Non-invasive assessment of liver alterations in Senning and Mustard patients.

BACKGROUND: Adults with congenital heart disease and ventricular dysfunction are prone to liver congestion, leading to fibrosis or cirrhosis but little is known about the prevalence of liver disease in atrial switch patients. Liver impairment may develop due to increased systemic venous pressures. This prospective study aimed to assess non-invasively hepatic abnormalities in adults who underwent Senning or Mustard procedures. METHODS: Hepatic involvement was assessed non-invasively clinically by laboratory analysis, hepatic fibrotic markers, sonography, and liver stiffness measurements [transient elastography (TE) and acoustic radiation force impulse imaging (ARFI)]. RESULTS: Overall, 24 adults who had undergone atrial switch operation (13 Senning, 11 Mustard; four female; median age 27.8 years; range 24-45 years) were enrolled. In liver stiffness measurements, only three patients had values within the normal reference. All other patients showed mild, moderate or severe liver fibrosis or cirrhosis, respectively. Using imaging and laboratory analysis, 71% of the subjects had signs of liver fibrosis (46%) or cirrhosis (25%). CONCLUSIONS: Non-invasive screening for liver congestion, fibrosis or cirrhosis could be meaningful in targeted screening for hepatic impairment in patients with TGA-ASO. As expert knowledge is essential, patients should be regularly controlled in highly specialised centres with cooperations between congenital cardiologists and hepatologists.

Placebo and Nocebo Effects in Patients With Takotsubo Cardiomyopathy and Heart-Healthy Controls.

The etiology of takotsubo cardiomyopathy (TTC)-a rare, reversible, and acquired form of cardiac diseases-is not yet fully explained. An exaggerated activation of the sympathetic-nervous-system (SNS) following stressful psychosocial life events is discussed to be of key importance. In this experimental study, we tested whether TTC patients, compared to heart-healthy controls, respond more strongly to supporting placebo interventions and stressful nocebo interventions targeting cardiac function. In a single experimental session, 20 female TTC patients and 20 age matched (mean age 61.5 years, ± 12.89) catheter-confirmed heart-healthy women were examined. Saline solution was administered three times i.v. to all participants, with the verbal suggestion they receive an inert substance with no effects on the heart (neutral condition), a drug that would support cardiac functions (positive condition), and a drug that would burden the heart (negative condition). Systolic and diastolic blood pressure (DBP/SBP), heart rate (HR), endocrine markers cortisol (µg/dl), copeptin (pmol/l), and subjective stress ratings (SUD) were assessed to examine alterations of the SNS and the hypothalamic-pituitary-adrenal axis (HPA). Before and after each intervention SUD was rated. One pre and three post serum cortisol and copeptin samples were assessed, and a long-term electrocardiogram as well as non-invasive, continuous blood pressure was recorded. The study design elucidated a significant increase of SUD levels as a response to the nocebo intervention, while perceived stress remained unaffected during the preceding neutral and positive interventions. Increasing SUD levels were accompanied by higher SBP and an anticipatory increase of HR shortly prior to the nocebo intervention. SBP increased also as a response to positive verbal suggestions (Bonferroni-corrected p-values > .05). Alterations of cortisol and copeptin due to the interventions and significant placebo effects failed to appear. Interestingly no differences between TCC patients and controls could be found.These findings do not support the assumption of an exaggerated activation of the SNS as a discriminatory factor for TTC. Since especially the nocebo intervention revealed negative subjective and objective effects, our results underscore the urgent need to consider carefully the impact of verbal suggestions in the interaction with cardiac patients in daily clinical routine. This study is registered at the Deutsches Register Klinischer Studien (DRKS00009296).

Postprocedural high-sensitivity troponin T and prognosis in patients with non-ST-segment elevation myocardial infarction treated with early percutaneous coronary intervention.

BACKGROUND: The association of postprocedural high-sensitivity troponin T (hs-TnT) with prognosis of non-ST-segment elevation myocardial infarction (NSTEMI) patients is incompletely investigated. AIM: To assess the prognostic value of hs-TnT in NSTEMI patients undergoing early percutaneous coronary intervention (PCI). METHODS: This study included 3783 patients with NSTEMI undergoing early PCI. Preprocedural and peak postprocedural hs-TnT was measured. Patients were divided into 3 groups: a group with postprocedural hs-TnT in the 1st tertile (hs-TnT <105ng/L; n=1264), a group with postprocedural hs-TnT in the 2nd tertile (hs-TnT ≥105ng/L to 470ng/L; n=1258) and a group with postprocedural hs-TnT in the 3rd tertile (hs-TnT >470ng/L; n=1261). The primary outcome was 1-year all-cause mortality. RESULTS: Overall, there were 299 deaths: 59 (5.5%), 98 (8.2%) and 142 deaths (12.6%) among patients of the 1st, 2nd and 3rd postprocedural hs-TnT tertiles (unadjusted hazard ratio [HR]=1.65, 95% confidence interval [CI] 1.20 to 2.67; P=0.002 for tertile 2 vs tertile 1 and unadjusted HR=2.41 [1.79-3.25]; P<0.001 for tertile 3 vs tertile 1). After adjustment postprocedural hs-TnT was independently associated with the risk of all-cause mortality (adjusted [HR]=1.22 [1.13-1.33], P<0.001 for 1 unit higher log hs-TnT). Postprocedural hs-TnT improved the risk prediction of the model of all-cause mortality (the C statistic of the model without [with baseline variables only] and with incorporation of postprocedural hs-TnT was 0.759 [0.732-0.782] and 0.772 [0.746-0.794], respectively; P<0.001). CONCLUSIONS: In patients with NSTEMI undergoing early PCI, postprocedural hs-TnT is independently associated with increased risk of mortality up to 1year after PCI.

Neutrophil gelatinase-associated lipocalin reflects inflammation and is not a reliable renal biomarker in neonates and infants after cardiopulmonary bypass: a prospective case-control study.

Introduction Acute kidney injury is a frequent complication after cardiac surgery with cardiopulmonary bypass in infants. Neutrophil gelatinase-associated lipocalin has been suggested to be a promising early biomarker of impending acute kidney injury. On the other hand, neutrophil gelatinase-associated lipocalin has been shown to be elevated in systemic inflammatory diseases without renal impairment. In this secondary analysis of data from our previous study on acute kidney injury after infant cardiac surgery, our hypothesis was that neutrophil gelatinase-associated lipocalin may be associated with surgery-related inflammation. METHODS: We prospectively enrolled 59 neonates and infants undergoing cardiopulmonary bypass surgery for CHD and measured neutrophil gelatinase-associated lipocalin in plasma and urine and interleukin-6 in the plasma. Values were correlated with postoperative acute kidney injury according to the paediatric Renal-Injury-Failure-Loss-Endstage classification. RESULTS: Overall, 48% (28/59) of patients developed acute kidney injury. Of these, 50% (14/28) were classified as injury and 11% (3/28) received renal replacement therapy. Both plasma and urinary neutrophil gelatinase-associated lipocalin values were not correlated with acute kidney injury occurrence. Plasma neutrophil gelatinase-associated lipocalin showed a strong correlation with interleukin-6. Urinary neutrophil gelatinase-associated lipocalin values correlated with cardiopulmonary bypass time. CONCLUSION: Our results suggest that plasma and urinary neutrophil gelatinase-associated lipocalin values are not reliable indicators of impending acute kidney injury in neonates and infants after cardiac surgery with cardiopulmonary bypass. Inflammation may have a major impact on plasma neutrophil gelatinase-associated lipocalin values in infant cardiac surgery. Urinary neutrophil gelatinase-associated lipocalin may add little prognostic value over cardiopulmonary bypass time.

Comparative prognostic value of postprocedural creatine kinase myocardial band and high-sensitivity troponin T in patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention.

OBJECTIVES: We aimed to assess the prognostic value of postprocedural creatine kinase myocardial band (CK-MB) and cardiac troponin (cTn) in patients with non-ST-segment elevation myocardial infarction (NSTEMI). BACKGROUND: Whether postprocedural CK-MB or cTn is a better biomarker to stratify the risk after percutaneous coronary intervention (PCI) remains unknown. METHODS: This study included 2,077 patients with NSTEMI undergoing early PCI. Peak postprocedural values of CK-MB and high-sensitivity cTn T (hs-cTnT) were analyzed. The primary outcome was 3-year mortality. RESULTS: The median values of peak postprocedural CK-MB and hs-cTnT were 18.3 U L-1 and 0.140 µg L-1 , respectively. Overall, 211 patients died during follow-up. There were 129 deaths in patients with CK-MB >the median value and 82 deaths in those with CK-MB ≤the median value (Kaplan-Meier estimates of 3-year mortality, 18.9% and 14.0%, respectively; hazard ratio [HR] = 1.52, 95% confidence interval [CI] 1.16-2.01; P < 0.001). There were 134 deaths in patients with hs-cTnT >the median value and 77 deaths in patients with hs-cTnT ≤the median value (Kaplan-Meier estimates of 3-year mortality, 19.9% and 13.2%, respectively; HR = 1.90 [1.44-2.52]; P < 0.001). After adjustment, peak postprocedural CK-MB (adjusted HR = 1.05 [1.02-1.07], P < 0.001 for each 24 U L-1 increment) and hs-cTnT (adjusted HR = 1.12 [1.01-1.25], P = 0.037 for each unit higher log hs-cTnT) remained independently associated with the risk of 3-year mortality. The C-statistic(s) of the model with CK-MB and hs-cTnT were 0.789 [0.757-0.817] and 0.793 [0.762-0.821], respectively (P = 0.585). CONCLUSION: In patients with NSTEMI undergoing early PCI, peak postprocedural CK-MB and hs-cTnT are independently associated with the risk of 3-year mortality. © 2017 Wiley Periodicals, Inc.

Non-invasive assessment of liver changes in Eisenmenger patients.

BACKGROUND: Eisenmenger syndrome as a severe form of cyanotic congenital heart disease results in a complex multisystemic disorder. Due to increased systemic venous pressure and the inability to ensure systemic perfusion and metabolic requirements, the liver may develop congestion, fibrosis or cirrhosis. This study aimed to assess hepatic abnormalities in Eisenmenger patients non-invasively. METHODS AND RESULTS: 10 adults with Eisenmenger syndrome (six female; median age 44.2years; range 23-62years) were enrolled and hepatic involvement was assessed - using clinical assessment, laboratory analysis, hepatic fibrotic markers, abdominal sonography and liver stiffness measurements (transient elastography (TE) and acoustic radiation force impulse imaging (ARFI)). Using imaging and laboratory analysis, 60% (6/10) of the Eisenmenger patients had signs of liver fibrosis (5/10) or cirrhosis (1/10). While TE, however, showed no relevant liver abnormalities in any Eisenmenger patient, ARFI detected liver fibrosis in 5/10 and cirrhosis and 1/10 patients. CONCLUSIONS: Adult Eisenmenger patients are at increased risk of hepatic impairment. Non-invasive screening could be helpful in detecting liver alterations. In our small series, however, TE could not detect fibrosis or cirrhosis in any affected patient, while ARFI was very reliable. Patients should be transferred to centres, where a multidisciplinary expert knowledge is available and a close collaboration between cardiologists and hepatologists exists.

Alkaline phosphatase and prognosis in patients with coronary artery disease.

BACKGROUND: The evidence on the association between alkaline phosphatase (ALP) and prognosis of patients with coronary artery disease (CAD) is limited. The aim of this study was to assess the association of ALP with the risk of mortality or coronary events in patients with CAD. MATERIALS AND METHODS: The study included 5540 patients with angiography-proven CAD treated with catheter-based coronary revascularization. Baseline ALP measurements were available for analysis in all patients. Patients were divided into three groups: a group with an ALP activity in the 1st tertile (ALP ≤ 65·5 U/L; n = 1855), a group with an ALP activity in the 2nd tertile (ALP > 65·5 to 85·7 U/L; n = 1839) and a group with an ALP in the 3rd tertile (ALP > 85·7 U/L; n = 1846). The primary outcome was all-cause mortality at 3-year follow-up. RESULTS: All-cause deaths (number [Kaplan-Meier estimates]) occurred in 443 patients: 117 (7·2%), 130 (8·1%) and 196 deaths (11·8%) among patients of the 1st, 2nd and 3rd ALP tertiles (unadjusted hazard ratio [HR] = 1·33, 95% confidence interval [CI]: 1·19 to 1·50; P < 0·001, calculated per tertile increment in the ALP activity). After adjustment in multivariable Cox proportional hazards model, ALP was independently associated with the risk of all-cause mortality (adjusted HR = 1·33 [1·18-1·51], P < 0·001, calculated per unit increment in log ALP). The multivariable model for all-cause mortality with baseline variables without ALP had a C statistic of 0·820 [0·797-0·843] which increased to 0·825 [0·804-0·849] after ALP inclusion; delta C statistic 0·005 [0·001-0·011]; P < 0·001. CONCLUSIONS: In patients with CAD, elevated ALP activity was independently associated with the risk of 3-year all-cause mortality.

Pharmacokinetics of tranexamic acid in neonates and infants undergoing cardiac surgery.

AIM: Tranexamic acid (TXA) continues to be one of the antifibrinolytics of choice during paediatric cardiac surgery. However, in infants less than 1 year of age, the optimal dosing based on pharmacokinetic (PK) considerations is still under discussion. METHODS: Forty-three children less than 1 year of age were enrolled, of whom 37 required the use of cardiopulmonary bypass (CPB) and six were operated on without CPB. Administration of 50 mg kg-1 TXA intravenously at the induction of anaesthesia was followed by 50 mg kg-1 into the CPB prime in the CPB group. Plasma concentrations of TXA were analysed by gas chromatography-mass spectrometry. PK data were investigated using nonlinear mixed-effect models. RESULTS: A two-compartment model was fitted, with the main covariates being allometrically scaled bodyweight, CPB, postmenstrual age (PMA). Intercompartmental clearance (Q), peripheral volume (V2), systemic clearance, (CL) and the central volume (V1) were calculated. Typical values of the PK parameter estimates were as follows: CL = 3.78 [95 % confidence interval (CI) 2.52, 5.05] l h-1 ; central volume of distribution = 13.6 (CI 11.7, 15.5) l; Q = 16.3 (CI 13.5, 19.2) l h-1 ; V2 = 18.0 (CI 16.1, 19.9) l. Independently of age, 10 mg kg-1 TXA as a bolus, a subsequent infusion of 10 mg kg-1 h-1 , then a 4 mg kg-1 bolus into the prime and a reduced infusion of 4 mg kg-1 h-1 after the start of CPB are required to maintain TXA concentrations continuously above 20 µg ml-1 , the threshold value for an effective inhibition of fibrinolysis and far lower than the usual peak concentrations (the '10-10-4-4 rule'). CONCLUSIONS: The introduction of a modified dosing regimen using a starting bolus followed by an infusion and a CPB prime bolus would prohibit the potential risk of seizures caused by high peak concentrations and also maintain therapeutic plasma concentration above 20 µg ml-1 .

Biomarker-based diagnosis of pacemaker and implantable cardioverter defibrillator pocket infections: A prospective, multicentre, case-control evaluation.

BACKGROUND: The use of cardiac implantable electronic devices (CIED) has risen steadily, yet the rate of cardiac device infections (CDI) has disproportionately increased. Amongst all cardiac device infections, the pocket infection is the most challenging diagnosis. Therefore, we aimed to improve diagnosis of such pocket infection by identifying relevant biomarkers. METHODS: We enrolled 25 consecutive patients with invasively and microbiologically confirmed pocket infection. None of the patients had any confounding conditions. Pre-operative levels of 14 biomarkers were compared in infected and control (n = 50) patients. Our selected biomarkers included white blood cell count (WBC), C-reactive protein (CRP), procalcitonin (PCT), lipopolysaccharide binding protein, high-sensitivity C-reactive protein (HS-CRP), polymorphonuclear-elastase, presepsin, various interleukins, tumor necrosis factor α (TNF-α), and granulocyte macrophage colony-stimulating factor (GM-CSF). RESULTS: Of the 25 patients with isolated pocket infection (70±13years, 76% male, 40% ICDs), none presented with leukocytosis. In contrast, they had higher serum levels of HS-CRP (p = 0.019) and PCT (p = 0.010) than control patients. Median PCT-level was 0.06 ng/mL (IQR 0.03-0.07 ng/mL) in the study group versus 0.03 ng/mL (IQR 0.02-0.04 ng/mL) in controls. An optimized PCT cut-off value of 0.05 ng/mL suggests pocket infection with a sensitivity of 60% and specificity of 82%. In addition TNF-α- and GM-CSF-levels were lower in the study group. Other biomarkers did not differ between groups. CONCLUSION: Diagnosis of isolated pocket infections requires clinical awareness, physical examination, evaluation of blood cultures and echocardiography assessment. Nevertheless, measurement of PCT- and HS-CRP-levels can aid diagnosis. However, no conclusion can be drawn from normal WBC-values. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01619267.

An Automated Assay for Growth Differentiation Factor 15.

BACKGROUND: Growth differentiation factor 15 (GDF-15) can serve as a biomarker for cardiovascular disease burden and risk. We evaluated a new, fully automated electrochemiluminescence immunoassay for measuring GDF-15. METHODS: Six laboratories independently characterized the Elecsys® GDF-15 assay (Roche Diagnostics) under routine conditions. Within-run precision (repeatability), within-laboratory precision (intermediate precision), and between-laboratory precision (reproducibility) were assessed. Plasma-serum sample correlation, reagent lot-to-lot reproducibility, and instrument comparisons were performed. The Elecsys assay was compared to a research immunoradiometric assay (IRMA) and a commercially available ELISA. GDF-15 concentrations were measured with the Elecsys assay in 739 apparently healthy individuals. RESULTS: CVs for within-run and within-laboratory precision ranged from 0.7% to 7.7% and 1.7% to 8.6%, respectively, for samples containing 670-16039 ng/L. CVs for between-laboratory precision ranged from 7.1% to 8.9% (766-14289 ng/L). Recovery of GDF-15 was comparable for serum, Li-heparin plasma, K2- and K3-EDTA plasma, and citrated plasma, between 2 reagent lots, and on the cobas e 411 and cobas e 601 analyzers (Roche Diagnostics). GDF-15 concentrations in the clinically relevant range (400-3000 ng/L) measured with the Elecsys assay showed a good correlation and agreement with those measured by IRMA or ELISA. GDF-15 concentrations in apparently healthy individuals increased with age but did not vary by sex. CONCLUSIONS: The Elecsys GDF-15 assay demonstrates a robust analytic performance under routine conditions and provides an automated method for measuring GDF-15 concentrations in serum and plasma.

Gamma-glutamyl transferase and atrial fibrillation in patients with coronary artery disease.

BACKGROUND: The association between gamma-glutamyl transferase (GGT) and atrial fibrillation (AF) in patients with coronary artery disease (CAD) is uncertain. METHODS: This study included 5501 consecutive patients with CAD, all of whom had baseline GGT measurements available. The primary endpoint was presence of AF. RESULTS: Overall 809 patients (14.7%) had AF on hospital admission. Patients with AF had significantly higher GGT activity compared with patients in sinus rhythm (median [25th-75th percentile]: 52.0 [32.9-96.0] U/L versus 34.8 [23.8-55.9] U/L, P<0.001). The prevalence of AF increased from 8.6% of patients in the first GGT decile to 30.3% of patients in the tenth decile (P<0.001). After multivariable adjustment, GGT activity remained independently associated with the probability of the presence of AF (adjusted adds ratio=1.66, 95% confidence interval 1.53-1.81, P<0.001 for each standard deviation increment in the GGT logarithmic scale). GGT predicted the probability of AF with an area under the receiver operating characteristic (ROC) curve of 0.6496, 95% confidence interval 0.6287 to 0.6705, P<0.001 indicating moderate strength to discriminate between patients with and without AF. CONCLUSIONS: In patients with CAD, elevated GGT activity is independently associated with the presence of AF. GGT may be a circulating marker of the risk for AF.

Rutoside and Hydrolytic Enzymes Do Not Attenuate Marathon-Induced Inflammation.

INTRODUCTION: Vigorous and prolonged exercise such as marathon running increases inflammatory markers and the risk of upper respiratory illness (URI) in athletes. Nutritional supplements are being tested as countermeasures of exercise-induced inflammation and immune dysfunction. METHODS: In this prospective randomized, double-blind, placebo-controlled phase I trial, healthy male runners (N = 138, age 42 ± 11 yr) were supplemented with rutoside (600-1200 mg·d) and hydrolytic enzymes (540-1080 mg·d bromelain, 288-576 mg·d trypsin) (WOB) or placebo (PL) for 1 wk before and 2 wk after the Munich Marathon 2013. Blood samples were collected 5 wk prerace and immediately, 24 h, and 72 h postrace and analyzed for inflammation biomarkers (interleukins [IL] 6 and 10, high-sensitivity C-reactive protein, and leukocytes). URI rates, assessed by the Wisconsin Upper Respiratory Symptom Survey, were compared between the study groups during the 2-wk period after the marathon race. URI was defined if the Wisconsin Upper Respiratory Symptom Survey score was equal or greater than seven, representing either one severe symptom or seven mild symptoms. RESULTS: Immediately postrace, the increase of IL-6 was not significantly different between the WOB and the PL groups (median [interquartile range]: WOB, 33.8 [22.5-58.8] ng·L; PL, 35.6 [24.8-61.29] ng·L; P = 0.758). No significant group differences were observed for increases of IL-10, high-sensitivity C-reactive protein, or leukocytes pre- to postrace (all P > 0.05). From race day until 2 wk after the marathon race, the percentage of individuals with at least one URI did not significantly differ between the groups (WOB, 50.0%; PL, 51.5%; P = 0.859). CONCLUSION: Supplementation with rutoside and hydrolytic enzymes before and after a marathon race did not attenuate postrace inflammation or decrease URI incidence in nonelite male marathon runners.

Oral thrombin inhibitor aggravates platelet adhesion and aggregation during arterial thrombosis.

In patients with atrial fibrillation, oral anticoagulation with oral thrombin inhibitors (OTIs), in contrast to vitamin K antagonists (VKAs), associates with a modest increase in acute coronary syndromes (ACSs). Whether this observation is causatively linked to OTI treatment and, if so, whether OTI action is the result of a lower antithrombotic efficacy of OTI compared to VKA or reflects a yet undefined prothrombotic activity of OTI remain unclear. We analyzed platelet function in patients receiving OTI or dose-adapted VKA under static and flow conditions. In vivo, we studied arterial thrombosis in OTI-, VKA-, and vehicle-treated mice using carotid ligation and wire injury models. Further, we examined thrombus formation on human atherosclerotic plaque homogenates under arterial shear to address the relevance to human pathology. Under static conditions, aggregation in the presence of ristocetin was increased in OTI-treated blood, whereas platelet reactivity and aggregation to other agonists were only marginally affected. Under flow conditions, firm platelet adhesion and thrombus formation on von Willebrand factor, collagen, and human atherosclerotic plaque were increased in the presence of OTI in comparison to VKA. OTI treatment was associated with increased thrombus formation in injured carotid arteries of mice. Inhibition or ablation of GPIbα-thrombin interactions abolished the effect of OTI on thrombus formation, suggesting a mechanistic role of the platelet receptor GPIbα and its thrombin-binding site. The effect of OTI was also abrogated in the presence of aspirin. In summary, OTI treatment has prothrombotic activity that might contribute to the increase in ACS observed clinically in patients.

High-Sensitivity Troponin T and Mortality After Elective Percutaneous Coronary Intervention.

BACKGROUND: The prognostic value of high-sensitivity troponin T (hs-TnT) elevation after elective percutaneous coronary intervention (PCI) in patients with or without raised baseline hs-TnT levels is unclear. OBJECTIVES: The goal of this study was to assess whether the prognostic value of post-procedural hs-TnT level after elective PCI depends on the baseline hs-TnT level. METHODS: This study included 5,626 patients undergoing elective PCI who had baseline and peak post-procedural hs-TnT measurements available. The primary outcome was 3-year mortality (with risk estimates calculated per SD increase of the log hs-TnT scale). RESULTS: Patients were divided into 4 groups: nonelevated baseline and post-procedural hs-TnT levels (hs-TnT ≤0.014 µg/l; n = 742); nonelevated baseline but elevated post-procedural hs-TnT levels (peak post-procedural hs-TnT >0.014 µg/l; n = 2,721); elevated baseline hs-TnT levels (hs-TnT >0.014 µg/l) with no further rise post-procedure (n = 516); and elevated baseline hs-TnT levels with a further rise post-procedure (n = 1,647). A total of 265 deaths occurred: 6 (1.6%) in patients with nonelevated baseline and post-procedural hs-TnT levels; 54 (3.8%) in patients with nonelevated baseline but elevated post-procedural hs-TnT levels; 50 (16.0%) in patients with elevated baseline hs-TnT levels with no further rise post-procedure; and 155 (18.2%) in patients with elevated baseline hs-TnT levels with a further rise post-procedure (p < 0.001). After adjustment, baseline hs-TnT levels (hazard ratio [HR]: 1.22; 95% confidence interval [CI]: 1.09 to 1.38; p < 0.001) but not peak post-procedural hs-TnT levels (HR: 1.04; 95% CI: 0.85 to 1.28; p = 0.679) were associated with an increased risk of mortality. Peak post-procedural hs-TnT findings were not associated with mortality in patients with nonelevated (HR: 0.93; 95% CI: 0.69 to 1.25; p = 0.653) or elevated (HR: 1.24; 95% CI: 0.91 to 1.69; p = 0.165) baseline hs-TnT levels. CONCLUSIONS: In patients with coronary artery disease undergoing elective PCI, an increase in post-procedural hs-TnT level did not offer prognostic information beyond that provided by the baseline level of the biomarker.

Valor pronóstico de la troponina T de alta sensibilidad tras intervención coronaria percutánea en pacientes con enfermedad coronaria estable / Prognostic value of high-sensitivity troponin T after percutaneous coronary intervention in patients with stable coronary artery disease

Introducción y objetivos: Está por clarificar el valor pronóstico de la troponina T de alta sensibilidad tras una intervención coronaria percutánea en pacientes con enfermedad coronaria estable. Esta cuestión clínicamente relevante se ha investigado en 3.463 pacientes consecutivos a los que se practicó una intervención coronaria percutánea. Métodos: En este estudio se incluyó a pacientes con enfermedad coronaria estable y un valor basal de troponina T de alta sensibilidad menor que el límite superior de referencia del percentil 99 (0,014 μg/l). Se determinó la troponina T de alta sensibilidad antes de la intervención y luego al cabo de 6, 12 y 24 h. El objetivo principal fue la mortalidad por cualquier causa. Resultados: Se clasificó a los pacientes en un grupo con un valor máximo de troponina T tras la intervención ≤ percentil 99 (n = 742), un grupo con un valor máximo de troponina T tras la intervención entre > percentil 99 y 5 veces el percentil 99 (n = 1.928) y un grupo con un valor máximo de troponina T tras la intervención > 5 veces el percentil 99 (n = 793). La edad avanzada, el índice de masa corporal más bajo, el valor de troponina basal, las lesiones complejas, las lesiones en bifurcación y la longitud del stent se asociaron de manera independiente a concentraciones de troponina T aumentadas después de la intervención. La mediana de seguimiento fue de 15,5 meses. Hubo 56 muertes: 5 pacientes (1,7%) con valor máximo de troponina T tras la intervención ≤ percentil 99, 35 (4,5%) con valor máximo de troponina T tras la intervención entre > percentil 99 y 5 veces el percentil 99, y 16 (4,3%) del grupo con valor máximo de troponina T tras la intervención > 5 veces el percentil 99 (hazard ratio = 1,50; intervalo de confianza del 95%, 1,01-2,25; p = 0,047). Tras el ajuste, el valor máximo de troponina T tras el procedimiento no mostró asociación independiente con la mortalidad tras la intervención coronaria percutánea (p = 0,094). Conclusiones: En los pacientes con enfermedad coronaria estable y sin elevación basal de la troponina T de alta sensibilidad, la elevación de esta después de una intervención coronaria percutánea no se asoció a mayor mortalidad tras el procedimiento (AU)

Introduction and objectives: The prognostic value of high-sensitivity troponin T after percutaneous coronary intervention in patients with stable coronary artery disease is unclear. We investigated this clinically relevant question in 3463 consecutive patients undergoing percutaneous coronary intervention. Methods: This study included patients with stable coronary artery disease and baseline high-sensitivity troponin T below the 99th percentile upper reference limit (0.014 μg/L). High-sensitivity troponin T was measured before and at 6, 12 and 24 hours after the procedure. The primary outcome was all-cause mortality. Results: Patients were divided into a group with peak postprocedural troponin T ≤ 99th percentile (n = 742), a group with peak postprocedural troponin T > 99th to 5 × 99th percentile (n = 1928), and a group with peak postprocedural troponin T > 5 × 99th percentile upper reference limit (n = 793). Advanced age, smaller body mass index, baseline troponin level, complex lesions, bifurcation lesions and stented length were independently associated with elevated troponin T levels after the procedure. The median follow-up was 15.5 months. There were 56 deaths: 5 deaths (1.7%) among patients with peak postprocedural troponin T ≤ 99th percentile, 35 deaths (4.5%) among patients with peak postprocedural troponin T > 99th to 5 × 99th percentile and 16 deaths (4.3%) among patients with peak postprocedural troponin T > 5 × 99th percentile upper reference limit (hazard ratio = 1.50; 95% confidence interval, 1.01-2.25; P = .047). After adjustment, peak postprocedural troponin T level was not independently associated with mortality after percutaneous coronary intervention (P = .094). Conclusions: In patients with stable coronary artery disease and without elevated baseline high-sensitivity troponin T, elevated high-sensitivity troponin T level after percutaneous coronary intervention was not associated with postprocedural mortality (AU)

Association of progression or regression of coronary artery atherosclerosis with long-term prognosis.

BACKGROUND: The association between coronary atherosclerosis progression or regression and long-term prognosis remains poorly defined. We assessed the association of atherosclerosis progression or regression with long-term mortality and factors that promote angiographic progression or regression of coronary atherosclerosis in patients with angiographically proven coronary artery disease. METHODS: The study included 605 patients with coronary artery disease who underwent coronary angiography at baseline and at 2 years later. Pan-coronary artery tree quantitative coronary angiography was performed. Of 6259 coronary segments (10.3 lesions per patient) analyzed, 1790 non-stented segments with ≥25% diameter stenosis at baseline were included. Atherosclerosis progression or regression was defined as a decrease or increase in the mean minimal lumen diameter (MLD) of the non-stented segments of ≥0.2 mm in the 2-year angiography compared to baseline angiography. The primary outcome was all-cause mortality. RESULTS: Based on the change in mean MLD between baseline and 2-year angiography, patients were divided into 3 groups: the group with progression of atherosclerosis (n=53; 8.8%), the group with no progression or regression of atherosclerosis (n=472; 78.0%) and the group with regression of atherosclerosis (n=80; 13.2%). There were 126 deaths over 8-year follow-up: 17 deaths among patients with progression, 103 deaths among patients with no progression/regression and 6 deaths among patients with regression (Kaplan-Meier estimates of mortality, 37.5%, 25.2% and 8.9%, respectively; adjusted hazard ratio=1.16, 95% confidence interval 1.05 to 1.29, P=.004 for 0.1 mm reduction in mean MLD). CONCLUSIONS: Progression or regression of coronary atherosclerosis in non-treated coronary segments was significantly associated with 8-year mortality.

Stimulators of the soluble guanylyl cyclase: promising functional insights from rare coding atherosclerosis-related GUCY1A3 variants.

Stimulators of the soluble guanylyl cyclase (sGC) are emerging therapeutic agents in cardiovascular diseases. Genetic alterations of the GUCY1A3 gene, which encodes the α1 subunit of the sGC, are associated with coronary artery disease. Studies investigating sGC stimulators in subjects with CAD and carrying risk-related variants in sGC are, however, lacking. Here, we functionally investigate the impact of coding GUCY1A3 variants on sGC activity and the therapeutic potential of sGC stimulators in vitro. In addition to a known loss-of-function variant, eight coding variants in GUCY1A3 were cloned and expressed in HEK 293 cells. Protein levels and dimerization capability with the ß1 subunit were analysed by immunoblotting and co-immunoprecipitation, respectively. All α1 variants found in MI patients dimerized with the ß1 subunit. Protein levels were reduced by 72 % in one variant (p < 0.01). Enzymatic activity was analysed using cGMP radioimmunoassay after stimulation with a nitric oxide (NO) donor. Five variants displayed decreased cGMP production upon NO stimulation (p < 0.001). The addition of the sGC stimulator BAY 41-2272 increased cGMP formation in all of these variants (p < 0.01). Except for the variant leading to decreased protein level, cGMP amounts reached the wildtype NO-induced level after addition of BAY 41-2272. In conclusion, rare coding variants in GUCY1A3 lead to reduced cGMP formation which can be rescued by a sGC stimulator in vitro. These results might therefore represent the starting point for discovery of novel treatment strategies for patients at risk with coding GUCY1A3 variants.

Prognostic Value of High-sensitivity Troponin T After Percutaneous Coronary Intervention in Patients With Stable Coronary Artery Disease.

INTRODUCTION AND OBJECTIVES: The prognostic value of high-sensitivity troponin T after percutaneous coronary intervention in patients with stable coronary artery disease is unclear. We investigated this clinically relevant question in 3463 consecutive patients undergoing percutaneous coronary intervention. METHODS: This study included patients with stable coronary artery disease and baseline high-sensitivity troponin T below the 99th percentile upper reference limit (0.014µg/L). High-sensitivity troponin T was measured before and at 6, 12 and 24hours after the procedure. The primary outcome was all-cause mortality. RESULTS: Patients were divided into a group with peak postprocedural troponin T≤99th percentile (n=742), a group with peak postprocedural troponin T>99th to 5×99th percentile (n=1928), and a group with peak postprocedural troponin T>5×99th percentile upper reference limit (n=793). Advanced age, smaller body mass index, baseline troponin level, complex lesions, bifurcation lesions and stented length were independently associated with elevated troponin T levels after the procedure. The median follow-up was 15.5 months. There were 56 deaths: 5 deaths (1.7%) among patients with peak postprocedural troponin T≤99th percentile, 35 deaths (4.5%) among patients with peak postprocedural troponin T>99th to 5×99th percentile and 16 deaths (4.3%) among patients with peak postprocedural troponin T>5×99th percentile upper reference limit (hazard ratio=1.50; 95% confidence interval, 1.01-2.25; P=.047). After adjustment, peak postprocedural troponin T level was not independently associated with mortality after percutaneous coronary intervention (P=.094). CONCLUSIONS: In patients with stable coronary artery disease and without elevated baseline high-sensitivity troponin T, elevated high-sensitivity troponin T level after percutaneous coronary intervention was not associated with postprocedural mortality.

Prognostic value of gamma-glutamyl transferase in patients with diabetes mellitus and coronary artery disease.

OBJECTIVES: The aim of the study was to investigate the association between gamma-glutamyl transferase (GGT) activity and mortality in patients with diabetes mellitus and coronary artery disease (CAD). DESIGN AND METHODS: The study included 1448 patients with diabetes and angiography-proven CAD who underwent percutaneous coronary intervention (PCI). Baseline GGT measurements were available in all patients. The primary outcome was 3-year mortality. RESULTS: Patients were divided into 3 groups: a group consisting of patients with a GGT activity in the 1st tertile (GGT≤29.4U/L; n=487), a group consisting of patients with a GGT activity in the 2nd tertile (GGT>29.4-52.5U/L; n=479) and a group consisting of patients with GGT in the 3rd tertile (GGT>52.5U/L; n=482). Overall, there were 179 deaths: 46 (11.9%), 49 (12.1%) and 84 deaths (21.4%) among patients of the 1st, 2nd and 3rd GGT tertiles, respectively (adjusted hazard ratio [HR]=1.25, 95% confidence interval [CI] 1.05-1.49, P=0.011). Cardiac death occurred in 101 patients: 22 (5.8%), 30 (7.2%) and 49 deaths (12.9%) among patients of the 1st, 2nd and 3rd GGT tertiles, respectively (adjusted HR=1.23 [0.96-1.58], P=0.104, with risk estimates calculated per standard deviation increase in the logarithmic scale of GGT). GGT improved the risk prediction of models of all-cause (P=0.020) but not cardiac (P=0.135) mortality (P values show the difference in C-statistics between the models without and with GGT). CONCLUSION: In patients with diabetes and CAD treated with PCI, elevated GGT was independently associated with the risk of 3-year all-cause mortality.

Relation of Gamma-Glutamyl Transferase to Cardiovascular Events in Patients With Acute Coronary Syndromes.

The prognostic value of gamma-glutamyl transferase (GGT) in patients with acute coronary syndromes (ACS) has been incompletely investigated. We investigated this clinically relevant question in 2,534 consecutive patients with ACS who underwent percutaneous coronary intervention (PCI). GGT activity was measured before PCI procedure in all patients. Statin therapy at hospital discharge was prescribed in 94% of the patients. The primary outcome was 3-year mortality. Patients were divided into 3 groups: the group with GGT in the first tertile (GGT <28 U/L; n = 848 patients), the group with GGT in the second tertile (GGT 28 to <50 U/L; n = 843 patients), and the group with GGT in the third tertile (GGT ≥50 U/L; n = 843 patients). The primary outcome (all-cause deaths) occurred in 250 patients: 70 deaths (9.7%) among patients of the first, 69 deaths (9.0%) among patients of the second, and 111 deaths (14.8%) among patients of the third GGT tertile (adjusted hazard ratio [HR] 1.24, 95% CI 1.08 to 1.42, p = 0.002) and cardiac and noncardiac deaths occurred in 157 (63%) and 93 patients (37%), respectively. GGT was associated with the increased risk of noncardiac mortality (adjusted HR 1.35 [1.09 to 1.66], p = 0.005) but not cardiac mortality (adjusted HR 1.16 [0.97 to 1.38], p = 0.098; all 3 risk estimates were calculated per SD increase in the logarithmic scale of GGT activity). In conclusion, in contemporary patients with ACS treated with PCI and on statin therapy, elevated GGT activity was associated with the increased risk of all-cause and noncardiac mortality but not with the risk of cardiac mortality.