Microvascular Disturbances Research Articles

Microvascular blood flow disturbances predict poor outcome of revascularization in CLTI patients

Abstract Background We have recently established hypoxic microvascular remodelling as a critical pathomechanistic factor that limits oxygen diffusion to muscle in chronic limb threatening ischaemia (CLTI). Using animal models of experimental hind limb ischaemia we have also displayed the biological relevance of post-ischaemic microvascular remodelling in skeletal muscle. Our results indicate that differential microvascular changes associate to muscle damage and repair. The natural microvascular dynamics that inherently promote muscle recovery are defected in CLTI patients. Particularly, a progressive arterialization of capillaries in CLTI muscle differentiates the dynamics of the microvasculature from initially assisting muscle regeneration to aggravating ischaemic damage. Methods To establish the clinical relevance of the post-ischaemic microvascular changes in CLTI, we now have studied the effect of microvascular remodelling on the outcome of CLTI patients undergoing surgical or endovascular revascularization. Contrast enhanced ultrasound was used preoperatively to determine the microvascular status of CLTI patients (n=36) scheduled for immediate revascularization. Outcome events such as: hospitalization; reoperation; leg amputation; or death, were postoperatively followed from medical records up to 6 months after revascularization. Patients were grouped according to muscle capillary transit time (Tct) being either similar (n=18) or shorter (n=18) to that in the contralateral legs of the patients, and treatment outcomes were compared between groups. Results The results display consistent increases in postoperative event rates in all measured outcomes in the ShortTct group as compared to controls (at 1 month 8 vs. 2 events (rate ratio 4.00 (95%CI: 0.85-18.84, p=0.080)); at 3 months 13 vs. 4 events (rate ratio 3.25 (95%CI: 1.06-9.97, p=0.039)); at 6 months 17 vs. 9 events (rate ratio 1.89 (95%CI: 0.84-4.24, p=0.123))). For example, 5 vs. 0; 7 vs. 1; and 7 vs. 4 reoperations were detected in the ShortTct group as compared to controls at 1, 3 and 6 months, respectively. By 6 months after initial revascularization also 2 deaths were recorded in the ShortTct group as compared to no deaths in the controls. Conclusions Despite still small samples size in this study, these results suggest that microvascular blood flow disturbances, such as short preoperative muscle capillary transit time, can predict poor outcome of CLTI patients after revascularization. Importantly, the results also identify patients with microvascular blood flow disturbances a subgroup of CLTI patients that should likely receive more specialized care to improve outcomes. The results also call for immediate actions from the scientific community to improve clinical detection of microvascular alterations and to develop strategies to normalize microvascular function in CLTI patients.

Multiple organ failure: What you need to know.

Multiple organ failure (MOF) remains a significant challenge for the acute care surgeon, often leading to poor patient outcomes. This comprehensive review explores the etiology, pathophysiology, clinical presentation, diagnosis, management strategies, prognosis, and prevention strategies associated with MOF and chronic critical illness. Understanding the intricate etiology and pathophysiology of MOF and chronic critical illness is essential for effectively managing these syndromes and developing targeted treatment strategies aimed at mitigating the underlying inflammatory, immune, and microvascular disturbances, in order to redirect patients onto a trajectory of recovery.

Treating ischemic stroke by improving vascular structure and promoting angiogenesis using Taohong Siwu Decoction: An integrative pharmacology strategy

Ethnopharmacological relevanceNeovessels represent a crucial therapeutic target and strategy for repairing ischemic tissue. Taohong Siwu Decoction (THSWD) exhibits potential in promoting angiogenesis to address ischemic stroke (IS). However, its impact on neovessel structure and function, alongside the underlying molecular mechanisms, remains elusive. Aim of the studyOur aim is to investigate the protective effects of THSWD on neovessel structure and function, as well as the associated molecular mechanisms, utilizing an integrative pharmacological approach. Materials and methodsWe initially employed behavioral tests, 2,3,5-triphenyltetrazolium chloride (TTC) staining, Haematoxylin-eosin (HE) staining, enzyme-linked immunosorbent assay (ELISA), Laser Doppler flowmetry (LDF), Evans blue staining, and immunofluorescence to evaluate the protective effects of THSWD on neovascular structure and function in middle cerebral artery occlusion/reperfusion (MCAO/R) rats. Subsequently, we utilized network pharmacology, metabolomics, and experimental validation to elucidate the underlying molecular mechanisms of THSWD in enhancing neovascular structure and function. ResultIn addition to significantly reducing neurological deficits and cerebral infarct volume, THSWD mitigated pathological damage, blood-brain barrier (BBB) leakage, and cerebral blood flow disruption. Moreover, it preserved neovascular structure and stimulated angiogenesis. THSWD demonstrated potential in ameliorating cerebral microvascular metabolic disturbances including lipoic acid metabolism, fructose and mannose metabolism, purine metabolism, and ether lipid metabolism. Consequently, it exhibited multifaceted therapeutic effects, encompassing anti-inflammatory, antioxidant, energy metabolism modulation, and antiplatelet aggregation properties. ConclusionTHSWD exhibited protective effects on cerebral vascular structure and function and facilitated angiogenesis by rectifying cerebral microvascular metabolic disturbances in MCAO/R rats. Furthermore, integrated pharmacology offers a promising approach for studying the intricate traditional Chinese medicine (TCM) system in IS treatment.

Chagas Cardiomyopathy and Myocardial Sympathetic Denervation.

More than a century since its discovery, the pathogenesis of Chagas heart disease (CHD) remains incompletely understood. The role of derangements in the autonomic control of the heart in triggering malignant arrhythmia before the appearance of contractile ventricular impairment was reviewed. Although previous investigations had demonstrated the anatomical and functional consequences of parasympathetic dysautonomia upon the heart rate control, only recently, coronary microvascular disturbances and sympathetic denervation at the ventricular level have been reported in patients and experimental models of CHD, exploring with nuclear medicine methods their impact on the progression of myocardial dysfunction and cardiac arrhythmias. More important than parasympathetic impaired sinus node regulation, recent evidence indicates that myocardial sympathetic denervation associated with coronary microvascular derangements is causally related to myocardial injury and arrhythmia in CHD. Additionally, 123I-MIBG imaging is a promising tool for risk stratification of progression of ventricular dysfunction and sudden death.

Abstract 13494: Histopathological Analysis Indicates a Significant Role of Myocardial Perfusion Disturbance in Tissue Lesion in Chronic Chagas’ Cardiomyopathy Experimental Model

Introduction: Coronary microvascular perfusion disturbance (MPD) is frequently found in Chronic Chagas' cardiomyopathy (CCC), but its role in tissue lesion and left ventricular dysfunction progression is still unclear. Hypothesis: As MPD is associated with more severe subendocardial myocardial injury, we tested the hypothesis that histopathological changes in subendocardial layer could be quantitatively correlated to MPD in experimental model of CCC in hamsters. Methods: Female Syrian hamsters (n=23) infected with 3.5x10 4 blood trypomastigote forms of T. cruzi ( Y strain ) and their respective controls (n=6) were studied. At 8 months after infection, the animals underwent in vivo high-resolution myocardial rest perfusion scintigraphy with 99m Tc-Sestamibi and transthoracic echocardiography. After euthanasia, the myocardial tissue was processed for quantitative histopathological analysis of mononuclear infiltrate index (MII) using hematoxylin-eosin staining and myocardial fibrosis using picrosirius staining in LV wall layers: subendocardium, mesocardium and subepicardium. Results: Fourteen animals (61%) presented rest MPD. The area of MPD was negatively correlated with LVEF (R=-0.5; p=0.02), and positively correlated with LV diastolic diameter (R=0.83; p<0.01). Animals with MPD exhibited increased extent of myocardial fibrosis in the subendocardial layer (0.67 + 0.18%) as compared to control animals (0.47 + 0.15%), p=0.03. However, the extent of total transmural fibrosis or fibrosis in other myocardial layers were similar among groups. The group with MPD presented higher values of MII in every myocardial layer as compared to controls and animals without MPD. However, only the MII in the subendocardial layer presented positive correlation with the extent of rest MPD (R=0.55, p=0.001). Conclusions: Our results indicate that MPD is significantly correlated with histopathological changes located in the subendocardial layer of LV walls. These results suggest that MPD may act as an amplifying and localizing factor for inflammation and fibrosis, suggesting a relevant role for myocardial hypoperfusion in the mechanisms of myocardial injury in CCC.

Vascular Endothelial Growth Factor as Potential Biomarker for COVID-19 Severity.

COVID-19 is characterized by immunological responses to viral replication and coherent with endothelitis, microvascular disturbance of lung vasculature and coagulopathy. Vascular Endothelial Growth Factor (VEGF) is a proangiogenic mediator regulating endothelial changes. It is induced by proinflammatory signaling and hypoxia. We sought to determine whether VEGF levels differ between SARS-CoV-2-positive patients of different disease severity and whether VEGF might be useful in risk stratification. After retrospective screening of all SARS-CoV-2-positive patients treated in Unfallkrankenhaus Berlin in 2020, we included those with documented VEGF measurement. We extracted laboratory values and clinical parameters. An exploratory data analysis was performed to detect possible relations between VEGF level and clinical disease features. We included 167 SARS-CoV-2-positive patients of which 139 suffered from COVID-19. Seventy-one of the COVID-19 patients had to be treated in the intensive care unit (ICU), those patients exhibited higher VEGF levels than those being admitted to normal wards (535 vs 279 pg/L, P < .001). APACHE-2 (Acute Physiology And Chronic Health Evaluation Score) correlated with mortality and patients with high values showed higher VEGF concentrations on admission (456 vs 875 pg/L, p = 0.006). Receiver operating characteristic analytic revealed that the occurrence of organ dysfunctions like acute respiratory distress syndrome (ARDS), shock, or acute kidney injury could be predicted by VEGF. It was significantly higher in patients who later died compared to survivors (637 vs 389 pg/mL, P = 0.041) and predicted mortality with same accuracy as established markers. In our cohort, association of VEGF above 277 pg/L on admission with risk of ARDS could be confirmed in logistic regression adjusting for possible confounding factors (odds ratio 3.1, 95% confidence interval: 1.34-7.7). Even though there are several limitations to this retrospective study it revealed that in COVID-19 patients VEGF can contribute to the prediction of necessity of ICU, mortality and the prediction of ARDS, kidney injury or shock. Its use in risk stratification and potential pathogenetic involvement should be further investigated.

Hemorheological and microvascular disturbances in patients with type 2 diabetes mellitus.

In the blood vessels the impaired hemorheological parameters in patients with type 2 diabetes mellitus (T2DM) could lead to elevated flow resistance, increased forces at the endothelial wall and to microvascular disturbances. The aim of the study is to investigate the hemorheological variables and the changes of the skin blood flow responses to cold stress in T2DM patients. The basic hemorheological parameters: hematocrit (Ht), fibrinogen (Fib), whole blood viscosity (WBV) and plasma viscosity (PV) were examined in 20 patients with T2DM and a control group of 10 healthy age and sex matched controls. The mechanisms of vascular tone regulation were investigated using the wavelet analysis of the skin temperature oscillations (WAST). The degrees of the microvascular tone changes were determined during a cold test in the endothelial (0.02-0.0095 Hz), neurogenic (0.05- 0.02 Hz) and myogenic (0.05- 0.14 Hz) frequency ranges. Significant increase of Fib and WBV in the patients in comparison to controls was found. The mean values of the amplitudes of the skin temperature (ST) pulsations decreased significantly during the cold stress only in the endothelial frequency range for the diabetic patients. The results of our study reveal parallel impairment of the blood rheological parameters and the cutaneous microcirculation in T2DM patients.

Focal Nodular Hyperplasia and Focal Nodular Hyperplasia-like Lesions.

Focal nodular hyperplasia (FNH) is a benign lesion occurring in a background of normal liver. FNH is seen most commonly in young women and can often be accurately diagnosed at imaging, including CT, MRI, or contrast-enhanced US. In the normal liver, FNH frequently must be differentiated from hepatocellular adenoma, which although benign, is managed differently because of the risks of hemorrhage and malignant transformation. When lesions that are histologically identical to FNH occur in a background of abnormal liver, they are termed FNH-like lesions. These lesions can be a source of diagnostic confusion and must be differentiated from malignancies. Radiologists' familiarity with the imaging appearance of FNH-like lesions and knowledge of the conditions that predispose a patient to their formation are critical to minimizing the risks of unnecessary intervention for these lesions, which are rarely symptomatic and carry no risk for malignant transformation. FNH is thought to form secondary to an underlying vascular disturbance, a theory supported by the predilection for formation of FNH-like lesions in patients with a variety of hepatic vascular abnormalities. These include abnormalities of hepatic outflow such as Budd-Chiari syndrome, abnormalities of hepatic inflow such as congenital absence of the portal vein, and hepatic microvascular disturbances, such as those that occur after exposure to certain chemotherapeutic agents. Familiarity with the imaging appearances of these varied conditions and knowledge of their association with formation of FNH-like lesions allow radiologists to identify with confidence these benign lesions that require no intervention. Online supplemental material is available for this article. ©RSNA, 2022.

Pentoxifylline Reduces Inflammation And Myocardial Perfusion Derangements In Experimental Chronic Chagas Cardiomyopathy In Hamsters.

Introduction Microvascular perfusion disturbance (MPD) is common in chronic Chagas cardiomyopathy (CCC) and may cause myocardial damage. Hypothesis Pentoxifylline (PT) is a phosphodiesterase inhibitor with anti-inflammatory properties that may lead to reduction of inflammation and MPD and attenuate the progression of the myocardial dysfunction in CCC. Methods We investigated 3 groups of hamsters: controls and treated with saline (CO, n=9), infected with T. cruzi and treated with saline (CH+SL, n=12), infected and treated with PT (CH+PT, n=12). After 6 months of infection and 60 days of PT (20 mg/kg/day, ip) or saline, the animals were submitted to echocardiography and to rest Sestamibi-Tc99m SPECT myocardial perfusion scintigraphy (MPS). The area of myocardial perfusion defects (PD) was assessed through the calculation of polar maps. After euthanasia, we performed a histopathological study of cardiac inflammation and gene expression of TNF-α. Results At baseline all groups showed similar areas of PD (CO: 0.0±0.0%, CH+SL:0.8±1.6%, CH+PT:1.9±3.0%, p>0.05) and LVEF (CO:53.4±5.6%, CH+SL:47.0±10.1%, CH+PT:53.9±6.5%, p>0.05). After treatment, there was a significant increase of the PD only in the CH+SL group (0.8±1.6 to 9.4±9.7%, p>0.05), and CH+PT animals exhibited PD area similar to CO animals 2.7±2.7% and 0.0±0.0%, respectively (p>0.05). Similar decrease of LVEF was seen in both infected groups: (CH+SL:40.0±13.7% and CH+PT:42.7±9.0%). No change of the LVEF was observed in CO (53.4±5.6%). Quantitative histological analysis revealed a larger number of nuclei of mononuclear inflammatory cells in CH+SL, 615.1±133.0 cel/mm² and CH+PT groups, 395.7±88.3 cel/mm² when compared to CO, 193.0 ± 25.7 cel/mm², p<0.001. A higher number of inflammatory cells was found in the CH+SL group when compared to the CH+PT group, p<0.001. TNF-α expression was higher in the CH+SL group (2.5±1.7) when compared to the CO (0.9±0.4), but similar to the CH+PT (2.4±1.7), p>0.9. There was a moderate correlation between PD and inflammatory cells (R=0.6) and LVEF (R=-0.7), p<0.0001 for both; and between LVEF and inflammatory cells (R=-0.4, p=0.01). Conclusions The prolonged use of PT in CCC animals was effective in reducing inflammation and progression of MPD evaluated in vivo. However, PT did not prevent the progression of left ventricular systolic dysfunction in this model. These results suggest that PD may represent a surrogate marker for inflammation and its potential use to monitor disease progression. Microvascular perfusion disturbance (MPD) is common in chronic Chagas cardiomyopathy (CCC) and may cause myocardial damage. Pentoxifylline (PT) is a phosphodiesterase inhibitor with anti-inflammatory properties that may lead to reduction of inflammation and MPD and attenuate the progression of the myocardial dysfunction in CCC. We investigated 3 groups of hamsters: controls and treated with saline (CO, n=9), infected with T. cruzi and treated with saline (CH+SL, n=12), infected and treated with PT (CH+PT, n=12). After 6 months of infection and 60 days of PT (20 mg/kg/day, ip) or saline, the animals were submitted to echocardiography and to rest Sestamibi-Tc99m SPECT myocardial perfusion scintigraphy (MPS). The area of myocardial perfusion defects (PD) was assessed through the calculation of polar maps. After euthanasia, we performed a histopathological study of cardiac inflammation and gene expression of TNF-α. At baseline all groups showed similar areas of PD (CO: 0.0±0.0%, CH+SL:0.8±1.6%, CH+PT:1.9±3.0%, p>0.05) and LVEF (CO:53.4±5.6%, CH+SL:47.0±10.1%, CH+PT:53.9±6.5%, p>0.05). After treatment, there was a significant increase of the PD only in the CH+SL group (0.8±1.6 to 9.4±9.7%, p>0.05), and CH+PT animals exhibited PD area similar to CO animals 2.7±2.7% and 0.0±0.0%, respectively (p>0.05). Similar decrease of LVEF was seen in both infected groups: (CH+SL:40.0±13.7% and CH+PT:42.7±9.0%). No change of the LVEF was observed in CO (53.4±5.6%). Quantitative histological analysis revealed a larger number of nuclei of mononuclear inflammatory cells in CH+SL, 615.1±133.0 cel/mm² and CH+PT groups, 395.7±88.3 cel/mm² when compared to CO, 193.0 ± 25.7 cel/mm², p<0.001. A higher number of inflammatory cells was found in the CH+SL group when compared to the CH+PT group, p<0.001. TNF-α expression was higher in the CH+SL group (2.5±1.7) when compared to the CO (0.9±0.4), but similar to the CH+PT (2.4±1.7), p>0.9. There was a moderate correlation between PD and inflammatory cells (R=0.6) and LVEF (R=-0.7), p<0.0001 for both; and between LVEF and inflammatory cells (R=-0.4, p=0.01). The prolonged use of PT in CCC animals was effective in reducing inflammation and progression of MPD evaluated in vivo. However, PT did not prevent the progression of left ventricular systolic dysfunction in this model. These results suggest that PD may represent a surrogate marker for inflammation and its potential use to monitor disease progression.

Basic mechanisms in cardiogenic shock: part 1-definition and pathophysiology.

Cardiogenic shock mortality rates remain high despite significant advances in cardiovascular medicine and the widespread uptake of mechanical circulatory support systems. Except for early invasive angiography and percutaneous coronary intervention of the infarct-related artery, the most widely used therapeutic measures are based on low-quality evidence. The grim prognosis and lack of high-quality data warrant further action. Part 1 of this two-part educational review defines cardiogenic shock and discusses current treatment strategies. In addition, we summarize current knowledge on basic mechanisms in the pathophysiology of cardiogenic shock, focusing on inflammation and microvascular disturbances, which may ultimately be translated into diagnostic or therapeutic approaches to improve the outcome of our patients.

Nicotinamide adenine dinucleotide fluorescence to assess microvascular disturbances in post-COVID-19 patients.

Nicotinamide adenine dinucleotide fluorescence to assess microvascular disturbances in post-COVID-19 patients.

Iptakalim improves cerebral microcirculation in mice after ischemic stroke by inhibiting pericyte contraction.

Pericytes are present tight around the intervals of capillaries, play an essential role in stabilizing the blood-brain barrier, regulating blood flow and immunomodulation, and persistent contraction of pericytes eventually leads to impaired blood flow and poor clinical outcomes in ischemic stroke. We previously show that iptakalim, an ATP-sensitive potassium (K-ATP) channel opener, exerts protective effects in neurons, and glia against ischemia-induced injury. In this study we investigated the impacts of iptakalim on pericytes contraction in stroke. Mice were subjected to cerebral artery occlusion (MCAO), then administered iptakalim (10 mg/kg, ip). We showed that iptakalim administration significantly promoted recovery of cerebral blood flow after cerebral ischemia and reperfusion. Furthermore, we found that iptakalim significantly inhibited pericytes contraction, decreased the number of obstructed capillaries, and improved cerebral microcirculation. Using a collagen gel contraction assay, we demonstrated that cultured pericytes subjected to oxygen-glucose deprivation (OGD) consistently contracted from 3 h till 24 h during reoxygenation, whereas iptakalim treatment (10 μM) notably restrained pericyte contraction from 6 h during reoxygenation. We further showed that iptakalim treatment promoted K-ATP channel opening via suppressing SUR2/EPAC1 complex formation. Consequently, it reduced calcium influx and ET-1 release. Taken together, our results demonstrate that iptakalim, targeted K-ATP channels, can improve microvascular disturbance by inhibiting pericyte contraction after ischemic stroke. Our work reveals that iptakalim might be developed as a promising pericyte regulator for treatment of stroke.

Polycythemia Vera: Is It Time to Rethink Treatment?

Introduction Polycythemia vera (PV) is the most frequent among the Philadelphia-negative myeloproliferative neoplasms (MPNs).1 PV is characterized by excessive myeloid cells production secondary to mutations in the Janus kinase 2 (JAK2) gene.2,3 The incidence rate is higher in the sixth decade of life and among males.4 Clinical phenotype is dominated by systemic symptoms, pruritus, and microvascular disturbances; splenomegaly may be detected in 30% of cases.5 In the long term, what impacts outcomes is the increased risk of thrombosis and evolution into post-PV myelofibrosis (PPV-MF) or blast phase (BP).6

Short and Long-Term Risk of Major Cardiovascular Events after Ischemic Stroke or Transient Ischemic Attack in Myeloproliferative Neoplasms

BACKGROUND. Very few previous studies have estimated the risk of recurrence after cerebral transient ischemic attack (TIA) or ischemic stroke (IS) in patients with myeloproliferative neoplasms (MPN). PRISM (Preventing Ischemic Stroke in Myeloproliferative Neoplasms) is an international investigator-driven study with three purposes: (1) to describe the clinical profile at presentation of ischemic TIA/IS in contemporary patients with polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF); (2) to evaluate the short and long-term outcomes beyond the acute phase and to explore their comparability with non MPN population; (3) to refine the risk assessment for recurrences and cardiovascular mortality.METHODS. From January 2005 through December 2015, 597 patients with objectively proven TIA (n= 270) or IS (n=327) at 22 sites of 5 countries were enrolled. We estimated the 1- and 5-year risk of composite cardiovascular (CV) outcome, including recurrent TIA, IS, myocardial infarction (AMI) and CV deaths, and analyzed the incidence of each single outcome by competing risk method.RESULTS. The distribution of single MPN and baseline blood counts were similar in IS and TIA groups; atrial fibrillation was observed in a minority of cases (4% TIA and 7% IS) as compared with the general population (11-18% and 20%-30%, respectively); other comorbidities were approximately half of those of non-MPN patients [ Weimar C et al, Arch Neurol 2002;59:1584; Buchwald F et al, Stroke 2016;47:2456; Amarenco P et al, N Engl J Med 2016;374:1533 ]; a substantial proportion of TIA cases had a higher history of microvascular disturbances while arterial hypertension was more frequent in IS than TIA. Secondary prophylaxis included aspirin, oral anticoagulants and cytoreductive therapy.After one year since the TIA index event, the incidence of cumulative outcome was 4.21%. However, no IS happened in the first 2 years after TIA and this event after 5 years happened in only 1.24% of cases. The corresponding incidence in the general population was 4.4% to 5.1% after one year and 12-16% after 5 years [ Weimar C et al, Arch Neurol 2002;59:1584; Buchwald F et al, Stroke 2016;47:2456; Amarenco P et al, N Engl J Med 2016;374:1533 ]. In contrast, new TIA episodes progressively increased year by year reaching 12% incidence after 5 years.After the IS index event, new strokes occurred with cumulative incidence lower than in the general population: after 1 and 5 years, the incidence was 2.03% and 6.52% vs 11.1%-12% and 26.4% of non-MPN patients [ Mohan KM et al, Stroke 2011;42:1489; Bergstrom L et al, Stroke 2017 Jul 13, AOP ]. The rate of deep venous thrombosis (DVT) in the first year, was higher after index IS than TIA, but was the same by 5 years (3.68% and 4.60%, respectively; p=0.47).Predictors of recurrent TIA and IS were the same index events (HR=2.41 and 4.41), and for recurrent TIA the remote history of cerebrovascular TIA episodes (HR=3.40) and microvascular disturbances (HR=2.30). Other prognostic factors of recurrent IS were arterial hypertension (HR=4.24) and occurrence of IS during the course of MPN (HR=4.27). On the contrary, cytoreductive therapy emerged as a strong protective factor able to reduce the probability of new strokes in 76% of patients (HR=0.24). The history of peripheral thrombosis, both venous and arterial events, independently predicted the occurrence of AMI (HR=6.30), while age over 60 years (HR=3.98), index IS (HR=3.61), occurrence after MPN diagnosis (HR=2.62), were all prognostically significant for CV mortality. During median follow-up of 4.2 years, major bleeding occurred with a frequency similar to that observed in the general population receiving long-term antiplatelet secondary prophylaxis (0.90 % pts/year) [ Li L et al, Lancet 2017 Jun 13, AOP ].CONCLUSION. Current antithrombotic therapy and cytoreductive drugs after index TIA and IS led to a reduction of cardio-vascular recurrences and mortality in a proportion of MPN patients greater than in general population. This would indicate that ischemic cerebral vascular events recognize a specific pathogenesis of thrombosis linked to the clonal disorder. Although the benefit-risk profile of secondary prophylaxis appears favorable, some high risk categories need new intervention strategies to be defined in prospective studies. DisclosuresIurlo:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Finazzi:Italfarmaco S.p.A.: Consultancy. Bonifacio:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Gaidano:Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Vannucchi:Shire: Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

MO226A NEW DIAGNOSTIC TOOL FOR CKD PATIENTS: CONTRAST-ENHANCED ULTRASONOGRAPHY. A SINGLE CENTER EXPERIENCE

Abstract Background and Aims Contrast-enhanced ultrasonography (CEUS) is a minimally invasive diagnostic tool available for diagnosing microvascular disturbances in tumors and many vascular pathologies. Unlike other radiological contrast agents, it is completely harmless for CKD patients and therefore it is used for the safe diagnosis of many diffuse or focal pathologies. Method We used CEUS examination in 50 CKD patients for the following pathologies: 10 atypical cysts, 15 liver focal lesions, 2 splenic focal lesions, 3 renal infarcts, 12 kidney focal lesions and 8 other organ involvements. Examination was made using a VOLUSON E8 machine (GE Medical System Kreztechnik GmbH Tiefenbach 15, Austria) with a 3.5 MHz convex array abdominal transducer. 2.4 ml of microbubble contrast-agent was administered intravenously and recording of the results were made for 3-5 minutes after injection. Results Depending on the organ vascular characteristics, contrast enhancement and/or wash-out were suggestive for the final diagnosis. In liver lesions there are three phases and in kidneys, spleen, gallbladder, adenopathies there are two vascular phases. We obtained a very good positive predictive value and sensitivity in detecting malignant lesions. Conclusion According to The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound they are used both for hepatic and Non-Hepatic Applications. Being non-invasive and non-irradiating it could be the main diagnostic examination in CKD population in the future.

Chagas Cardiomyopathy: From Romaña Sign to Heart Failure and Sudden Cardiac Death.

Despite nearly a century of research and accounting for the highest disease burden of any parasitic disease in the Western Hemisphere, Chagas disease (CD) is still a challenging diagnosis, primarily due to its poor recognition outside of Latin America. Although initially considered endemic to Central and South America, globalization, urbanization, and increased migration have spread the disease worldwide in the last few years, making it a significant public health threat. The international medical community’s apparent lack of interest in this disease that was previously thought to be geographically restricted has delayed research on the complex host–parasite relationship that determines myocardial involvement and its differential behavior from other forms of cardiomyopathy, particularly regarding treatment strategies. Multiple cellular and molecular mechanisms that contribute to degenerative, inflammatory, and fibrotic myocardial responses have been identified and warrant further research to expand the therapeutic arsenal and impact the high burden attributed to CD. Altogether, cardiac dysautonomia, microvascular disturbances, parasite-mediated myocardial damage, and chronic immune-mediated injury are responsible for the disease’s clinical manifestations, ranging from asymptomatic disease to severe cardiac and gastrointestinal involvement. It is crucial for healthcare workers to better understand CD transmission and disease dynamics, including its behavior on both its acute and chronic phases, to make adequate and evidence-based decisions regarding the disease. This review aims to summarize the most recent information on the epidemiology, pathogenesis, clinical presentation, diagnosis, screening, and treatment of CD, emphasizing on Chagasic cardiomyopathy’s (Ch-CMP) clinical presentation and pathobiological mechanisms leading to sudden cardiac death.

Impaired cerebral microcirculation in isolated REM sleep behaviour disorder.

During the prodromal period of Parkinson's disease and other α-synucleinopathy-related parkinsonisms, neurodegeneration is thought to progressively affect deep brain nuclei, such as the locus coeruleus, caudal raphe nucleus, substantia nigra, and the forebrain nucleus basalis of Meynert. Besides their involvement in the regulation of mood, sleep, behaviour, and memory functions, these nuclei also innervate parenchymal arterioles and capillaries throughout the cortex, possibly to ensure that oxygen supplies are adjusted according to the needs of neural activity. The aim of this study was to examine whether patients with isolated REM sleep behaviour disorder, a parasomnia considered to be a prodromal phenotype of α-synucleinopathies, reveal microvascular flow disturbances consistent with disrupted central blood flow control. We applied dynamic susceptibility contrast MRI to characterize the microscopic distribution of cerebral blood flow in the cortex of 20 polysomnographic-confirmed patients with isolated REM sleep behaviour disorder (17 males, age range: 54-77 years) and 25 healthy matched controls (25 males, age range: 58-76 years). Patients and controls were cognitively tested by Montreal Cognitive Assessment and Mini Mental State Examination. Results revealed profound hypoperfusion and microvascular flow disturbances throughout the cortex in patients compared to controls. In patients, the microvascular flow disturbances were seen in cortical areas associated with language comprehension, visual processing and recognition and were associated with impaired cognitive performance. We conclude that cortical blood flow abnormalities, possibly related to impaired neurogenic control, are present in patients with isolated REM sleep behaviour disorder and associated with cognitive dysfunction. We hypothesize that pharmacological restoration of perivascular neurotransmitter levels could help maintain cognitive function in patients with this prodromal phenotype of parkinsonism.

Post-treatment with yiqifumai injection and its main ingredients attenuates lipopolysaccharide-induced microvascular disturbance in mesentery and ileum.

To investigate the effect of Yiqifumai injection (YQFM), a compound Chinese medicine, and its main active ingredients on lipopolysaccharide (LPS)-induced microvascular disturbance in mesentery and ileum. Rats were infused with LPS (5mg/kg/h) for 90min. Thirty minutes after initiation of LPS administration, YQFM (160mg/kg/h), Rb1 (5mg/kg/h), Sch (2.5mg/kg/h), or Rb1+Sch (5mg/kg/h+2.5mg/kg/h) was infused until 90min. Human umbilical vein endothelial cells (HUVECs) were incubated with LPS (100ng/ml) for 90min. YQFM (1mg/ml), Rb1 (100µM), Sch (100µM), or Rb1+Sch (200µM) was added 30min after initiation of LPS stimulation. Yiqifumai injection and Rb1+Sch inhibited mesenteric venule hyperpermeability, suppressed microvillar erosion and submucosal edema, and protected claudin-5 from downregulation and interleukin-1β from upregulation in ileal tissues after LPS. Study in HUVECs confirmed the effect of YQFM and Rb1+Sch on JAM-1 after LPS and revealed a similar effect on other junction proteins. Moreover, YQFM and Rb1+Sch attenuated the dysfunctional energy metabolism and the activation of TLR-4/Src/NF-κB signaling with Rb1 and Sch being partially effective. These results demonstrated the beneficial effect of post-treatment with YQFM, which is attributable to its main ingredient Rb1 and Sch, and likely mediated by targeting TLR-4/Src/NF-κB signaling pathway.

Histopathological Analysis of the Pro-Arrhythmogenic Changes in a Suspected Chagas Disease Sudden Death

Background Sudden death is the principal cause of fatality in Chagas disease, afflicting to non-symptomatic patients younger than 50-years. For this, sudden death associated with chagasic malignant arrhythmias is underdiagnosed and their pathophysiological basis is poorly understood. Aims In this sense, this work aimed to analyze the histopathological alterations in cardiac structures specialized in the generation/conduction of action potential in an anatomopathological case of non-diagnosed sudden death living in a Chagasic endemic area. Methods The donor was a woman, 62-year-old, which ingressed without vital signs to the emergency room of “Antonio María Pineda” hospital, without any apparent antecedents of cardiac disease. The gross examination was normal, with no external evidence of structural/ischemic disease. Results Microscopic examination revealed nodal like cell depopulation, microvascular disturbances, chronic myocarditis with mononuclear and mast cell infiltrate plus extracellular matrix reaction, and profuse damage of neural structures placed in nodal region. Amastigote nest of Trypanosoma cruzi (T. cruzi) was detected. Conclusion These findings suggest a complex association among parasite persistence, sinus disease, micro-ischemia foci, and neural inflammation in the genesis of malignant arrhythmias of Chagas disease despite the absence of structural disease or massive necrosis. It is important to perform a protocol of examination for no explained sudden death cases in chagasic endemic countries, to avoid misdiagnosed of sudden death associated with Chagas disease.

Peripapillary perfused capillary density in true versus pseudoexfoliation syndrome: An OCTA study.

PurposeTo compare peripapillary perfused capillary density (PCD) among eyes with true exfoliation syndrome (TEX), eyes with pseudoexfoliation syndrome (PEX), and healthy control eyes.Materials and methodsIn this observational cross-sectional study, eyes with and without TEX or PEX were assessed by optical coherence tomography angiography (OCTA) imaging. Bilateral OCTA images (4.5 × 4.5 mm2) centered at the optic nerve head were obtained using a commercial spectral domain OCTA system. Optic nerve head perfusion was quantified using the split-spectrum amplitude decorrelation angiography algorithm. Categorical and continuous variables were compared using the chi-squared test and one-way analysis of variance, respectively. The generalized estimating equation was used to adjust for confounding factors and determine inter-ocular associations.ResultsWe enrolled 39 eyes with TEX, 31 eyes with PEX, and 32 control eyes. There were no significant differences among the three groups regarding age, intraocular pressure, cup-to-disc ratio, blood pressure, or axial length (all p>0.05). There were significant differences in global PCD among the three groups (p = 0.01). There were significant differences in annular PCD between the TEX and PEX groups (p = 0.027).ConclusionsWhile both global and annular PCDs did not differ between the TEX and control groups, greater loss of annular PCD in the PEX group than in the TEX and control groups suggests more pronounced microvascular disturbance in PEX.Synopsis/PrecisGreater microvascular attenuation in PEX compared with TEX and normal control measured by OCTA.