Acute Ischemic Syndromes Research Articles

Myocardial Ischemic Syndromes: A New Nomenclature to Harmonize Evolving International Clinical Practice Guidelines.

Since the 1960s, cardiologists have adopted several binary classification systems for acute myocardial infarction (MI) that facilitated improved patient management. Conversely, for chronic stable manifestations of myocardial ischemia, various classifications have emerged over time, often with conflicting terminology-eg, "stable coronary artery disease" (CAD), "stable ischemic heart disease," and "chronic coronary syndromes" (CCS). While the 2019 European guidelines introduced CCS to impart symmetry with "acute coronary syndromes" (ACS), the 2023 American guidelines endorsed the alternative term "chronic coronary disease." An unintended consequence of these competing classifications is perpetuation of the restrictive terms "coronary" and 'disease', often connoting only a singular obstructive CAD mechanism. It is now important to advance a more broadly inclusive terminology for both obstructive and non-obstructive causes of angina and myocardial ischemia that fosters conceptual clarity and unifies dyssynchronous nomenclatures across guidelines. We, therefore, propose a new binary classification of "acute myocardial ischemic syndromes" and "non-acute myocardial ischemic syndromes," which comprises both obstructive epicardial and non-obstructive pathogenetic mechanisms, including microvascular dysfunction, vasospastic disorders, and non-coronary causes. We herein retain accepted categories of ACS, ST-segment elevation MI, and non-ST-segment elevation MI, as important subsets for which revascularization is of proven clinical benefit, as well as new terms like ischemia and MI with non-obstructive coronary arteries. Overall, such a more encompassing nomenclature better aligns, unifies, and harmonizes different pathophysiologic causes of myocardial ischemia and should result in more refined diagnostic and therapeutic approaches targeted to the multiple pathobiological precipitants of angina pectoris, ischemia, and infarction.

Myocardial ischaemic syndromes: a new nomenclature to harmonize evolving international clinical practice guidelines.

Since the 1960s, cardiologists have adopted several binary classification systems for acute myocardial infarction (MI) that facilitated improved patient management. Conversely, for chronic stable manifestations of myocardial ischaemia, various classifications have emerged over time, often with conflicting terminology-e.g. 'stable coronary artery disease' (CAD), 'stable ischaemic heart disease', and 'chronic coronary syndromes' (CCS). While the 2019 European guidelines introduced CCS to impart symmetry with 'acute coronary syndromes' (ACS), the 2023 American guidelines endorsed the alternative term 'chronic coronary disease'. An unintended consequence of these competing classifications is perpetuation of the restrictive terms 'coronary' and 'disease', often connoting only a singular obstructive CAD mechanism. It is now important to advance a more broadly inclusive terminology for both obstructive and non-obstructive causes of angina and myocardial ischaemia that fosters conceptual clarity and unifies dyssynchronous nomenclatures across guidelines. We, therefore, propose a new binary classification of 'acute myocardial ischaemic syndromes' and 'non-acute myocardial ischaemic syndromes', which comprises both obstructive epicardial and non-obstructive pathogenetic mechanisms, including microvascular dysfunction, vasospastic disorders, and non-coronary causes. We herein retain accepted categories of ACS, ST-segment elevation MI, and non-ST-segment elevation MI, as important subsets for which revascularization is of proven clinical benefit, as well as new terms like ischaemia and MI with non-obstructive coronary arteries. Overall, such a more encompassing nomenclature better aligns, unifies, and harmonizes different pathophysiologic causes of myocardial ischaemia and should result in more refined diagnostic and therapeutic approaches targeted to the multiple pathobiological precipitants of angina pectoris, ischaemia and infarction.

Characterizing Mechanisms of Ischemia in Patients With Myocardial Bridges.

Myocardial bridges (MBs) are prevalent and can be associated with acute and chronic ischemic syndromes. We sought to determine the substrates for ischemia in patients with angina with nonobstructive coronary arteries and a MB in the left anterior descending artery. Patients with angina with nonobstructive coronary arteries underwent the acquisition of intracoronary pressure and flow during rest, supine bicycle exercise, and adenosine infusion. Coronary wave intensity analysis was performed, with perfusion efficiency defined as accelerating wave energy/total wave energy (%). Epicardial endothelial dysfunction was defined as a reduction in epicardial vessel diameter ≥20% in response to intracoronary acetylcholine infusion. Patients with angina with nonobstructive coronary arteries and a MB were compared with 2 angina with nonobstructive coronary arteries groups with no MB: 1 with coronary microvascular disease (CMD: coronary flow reserve, <2.5) and 1 with normal coronary flow reserve (reference: coronary flow reserve, ≥2.5). Ninety-two patients were enrolled in the study (30 MB, 33 CMD, and 29 reference). Fractional flow reserve in these 3 groups was 0.86±0.05, 0.92±0.04, and 0.94±0.05; coronary flow reserve was 2.5±0.5, 2.0±0.3, and 3.2±0.6. Perfusion efficiency increased numerically during exercise in the reference group (65±9%-69±13%; P=0.063) but decreased in the CMD (68±10%-50±10%; P<0.001) and MB (66±9%-55±9%; P<0.001) groups. The reduction in perfusion efficiency had distinct causes: in CMD, this was driven by microcirculation-derived energy in early diastole, whereas in MB, this was driven by diminished accelerating wave energy, due to the upstream bridge, in early systole. Epicardial endothelial dysfunction was more common in the MB group (54% versus 29% reference and 38% CMD). Overall, 93% of patients with a MB had an identifiable ischemic substrate. MBs led to impaired coronary perfusion efficiency during exercise, which was due to diminished accelerating wave energy in early systole compared with the reference group. Additionally, there was a high prevalence of endothelial and microvascular dysfunction. These ischemic mechanisms may represent distinct treatment targets.

Abstract 13079: Reduced Apoj-Glyc Serum Levels Identify Patients With Cardiac Ischemic Events Among Those Attending the Emergency Department With Chest Pain

Introduction: Glycosylated apolipoprotein J (ApoJ-Glyc) has been suggested to be a marker for the early detection of myocardial ischemia. Ischemia induces an intracellular accumulation of non-glycosylated ApoJ that mirrors a reduction in ApoJ-Glyc serum concentration in acute ischemic syndromes. Objective: The EDICA clinical trial - multi-centre, international, diagnostic study (NCT04119882)- was carried out to assess the performance of ApoJ-Glyc as a biomarker for the early detection of myocardial ischemia in patients attending the A&amp;E department with chest pain suggestive of acute coronary syndrome (ACS). Methods: EDICA assessed 404 patients. Blood samples were obtained on admission, for assessment of high sensitivity-troponin (hs-Tn) and ApoJ-Glyc. ApoJ-Glyc serum levels were analyzed with a novel ELISA, targeting a specific glycosylated variant of ApoJ (ApoJ-GlycA6). Results: Based on clinical diagnostic tests, 291 patients were given a final diagnosis of “non-ischemic” event and 113 patients were considered to have had an ischemic event (33 STEMI, 48 NSTEMI, 27 Unstable Angina and 5 “unclassifiable” ACS). ApoJ-GlycA6 levels were significantly lower on admission in ischemic patients, compared with non-ischemic patients (66 [46-90] vs. 73 [56-95] μg/ml, respectively; P=0.04). Ischemic patients who underwent PCI and had a pre-PCI TIMI 0-2 flow showed significantly lower ApoJ-GlycA6 levels at admission compared with non-ischemic patients (64 [37-81] vs. 73 [56-95] μg/ml; P=0.01). Of interest, 51% of ischemic patients, had “inconclusive” or negative hs-Tn at admission. Among these, ApoJ-GlycA6 identified the ischemic event in 48% (&lt;66 μg/ml). Conclusions: ApoJ-Glyc concentration decreased in patients with documented myocardial ischemia, compared with patients with a final diagnosis of “non-ischaemic” event. Patients with reduced TIMI flow indicative of poorer myocardial perfusion were among those with the lowest ApoJ-Glyc concentration. ApoJ-Glyc was low in ischemic patients irrespective of hs-Tn concentration. The results confirm the potential role of ApoJ-Glyc as a biomarker for the early detection of cardiac ischemia that could provide complementary information to that afforded by current biomarkers and diagnostic tests.

Inflammation during the life cycle of the atherosclerotic plaque.

Inflammation orchestrates each stage of the life cycle of atherosclerotic plaques. Indeed, inflammatory mediators likely link many traditional and emerging risk factors with atherogenesis. Atheroma initiation involves endothelial activation with recruitment of leucocytes to the arterial intima, where they interact with lipoproteins or their derivatives that have accumulated in this layer. The prolonged and usually clinically silent progression of atherosclerosis involves periods of smouldering inflammation, punctuated by episodes of acute activation that may arise from inflammatory mediators released from sites of extravascular injury or infection or from subclinical disruptions of the plaque. Smooth muscle cells and infiltrating leucocytes can proliferate but also undergo various forms of cell death that typically lead to formation of a lipid-rich 'necrotic' core within the evolving intimal lesion. Extracellular matrix synthesized by smooth muscle cells can form a fibrous cap that overlies the lesion's core. Thus, during progression of atheroma, cells not only procreate but perish. Inflammatory mediators participate in both processes. The ultimate clinical complication of atherosclerotic plaques involves disruption that provokes thrombosis, either by fracture of the plaque's fibrous cap or superficial erosion. The consequent clots can cause acute ischaemic syndromes if they embarrass perfusion. Incorporation of the thrombi can promote plaque healing and progressive intimal thickening that can aggravate stenosis and further limit downstream blood flow. Inflammatory mediators regulate many aspects of both plaque disruption and healing process. Thus, inflammatory processes contribute to all phases of the life cycle of atherosclerotic plaques, and represent ripe targets for mitigating the disease.

A nephroprotective iodinated contrast agent with cardioprotective properties: A pilot study.

Background and PurposeEvaluation and treatment of acute ischemic syndromes, in the heart and brain, require vessel visualization by iodinated X‐ray contrast agents. However, these contrast agents can induce injury, in both the kidneys and target organs themselves. Sulfobutylether beta cyclodextrin (SBECD) added to iohexol (SBECD‐iohexol) (Captisol Enabled‐iohexol, Ligand Pharmaceuticals, Inc, San Diego, CA) is currently in clinical trials in cardiovascular procedures, to determine its relative renal safety in high‐risk patients. Preclinical studies showed that SBECD‐iohexol reduced contrast‐induced acute kidney injury in rodent models by blocking apoptosis. The current study was undertaken to determine whether SBECD‐iohexol is also cardioprotective, in the male rat ischemia‐reperfusion model, compared to iohexol alone.MethodsAfter anesthesia, the left coronary artery was ligated for 30 min and the ligation released and reperfusion followed for 2 h prior to sacrifice. Groups 1–4 were injected in the tail vein 10 min prior to ischemia with: (1) vehicle; (2) iohexol; (3) SBECD; and (4) SBECD‐iohexol. Infarct size, hemodynamics, and serum markers were measured.ResultsAn eight‐fold increase in serum creatine kinase in the iohexol‐alone group was observed, compared with no increase in the SBECD‐iohexol group. The mean arterial pressure and rate pressure product were depressed in the iohexol‐alone group, but not in the SBECD‐iohexol group, or controls. No difference in infarct size or serum creatinine among the groups was observed.ConclusionThe results of this study suggest that SBECD‐iohexol is superior to iohexol alone, for both the preservation of cardiomyocyte integrity and preservation of myocardial function in myocardial ischemia.

From Mitochondria to Atherosclerosis: The Inflammation Path.

Inflammation is a key process in metazoan organisms due to its relevance for innate defense against infections and tissue damage. However, inflammation is also implicated in pathological processes such as atherosclerosis. Atherosclerosis is a chronic inflammatory disease of the arterial wall where unstable atherosclerotic plaque rupture causing platelet aggregation and thrombosis may compromise the arterial lumen, leading to acute or chronic ischemic syndromes. In this review, we will focus on the role of mitochondria in atherosclerosis while keeping inflammation as a link. Mitochondria are the main source of cellular energy. Under stress, mitochondria are also capable of controlling inflammation through the production of reactive oxygen species (ROS) and the release of mitochondrial components, such as mitochondrial DNA (mtDNA), into the cytoplasm or into the extracellular matrix, where they act as danger signals when recognized by innate immune receptors. Primary or secondary mitochondrial dysfunctions are associated with the initiation and progression of atherosclerosis by elevating the production of ROS, altering mitochondrial dynamics and energy supply, as well as promoting inflammation. Knowing and understanding the pathways behind mitochondrial-based inflammation in atheroma progression is essential to discovering alternative or complementary treatments.

Association between the Average Ratio of Platelet Volume and the Presence of Mural Thrombus in Post-Myocardial Infarction

Cardiovascular disease is a serious public health problem, responsible for 31% of all deaths worldwide. Population growth, urbanization and the lack of proper policies to control modifiable risk factors lead to an increased number in cases. Associated with this, we have new factors such as stress, pollution, income, unemployment, among others, which, associated with classical factors, increase the speed of atherosclerosis development. Acute ischemic syndromes are some of the worst consequences of the evolution of atherosclerosis, with mortality rates varying [...]

Central Genesis of Dysrhythmia

Introduction: The central nervous system is the generator of the dynamic balance between cholinergic and noradrenergic activity. Different behavioral tendencies are observed in subjects with prevalent parasympatic tone (defense strategy, energy sparing, dissociation) compared to those with sympathic one (relational interaction, high energy expenditure). These responses may influence susceptibility and vulnerability to diseases. The aim of our study was to examine cardiovascular function from the heart to the periphery by 24 hours detection of both heart and pulse rate in cerebrovascular conditions. Materials and Methods: We recruited 113 Acute Ischaemic Syndromes (AIS, age 73,43 sd 12,34), 32 Chronic Cerebro-Vascular Diseases (CCVD, age 75,95 sd 8,06), 30 Other Neurological Diseases (OND, age 50,09 sd 15,05). Cardiovascular reactivity (CR) was defined by beat indices, ratio (R) or difference (D) between higher maximal or minimal heart rate (HR) on higher maximal or minimal pulse rate (PR). A value &lt; 1 or &gt; 1 were considered as negative (NCR) or positive CR (PCR), respectively. Results: Max PR was significantly higher in CCVD and AIS compared to OND. Max CR was lower in CCVD and AIS compared to OND. Increased levels of glycosylated hemoglobin, cardiac biomarkers, abnormal findings at Holter ECG and Echocardiography were particularly observed in case of NCR. Conclusions: NCR may interfere with normal activity of daily living. Higher Hachinski ischaemic scores in these patients point out a higher ischaemic load. Moreover, NCR identified a category of acute patients with worst outcomes, requiring prompt intensive care because of higher risk of complications and mortality. Our observations may be useful for better choosing among therapeutical options, planning rehabilitation and health enhancing physical activity in aging. Moreover, they may reduce the risk of injuries for training overload in athletes.

Bleeding and Transfusion

This review describes the approaches taken for patient with massive hemorrhage, a derangement of hemostasis, and anemia. For hemorrhage, control of the source of bleeding, restoration of the blood volume, and management of the coagulopathy is presented. Exclusion of technical causes of bleeding, an initial assessment of potential coagulopathy, and an interpretation of coagulation parameters is described for derangements of hemostasis. For anemia, acute coronary artery ischemic syndromes and neurologic conditions are described. Additionally, bleeding disorders are presented. Figures depict various algorithms related to decision-making and treatment. Tables show the management of the patient with an increased International Normalized Ratio, coagulopathy scores, classification and management of Von Willebrand disease, and tests of platelet function. This review contains 83 references.

Case report: Posterior myocardial infarction in presence of right bundle branch block: an old concept with new findings

BackgroundThe diagnosis of acute ischaemic coronary syndromes in presence of an intra-ventricular conduction disturbance represents a clinical challenge. In the cardiac segmentation model the posterior wall is replaced by the basal inferior segment. However, in the clinical scenario of acute coronary syndrome the concept of posterior myocardial infarction (PMI) endures. The association of a PMI and right bundle branch block (RBBB) is a rare condition characterised by broad R waves and ventricular repolarization disorders in right precordial leads in both entities, which could lead to misinterpretation and delay in reperfusion therapy.Case SummaryWe describe a case report of a 74-year-old man with acute chest pain and an electrocardiogram with broad R waves, a 4 mm ST-segment downsloping (excessively discordant) in right precordial leads, RBBB, and ST-segment elevation in posterior leads. There was resolution of ST-segment downsloping in right precordial leads after percutaneous coronary intervention and stenting of the circumflex artery, with disturbance of the repolarization process only attributable to RBBB.DiscussionPatients with acute chest pain with RBBB and a ST segment with an excessive downsloping (out of proportion of what is expected in isolated RBBB) suggest PMI with occlusion of the circumflex coronary artery.

Correction to: 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.

Correction to: 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association.

American Telemedicine Association: Telestroke Guidelines.

The following telestroke guidelines were developed to assist practitioners in providing assessment, diagnosis, management, and/or remote consultative support to patients exhibiting symptoms and signs consistent with an acute stroke syndrome, using telemedicine communication technologies. Although telestroke practices may include the more broad utilization of telemedicine across the entire continuum of stroke care, with some even consulting on all neurologic emergencies, this document focuses on the acute phase of stroke, including both pre- and in-hospital encounters for cerebrovascular neurological emergencies. These guidelines describe a network of audiovisual communication and computer systems for delivery of telestroke clinical services and include operations, management, administration, and economic recommendations. These interactive encounters link patients with acute ischemic and hemorrhagic stroke syndromes with acute care facilities with remote and on-site healthcare practitioners providing access to expertise, enhancing clinical practice, and improving quality outcomes and metrics. These guidelines apply specifically to telestroke services and they do not prescribe or recommend overall clinical protocols for stroke patient care. Rather, the focus is on the unique aspects of delivering collaborative bedside and remote care through the telestroke model.

0286 : Predictive factors of cardiogenic shock in acute phase of acute coronary syndrome: prospective study

Cardiogenic shock is usually considered a sequel of ST-segment elevation myocardial infarction. This study assessed the incidence and Predictive factors of cardiogenic shock developing after enrollment among patients with and without ST-segment elevation. Among 198 patients who did not present with cardiogenic shock, 80 (40%) had and 100 (50%) did not have ST-segment elevation on the enrollment ECG. Cardiogenic shock developed in 7.2% Of ST-segment elevation patients compared with 5.5% of patients without ST-segment. Shock developed significantly later among patients without ST-segment elevation. The main cause of cardiogenic shock was primitive in connection with impaired LV systolic function, followed by a severe ventricular arrhythmia. Vasopressor therapy was prescribed in 85.7% of patients. A systolic electro drive probe was placed in 28%. An external shock was performed in 28%. The hospital mortality was 40%. Independent predictors of cardiogenic shock occurred are the extended territory VD (p < 0.004) ; the biventricular dysfunction (p < 0.002), severe ischemic mitral regurgitation (p < 0.003), high blood glucose (p <0.005), elevated troponins (p < 0.004), and TIMI flow < 2 (p < 0, 0001). Cardiogenic shock occurs in the setting of acute ischemic syndromes remains a therapeutic challenge. Patient characteristics, timing, clinical course, echocardiographic and angiographic findings differ between the 2 groups. The author hereby declares no conflict of interest

Chapter 66 - Endovascular treatment of acute ischemic stroke

Endovascular thrombectomy is an effective treatment for major acute ischemic stroke syndromes caused by major anterior circulation artery occlusions (commonly referred to as large vessel occlusion) and is superior to intravenous thrombolysis and medical management. Treatment should occur as quickly as is reasonably possible. All patients with moderate to severe symptoms (National Institutes of Health stroke scale >8) and a treatable occlusion should be considered. The use of neuroimaging is critical to exclude hemorrhage and large ischemic cores. Very shortly after stroke onset (<3 hours) computed tomography (CT) and CT angiography provide sufficient information to proceed; diffusion magnetic resonance imaging (MRI) is less reliable during this early stage. After 3 hours from onset diffusion MRI is the most reliable method to define ischemic core size and should be used in centers that can offer it rapidly. Recanalization is highly effective with a stentriever or using a direct aspiration technique, with the patient awake or under conscious sedation rather than general anesthesia, if it may be performed safely. After thrombectomy the patient should be admitted to an intensive care setting and inpatient rehabilitation undertaken as soon as feasible. Patient outcomes should be assessed at 3 months, preferably using the modified Rankin score.

Lambl's excrescences: A case report and review of the literature.

Lambl's excrescences are filamentous extensions of cardiac valves, mostly asymptomatic but rarely associated with catastrophic thromboembolic events such as acute ischemic stroke and acute coronary syndromes. Numerous case reports cited in the literature have addressed various spectrum of presentation of these syndromes and their outcomes based on therapies used. We encountered such a patient from our own experience who presented with an acute ischemic stroke with no other identifiable cause other than the Lambl's excrescences. We subsequently carried out an extensive literature search and based on our interpretation of the outcomes we decided to treat the patient to the best of our understanding. In the proceeding section we describe the case and the discussion and our rationale to treat the patient accordingly.

Abstract 13709: High-Density Lipoprotein is a Novel Activator of Cardiac Glucose Metabolism in both Healthy and Insulin Resistant Myocardium

Aims: High-density lipoprotein (HDL) is known to increase skeletal muscle glucose uptake, but whether this action extends to the myocardium and has relevance in the setting of ischemia is unknown. This study aimed to determine the effect of HDL on cardiac glucose metabolism both in vitro and in vivo, including during ischemia/reperfusion injury. Methods and Results: HDL treatment (50μg/mL) increased glucose uptake (147±10%), glycolysis (154±11%) and glucose oxidation (130±6%) in neonatal ventricular cardiomyocytes compared to saline control. HDL rapidly activated the Akt pathway and an Akt inhibitor (Akti 1/2) abolished HDL-mediated glucose uptake, suggesting an Akt-dependent mechanism. To determine the upstream receptor mechanism HDL binding to sphingosine-1-phosphate (S1P) receptors was blocked with either 1uM VPC23019 (S1P1&amp;3 antagonist) or 1uM CAY10444 (S1P3 antagonist). Both similarly inhibited HDL-mediated glucose uptake. S1P is a known activator of the Akt pathway, thus our data suggests the S1P component of HDL increases glucose uptake via S1P3 activation of the Akt pathway. The effect of a single intravenous bolus of reconstituted HDL (CSL-111; 80mg/kg) in chow diet (CD) and high fat diet (HFD) insulin resistant C57Bl6 mice was investigated during an oral glucose tolerance test (OGTT). CSL-111 treatment increased cardiac muscle glucose clearance in both CD (168±16%) and HFD (138±11%) mice compared to saline infusion during the OGTT. To assess whether CSL-111 could increase cardiac glucose uptake in an ischemic setting, a single bolus of CSL-111 (80mg/kg) was given at the beginning of reperfusion in mice following left anterior descending artery (LAD) ligation. CSL-111 trended to increase cardiac glucose uptake ([18F]Fluorodeoxyglucose tracer and PET-CT imaging) by 66% (chow) and 81% (HFD) (treatment effect p=0.07) 1 hour post-reperfusion following LAD surgery. Furthermore, CSL-111 improved long term cardiac functional recovery. Conclusion: These data show that HDL increases glucose uptake and utilisation in the heart suggesting a role for HDL therapies in preserving functional myocardium subsequent to acute coronary ischemic syndromes.

Real-World Registry Study Confirms Fondaparinux Over Low-Molecular-Weight Heparin for NSTEMI

The pivotal Fifth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-5) trial demonstrated that fondaparinux was non-inferior to enoxaparin in reducing ischaemic outcomes in patients with a non-ST segment elevation myocardial infarction (NSTEMI). However, fondaparinux was associated with a lower number of patients experiencing major bleeding events. Based on these results suggesting a better benefit-to-risk ratio over enoxaparin, the European Society of Cardiology recommended fondaparinux as the first-line anticoagulation therapy in patients with an NSTEMI in 2007. A registry study conducted in Sweden provides real-life clinical data and confirms the clinical relevance of fondaparinux use over low-molecular-weight heparin in routine clinical care. This article aims to review the place of fondaparinux in acute coronary syndrome patients, and to provide an analysis of clinical trial data along with real-life data.

Deferoxamine, Cerebrovascular Hemodynamics, and Vascular Aging: Potential Role for Hypoxia-Inducible Transcription Factor-1-Regulated Pathways.

Iron chelation therapy is emerging as a novel neuroprotective strategy. The mechanisms of neuroprotection are diverse and include both neuronal and vascular pathways. We sought to examine the effect of iron chelation on cerebrovascular function in healthy aging and to explore whether hypoxia-inducible transcription factor-1 activation may be temporally correlated with vascular changes. We assessed cerebrovascular function (autoregulation, vasoreactivity, and neurovascular coupling) and serum concentrations of vascular endothelial growth factor and erythropoietin, as representative measures of hypoxia-inducible transcription factor-1 activation, during 6 hours of deferoxamine infusion in 24 young and 24 older healthy volunteers in a randomized, blinded, placebo-controlled cross-over study design. Cerebrovascular function was assessed using the transcranial Doppler ultrasound. Vascular endothelial growth factor and erythropoietin serum protein assays were conducted using the Meso Scale Discovery platform. Deferoxamine elicited a strong age- and time-dependent increase in the plasma concentrations of erythropoietin and vascular endothelial growth factor, which persisted ≤3 hours post infusion (age effect P=0.04; treatment×time P<0.01). Deferoxamine infusion also resulted in a significant time- and age-dependent improvement in cerebral vasoreactivity (treatment×time P<0.01; age P<0.01) and cerebral autoregulation (gain: age×time×treatment P=0.04). Deferoxamine infusion improved cerebrovascular function, particularly in older individuals. The temporal association between improved cerebrovascular function and increased serum vascular endothelial growth factor and erythropoietin concentrations is supportive of shared hypoxia-inducible transcription factor-1-regulated pathways. Therefore, pharmacological activation of hypoxia-inducible transcription factor-1 to enhance cerebrovascular function may be a promising neuroprotective strategy in acute and chronic ischemic syndromes, especially in elderly patients. URL: http://www.clinicaltrials.gov. Unique identifier: NCT013655104.

Thrombosis formation on atherosclerotic lesions and plaque rupture

Atherosclerosis is a silent chronic vascular pathology that is the cause of the majority of cardiovascular ischaemic events. The evolution of vascular disease involves a combination of endothelial dysfunction, extensive lipid deposition in the intima, exacerbated innate and adaptive immune responses, proliferation of vascular smooth muscle cells and remodelling of the extracellular matrix, resulting in the formation of an atherosclerotic plaque. High-risk plaques have a large acellular lipid-rich necrotic core with an overlying thin fibrous cap infiltrated by inflammatory cells and diffuse calcification. The formation of new fragile and leaky vessels that invade the expanding intima contributes to enlarge the necrotic core increasing the vulnerability of the plaque. In addition, biomechanical, haemodynamic and physical factors contribute to plaque destabilization. Upon erosion or rupture, these high-risk lipid-rich vulnerable plaques expose vascular structures or necrotic core components to the circulation, which causes the activation of tissue factor and the subsequent formation of a fibrin monolayer (coagulation cascade) and, concomitantly, the recruitment of circulating platelets and inflammatory cells. The interaction between exposed atherosclerotic plaque components, platelet receptors and coagulation factors eventually leads to platelet activation, aggregation and the subsequent formation of a superimposed thrombus (i.e. atherothrombosis) which may compromise the arterial lumen leading to the presentation of acute ischaemic syndromes. In this review, we will describe the progression of the atherosclerotic lesion along with the main morphological characteristics that predispose to plaque rupture, and discuss the multifaceted mechanisms that drive platelet activation and subsequent thrombus formation. Finally, we will consider the current scientific challenges and future research directions.