-
Microvascular Research Nov 2023Livedoid vasculopathy (LV) is a rare, disabling disease characterized by painful ulcers, livedo reticularis and atrophy blanche. Hypercoagulation, endothelial, and...
BACKGROUND
Livedoid vasculopathy (LV) is a rare, disabling disease characterized by painful ulcers, livedo reticularis and atrophy blanche. Hypercoagulation, endothelial, and microcirculatory dysfunction are believed to be responsible for the pathogenesis of this difficult-to-treat disease.
OBJECTIVES
This study sought to investigate the frequency of endothelial dysfunction, hypercoagulability, and nailfold capillaroscopic features in LV patients to shed light on its etiology.
METHODS
This case-control study included 16 patients with LV, 24 with systemic sclerosis (SSc), and 23 control subjects. Serum markers of endothelial dysfunction soluble endoglin, endocan, endothelin-1, lipoprotein a, plasminogen activator inhibitor-1 (PAI-1), soluble thrombomodulin, and von Willebrand factor were measured using enzyme-linked immunosorbent assays. Flow-mediated dilation and carotid intima-media thickness were examined as markers of endothelial dysfunction, and microcirculation was assessed with nailfold capillaroscopy. Thrombophilia-related parameters, including gene polymorphisms of factor V Leiden, prothrombin, PAI-1 genes, methylenetetrahydrofolate reductase (MTHFR) and factor XIII mutation and serum levels of protein C, protein S, antithrombin, homocysteine, D-dimer and antiphospholipid antibodies were investigated in LV patients.
RESULTS
Plasminogen activator inhibitor-1 and soluble thrombomodulin levels were significantly higher in LV patients compared to control subjects (2.3 [2.05-2.79] ng/ml vs. 1.89 [1.43-2.33] ng/ml, p = 0.007; 1.15 [0.88-1.4] ng/ml vs. 0.76 [0.56-0.9] ng/ml, p = 0.004, respectively). Flow-mediated dilation was 25.4 % lower in the LV patients compared to the control group (14.77 % [11.26-18.26] vs. 19.80 % [16.47-24.88], p = 0.034). Capillaroscopic features, including ramifications (75 % vs. 8.7 %, p < 0.001), avascular areas (25 % vs. 0 %, p = 0.011) and dilatations (33.2 % vs. 0 %, p = 0.016), were significantly higher in LV patients than in controls. LV patients had multiple biochemical or genetic abnormalities related to thrombophilia, including heterozygous factor V Leiden mutations (6.3 %), MTHFR (C677T) mutations (heterozygous 43.8 %, homozygous 18.8 %), MTHFR (A1298C) mutations (heterozygous 37.5 %, homozygous 12.5 %), factor XIII heterozygous mutation (12.5 %), antithrombin deficiency (31.3 %), protein S deficiency (12.5 %), hyperhomocysteinemia (31.3 %), D-dimer elevation (25 %), anti-β2-glycoprotein I (12.5 %), lupus anticoagulant antibodies (6.3 %), and anticardiolipin antibodies (6.3 %).
CONCLUSIONS
In conclusion, LV patients were characterized by an increased presence of thrombophilia-related parameters, and also exhibited vascular endothelial and microcirculatory dysfunction, resembling SSc. These findings support the complex interaction of thrombophilia, endothelial dysfunction, and microcirculation dysregulation in the pathogenesis of LV. Thus, the treatment of LV patients should be individualized, based on the identification of the predominant pathological pathways.
Topics: Humans; Livedo Reticularis; Plasminogen Activator Inhibitor 1; Thrombomodulin; Case-Control Studies; Factor XIII; Carotid Intima-Media Thickness; Microcirculation; Microscopic Angioscopy; Thrombophilia; Livedoid Vasculopathy; Antithrombins
PubMed: 37543163
DOI: 10.1016/j.mvr.2023.104591 -
Frontiers in Immunology 2023Sepsis represents a global health concern, and patients with severe sepsis are at risk of experiencing MODS (multiple organ dysfunction syndrome), which is associated... (Review)
Review
Sepsis represents a global health concern, and patients with severe sepsis are at risk of experiencing MODS (multiple organ dysfunction syndrome), which is associated with elevated mortality rates and a poorer prognosis. The development of sepsis involves hyperactive inflammation, immune disorder, and disrupted microcirculation. It is crucial to identify targets within these processes to develop therapeutic interventions. One such potential target is Panx1 (pannexin-1), a widely expressed transmembrane protein that facilitates the passage of molecules smaller than 1 KDa, such as ATP. Accumulating evidence has implicated the involvement of Panx1 in sepsis-associated MODS. It attracts immune cells via the purinergic signaling pathway, mediates immune responses via the Panx1-IL-33 axis, promotes immune cell apoptosis, regulates blood flow by modulating VSMCs' and vascular endothelial cells' tension, and disrupts microcirculation by elevating endothelial permeability and promoting microthrombosis. At the level of organs, Panx1 contributes to inflammatory injury in multiple organs. Panx1 primarily exacerbates injury and hinders recovery, making it a potential target for sepsis-induced MODS. While no drugs have been developed explicitly against Panx1, some compounds that inhibit Panx1 hemichannels have been used extensively in experiments. However, given that Panx1's role may vary during different phases of sepsis, more investigations are required before interventions against Panx1 can be applied in clinical. Overall, Panx1 may be a promising target for sepsis-induced MODS. Nevertheless, further research is needed to understand its complex role in different stages of sepsis fully and to develop suitable pharmaceutical interventions for clinical use.
Topics: Humans; Endothelial Cells; Multiple Organ Failure; Apoptosis; Inflammation; Membrane Proteins
PubMed: 37711629
DOI: 10.3389/fimmu.2023.1217366 -
European Heart Journal Aug 2023The microvascular resistance reserve (MRR) was introduced as a means to characterize the vasodilator reserve capacity of the coronary microcirculation while accounting...
AIMS
The microvascular resistance reserve (MRR) was introduced as a means to characterize the vasodilator reserve capacity of the coronary microcirculation while accounting for the influence of concomitant epicardial disease and the impact of administration of potent vasodilators on aortic pressure. This study aimed to evaluate the diagnostic and prognostic performance of MRR.
METHODS AND RESULTS
A total of 1481 patients with stable symptoms and a clinical indication for coronary angiography were included from the global ILIAS Registry. MRR was derived as a function of the coronary flow reserve (CFR) divided by the fractional flow reserve (FFR) and corrected for driving pressure. The median MRR was 2.97 [Q1-Q3: 2.32-3.86] and the overall relationship between MRR and CFR was good [correlation coefficient (Rs) = 0.88, P < 0.005]. The difference between CFR and MRR increased with decreasing FFR [coefficient of determination (R2) = 0.34; Coef.-2.88, 95% confidence interval (CI): -3.05--2.73; P < 0.005]. MRR was independently associated with major adverse cardiac events (MACE) at 5-year follow-up [hazard ratio (HR) 0.78; 95% CI 0.63-0.95; P = 0.024] and with target vessel failure (TVF) at 5-year follow-up (HR 0.83; 95% CI 0.76-0.97; P = 0.047). The optimal cut-off value of MRR was 3.0. Based on this cut-off value, only abnormal MRR was significantly associated with MACE and TVF at 5-year follow-up in vessels with functionally significant epicardial disease (FFR <0.75).
CONCLUSION
MRR seems a robust indicator of the microvascular vasodilator reserve capacity. Moreover, in line with its theoretical background, this study suggests a diagnostic advantage of MRR over other indices of vasodilatory capacity in patients with hemodynamically significant epicardial coronary artery disease.
Topics: Humans; Prognosis; Coronary Stenosis; Fractional Flow Reserve, Myocardial; Coronary Artery Disease; Coronary Angiography; Vasodilator Agents; Registries; Coronary Vessels; Predictive Value of Tests; Microcirculation
PubMed: 37350567
DOI: 10.1093/eurheartj/ehad378 -
JACC. Cardiovascular Interventions Nov 2023Coronary flow reserve (CFR) and microvascular resistance reserve (MRR) can, in principle, be derived by any method assessing coronary flow.
BACKGROUND
Coronary flow reserve (CFR) and microvascular resistance reserve (MRR) can, in principle, be derived by any method assessing coronary flow.
OBJECTIVES
The aim of this study was to compare CFR and MRR as derived by continuous (CFR and MRR) and bolus thermodilution (CFR and MRR).
METHODS
A total of 175 patients with chest pain and nonobstructive coronary artery disease were studied. Bolus and continuous thermodilution measurements were performed in the left anterior descending coronary artery. MRR was calculated as the ratio of CFR to fractional flow reserve and corrected for changes in systemic pressure. In 102 patients, bolus and continuous thermodilution measurements were performed in duplicate to assess test-retest reliability.
RESULTS
Mean CFR was higher than CFR (3.47 ± 1.42 and 2.67 ± 0.81 [P < 0.001], mean difference 0.80, upper limit of agreement 3.92, lower limit of agreement -2.32). Mean MRR was also higher than MRR (4.40 ± 1.99 and 3.22 ± 1.02 [P < 0.001], mean difference 1.2, upper limit of agreement 5.08, lower limit of agreement -2.71). The correlation between CFR and MRR values obtained using both methods was significant but weak (CFR, r = 0.28 [95% CI: 0.14-0.41]; MRR, r = 0.26 [95% CI: 0.16-0.39]; P < 0.001 for both). The precision of both CFR and MRR was higher when assessed using continuous thermodilution compared with bolus thermodilution (repeatability coefficients of 0.89 and 2.79 for CFR and CFR, respectively, and 1.01 and 3.05 for MRR and MRR, respectively).
CONCLUSIONS
Compared with bolus thermodilution, continuous thermodilution yields lower values of CFR and MRR accompanied by an almost 3-fold reduction of the variability in the measured results.
Topics: Humans; Coronary Circulation; Fractional Flow Reserve, Myocardial; Thermodilution; Reproducibility of Results; Treatment Outcome; Coronary Vessels; Microcirculation
PubMed: 38030361
DOI: 10.1016/j.jcin.2023.09.027 -
PLoS Pathogens Oct 2023The pathophysiology of severe falciparum malaria involves a complex interaction between the host, parasite, and gut microbes. In this review, we focus on understanding... (Review)
Review
The pathophysiology of severe falciparum malaria involves a complex interaction between the host, parasite, and gut microbes. In this review, we focus on understanding parasite-induced intestinal injury and changes in the human intestinal microbiota composition in patients with Plasmodium falciparum malaria. During the blood stage of P. falciparum infection, infected red blood cells adhere to the vascular endothelium, leading to widespread microcirculatory obstruction in critical tissues, including the splanchnic vasculature. This process may cause intestinal injury and gut leakage. Epidemiological studies indicate higher rates of concurrent bacteraemia in severe malaria cases. Furthermore, severe malaria patients exhibit alterations in the composition and diversity of the intestinal microbiota, although the exact contribution to pathophysiology remains unclear. Mouse studies have demonstrated that the gut microbiota composition can impact susceptibility to Plasmodium infections. In patients with severe malaria, the microbiota shows an enrichment of pathobionts, including pathogens that are known to cause concomitant bloodstream infections. Microbial metabolites have also been detected in the plasma of severe malaria patients, potentially contributing to metabolic acidosis and other clinical complications. However, establishing causal relationships requires intervention studies targeting the gut microbiota.
Topics: Humans; Animals; Mice; Gastrointestinal Microbiome; Microcirculation; Malaria, Falciparum; Malaria; Intestinal Diseases; Plasmodium falciparum
PubMed: 37856470
DOI: 10.1371/journal.ppat.1011661 -
Angiology Jan 2024Vascular sequelae following (SARS-CoV-2 coronavirus disease) (COVID)-19 infection are considered as "Long Covid (LC)" disease, when occurring 12 weeks after the... (Review)
Review
Vascular sequelae following (SARS-CoV-2 coronavirus disease) (COVID)-19 infection are considered as "Long Covid (LC)" disease, when occurring 12 weeks after the original infection. The paucity of specific data can be obviated by translating pathophysiological elements from the original Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) infection (In a microcirculatory system, a first "endotheliitis," is often followed by production of "Neutrophil Extracellular Trap," and can evolve into a more complex leukocytoklastic-like and hyperimmune vasculitis. In medium/large-sized vessels, this corresponds to endothelial dysfunction, leading to an accelerated progression of pre-existing atherosclerotic plaques through an increased deposition of platelets, circulating inflammatory cells and proteins. Associated dysregulated immune and pro-coagulant conditions can directly cause thrombo-embolic arterial or venous complications. In order to implement appropriate treatment, physicians need to consider vascular pathologies observed after SARS-Cov-2 infections as possible "LC" disease.
Topics: Humans; COVID-19; SARS-CoV-2; Post-Acute COVID-19 Syndrome; Microcirculation; Blood Platelets
PubMed: 36652923
DOI: 10.1177/00033197231153204 -
Clinical Cancer Research : An Official... Jul 2023Several approaches for overcoming immunotherapy resistance in pancreatic and colorectal cancer syngeneic models were assessed using heparin and immunotherapy. Beneficial...
Several approaches for overcoming immunotherapy resistance in pancreatic and colorectal cancer syngeneic models were assessed using heparin and immunotherapy. Beneficial responses were attributed to heparin-induced vascular normalization, ensuing CD8+ T-cell infiltration, and M1 macrophage polarization, suggesting the potential for heparin-anchored therapies in cold tumors such as pancreatic cancer. See related article by Wei et al., p. 2525.
Topics: Humans; Heparin; Anticoagulants; Microcirculation; Pancreatic Neoplasms; Immunotherapy; CD8-Positive T-Lymphocytes
PubMed: 37099035
DOI: 10.1158/1078-0432.CCR-23-0346 -
Circulation Jan 2024Angina with nonobstructive coronary arteries is a common condition for which no effective treatment has been established. We hypothesized that the measurement of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Angina with nonobstructive coronary arteries is a common condition for which no effective treatment has been established. We hypothesized that the measurement of coronary flow reserve (CFR) allows identification of patients with angina with nonobstructive coronary arteries who would benefit from anti-ischemic therapy.
METHODS
Patients with angina with nonobstructive coronary arteries underwent blinded invasive CFR measurement and were randomly assigned to receive 4 weeks of amlodipine or ranolazine. After a 1-week washout, they crossed over to the other drug for 4 weeks; final assessment was after the cessation of study medication for another 4 weeks. The primary outcome was change in treadmill exercise time, and the secondary outcome was change in Seattle Angina Questionnaire summary score in response to anti-ischemic therapy. Analysis was on a per protocol basis according to the following classification: coronary microvascular disease (CMD group) if CFR<2.5 and reference group if CFR≥2.5. The study protocol was registered before the first patient was enrolled (International Standard Randomised Controlled Trial Number: ISRCTN94728379).
RESULTS
Eighty-seven patients (61±8 years of age; 62% women) underwent random assignment (57 CMD group and 30 reference group). Baseline exercise time and Seattle Angina Questionnaire summary scores were similar between groups. The CMD group had a greater increment (delta) in exercise time than the reference group in response to both amlodipine (difference in delta, 82 s [95% CI, 37-126 s]; <0.001) and ranolazine (difference in delta, 68 s [95% CI, 21-115 s]; =0.005). The CMD group reported a greater increment (delta) in Seattle Angina Questionnaire summary score than the reference group in response to ranolazine (difference in delta, 7 points [95% CI, 0-15]; =0.048), but not to amlodipine (difference in delta, 2 points [95% CI, -5 to 8]; =0.549).
CONCLUSIONS
Among phenotypically similar patients with angina with nonobstructive coronary arteries, only those with an impaired CFR derive benefit from anti-ischemic therapy. These findings support measurement of CFR to diagnose and guide management of this otherwise heterogeneous patient group.
Topics: Female; Humans; Male; Amlodipine; Coronary Artery Disease; Coronary Circulation; Cross-Over Studies; Microcirculation; Microvascular Angina; Myocardial Ischemia; Phenotype; Ranolazine; Middle Aged; Aged
PubMed: 37905403
DOI: 10.1161/CIRCULATIONAHA.123.066680 -
Journal of Hypertension Oct 2023Microcirculation is pervasive and orchestrates a profound regulatory cross-talk with the surrounding tissue and organs. Similarly, it is one of the earliest biological...
The importance of microvascular inflammation in ageing and age-related diseases: a position paper from the ESH working group on small arteries, section of microvascular inflammation.
Microcirculation is pervasive and orchestrates a profound regulatory cross-talk with the surrounding tissue and organs. Similarly, it is one of the earliest biological systems targeted by environmental stressors and consequently involved in the development and progression of ageing and age-related disease. Microvascular dysfunction, if not targeted, leads to a steady derangement of the phenotype, which cumulates comorbidities and eventually results in a nonrescuable, very high-cardiovascular risk. Along the broad spectrum of pathologies, both shared and distinct molecular pathways and pathophysiological alteration are involved in the disruption of microvascular homeostasis, all pointing to microvascular inflammation as the putative primary culprit. This position paper explores the presence and the detrimental contribution of microvascular inflammation across the whole spectrum of chronic age-related diseases, which characterise the 21st-century healthcare landscape. The manuscript aims to strongly affirm the centrality of microvascular inflammation by recapitulating the current evidence and providing a clear synoptic view of the whole cardiometabolic derangement. Indeed, there is an urgent need for further mechanistic exploration to identify clear, very early or disease-specific molecular targets to provide an effective therapeutic strategy against the otherwise unstoppable rising prevalence of age-related diseases.
Topics: Humans; Inflammation; Arteries; Chronic Disease; Microcirculation
PubMed: 37382158
DOI: 10.1097/HJH.0000000000003503 -
Current Cardiology Reports Aug 2023Current non-invasive tests for evaluating patients with peripheral artery disease (PAD) have significant limitations for early detection and management of patients with... (Review)
Review
PURPOSE OF REVIEW
Current non-invasive tests for evaluating patients with peripheral artery disease (PAD) have significant limitations for early detection and management of patients with PAD and are generally focused on the evaluation of large vessel disease. PAD often involves disease of microcirculation and altered metabolism. Therefore, there is a critical need for reliable quantitative non-invasive tools that can assess limb microvascular perfusion and function in the setting of PAD.
RECENT FINDINGS
Recent developments in positron emission tomography (PET) imaging have enabled the quantification of blood flow to the lower extremities, the assessment of the viability of skeletal muscles, and the evaluation of vascular inflammation and microcalcification and angiogenesis in the lower extremities. These unique capabilities differentiate PET imaging from current routine screening and imaging methods. The purpose of this review is to highlight the promising role of PET in the early detection and management of PAD providing a summary of the current preclinical and clinical research related to PET imaging in patients with PAD and related advancement of PET scanner technology.
Topics: Humans; Peripheral Arterial Disease; Positron-Emission Tomography; Lower Extremity; Muscle, Skeletal; Microcirculation
PubMed: 37314651
DOI: 10.1007/s11886-023-01904-8