Cardiac PET/MRI: Recent Developments and Future Aspects.

Positron emission tomography/magnetic resonance (PET/MRI) hybrid imaging is now available for over a decade and although the quantity of installed systems is rather low, the number of emerging applications for cardiovascular diseases is still growing. PET/MRI provides integrated images of high quality anatomical and functional assessment obtained by MRI with the possibilities of PET for quantification of molecular parameters such as metabolism, inflammation, and perfusion. In recent years, sequential co-registration of myocardial tissue characterization with its molecular data had become an increasingly helpful tool in clinical practice and an integrated device simplifies this task. This review summarizes recent developments and future possibilities in the use of the PET/MRI in the diagnosis and treatment of cardiovascular disorders.

Pulmonary embolism in COVID-19 pneumonia patients admitted to temporary hospital - The follow-up study.

PURPOSE: Coronavirus disease 2019 (COVID-19) is linked with major coagulation disorders, especially higher risk of developing pulmonary embolism (PE). Our study summarizes COVID-19 patients' management with concomitant PE during the first weeks of pandemic and underlines the importance of D-dimer concentration assessment at admission in terms of prognosis. MATERIAL AND METHODS: Study group consisted of 107 outpatients (mean age 68.91 â€‹± â€‹12.83 years) admitted to the Temporary COVID-19 Hospital in Bialystok, Poland with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and suspicion of PE based on elevated D-dimer concentration (>500 â€‹µg/l) and/or low saturation rate (<90%). The clinical follow-up lasted 6 months. Death or re-hospitalization were used as composite clinical endpoint (CEP). RESULTS: Cumulative incidence of PE was 62.3% (73/107 patients). Most of the patients were in the intermediate PE risk group according to the pulmonary embolism severity index (PESI) score. The mean total computed tomography (CT) lung involvement of COVID-19 findings was 48.42 â€‹± â€‹27.71%. Neither D-dimers nor NT-proBNP concentrations correlated significantly with the percentage of lung abnormalities in CT. Patients with baseline D-dimer concentration higher than 1429 â€‹µg/l had worse prognosis in 6-months observation, log-rank test, p â€‹= â€‹0.009. CONCLUSIONS: Ongoing SARS-CoV-2 infection along with massive involvement of lung tissue and concomitant thrombi in pulmonary arteries are challenging for physicians. It seems that simple D-dimer concentration assessment at admission may be a helpful tool not only to predict PE but also to estimate the long-term prognosis.

The impact of specific pulmonary arterial hypertension therapy on cardiac fluorodeoxyglucose distribution in PET/MRI hybrid imaging-follow-up study.

BACKGROUND: PET/MRI hybrid imaging in pulmonary arterial hypertension (PAH) provides important prognostic information identifying patients who might benefit from early therapy escalation, as right ventricle (RV) metabolic alterations are linked with hemodynamics and might precede clinical deterioration. Now, we hypothesize that adequate PAH therapy escalation may result in reversal of unfavourable increased glucose uptake of RV, which is associated with improved prognosis. METHODS: Out of twenty-six initially clinically stable PAH patients who had baseline PET/MRI scans, twenty (49.9 ± 14.9 years) had second PET/MRI after 24 months. SUVRV/SUVLV ratio was used to estimate and compare cardiac glucose uptake. Occurrences of clinical endpoints (CEP), defined as death or clinical deterioration, were assessed during 48-month follow-up from baseline. RESULTS: In first 24 months of observation, sixteen patients had CEP and needed PAH therapy escalation. At follow-up visits, we observed significant improvement of RV ejection fraction (45.1 ± 9.6% to 52.4 ± 12.9%, p = 0.01), mean pulmonary artery pressure (50.5 ± 18.3 to 42.8 ± 18.6 mmHg, p = 0.03), and SUVRV/SUVLV, which tended to decrease (mean change -0.20 ± 0.74). Patients with baseline SUVRV/SUVLV value higher than 0.54 had worse prognosis in 48 months observation (log-rank test, p = 0.0007); follow up SUVRV/SUVLV > 1 predicted CEP in the following 24 months, regardless of previously escalated treatment. CONCLUSIONS: PAH therapy escalation may influence RV glucose metabolism, what seems to be related with patients' prognosis. PET/MRI assessment may predict clinical deterioration regardless of previous clinical course, however its clinical significance in PAH requires further studies. Importantly, even mild alterations of RV glucose metabolism predict clinical deterioration in long follow-up. Clinical Trial Registration ClinicalTrials.gov, NCT03688698, 05/01/2016, https://clinicaltrials.gov/ct2/show/study/NCT03688698?term=NCT03688698&draw=2&rank=1.

Platelet sTWEAK and plasma IL-6 are associated with 18F-fluorodeoxyglucose uptake in right ventricles of patients with pulmonary arterial hypertension: A pilot study.

BACKGROUND: Cytokines soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and interleukin 6 (IL-6) are involved in immune response, proliferation, apoptosis, and cardiovascular pathologies. We have previously confirmed that changes of their platelet or plasma contents are associated with pulmonary arterial hypertension (PAH). The positron emission tomography/magnetic resonance imaging (PET/MRI) hybrid imaging provides detailed insight into right ventricle (RV) hemodynamic and metabolic function. OBJECTIVES: To evaluate the relationship between RV parameters obtained using PET/MRI and concentrations of plasma and platelet sTWEAK and IL-6 in stable PAH patients. MATERIAL AND METHODS: Eighteen stable PAH patients (48.44 ±16.7 years) had simultaneous PET/MRI scans with 18F-fluorodeoxyglucose (18F-FDG) performed. Its uptake was presented as a standardized uptake value (SUV) for RV and left ventricle (LV). Cytokines concentrations were measured in platelet-poor plasma and platelet lysate. Follow-up time of this study was 58 months; the combined endpoint (CEP) was defined as death or clinical deterioration. RESULTS: We observed significant correlations between platelet sTWEAK levels, plasma IL-6 and PET parameter SUVRV/LV (r = -0.57, p = 0.011; r = 0.50, p = 0.032, respectively). In logistic regression, platelet sTWEAK and IL-6 were both prognostic factors for unfavorable ratio of SUVRV/LV higher than 1 (hazard ratio (HR) = 0.44, 95% confidence interval (95% CI): [0.23; 0.84], p = 0.017; and HR = 3.62, 95% CI: [1.21; 10.17], p = 0.011, respectively). Furthermore, their concentrations were related with prognostically important higher late gadolinium enhancement mass index (LGEMI) and RV global longitudinal strain/systolic pulmonary artery pressure (RV GLS/sPAP) values. Patients who had CEP in follow-up (n = 13) had significantly lower platelet sTWEAK content and higher plasma IL-6 at baseline than stable patients. Lower platelet sTWEAK was related to a worse prognosis in log-rank test (p = 0.006). Platelet sTWEAK and plasma IL-6 together with RV GLS/sPAP, RV ejection fraction (RVEF), mean pulmonary arterial pressure (mPAP), and SUVRV/LV were significantly associated with time to CEP in univariate Cox analysis. CONCLUSIONS: The sTWEAK and IL-6 concentrations in PAH patients are linked with metabolic and functional changes of RV visualized in PET/MRI, and both sTWEAK and IL-6 predict clinical deterioration.

Echocardiographic Assessment of Right Ventricular-Arterial Coupling in Predicting Prognosis of Pulmonary Arterial Hypertension Patients.

In response to an increased afterload in pulmonary arterial hypertension (PAH), the right ventricle (RV) adapts by remodeling and increasing contractility. The idea of coupling refers to maintaining a relatively constant relationship between ventricular contractility and afterload. Twenty-eight stable PAH patients (mean age 49.5 ± 15.5 years) were enrolled into the study. The follow-up time of this study was 58 months, and the combined endpoint (CEP) was defined as death or clinical deterioration. We used echo TAPSE as a surrogate of RV contractility and estimated systolic pulmonary artery pressure (sPAP) reflecting RV afterload. Ventricular-arterial coupling was evaluated by the ratio between these two parameters (TAPSE/sPAP). In the PAH group, the mean pulmonary artery pressure (mPAP) was 47.29 ± 15.3 mmHg. The mean echo-estimated TAPSE/sPAP was 0.34 ± 0.19 mm/mmHg and was comparable in value and prognostic usefulness to the parameter derived from magnetic resonance and catheterization (ROC analysis). Patients who had CEP (n = 21) had a significantly higher mPAP (53.11 ± 17.11 mmHg vs. 34.86 ± 8.49 mmHg, p = 0.03) and lower TAPSE/sPAP (0.30 ± 0.21 vs. 0.43 ± 0.23, p = 0.04). Patients with a TAPSE/sPAP lower than 0.25 mm/mmHg had worse prognosis, with log-rank test p = 0.001. the echocardiographic estimation of TAPSE/sPAP offers an easy, reliable, non-invasive prognostic parameter for the comprehensive assessment of hemodynamic adaptation in PAH patients.

Multimodal assessment of right ventricle overload-metabolic and clinical consequences in pulmonary arterial hypertension.

BACKGROUND: In pulmonary arterial hypertension (PAH) increased afterload leads to adaptive processes of the right ventricle (RV) that help to maintain arterio-ventricular coupling of RV and preserve cardiac output, but with time the adaptive mechanisms fail. In this study, we propose a multimodal approach which allows to estimate prognostic value of RV coupling parameters in PAH patients. METHODS: Twenty-seven stable PAH patients (49.5 ± 15.5 years) and 12 controls underwent cardiovascular magnetic resonance (CMR). CMR feature tracking analysis was performed for RV global longitudinal strain assessment (RV GLS). RV-arterial coupling was evaluated by combination of RV GLS and three proposed surrogates of RV afterload-pulmonary artery systolic pressure (PASP), pulmonary vascular resistance (PVR) and pulmonary artery compliance (PAC). 18-FDG positron emission tomography (PET) analysis was used to assess RV glucose uptake presented as SUVRV/LV. Follow-up time of this study was 25 months and the clinical end-point was defined as death or clinical deterioration. RESULTS: Coupling parameters (RV GLS/PASP, RV GLS/PVR and RV GLS*PAC) significantly correlated with RV function and standardized uptake value (SUVRV/LV). Patients who experienced a clinical end-point (n = 18) had a significantly worse coupling parameters at the baseline visit. RV GLS/PASP had the highest area under curve in predicting a clinical end-point and patients with a value higher than (-)0.29%/mmHg had significantly worse prognosis. It was also a statistically significant predictor of clinical end-point in multivariate analysis (adjusted R2 = 0.68; p < 0.001). CONCLUSIONS: Coupling parameters are linked with RV hemodynamics and glucose metabolism in PAH. Combining CMR and hemodynamic measurements offers more comprehensive assessment of RV function required for prognostication of PAH patients. TRIAL REGISTRATION: NCT03688698, 09/26/2018, retrospectively registered; Protocol ID: 2017/25/N/NZ5/02689.

Prognostic role of PET/MRI hybrid imaging in patients with pulmonary arterial hypertension.

OBJECTIVE: Right ventricular (RV) function is a major determinant of survival in patients with pulmonary arterial hypertension (PAH). Metabolic alterations may precede haemodynamic and clinical deterioration. Increased RV fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) was recently associated with progressive RV dysfunction in MRI, but the prognostic value of their combination has not been established. METHODS: Twenty-six clinically stable patients with PAH (49.9±15.2 years) and 12 healthy subjects (control group, 44.7±13.5 years) had simultaneous PET/MRI scans. FDG uptake was quantified as mean standardised uptake value (SUV) for both left ventricle (LV) and RV. Mean follow-up time of this study was 14.2±7.3 months and the clinical end point was defined as death or clinical deterioration. RESULTS: Median SUVRV/SUVLV ratio was 1.02 (IQR 0.42-1.21) in PAH group and 0.16 (0.13-0.25) in controls, p<0.001. In PAH group, SUVRV/SUVLV significantly correlated with RV haemodynamic deterioration. In comparison to the stable ones, 12 patients who experienced clinical end point had significantly higher baseline SUVRV/SUVLV ratio (1.21 (IQR 0.87-1.95) vs 0.53 (0.24-1.08), p=0.01) and lower RV ejection fraction (RVEF) (37.9±5.2 vs 46.8±5.7, p=0.03). Cox regression revealed that SUVRV/SUVLV ratio was significantly associated with the time to clinical end point. Kaplan-Meier analysis showed that combination of RVEF from MRI and SUVRV/SUVLV assessment may help to predict prognosis. CONCLUSIONS: Increased RV glucose uptake in PET and decreased RVEF identify patients with PAH with worse prognosis. Combining parameters from PET and MRI may help to identify patients at higher risk who potentially benefit from therapy escalation, but this hypothesis requires prospective validation.

Prognostic value of late gadolinium enhancement mass index in patients with pulmonary arterial hypertension.

PURPOSE: Dysfunction of the right ventricle (RV) is an important determinant of survival in patients with pulmonary arterial hypertension (PAH). The presence of late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR) at RV insertion points (RVIPs) has been found in majority of PAH patients and was associated with parameters of RV dysfunction. We hypothesize, that more detailed quantification of LGE may provide additional prognostic information. MATERIAL AND METHODS: Twenty-eight stable PAH patients (mean age 49.9 â€‹± â€‹15.9 years) and 12 healthy subjects (control group, 44.8 â€‹± â€‹13.5 years) were enrolled into the study. Septal LGE mass was quantified at the RVIPs and subsequently indexed by subject's body surface area. Mean follow-up time of this study was 16.6 â€‹± â€‹7.5 months and the clinical end-point (CEP) was defined as death or clinical deterioration. RESULTS: Median LGE mass index (LGEMI) at the RVIPs was 2.75 â€‹g/m2 [1.41-4.85]. We observed statistically significant correlations between LGEMI and hemodynamic parameters obtained from right heart catheterization - mPAP (r â€‹= â€‹0.61, p â€‹= â€‹0.001); PVR (r â€‹= â€‹0.52, p â€‹= â€‹0.007) and from CMR - RVEF (r â€‹= â€‹-0.54, p â€‹= â€‹0.005); RV global longitudinal strain (r â€‹= â€‹0.42, p â€‹= â€‹0.03). Patients who had CEP (n â€‹= â€‹16) had a significantly higher LGEMI (4.49 [2.75-6.17] vs 1.67 [0.74-2.7], p â€‹= â€‹0.01); univariate Cox analysis confirmed prognostic value of LGEMI. Furthermore, PAH patients with LGEMI higher than median had worse prognosis in Kaplan-Meier analysis (log-rank test, p â€‹= â€‹0.0006). CONCLUSIONS: The body surface indexed mass of LGE at RV septal insertion points are suggestive of RV hemodynamic dysfunction and could be a useful non-invasive marker of PAH prognosis.

Altered microRNA dynamics in acute coronary syndrome.

INTRODUCTION: In the course of acute myocardial infarction (AMI) cardiomyocyte injury, activation and destruction of endothelial cells together with inflammation lead to miRNA expression alterations. AIM: To assess levels of circulating cardiac-specific (miR-1) and endothelial-specific (miR-126) miRNAs in the acute phase of AMI and after a follow-up period. MATERIAL AND METHODS: Seventeen AMI patients (mean age: 64.24 ±13.83 years, mean left ventricle ejection fraction (LVEF): 42.6 ±9.65%), treated with primary percutaneous coronary intervention within the first 12 h, had plasma miRNAs isolated (quantitative real-time PCR, Exiqon) on admission and after 19.2 ±5.9 weeks. Measurements were also performed in a control group of healthy volunteers matched for age and sex. RESULTS: Concentrations of both miRNAs were significantly higher in AMI patients as compared to healthy controls: miR-1: 5.93 (3.15-14.92) vs. 1.46 (0.06-2.96), p = 0.04; miR-126: 4.5 (3.11-7.64) vs. 0.54 (0.36-0.99), p = 0.00003, respectively. Levels of both miRNAs significantly decreased after the follow-up period: miR-1: 5.93 (3.15-14.92) vs. 1.34 (0.04-2.34), p = 0.002; miR-126: 4.5 (3.11-7.64) vs. 1.18 (0.49-1.68), p = 0.0005). Moreover, miR-1 correlated positively with maximal troponin I concentration (r = 0.59, p = 0.02) and negatively with LVEF (r = -0.76, p = 0.0004). CONCLUSIONS: In our study, miR-1 emerged as a marker of cardiomyocyte injury and loss of myocardial contractility, whereas dynamics of miR-126 concentration may reflect endothelial activation and damage in the most extreme stage of atherosclerosis, followed by angiogenesis in ischemic myocardium. However, to fully elucidate the role of miR-1 and miR-126 as biomarkers of AMI and future therapeutic targets, further research is required.

Increased platelet content of SDF-1alpha is associated with worse prognosis in patients with pulmonary prterial hypertension.

Inflammatory processes and platelet activity play an important role in the pathophysiology of pulmonary arterial hypertension (PAH). Enhanced IL-6 signaling and higher concentration of stromal-derived factor alpha (SDF-1) have been previously shown to be linked with prognosis in PAH. We hypothesized that platelets of PAH patients have higher content of IL-6 and SDF-1 and thus are involved in disease progression. We enrolled into study 22 PAH patients and 18 healthy controls. Patients with PAH presented significantly higher plasma concentrations and platelet contents of IL-6, sIL-6R, and SDF-1 than healthy subjects (platelet content normalized to protein concentration: IL-6 (0.85*10-10 [0.29 - 1.37] vs. 0.45*10-10 [0.19-0.65], sIL-6R 1.54*10-7 [1.32-2.21] vs. 1.14*10-7 [1.01-1.28] and SDF-1 (2.72*10-7 [1.85-3.23] vs. 1.70*10-7 [1.43-2.60], all p < 0.05). Patients with disease progression (death, WHO class worsening, or therapy escalation, n = 10) had a significantly higher platelet SDF-1/total platelet protein ratio (3.68*10-7 [2.45-4.62] vs. 1.69*10-7 [1.04-2.28], p = 0.001), with no significant differences between plasma levels. Kaplan-Meier analysis revealed that patients with higher platelet SDF-1/total platelet protein ratio had more frequently deterioration of PAH in the follow-up (15.24 ± 4.26 months, log-rank test, p = 0.01). Concentrations of IL-6, sIL-6 receptor and SDF-1 in plasma and platelets are elevated in PAH patients. Higher content of SDF-1 in platelets is associated with poorer prognosis. Our study, despite of limitation due to small number of enrolled patients, suggests that activated platelets may be an important source of cytokines at the site of endothelial injury, but their exact role in the pathogenesis of PAH requires further investigation.

Fluid therapy in non-septic, refractory acute decompensated heart failure patients - The cautious role of central venous pressure.

PURPOSE: Fluid therapy in congestive acute decompensated heart failure (ADHF) patients might be inappropriate and worsening the prognosis. The aim of our study was to analyze the effect of fluid administration on mortality in non-septic, ADHF patients with reduced ejection fraction. MATERIAL AND METHODS: We analyzed 41 ADHF consecutive 'cold-wet' patients (mean age 69.3 ± 14.9 years, 27 men, LVEF 22.8 ± 11.1%, lactates 2.2 ± 1.6 mmol/L) without sepsis. At admission central venous pressure (CVP) was measured (17.6 ± 7.2 cm H2O), and ultrasound examination of inferior vena cava (IVC) was performed (IVC min. 18.6 ± 7.3 mm and IVC max. 24.6 ± 4.3 mm). Moreover, the groups were compared (survivors vs. non-survivors as well as 1st and 4th quartile of CVP). RESULTS: Altogether 17 (41%) patients died: 16 (39%) during a mean of 11.2 ± 7.8 days of hospitalization and 1 during a 30-day follow up. Patients in the lowest CVP quartile (<13 cm H2O) had significantly worse in-hospital survival as compared to patients in the highest quartile (>24 cm H2O), P = 0.012. Higher intravenous fluid volumes within the first 24 h were infused in patients in the lowest CVP quartile as compared to the highest CVP quartile (1791.7 ± 1357.8 mL vs. 754.5 ± 631.4 mL, P = 0.046). Moreover, more fluids were infused in a group of patients who died during a hospital stay and at 30-day follow up (1362.8 ± 752.7 mL vs. 722.7 ± 1046.5 mL, P = 0.004; 1348.8 ± 731.0 mL vs. 703.6 ± 1068.4 mL, P = 0.002, respectively). CONCLUSIONS: CVP-guided intravenous fluid therapy is a common practice which in high risk ADHF 'cold-wet' patients might be harmful and should rather be avoided. Lower CVP seems to be related with worse prognosis.

Persistently elevated plasma heart-type fatty acid binding protein concentration is related with poor outcome in acute decompensated heart failure patients.

BACKGROUND: The aim of the study was to determine clinical and prognostic role of repeated heart-type fatty acid binding protein (hFABP) measurements in acute decompensated HF (ADHF) patients. METHODS: In seventy-seven ADHF patients (III and IV NYHA class, mean age 70 ±â€¯12.7 years, mean left ventricle ejection fraction [LVEF] 29.73 ±â€¯13.3%) plasma hFABPs concentrations (SunRed Biological Technology) were measured twice - on admission and at discharge (mean time of hospitalization 10.7 ±â€¯4.9 days). Combined end point (CEP), assessed after mean 9.2 ±â€¯7.3 months, was defined as death or the need of HF re-hospitalization. RESULTS: Median hFABP concentration on admission was significantly lower than at discharge. hFABP concentrations on admission significantly correlated with echocardiographic parameters of LV remodeling. Among fifty-six patients (72.7%) who reached CEP, significantly higher admission and discharge hFABP concentrations were found. Patients with plasma discharge hFABP concentrations higher than 7.8 ng/mL were at higher risk of CEP (log-rank test, p = 0.01). Logistic stepwise regression analysis revealed discharge hFABP, LVEF and left ventricle mass index independent and significant predictors of CEP (p < 0.05). CONCLUSIONS: In ADHF patients plasma hFABP admission concentrations are related with LV remodeling. Persistently elevated hFABP concentrations have prognostic value, as may reflect continuous myocardial damage despite effective treatment and clinical improvement.

The role of platelets in the development and progression of pulmonary arterial hypertension.

Pulmonary arterial hypertension is a multifactorial disease characterized by vasoconstriction, vascular remodeling, inflammation and thrombosis. Although an increasing number of research confirmed that pulmonary artery endothelial cells, pulmonary artery smooth muscle cells as well as platelets have a role in the pulmonary arterial hypertension pathogenesis, it is still unclear what integrates these factors. In this paper, we review the evidence that platelets through releasing a large variety of chemokines could actively impact the pulmonary arterial hypertension pathogenesis and development. A recent publication revealed that not only an excess of platelet derived cytokines, but also a deficiency may be associated with pulmonary arterial hypertension development and progression. Hence, a simple platelet blockade may not be a correct action to treat pulmonary arterial hypertension. Our review aims to analyse the interactions between the platelets and different types of cells involved in pulmonary arterial hypertension pathogenesis. This knowledge could help to find novel therapeutic options and improve prognosis in this devastating disease.

The significance of diminished sTWEAK and P-selectin content in platelets of patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by proliferative changes in pulmonary arteries. There is growing evidence suggesting that soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and P-selectin could be involved in PAH development and progression. Here we investigate whether circulating platelets may be a source of sTWEAK and contribute to diminished availability of sTWEAK and P-selectin in PAH patients. We have prospectively enrolled two independent study groups of stable patients with confirmed PAH and age matched controls: derivation (10 PAH; 15 controls) and validation (20 PAH; 12 controls). P-selectin and sTWEAK concentrations were measured in platelet-poor plasma and platelet lysate. To avoid procedural bias, in each group we employed different protocols for platelet isolation. Consistently, both in derivation and validation groups PAH patients presented significantly lower sTWEAK content in platelets than control group with no significant differences in plasma levels. Similarly, patients presented comparable to controls plasma P-selectin concentrations and lower concentration in platelet lysate. Kaplan-Meier analysis revealed that patients with low platelet sTWEAK/total protein concentration ratio had more frequently detoriation of PAH in the follow-up (16.51 ±â€¯3.32 months), log-rank test, p = .03. Patients diagnosed with pulmonary arterial hypertension present diminished sTWEAK and P-selectin storage capacity in platelets. Thrombocytes appear to be a major source of sTWEAK that could be released upon local injury and its decreased availability could have an impact on pathophysiology and prognosis in PAH.

Perioperative thrombocytopenia predicts poor outcome in patients undergoing transcatheter aortic valve implantation.

PURPOSE: To determine the time point at which thrombocytopenia after TAVI procedure is an indicator of the worst prognosis, with special consideration of perioperative platelet and coagulation activation as its potential causes. METHODS: Thirty two patients (mean age 78.5±7.9years, 62% females) qualified for TAVI procedure were prospectively evaluated. Platelet counts were assessed at baseline and for the next three postoperative (POD) days. Platelet activation was evaluated by P-selectin (PS, serum, ELISA) and platelet factor 4 (PF-4, CTAD plasma), and blood coagulation activation by prothrombin fragments 1+2 (F1+2, plasma, ELISA). Composite end point (CEP) including death and the need of cardiovascular rehospitalization was assessed after a mean of 14.1±6.7months. RESULTS: During the follow up period half of the patients reached CEP. Thrombocytopenia was more profound and frequent in patients with CEP as compared to those without (p<0.05). No differences regarding either the biomarkers of platelet (PS, PF-4) or coagulation (F1+F2) activation between the groups with and without CEP were found. Patients with moderate-to-severe thrombocytopenia at baseline had worse prognosis (log-rank test, p=0.0003). Based on the receiver operating characteristic curve analysis, the differences between platelet count on each postoperative day and the baseline count did not have any predictive value in CEP occurrence. CONCLUSIONS: Patients with thrombocytopenia following TAVI procedure have poor prognosis, however, the changes on the particular days are not more important than initial platelet count. Further studies are needed to evaluate platelet and blood coagulation activation as potential causes of thrombocytopenia and impaired prognosis related to it.

The causes of thrombocytopenia after transcatheter aortic valve implantation.

INTRODUCTION: Even though thrombocytopenia following transcatheter aortic valve implantation (TAVI) has been described, further investigation of this phenomenon is needed. AIMS: To determine which factors may explain the fall in platelet count that occurs after implantation of a TAVI device, including markers of platelet and blood coagulation activation. MATERIAL AND METHODS: 32 patients without previous indications for dual antiplatelet therapy (mean age 78.5±7.9 years, 62% females) with severe aortic valve stenosis (mean gradient 54.6±16.9mmHg) who qualified for TAVI procedure (Edwards Sapien XT) were prospectively analyzed. Platelet counts were analyzed before the surgery, on the day of the procedure and for the three following postoperative days (POD 1 to 3). To assess platelet activation P-selectin (PS, serum) and platelet factor 4 (PF-4, CTAD plasma) were measured, whereas for the evaluation of coagulation activation prothrombin fragments 1+2 (F1+2, plasma) were assessed before the procedure, on POD-1 and POD-3 (ELISA). RESULTS: During the postoperative period a significant platelet count drop, the most evident on POD-2, was observed followed by a platelet count raise. The platelet count drop correlated directly with the amount of iodinated contrast agent (r=0.42, p=0.016) and inversely with baseline mean platelet volume (r=-0.37, p=0.046). Neither clinical nor perioperative parameters, except contrast medium, influenced platelet count decrease. No significant differences regarding the concentration of the evaluated markers in patients with and without thrombocytopenia were found. PF-4 and F1+2 significantly changed during the study (p<0.05). Greater acute PF-4 decrease correlated with greater acute platelet count drop (r=0.48, p=0.043), and during the study slower PF-4 increase correlated with higher platelet count increase on POD-3 (r=-0.505, p=0.032). Lower baseline PS correlated with lower baseline platelet count and higher platelet count increase on POD-3 (r=0.45, p=0.04 and =-0.55, p=0.02, respectively). No significant correlations between F1+2 concentrations and platelet count changes have been found. CONCLUSIONS: Platelet reduction shortly after TAVI procedure is related to the amount of contrast agent applied during the procedure. Platelet activation and blood coagulation along with impaired baseline platelet renewal might be the mechanisms of thrombocytopenia following TAVI procedure.

Activity of the kynurenine pathway and its interplay with immunity in patients with pulmonary arterial hypertension.

OBJECTIVE: We evaluated blood concentrations of kynurenine pathway metabolites, natural and induced regulatory T cells (nTreg, iTreg), and Th17 cells in order to examine the activity of the kynurenine pathway and its relation to immune status in patients with pulmonary arterial hypertension (PAH). METHODS: Plasma concentrations of tryptophan, kynurenine, kynurenic acid, anthranilic acid, and 3-hydroxykynurenine were quantified in 26 patients with PAH (vs 30 healthy controls) at baseline and after 6 months, and assessed them in relation to clinical parameters, frequencies of lymphocyte subsets, and outcome. RESULTS: The PAH group presented higher concentrations of tryptophan (52.9 (IQR 46.3-57.5) vs 40.3 (35.2-46.3) µmol/L, p=0.00003), kynurenine 2.8 (2.4-3.4) vs 1.9 (1.5-2.3) µmol/L, p=0.000007), kynurenine/tryptophan ratio (0.051 (0.044-0.064) vs 0.043 (0.039-0.055), p=0.03), iTreg frequencies (10.5 (8.8-13.9)% vs 6.8 (5.2-9.5)%, p=0.002) and iTreg/Th17 (1.73 (1.2-2.8) vs 0.93 (0.61-1.27), p=0.003) together with lower ratios of kynurenic acid/kynurenine, 3-hydroxykynurenine/kynurenine, and anthranilic acid/kynurenine. Kynurenine concentrations and kynurenine/tryptophan ratio correlated positively with iTreg/Th17, and inversely with Th17 subsets, whereas kynurenic acid/kynurenine and anthranilic acid/kynurenine ratios correlated positively with Th17. Adverse outcomes occurred in 9 of 26 patients and they showed higher baseline concentrations of kynurenine (3.6 (2.8-4.3) vs 2.7 (2.1-3.2) µmol/L, p=0.033). Median kynurenine values ≥3.4 µmol/L (67% sensitivity, 94% specificity) identified patients with a worse clinical course. CONCLUSIONS: PAH is characterised by upregulated tryptophan metabolism and enhanced biosynthesis of kynurenine. Elevated kynurenine concentration is associated with an adverse clinical course. Dysregulated immunity, delineated by Treg-Th17 imbalance, is directly related to diverse activation of the kynurenine pathway, indicating the potential interplay between kynurenines and the immune system in PAH.

In-silico identification of cardiovascular disease-related SNPs affecting predicted microRNA target sites.

INTRODUCTION: MicroRNAs (miRNAs) are small RNAs that play an important role in the regulation of gene expression. miRNA dysregulation has been associated with phenotypic changes, including cardiovascular diseases (CVDs). OBJECTIVES: The aim of the study was to obtain a list of single nucleotide polymorphisms (SNPs) related to CVDs, with computationally predicted effect on miRNA binding sites, which would verify the hypothesis that miRNA dysregulation can lead to the development of CVDs. MATERIALS AND METHODS: SNPs, CVDs, and miRNAs were the 3 factors subjected to analysis. Based on the publicly available databases, we created a set of SNPs associated with the phenotype of interest and of SNPs located in known miRNA binding sites. We then merged the records assigned by the same SNP, which allowed us to indicate miRNA target sites, whose variants may be associated with CVDs. The results were supplemented with the additional data such as miRNA and mRNA coexpression, differences in the expression between various tissues, and Expression Quantitative Trait Locus analysis. Only in-silico methods, on the basis of publically available information tools and databases, were used. RESULTS: We obtained a list of 47 entries, constituting unique miRNA-SNP allele-phenotype linkages. CONCLUSIONS: Computational approach supports the hypothesis of the linkage between alterations in miRNA function and numerous CVDs. Given the high frequency of SNP incidence, this pathomechanism may be common in the population. Although the obtained results need to be further experimentally validated, limiting the number of interactions to the most probable ones will facilitate the identification of clinically significant associations.