Proenkephalin Improves Cardio-Renal Risk Prediction in Acute Coronary Syndromes: The KID-ACS Score.

BACKGROUND AND AIMS: Circulating proenkephalin (PENK) is a stable endogenous polypeptide with fast response to glomerular dysfunction and tubular damage. This study examined the predictive value of PENK for renal outcomes and mortality in patients with acute coronary syndromes (ACS). METHODS: Proenkephalin was measured in plasma in a prospective multicentre ACS cohort from Switzerland (n=4787) and in validation cohorts from the UK (n=1141), Czechia (n=927), and Germany (n=220). A biomarker-enhanced risk score (KID-ACS score) for simultaneous prediction of in-hospital acute kidney injury (AKI) and 30-day mortality was derived and externally validated. RESULTS: On multivariable adjustment for established risk factors, circulating PENK remained associated with in-hospital AKI (per log2 increase: adjusted odds ratio [OR] 1.53, 95% confidence interval [CI] 1.13-2.09, P=0.007) and 30-day mortality (adjusted hazard ratio [HR] 2.73, 95% CI 1.85-4.02, P<0.001). The KID-ACS score integrates PENK and showed an area under the receiver operating characteristic curve (AUC) of 0.72 (95% CI 0.68-0.76) for in-hospital AKI, and of 0.91 (95% CI 0.87-0.95) for 30-day mortality in the derivation cohort. Upon external validation, KID-ACS achieved similarly high performance for in-hospital AKI (Zurich: AUC 0.73, 95% CI 0.70-0.77; Czechia: AUC 0.75, 95% CI 0.68-0.81; Germany: AUC 0.71, 95% CI 0.55-0.87) and 30-day mortality (UK: AUC 0.87, 95% CI 0.83-0.91; Czechia: AUC 0.91, 95% CI 0.87-0.94; Germany: AUC 0.96, 95% CI 0.92-1.00) outperforming the CA-AKI score and the GRACE 2.0 score, respectively. CONCLUSIONS: Circulating PENK offers incremental value for predicting in-hospital AKI and mortality in ACS. The simple 6-item KID-ACS risk score integrates PENK and provides a novel tool for simultaneous assessment of renal and mortality risk in patients with ACS.

Bioactive adrenomedullin and interleukin-6 in COVID-19: potential biomarkers of acute kidney injury and critical illness.

BACKGROUND: The aim of this study was to investigate whether bioactive adrenomedullin (bio-ADM) and interleukin-6 (IL-6) are related to acute kidney injury (AKI) and severe illness in COVID-19 patients. METHODS: 153 patients with COVID-19 admitted to the emergency department (ED) were included. Blood samples were collected from each patient at admission. Bio-ADM and IL-6, as well as DPP3 and routinely measured markers were evaluated regarding the endpoints AKI (22/128 hospitalized patients) and a composite endpoint of admission to intensive care unit and/or in-hospital death (n = 26/153 patients). RESULTS: Bio-ADM and IL-6 were significantly elevated in COVID-19 patients with AKI compared to COVID-19 patients without AKI (each p < 0.001). According to ROC analyses IL-6 and bio-ADM had the largest AUC (0.84 and 0.81) regarding the detection of AKI. Furthermore, bio-ADM and IL-6 were significantly elevated in COVID-19 patients reaching the composite endpoint (each p < 0.001). Regarding the composite endpoint ROC analysis showed an AUC of 0.89 for IL-6 and 0.83 for bio-ADM in COVID-19 patients. In the multivariable logistic model bio-ADM and IL-6 presented as independent significant predictors regarding both endpoints AKI and the composite endpoint in COVID-19 patients (as well as creatinine regarding the composite endpoint; each p < 0.05), opposite to leukocytes, C-reactive protein (CRP) and dipeptidyl peptidase 3 (DPP3; each p = n.s.). CONCLUSION: Elevated levels of bio-ADM and IL-6 are associated with AKI and critical illness in patients with COVID-19. Therefore, both biomarkers may be potential tools in risk stratification in COVID-19 patients at presentation in the ED.

Urinary NT-proBNP compared head-to-head to plasmatic NT-proBNP in a real life collective with an ICD.

AIMS: Plasma NT-proBNP is an established marker of heart failure. Previous studies suggested urinary NT-proBNP has potential as marker of chronic heart failure as well. The objective of this study was to compare urinary NT-proBNP to plasma NT-proBNP in a real-life collective of patients with an ICD, especially regarding ICD-therapies. METHODS & RESULTS: NT-proBNP was assessed in plasma and fresh spot urine (the latter related to urinary creatinine) from 322 patients of our ICD outpatient clinic. 54 healthy individuals served as a control group. Follow-up regarding mortality and ICD therapies was performed after 32 months (IQR 5- 35 months). Plasma and urinary NT-proBNP was positively correlated (r=0.89, p<0,001). According to ROC analysis urinary NT-proBNP detected LV dysfunction (EF<35% vs. healthy CTRL) with very satisfying predictive values (AUC 0.95), but plasma NT-proBNP showed slightly better values (AUC 0.99). Patients who received appropriate ICD-shock-therapies showed significantly higher plasma (p<0.001) as well as urinary NT-proBNP levels (p=0.011) compared to patients without shock-therapy. In Kaplan-Meier analysis, plasma as well as urinary NT-proBNP levels > Youden-Index showed significantly higher event rates for appropriate ICD-shock therapies (p<0.001 and p=0.016) and the combined endpoint of all-cause-mortality and shock therapies (each p<0.001). Urinary and plasma NT-proBNP were independent predictors for appropriate ICD-shock-therapies and for the combined endpoint of all-cause mortality and appropriate ICD-shock-therapies (each p<0.001). CONCLUSION: Urinary NT-proBNP as a marker for LV dysfunction and symptomatic heart failure showed promising predictive values. Associations between plasma as well as urinary NT-proBNP and ICD shock-therapies could be shown.

Restoration of von Willebrand factor after transcatheter aortic valve replacement-A possible cause for posttranscatheter aortic valve replacement thrombocytopenia?

OBJECTIVES: The aim of the current study was to analyze the clinical and procedural predictors of thrombocytopenia and the relationship between the decrease in platelet count (DPC) and change in vWF function (ΔvWF) after transcatheter aortic valve replacement (TAVR). BACKGROUND: TAVR often causes temporary thrombocytopenia. At the same time, TAVR leads to a restoration of von Willebrand factor (vWF) function. METHODS: One hundred and forty-one patients with severe aortic stenosis undergoing TAVR were included in the study. Platelet count and vWF function (vWF:Ac/Ag ratio) were assessed at baseline and 6 h after TAVR. Thrombocytopenia was defined as platelet count <150/nL. RESULTS: Median platelet count at baseline was 214/nL (interquartile range [IQR]: 176-261) and decreased significantly to 184/nL (IQR: 145-222) 6 h after TAVR. The number of patients with thrombocytopenia increased from 12.8% at baseline to 29.1% after 6 h. DPC 6 h after TAVR showed a significant correlation with ΔvWF (r = - 0.254, p = 0.002). Patients with DPC > 20% had significantly higher ΔvWF (10.9% vs. 6.5%, p = 0.021). Obese patients showed a significantly lower DPC (11.8% vs. 19.9%, p = 0.001). In multivariate analysis, ΔvWF 6 h after TAVR was the only significant predictor for DPC > 20% (p = 0.017). CONCLUSIONS: The restoration of vWF after TAVR is a significant predictor for DPC after TAVR. An increased platelet consumption due to vWF restoration could play a key role in the development of thrombocytopenia after TAVR.

Urinary N-Terminal Pro-Brain Natriuretic Peptide Predicts Acute Kidney Injury and Severe Disease in COVID-19.

INTRODUCTION: The ongoing COVID-19 pandemic is placing an extraordinary burden on our health care system with its limited resources. Accurate triage of patients is necessary to ensure medical care for those most severely affected. In this regard, biomarkers could contribute to risk evaluation. The aim of this prospective observational clinical study was to assess the relationship between urinary N-terminal pro-brain natriuretic peptide (NT-proBNP) and acute kidney injury (AKI) as well as severe disease in patients with COVID-19. METHODS: 125 patients treated with an acute respiratory infection in the emergency department of the University Hospital Regensburg were analyzed. These patients were divided into a COVID-19 cohort (n = 91) and a cohort with infections not caused by severe acute respiratory syndrome-coronavirus-2 (n = 34). NT-proBNP was determined from serum and fresh urine samples collected in the emergency department. Clinical endpoints were the development of AKI and a composite one consisting of AKI, intensive care unit admission, and in-hospital death. RESULTS: 11 (12.1%) COVID-19 patients developed AKI during hospitalization, whereas 15 (16.5%) reached the composite endpoint. Urinary NT-proBNP was significantly elevated in COVID-19 patients who suffered AKI or reached the composite endpoint (each p < 0.005). In a multivariate regression analysis adjusted for age, chronic kidney disease, chronic heart failure, and arterial hypertension, urinary NT-proBNP was identified as independent predictor of AKI (p = 0.017, OR = 3.91 [CI: 1.28-11.97] per standard deviation [SD]), as well as of the composite endpoint (p = 0.026, OR 2.66 [CI: 1.13-6.28] per SD). CONCLUSION: Urinary NT-proBNP might help identify patients at risk for AKI and severe disease progression in COVID-19.

Secondary prevention implantable cardioverter-defibrillator (ICD) therapy: value in octogenarians.

BACKGROUND: Implantable cardioverter-defibrillator (ICD) therapy is well established for secondary prevention, but studies on the efficacy and safety in elderly patients are still lacking. This retrospective study compared the outcome after ICD implantation between octogenarians and other age groups. METHODS: Data were obtained from a local ICD registry. Patients who received ICD implantation for secondary prevention at our department were included. All-cause mortality, appropriate ICD therapy and acute adverse events requiring surgical intervention were compared between different age groups. RESULTS: 519 patients were enrolled, 34 of whom were aged ≥ 80 years. During the median follow-up of 35 months after ICD implantation 129 patients (annual mortality rate 5.0%) had died, including 16 patients aged ≥ 80 years (annual mortality rate 9.4%). The mortality rate of patients aged ≥ 80 years was significantly higher than that of patients aged ≤ 69 years (p < 0.001), but similar to that of patients aged 70-79 years. Age at the time of ICD implantation was an independent predictor of all-cause mortality (p < 0.001). 29.7% of patients had appropriate ICD therapy with no difference between age groups. Acute adverse events leading to surgical intervention were low (n = 13) and not age-related. CONCLUSION: Age is an independent predictor of mortality after ICD implantation for secondary prevention. Mortality rates did not differ significantly between octogenarians and other elderly aged 70-79 years. Appropriate ICD therapy and acute adverse events leading to surgical intervention were not age-related. Implantable cardioverter-defibrillator therapy for secondary prevention seems to be an effective and safe treatment modality in octogenarians.

Novel Implantable Cardioverter Defibrillator Programming With High Rate Cut-Off, Long Detection Intervals and Multiple Anti-Tachycardia Pacing Reduces Mortality.

BACKGROUND: Implantable cardioverter defibrillator (ICD) therapies, even when appropriate, are associated with increased risk. Therapy-reducing strategies have been shown to reduce the mortality rate.Methods and Results:In total, 895 patients with ICD and cardiac resynchronization therapy with defibrillation function (CRT-D) were included in the study; of these, 506 (57%) patients undergoing secondary prevention were included. Devices implanted before May 2014 were programmed according to conventional programming (CP), the others according to our novel programming (NP) with high rate cut-off, longer detection intervals and 4-6 anti-tachycardia pacing (ATP) trains in the ventricular tachycardia (VT) zone. Time-to-first-event for mortality, appropriate and inappropriate therapies were analyzed. Follow-up time was 24.0 months (IQR 13.0-24.0 months). There was a significant reduction in mortality rate (11.4% vs. 25.4%, P<0.001) and in the rate of appropriate (18.8% vs. 42.2%, P<0.001) and inappropriate therapies (5.2% vs. 18.0%, P<0.001) with NP according to Kaplan-Meier analyses. In multivariate analysis, NP (hazard ratio [HR]=0.35; P<0.001), chronic kidney disease (HR=1.55), reduced ejection fraction (EF) (HR=1.35), secondary ICD indication (HR=2.35) and age at implantation (HR=1.02) were associated with mortality reduction. NP was also associated with significant reduction in the rate of appropriate and inappropriate therapies. These results were consistent after stratification for primary and secondary prevention. CONCLUSIONS: Novel ICD programming reduced mortality and morbidity due to appropriate or inappropriate ICD therapies in secondary as well as in primary ICD indication.

Heart failure with recovered ejection fraction (HFrecEF): A new entity with improved cardiac outcome.

BACKGROUND: Aim of the study was a better characterization of heart failure (HF) with recovered ejection fraction (HFrecEF) and undulating EF (HFuEF) with regard to re-hospitalization due to congestive HF (CHF), adequate electric therapies (AETs) and mortality compared to HF with reduced EF (HFrEF), mid-range EF (HFmrEF) and preserved EF (pEF). METHODS: Retrospective study of 342 participants with an implantable cardioverter defibrillator (ICD) for primary or secondary prevention. Type of HF was classified according to left ventricular EF with 4.7 ± 3.1 investigations for each patient. RESULTS: Re-hospitalization due to CHF was similar in HFrecEF (7 (9.5%)), HFmrEF (2(9.0%)) and pEF (8(12.9%); p = n.s.) and significantly higher in HFrEF (62(38.0%)) and HFuEF (6(28.6%); p < .001 compared to HFrecEF and HFrEF). AETs were significantly lower in HFrecEF (13(17.6%)) compared to HFrEF (57(35.0%)), HFmrEF (7(31.8%)), pEF (18(29.0%)) and HFuEF (6(28.6%); each p < .01 compared to HFrecEF). Mortality was similar in HFrecEF (6(8.1%)) compared to HFuEF (0(0%)), pEF (4(6.5%)) and HFmrEF (2(9.0%), p = n.s.) and significantly lower compared to HFrEF (52(31.9%), p < .001). HFrEF was the strongest predictor for mortality besides age and chronic renal insufficiency according to Cox Regression (each p < .05) opposite to arterial hypertension, diabetes, type of cardiomyopathy and secondary prevention ICD indication (each p = n.s.). CONCLUSIONS: HFrecEF indicates as a new entity of HF with similar prognosis as pEF and HFmrEF with regard to re-hospitalization due to CHF and mortality and even better prognosis with regard to AETs. HFuEF showed similar rates of re-hospitalization due to CHF and AETs compared to HFrEF, but lower rates of mortality.

Alterations of the renin angiotensin system in human end-stage heart failure before and after mechanical cardiac unloading by LVAD support.

Heart transplantation is often an unrealizable therapeutic option for end-stage heart failure, which is why mechanical left ventricular assist devices (LVADs) become an increasingly important therapeutic alternative. Currently, there is a lack of information about molecular mechanisms which are influenced by LVADs, particularly regarding the pathophysiologically critical renin angiotensin system (RAS). We, therefore, determined regulation patterns of key components of the RAS and the ß-arrestin signaling pathways in left ventricular (LV) tissue specimens from 8 patients with end-stage ischemic cardiomyopathy (ICM) and 12 patients with terminal dilated cardiomyopathy (DCM) before and after LVAD implantation and compared them with non-failing (NF) left ventricular tissue samples: AT1R, AT2R, ACE, ACE2, MasR, and ADAM17 were analyzed by polymerase chain reaction. ERK, phosphorylated ERK, p38, phosphorylated p38, JNK, phosphorylated JNK, GRK2, ß-arrestin 2, PI3K, Akt, and phosphorylated Akt were determined by Western blot analysis. Angiotensin I and Angiotensin II were quantified by mass spectrometry. Patients were predominantly middle-aged (53 ± 10 years) men with severely impaired LV function (LVEF 19 ± 8%), when receiving LVAD therapy for a mean duration of 331 ± 317 days. Baseline characteristics did not differ significantly between ICM and DCM patients. By comparing failing with non-failing left ventricles, i.e., before LVAD implantation, a downregulation of AT1R, AT2R, and MasR and an upregulation of ACE, ACE2, GRK, ß-arrestin, ERK, PI3K, and Akt were seen. Following LVAD support, then angiotensin I, ACE2, GRK, and ß-arrestin were downregulated and AT2R, JNK, and p38 were upregulated. ACE, angiotensin II, AT1R, ADAM17, MasR, ERK, PI3K, and Akt remained unchanged. Some regulation patterns were influenced by the underlying etiology of heart failure, the severity of LV dysfunction at baseline, and the duration of LVAD therapy. Key components of the RAS and ß-arrestin signaling pathways were divergently altered in failing left ventricles both before and after LVAD implantation, whereas a remarkable fraction remained unchanged. This indicates a rather incomplete molecular reverse remodeling, whose functional relevance has to be further evaluated.

High Predictive Value of Adenosine Provocation in Predicting Atrial Fibrillation Recurrence After Pulmonary Vein Isolation With Visually Guided Laser Balloon Compared With Radiofrequency Ablation.

BACKGROUND: We recently demonstrated that the acute reconnection rate detected with adenosine provocation test (APT) was significantly lower after pulmonary vein isolation (PVI) with visually guided laser balloon ablation (VGLB) than with RF ablation (RF). We evaluated the recurrence rate of atrial arrhythmias at 12 months after VGLB vs. RF and the significance of APT results for the outcome.Methods and Results:Fifty patients with paroxysmal AF were randomized to either RF or VGLB ablation in a 1 : 1 fashion. After PVI each PV underwent an APT. All patients underwent a 3-day Holter and clinical follow-up every 3 months. Significantly less PVs reconnected during APT in the VGLB-arm (10 PV (10.8%) vs. 29 PV (30.9%); P=0.001). Significantly less patients had a recurrence of atrial arrhythmia in the VGLB-arm (3 vs. 9; P=0.047). In the VGLB-arm no recurrence was seen in those patients with a negative APT (negative predictive value (NPV)=100%). Only 3 of the 8 patients with a positive APT in the VGLB-arm had a recurrence (positive PV (PPV)=37%). Recurrences in the RF-arm were seen in 3 patients with positive APT as well as in 6 patients with negative APT (PPV=18% and NPV=33%). CONCLUSIONS: There was significantly less recurrence of atrial arrhythmias at 12 months after PVI with VGLB. A negative APT after PVI with VGBL predicted freedom from AF with a very high NPV meaning that the high acute efficiency of the VGLB persisted long term.

N-acetyl-b-D-glucosaminidase: A potential cardiorenal biomarker with a relevant impact on ICD shock therapies and mortality.

AIMS: Chronic heart failure may lead to chronic kidney disease. Previous studies suggest tubular markers N-acetyl-b-D-glucosaminidase (NAG) and Kidney-injury-molecule-1 (KIM-1) as potential markers for the cardiorenal syndrome (CRS). The prognostic value of NAG and KIM-1 regarding implantable cardioverter defibrillator (ICD) shock therapies is unknown. METHODS: We included 314 patients with an ICD and collected plasma and urine samples. Urine-values of NAG and KIM-1 got related to urinary creatinine. Outcomes of interest were sustained adequate shock therapies and a combined endpoint of all-cause mortality, rehospitalisation due to congestive heart failure and adequate shock therapies. Follow up time was 32 months (IQR 6-35 months). RESULTS: KIM-1 and NAG were positively correlated with NT-proBNP (KIM-1: r = .34, P < .001; NAG: r = .47, P < .001). NAG was significantly elevated in patients with primary prevention compared with secondary prevention ICD indication (P = .003). According to Kaplan Meier analysis, NAG as well as NT-proBNP were significant predictors for adequate ICD shock therapies and for the combined endpoint (each P < .001). Elevated KIM-1 showed no significant differences (each P = n.s.). In multivariate cox regression analysis, NAG as well as NT-proBNP were both independent predictors for adequate ICD shock therapies as well as the combined endpoint, beside ejection fraction <35% (each P < .05). Diabetes, primary prevention ICD indication, coronary artery disease, eGFR and age were no significant predictors for both endpoints (each P = n.s.). CONCLUSION: Similar to NT-proBNP, NAG showed promising value for overall prognostication in ICD patients. Especially, NAG seems to incorporate an additional prognostic value regarding occurrence of ICD shock therapies.

N-acety-b-D-glucosaminidase: A potential biomarker for early detection of acute kidney injury in acute chest pain.

AIM: Acute kidney injury (AKI) is often underdiagnosed due to several limitations of the renal marker creatinine. Tubular urinary biomarkers may substantially contribute to diagnose AKI early. For early detection of AKI, we evaluated for the first time N-acetyl-ß-d-glucosaminidase (NAG), Kidney-injury-molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in acute chest pain. METHODS: We included 402 chest pain patients aged 18 to 95 years seen in the emergency department. From 311 subjects, blood and urine samples were collected. RESULTS: Thirty-three patients developed an AKI and showed a significant increase in all three tubular markers compared to patients without AKI (each P < .001). According to receiver operating characteristic (ROC) analysis, combining NAG and creatinine showed a significantly increased area under the curve (AUC) compared to creatinine alone (AUC: 0.75 vs 0.87; P < .001). KIM-1, NGAL and cystatin C showed no significant differences in AUC compared to creatinine. In 120 individuals with blood and urine sampling before contrast media exposure, ROC analysis showed a significantly improved diagnostic performance for the combination of both (AUC: 0.83 vs creatinine AUC: 0.66; P = .004). AKI occurrence showed no dependency from CM volume. NAG presented as an independent AKI predictor beside creatinine, age, the diagnosis of myocardial infarction and mean arterial pressure. Regarding the prognostic value for renal replacement therapy, the combination of NAG and creatinine showed a significantly lager AUC than creatinine (AUC: 0.95 vs AUC: 0.85; P < .001). CONCLUSION: NAG presented as a promising marker of impending AKI and the necessity of renal replacement therapy.

Radiotherapy of patients with cardiac implantable electronic devices according to the DEGRO/DGK guideline-is the risk of relevant errors overestimated?

PURPOSE: Ionizing radiation is able to cause severe damage to cardiac implantable electronic devices (CIED). In Germany, the DEGRO/DGK guideline recommends close monitoring of patients with CIEDs undergoing radiotherapy (RT). Nevertheless, especially in the era of intensity-modulated techniques and predominant use of 6 MV photons, errors of CIEDs are rare events. Therefore, we performed daily CIED controls and hypothesized that no relevant device interaction would occur in our cohort. METHODS: From 2014 to 2018, we collected data of 51 patients (62 courses) with daily interrogation (n = 1046) of CIED. The dose to the skin above the CIED was measured by semiconductor or ion chamber dosimetry at least once per RT course. In many cases the dose was also calculated. RESULTS: The prescribed dose to the planning target volume (PTV) ranged from 7.5 to 78.0 Gy (IQR 27.8-61.0 Gy). The median measured cumulative dose to the skin above the CIED was 0.17 Gy, whereas the median calculated dose was 1.03 Gy. No error occurred in the group with maximum beam energy >10 MeV. Three events without clinical relevance could be recognized in the group with an intensity-modulated technique at 6 MV. None of the three concerned devices were located directly within the PTV. CONCLUSION: Errors of CIEDs during RT are rare events. The approach according to the DEGRO/DGK guideline is safe, but also consumes resources. In our cohort it was not compulsory to relocate any CIED. Clinically relevant events are uncommon, so it remains debatable which procedure is necessary. Daily controls could be avoided in some selected cases without compromising patient safety.

A RAndomized Trial to compare the acute reconnection after pulmonary vein ISolation with Laser-BalloON versus radiofrequency Ablation: RATISBONA trial.

INTRODUCTION: Dormant conduction and acute reconnection in the pulmonary veins (PV) during a PV isolation can be detected by performing an adenosine provocation test (APT). Visually guided laser balloon ablation (VGLB) creates deep transmural lesions, thus causing less acute reconnection. This study compared the acute PV reconnection rate after isolation with VGLB or with RF using an APT. METHODS AND RESULTS: Patients with paroxysmal AF were randomized to PVI with the VGLB or RF ablation. Each PV underwent an APT at least 20 minutes after successful isolation with injection of 18 mg adenosine. Primary endpoint was the difference between the two ablation methods regarding acute PV reconnection rate detected with APT. A total of 50 patients were randomized into the study (25 VGLB). The basic characteristics and mean procedure time were not different between the two groups. Note that 96% of the 97 targeted PVs in the VGLB group and 98% of the 96 targeted PVs in the RF group could be isolated (P  =  0.41). APT was performed at similar times (after 28 minutes in VGLB-arm vs. after 31.5 minutes in RF-arm; P  =  0.12). Significantly less PVs were reconnected during APT in the VGLB group than in the RF group (10 PV [10.8%] vs. 29 PV [30.9%]; P  =  0.001). CONCLUSION: The acute PV reconnection rate is significantly less after PVI with VGBL than with RF. The clinical significance of this apparently better procedural efficiency of the VGBL ablation should be assessed with new randomized studies looking at AF recurrence.

Cardiac unloading by LVAD support differentially influences components of the cGMP-PKG signaling pathway in ischemic and dilated cardiomyopathy.

Implantation of left ventricular assist devices (LVADs) as bridge to transplant in end-stage heart failure allows for analyzing reverse remodeling processes of the supported heart. Whether this therapy influences the cGMP-PKG signaling pathway, which is currently under thorough investigation for developing new heart failure therapeutics, is unknown. In fourteen end-stage heart failure patients (8 with dilated cardiomyopathy, DCM; 6 with ischemic cardiomyopathy, ICM) tissue specimens of left ventricles were collected at LVAD implantation and afterwards at receiver heart explantation, respectively. Then the expressions of key components of the cGMP-PKG signaling pathway were determined by polymerase chain reaction (ANP; BNP; natriuretic peptide receptor A, NPR-A; natriuretic peptide receptor C, NPR-C; neprilysin; NOS3; soluble guanylyl cyclase, sGC; PDE5; cGMP-dependent protein kinase G, PKG) and enzyme-linked immunosorbent assay (cGMP), respectively. Patients were predominantly male, 52 ± 10 years old, were receiving recommended heart failure therapy, and had their donor organ implanted after 351 ± 317 days of LVAD support. Except for more DCM patients with ICD therapy, no significant differences were detected between ICM and DCM, which also applies to the expression of cGMP-PKG pathway components at baseline. After LVAD support, ANP, NPR-C, and cGMP were significantly down-regulated and neprilysin, PDE5, and PKG I expressions were reduced with borderline significance in DCM, but not in ICM patients. Multiple significant correlations were found for expression differences (i.e., expression at LVAD implantation minus expression at heart transplantation) both in DCM and ICM, even though there was a closer connection between the NO and NP side of the cGMP-PKG pathway in DCM patients. Furthermore, duration of LVAD support negatively correlated with expression differences of PKG I, PDE5, and sGC in ICM, but not in DCM. Originating from the same activation level at LVAD implantation, cardiac unloading significantly alters key components of the cGMP-PKG pathway in DCM, but not in ICM patients. This etiology-specific regulation should be considered when analyzing therapeutic interventions with effects on this signaling pathway.

Analytical and Clinical Validation of a Point-of-Care Cardiac Troponin T Test with an Improved Detection Limit.

BACKGROUND: The point-of-care test Roche CARDIAC POC Troponin T (PoC TnT) is an improved assay which has been developed for the Roche cobas h 232 system. METHODS: We performed a multicentre evaluation (four sites) to assess the analytical performance of the PoC TnT assay and to compare it with the central laboratory Elecsys® troponin T high sensitive (lab cTnT-hs) assay. RESULTS: The relative mean differences found in method comparisons of PoC TnT vs. lab cTnT-hs ranged from -4.1% to +6.8%. Additionally, there was good concordance between PoC TnT and lab cTnT-hs for the number of samples with troponin T values below the measuring range of 40 ng/L. Lot-to-lot differences of PoC TnT ranged from -8.6% to +4.6%. Within-series coefficients of variation (CV) resulting from 81 ten-fold measurements with patient samples were 9.3%, 11.8%, and 12.9% in the low (40 to < 200 ng/L), medium (200 to < 600 ng/L), and high (600 to 2000 ng/L) measuring range, respectively. Using the system quality control, the mean CV for between-day imprecision was 11.3%. No interference was observed by triglycerides (up to 11.4 mmol/L), bilirubin (up to 376 µmol/L), hemoglobin (up to 0.12 mmol/L), biotin (up to 30 µg/L), rheumatoid factor (up to 200 IU/mL), or with 52 standard or cardiovascular drugs at therapeutic concentrations. There was no influence on the results by varying hematocrit values in a range from 25% to 53%. However, interferences with human anti-mouse antibodies were found. No significant influence on the results was found with PoC TnT by using sample volumes between 135 to 165 µL. High troponin T concentrations up to 500 µg/L did not lead to false low results, indicating no high-concentration hook effect. No cross-reactivity was found between the PoC TnT assay and human skeletal troponin T up to 1000 µg/L (< 0.05%). Diagnostic sensitivity and specificity data of a subpopulation (23 patients) of this study are in agreement with results of another large pre-hospital study. CONCLUSIONS: The PoC TnT assay showed good analytical performance with excellent concordance with the calibration and reference laboratory method. It should therefore be suitable for its intended use in point-of-care settings.

N-acteyl-ß-D-glucosaminidase and kidney injury molecule-1: New predictors for long-term progression of chronic kidney disease in patients with heart failure.

AIM: Patients with chronic heart failure (CHF) are often characterized by the cardiorenal syndrome (CRS). The aim of the present study was to assess whether novel markers of kidney injury are able to predict progression of chronic kidney disease (CKD) in patients with CHF. METHODS: New renal biomarkers, N-acteyl-ß-D-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1) and Neutrophil Gelatinase-Associated Lipocalin (NGAL), were assessed from urine samples of 149 patients with chronic heart failure. During a 5-year-follow-up, renal function was assessed by creatinine and estimated glomerular filtration rate (eGFR CKD EPI) and was available for 138 patients. Further, data regarding all-cause mortality was obtained. RESULTS: Twenty-six patients (18.8%) developed a progression of CKD during the follow-up period, as defined by decline in eGFR category accompanied by a ≥25% drop in eGFR form baseline. No difference regarding age, sex, body mass index, hypertension, diabetes or EF was present between patients with and without CKD progression (each P = n.s.). At baseline, creatinine concentrations and eGFR were significantly different between both groups (sCr: 1.50 ± 0.67 vs 1.04 ± 0.37, P = < 0.001; eGFR: 47.8 ± 12.3 vs. 77.3 ± 23.5 mL/min per 1.73m(2) , each P < 0.001). In a Kaplan-Meier-analysis, KIM-1 and NAG were significant predictors for CKD progression (both P < 0.05). In Cox regression analysis, NAG > median (OR 3.25,P = 0.013), initial eGFR (OR 0.94, P < 0.001) and diuretic use (OR 3.92, P = 0.001) were independent predictors of CKD progression. Further, KIM-1 and NAG were also independent predictors of a combined endpoint of CKD progression and all-cause mortality by Cox regression analysis (each P < 0.05). The combination of both markers showed additive value regarding both endpoints. NGAL showed no association with CKD progression. CONCLUSIONS: During long-term follow-up chronic heart failure patients with CKD show a relevant disease progression. The current study emphasizes a strong association of the tubular biomarkers NAG and KIM-1 with CKD progression in chronic heart failure and suggests their usefulness as cardiorenal markers.

Unmasking the dormant pulmonary vein conduction with adenosine administration after pulmonary vein isolation with laser energy.

AIMS: The isolation of the pulmonary veins (PVs) is the mainstay of atrial fibrillation (AF) ablation, which with current ablation techniques can be achieved in almost all cases. Reconnection of PVs constitutes the most frequent cause of AF recurrence. Visually guided laser balloon ablation (VGLA) is a novel system with very high rate of persistence of pulmonary vein isolation (PVI) three months after the first procedure shown in preclinical and clinical studies. We aimed to determine the acute efficiency of the laser energy during PVI with the help of adenosine provocation. METHODS AND RESULTS: Twenty-six patients (19 male; mean age 64 ± 9 years) with symptomatic paroxysmal AF were included in the study. Pulmonary vein isolation was performed using the VGLA system. After successful PVI, we studied the effects of intravenous adenosine (18 mg) on activation of each PV at least 20 min after PVI. A total of 104 PVs were targeted. The balloon catheter could not be placed in two PVs. Of the remaining 102 PVs 99 (97% of the ablated PVs) could be successfully isolated. Adenosine was administered for each isolated PV in 25 patients. Only six PVs (6.7%) in five patients (20%) showed a PV reconnection during adenosine provocation. CONCLUSION: Pulmonary vein isolation with VGLA is a feasible technique for PVI with a very effective acute lesion formation. The clinical significance of this low reconnection rate has to be determined.