Acute Infarction Research Articles

Total Basilar Artery Thrombosis Presenting with Recurrent Transient Ischemic Attacks (TIAs): A Case Report

<p><strong>Background</strong>: Managing acute ischemic stroke in patients with significant comorbidities, such as hypertension, heart failure, and substance abuse, presents unique challenges. Timely intervention is critical, but the risk of complications and poor prognosis is high.<br /><strong>Case Presentation</strong>: A 46-year-old male with a history of smoking, drug abuse, poorly controlled hypertension, and dilated cardiomyopathy with an ejection fraction of 25%-30% presented with sudden left-sided weakness, facial droop, and dysarthria. The initial National Institutes of Health Stroke Scal score was 6. Computed tomography (CT) brain showed no acute infarctions but revealed chronic lacunar infarctions and atrophy. CT angiography identified significant vascular abnormalities, including right internal carotid artery attenuation and non-visualization of both intracranial vertebral and basilar arteries. Intravenous thrombolysis (tPA) led to initial improvement, but recurrent strokes or transient ischemic attacks (TIAs) followed, leading to intubation and mechanical ventilation. Magnetic resonance imaging revealed evolving infarctions in the pons and cerebellum. A basilar artery thrombectomy was successfully performed, but postoperative complications included spontaneous pneumothorax and femoral artery pseudoaneurysm, requiring further interventions. Due to extensive posterior circulation infarction, the patient had a poor neurological prognosis and was placed on do not resuscitate status.<br /><strong>Conclusion</strong>: This case highlights the complexities of treating acute ischemic stroke in patients with substantial comorbidities. While interventions such as thrombolysis and thrombectomy are critical, they carry risks. A multidisciplinary approach is necessary to balance immediate treatment with considerations of long-term prognosis and quality of life. </p>

Acute Cerebrovascular Accident in Pregnancy Due to Hyperhomocysteinaemia Secondary to Vitamin B12 Deficiency: A Case Report

Stroke in pregnancy is rare but is one of the leading causes of morbidity and mortality in developed countries. Pregnancy, as a prothrombotic state, acts as a precursor for stroke. Preeclampsia, eclampsia, amniotic fluid embolism, hypertension, diabetes, and many other factors predispose to the development of stroke. Endothelial cell injury leading to arteriosclerosis, causing a stroke, has been associated with raised homocysteine levels. Hereby, the authors present a case of a 26-year-old Gravida 3 Pregnancy 1 Live 1 Abortion 1 (G3P1L1A1) at 35 weeks gestation with a cephalic presentation who complained of a headache for two days, sudden onset of weakness in the right upper limb and lower limb with an inability to walk without support and inability to speak since 12 hours, associated with one episode of vomiting. Magnetic Resonance Imaging (MRI) brain showed acute infarcts in the left fronto-parietal lobes and capsule region with haemorrhagic transformation in the left frontal lobe. Serum vitamin B12 measured by Electroluminescence Assay (ECLA) was found to be low at 113pg/mL (normal range -191-771pg/mL). Serum homocysteine levels measured by enzymatic method were elevated at 46 umol/L (normal range 3-18 umol/L). A diagnosis at 34 weeks of pregnancy with acute cerebrovascular accident with right hemiparesis with Broca’s aphasia due to hyperhomocysteinaemia secondary to vitamin B12 deficiency was made. Prompt diagnosis and treatment are known to decrease morbidity in women with cerebrovascular accidents. MRI brain with venogram is known to be the gold standard procedure in diagnosing stroke. Thrombolytic therapy has proven beneficial in the treatment of the disease and in preventing its progression. Prenatal and natal supplementation with folic acid/vitamin B12 in the first trimester of pregnancy prevents Vitamin B12 deficiency and raised homocysteine levels in the maternal serum, thereby decreasing the incidence of stroke.

Sudden Vision Loss: More than Just an Ophthalmic Diagnosis! A Case Report

Abstract A 66-year-old patient of asian background from the US was admitted with confusion and behavioral changes for the last 10 days. The patient was on rituximab for RA (Rheumatoid arthritis). He had a normal computed tomography (CT) head and blood tests showed hyponatremia and acute kidney injury. Cerebrospinal fluid (CSF) showed raised CSF pressure 30 cmH20, raised protein and considerably high lymphocyte count. Mycobacteria tuberculous was isolated from one of her sputum cultures after having several negative sputum cultures, and consequently, the patient was treated for tuberculous meningitis. During admission, he had worsening of GCS (Glasgow coma scale), and he was admitted to ITU (intensive care unit) where he developed acute ischaemic stroke. He was treated for acute infarct and TBM (tuberculous meningitis), and was discharged on anti-tuberculous medications. It was a unique presentation in an immunocompromised patient with sudden deterioration and confusion, however, without neck stiffness or typical meningitis features. His condition improved with the commencement of the anti-tuberculosis therapy and was discharged from the hospital, and the patient traveled back to the US (United States) following discharge. During his stay, he was started on anti-tuberculous therapy early on due to high suspicion of Tb. The positive sputum culture was reported only after he had traveled back to the US and the same was conveyed to the patient’s GP (general practitioner) in the US.

Occult Pheochromocytoma and Acute Ischaemic Stroke in Young Adult: Cause or Association

Pheochromocytoma is a rare catecholamine-secreting tumours of chromaffin tissues that cause a constellation of symptoms. It is closely associated with endocrine hypertension that can be masked, sustained or paroxysmal leading to hypertensive crisis, resulting in vascular and non-vascular complications and rarely cerebral ischaemia and stroke. A healthy 22 year old male reported with acute Right upper limb(RUL) monoplegia and Motor aphasia for five days with raised blood pressure levels. hypertonia was present, deep tendon reflexes were exaggerated in RUL and Right Plantar was extensor. General and systemic findings were nonsignificant . Routine investigations showed thrombocytosis and M.R.I. Brain was suggestive of acute infarction of Left Parieto-Temporal region. Renal doppler, Carotid Intima Media Thickness, Cerebral Angiogram, 2D-E.C.H.O. and Fundoscopy were normal. AntinuclearAntibody was negative. Contrast CT of abdomen revealed right adrenal mass suggestive of isolated Pheochromocytoma. Vanyl-Mandelic Acid was positive. Patient was stabilised and managed conservatively for 4 weeks followed by adrenalectomy and appropriate medical therapy. Patient is on regular followup and does not seem to require any antihypertensives or any other intervention. Pheochromocytoma is a notorious tumor and a great masquerader specially in young adults. A keen eye, routine checkups and evaluation is the key to detecting and preventing its associated morbidity and mortality.

Lateral medullary infarction in a patient with Moyamoya disease associated with RNF213 variants: a case report

Background: Moyamoya disease (MMD) is a rare cerebrovascular disease radiologically characterized by progressive bilateral occlusion of the distal portion of the internal carotid artery and compensating collaterals. Herein, we report a case of medullary infarction in a patient with MMD.Case Report: We present the case of a 54-year-old male with hypertension, hyperlipidemia, and unstable angina with sudden onset dysarthria and ataxia. Diffusion-weighted and T2-weighted images of magnetic resonance imaging showed a high-signal intensity lesion on the right lateral medulla, suggestive of acute infarction. Transfemoral cerebral angiography also demonstrated bilateral middle cerebral artery (MCA) occlusion. Testing of the ring finger protein 213 (RNF213) gene revealed a homozygous p.R4810K variant that was possibly associated with posterior circulation involvement.Conclusion: When the MCA is occluded in MMD, there is a possibility that medullary infarction may occur due to the mechanism of increased hemodynamic stress on the anastomotic posterior vessels.

Exploring the Relationship between Lesion Morphology and Pathogenesis in Acute Small Subcortical Infarction

Introduction: Acute small subcortical infarctions (SSIs) result from occlusions of small penetrating arteries, and the underlying pathological factors can have different clinical implications. The objective of this study was to assess the clinical relevance of acute SSIs based on their sizes and morphologies. Methods: This retrospective case-control study analyzed clinical and imaging data of stroke patients with acute SSIs in penetrating artery territories who underwent magnetic resonance imaging within 5 days of stroke onset, registered between 2016 and 2020. We categorized these patients into three groups based on size and morphology: diameter Results: We analyzed 726 stroke patients with SSIs, among whom 573 had a diameter p 50% (aOR, 3.8; 95% CI, 2.1–7.0) than a diameter of Conclusion: Our study suggests that the sizes and morphologies of acute SSIs may indicate different underlying pathologies and be linked to diverse clinical outcomes. Our findings also challenge the current imaging criteria for embolic stroke of undetermined source, as we did not find a link between large subcortical infarction and cardioembolic stroke.

STUDY OF “MAGNETIC RESONANCE IMAGING IN STROKE PATIENTS AT A TERTIARY HEALTH CARE CENTER”

Background: One of the main causes of mortality and disability worldwide is stroke. Cerebral infarction, non-traumatic subarachnoid hemorrhage, primary intracranial hemorrhage, and various dural sinus/cerebral vein obstruction are the different types of stroke. About 80–90% of strokes are ischemic strokes, which are the most frequent form of stroke. Aim of the Study: The aim of this study was to study “Magnetic resonance imaging in stroke patients at a tertiary health care center.” Methods: This was 18-month cross-sectional research conducted in the Department of Radiodiagnosis at the Shrisatyasai Medical College and Research Institute in Chengalpattu, Tamil Nadu, from December 2020 to June 2021. Results: In the present study, middle cerebral artery is 43.3%, posterior cerebral artery (PCA) is 16.7%, anterior cerebral artery is 13.3%, lacunar infarcts is 16.7%, multiple infarcts is 8.3%, and basilar excluding PCA is 1.7% in the present study. About 73.3% of the patients (44/60) had infarcts, 10% had hemorrhage (6/60), and 16.7% had stroke mimics (10/60). Conclusion: DWI is a better imaging method than conventional MRI in detecting early ischemic lesions in stroke patients with Sensitivity of 94% and specificity of 100% was observed among acute infarct patients.

Decrease of prothrombin level during thrombolysis in acute myocardium infarction.

Previously, the direct interactions of Bβ26-42 fibrin residues with prothrombin were demonstrated. It was also shown that forming prothrombin complexes with E- or DDE-fragments causes non-enzymatic prothrombin activation. The direct measuring of the prothrombin level in the blood plasma of patients with acute myocardial infarction (AMI) allowed us to find a situation where such an activation can occur in vivo. Blood coagulation parameters in the blood plasma of patients with AMI were measured at 2 hours, three days, and seven days after the thrombolysis by streptokinase accompanied with intravenous administration of anticoagulants: unfractionated high molecular weight heparin (HMWH) and low-molecular-weight heparin (LMWH). The prothrombin level in the blood plasma of patients with AMI was normal before thrombolytic therapy and substantially decreased after streptokinase administration. This effect was prominent in the case of concomitant anticoagulant therapy with LMWH and was not observed when HMWH was applied. It can be explained by the fact that LMWH preferentially inhibits factor Xa, while the HMWH is an effective inhibitor of both factor Xa and thrombin. This observation suggested that the prothrombin level decrease was caused by the thrombin-like activity and possible autolysis of prothrombin by thrombin. Also, thrombolytic therapy with streptokinase caused the accumulation of fibrin degradation products (FDPs), some of which were able to bind prothrombin. The dramatic decrease of prothrombin level in the blood plasma of patients with AMI during thrombolysis allowed us to conclude the non-enzymatic prothrombin activation with the following autolysis of prothrombin that contributes to the pathology.

Deep learning reconstruction for improving the visualization of acute brain infarct on computed tomography.

This study aimed to investigate the impact of deep learning reconstruction (DLR) on acute infarct depiction compared with hybrid iterative reconstruction (Hybrid IR). This retrospective study included 29 (75.8 ± 13.2years, 20 males) and 26 (64.4 ± 12.4years, 18 males) patients with and without acute infarction, respectively. Unenhanced head CT images were reconstructed with DLR and Hybrid IR. In qualitative analyses, three readers evaluated the conspicuity of lesions based on five regions and image quality. A radiologist placed regions of interest on the lateral ventricle, putamen, and white matter in quantitative analyses, and the standard deviation of CT attenuation (i.e., quantitative image noise) was recorded. Conspicuity of acute infarct in DLR was superior to that in Hybrid IR, and a statistically significant difference was observed for two readers (p ≤ 0.038). Conspicuity of acute infarct with time from onset to CT imaging at < 24h in DLR was significantly improved compared with Hybrid IR for all readers (p ≤ 0.020). Image noise in DLR was significantly reduced compared with Hybrid IR with both the qualitative and quantitative analyses (p < 0.001 for all). DLR in head CT helped improve acute infarct depiction, especially those with time from onset to CT imaging at < 24h.

THE ANNEXIN-A1 MIMETIC RTP-026 PROMOTES ACUTE CARDIOPROTECTION THROUGH MODULATION OF IMMUNE CELL ACTIVATION

The cardio-protective and immuno-regulatory properties of RTP-026, a synthetic peptide that spans the Annexin-A1 (AnxA1) N-terminal region, were tested in rat acute myocardial infarction. In vitro, selective activation of formyl-peptide receptor type 2 (FPR2) by RTP-026 occurred with apparent EC50 in the 10-30nM range. With human primary cells, RTP-026 counteracted extension of neutrophil life-span and augmented phagocytosis of fluorescent E.coli by blood myeloid cells. An in vivo model of rat acute infarction was used to quantify tissue injury and phenotype immune cells in myocardium and blood. The rat left anterior descending coronary artery was occluded and then reopened for 2-hour or 24-hour reperfusion. For the 2-hour reperfusion protocol, RTP-026 (25-500µg/kg; given i.v. at the start of reperfusion) significantly reduced infarct size by ∼50 %, with maximal efficacy at 50µg/kg. Analyses of cardiac immune cells showed that RTP-026 reduced neutrophil and classical monocyte recruitment to the damaged heart. In the blood, RTP-026 (50µg/kg) attenuated activation of neutrophils and monocytes monitored through CD62L and CD54 expression. Modulation of vascular inflammation by RTP-026 was demonstrated by reduction in plasma levels of mediators like TNF-α, IL-1β, KC, PGE2 and PGF2α⊡ For the 24-hour reperfusion protocol, RTP-026 (30µg/kg given i.v. at 0, 3 and 6h reperfusion) reduced necrotic myocardium by ∼40 %. RTP-026 modulate immune cell responses and decreases infarct size of the heart in preclinical settings. Tempering over-exuberant immune cell activation by RTP-026 is a suitable approach to translate the biology of AnxA1 for therapeutic purposes.

MAGNETIC RESONANCE ANGIOGRAPHY AND BRAIN ISCHEMIA IN PATIENTS WITH ACUTE STROKE

This research investigates if Magnetic Resonance Angiography (MRA) can detect arterial disorders in patients with acute ischemic stroke with diffusion-positive infarction. The study was conducted at KRL Hospital in Islamabad from May 1, 2022, to September 30, 2022, after receiving ethical approval from the institutional review board. The study included participants between the ages of 45 and 60 of any gender who had symptoms of localized cerebral ischemia lasting less than 24 hours and were referred for MRI evaluation. Non-probability consecutive sampling was used to select participants. The Chi-square test compared MRA findings of vascular illness with MRI findings of brain parenchymal abnormalities. Out of 95 individuals, 89 (93.6%) showed a statistically significant correlation (p=0.001) between the arterial lesion and acute infarctions in the same region of the brain parenchyma on MRI. Only 6 (6.3%) of the 95 individuals showed a discrepancy between the location of the infarction on MRI and the results of the MRA. This study's findings suggest a significant positive association (95.34%) between MRA and MR diffusion restriction in acute ischemic strokes. This association supports the theory that an arterial vasculopathy is the underlying cause of the MR signal. However, in some cases, the discrepancy between MRA and infarction location might be due to an occlusive illness of an arterial branch that MRA did not detect.

Spinal Cord Infarction Owing to Likely Fibrocartilaginous Embolism

Fibrocartilaginous embolism (FCE) is one of the rare causes of acute spinal cord infarction. We report the case of a previously healthy 16-year-old adolescent with a presentation suggestive of this condition. A few hours after lifting heavy objects, he developed sudden paraplegia. On examination, he had flaccid areflexic paraplegia, and thermoalgic anesthesia below the level of the D4 dermatome. Magnetic resonance imaging (MRI) of the spine confirmed the diagnosis of spinal infarction, FCE was retained as a likely cause after eliminating other differential diagnoses. Although FCE is rare, it should be kept as one of the differential diagnoses of an acute neurological deficit of the spinal cord.

Autonomic Responses During Acute Anterior Versus Inferior Myocardial Infarction: A Systematic Review and Meta-Analysis.

Autonomic responses elicited by myocardial infarction varydepending on the site of injury, but accurate assessment using heart rate variability during the acute phase is limited. We systematically searched PubMed without language restrictions throughout July 2023. We reviewed studies reporting autonomic indices separately for anterior and inferior infarcts, followed by a meta-analysis of those reporting the standard deviation of the inter-beat interval between normal sinus beats during the initial 24 hours after the onset of symptoms. Six studies were included, comprising 341 patients (165 anterior, 176 inferior infarcts), all with satisfactory scores on the Newcastle-Ottawa quality scale. The estimated average of the standardized mean difference (based on the random-effects model) was -0.722 (95% confidence intervals: -0.943 to -0.501), which differed from zero (z=-6.416, p<0.0001). This finding indicates sympathetic and vagal dominance during acute anterior and inferior infarcts, respectively, with excessive responses likely contributing to early arrhythmogenesis. Despite the amelioration of autonomic dysfunction by revascularization, infarct location should be considered when commencing β-adrenergic receptor blockade, especially after delayed procedures.

Association between arterial tortuosity and early neurological deterioration in lenticulostriate artery infarction

Early neurological deterioration (END) in lenticulostriate artery (LSA) infarction is associated with perforating artery hypoperfusion. As middle cerebral artery (MCA) tortuosity may alter hemodynamics, we investigated the association between MCA tortuosity and END in LSA infarction. We reviewed patients with acute LSA infarction without significant MCA stenosis. END was defined as an increase of ≥ 2 or ≥ 1 in the National Institutes of Health Stroke Scale (NIHSS) total or motor score, respectively, within first 72 h. The MCA tortuosity index (actual /straight length) was measured. Stroke mechanisms were categorized as branch atheromatous disease (BAD; lesions > 10 mm and 4 axial slices) and lipohyalinotic degeneration (LD; lesion smaller than BAD). Factors associated with END in LD and BAD were investigated. END occurred in 104/390 (26.7%) patients. A high MCA tortuosity index (adjusted odds ratio, aOR 10.63, 95% confidence interval [2.57–44.08], p = 0.001) was independently associated with END. In patients with BAD, high initial NIHSS score (aOR 1.40 [1.03–1.89], p = 0.031) and presence of parental artery disease (stenosis < 50%; aOR 10.38 [1.85–58.08], p = 0.008) were associated with END. In patients with LD, high MCA tortuosity (aOR 41.78 [7.37–237.04], p < 0.001) was associated with END. The mechanism causing END in patients with LD and BAD may differ.

Central positional nystagmus due to acute medial medullary infarction

A 70-year-old male with risk factors for vascular disease presented with dizziness and instability. The patient showed horizontal geotropic nystagmus when turning his head while lying down, with larger slow phase velocity observed when turning to the left. There were no other neurological deficits. Video head impulse tests and vestibular evoked myogenic potentials were normal. The initial magnetic resonance imaging (MRI) findings were negative; however, the patient experienced subsequent right-side weakness, right tilting, and recurrent episodes of vertigo. A follow-up MRI revealed an acute left medial medullary infarction, which seems to have caused the paroxysmal geotropic central positional nystagmus in this patient.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition with evolocumab decreases myocardial inflammation in individuals with acute coronary syndrome (ACS)

Abstract Background/Introduction Although inflammation is commonly present and often beneficial in the period following tissue injury, prolonged inflammation may impair healing and repair following acute ischemic injury. In addition to its impact on cholesterol metabolism PCSK9 is elevated in patients with inflammatory diseases and is thought to be a pro-inflammatory mediator. The presence and early trajectory of myocardial inflammation, and the impact of PCSK9 inhibition on that trajectory, in patients with an acute myocardial infarction have not been characterized. Purpose Our goals were to assess myocardial inflammation in patients with an acute myocardial infarction using 18F-FDG-PET scans obtained at the time of hospitalization for the infarction and at 30-days following the infarction and the impact of PCSK9 inhibition with evolocumab on inflammation in a placebo-controlled, randomized trial. Methods Fifty-five participants from the Evolocumab in Acute Coronary Syndrome trials, with a NSTEMI and a troponin-I of &amp;gt; 5 ng/ml or with a STEMI were randomized to placebo (n=30) or to 420 mg SQ of evolocumab (n=25) within 24 hours of admission. 18F-FDG-PET scans were performed within five days (2 [1-4]) of randomization and at 30 days. The myocardial mean Standardized Uptake Value (SUV) in the two randomized groups at baseline and the changes from baseline to 30 days were compared. All participants received guideline-directed therapies for acute infarction. Results Mean±SD age of the cohort was 57±13 years, 22% were African American, and 36% were women. There were no significant differences in demographic or clinical characteristics between the two groups. Mean SUV at baseline did not differ between the placebo (2.4±0.5) and the evolocumab (2.7±0.7) groups, p=0.25 for the between groups comparison. Mean SUV decreased in both groups, from 2.4±0.5 to 2.1±0.7 in the placebo group (p=0.05) and from 2.7±0.7 to 1.9±0.5 in the evolocumab group (p &amp;lt;0.0001), and the decrease was less in the placebo group, p=0.039 for the between groups comparison. The percent-change in the placebo group (-10.4%±36%) was also less than the percent change in the evolocumab group (-26.7%±20%), p = 0.04 for the between groups comparison. In addition, the percent of participants in whom the mean SUV units decreased was lower in the placebo group (60%) than in the evolocumab group (88%,), p=0.03 for the between groups comparison. Conclusion Myocardial inflammation assessed using 18F-FDG-PET decreases but is still present 30 days following an acute myocardial infarction. PCSK9 inhibition with evolocumab given within the first 24 hours of admission improves resolution of the inflammation. In addition to its marked impact on lipid levels, PCSK9 inhibition has significant anti-inflammatory effects in the early post-infarction setting.

Malonate protection against acute infarction in isolated mouse hearts is lost in the presence of insulin

Abstract Background &amp; Objectives Malonate, an inhibitor of mitochondrial succinate dehydrogenase (SDH), is a promising novel protectant against acute ischaemia-reperfusion injury (IRI) through reduction of ischaemic succinate accumulation and ROS production during early reperfusion. Malonate is still protective when given only at reperfusion, making it an ideal agent for treating AMI patients. However, numerous studies demonstrated that the metabolic milieu could affect the potency of cardioprotective treatments. Therefore, in this study, we explored whether and how the severity of cardiac I/R injury and cardioprotection by malonate is affected by the metabolic milieu. We hypothesized that protection by malonate is affected by metabolic milie. Methods Isolated Langendorff-perfused hearts (n=8 to 19 per group) of C57Bl/6N mice were perfused with perfusate to which substrates and hormones were added in a step-wise manner: 1) glucose (G), 2) glucose + glutamine (GG), 3) glucose + glutamine + palmitate (GGP), or 4) glucose + glutamine + palmitate + insulin (GGPI), and subjected to 30 min ischaemia (I) and 90 min reperfusion (R). Heart were treated with malonate (5mM) or vehicle (saline) during the first 5 min of reperfusion only. Cardiac function of the left ventricle was monitored by a balloon in the left ventricle. Coronary effluent was collected at 7 time points of reperfusion to detect the activity of lactate dehydrogenase (LDH) as an indicator of cell death. At the end reperfusion, hearts were used for infarct size determination through TTC staining. Data are presented as mean ± SD. Results Going from glucose-only perfusate to a perfusate containing all examined substrates and hormones, the severity of cardiac I/R injury increased: infarct size (%) went from 31.9 ± 10.9% to 37.7 ± 10.6% to 52.3 ± 14.2%, and finally to 68 ± 9.9 %. Similar trends for increased IRI were observed for LDH, End-Diastolic Pressure (EDP) and recovery of the Rate-Pressure Product (RPP). When compared with vehicle control, malonate significantly decreased IS% (control vs malonate: 31.9 ± 10.9% vs. 23.3 ± 4.8%, 37.7 ± 10.6% vs. 20.9 ± 8.5%, 68 ± 9.9% vs. 40.2 ± 9.2 %), and increased the RRP recovery (64.1 ± 16.6 %vs. 83.3 ± 17.9 %, 55.6 ± 11% vs. 72.3 ± 4%, 39.3 ± 15.6% vs. 55.9 ± 8.3%) in the G, GG and GGP group. The EDP was significantly decreased by malonate in the G and GG group (32.8 ± 14.3 mmHg vs. 20.9 ± 9.8 mmHg, 35.1 ± 8.7 mmHg vs. 22.2 ± 8.6 mmHg ). LDH was only significantly decreased by malonate in the GG group (35.2 ± 12.9 vs. 17.1 ± 7.7 U / GWW). Most importantly, adding insulin to the perfusate nullified protection by malonate for all four outcomes. Conclusions The severity of cardiac I/R injury is lowest with glucose-only perfusate, and increased with increased complexity of the metabolic milieu. Although malonate is a strong protectant against cardiac IRI for most metabolic milieus, in the isolated heart, protection is lost in the presence of insulin.

Myocardial salvage and infarct characteristics in patients with ST-elevation myocardial infarction classified by ORBI risk score

Abstract Background The Observatoire Régional Breton sur l'Infarctus (ORBI) [1] risk score was developed to predict in-hospital cardiogenic shock (CS) development in patients with ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention. The association between infarct characteristics determined by cardiac magnetic resonance imaging (CMR) and ORBI risk classification have not previously been reported in patients with STEMI. Methods The Third DANish Study of Optimal Acute Treatment of Patients With ST-Segment Elevation Myocardial Infarction (DANAMI 3) trial investigated multiple revascularization strategies in patients with STEMI. CS on admission was an exclusion criterion, thus only low and intermediate scores were included. Stratification into ‘low’ (0-7) and ‘intermediate-high’ (&amp;gt;=8) ORBI risk score was performed (n=1,396), and CMR data from admission and three months follow-up at the largest participating centre were analysed using logistic- and Cox-regression (n=534, 38%). Results A total of 1,149 (82%) were ‘low’ risk, and 247 (18%) ‘intermediate-high’ risk. Patients with ‘intermediate-high’ risk were older (median age 71 (interquartile range (IQR) 61-78) vs. 60 (52-68), p&amp;lt;0.001), and more had an admission systolic blood pressure &amp;lt; 90 mm Hg (4.9% vs. 1.4%, p=0.002), and heart rate &amp;gt; 100 bpm (30% vs. 5%, p&amp;lt;0.001). Left ventricular ejection fraction was lower at discharge (40% (30-50%) vs. 50% (45-55%), p&amp;lt;0.001), and more had an anterior infarction (61% vs. 38%, p&amp;lt;0.001) compared to ‘low’ risk patients. Moreover, median peak troponin was higher (5010 ng/L (2195-9930) vs. 2820 ng/L (1138-5805), p&amp;lt;0.001). Aside from hypertension (52% vs. 39%, p&amp;lt;0.001), there were no differences in factors not covered by the ORBI score. In patients with ‘intermediate-high’ risk, both median acute and final infarct size were larger compared to those with ‘low’ risk (21% (12-28%) vs. 15% (7-24%), p=0.004, and 15% (10-26%) vs. 10% (4-17%), p&amp;lt;0.001). Median final salvage index was lower (0.66 (0.47-0.76) vs. 0.69 (0.55-0.87), p=0.048). ‘Intermediate-high’ risk was associated with higher odds of an above-median acute infarct size (odds ratio (OR) 2.02 (95% confidence interval (CI) 1.13-3.68) p=0.019), final infarct size (OR 3.00 (1.65-5.37), p&amp;lt;0.001), and lower odds of an above-median final salvage index (OR 0.52 (0.29-0.91), p=0.026). One-year mortality was higher in patients with ‘intermediate-high’ (9.7% (95%CI 5.9-13)) compared to "low" risk patients (1.9% (1.1-2.7), p&amp;lt;0.001). In univariate analyses, ‘intermediate-high’ risk was associated with a higher mortality risk (hazard ratio 5.31 (95%CI 2.98-9.48), p&amp;lt;0.001). Conclusions In patients with STEMI, an intermediate-high ORBI risk score of &amp;gt;=8 was associated with larger infarct size and less myocardial salvage, and a 5-time higher mortality risk relative to the overall favorable outcomes in those with a low-risk score.Kaplan-Meier Plot, one-year survival

A novel technology for heart failure that utilizes the respiratory effort to shift fluids from the lung and alleviate cardiac workloads; feasibility study in sheep

Abstract Introduction Hemodynamic congestion is governed by inflow from RV and drainage through LV. However, ventricle functions are affected by the intrathoracic/pleural pressure: Negative pleural pressure (PPL) increases RV outflow while decreasing LV outflow, and vice versa at high PPL. Cardiac decompensation is associated with an increase in the respiratory effort (the peak-to-peak changes in PPL). We suggest to utilize this respiratory effort to shift fluid out of the lung and alleviate hemodynamic congestion. It is done by pacing the heart when PPL is high and the LV stroke volume is larger than the RV stroke volume. Purpose To test the feasibility of the novel technology in sheep. To verify that it is possible to modify the distribution of the heart beat within the respiratory cycle (slightly modify the rhythm according to the PPL) with insignificant effect on mean heart rate. Methods The utility was validated in sheep (N=9), under spontaneous breathing before and after induction of acute infarction by balloon inflation in the mid-LAD artery. The device senses the intracardiac electrical activity and respiratory effort and paces the right atrium when the PPL is high. The R-R interval of the paced beats was shorter than the sinus R-R interval by less than 10%. The effects of PPL and device pacing on LV and RV stroke-volumes were derived from simultaneous measurements of RV and LV pressure-volume loops, utilizing two impedance catheters (CD-Leycom) within both ventricles. Results The respiratory effort had significant effects on RV and LV outputs before and after infarction. The stroke volumes of the two ventricles were in antiphase! At low PPL the RV output increased while the LV decreased by about 10%, and the opposite occurred at high PPL. The pacing increased cardiac beating probability at high PPL. Sequential pacing for one minute increased the systolic pressure by 5 mmHg while decreasing the pulmonary artery pressure. Based on the pressure-volume loops, each paced breath cycle increased the LV outflow by 1.14 ml and decreased RV outflow by 0.36ml, yielding a shift of 1.5 ml from the lung. Interestingly, it was associated with a decrease in the sinus rate, which further decreased cardiac beating at low PPL and may represent a decrease in sympathetic tone. Conclusions Pacing only 1% of the ∼20,000 daily breath-cycles can shift 300 ml from the lung per day! The technology is agnostic of the heart-failure etiology. Preclinical studies in a model of chronic heart failure are required to further validate the novel approach.

Inhibition of ADAM10-mediated CX3CL1 shedding promotes survival and cardiac function early after myocardial infarction

Abstract Background and Purpose The metalloprotease ADAM10 has been implicated in immune regulatory processes, is upregulated in response to specific heart pathologies e.g. ischemic heart failure, and elevated serum levels of the ADAM10 substrates CX3CL1 and CXCL16 have been reported following infarction. The causal role of ADAM10 in cardiovascular diseases, however, is not known yet. By using human tissue biopsies, a cardiomyocyte-specific ADAM10 knockout mouse model (ADAM10 KO), and pharmacological ADAM10 inhibition we here comprehensively characterize the role of ADAM10 in the heart and in cardiac disease. Methods and Results We show that ADAM10 protein levels are upregulated in patients with ischemic cardiomyopathy (2.5-fold) and ADAM10 mRNA expression correlates with expression of atrial (NPPA) and brain natriuretic peptide (NPPB) mRNA. Upon infarction, ADAM10 expression is specifically induced in cardiomyocytes, and cardiomyocyte-specific ADAM10 KO as well as pharmacological inhibition (GI254023X) for only three days significantly improves overall survival, reduces scar size, and preserves cardiac function. Mechanistically, flow cytometry and bulk RNA sequencing identify a ADAM10/CX3CL1 axis to control neutrophil bone marrow egress and heart tissue infiltration after infarction. Diminished neutrophil migration results in long-term reduction of IL-1β-driven inflammation. Using cell culture experiments with ADAM10/CX3CL1 knockdown cardiomyocytes, we show that ADAM10-mediated ectodomain shedding of CX3CL1 specifically regulates neutrophil but not macrophage chemotaxis revealing a novel conceptual insight into how acute infarction triggers chemotactic signaling via ectodomain shedding. Conclusion Pharmacological and genetic targeting of the membrane sheddase ADAM10 is highly efficient for improving post-infarction cardiac function and survival via abolished post-translational CX3CL1 processing, neutrophil infiltration and IL-1β-dependent inflammation. Thus, our data reveal a novel therapeutic concept, which may close a clinically relevant therapeutic gap early after myocardial infarction.