Inflammatory Biomarkers in the Short-Term Prognosis of Venous Thromboembolism: A Narrative Review.

The relationship between inflammation and venous thrombosis is not well understood. An inflammatory response may be both the cause and consequence of venous thromboembolism (VTE). In fact, several risk factors of VTE modulate thrombosis through inflammatory markers. Acute pulmonary embolism (PE) is burdened by a remarkable mortality rate, up to 34% in severely ill patients presenting with hemodynamic instability. Initial mortality risk stratification is based on hemodynamic instability. Patients with a situation of hemodynamic stability require immediate further risk assessment based on clinical, imaging, and circulating biomarkers, as well as the presence of comorbidities. Some inflammatory biomarkers have shown potential usefulness in the risk stratification of patients with VTE, especially acute PE. C-reactive protein on admission is associated with 30-day mortality and bleeding in VTE patients. P-selectin is associated with right ventricle dysfunction in PE patients and might be associated with VTE recurrences and the extension of thrombosis. Tissue factor microparticles are associated with VTE recurrence in cancer-associated thrombosis. Other inflammatory biomarkers present scarce evidence (inflammatory cytokines, erythrocyte sedimentation rate, fibrinogen, leukocyte count). In this manuscript, we will review the prognostic role of different inflammatory biomarkers available both for clinical practice and research in VTE patients.

Agonistic Anti-CD40 Antibody Triggers an Acute Liver Crisis With Systemic Inflammation in Humanized Sickle Cell Disease Mice.

Sickle cell disease (SCD) is an inherited hemolytic disorder, defined by a point mutation in the ß-globin gene. Stress conditions such as infection, inflammation, dehydration, and hypoxia trigger erythrocyte sickling. Sickled red blood cells (RBCs) hemolyze more rapidly, show impaired deformability, and increased adhesive properties to the endothelium. In a proinflammatory, pro-coagulative environment with preexisting endothelial dysfunction, sickled RBCs promote vascular occlusion. Hepatobiliary involvement related to the sickling process, such as an acute sickle hepatic crisis, is observed in about 10% of acute sickle cell crisis incidents. In mice, ligation of CD40 with an agonistic antibody leads to a macrophage activation in the liver, triggering a sequence of systemic inflammation, endothelial cell activation, thrombosis, and focal ischemia. We found that anti-CD40 antibody injection in sickle cell mice induces a systemic inflammatory and hemodynamic response with accelerated hemolysis, extensive vaso-occlusion, and large ischemic infarctions in the liver mimicking an acute hepatic crisis. Administration of the tumor necrosis factor-α (TNF-α) blocker, etanercept, and the heme scavenger protein, hemopexin attenuated end-organ damage. These data collectively suggest that anti-CD40 administration offers a novel acute liver crisis model in humanized sickle mice, allowing for evaluation of therapeutic proof-of-concept.

Clinically inapparent right heart dysfunction is associated with reduced myofilament force development in coronary artery disease.

BACKGROUND: Right ventricular dysfunction after CABG is associated with poor peri- and postoperative outcomes. We aimed to identify clinical and experimental predictors for preoperative inapparent right ventricular dysfunction and therefore hypothesized that reduced myofilament force development as well as altered levels of biomarkers might predict inapparent right ventricular dysfunction. METHODS: From 08/2016 to 02/2018, 218 patients scheduled for CABG were divided into two groups (TAPSE ≥ 20 mm, n = 178; TAPSE < 20 mm, n = 40). Baseline serum samples for biomarkers (Galectin, TGFß1, N Acyl-SDMA, Arginine, ADMA and Pentraxin-3), clinical laboratory and transthoracic echocardiographic parameters were evaluated. To examine the myocardial apparatus of the right ventricle intraoperative right auricular tissue was harvested for stepwise skinned fiber force measurements. RESULTS: Patients with TAPSE < 20 mm had a higher incidence of DM (55 vs. 34%, p = 0.018), preoperative AFib (43 vs. 16%, p < 0.001), reduced GFR (67 ± 18 vs. 77 ± 24 ml/min/1.73 m2, p = 0.013), larger LA area (22 ± 6 vs. 20 ± 5 cm2, p = 0.005) and reduced LVEF (50 vs. 55%, p = 0.008). Furthermore, higher serum ADMA (0.70 ± 0.13 vs. 0.65 ± 0.15 µmol/l, p = 0.046) and higher serum Pentraxin-3 levels (3371 ± 1068 vs. 2681 ± 1353 pg/dl, p = 0.004) were observed in these patients. Skinned fiber force measurements showed significant lower values at almost every step of calcium concentration (pCa 4.52 to pCa 5.5, p < 0.01 and pCa 5.75-6.0, p < 0.05). Multivariable analysis revealed DM (OR 2.53, CI 1.12-5.73, Euro Score II (OR 1.34, CI 1.02-1.78), preoperative AF (OR 4.86, CI 2.06-11.47), GFR (OR 7.72, CI 1.87-31.96), albumin (OR 1.56, CI 0.52-2.60), Pentraxin-3 (OR 19.68, CI 14.13-25.24), depressed LVEF (OR 8.61, CI 6.37-10.86), lower force values: (pCa 5.4; OR 2.34, CI 0.40-4.29 and pCa 5.2; OR 2.00, CI 0.39-3.60) as predictors for clinical inapparent right heart dysfunction. CONCLUSIONS: These preliminary data showed that inapparent right heart dysfunction in CAD is already associated with reduced force development of the contractile apparatus.

Type IV Collagen 7s Reflects Central Venous Pressure and Right Ventricular End-Diastolic Pressure in Patients with Congenital Heart Disease After Biventricular Repair.

After congenital heart disease repair, right heart dysfunction facilitates venous stasis and elevated central venous pressure; however, methods to evaluate right heart dysfunction are limited. We aimed to evaluate right heart function using liver biomarkers. We investigated 62 patients more than 5 years after congenital heart surgery. The patients underwent cardiac catheterization in our hospital between January 2015 and December 2019. To evaluate liver status, type IV collagen 7s, procollagen type III peptide, and hyaluronic acid levels were measured. The mean age of the 62 patients was 14.0 ± 7.2 years. The mean central venous pressure was 6.8 ± 3.5 mmHg and mean right ventricular end-diastolic pressure was 7.9 ± 3.5 mmHg. The mean levels of serum type IV collagen 7s, procollagen type III peptide, and hyaluronic acid were 5.9 ± 1.6 ng/mL, 24.3 ± 15.5 ng/mL, and 18.5 ± 13.6 ng/mL, respectively. There was a good correlation between central venous pressure, right ventricular end-diastolic pressure and type IV collagen 7s (r = 0.67 and r = 0.64). There was no correlation between central venous pressure and the procollagen type III peptide (r = 0.003), and slight correlation between central venous pressure and hyaluronic acid (r = 0.31). There was no correlation between right ventricular end-diastolic pressure and the procollagen type III peptide (r = 0.003), and slight correlation between right ventricular end-diastolic pressure and hyaluronic acid (r = 0.31). We found that changes in the hemodynamics of the right heart system can be evaluated using liver fibrosis markers. Type IV collagen 7s reflects central venous pressure and right ventricular end-diastolic pressure in postoperative patients with congenital heart disease.

Expression of ApoA5 and its function in the right ventricular failing and remodeling secondary to pulmonary hypertension.

Right heart failure and right ventricular (RV) remodeling were the main reason for mortality of pulmonary hypertension (PH) patients. Apolipoprotein AV (ApoA5) is a key regulator of plasma triglyceride and have multifunction in several target organs. We detected decreased ApoA5 in serum of patients with PH and both in serum and RV of monocrotaline-induced PH model. Exogenously, overexpression ApoA5 by adenovirus showed protective effects on RV failure and RV fibrosis secondary to PH. In addition, in vitro experiments showed ApoA5 attenuated the activation of fibroblast induced by transforming growth factor ß1 and synthesis and secretion of extracellular matrix by inhibiting focal adhesion kinase-c-Jun N-terminal kinase-Smad3 pathway. Finally, we suggest that ApoA5 may potentially be a pivotal target for RV failure and fibrosis secondary of PH.

Systemic right ventricle in elderly patients with congenitally corrected transposition of the great arteries: Clinical profile, cardiac biomarkers, and echocardiographic parameters.

OBJECTIVE: The number of patients with congenitally corrected transposition of the great arteries (ccTGA) surviving to old age is increasing. This study therefore sought to characterize 'geriatric' systemic right ventricle (sRV) in terms of clinical profile, cardiac biomarkers, and echocardiography-derived function when compared with findings in younger patients. METHODS: A single-center cross-sectional study of adults with ccTGA was performed. Patients underwent clinical assessment; transthoracic echocardiography; and venous blood sampling including N-terminal pro-B-type natriuretic peptide (NTproBNP), galectin-3, and soluble suppression of tumorgenicity 2 (sST2) measurements. In the echocardiographic study, the sRV function was assessed using fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), systolic pulsed-wave Doppler velocity (s'), and longitudinal strain (LS). RESULTS: Ten patients with ccTGA aged 60 years or older and 53 patients younger than 60 years of age were included. There were significantly more individuals with hypertension (40% vs. 5.7%), dyslipidaemia (50% vs. 5.7%), and atrial fibrillation (70% vs. 20.7%) in the older group; similarly, we found higher NTproBNP (2706 pg/mL vs. 784.7 pg/mL; p<0.001), and galectin-3 (10.15 ng/mL vs. 7.24 ng/mL; p=0.007) concentrations in elderly ccTGA individuals, while sST2 content did not vary significantly according to age. Upon echocardiographic assessment, lower sRV FAC (28.6% vs. 36.1%; p=0.028) and LS (-12% vs. -15.5%; p=0.017) values were observed in patients aged 60 years or older. TAPSE and s' did not differ between the age groups. CONCLUSION: Careful screening for acquired comorbidities, particularly atrial fibrillation, in elderly ccTGA patients is warranted. Examining selected cardiac biomarkers and echocardiography-derived parameters are useful in the assessment of the aging sRV.

Iron deficiency is a possible risk factor causing right heart failure in Tibetan children living in high altitude area.

The aim of the study is to discuss the risk factor of right heart failure (RHF) especially the association of iron deficiency with RHF in Tibetan children who live in high altitude area. In this retrospective study, we collected the data of Tibetan children from January 2011 to December 2018 in our hospital. The patients included in the study had the following data: age, gender, ferritin, echocardiography, hemoglobin, C-reaction protein, and altitude of residence. According to whether RHF was diagnosed, the patients were divided into RHF group and non-RHF group. Totally 133 patients were included with 59 in RHF group and 74 in non-RHF group. In single factor analysis, age (P = .008), altitude of residence (P < .001), ferritin (P < .001), and pulmonary arterial systolic pressure (P < .001) showed significant difference between the 2 groups. Binary logistic regression was performed to further identify the association of the clinical factors with RHF. Higher pulmonary arterial systolic pressure (odds ratio: 29.303, 95% confidence interval: 5.249-163.589, P < .001) and lower ferritin level (odds ratio: 5.849, 95% confidence interval: 1.585-21.593, P = .008) were independent risk factors associated with RHF. In receiver-operating characteristic curve, the optimal cutoff value of ferritin level was 14.6 µg/L with the sensitivity of 81.4% and specificity of 89.2%. As continuous variable, the correlation between ferritin and RHF was not certain (P = .281). Due to the possibility that iron deficiency be a risk factor of RHF in Tibetan children, prevention and treatment of iron deficiency might be a potential way in reducing the incidence of RHF in this high altitude area.

Biomarkers and Right Ventricular Dysfunction.

Right ventricular failure is common in critically ill patients, as it frequently results from pulmonary embolism or pulmonary hypertension, and can complicate sepsis and the acute respiratory distress syndrome. Right ventricular dysfunction can be challenging to manage and is associated with poor outcomes in this wide array of disease. Laboratory biomarkers are rapid, noninvasive, accurate, and widely available and thus are useful in the diagnosis and management of right ventricular dysfunction in the critically ill patient. This article discusses the pathophysiology of right ventricular failure and reviews the applications of commonly used biomarkers in right ventricular dysfunction in critical care.

Right ventricular failure following left ventricular assist device implantation is associated with a preoperative pro-inflammatory response.

BACKGROUND: Systemic inflammation during implant of a durable left ventricular assist device (LVAD) may contribute to adverse outcomes. We investigated the association of the preoperative inflammatory markers with subsequent right ventricular failure (RVF). MATERIALS AND METHODS: Prospective data was collected on 489 patients from 2003 through 2017 who underwent implantation of a durable LVAD. Uni- and multivariable correlation with leukocytosis was determined using linear and binary logistic regression. The population was also separated into low (< 10.5 K/ul, n = 362) and high (> 10.5 K/ul, n = 127) white blood cell count (WBC) groups. Mantel-Cox statistics was used to analyze survival data. RESULTS: Postop RVF was associated with a higher preop WBC (11.3 + 5.7 vs 8.7 + 3.1) and C-reactive protein (CRP, 5.6 + 4.4 vs 3.3 + 4.7) levels. Multivariable analysis identified an independent association between increased WBC preoperatively with increased lactate dehydrogenase (LDH, P < 0.001), heart rate (P < 0.001), CRP (P = 0.006), creatinine (P = 0.048), and INR (P = 0.049). The high WBC group was more likely to be on preoperative temporary circulatory support (17.3% vs 6.4%, P < 0.001) with a trend towards greater use of an intra-aortic balloon pump (55.9% vs 47.2%, P = 0.093). The high WBC group had poorer mid-term survival (P = 0.042). CONCLUSIONS: Postop RVF is associated with a preoperative pro-inflammatory environment. This may be secondary to the increased systemic stress of decompensated heart failure. Systemic inflammation in the decompensated heart failure may contribute to RVF after LVAD implant.

Elevated 1-h post-load plasma glucose is associated with right ventricular morphofunctional parameters in hypertensive patients.

PURPOSE: Emerging data demonstrate that type 2 diabetes mellitus (T2DM) is associated with right ventricular (RV) dysfunction. A cutoff point of 155 mg/dL for the 1-hour (h) post-load plasma glucose, during oral glucose tolerance test (OGTT), identifies patients with normal glucose tolerance (NGT) at high risk to develop T2DM and cardiovascular (CV) disease. We investigated if 1-h post-load glucose may affect RV geometry and function in a group of never-treated hypertensive individuals. METHODS: We enrolled 446 Caucasian newly diagnosed hypertensive outpatients. All patients underwent an OGTT and a standard echocardiography. The tricuspid annular plane systolic excursion (TAPSE) and the RV fractional area change (RVFAC) were measured together with systolic pulmonary arterial pressure (s-PAP) and pulmonary vascular resistances (PVR). Insulin sensitivity was evaluated using the Matsuda index. RESULTS: Among all partecipants, 296 had NGT, 100 impaired glucose tolerance (IGT), and 50 T2DM. Considering the cutoff point of 155 mg/dl for 1-h glucose, NGT subjects were stratified into two groups: NGT < 155 (n = 207), NGT ≥ 155 (n = 89). Subjects NGT ≥ 155 presented a worse metabolic and inflammatory profile than NGT < 155. RV functional parameters (TAPSE, RVFAC, TAPSE/s-PAP, and TAPSE/PVR) were significantly reduced in NGT ≥ 155 subjects compared with NGT < 155 patients. On the contrary, s-PAP and PVR were significantly higher. At multiple regression analysis, 1-h glucose was the strongest predictor of TAPSE in NGT ≥ 155, IGT, and T2DM. CONCLUSIONS: The presence of RV impairment in hypertensive NGT ≥ 155 subjects further complicates their CV burden and it may, at least in part, justify the worse clinical outcome in this setting of patients.

17ß-estradiol preserves right ventricular function in rats with pulmonary arterial hypertension: an echocardiographic and histochemical study.

Pulmonary arterial hypertension (PAH) is more prevalent in females. Paradoxically, female patients have better right ventricular (RV) function and higher survival rates than males. However, the effects of 17ß-estradiol (E2) on RV function in PAH has not been studied. Twenty-four male rats were exposed to monocrotaline (MCT) to induce experimental PAH, while treated with E2 or vehicle respectively. Together with eight control rats, thirty-two rats were examined by echocardiography 4 weeks after drug administration. Echocardiographic measurement of RV function included: tricuspid annular plane systolic excursion (TAPSE), RV index of myocardial performance (RIMP), RV fractional area change (RVFAC) and tricuspid annular systolic velocity (s'). RV free wall longitudinal strain (RVLSFW) and RV longitudinal shortening fraction (RVLSF) were also used to quantify RV function. RV morphology was determined by echocardiographic and histological analysis. TAPSE, RVFAC and s' were reduced, and RIMP was elevated in the MCT-treated group and vehicle-treated group, when compared with control group (P < 0.01). TAPSE, RVFAC and s' in the E2 group were higher, while RIMP was lower than those in the MCT-treated group and vehicle-treated group (P < 0.01). Myocardial functional parameters (RVLSFW and RVLSF) were also higher in the E2 group. Enhanced serum E2 levels were closely correlated with the improvement in RV functional parameters and enhancement of serum BNP levels (P < 0.01 for all groups). RV function decreased significantly in male rats with MCT-induced PAH, while E2 exhibited a protective effect on RV function, suggesting that E2 is a critical modulator of sex differences in PAH.

A potential contribution of trappin-2 to the development of vasculopathy in systemic sclerosis.

BACKGROUND: Trappin-2/pre-elafin is an endogenous inhibitor of human neutrophil elastase involved in inflammation, innate immunity and vascular remodelling, which consist of the complex pathological process of systemic sclerosis (SSc). OBJECTIVES: To clarify the potential role of trappin-2 in SSc. METHODS: Serum trappin-2 levels were determined by enzyme-linked immunosorbent assay in 51 SSc and 18 healthy subjects. Trappin-2 expression was evaluated in SSc lesional skin and cultured endothelial cells treated with FLI1 siRNA by immunohistochemistry, reverse transcription-real-time PCR and/or immunoblotting. Friend leukaemia virus integration 1 (Fli1) binding to the PI3 promoter was assessed by chromatin immunoprecipitation. RESULTS: Since serum trappin-2 levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction, SSc patients with normal renal function were analysed. Although serum trappin-2 levels were comparable between diffuse cutaneous SSc, limited cutaneous SSc and control subjects, the prevalence of digital ulcers or elevated right ventricular systolic pressure (RVSP) was significantly higher in SSc patients with elevated serum trappin-2 levels than in those with normal levels. Furthermore, serum trappin-2 levels were significantly increased in SSc patients with digital ulcers or elevated RVSP compared to those without. Moreover, serum trappin-2 levels positively correlated with RVSP values in SSc patients. Importantly, trappin-2 expression was enhanced in small vessels of SSc lesional skin. In cultured endothelial cells, trappin-2 expression was elevated by gene silencing of FLI1 at mRNA and protein levels and Fli1 occupied the PI3 promoter. CONCLUSIONS: Endothelial trappin-2 up-regulation partially due to Fli1 deficiency can be associated with the development of SSc vasculopathy.

Intestinal fatty acid-binding protein as a predictor of prognosis in postoperative cardiac surgery patients.

During the perioperative period of cardiac disease, as many risk factors exist, such as primary cardiac diseases, the use of vasopressors, ischemia-reperfusion injury during cardiopulmonary bypass (CPB), and surgical stress, the gut suffered from ischemia, anoxia and oxidative stress, which would lead to the enterocyte injury. The aim of this study was to explore whether serum intestinal fatty acid-binding protein (IFABP), which is excreted specifically from damaged intestinal enterocytes, as a predictor of prognosis in postoperative cardiac surgery patients.From January 2017 to December 2017, 40 postoperative cardiac surgery patients were enrolled in this observational study. Serum IFABP levels and prognostic biomarkers were recorded at intensive care unit (ICU) admission.The serum IFABP levels were significantly higher in postoperative cardiac surgery patients who complicated with multiple organ dysfunction syndrome (MODS) (median, 883.20 pg/mL vs 426.10 pg/mL; P < .001), infective complications (median, 917.70 pg/mL vs 409.40 pg/mL; P < .001), or who stayed in ICU beyond 4 days (median, 807.65 pg/mL vs 426.10 pg/mL; P < .001). Moreover, in patients who suffered from right ventricular dysfunction, the serum IFABP levels were significantly higher (median, 737.85 pg/mL vs 445.55 pg/mL; P = .016). The serum IFABP levels also showed great precision for the prediction of MODS (the area under curve, AUC 0.923), infective complications (AUC 0.961) and ICU stay beyond 4 days (AUC 0.853). And it correlated significantly with the acute physiology and chronic health evaluation (APACHE) II score (P < .05), sequential organ failure assessment (SOFA) score (P < .05), and acute gastrointestinal injury (AGI) grade (P < .001).The serum IFABP level at ICU admission is a valuable, convenient, and objective early predictor of prognosis in postoperative cardiac surgery patients.

Role of myocardial collagen degradation and fibrosis in right ventricle dysfunction in transposition of the great arteries after atrial switch.

BACKGROUND: Heart failure is a serious event in patients with transposition of the great arteries (D-TGA) after atrial redirection surgery. We aimed to determine the association between myocardial fibrosis and systolic and diastolic systemic right ventricle (sRV) dysfunction. METHODS: Diastolic and systolic function of sRV was prospectively assessed using echocardiography and cardiac magnetic resonance imaging (CMR) in 48 patients with atrially switched D-TGA and 26 healthy subjects. Diastolic function of the subaortic ventricle was assessed by echocardiography Doppler and DTI. In CMR, ejection fraction of sRV and wall stress defined as the product of the systolic blood pressure and volume/mass ratio were assessed. Fibrosis extent within sRV myocardium was evaluated using gadolinium-enhanced magnetic resonance and serum collagen turnover biomarkers. RESULTS: Late gadolinium enhancement (LGE) was found in 35% of D-TGA patients, and the collagen degradation biomarker pro-MMP1:TIMP1 ratio was significantly increased in D-TGA patients compared to healthy subjects (1.0 × 10-2vs. 2.5 × 10-2, p = 0.04). Increase in sRV wall stress was significantly associated with LGE (p = 0.01) and pro-MMP1:TIMP1 ratio (r = 0.77, p < 0.01). After adjustment for age, sex, BMI, blood pressure and cardiac treatment, pro-MMP1:TIMP1 ratio was the strongest determinant of sRVEF (R2 = 0.85, p < 0.01). Pro-MMP1:TIMP1 ratio was also significantly correlated with the early diastolic filling parameter E/E' (r = 0.53, p = 0.02), but this was not anymore the case after adjustment. CONCLUSIONS: Diastolic and systolic sRV dysfunction is related to myocardial collagen degradation and fibrosis. Research in medical therapies that reduce systemic sRV afterload and limit collagen degradation is warranted in this setting.

D-Dimer and thrombus burden in acute pulmonary embolism.

BACKGROUND: Thrombus burden in pulmonary embolism (PE) is associated with higher D-Dimer-levels and poorer prognosis. We aimed to investigate i) the influence of right ventricular dysfunction (RVD), deep venous thrombosis (DVT), and high-risk PE-status on D-Dimer-levels and ii) effectiveness of D-Dimer to predict RVD in normotensive PE patients. METHODS: Overall, 161 PE patients were analyzed retrospectively, classified in 5 subgroups of thrombus burden according to clinical indications and compared regarding D-Dimer-levels. Linear regression models were computed to investigate the association between D-Dimer and the groups. In hemodynamically stable PE patients, a ROC curve was calculated to assess the effectiveness of D-Dimer for predicting RVD. RESULTS: Overall, 161 patients (60.9% females, 54.0% aged >70 years) were included in this analysis. The D-Dimer-level was associated with group-category in a univariate linear regression model (ß 0.050 (95%CI 0.002-0.099), P = .043). After adjustment for age, sex, cancer, and pneumonia in a multivariate model we observed an association between D-Dimer and group-category with borderline significance (ß 0.047 (95%CI 0.002-0.096), P = .058). The Kruskal-Wallis test demonstrated that D-Dimer increased significantly with higher group-category. In 129 normotensive patients, patients with RVD had significantly higher D-Dimer values compared to those without (1.73 (1.11/3.48) vs 1.17 (0.65/2.90) mg/l, P = .049). A ROC curve showed an AUC of 0.61, gender non-specific, with calculated optimal cut-off of 1.18 mg/l. Multi-variate logistic regression model confirmed an association between D-Dimer >1.18 mg/l and RVD (OR2.721 (95%CI 1.196-6.190), P = .017). CONCLUSIONS: Thrombus burden in PE is related to elevated D-Dimer levels, and D-Dimer values >1.18 mg/l were predictive for RVD in normotensive patients. D-Dimer levels were influenced by DVT, but not by cancer, pneumonia, age, or renal impairment.

Interleukin-6 is independently associated with right ventricular function in pulmonary arterial hypertension.

BACKGROUND: An elevated serum level of interleukin-6 (IL-6) in pulmonary arterial hypertension (PAH) patients results in a greater symptom burden and increased mortality; however, the mechanisms underlying these observations remain unclear. Because both pre-clinical and clinical data associate elevated IL-6 levels with impaired cardiac function, we hypothesized that the adverse effects of IL-6 in PAH result, in part, from right ventricular (RV) dysfunction. METHODS: We analyzed the relationship between IL-6 and RV function in 40 patients with PAH identified in our institutional PAH registry. Serum IL-6 levels was quantified by enzyme-linked immunoassay. RESULTS: PAH patients had higher IL-6 levels than age- and gender-matched controls. Circulating IL-6 levels correlated inversely with echocardiography-based measures of RV function and RV-pulmonary artery (RV-PA) coupling. When dividing PAH patients by median IL-6 level, patients with higher IL-6 had significantly worse RV function (fractional area change [FAC] 23 ± 12% vs 38 ± 11%, tricuspid annular plane systolic excursion [TAPSE] 1.3 ± 0.3 cm vs 2.1 ± 0.5 cm), impaired RV-PA coupling (0.6 ± 0.5%/mm Hg vs 0.9 ± 0.5%/mm Hg), higher right atrial pressure (13 ± 7 mm Hg vs 9 ± 5 mm Hg), reduced cardiac index (2.0 ± 0.5 liters/min/m2 vs 2.8 ± 1.0 liters/min/m2) and lower stroke volume (48 ± 20 ml vs 70 ± 28 ml). In contrast, the relationships between IL-6 and mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR) and pulmonary arterial compliance (PAC) were not significant. Finally, IL-6 was independently associated with RV function and RV-PA coupling after adjusting for static (PVR) and pulsatile (PAC) after-load on the RV. CONCLUSIONS: Serum IL-6 levels are independently associated with RV function and RV-PA coupling in PAH. Patients with higher IL-6 levels have more severe RV dysfunction and diminished RV-PA coupling despite a comparable severity of pulmonary vascular disease.

Glucose Homeostasis, Pancreatic Endocrine Function, and Outcomes in Advanced Heart Failure.

BACKGROUND: The mechanisms and relevance of impaired glucose homeostasis in advanced heart failure (HF) are poorly understood. The study goals were to examine glucose regulation, pancreatic endocrine function, and metabolic factors related to prognosis in patients with nondiabetic advanced HF. METHODS AND RESULTS: In total, 140 advanced HF patients without known diabetes mellitus and 21 sex-, age-, and body mass index-matched controls underwent body composition assessment, oral glucose tolerance testing, and measurement of glucose-regulating hormones to model pancreatic ß-cell secretory response. Compared with controls, HF patients had similar fasting glucose and insulin levels but higher levels after oral glucose tolerance testing. Insulin secretion was not impaired, but with increasing HF severity, there was a reduction in glucose, insulin, and insulin/glucagon ratio-a signature of starvation. The insulin/C-peptide ratio was decreased in HF, indicating enhanced insulin clearance, and this was correlated with lower cardiac output, hepatic insufficiency, right ventricular dysfunction, and body wasting. After a median of 449 days, 41% of patients experienced an adverse event (death, urgent transplant, or assist device). Increased glucagon and, paradoxically, low fasting plasma glucose displayed the strongest relations to outcome (P=0.01). Patients in the lowest quartile of fasting plasma glucose (3.8-5.1 mmol·L-1, 68-101 mg·dL-1) had 3-times higher event risk than in the top quartile (6.0-7.9 mmol·L-1, 108-142 mg·dL-1; relative risk: 3.05 [95% confidence interval, 1.46-6.77]; P=0.002). CONCLUSIONS: Low fasting plasma glucose and increased glucagon are robust metabolic predictors of adverse events in advanced HF. Pancreatic insulin secretion is preserved in advanced HF, but levels decrease with increasing HF severity due to enhanced insulin clearance that is coupled with right heart failure and cardiac cachexia.

NT-proBNP as Marker of Ventricular Dilatation and Pulmonary Regurgitation After Surgical Correction of Tetralogy of Fallot: A MRI Validation Study.

The goal of this study is to evaluate whether NT-proBNP plasma levels may help as a screening biomarker for monitoring right ventricular dilatation, pulmonary regurgitation and the onset of heart failure in patients with repaired Tetralogy of Fallot. Our single-centre observational prospective study involved 43 patients (15.1 years, SD = 8) with corrected Tetralogy of Fallot. Data collection included: clinical parameters (electrocardiogram, chest X-ray, NYHA scale, time since last surgery), biochemistry (NT-proBNP levels) and MRI values (ventricular volumetry, pulmonary flow assessment). Mean time since last surgery was 13.5 years (SD = 7.8). There was a statistically significant correlation between the NT-proBNP levels (187.4 pg/ml, SD = 154.9) and right ventricular dilatation for both the right ventricular end-diastolic volume (124.9 ml/m2, SD = 31.2) (Pearson = 0.19, p < 0.01) and end-systolic volume (56.1 ml/m2, SD = 18.8) (Pearson = 0.21, p < 0.01) and also with the pulmonary regurgitation fraction (36.5%, SD = 16, Pearson = 0.12, p < 0.01). No significant correlation was found between NT-proBNP and right ventricular ejection fraction (54.6%, SD = 10.6, Pearson = -0.07), left ventricular ejection fraction (59.9%, SD = 7.1, Pearson = -0.18) or any clinical parameters. The receiver operating curve analysis evidenced that a NT-proBNP cut-off value above 133.2 pg/ml predicted the presence of dilated right ventricular end-diastolic and end-systolic volumes over centile 95 (sensitivity 82 and 83% and specificity 93 and 79%, respectively). In conclusion, in patients with surgically corrected Tetralogy of Fallot, NT-proBNP levels correlate with right ventricular dilatation and the degree of pulmonary regurgitation. Ambulatory determination of NT-proBNP might be an easy, readily available and cost-effective alternative for MRI follow-up evaluation of these patients.

The shrunken pore syndrome is associated with declined right ventricular systolic function in a heart failure population - the HARVEST study.

The close relationship between heart and kidney diseases was studied with respect to the 'Shrunken pore syndrome' that is characterized by a difference in renal filtration between cystatin C and creatinine. Patients were retrieved from the HeARt and brain failure inVESTigation trail (HARVEST) which is an ongoing study undertaken in individuals hospitalized for the diagnosis of heart failure. Ninety-five of 116 patients who underwent transthoracic echocardiograms (TTE) were eligible for this study. We used four different formulas for estimated glomerular filtration rate (eGFR); CKD-EPIcreatinine, CKD-EPIcystatin C, LMrev and CAPA. Presence of the syndrome was defined as eGFR cystatin C ≤ 60% of eGFR creatinine and absence of the syndrome as eGFR cystatin C >90% and <110% of eGFR creatinine. In a linear regression model, adjusted for age and sex, and the 'Shrunken pore syndrome' defined by the equation pair CAPA and LMrev and the equation pair CKD-EPIcystatin C and CKD-EPIcreatinine, echocardiographic parameters were studied. The 'Shrunken pore syndrome' showed statistically significant associations with measurements of right ventricular (RV) systolic function; (TAPSE and RV S') (according to the equation pair CKD-EPIcystatin C and CKD-EPIcreatinine). In conclusion, heart failure patients with the 'Shrunken pore syndrome' are at increased risk of having RV systolic dysfunction whilst heart failure patients without 'Shrunken pore syndrome' seem protected. These findings may indicate common pathophysiological events in the kidneys and the heart explaining the observed increased risk of mortality in subjects with the 'Shrunken pore syndrome'.