A review of the immune response stimulated by xenogenic tissue heart valves.

Valvular heart disease continues to afflict millions of people around the world. In many cases, the only corrective treatment for valvular heart disease is valve replacement. Valve replacement options are currently limited, and the most common construct utilized are xenogenic tissue heart valves. The main limitation with the use of this valve type is the development of valvular deterioration. Valve deterioration results in intrinsic permanent changes in the valve structure, often leading to hemodynamic compromise and clinical symptoms of valve re-stenosis. A significant amount of research has been performed regarding the incidence of valve deterioration and determination of significant risk factors for its development. As a result, many believe that the underlying driver of valve deterioration is a chronic immune-mediated rejection process of the foreign xenogenic-derived tissue. The underlying mechanisms of how this occurs are an area of ongoing research and active debate. In this review, we provide an overview of the important components of the immune system and how they respond to xenografts. A review of the proposed mechanisms of xenogenic heart valve deterioration is provided including the immune response to xenografts. Finally, we discuss the role of strategies to combat valve degeneration such as preservation protocols, epitope modification and decellularization.

Retrospective analysis of the hemodynamic consequences of prehospital supplemental oxygen in acute stroke.

OBJECTIVE: Hyperoxia, the delivery of high levels of supplemental oxygen (sO2) despite normoxia, may increase cerebral oxygenation to penumbral tissue and improve stroke outcomes. However, it may also alter peripheral hemodynamic profiles with potential negative effects on cerebral blood flow (CBF). This study examines the hemodynamic consequences of prehospital sO2 in stroke. METHODS: A retrospective analysis of adult acute stroke patients (aged ≥18 years) presenting via EMS to an academic Comprehensive Stroke Center between January 1, 2013 and December 31, 2017 was conducted using demographic and clinical characteristics obtained from Get with the Guidelines-Stroke registry and subjects' medical records. Outcomes were compared across three groups based on prehospital oxygen saturation and sO2 administration. Chi-square, ANOVA, and multivariable linear regression were used to determine if sO2 was associated with differences in peripheral hemodynamic profiles. RESULTS: All subjects had similar initial EMS vitals except for oxygen saturation. However, both univariate and multivariable analysis revealed that hyperoxia subjects had slightly lower average ED mean arterial pressures (MAP) compared to normoxia (Cohen's d = 0.313). CONCLUSIONS: Prehospital-initiated hyperoxia for acute stroke is associated with a small, but significant decrease in average ED MAP, without changes in heart rate, compared to normoxia. While limited by the inability to link changes in peripheral hemodynamical profiles directly to changes in CBF, this study suggests that hyperoxia may result in a relative hypotension. Further studies are needed to determine if this small change in peripheral vascular resistance translates into a clinically significant reduced CBF.

Baroreceptor denervation reduces inflammatory status but worsens cardiovascular collapse during systemic inflammation.

Beyond the regulation of cardiovascular function, baroreceptor afferents play polymodal roles in health and disease. Sepsis is a life-threatening condition characterized by systemic inflammation (SI) and hemodynamic dysfunction. We hypothesized that baroreceptor denervation worsens lipopolysaccharide (LPS) induced-hemodynamic collapse and SI in conscious rats. We combined: (a) hemodynamic and thermoregulatory recordings after LPS administration at a septic-like non-lethal dose (b) analysis of the cardiovascular complexity, (c) evaluation of vascular function in mesenteric resistance vessels, and (d) measurements of inflammatory cytokines (plasma and spleen). LPS-induced drop in blood pressure was higher in sino-aortic denervated (SAD) rats. LPS-induced hemodynamic collapse was associated with SAD-dependent autonomic disbalance. LPS-induced vascular dysfunction was not affected by SAD. Surprisingly, SAD blunted LPS-induced surges of plasma and spleen cytokines. These data indicate that baroreceptor afferents are key to alleviate LPS-induced hemodynamic collapse, affecting the autonomic control of cardiovascular function, without affecting resistance blood vessels. Moreover, baroreflex modulation of the LPS-induced SI and hemodynamic collapse are not dependent of each other given that baroreceptor denervation worsened hypotension and reduced SI.

Resuscitation From Hemorrhagic Shock With Fresh and Stored Blood and Polymerized Hemoglobin.

BACKGROUND: Hemoglobin (Hb)-based oxygen carriers (HBOCs) have been proposed as alternatives to blood for decades. Previous studies demonstrated that large molecular diameter HBOCs based on polymerized bovine Hb (PolybHb) attenuate Hb side-effects and toxicity. The objective of this study was to test the safety and efficacy of tense state PolybHb after long-term storage. METHODS AND RESULTS: PolybHb was subjected to diafiltration to remove low molecular weight (< 500 kDa) species and stored for 2 years. PolybHb was studied in parallel with blood, collected from rats and stored leukodepleted under blood bank conditions for 3 weeks. Rats were hemorrhaged and resuscitated to 90% of the blood pressure before the hemorrhage with fresh blood, stored blood, fresh PolybHb, or 2-year-stored PolybHb. Hemorrhagic shock impaired oxygen delivery and cardiac function. Resuscitation restored blood pressure and cardiac function, but stored blood required a significantly larger transfusion volume to recover from shock compared with fresh blood and PolybHb (fresh and stored). Stored blood transfusion elevated markers of organ damage compared with all other groups. CONCLUSIONS: These studies indicate that large molecular diameter PolybHb is as efficacious as fresh blood in restoring cardiac function and confirm the lack of degradation of PolybHb's safety or efficacy during long-term storage.

Microcirculation-guided protection strategy in hemodynamic therapy.

Microcirculatory shock is a condition defined by the presence of tissue hypoperfusion despite the normalization of systemic and regional blood flow. Currently, more evidence shows that intrinsic septic shock is microcirculatory shock, which results in septic shock that is difficult to resuscitate. At present, treatments are aimed at recovering macro-circulation functions and include fluid resuscitation, vasoactive drugs, positive inotropic drugs, de-obstruction, and even mechanical assistance to improve oxygen delivery. However, the application of these treatments to more accurately improve microcirculation or avoid further microcirculatory damage is more important in clinics. In this article, we discuss the need for microcirculation protection and microcirculation-guided protection strategies in hemodynamic therapies.

Autoimmune Disease-Associated Hypertension.

PURPOSE OF REVIEW: To highlight important new findings on the topic of autoimmune disease-associated hypertension. RECENT FINDINGS: Autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis are associated with an increased risk for hypertension and cardiovascular disease. A complex interaction among genetic, environmental, hormonal, and metabolic factors contribute to autoimmune disease susceptibility while promoting chronic inflammation that can lead to alterations in blood pressure. Recent studies emphasize an important mechanistic role for autoantibodies in autoimmune disease-associated hypertension. Moving forward, understanding how sex hormones, neutrophils, and mitochondrial dysfunction contribute to hypertension in autoimmune disease will be important. This review examines the prevalent hypertension in autoimmune disease with a focus on the impact of immune system dysfunction on vascular dysfunction and renal hemodynamics as primary mediators with oxidative stress as a main contributor.

Donor-specific antibodies are associated with micro- and macrovascular coronary disease, restrictive myocardial damage, and poor outcome in heart-transplanted patients.

AIMS: We examined the relationship between donor-specific HLA antibody (DSA) presence and graft function, hemodynamics, cardiac allograft vasculopathy (CAV), and major adverse cardiac events (MACE) in stable long-term heart-transplanted (HTx) patients. METHODS: Sera from 79 patients (median 7.5 years after HTx) were analyzed for DSA presence. Graft function was evaluated by echocardiography and right heart catheterization. CAV burden was determined by coronary angiography, optical coherence tomography (OCT), and coronary flow velocity reserve (CFVR). Patients were prospectively followed after DSA assessment. MACE included significant CAV progression, heart failure, treated rejection, and cardiovascular death. RESULTS: Sixty patients had no DSA, and 19 patients were sensitized. The vasculopathy burden by angiography, OCT, and CFVR was more pronounced in DSA-positive patients than in DSA-negative patients. DSA-positive patients had higher pulmonary capillary wedge pressure (16 [8; 21] vs 9 mm Hg [7; 11], P<.05) and right atrial pressure (8 [6; 9] vs 4 mm Hg [2; 6], P<.01) and lower global longitudinal strain (-13% [-10; -15] vs -16% [-14; -17], P<.01) than DSA-negative patients. DSA presence was a strong MACE predictor (HR 4.7 (95% CI 2.0-11.4), P<.001). CONCLUSIONS: DSA-positive patients had higher vasculopathy burden, higher filling pressures, and lower longitudinal myocardial deformation than DSA-negative patients. The DSA presence was a strong MACE predictor.

Haemodynamic improvement of older, previously replaced mechanical mitral valves by removal of the subvalvular pannus in redo cardiac surgery.

Patients requiring redo cardiac surgery for diseased heart valves other than mitral valves may show increased pressure gradients and reduced valve areas of previously placed mechanical mitral valves due to subvalvular pannus formation. We treated four women who had mechanical mitral valves inserted greater than or equal to 20 years earlier and who presented with circular pannus that protruded into the lower margin of the valve ring but did not impede leaflet motion. Pannus removal improved the haemodynamic function of the mitral valve.

Microcirculatory changes in children undergoing cardiac surgery: a prospective observational study.

BACKGROUND: The effects of cardiac surgery on the microcirculation of children are unknown. The aim of this study was to assess the microcirculatory changes in children undergoing surgery for correction of congenital heart disease. METHODS: We used a videomicroscope (Sidestream Dark Field, SDF) in a convenience sample of 24 children

Conjunctival microvascular hemodynamics following vaso-occlusive crisis in sickle cell disease.

Painful vaso-occlusive crisis (VOC) is the clinical hallmark of sickle cell disease (SCD). Microcirculatory hemodynamic changes following painful VOC may be indicative of future development of VOC events in subjects with SCD. The purpose of the present study was to determine alterations in conjunctival microvascular hemodynamics during non-crisis state in SCD subjects with a history of VOC. Conjunctival microcirculation imaging was performed to measure conjunctival diameter (D) and axial blood velocity (V) in 10 control and 30 SCD subjects. SCD subjects were categorized into two groups based on their history of VOC within a 2-year period before imaging (with or without VOC-H) and also based on whether there was progression in the rate of VOCs during a 2-year period following imaging as compared to before imaging (with or without VOC-P). Conjunctival V was significantly higher in SCD subjects with VOC-H than in both control subjects and SCD subjects without VOC-H (P≤0.03). Conjunctival V was also significantly higher in SCD subjects with VOC-P compared with control subjects and SCD subjects without VOC-P (P≤0.03). Assessment of the conjunctival microcirculation may be useful for understanding hemodynamic changes that lead to VOC events in SCD subjects.

Markers of immunity and bacterial translocation in cirrhosis.

Bacterial translocation (BT), the migration of enteric bacteria to extraintestinal sites, is related to immune stimulation and haemodynamic changes in experimental cirrhosis. These changes may be highly relevant to patients with cirrhosis, where changes in the circulation cause serious complications. The optimal surrogate marker of BT in patients with cirrhosis, however, is a matter of controversy. In the first study, we investigated the relationship between markers of inflammation, haemodynamics and prognosis in 45 patients and 12 controls. We found high-sensitive C-reactive protein to be correlated to portal hypertension, a clinically relevant haemodynamic alteration, and appeared to be associated with increased mortality. To assess the consequences of BT on immunity, we developed an assay for the detection of bacterial DNA (bDNA), a novel marker of BT. Using the assay in the second study, in 38 patients with ascites, we found no association between bDNA and immunity, in contrast to some previous findings. In the final paper, exploring one possible translocation route, we hypothesized a difference in bDNA levels between the blood from the veins draining the gut on one hand and the liver on the other. Collecting samples during the insertion of a shunt between the two vessels in 28 patients, our finding did not suggest marked differences in bDNA, but conversely to expectations, suggested marked hepatic production of two markers of inflammation. The main results of the present thesis support some concepts of current thinking on cirrhosis pathophysiology, including the relationship of markers of inflammation to  haemodynamics, disease stage and prognosis. Our results also add to a growing body of evidence suggesting that bDNA is not a clinically relevant marker of BT.

[Arterial hypertension: an expanding pathogenic continuum and therapeutic limitations].

The paper considers the role of the immune system, endoplasmic network stress, metabolic dysregulation, and epigenetic mechanisms in the pathogenesis of essential hypertension, as well as the limited possibilities of therapy with existing antihypertensive agents.

Myocardial infarction accelerates glomerular injury and microalbuminuria in diabetic rats via local hemodynamics and immunity.

BACKGROUND: Clinically, approximately one-third of patients with chronic heart failure (CHF) exhibit some degree of renal dysfunction. This renal dysfunction is referred to as cardiorenal syndrome (CRS) and plays an important role in the poor prognosis of CHF. Mounting evidence suggests that diabetes is the most common underlying risk factor for CRS. However, the underlying pathophysiological mechanisms are poorly understood. METHODS: We performed the following comparisons in two separate protocols: 1) surgically induced myocardial infarction rats (MI, n=10), sham operation rats (Ctr, n=10) and MI rats treated with Fasudil, a Rho-kinase inhibitor (MI+Fas, n=9); and 2) STZ-induced type 1 diabetic rats (DB, n=10), DB+MI rats (n=10) and DB+MI rats treated with Fasudil (DB+MI+Fas, n=9). Renal hemodynamics and vasoconstrictor reactivity were evaluated using the DMT myograph system. Renal immunity was evaluated by flow cytometry, electron microscopy, immunofluorescence, etc. RESULTS: Twelve weeks after the operation, compared with DB or MI rats, DB+MI rats exhibited the following characteristics: 1) significantly increased glomerular enlargement, fibrosis, glomerulosclerosis, podocyte injury and microalbuminuria; 2) significantly increased vasoconstrictor reactivity of the renal interlobular arteries and renal venous pressure; 3) significantly increased infiltration of CD3+ and CD4+ T cells and decreased Treg/Th17 ratios; and 4) significantly increased glomerular deposition of IgG and C4. In contrast, rats with MI only showed mildly accelerated glomerular remodeling and microalbuminuria, with little change in renal hemodynamics and immunity. Fasudil treatment significantly improved the renal lesions in DB+MI rats but not MI rats. CONCLUSIONS: Post-MI cardiac dysfunction significantly accelerated glomerular remodeling, podocyte injury and microalbuminuria in STZ-induced diabetic rats. These changes were accompanied by altered local hemodynamics and immunity.

[The endocrine heart and inflammation]. / El corazón endocrino y el proceso inflamatorio.

The endocrine heart produces the polypeptide hormones Atrial Natriuretic Factor (ANF or ANP) and Brain Natriuretic Peptide (BNP). Through the peripheral actions of these hormones the heart contributes to the regulation of the cardiac preload and afterload. More recently, new functions for these hormones have been described including the modulation of the immune response. Plasma levels of BNP but not those of ANF, increase following an acute rejection episode of a cardiac allotransplant but return to levels pre-rejection with successful treatment. This observation constitutes the first observation leading to characterizing the interactions of BNP with the immune response. Several other pathologies with an inflammatory component are now known to be associated with an increase in the production of BNP. Such an increase is due to an increase in the transcriptional activity of the BNP gene induced by cytokines and related substances. In vitro investigations have shown that an increase in BNP directly modulates immunological activity. Inflammation and hemodynamic changes co-exist in several cardiovascular diseases and therefore it may be beneficial to measure circulating levels of both ANF and BNP as biomarkers of changes in intravascular volume and of changes in intravascular volume plus inflammation, respectively. Changes in plasma ANF, that are relatively larger than those of BNP, might be an indication of hemodynamic deterioration while important changes in circulating BNP could indicate a worsening of the inflammatory process.

El corazón endocrino y el proceso inflamatorio / [The endocrine heart and inflammation].

The endocrine heart produces the polypeptide hormones Atrial Natriuretic Factor (ANF or ANP) and Brain Natriuretic Peptide (BNP). Through the peripheral actions of these hormones the heart contributes to the regulation of the cardiac preload and afterload. More recently, new functions for these hormones have been described including the modulation of the immune response. Plasma levels of BNP but not those of ANF, increase following an acute rejection episode of a cardiac allotransplant but return to levels pre-rejection with successful treatment. This observation constitutes the first observation leading to characterizing the interactions of BNP with the immune response. Several other pathologies with an inflammatory component are now known to be associated with an increase in the production of BNP. Such an increase is due to an increase in the transcriptional activity of the BNP gene induced by cytokines and related substances. In vitro investigations have shown that an increase in BNP directly modulates immunological activity. Inflammation and hemodynamic changes co-exist in several cardiovascular diseases and therefore it may be beneficial to measure circulating levels of both ANF and BNP as biomarkers of changes in intravascular volume and of changes in intravascular volume plus inflammation, respectively. Changes in plasma ANF, that are relatively larger than those of BNP, might be an indication of hemodynamic deterioration while important changes in circulating BNP could indicate a worsening of the inflammatory process.

Protein-bound uremic toxins stimulate crosstalk between leukocytes and vessel wall.

Leukocyte activation and endothelial damage both contribute to cardiovascular disease, a major cause of morbidity and mortality in CKD. Experimental in vitro data link several protein-bound uremic retention solutes to the modulation of inflammatory stimuli, including endothelium and leukocyte responses and cardiovascular damage, corroborating observational in vivo data. However, the impact of these uremic toxins on the crosstalk between endothelium and leukocytes has not been assessed. This study evaluated the effects of acute and continuous exposure to uremic levels of indoxylsulfate (IS), p-cresylsulfate (pCS), and p-cresylglucuronide (pCG) on the recruitment of circulating leukocytes in the rat peritoneal vascular bed using intravital microscopy. Superfusion with IS induced strong leukocyte adhesion, enhanced extravasation, and interrupted blood flow, whereas pCS caused a rapid increase in leukocyte rolling. Superfusion with pCS and pCG combined caused impaired blood flow and vascular leakage but did not further enhance leukocyte rolling over pCS alone. Intravenous infusion with IS confirmed the superfusion results and caused shedding of heparan sulfate, pointing to disruption of the glycocalyx as the mechanism likely mediating IS-induced flow stagnation. These results provide the first clear in vivo evidence that IS, pCS, and pCG exert proinflammatory effects that contribute to vascular damage by stimulating crosstalk between leukocytes and vessels.

Sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic-induced atherosclerosis susceptibility.

BACKGROUND: The molecular basis for the focal nature of atherosclerotic lesions is poorly understood. Here, we explored whether disturbed flow patterns activate an innate immune response to form the NLRP3 inflammasome scaffold in vascular endothelial cells via sterol regulatory element binding protein 2 (SREBP2). METHODS AND RESULTS: Oscillatory flow activates SREBP2 and induces NLRP3 inflammasome in endothelial cells. The underlying mechanisms involve SREBP2 transactivating NADPH oxidase 2 and NLRP3. Consistently, SREBP2, NADPH oxidase 2, and NLRP3 levels were elevated in atheroprone areas of mouse aortas, suggesting that the SREBP2-activated NLRP3 inflammasome causes functionally disturbed endothelium with increased inflammation. Mimicking the effect of atheroprone flow, endothelial cell-specific overexpression of the activated form of SREBP2 synergized with hyperlipidemia to increase atherosclerosis in the atheroresistant areas of mouse aortas. CONCLUSIONS: Atheroprone flow induces NLRP3 inflammasome in endothelium through SREBP2 activation. This increased innate immunity in endothelium synergizes with hyperlipidemia to cause topographical distribution of atherosclerotic lesions.

Myocardial gene expression profiles and cardiodepressant autoantibodies predict response of patients with dilated cardiomyopathy to immunoadsorption therapy.

AIMS: Immunoadsorption with subsequent immunoglobulin G substitution (IA/IgG) represents a novel therapeutic approach in the treatment of dilated cardiomyopathy (DCM) which leads to the improvement of left ventricular ejection fraction (LVEF). However, response to this therapeutic intervention shows wide inter-individual variability. In this pilot study, we tested the value of clinical, biochemical, and molecular parameters for the prediction of the response of patients with DCM to IA/IgG. METHODS AND RESULTS: Forty DCM patients underwent endomyocardial biopsies (EMBs) before IA/IgG. In eight patients with normal LVEF (controls), EMBs were obtained for clinical reasons. Clinical parameters, negative inotropic activity (NIA) of antibodies on isolated rat cardiomyocytes, and gene expression profiles of EMBs were analysed. Dilated cardiomyopathy patients displaying improvement of LVEF (≥20 relative and ≥5% absolute) 6 months after IA/IgG were considered responders. Compared with non-responders (n = 16), responders (n = 24) displayed shorter disease duration (P = 0.006), smaller LV internal diameter in diastole (P = 0.019), and stronger NIA of antibodies. Antibodies obtained from controls were devoid of NIA. Myocardial gene expression patterns were different in responders and non-responders for genes of oxidative phosphorylation, mitochondrial dysfunction, hypertrophy, and ubiquitin-proteasome pathway. The integration of scores of NIA and expression levels of four genes allowed robust discrimination of responders from non-responders at baseline (BL) [sensitivity of 100% (95% CI 85.8-100%); specificity up to 100% (95% CI 79.4-100%); cut-off value: -0.28] and was superior to scores derived from antibodies, gene expression, or clinical parameters only. CONCLUSION: Combined assessment of NIA of antibodies and gene expression patterns of DCM patients at BL predicts response to IA/IgG therapy and may enable appropriate selection of patients who benefit from this therapeutic intervention.