-lowering drugs between 1 January 2013 and 31 December 2021, and followed until 30 September 2022. New users of GLP-1RAs were matched based on age, demographics, comorbidities and medication use by using 1:1 propensity matching with other glucose-lowering drugs. The primary outcome was the new onset of adverse CVEs, including heart failure, composite incidence of major adverse cardiovascular events (MACE; defined as unstable angina, myocardial infarction, or coronary artery procedures or surgeries) and composite cerebrovascular events (defined as the first occurrence of stroke, transient ischaemic attack, cerebral infarction, carotid intervention or surgery), and the secondary outcome was all-cause mortality. Cox proportional hazards models were used to estimate HRs. The study involved 2,835,398 patients with both NAFLD and type 2 diabetes. When compared with the sodium-glucose cotransporter 2 (SGLT2) inhibitors group, the GLP-1RAs group showed no evidence of a difference in terms of new-onset heart failure (HR 0.97; 95% CI 0.93, 1.01), MACE (HR 0.95; 95% CI 0.90, 1.01) and cerebrovascular events (HR 0.99; 95% CI 0.94, 1.03). Furthermore, the two groups had no evidence of a difference in mortality rate (HR 1.06; 95% CI 0.97, 1.15). Similar results were observed across sensitivity analyses. Compared with other second- or third-line glucose-lowering medications, the GLP-1RAs demonstrated a lower rate of adverse CVEs, including heart failure (HR 0.88; 95% CI 0.85, 0.92), MACE (HR 0.89; 95% CI 0.85, 0.94), cerebrovascular events (HR 0.93; 95% CI 0.89, 0.96) and all-cause mortality rate (HR 0.70; 95% CI 0.66, 0.75). In individuals with NAFLD and type 2 diabetes, GLP-1RAs are associated with lower incidences of adverse CVEs and all-cause mortality compared with metformin or other second- and third-line glucose-lowering medications. However, there was no significant difference in adverse CVEs or all-cause mortality when compared with those taking SGLT2 inhibitors.

A review of the risk and precipitating factors for spontaneous coronary artery dissection.

Spontaneous coronary artery dissection (SCAD) accounts for 1%-4% of cases of acute coronary syndrome (ACS). SCAD is caused by separation occurring within or between any of the three tunics of the coronary artery wall. This leads to intramural hematoma and/or formation of false lumen in the artery, which leads to ischemic changes or infarction of the myocardium. The incidence of SCAD is higher in women than in men, with a ratio of approximately 9:1. It is estimated that SCAD is responsible for 35% of ACS cases in women under the age of 60. The high frequency is particularly observed during pregnancy and in the peripartum period (first week). Traditional risk factors are rare in patients with SCAD, except for hypertension. Patients diagnosed with SCAD have different combinations of risk factors compared with patients who have atherosclerotic changes in their coronary arteries. We presented the most common so-called "non-traditional" risk factors associated with SCAD patients. In the literature, there are few diseases frequently associated with SCAD, and they are identified as predisposing factors. The predominant cause is fibromuscular dysplasia, followed by inherited connective tissue disorders, systemic inflammatory diseases, pregnancy, use of sex hormones or steroids, use of cocaine or amphetamines, thyroid disorders, migraine, and tinnitus. In recent years, the genetic predisposition for SCAD is also recognized as a predisposing factor. The precipitating factors are also different in women (emotional stress) compared with those in men (physical stress). Women experiencing SCAD frequently describe symptoms of anxiety and depression. These conditions could increase shear stress on the arterial wall and dissection of the coronary artery wall. Despite the advancement of SCAD, we can find significant differences in the clinical presentation between women and men. When evaluating patients with chest pain or other ACS symptoms who have a low cardiovascular risk, particularly female patients, it is important to consider the possibility of ACS due to SCAD, particularly in conditions often associated with SCAD. This will increase the recognition of SCAD and the timely treatment of affected patients.

Early and late chorioretinal complications of preeclampsia

Preeclampsia remains a serious problem of obstetric practice, the growth of severe forms of this complication of pregnancy is predicted in the future, which determines the scientific interest of specialists in the search for new markers of preeclampsia to prevent the progression of preeclampsia and maternal mortality. The ocular fundus is an area where vessels can be observed in real time, in addition, the structure of the retina predisposes to the development of edema, up to retinal detachment in severe preeclampsia. In the last decade, new diagnostic equipment has become available to study chorioretinal changes at the stage of preclinical manifestations. In order to study early and late complications of pre-eclampsia from the retina and vasculature, we analyzed domestic and foreign scientific sources published in the last five years. According to a number of authors, changes in the visual organ of varying degrees of severity in preeclampsia occur in 100% of cases. It is established that the key role in the pathogenesis of vascular disorders in preeclampsia belongs to endothelial dysfunction. Preeclampsia may be accompanied by hemorrhagic and ischemic retinal infarcts, retinal pigment epithelium detachment, corkscrew-shaped tortuosity of arterioles in the periphery of the retina, retinal detachment, optic disc edema, less frequently vitreous hemorrhages, lesions of the optic nerve, conjunctiva and cerebral cortex in the area of visual centers, which may resolve against the background of therapy when the patient's general condition improves. However, in some women endothelial dysfunction may persist for many years, the most frequent late complications of preeclampsia are retinal detachment and diabetic retinopathy. Along with traditional methods of ophthalmoscopy of the eye fundus for diagnostics of chorioretinal complications OCT for determination of serous retinal detachment, subretinal deposits and other pathologies of the vasculature, USDG of the central retinal artery, posterior short ciliary arteries, ocular artery for diagnostics of ophthalmologic complications of preeclampsia can be used. As a result of the analysis of scientific data, conclusions are drawn about the association of preeclampsia with the development of certain early and distant chorioretinal complications. The search for new, earlier changes on the ocular fundus may serve for early diagnosis of preeclampsia, prevention of severe complications of pregnancy.

Carotid endarterectomy compared with carotid artery stenting for extracranial carotid artery stenosis: a retrospective single-centre study

Aim: One of the main risk factors for an ischemic stroke is significant carotid artery stenosis, and extracranial severe carotid artery stenosis accounts for 20% of ischemic strokes. Prior to the development of carotid artery stenting (CAS), the only effective and reliable treatment for carotid artery stenosis was carotid endarterectomy (CEA). This study compares the results of CAS and CEA in patients with significant carotid artery stenosis. Methods: Between 2018 and 2022, hospital records of all patients who underwent carotid artery revascularization at the institution were retrospectively analyzed. Patients were divided into two groups depending on whether CEA or CAS was performed for carotid revascularization. Propensity score matching was performed to reduce bias by equating the baseline clinical characteristics of the groups. To compare 30-day, 1-year, and long-term outcomes, rates of transient ischemic attack (TIA), myocardial infarction, stroke, all-cause mortality, and composite endpoints were analyzed. Results: After PSM, 76 patients each in the CEA and CAS groups were compared. The mean age was 69.80 years ± 11.35 years and 121 (80%) were male. The patients were followed up for a mean of 33 months ± 6 months. The incidence of TIA in the perioperative period [9 (12%) vs. 4 (5%); P < 0.05], TIA and composite endpoint at 1-year period [11 (15%) vs. 2 (3%); P < 0.05 and 27 (36%) vs. 16 (21%); P < 0.05, respectively] were significantly higher in the CAS group than in the CEA group. No difference was observed between the groups in the long-term. Conclusions: There was no noticeable difference between the CEA and CAS groups in the examination of cases with severe carotid artery stenosis in terms of 1-month, and 1-year results (apart from TIA and composite endpoints), or long-term outcomes. Extracranial carotid artery stenosis can be treated safely and effectively also by CAS.

Risk of Postoperative Ischemic Stroke and Myocardial Infarction in Patients Operated for Cancer.

Risk assessment for ischemic stroke (IS) and myocardial infarction (MI) is done routinely before surgery, but the increase in risks associated with surgery is not known. The aim of this study is to assess the risk of arterial ischemic events during the first year after oncological surgery. We used Swedish healthcare databases to identify 443,300 patients who underwent cancer surgery between 1987 and 2016 and 4,127,761 matched comparison subjects. We estimated odds ratios (ORs) for myocardial infarction and ischemic stroke during the hospitalization with logistic regression and calculated 1-year cumulative incidences and hazard ratios (HRs) with 95% confidence intervals (CIs) for the outcomes after discharge. The cumulative incidences of myocardial infarction and ischemic stroke during the first postoperative year were 1.33% and 1.25%, respectively. In the comparison cohort, the corresponding 1-year cumulative incidences were 1.04% and 1.00%. During the hospitalization, the OR for myocardial infarction was 8.81 (95% CI 8.24-9.42) and the OR for ischemic stroke was 6.71 (95% CI 6.22-7.23). After discharge, the average HR during follow-up for 365 days was 0.90 (95% CI 0.87-0.93) for myocardial infarction and 1.02 (95% CI 0.99-1.05) for ischemic stroke. We found an overall increased risk of IS and MI during the first year after cancer surgery that was attributable to events occurring during the hospitalization period. After discharge from the hospital, the overall risk of myocardial infarction was lower among the cancer surgery patients than among matched comparison subjects.

Protective effect of cilostazol on vascular injury in rats with acute ischemic stroke complicated with chronic renal failure

Chronic renal failure (CRF) resulting in vascular calcification, which does damage to blood vessels and endothelium, is an independent risk factor for stroke. It has been reported that cilostazol has a protective effect on the focal cerebral ischemic infarct. However, its impact on vascular injury in CRF combined stroke and its molecular protection mechanism have not been investigated. In this study, we carried out the effect of cilostazol on CRF combined stroke rats, and the results confirmed that it improved the neurobehavior, renal function as well as pathologic changes in both the kidney and brain. In addition, the inflammation and oxidative stress factors in the kidney and brain were suppressed. Moreover, the rates of brain edema and infarction were decreased. The injured brain-blood barrier (BBB) was recovered with less Evans blue extravasation and more expressions of zonula occludens-1(ZO-1) and occludin. More cerebral blood flow (CBF) in the ipsilateral hemisphere and more expression of CD31 and vascular endothelial growth factor (VEGF) in brain and kidney were found in the cilostazol group. Furthermore, cell apoptosis and cell autophagy became less, on the contrary, proteins of vascular endothelial growth factor receptor 2 (VEGFR2) after the cilostazol treatment were increased. More importantly, this protective effect is related to the pathway of Janus Kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), mammalian target of rapamycin (mTOR), and the hypoxia inducible factor-1α (HIF-1α). In conclusion, our results confirmed that cilostazol exerted a protective effect on the brain and kidney function, specifically in vascular injury, oxidative stress, cell apoptosis, cell autophagy, and inflammation response in CRF combined with stroke rats which were related to the upregulation of JAK/STAT3/mTOR signal pathway.

VDAC1, as a downstream molecule of MLKL, participates in OGD/R-induced necroptosis by inducing mitochondrial damage

Ischemia-reperfusion (I/R) injury constitutes a significant risk factor for a range of diseases, including ischemic stroke, myocardial infarction, and trauma. Following the restoration of blood flow post-tissue ischemia, oxidative stress can lead to various forms of cell death, including necrosis, apoptosis, autophagy, and necroptosis. Recent evidence has highlighted the crucial role of mitochondrial dysfunction in I/R injury. Nevertheless, there remains much to be explored regarding the molecular signaling network governing cell death under conditions of oxidative stress. Voltage-dependent anion channel 1 (VDAC1), a major component in the outer mitochondrial membrane, is closely involved in the regulation of cell death. In a cellular model of oxygen-glucose deprivation and reoxygenation (OGD/R), which effectively simulates I/R injury in vitro, our study reveals that OGD/R induces VDAC1 oligomerization, consequently exacerbating cell death. Furthermore, we have revealed the translocation of mixed lineage kinase domain-like protein (MLKL) to the mitochondria, where it interacts with VDAC1 following OGD/R injury, leading to an increased mitochondrial membrane permeability. Notably, the inhibition of MLKL by necrosulfonamide hinders the binding of MLKL to VDAC1, primarily by affecting the membrane translocation of MLKL, and reduces OGD/R-induced VDAC1 oligomerization. Collectively, our findings provide preliminary evidence of the functional association between MLKL and VDAC1 in the regulation of necroptosis.

Aortic Arch Plaques and the Long-Term Risk of Stroke and Cardiovascular Events in the Statin Era.

Aortic arch plaques are associated with an increased risk of ischemic stroke in patients with cryptogenic stroke or prior embolic events. However, this relationship is unclear in the community. We investigated (1) the long-term risk of stroke and cardiovascular events associated with arch plaques and (2) whether statin therapy prescribed for any indication modified the association. A total of 934 stroke-free participants (72±9 years; 37% men) from the CABL study (Cardiovascular Abnormalities and Brain Lesion) were evaluated. Arch plaques were assessed by suprasternal transthoracic echocardiography; plaques ≥4 mm in thickness were classified as large plaques. The primary outcome was ischemic stroke; the secondary outcome was combined cardiovascular events (ischemic stroke, myocardial infarction, and cardiovascular death). The plaque-related risk of outcomes was also analyzed according to the presence of statin treatment. No plaque was used as a reference. Aortic arch plaques were present in 645 participants (69.1%), with large plaques in 114 (12.2%). During a mean follow-up of 11.3±3.6 years, 236 (25.3%) cardiovascular events occurred (76 ischemic strokes, 27 myocardial infarctions, and 133 cardiovascular deaths). Large arch plaques were independently associated with combined events (adjusted hazard ratio, 2.19 [95% CI, 1.40-3.43]) but not stroke alone (adjusted hazard ratio, 1.09 [95% CI, 0.50-2.38]). The association between large plaques and cardiovascular events was significant in participants receiving statins (adjusted hazard ratio, 2.57 [95% CI, 1.52-4.37]) but not in others; however, participants on statin treatment also had a worse risk profile (higher body mass index, greater frequencies of hypertension, diabetes, and coronary artery disease). Aortic arch plaques may be a marker of cardiovascular risk rather than a direct embolic stroke source in older adults without prior stroke. The efficacy of broader cardiovascular risk factors control, beyond cholesterol levels alone, for primary prevention of cardiovascular events in individuals with aortic arch plaques may require further investigation.

SRSF3 Alleviates Ischemic Cerebral Infarction Damage by Activating the PI3K/AKT Pathway

Background: Ischemic cerebral infarction is one of cerebrovascular diseases with high incidence, disability rate, and mortality globally, and neuronal cell apoptosis is a crucial cause of brain injury during cerebral infarction. Methods: A middle cerebral artery occlusion (MCAO) model was built in Sprague-Dawley rats to simulate ischemic cerebral infarction. An in vitro model of ischemic cerebral infarction was constructed in BV2 cells with the treatment of oxygen-glucose deprivation (OGD). The role and mechanism of serine/arginine-rich splicing factor 3 (SRSF3) in ischemic cerebral infarction were investigated both in animal and cell models. Results: The expression of SRSF3 was downregulated in MCAO-treated rats. Overexpression of SRSF3 reduced the neurological scores, brain water content, and infarct volume in MCAO-induced rats. Increased apoptosis in neurons accompanied with the abnormal expressions of apoptosis-related proteins in MCAO-induced rats were revised with the upregulation of SRSF3. Also, a diminished cell viability and elevated apoptosis rate were indicated in OGD-induced BV2 cells, which were reversed with the overexpression of SRSF3. Besides, OGD induced an enhancement in the relative protein expression of programmed cell death protein 4 (PDCD4) and a reduction in the relative expression of p-PI3K/PI3K and p-AKT/AKT, which were inverted with the upregulation of SRSF3 in BV2 cells. Overexpression of PDCD4 abolished the role of SRSF3 in cell viability, apoptosis rate, and the level of the PI3K/AKT pathway in OGD-induced BV2 cells. Conclusion: SRSF3 improved ischemic cerebral infarction via PDCD4 in vivo and in vitro, which was closely associated with the PI3K/AKT signaling pathway.

Is the mechanism of synchronous cardiocerebral infarction (CCI) different from that of metachronous CCI?

Background: Cardiocerebral infarction (CCI) is the simultaneous occurrence of acute ischemic stroke (AIS) and myocardial infarction (MI) at the same time (synchronous), or one after another (metachronous). This study aimed to investigate the differences in the underlying mechanisms between synchronous and metachronous CCI. Methods: This study analyzed patients with AIS registered in the Clinical Research Collaboration for Stroke in Korea Prospective Registry at a single Stroke Center from January 2019 to December 2022. Patients with synchronous and metachronous CCI (MI within 72 hours after AIS) were included. Severity at admission and modified Rankin Scale scores 3 months after treatment were assessed.Results: Among 3,319 AIS patients, 12 (0.36%) were diagnosed with acute CCI (male: 8; mean age, 69.614.0 years). Of these, six (0.18%) had synchronous CCI, while the other six had metachronous CCI. The synchronous CCI group exhibited lower neurological severity at admission than the metachronous CCI group (median National Institutes of Health Stroke Scale, 3.5 vs. 12.5). Among the 12 patients, seven (58%) had ST-elevation myocardial infarction (STEMI), with five (83%) of the synchronous CCI cases presenting as STEMI. Two cases of new-onset atrial fibrillation occurred exclusively in patients with synchronous CCI. Also, one case with synchronous CCI had a thrombus in the left ventricle.Conclusion: Acute CCI is rare and manifests with varying degrees of severity. Our study suggests that AIS in synchronous CCI may be secondary to embolism caused by a preceding MI. In contrast, metachronous CCI exhibits diverse mechanisms, including secondary myocardial injury resulting from a preceding severe AIS.

Strokes in Critically Ill COVID-19 Patients Diagnosed After Deep Sedation: A Single-Center Case Series.

In the Philippines, acute cerebrovascular disease is a common neurologic complication in coronavirus disease 2019 (COVID-19) patients. Because of sedation and limited neurological examination, the diagnosis of stroke in critically ill patients with COVID-19 may be delayed. This retrospective analysis was done on the medical records of adult patients with critical COVID-19 in 2021-2022 who were brought to a tertiary hospital in the Philippines, placed on mechanical ventilation, and later discovered to have had an ischemic or hemorrhagic stroke while under deep sedation. The study aimed to explore the delayed diagnosis of cerebrovascular disease clinically concealed by deep sedation and emphasizes the importance of a collaborative, multi-specialty approach to managing such patients. There were nine patients with strokes discovered on imaging after deep sedation due to severe COVID-19 infection. The median age of the cases was 63 years, and 55.5% (n=5) were males. Three of the nine patients had an ischemic stroke with hemorrhagic conversion, three with ischemic infarction, and the other three had a primary intracerebral hemorrhage. This series shows a pattern of delayed diagnosis of cerebrovascular disease clinically concealed by deep sedation that was essential in managing acute respiratory distress syndrome in the background of severe COVID-19 infection before the emergence of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) variants and the discovery of COVID-19 vaccines. The study demonstrates the significance of managing this unique population of patients in a collaborative and multi-specialty manner. With the continuing threat of SARS-CoV-2 and its variants, there is a need to strike a balance between the risks of ischemic and hemorrhagic stroke in COVID-19 infection and the care of this patient population.

Cognitive performance following stroke, transient ischaemic attack, myocardial infarction, and hospitalisation: an individual participant data meta-analysis of six randomised controlled trials

Survivors of stroke are often concerned about cognitive problems, and information on the risk of cognitive problems often comes from small studies. We aimed to estimate years of cognitive ageing associated with stroke compared with transient ischaemic attack, myocardial infarction, and other hospitalisations in a large population. Using data from six randomised controlled trials (ORIGIN, ONTARGET, TRANSCEND, COMPASS, HOPE-3, and NAVIGATE ESUS), we completed an individual participant data meta-analysis using data requested from the Public Health Research Institute to estimate the association of stroke (by type and severity), transient ischaemic attack, myocardial infarction, and other hospitalisations with cognitive performance measured at the end of each trial. We included participants in any of these randomised controlled trials with a cognitive assessment at baseline and at least one other timepoint. Cognitive performance was measured with the Mini-Mental State Examination or the Montreal Cognitive Assessment, transformed into Z scores. We estimated Z score differences in end of trial cognitive performance between people with and without events and calculated corresponding years of cognitive ageing in these trials, and additionally calculated using a population representative cohort-the Cognitive Function and Ageing Study. In 64 106 participants from 55 countries, compared with no event, stroke was associated with 18 years of cognitive ageing (1487 strokes included in the model, 95% CI 10 to 28; p<0·0001) and transient ischaemic attack with 3 years (660 transient ischaemic attacks included in the model, 0 to 6; p=0·021). Myocardial infarction (p=0·60) and other hospitalisations (p=0·26) were not associated with cognitive ageing. The mean difference in SD compared with people without an event was -0·84 (95% CI -0·91 to -0·76; p<0·0001) for disabling stroke, and -0·12 (-0·19 to -0·05; p=0·0012) for non-disabling stroke. Haemorrhagic stroke was associated with worse cognition (-0·75, -0·95 to -0·55; p<0·0001) than ischaemic stroke (-0·42, -0·48 to -0·36; p <0·0001). Stroke has a substantial effect on cognition. The effects of transient ischaemic attack were small, whereas myocardial infarction and hospitalisation had a neutral effect. Prevention of stroke could lead to a reduction in cognitive ageing in those at greatest risk. Population Health Research Institute and Chief Scientist Office of Scotland.

Effects of Biodegradable Biomaterials Combined with Bone Marrow Mesenchymal Stem Cells Transplantation on Neurological Function in Rats with Ischemic Cerebral Infarction

The aim of this research was to explore the effects of degradable biomaterial self-polypeptide nanofiber scaffolds plus bone marrow mesenchymal stem cells (BMSCs) on the behavior and neurological function of rats with focal ischemic cerebral infarction (ICI). BMSCs were isolated and cultured. The self-assembling peptides and BMSCs were mixed to prepare self-assembling peptides/BMSCs (SAP/BMSCs) material. BMSCs and SAP/BMSCs were injected into the carotid artery of rats in Model group. The rats without ligation were used as Sham group. Longa 5 and modified neurological severity scores (mNSS) of each group were evaluated. The adhesive removal test and forelimb asymmetry test were used to examine the behavior of the rats. The brain tissues were collected, and the infarct size, neuronal apoptosis, and the protein expression of Nogo-A and lipoprotein a (LPA) in the hippocampus were detected by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining, TdT-mediated dUTP nick end labeling (TUNEL) staining, enzyme-linked immunosorbent assay (ELISA), and Western blot. The results indicated that the fiber diameter of the self-polymerizing peptide material was about 12 nm, and the length was about 100-250 nm. The cells grew well after composite BMSCs. Compared with Sham group, Longa 5, mNSS score, adhesive removal time, forelimb asymmetry test score, cerebral infarction volume, and neuronal apoptosis rate were increased, interleukin 6 (IL-6) and Tumor Necrosis Factor alpha (TNF-α) were raised, IL-10 was decreased, and Nogo-A and LPA protein was increased in Model group (P &lt; 0.05). As against Model group, Longa 5, mNSS score, adhesive removal time, forelimb asymmetry test score, cerebral infarction volume, neuronal apoptosis rate, IL-6 and TNF-α were clearly decreased, and IL-10 was raised, and Nogo-A and LPA protein was clearly decreased in BMSCs and SAP/BMSCs groups (P &lt; 0.05). As against BMSCs group, Longa 5, mNSS score, adhesive removal time, forelimb asymmetry test score, cerebral infarction volume, and neuronal apoptosis rate were clearly decreased, and IL-6 and TNF-α were decreased, and IL-10 was raised, and Nogo-A and LPA protein was decreased in SAP/BMSCs group (P &lt; 0.05). Early transplantation of BMSCs can improve the neurobehavioral symptoms of ICI rats and inhibit neuronal apoptosis and inflammatory response. The effect of self-polymerizing peptide nanofiber scaffold plus BMSCs transplantation in ICI is superior to the transplantation of BMSCs alone.

Utility of accessible neuroimaging markers of cerebrovascular disease in identifying cerebral amyloidosis across the Alzheimer’s disease spectrum

AbstractBackgroundAlzheimer’s disease (AD) is defined by the presence of cognitive impairment and cerebral amyloidosis and is associated with several cerebrovascular disease (CVD) risk factors including age, apolipoprotein‐E ε4 (APOE‐ε4) genotype, hypertension, diabetes and hyperlipidemia. Despite this association, the clinical utility of individual CVD biomarkers in screening for AD pathology is understudied. Therefore, we sought to examine the relationship between cerebral amyloidosis and magnetic resonance imaging (MRI)‐based CVD measures, including cerebral microbleeds, ischemic infarction, and white matter hyperintensities (WMH). We hypothesized that CVD biomarker burden would be positively associated with amyloidosis. Given recent studies have shown plasma phospho‐tau181 (P‐tau181) is a promising early biomarker of amyloidosis, we further hypothesized that combining P‐tau181 with CVD biomarkers would predict amyloid status in cognitively unimpaired and impaired persons.MethodParticipant data were extracted from the Alzheimer’s Disease Neuroimaging Initiative database (N = 1,430). Volumetric data (WMH volume [WMHv], medial temporal lobe volume [MTLv]) were normalized and log‐transformed. Adjusted odds ratio (OR) was calculated using logistic regression with dichotomized amyloid‐PET status as the outcome. Area under the curve (AUC) was compared by the likelihood ratio test.ResultAfter adjustment for age, sex, APOE‐ε4 status, MTLv, cognition (MoCA), and other CVD biomarkers of interest, we found that WMHv alone was significantly associated with amyloidosis in both cognitively impaired (OR = 1.21) and unimpaired (OR = 1.25) persons. We then developed an accessible diagnostic model incorporating WMHv, significant covariates and plasma P‐tau181. Addition of P‐tau181 to the model improved diagnostic accuracy in cognitively impaired persons (AUC = 0.85 to 0.87, p &lt; 0.001), and did not attenuate the relationship between WMHv and amyloidosis.ConclusionWe newly identify WMH, but not other CVD lesions, as predictive of amyloidosis in both preclinical and symptomatic AD. The current study adds to the literature regarding which CVD biomarkers are most predictive of AD pathology. Measurement of WMH alongside P‐tau181 and other biomarkers may produce an accessible screening algorithm for AD. Study generalizability is limited by ascertainment bias and lack of diversity. Future research will compare the performance of WMH to standard AD biomarkers in a more diverse, community‐based sample.

Functional Outcome and Mortality Predictors in Patients with Cerebral Ischemic Infarction After Decompressive Craniectomy: Cross-Sectional Study

Surgeons commonly perform Decompressive craniectomy (DC) to manage patients with cerebral ischemic infarction. However, there are conflicting data on the long-term functional outcomes following DC. Therefore, this study aims to determine the functional outcome of patients with cerebral ischemic infarction after DC. This prospective and retrospective cross-sectional study included 148 patients with cerebral ischemic infarction who underwent DC at Ghaem Hospital, Mashhad, Iran, from March 2011 to March 2021. The Modified Rankin Scale (mRS) assesses disability in these patients and determines the recovery and degree of long-term functional outcomes. Demographic and clinical data were extracted and recorded in a researcher-made questionnaire. In summary, the follow-up revealed a survival rate of 39.2% among patients with ischemic stroke. The comparison of the mean infarct volume in patients with various mRS scores showed that the mean infarct volume was significantly higher in patients with unfavorable functional outcomes, based on mRS scores at discharge (P= 0.05), 3months mRS (P < 0.01), and mRS score at final follow-up (P= 0.01). Final mortality was higher in patients with higher mRS scores at discharge, after 3months, and final follow-up (P < 0.01). Older age and infarction volume can predict mRS and mortality in patients with ischemic stroke (P < 0.01). The present study showed that mortality and mRS scores at various times are associated with infarction volume and older age in patients with ischemic stroke.

A Mouse Model of CD19 CAR - T Cell Therapy Reveals Mechanism of Cytopenia

Immunotherapy with Chimeric Antigen Receptor (CAR) T cells against CD19 can cure patients with refractory B cell lymphoma and leukemia. However, complications of CAR-T cell therapy can cause morbidity. Among the complications of CAR-T cell therapy is cytopenia, i.e. decreased peripheral blood counts of platelets, leukocytes and / or erythrocytes. The exact mechanism of this side - effect is not known, retrospective analysis showed it affects 10-20% of patients and is linked with the severity of cytokine release syndrome (Juluri et al, PMID34666344). We have previously developed a mouse model of CAR-T cell therapy using C56BL/6 mouse expressing human CD19 under a B- Cell specific promoter (Pennell et al, PMID29735365). The recipient mice are heterozygous for human hCD19 on CD45.2 background. Congenic C56BL/6 CD45.1 mice served as T cell donors. The aim of this study was to investigate if the mouse model recapitulates cytopenia seen in patients after CAR-T cell therapy. C56BL/6 recipient mice were treated with lymphodepleting chemotherapy (Cyclophosphamide (CY) 300 mg/kg) and infused with 1) no T cells 2) control T cells transfected with hEGFR 3) T cells transfected with CD19 CAR with hCD137 and hCD3zeta signaling domains. The chosen dose of infused T cells at 0.3E+6 per animal was low, approximately 10x below the lethal dose and 3x less than IC50 dose, to reduce early mortality. The animals were weighed and examined regularly, and appearance and activity were scored from 0 (healthy) to 8 (moribund). Total of 30 animals per group were harvested at 5 time points, 6 mice each, on days 5, 12, 26, 40 and 54. Peripheral blood counts were measured using HemaVet CBC counter. Flow cytometry was performed on blood and bone marrow. Spleens, long bones (femur, tibia) and sternum were harvested for histopathologic assessment. Multiparametric immunohistochemistry (IHC) was performed using Codex (Phenocycler, Akoya). The mice receiving CAR-19 T cells showed significant, but transient loss of weight and transient increase in morbidity score during the first 2 weeks. Mortality was not significantly different between groups: 0, 1 and 2 deceased animals in CY, control T and CAR-T cell groups, respectively. We observed transient significant cytopenia in the CAR-T cell treated mice, with significantly lower platelet counts on day 5 (p&amp;lt;0.05) and lower White Blood Cell counts on days 12 (p&amp;lt;0.06) and day 26 (p&amp;lt;0.05). These changes were associated with 100-fold larger expansion of CAR-T cells in blood as compared to the control hEGFR T cells and 20-fold higher relative expansion of CAR-T cells in the bone marrow. Multiparametric IHC showed loss of B cell follicles and increased density of donor T cells in the CAR-T cells recipients compared to hEGFR T cell control. Pathologic evaluation of sternums revealed individual segments (sternebra) with necrosis of the hematopoietic elements at the first time point (day 5). At subsequent time points there were progressive changes reminiscent of evolution of infarct with organization, proliferation of fibroblasts and fibrosis with increased osteogenesis and finally with regression of mesenchymal elements and reestablishment of hematopoiesis (Figure 1). The number of segments with necrosis and sequalae was significantly higher in the CAR-T cell group as compared to the hEGFR T cell control (p=0.0005). The necrosis of hematopoietic elements within individual sternum segments involved at the most 3 segments out of 6. The involved segments appeared to distribute randomly: either adjacent or separated by viable segments. The necrotic segments showed paucity of erythrocytes with foci of recent erythrocyte extravasation consistent with ischemic infarct. The mouse model of CAR-T cell therapy against CD19 recapitulates cytopenia in early post - treatment period. The observed pattern of necrosis of the hematopoietic elements in entire segments suggests compromised blood supply. We hypothesize sternebra are more susceptible to necrosis due to limited blood supply, separate for each segment. We hypothesize that occlusion of arteries or capillaries in the bone marrow may contribute to the mechanism of cytopenia following CAR-T cell therapy. Prior retrospective analysis linked the cytopenia with increased levels of inflammatory mediators of Cytokine Release Syndrome. The present findings highlight a role of local factors in situ, which may be influenced by systemic cytokines.

Rare Germline Loss-of-Function Variants in HSP47 ( SERPINH1) Are Associated with an Intermediate Osteogenesis Imperfecta Phenotype Characterized By Atopic Inflammation and Increased Risk of Thrombosis

Background: There has been considerable interest in the collagen-specific chaperone HSP47 ( SERPINH1) as a potential drug target for the treatment of cirrhosis, fibrotic disease, and more recently, thrombosis (Thienel et al., Science 380, 178-187, 2023). While homozygous or compound heterozygous loss of function in SERPINH1 is known to cause a rare form of osteogenesis imperfecta (OI) in humans, little is known about the clinical effects of moderately decreased HSP47 activity. In order to assess the potential safety and efficacy of an antithrombotic strategy based on HSP47 blockade, we evaluated the clinical impacts of heterozygous loss-of-function variants in SERPINH1 in a dataset of over 400,000 individuals. Aims: Determine the clinical effects of SERPINH1 loss of function in a large-scale whole exome sequencing dataset. Methods: The UK Biobank (UKBB) contains paired whole exome sequencing and clinical data on 415,921 subjects in addition to plasma proteomics data for a subset of participants (N= 48,892). We identified all rare (MAF&amp;lt;0.1%)variants in SERPINH1 that were predicted in silico to alter protein activity (functional impact score ≥0.7). Using Firth's logistic regression, we controlled for age, sex, ancestry, and other risk factors and assessed the association between the presence of qualifying SERPINH1 variants and four thrombotic disorders: venous thromboembolism (VTE), non-cardioembolic ischemic stroke (NCEIS), myocardial infarction (MI), and peripheral arterial disease (PAD). Replication was performed in a composite dataset from the NIH All of Us program and the Mass General Brigham (MGB) Biobank (N=150,017). We also evaluated differences in the plasma levels of 1,472 proteins (Olink Explore 1536 proteomics panel) between carriers and non-carriers of qualifying SERPINH1 variants. Results: Rare qualifying variants in SERPINH1 were identified in 382 UKBB participants (100% heterozygous). On average, SERPINH1 variant carriers were of significantly shorter stature (P=3.97 x 10-5) and lower weight (P=0.006) than individuals without such variants, and this effect was more pronounced in subjects with higher functional impact scores ( Figure 1). By contrast, bone mineral density did not differ significantly as measured by calcaneal quantitative ultrasound and femur shaft dual x-ray absorptiometry. The presence of SERPINH1 variants was associated with significantly increased risk of VTE (OR=1.87, 95% CI: 1.21-2.76, P=0.006), MI (OR=1.98, 95% CI: 1.27-2.96, P=0.003), PAD (OR=2.37, 95% CI: 1.29-3.98, P=0.007), and NCEIS (OR=2.67, 95% CI: 1.24-4.98, P=0.015). Restricting the analysis to high-confidence loss-of-function variants (i.e., nonsense, frameshift, and essential splice site mutations) markedly boosted effect size estimates for MI, PAD, and NCEIS. The VTE and MI disease associations replicated in the composite dataset (VTE OR=3.29, 95% CI: 1.46-7.39, P=0.004; MI OR=2.31, 95% CI: 1.05-5.08, P=0.038). Additionally, the association with NCEIS demonstrated a strong trend towards significance in the replication dataset (OR=2.08, 95% CI: 0.90-4.83, P=0.088). Plasma proteome analysis showed a significant increase in several proteins related to asthma, atopic inflammation, and/or eosinophil activation among individuals with qualifying SERPINH1 variants, including RNASE3, DPP10, TSPAN1, CCL20, and IL10RA ( Figure 2). In order to further investigate these differences in circulating protein profile, we assessed the risk of obstructive asthma in a meta-analysis of the UKBB, All of Us, and MGB datasets (total N=565,455) and found that SERPINH1 variant carriers were significantly more likely to have disease (OR=1.32, 95% CI: 1.03-1.69, P=0.026). Conclusions: Loss of function in SERPINH1 is associated with a significantly increased risk of both venous and arterial thrombosis, raising concerns that long-term therapeutic inhibition of HSP47 may not be a safe or effective antithrombotic strategy. Our data indicate that SERPINH1 variant carriers experience higher levels of eosinophil-driven inflammation, which has consistently been linked to cardiovascular disease. Further, heterozygous SERPINH1 variant carriers appear to have an intermediate OI phenotype characterized by shorter stature but without significant differences in bone mineral density compared to non-carriers.

Complex Combination of Pulmonary Embolism, Stroke, and ST-Segment Elevation Myocardial Infarction in Young Patient with Recent COVID-19 Infection and Newly Diagnosed Lung Carcinoma

BACKGROUND: Ischemic stroke, pulmonary embolism (PE), and acute ST-segment elevation myocardial infarction (STEMI) are very rarely all present in younger patients without classical risk factors or a family history of dyslipidemia or cardiovascular disease. They represent a medical emergency and necessitate fast diagnosis, treatment, and search for etiology, not explained purely by atherosclerosis. Thrombophilia testing should be considered in younger patients with several major thrombotic episodes, although there is much disagreement concerning the importance of homocysteine level testing in patients with arterial and venous thrombotic events, including PE. COVID-19 infection may trigger several thrombotic complications caused by unique immunothrombotic processes. CASE PRESENTATION: A 44-year-old patient complaining of chest pain was admitted at our clinic due to acute anterior STEMI. He has a previous medical history of ischemic stroke, COVID-19 infection, and PE in the past 2 months. Newly, diagnosed lung adenocarcinoma was confirmed by biopsy 10 days before STEMI admission, without surgical or previous hemotherapy. The patient was on regular anticoagulant therapy with rivaroxaban 20 mg OAD and antiplatelet therapy with Aspirin due to previous PE and ischemic stroke. Patient denied standard risk factors, family history for cardiovascular disease or any previous minor or major bleedings, history of anemia, liver, or renal dysfunction. Acute stroke was confirmed by brain computed tomography imaging. Thrombophilia panel testing revealed homozygote mutations for MTHFR 677 gene, heterozygote mutation for integrin subunit alpha 2, and fibrinogen B beta chain) genes. The patient was treated with low molecular weight heparin, aspirin, clopidogrel, and heart failure therapy in the acute phase. Clinical consultations were performed with a team of doctors which included a cardiologist, neurologist, and oncologist. Patients have a high bleeding risk, assessed by HAS-BLEED score of 4. CONCLUSION: Our patient is a rare case of serious multi-vascular thrombotic events with underlying thrombophilia, lung cancer, and past COVID-19 infection complicated by pulmonary embolism, ischemic stroke, and STEMI.

Right Mini-Thoracotomy in the Surgical Treatment of Structural Heart Diseases (SHDs): An Institutional Experience

Introduction: Surgical treatment of structural heart diseases continues to predominantly involve median sternotomy, despite the ongoing trends favoring minimally invasive approaches that have persisted for many years. In this study, we present data on structural heart disease (SHD) surgeries conducted by our institute using a right mini-thoracotomy approach. Patients and Methods: This single-center retrospective study included 58 patients who underwent right minithoracotomy procedures between February 2018 and June 1, 2023. Preoperative demographic and medical data were collected from patient files and records. Perioperative and 30-day outcome data were obtained through the national electronic record system. Results: The average age of the participants was 39.9. Female patients accounted for 31.6% (n= 18) of the participants. The majority of surgeries in this study involved peripheral cannulation and conventional cardioplegia. Mitral valve repair and atrial septal defect closure were the most common procedures performed. Intraoperative outcomes showed favorable results, with no instances of significant bleeding, structural complications, or mortality. Regarding the postoperative 30-day outcomes, the stroke rate was 1.8% (n= 1) among the patients. There were no reported cases of transient ischemic attack (TIA), myocardial infarction (MI), and mortality. The conversion to median sternotomy occurred in 3.4% (n= 2) of the cases. Reoperation and reexploration were required in 1.8% (n= 1) of the cases. The mean length of stay in the ICU was 1.7 days, while the mean length of ward stay was 4.2 days. Conclusion: This study contributes to the evidence supporting the shift towards minimally invasive approaches in the surgical management of structural heart disease. The low rate of intraoperative conversion, absence of major complications, and favorable postoperative outcomes highlight the safety and feasibility of right mini-thoracotomy. Continued advancements in surgical techniques and clinical expertise are expected to further optimize patient outcomes and improve the quality of care in this field.