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Thrombosis Research Feb 2024Hemolysis is a known risk factor for thrombosis resulting in critical limb ischemia and microcirculatory disturbance and organ failure. Intravasal hemolysis may lead to...
BACKGROUND AND AIMS
Hemolysis is a known risk factor for thrombosis resulting in critical limb ischemia and microcirculatory disturbance and organ failure. Intravasal hemolysis may lead to life-threatening complications due to uncontrolled thrombo-inflammation. Until now, conventional antithrombotic therapies failed to control development and progression of these thrombotic events. Thus, the pathophysiology of these thrombotic events needs to be investigated to unravel underlying pathways and thereby identify targets for novel treatment strategies.
METHODS
Here we used classical experimental set-ups as well as high-end flow cytometry, metabolomics and lipidomic analysis to in-depth analyze the effects of hemin on platelet physiology and morphology.
RESULTS
Hemin does strongly and swiftly induce platelet activation and this process is modulated by the sGC-cGMP-cGKI signaling axis. cGMP modulation also reduced the pro-aggregatory potential of plasma derived from patients with hemolysis. Furthermore, hemin-induced platelet death evokes distinct platelet subpopulations. Typical cell death markers, such as ROS, were induced by hemin-stimulation and the platelet lipidome was specifically altered by high hemin concentration. Specifically, arachidonic acid derivates, such as PGE, TXB or 12-HHT, were significantly increased. Balancing the cGMP levels by modulation of the sGC-cGMP-cGKI axis diminished the ferroptotic effect of hemin.
CONCLUSION
We found that cGMP modulates hemin-induced platelet activation and thrombus formation in vitro and cGMP effects hemin-mediated platelet death and changes in the platelet lipidome. Thus, it is tempting to speculate that modulating platelet cGMP levels may be a novel strategy to control thrombosis and critical limb ischemia in patients with hemolytic crisis.
Topics: Humans; Hemin; Chronic Limb-Threatening Ischemia; Hemolysis; Microcirculation; Blood Platelets; Thrombosis
PubMed: 38171216
DOI: 10.1016/j.thromres.2023.12.008 -
BMC Cardiovascular Disorders Aug 2023This study aimed to determine the effect of short-term remote ischemic preconditioning (RIPC) on coronary blood flow and microcirculation function using the quantitative... (Randomized Controlled Trial)
Randomized Controlled Trial
This study aimed to determine the effect of short-term remote ischemic preconditioning (RIPC) on coronary blood flow and microcirculation function using the quantitative flow ratio (QFR) and index of microcirculatory resistance (IMR). We randomly divided 129 patients undergoing coronary angiography (CAG) into RIPC and control groups. Following the first CAG, we randomly divided the patients further into the unilateral upper limb and lower limb groups for four cycles of ischemia/reperfusion circulation; subsequently, we performed the second CAG. During each CAG, contrast-flow QFR (cQFR), fixed-flow QFR (fQFR), and IMR (in patients with cardiac syndrome X) were calculated and compared. We measured 253 coronary arteries in 129 patients. Compared to the control group, the average cQFR of the RIPC group increased significantly after RIPC. Additionally, 23 patients with cardiac syndrome X (IMR > 30) were included in this study. Compared to the control group, IMR and the difference between cQFR and fQFR (cQFR-fQFR) both decreased significantly after receiving RIPC. The application of RIPC can increase coronary blood flow and improve coronary microcirculation function.
Topics: Humans; Cardiovascular Physiological Phenomena; Heart; Ischemic Preconditioning; Microcirculation; Microvascular Angina
PubMed: 37592218
DOI: 10.1186/s12872-023-03419-0 -
European Heart Journal. Cardiovascular... Dec 2023The beneficial cardiovascular effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors irrespective of the presence of diabetes mellitus are nowadays well... (Review)
Review
AIMS
The beneficial cardiovascular effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors irrespective of the presence of diabetes mellitus are nowadays well established and they already constitute a significant pillar for the management of heart failure, irrespective of the ejection fraction. The exact underlying mechanisms accountable for these effects, however, remain largely unknown. The direct effect on endothelial function and microcirculation is one of the most well studied. The broad range of studies presented in this review aims to link all available data from the bench to bedside and highlight the existing gaps as well as the future directions in the investigations concerning the effects of SGLT2 inhibitors on the endothelium and the microcirculation.
METHODS AND RESULTS
An extensive search has been conducted using the MEDLINE/PubMed database in order to identify the relevant studies. Preclinical data suggest that SGLT2 inhibitors directly affect endothelial function independently of glucose and specifically via several interplaying molecular pathways, resulting in improved vasodilation, increased NO production, enhanced mitochondrial homeostasis, endothelial cell viability, and angiogenesis as well as attenuation of oxidative stress and inflammation. Clinical data systematically confirm this beneficial effect on the endothelium, whereas the evidence concerning the effect on the microcirculation is conflicting.
CONCLUSION
Preclinical and clinical studies indicate that SGLT2 inhibitors attenuate endothelial and microvascular dysfunction via a combination of mechanisms, which play a role in their beneficial cardiovascular effect.
Topics: Humans; Sodium-Glucose Transporter 2 Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Microcirculation; Glucose; Endothelium
PubMed: 37500266
DOI: 10.1093/ehjcvp/pvad053 -
BMC Anesthesiology Sep 2023Previous studies indicate supplemental vitamin C improves microcirculation and reduces glycocalyx shedding in septic animals. Our randomized, double-blind,... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of high-dose intravenous ascorbic acid on microcirculation and endothelial glycocalyx during sepsis and septic shock: a double-blind, randomized, placebo-controlled study.
Previous studies indicate supplemental vitamin C improves microcirculation and reduces glycocalyx shedding in septic animals. Our randomized, double-blind, placebo-controlled trial aimed to investigate whether a high dose of intravenous ascorbic acid (AA) might improve microcirculation and affect glycocalyx in septic patients. In our study, 23 septic patients were supplemented with a high dose (50 mg/kg every 6 h) of intravenous AA or placebo for 96 h. Sublingual microcirculation was examined using a handheld Cytocam-incident dark field (IDF) video microscope. A sidestream dark field video microscope (SDF), connected to the GlycoCheck software (GlycoCheck ICU®; Maastricht University Medical Center, Maastricht, the Netherlands), was employed to observe glycocalyx. We found a significantly higher proportion of perfused small vessels (PPV) 6 h after the beginning of the trial in the experimental group compared with placebo. As an indicator of glycocalyx thickness, the perfused boundary region was lower in capillaries of the 5-9 μm diameter in the AA group than placebo after the first dose of AA. Our data suggest that high-dose parenteral AA tends to improve microcirculation and glycocalyx in the early period of septic shock. The study was retrospectively registered in the clinicaltrials.gov database on 26/02/2021 (registration number NCT04773717).
Topics: Ascorbic Acid; Glycocalyx; Microcirculation; Sepsis; Shock, Septic; Humans
PubMed: 37700249
DOI: 10.1186/s12871-023-02265-z -
Journal of Thrombosis and Thrombolysis Oct 2023Coronary microvascular endothelial cells (CMECs) react to changes in coronary blood flow and myocardial metabolites and regulate coronary blood flow by balancing... (Review)
Review
Coronary microvascular endothelial cells (CMECs) react to changes in coronary blood flow and myocardial metabolites and regulate coronary blood flow by balancing vasoconstrictors-such as endothelin-1-and the vessel dilators prostaglandin, nitric oxide, and endothelium-dependent hyperpolarizing factor. Coronary microvascular endothelial cell dysfunction is caused by several cardiovascular risk factors and chronic rheumatic diseases that impact CMEC blood flow regulation, resulting in coronary microcirculation dysfunction (CMD). The mechanisms of CMEC dysfunction are not fully understood. However, the following could be important mechanisms: the overexpression and activation of nicotinamide adenine dinucleotide phosphate oxidase (Nox), and mineralocorticoid receptors; the involvement of reactive oxygen species (ROS) caused by a decreased expression of sirtuins (SIRT3/SIRT1); forkhead box O3; and a decreased SK/IK expression in the endothelium-dependent hyperpolarizing factor electrical signal pathway. In addition, p66Shc is an adapter protein that promotes oxidative stress; although there are no studies on its involvement with cardiac microvessels, it is possible it plays an important role in CMD.
Topics: Humans; Src Homology 2 Domain-Containing, Transforming Protein 1; Microcirculation; Endothelial Cells; Vascular Diseases; Myocardial Ischemia; Coronary Vessels; Endothelium, Vascular
PubMed: 37466848
DOI: 10.1007/s11239-023-02862-2 -
Nature Reviews. Cardiology May 2024Despite prompt epicardial recanalization in patients presenting with ST-segment elevation myocardial infarction (STEMI), coronary microvascular obstruction and... (Review)
Review
Despite prompt epicardial recanalization in patients presenting with ST-segment elevation myocardial infarction (STEMI), coronary microvascular obstruction and dysfunction (CMVO) is still fairly common and is associated with poor prognosis. Various pharmacological and mechanical strategies to treat CMVO have been proposed, but the positive results reported in preclinical and small proof-of-concept studies have not translated into benefits in large clinical trials conducted in the modern treatment setting of patients with STEMI. Therefore, the optimal management of these patients remains a topic of debate. In this Review, we appraise the pathophysiological mechanisms of CMVO, explore the evidence and provide future perspectives on strategies to be implemented to reduce the incidence of CMVO and improve prognosis in patients with STEMI.
Topics: Humans; ST Elevation Myocardial Infarction; Coronary Circulation; Percutaneous Coronary Intervention; Myocardial Infarction; Prognosis; Microcirculation
PubMed: 38001231
DOI: 10.1038/s41569-023-00953-4 -
British Journal of Anaesthesia Jan 2024The microcirculation describes the network of the smallest vessels in our cardiovascular system. On a microcirculatory level, oxygen delivery is determined by the flow... (Review)
Review
The microcirculation describes the network of the smallest vessels in our cardiovascular system. On a microcirculatory level, oxygen delivery is determined by the flow of oxygen-carrying red blood cells in a given single capillary (capillary red blood cell flow) and the density of the capillary network in a given tissue volume (capillary vessel density). Handheld vital videomicroscopy enables visualisation of the capillary bed on the surface of organs and tissues but currently is only used for research. Measurements are generally possible on all organ surfaces but are most often performed in the sublingual area. In patients presenting for elective surgery, the sublingual microcirculation is usually intact and functional. Induction of general anaesthesia slightly decreases capillary red blood cell flow and increases capillary vessel density. During elective, even major, noncardiac surgery, the sublingual microcirculation is preserved and remains functional, presumably because elective noncardiac surgery is scheduled trauma and haemodynamic alterations are immediately treated by anaesthesiologists, usually restoring the macrocirculation before the microcirculation is substantially impaired. Additionally, surgery is regional trauma and thus likely causes regional, rather than systemic, impairment of the microcirculation. Whether or not the sublingual microcirculation is impaired after noncardiac surgery remains a subject of ongoing research. Similarly, it remains unclear if cardiac surgery, especially with cardiopulmonary bypass, impairs the sublingual microcirculation. The effects of therapeutic interventions specifically targeting the microcirculation remain to be elucidated and tested. Future research should focus on further improving microcirculation monitoring methods and investigating how regional microcirculation monitoring can inform clinical decision-making and treatment.
Topics: Humans; Microcirculation; Perioperative Medicine; Mouth Floor; Cardiac Surgical Procedures; Oxygen
PubMed: 38030549
DOI: 10.1016/j.bja.2023.10.033 -
Pharmacological interventions targeting the microcirculation following traumatic spinal cord injury.Neural Regeneration Research Jan 2024Traumatic spinal cord injury is a devastating disorder characterized by sensory, motor, and autonomic dysfunction that severely compromises an individual's ability to... (Review)
Review
Traumatic spinal cord injury is a devastating disorder characterized by sensory, motor, and autonomic dysfunction that severely compromises an individual's ability to perform activities of daily living. These adverse outcomes are closely related to the complex mechanism of spinal cord injury, the limited regenerative capacity of central neurons, and the inhibitory environment formed by traumatic injury. Disruption to the microcirculation is an important pathophysiological mechanism of spinal cord injury. A number of therapeutic agents have been shown to improve the injury environment, mitigate secondary damage, and/or promote regeneration and repair. Among them, the spinal cord microcirculation has become an important target for the treatment of spinal cord injury. Drug interventions targeting the microcirculation can improve the microenvironment and promote recovery following spinal cord injury. These drugs target the structure and function of the spinal cord microcirculation and are essential for maintaining the normal function of spinal neurons, axons, and glial cells. This review discusses the pathophysiological role of spinal cord microcirculation in spinal cord injury, including its structure and histopathological changes. Further, it summarizes the progress of drug therapies targeting the spinal cord microcirculation after spinal cord injury.
PubMed: 37488841
DOI: 10.4103/1673-5374.375304 -
Medicina (Kaunas, Lithuania) Dec 2023Coronary microvascular dysfunction (CMD) is a clinical entity linked with various risk factors that significantly affect cardiac morbidity and mortality. Hypertension,... (Review)
Review
Coronary microvascular dysfunction (CMD) is a clinical entity linked with various risk factors that significantly affect cardiac morbidity and mortality. Hypertension, one of the most important, causes both functional and structural alterations in the microvasculature, promoting the occurrence and progression of microvascular angina. Endothelial dysfunction and capillary rarefaction play the most significant role in the development of CMD among patients with hypertension. CMD is also related to several hypertension-induced morphological and functional changes in the myocardium in the subclinical and early clinical stages, including left ventricular hypertrophy, interstitial myocardial fibrosis, and diastolic dysfunction. This indicates the fact that CMD, especially if associated with hypertension, is a subclinical marker of end-organ damage and heart failure, particularly that with preserved ejection fraction. This is why it is important to search for microvascular angina in every patient with hypertension and chest pain not associated with obstructive coronary artery disease. Several highly sensitive and specific non-invasive and invasive diagnostic modalities have been developed to evaluate the presence and severity of CMD and also to investigate and guide the treatment of additional complications that can affect further prognosis. This comprehensive review provides insight into the main pathophysiological mechanisms of CMD in hypertensive patients, offering an integrated diagnostic approach as well as an overview of currently available therapeutical modalities.
Topics: Humans; Microvascular Angina; Coronary Circulation; Myocardial Ischemia; Coronary Artery Disease; Hypertension; Cardiomyopathies; Microcirculation; Coronary Vessels
PubMed: 38138252
DOI: 10.3390/medicina59122149 -
The Journal of Heart and Lung... Sep 2023Reduced arterial pulsatility in continuous-flow left ventricular assist devices (CF-LVAD) patients has been implicated in clinical complications. Consequently, recent...
BACKGROUND
Reduced arterial pulsatility in continuous-flow left ventricular assist devices (CF-LVAD) patients has been implicated in clinical complications. Consequently, recent improvements in clinical outcomes have been attributed to the "artificial pulse" technology inherent to the HeartMate3 (HM3) LVAD. However, the effect of the "artificial pulse" on arterial flow, transmission of pulsatility into the microcirculation and its association with LVAD pump parameters is not known.
METHODS
The local flow oscillation (pulsatility index, PI) of common carotid arteries (CCAs), middle cerebral arteries (MCAs) and central retinal arteries (CRAs-representing the microcirculation) were quantified by 2D-aligned, angle-corrected Doppler ultrasound in 148 participants: healthy controls, n = 32; heart failure (HF), n = 43; HeartMate II (HMII), n = 32; HM3, n = 41.
RESULTS
In HM3 patients, 2D-Doppler PI in beats with "artificial pulse" and beats with "continuous-flow" was similar to that of HMII patients across the macro- and microcirculation. Additionally, peak systolic velocity did not differ between HM3 and HMII patients. Transmission of PI into the microcirculation was higher in both HM3 (during the beats with "artificial pulse") and in HMII patients compared with HF patients. LVAD pump speed was inversely associated with microvascular PI in HMII and HM3 (HMII, r = 0.51, p < 0.0001; HM3 "continuous-flow," r = 0.32, p = 0.0009; HM3 "artificial pulse," r = 0.23, p = 0.007), while LVAD pump PI was only associated with microcirculatory PI in HMII patients.
CONCLUSIONS
The "artificial pulse" of the HM3 is detectable in the macro- and microcirculation but without creating a significant alteration in PI compared with HMII patients. Increased transmission of pulsatility and the association between pump speed and PI in the microcirculation indicate that the future clinical care of HM3 patients may involve individualized pump settings according to the microcirculatory PI in specific end-organs.
Topics: Humans; Microcirculation; Heart-Assist Devices; Heart Failure; Heart Rate; Middle Cerebral Artery
PubMed: 37098374
DOI: 10.1016/j.healun.2023.04.002