Impaired Reperfusion Research Articles

Latent cytomegalovirus infection associates with impairments in myocardial reperfusion, left-ventricular function, and quality of life after ST-elevation myocardial infarction

Abstract Introduction Cytomegalovirus (CMV) is a ubiquitous herpesvirus affecting the majority of adults in European countries. CMV influences T-lymphocyte biology throughout life. We have previously associated CMV status with adverse left ventricular (LV) remodeling after ST-elevation myocardial infarction (STEMI) in a single-centre study. In this study, we aimed to assess the external validity of these findings. Methods This study is a retrospective analysis of 354 patients presenting with STEMI, who were recruited to A Trial of Low-Dose Adjunctive Alteplase During Primary PCI (T-TIME) and had blood samples archived. The participants underwent immediate coronary angiography and percutaneous coronary intervention (PCI), serial cardiovascular magnetic resonance (CMR) imaging at 2-7 days and 3 months post-STEMI, and serial assessment of health-related quality of life with the standardised EQ-5D visual analogue scale (VAS). CMV IgG titre was measured in cryopreserved samples from each patient, and patients were categorised as CMV negative, low-positive or high-positive. All analyses were adjusted for infarct location. Results Of 354 patients, 175 (49.4%) were CMV IgG titre negative, 89 (25.1%) were low-positive and 90 (25.4%) were high-positive. CMV+ patients were older (62.5 vs 58.7 years) and more likely to be non-White (6.7% vs 2.3%). CMV+ patients displayed several adverse outcomes. First, myocardial reperfusion was impaired. Thrombolysis in myocardial infarction (TIMI) flow grade 3 after PCI, indicating complete reperfusion, was less common in CMV+ patients (76.0% vs 84.6%; p=0.042). CMV+ patients also had a higher TIMI frame count after PCI (p=0.021), and non-significantly less ST-segment resolution at 60 minutes (38.8% vs 48.4%; p=0.066). Impaired myocardial reperfusion appeared to lead to impaired LV function, with LV ejection fraction (LVEF) measured on early CMR lower in CMV+ patients (42.6% vs 45.3%, p=0.004). At 3 months, LV function remained impaired in CMV+ patients (LVEF: 47.8% vs 49.7%; p=0.035). This was mirrored by CMV+ patients displaying higher NT-pro BNP levels at 2-7 days (1381 vs 1172pg/mL, p=0.097) and 3 months (575 vs 338pg/mL, p=0.021). Finally, impaired LV function appeared to affect quality of life. Over 3 months, in contrast to CMV-negative patients, those with the highest CMV IgG experienced almost no improvement in quality of life, measured by change in the EQ-5D VAS (negative: +9.93; high-positive: +0.70; p=0.0002). Conclusion CMV+ patients with STEMI experience worse outcomes, with impaired reperfusion, persistently reduced LV function and less improvement in health-related quality of life over 3 months. We hypothesise that the effect of CMV is mediated through immune activation. Future research should explore the mechanisms by which CMV-specific lymphocytes interact with myocardial reperfusion and repair post-STEMI.

Clinical significance of 12-lead electrocardiogram QRS scores on admission in ST-segment elevation myocardial infarction

Abstract Background A QRS scoring system by 12-lead electrocardiography (ECG) is a quick and simple method to evaluate degree and extension of myocardial infarction. Previous studies have shown that high QRS scores (≥5) at hospitalization (before reperfusion) related to impaired myocardial reperfusion during percutaneous coronary intervention (PCI) and subsequent poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI) (Figure 1). However, the pathogenesis and associated factors with high QRS scores remain poorly defined. Therefore, this study aimed to explore clinical and lesion characteristics associated with QRS scores at hospitalization in patients with STEMI. Methods This retrospective observational study enrolled 138 broad anterior-wall STEMI patients who underwent PCI in the proximal left anterior descending artery and achieved reperfusion within 3 hours of onset. Patients were divided by QRS scores at hospitalization into low (<5: n=97) and high (≥5: n=41) QRS-scores, and clinical and lesion characteristics were compared between the 2 groups. Lesion characteristics were evaluated by intravascular ultrasound (IVUS). Results Despite early phase of STEMI, QRS scores at hospitalization varied (3 [2-5] points). Clinical characteristics, including onset-to-door time (66 [41-101] min vs. 55 [42-76] min) and onset-to-reperfusion time (112 [88-145] min vs. 106 [81-120] min), were comparable between patients with low and high QRS-scores. In contrast, significantly higher percentages of lipid plaques, plaque rupture and large thrombus were seen at the culprit lesion sites in patients with high versus low QRS scores (Figure 2). As a result, patients with high QRS scores had higher incidence of no-reflow phenomenon during PCI (36.6% vs. 12.6%, p<0.05) and larger infarct size assessed by peak CK values (5333 [3307-7443] IU/l vs. 1941 [759-3559], p<0.05) compared with those with low QRS-scores. Conclusions High QRS scores at hospitalization were associated with vulnerable lesion characteristics, as well as impaired coronary reperfusion and large infarct size. Although the exact mechanisms of the associations require future studies, QRS scores may help risk stratification before reperfusion and prognostic prediction after reperfusion.Figure 1.Figure 2.

Impact of diabetes on epicardial reperfusion and mortality in a contemporary STEMI population undergoing mechanical reperfusion: insights from the ISACS STEMI COVID 19 Registry

Background and AimDiabetes has been shown in last decades to be associated with a significantly higher mortality among patients with ST‐segment elevation myocardial infarction (STEMI) treated with primary PCI (PPCI). Therefore, the aim of current study was to evaluate the impact of diabetes on times delays, reperfusion and mortality in a contemporary STEMI population undergoing PPCI, including treatment during the COVID pandemic. Methods and ResultsThe ISACS-STEMI COVID-19 is a large-scale retrospective multicenter registry involving PPCI centers from Europe, Latin America, South-East Asia and North-Africa, including patients treated from 1st of March until June 30, 2019 and 2020. Primary study endpoint of this analysis was in-hospital mortality. Secondary endpoints were postprocedural TIMI 0-2 flow and 30-day mortality. Our population is represented by 16083 STEMI patients. A total of 3812 (23,7%) patients suffered from diabetes. They were older, more often males as compared to non-diabetes. Diabetic patients were less often active smokers and had less often a positive family history of CAD, but they were more often affected by hypertension and hypercholesterolemia, with higher prevalence of previous STEMI and previous CABG. Diabetic patients had longer ischemia time, had more often anterior MI, cardiogenic shock, rescue PCI and multivessel disease. They had less often out-of-hospital cardiac arrest and in-stent thrombosis, received more often a mechanical support, received less often a coronary stent and DES. Diabetes was associated with a significantly impaired postprocedural TIMI flow (TIMI 0-2: 9.8% vs 7.2%, adjusted OR [95% CI] = 1.17 [1.02-1.38], p = 0.024) and higher mortality (in-hospital: 9.1% vs 4.8%, Adjusted OR [95% CI] =1.70 [1.43-2.02], p < 0.001); 30-day mortality (10.8% vs 6%, Adjusted HR [95% CI] =1.46 [1.26-1.68], p < 0.001) as compared to non-diabetes, particularly during the pandemic. ConclusionsOur study showed that in a contemporary STEMI population undergoing PPCI, diabetes is significantly associated with impaired epicardial reperfusion that translates into higher in-hospital and 30-day mortality, particularly during the pandemic.

A Prediction Nomogram for No-Reflow in Acute Myocardial Infarction Patients after Primary Percutaneous Coronary Intervention.

The coronary no-reflow (NR) phenomenon is an independent predictor of major adverse cardiac events (MACEs). This study aimed to establish a clinical and comprehensive nomogram for predicting NR in acute myocardial infarction (AMI) patients after primary percutaneous coronary intervention (pPCI). The multivariable logistic regression analysis was performed to determine the NR-related factors. A nomogram was established via several clinical and biochemical factors, and the performance was evaluated via discrimination, calibration, and clinical factors. The study consisted of 3041 AMI patients after pPCI, including 2129 patients in the training set (70%) and 912 patients in the validation set (30%). The NR event was 238 in the training set and 87 in the validation set. The level of N-terminal prohormone B-type natriuretic peptide (NT-proBNP), basophil count (BASO), neutrophil count (NEUBC), D-dimer, hemoglobin (Hb), and red blood cell distribution width (RDW.CV) in NR patients showed statistically significant differences. In the training set, the C-index was 0.712, 95% CI 0.677 to 0.748. In the validation set, the C-index was 0.663, 95% CI 0.604 to 0.722. A nomogram that may predict NR in AMI patients undergoing pPCI was established and validated. We hope this nomogram can be used for NR risk assessment and clinical decision-making and significantly prevent potentially impaired reperfusion associated with NR.

Cardiac extracellular matrix at microvascular obstruction area after reperfused myocardial infarction: a morphometric study

Abstract Background Extracellular matrix (ECM), a structural and biomechanical support to cardiomyocytes, suffers substantial alterations after myocardial infarction (MI). Despite a complete reopening at epicardial level, hypoperfusion within the infarcted myocardium, known as microvascular obstruction (MVO), occurs. Extensive clinical studies and meta-analysis reported the association between the magnitude of MVO and the appearance of adverse remodeling; thus, scrutinizing ECM composition within the infarcted areas with impaired tissue-level reperfusion could provide fundamental insight regarding MVO pathophysiology. Purpose To histologically compare ECM composition within the infarct zone regarding the presence or absence of MVO using an experimental swine model of reperfused MI. Methods MI was induced in swine (n=10) by transitory 90-min coronary occlusion followed by 7 days of reperfusion. Prior to euthanasia, intracoronary thioflavin-S was infused. Within the infarcted myocardium, regions displaying MVO (thioflavin-S-) or no MVO (thioflavin-S+) were isolated and stained to morphometrically compare ECM composition. Results Regarding cellularity, areas with MVO displayed an enlarged presence of neutrophils and lymphocytes, whilst no differences in the amount of macrophages and myofibroblasts were detected in comparison to no MVO-myocardium. Those regions with macroscopic MVO showed lower capillary density than those without MVO. According to the fibers and ground substance, a significant reduction in the extension of type I collagen, laminin, and fibronectin together with an augmentation of glycosaminoglycan were noted in areas showing MVO compared to those without microvascular injury. No changes in the amount of type III collagen was observed. Conclusion The ECM composition in infarcted regions with MVO displays a higher presence of inflammatory infiltrate and glycosaminoglycans as well as a reduced amount of microvessels and fibers compared to those areas without microvascular hypoperfusion. These characteristics might underlie the development of adverse ventricular remodeling in MI patients with extensive MVO.

Type 2 cytokines promote angiogenesis in ischemic muscle via endothelial IL-4Rα signaling

Peripheral arterial disease (PAD) is one of the leading causes of cardiovascular morbidity and mortality worldwide, yet current trials on therapeutic angiogenesis remain suboptimal. Type 2 immunity is critical for post-ischemic regeneration, but its regulatory role in revascularization is poorly characterized. Here, we show that type 2 cytokines, interleukin-4 (IL-4) and interleukin-13 (IL-13), are the key mediators in post-ischemic angiogenesis. IL-4/IL-13-deficient mice exhibit impaired reperfusion and muscle repair in an experimental model of PAD. We find that deletion of IL-4Rα in the endothelial compartment, rather than the myeloid compartment, leads to remarkable impairment in revascularization. Mechanistically, IL-4/IL-13 promote endothelial cell proliferation, migration, and tube formation via IL-4Rα/STAT6 signaling. Furthermore, attenuated IL-4/IL-13 expression is associated with the angiogenesis deficit in the setting of diabetic PAD, while IL-4/IL-13 treatment rescues this defective regeneration. Our findings reveal the therapeutic potential of type 2 cytokines in treating patients with muscle ischemia.

Impaired renal ischemia reperfusion recovery after bilateral renal artery ligation in rats treated with adenine: role of renal mitochondria.

Vascular calcification (VC) and ischemia reperfusion (IR) injury is characterised to have mitochondrial dysfunction. However, the impact of dysfunctional mitochondria associated with vascular calcified rat kidney challenged to IR is not explored and is addressed in the present study. Male Wistar rats were treated with adenine for 20 days to induce chronic kidney dysfunction and VC. After 63 days, renal IR protocol was performed with subsequent recovery for 24h and 7 days. Various mitochondrial parameters and biochemical assays were performed to assess kidney function, IR injury and its recovery. Adenine-induced rats with VC, decreased creatinine clearance (CrCl), and severe tissue injury demonstrated an increase in renal tissue damage and decreased CrCl after 24h of IR (CrCl in ml: IR-0.220.02, VC-IR-0.050.01). Incidentally, the 24h IR pathology in kidney was similar in both VC-IR and normal rat IR. But, the magnitude of dysfunction was higher with VC-IR due to pre-existing basal tissue alterations. We found severed deterioration in mitochondrial quantity and quality supported by low bioenergetic function in both VC basal tissue and IR challenged sample. However, post 7 days of IR, unlike normal rat IR, VC rat IR did not improve CrCl and corresponding mitochondrial damage in terms of quantity and its function were observed. Based on the above findings, we conclude that IR in VC rat adversely affect the post-surgical recovery, mainly due to the ineffective renal mitochondrial functional restoration from the surgery.

Microbleeds Due to Reperfusion Enhance Early Seizures after Carotid Ligation in a Rat Ischemic Model.

Impaired reperfusion in ischemic brain disease is a condition that we are increasingly confronted with owing to recent advances in reperfusion therapy. In the present study, rat models of reperfusion were investigated to determine the causes of acute seizures using magnetic resonance imaging (MRI) and histopathological specimens. Rat models of bilateral common carotid artery ligation followed by reperfusion and complete occlusion were created. We compared the incidence of seizures, mortality within 24 h, MRI, and magnetic resonance spectroscopy (MRS) to evaluate ischemic or hemorrhagic changes and metabolites in the brain parenchyma. In addition, the histopathological specimens were compared with those observed on MRI. In multivariate analysis, the predictive factors of mortality were seizure (odds ratios (OR), 106.572), reperfusion or occlusion (OR, 0.056), and the apparent diffusion coefficient value of the striatum (OR, 0.396). The predictive factors of a convulsive seizure were reperfusion or occlusion (OR, 0.007) and the number of round-shaped hyposignals (RHS) on susceptibility-weighted imaging (SWI) (OR, 2.072). The incidence of convulsive seizures was significantly correlated with the number of RHS in the reperfusion model. RHS on SWI was confirmed pathologically as microbleeds in the extravasation of the brain parenchyma and was distributed around the hippocampus and cingulum bundle. MRS analysis showed that the N-acetyl aspartate level was significantly lower in the reperfusion group than in the occlusion group. In the reperfusion model, RHS on SWI was a risk factor for convulsive seizures. The location of the RHS also influenced the incidence of convulsive seizures.

#3650 LINACLOTIDE IS PROTECTIVE AGAINST RENAL ISCHEMIA-REPERFUSION INJURY

Abstract Background and Aims Renal ischemia-reperfusion injury is associated with delayed graft function and poor long-term graft survival following transplantation. Linaclotide is a guanylate cyclase C (GC-C) receptor agonist that increases intracellular cGMP concentrations and promotes intestinal transport capacity by activating the GC-C receptor. Since CKD is a deficiency of cGMP in the kidney, increasing cGMP in the kidney by linaclotide would suppress fibrosis, protecting the kidney. Method An AKI rat model of unilateral nephrectomy plus contralateral ischaemia (30 min) and impaired reperfusion (up to 14 days) was used. Linaclotide was administered before and after surgery for 2 weeks, and blood and renal tissue samples were collected to determine its effect on renal function and whether it was protective against the progression of CKD. Results In the I/R injury+ group, creatinine levels were lower in the linaclotide-treated group than in the non-treated group. Sirius red staining showed significant improvement in fibrosis. The hydroxyproline content of kidneys was determined by the basic hydroxyproline method. RNA seq showed that genes down-regulated in I/R injury+ were the oxidative stress markers SOD3 and Gpx1. The expression of genes down-regulated in I/R injury+ was up-regulated to a degree similar to that in I/R injury- by treatment with linaclotide. These data suggest that linaclotide may ameliorate renal fibrosis by suppressing renal dysfunction through its antioxidant effects. Conclusion The antioxidant effect of linaclotide was found to suppress the decrease in renal function caused by I/R. We would like to apply this finding to human renal transplantation in the future to prevent renal function deterioration due to I/R.

ICAM1 expression by the microvasculature impairs capillary perfusion which compromises hind limb ischemia recovery in diabetic mice

Chronic limb threatening ischemia (CLTI), which is one of the major complications of diabetes, is associated with poor limb and cardiovascular prognoses, along with a dramatic decrease in life expectancy. However, the pathophysiology of this disease is poorly understood and therapeutic targets are missing. Our objective is to explore the contribution of endothelial dysfunction in the development of CLTI in diabetic mice. Hind limb ischemia (HLI) was induced by ligation and resection of the femoral artery in C57BL6/J male mice, in which insulin resistance was induced by a high fat diet, and hyperglycaemia was induced one month later by low dose streptozotocin administrations. According to our previous investigations, ischemic foot re-perfusion, assessed via laser doppler perfusion imaging, was significantly reduced in diabetic animal 28 days after HLI surgery was performed (ratio blood flow in the ischemic leg vs non ischemic leg = 0.27 ± 0.09 vs 0.44 ± 0.21 in control mice; P = 0.03), even though angiogenesis was identical in both groups. On the contrary, we found that impaired ischemic foot re-perfusion was associated with an increased endothelial cell activation attested by an increased ICAM1 expression (P < 0.0001). We then hypothesized that ICAM1, by interacting with white blood cells (WBC), may compromise the perfusion of capillaries with a diameter smaller than a WBC. Accordingly, we found that WBC circulation velocity in the microvasculature was significantly diminished in diabetic mice (533 ± 169 μm/s vs 960 ± 188 in control mice; P = 0.004) and associated with a decreased percentage of capillaries perfusion by BS-1 lectin (78.5 ± 10.5% vs 96.1 ± 5.7 in control mice; P = 0.03). With the aim to test whether ICAM1 overexpression may be responsible for impaired ischemic foot re-perfusion, diabetic mice were administered with anti-ICAM1 antibodies or isotype control for 14 days, starting 14 days after HLI surgery was performed. We found that anti-ICAM1 therapy significantly increased WBC circulation velocity within the microvasculature (779 ± 113 μm/s vs 447 ± 107 in mice treated with isotype control; P < 0.0001) and the percentage of perfused capillary (P = 0.009). Altogether, our results demonstrate that ICAM1 overexpression may compromise hind limb ischemia recovery in diabetic mice by decreasing WBC circulation velocity and impairing capillary perfusion.

Abstract 603: Type 2 Cytokines Promote Angiogenesis In Ischemic Muscle Via Endothelial Il-4rα Signaling

Peripheral arterial disease (PAD) is one of the leading causes of cardiovascular morbidity and mortality worldwide, yet current trials on therapeutic angiogenesis remain suboptimal. Type 2 immunity is critical for post-ischemic regeneration, but its regulatory role in revascularization is poorly characterized. Here, we show that type 2 cytokines, interleukin-4 (IL-4) and interleukin-13 (IL-13), are the key mediators in post-ischemic angiogenesis. IL-4/IL-13-deficent mice exhibited impaired reperfusion and muscle repair in experimental model of PAD. Surprisingly, we found that deletion of IL-4Rα in the endothelial compartment, rather than the myeloid compartment, led to remarkable revascularization impairment. Mechanistically, IL-4/IL-13 promoted endothelial cells proliferation, migration and tube formation via IL-4Rα/STAT6 signaling. Furthermore, attenuated IL-4/IL-13 expression was found to be associated with the angiogenesis deficit in the setting of diabetic PAD, while IL-4/IL-13 treatment rescued this defective regeneration. Our findings reveal the therapeutic potential of type 2 cytokines in treating patients with muscle ischemia.

Abstract TMP5: Intravenous Thrombolysis Influence After Successful Mechanical Thrombectomy For Large Vessel Occlusion; Not To Skip Tpa Yet!

Background: Despite the high rates of successful reperfusion in the randomized mechanical thrombectomy (MT) trials, only 27% of large vessel occlusion (LVO) patients treated successfully with MT achieved functional independence at 90 days. One proposed theory is impaired distal reperfusion with persistent small thrombi within the microcirculation despite complete recanalization “the no-Reflow phenomenon”. These distal small thrombi would be more suitable to dissolve by thrombolytics. Methods: This is a retrospective cohort obtained from Get with the guidelines stroke (GWGS) database available at Medical University of South Carolina Comprehensive Stroke Center (CSC) for LVO patients presented within 4.5 hours of last known well (LNW) between January/2018- June/2022. We aim to investigate the influence of intravenous thrombolysis (IVTPA) on the functional independence mRS (0-2) after a successful MT defined as modified thrombolysis score (mTICI2c-3). Results: Of 188 LVO patients who achieved successful reperfusion (TICI2c-3) during the study period, 93 (49%) arrived at our CSC within 4.5 hours of LSW, of them 40 patients (43%) received IVTPA. There was no difference in age, gender, race and initial NIHSS between patients who received IVTPA and those who did not receive IVTPA. Patients received IVTPA arrived at the CSC earlier [median LNW 60 min IQR (51 - 151) vs 165 min (IQR 103- 214), p = &lt;0.001), and had higher ASPECTS score [median 9, IQR (8-10) vs 7, IQR (7-10) p= 0.027]. There was no difference in the collaterals score, clot burden score, site of LVO, tandem nature, door to reperfusion times, post-procedural intracranial hemorrhage or stroke etiology between the two groups. Discharge functional independence mRS (0-2) was achieved more in IVTPA group 65% vs 42% p= 0.025. After adjusting for ASPECTS score, IVTPA patients had higher odds of achieving mRS (0-2) at discharge compared to patients who did not receive IVTPA within 4.5 hours of LNW [aOR 2.42, 95%CI (1.02- 5.75), p= 0.046]. Conclusion: Intravenous thrombolysis can still influence LVO stroke patients' outcomes with complete revascularization. This positive effect might be related to distal microthrombi thrombolysis and subsequent improvement of the microcirculation flow beyond the occlusion site

Sex Difference in Capillary Reperfusion After Transient Middle Cerebral Artery Occlusion in Diabetic Mice.

Type 2 diabetes (DM2) exacerbates stroke injury, reduces efficacy of endovascular therapy, and worsens long-term functional outcome. Sex differences exist in stroke incidence, response to therapy, poststroke microvascular dysfunction, and functional recovery. In this study, we tested the hypotheses that poor outcome after stroke in the setting of DM2 is linked to impaired microvascular tissue reperfusion and that male and female DM2 mice exhibit different microvascular reperfusion response after transient middle cerebral artery occlusion (MCAO). Transient MCAO was induced for 60 minutes using an intraluminal filament in young adult DM2 and nondiabetic control male and female mice. Capillary flux in deep cortical layers was assessed using optical coherence tomography-based optical microangiography (OMAG), and associated regional brain infarct size was evaluated by hematoxylin and eosin staining. Compared to baseline, MCAO reduced absolute capillary red blood cell flux by 84% at 24 hours post-MCAO in male DM2 (P<0.001) but not male control mice. When normalized to pre-MCAO baseline, red blood cell flux 24 hours after stroke was 64% lower in male DM2 mice than male nondiabetic controls (P<0.01). In females, MCAO decreased capillary flux by 48% at 24 hours post-MCAO compared with baseline in DM2 (P<0.05) but not in control mice. Red blood cell flux of female DM2 mice did not differ from that of nondiabetic controls either before or 24 hours after MCAO. Furthermore, normalized capillary flux 24 hours after MCAO failed to differ between female DM2 mice and nondiabetic controls. Concomitantly, male but not female DM2 mice experienced 25% larger infarct in caudate-putamen versus respective nondiabetic controls (P<0.05). DM2 impairs capillary perfusion and exacerbates ischemic deep brain injury in male but not female young adult mice. Premenopausal females appear to be protected against DM2-related capillary dysfunction and brain injury.

Author Response: Prevalence and Significance of Impaired Microvascular Tissue Reperfusion Despite Macrovascular Angiographic Reperfusion (No-Reflow).

We thank the readers for their interest in our research.1 Methodological differences may account for the discrepancy in the reported rates of no-reflow. Using prospective trial data with prespecified follow-up perfusion imaging, we assessed 146 of 147 (99%, 1 patient was excluded because of hemicraniectomy) patients with TICI 2c/3 angiographic reperfusion,1 while only 25% (n = 51/203) were assessed in the study by Ter Schiphorst et al.2 This is important because the association between no-reflow and poor neurologic recovery (24-hour NIHSS 7 [no-reflow] vs 2 [without no-reflow]; p < 0.0001) may confer inherent selection bias in observational studies because patients with more severe symptoms, such as those with no-reflow, may be less likely to complete prolonged research MRIs and therefore be excluded from analysis. Despite intermodality differences, a recent study by Rosso et al. found a similar rate of hypoperfusion on arterial spin labeling among patients with complete recanalization (n = 34/140; 24.3%),3 compared with our analysis (25.3%) using perfusion-weighted imaging and CT perfusion.1 Rosso et al. added to the growing body of literature that demonstrates a remarkably consistent prevalence of no-reflow across imaging modalities (transcranial Doppler 27.9%,4 single-photon emission computed tomography 25%5), which is in support of the external validity of our results.

Reader Response: Prevalence and Significance of Impaired Microvascular Tissue Reperfusion Despite Macrovascular Angiographic Reperfusion (No-Reflow).

Ng et al.1 recently reported a 25% prevalence of hypoperfusion—a >15% reduction of cerebral blood flow (CBF) or cerebral blood volume (CBV) from the mirror region on CT perfusion imaging—within the 24-hour infarct window, despite complete anterior circulation recanalization (TICI 2c/3), which negatively affected functional outcome. These findings contrast with our earlier finding of 6% (2/33) hypoperfused infarcts, where the 24-hour arterial spin labeling (ASL)-CBF images were analyzed according to the Alberta Stroke Program Early CT Score (ASPECTS) template.2 We have reanalyzed our data set considering the entire middle cerebral arterial (MCA) territory, irrespective of ASPECTS. After excluding areas with confluent hemorrhagic transformation or parenchymal hematoma on the 24-hour MRI, consensus by 2 raters (kappa = 0.752) identified only 2 additional patients exhibiting patchy mild-to-moderate hypoperfusion with volumes too small to be reliably measured on ASL images, for a total prevalence of 4 of 33 patients (12%). After excluding patients with missing mRS (n = 2) or associated infarcts outside the MCA territory (n = 5), univariate analysis showed no significant association of “no-reflow” presence with a 3-month mRS of 0–1 or 0–2. A multivariate analysis was precluded by low occurrence of no-reflow. Taken together with this article and another recent report,3 the prevalence of no-reflow after recanalized MCA stroke appears to stand ∼15–20%, depending on the perfusion modality used, and often involves small areas. The true impact on clinical outcome remains unclear.3

Editors' Note: Prevalence and Significance of Impaired Microvascular Tissue Reperfusion Despite Macrovascular Angiographic Reperfusion (No-Reflow).

Pooling data from the EXTEND-IA, EXTEND-IA TNK, and EXTEND IA-TNK part 2 clinical trials, Dr. Ng et al. found that persistent hypoperfusion (“no-reflow”) on follow-up perfusion imaging after successful recanalization was common and associated with poor clinical outcomes. One in 4 patients had perfusion imaging evidence of “no-reflow” at 24 hours, and this radiographic finding accounted for 60% of the final infarct volume and was associated with a 4-fold higher odds of being functionally dependent or dead by day 90. Dr. Schiphorst et al. sought to validate these findings using their data set but found the prevalence of “no-reflow” occurred in half as many patients. They also emphasize that the relationship of no-reflow and clinical outcome is uncertain. Nonetheless, inherent methodologic differences in these studies, specifically selection bias for 24-hour perfusion imaging may account for the variability in findings. The systematic use of perfusion imaging in 99% of included patients from the pooled analysis by Ng et al. and larger sample size make for a convincing argument that postreperfusion hypoperfusion is not only common, but a useful prognostic factor. Pooling data from the EXTEND-IA, EXTEND-IA TNK, and EXTEND IA-TNK part 2 clinical trials, Dr. Ng et al. found that persistent hypoperfusion (“no-reflow”) on follow-up perfusion imaging after successful recanalization was common and associated with poor clinical outcomes. One in 4 patients had perfusion imaging evidence of “no-reflow” at 24 hours, and this radiographic finding accounted for 60% of the final infarct volume and was associated with a 4-fold higher odds of being functionally dependent or dead by day 90. Dr. Schiphorst et al. sought to validate these findings using their data set but found the prevalence of “no-reflow” occurred in half as many patients. They also emphasize that the relationship of no-reflow and clinical outcome is uncertain. Nonetheless, inherent methodologic differences in these studies, specifically selection bias for 24-hour perfusion imaging may account for the variability in findings. The systematic use of perfusion imaging in 99% of included patients from the pooled analysis by Ng et al. and larger sample size make for a convincing argument that postreperfusion hypoperfusion is not only common, but a useful prognostic factor.

SARS-CoV-2 Positivity, Stent Thrombosis, and 30-day Mortality in STEMI Patients Undergoing Mechanical Reperfusion.

SARS-Cov-2 has been suggested to promote thrombotic complications and higher mortality. The aim of the present study was to evaluate the impact of SARS-CoV-2 positivity on in-hospital outcome and 30-day mortality in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) enrolled in the International Survey on Acute Coronary Syndromes ST-segment elevation Myocardial Infarction (ISACS-STEMI COVID-19 registry. The 109 SARS-CoV-2 positive patients were compared with 2005 SARS-CoV-2 negative patients. Positive patients were older (P = .002), less often active smokers (P = .002), and hypercholesterolemic (P = .006), they presented more often later than 12h (P = .037), more often to the hub and were more often in cardiogenic shock (P = .02), or requiring rescue percutaneous coronary intervention after failed thrombolysis (P < .0001). Lower postprocedural Thrombolysis in Myocardial Infarction 3 flow (P = .029) and more thrombectomy (P = .046) were observed. SARS-CoV-2 was associated with a significantly higher in-hospital mortality (25.7 vs 7%, adjusted Odds Ratio (OR) [95% Confidence Interval] = 3.2 [1.71-5.99], P < .001) in-hospital definite in-stent thrombosis (6.4 vs 1.1%, adjusted Odds Ratio [95% CI] = 6.26 [2.41-16.25], P < .001) and 30-day mortality (34.4 vs 8.5%, adjusted Hazard Ratio [95% CI] = 2.16 [1.45-3.23], P < .001), confirming that SARS-CoV-2 positivity is associated with impaired reperfusion, with negative prognostic consequences.

Angiographic and clinical outcome of SARS-CoV-2 positive patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: A collaborative, individual patient data meta-analysis of six registry-based studies

BackgroundThe characteristics and outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients with ST-Elevation Myocardial Infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) are still poorly known. MethodsThe PANDEMIC study was an investigator-initiated, collaborative, individual patient data (IPD) meta-analysis of registry-based studies. MEDLINE, ScienceDirect, Web of Sciences, and SCOPUS were searched to identify all registry-based studies describing the characteristics and outcome of SARS-CoV-2-positive STEMI patients undergoing PPCI. The control group consisted of SARS-CoV-2-negative STEMI patients undergoing PPCI in the same time period from the ISACS-STEMI COVID 19 registry. The primary outcome was in-hospital mortality; the secondary outcome was postprocedural reperfusion assessed by TIMI flow. ResultsOf 8 registry-based studies identified, IPD were obtained from 6 studies including 941 SARS-CoV-2-positive patients; the control group included 2005 SARS-CoV-2-negative patients. SARS-CoV-2-positive patients showed a significantly higher in-hospital mortality (p < 0.001) and worse postprocedural TIMI flow (<3, p < 0.001) compared with SARS-CoV-2-negative subjects. The increased risk for SARS-CoV-2-positive patients was significantly higher in males compared to females for both the primary (pinteraction = 0.001) and secondary outcome (pinteraction = 0.023). In SARS-CoV-2-positive patients, age ≥ 75 years (OR = 5.72; 95%CI: 1.77–18.5), impaired postprocedural TIMI flow (OR = 11.72; 95%CI: 2.64–52.10), and cardiogenic shock at presentation (OR = 11.02; 95%CI: 2.84–42.80) were independent predictors of mortality. ConclusionsIn STEMI patients undergoing PPCI, SARS-CoV-2 positivity is independently associated with impaired reperfusion and with a higher risk of in-hospital mortality, especially among male patients. Age ≥ 75 years, cardiogenic shock, and impaired postprocedural TIMI flow independently predict mortality in this high-risk population.

Endovascular Treatment of an Elderly Diabetic Patient with a Circular Myocardial Infarction in Cardiogenic Shock Complicated by Stent Thrombosis

The most common cause of cardiogenic shock (CS) is acute myocardial infarction (AMI), which is diagnosed in approximately 5–8% of patients hospitalized for AMI and is more common in patients with acute ST-segment elevation myocardial infarction (STEMI). CS is caused by severe myocardial dysfunction, which leads to a decrease in cardiac output, hypoperfusion of the end organs, and hypoxia. Mortality in diabetic patients with AMI is high. Besides the fact that type 2 diabetes mellitus (DM2) contributes to the progression of coronary atherosclerosis, coronary pathology in this category of patients occurs against the background of a specific diabetic myocardial lesion – diabetic cardiomyopathy. Against the background of cardiomyopathy, acute heart failure is more often developed with a decrease in global myocardial contractility up to CS, which increases hospital-acquired mortality in MI by more than 15 times. The increased risk of death observed in patients with DM2 in the acute period of myocardial infarction (MI) persists for several years, and therefore, at present, in patients with the acute coronary syndrome (ACS) and diabetes, an early invasive strategy is preferable to a conservative strategy. The SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial demonstrated that in patients with CS complicating AMI, emergency revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) improved long-term survival when compared with initial intensive medical therapy. However, in the CULPRIT-SHOCK (Culprit Lesion Only PCI Versus Multivessel PCI in Cardiogenic Shock) study, stenting of non-infarct-dependent coronary arteries in CS increases the risks of major cardiac events, as well as the number of repeated revascularizations within 30 days and 1 year. Patients with multivessel lesions, in most cases, are elderly patients (75–90 years old) who have age restrictions on taking the loading dose at the prehospital stage. Such a loading dose of clopidogrel may not be sufficient to saturate the patient in fact, despite optimal epicardial recanalization, a large proportion of patients still experience impaired reperfusion and in-stent thrombosis. A large body of evidence has been accumulated on the benefits of glycoprotein (GP) IIb-IIIa inhibitors in terms of prevention of stent thrombosis, and benefits in mortality, especially among high-risk patients, and as an upstream strategy.

Clinical Significance and Influencing Factors of Microvascular Tissue Reperfusion After Macrovascular Recanalization.

The relevance of impaired microvascular tissue reperfusion despite successful macrovascular angiographic reperfusion (no-reflow) in acute ischemic stroke (AIS) remains controversial. In this study, we aimed to investigate the impact of tissue optimal reperfusion (TOR) and its influencing factors. From December 1, 2020 to December 1, 2021, AIS patients with successful recanalization (modified Thrombolysis in Cerebral Infarction score [mTICI] ≥ 2b) after mechanical thrombectomy (MT) were retrospectively reviewed. Computed tomography perfusion was performed before and after MT. Successful reperfusion was assessed by TOR, defined as > 90% reduction of the Tmax > 6s lesion volumes between baseline and early follow-up perfusion profiles. The impact of TOR on functional outcomes after successful recanalization and influencing factors for TOR were both investigated. Sixty-three patients were included, including 44 cases in the TOR group and 19 cases in the non-TOR group. The TOR group had a higher rate of favorable outcome (aOR 4.366, 95%CI 1.159-16.445, p = 0.030) and NIHSS improvement (aOR 5.089, 95%CI 1.340-19.322, p = 0.017) than the non-TOR group. Multivariable logistic regression showed baseline glucose (OR 0.648, 95%CI 0.492-0.854, p = 0.002) and mTICI 2c/3 (OR 10.984, 95%CI 2.220-54.343, p = 0.003) predicted TOR in model 1; in model 2, postoperative glucose (OR 0.468, 95%CI 0.278-0.787, p = 0.004) and mTICI 2c/3 (OR 9.436, 95%CI 1.889-47.144, p = 0.006) were predictive. TOR was strongly associated with good functional outcomes after successful recanalization of MT. Higher mTICI grade and lower perioperative glucose level may predict microvascular tissue reperfusion.