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We sought to explore whether classification of patients with heart failure and mid-range (HFmrEF) or preserved ejection fraction (HFpEF) according to their left ventricular ejection fraction (LVEF) identifies differences in their exercise hemodynamic profile, and whether classification according to an index of right ventricular (RV) function improves differentiation. Patients with HFmrEF and HFpEF have hemodynamic compromise on exertion. The classification according to LVEF implies a key role of the left ventricle. However, RV involvement in exercise limitation is increasingly recognized. The tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure (TAPSE/PASP) ratio is an index of RV and pulmonary vascular function. Whether exercise hemodynamics differ more between HFmrEF and HFpEF than between TAPSE/PASP tertiles is unknown. We analyzed 166 patients with HFpEF (LVEF ≥ 50%) or HFmrEF (LVEF 40–49%) who underwent basic diagnostics (laboratory testing, echocardiography at rest, and cardiopulmonary exercise testing [CPET]) and exercise with right heart catheterization. Hemodynamics were compared according to echocardiographic left ventricular or RV function. Exercise hemodynamics (e.g. pulmonary arterial wedge pressure/cardiac output [CO] slope, CO increase during exercise, and maximum total pulmonary resistance) showed no difference between HFpEF and HFmrEF, but significantly differed across TAPSE/PASP tertiles and were associated with CPET results. N-terminal pro-brain natriuretic peptide concentration also differed significantly across TAPSE/PASP tertiles but not between HFpEF and HFmrEF. In patients with HFpEF or HFmrEF, TAPSE/PASP emerged as a more appropriate stratification parameter than LVEF to predict clinically relevant impairment of exercise hemodynamics. Stratification of exercise hemodynamics in patients with HFpEF or HFmrEF according to LVEF or TAPSE/PASP, showing significant distinctions only with the RV-based strategy. All data are shown as median [upper limit of interquartile range] and were calculated using the independent-samples Mann–Whitney U test or Kruskal–Wallis test. PVR pulmonary vascular resistance; max maximum level during exercise.

Chronic thromboembolic pulmonary hypertension constitutes a significant late sequela of pulmonary embolism. It is defined by precapillary pulmonary hypertension with mismatched perfusion defects and pulmonary arterial lesions after at least 3 months of effective anticoagulation. Symptomatic patients who do not have pulmonary hypertension yet fulfill all other criteria are diagnosed with chronic thromboembolic disease. The treatment of chronic thromboembolic pulmonary hypertension is based on 3 pillars: pulmonary endarterectomy, pulmonary arterial hypertension-targeted medication, and balloon pulmonary angioplasty. Surgical pulmonary endarterectomy is the standard of care and can be performed in 2/3 of all patients. Targeted medication with or without balloon pulmonary angioplasty is reserved for inoperable patients or those with residual pulmonary hypertension after surgical treatment. Despite the lack of profound evidence, the treatment of chronic thromboembolic disease is similar to that of patients with pulmonary hypertension: pulmonary endarterectomy is offered to operable individuals, whereas balloon pulmonary angioplasty is considered in inoperable patients. Since therapeutic strategies are complex, and diagnostic and therapeutic procedures-demanding, treatment in a specialized, experienced center is mandatory.

Myocardial infarction (MI) not only defines acute MI with obstructed coronary arteries (T1MI) but also myocardial necrosis caused by myocardial oxygen supply/demand mismatch as type 2 MI (T2MI); only T1MI patients benefit from an early invasive management. Myeloid-related protein(MRP)-8/14 is a biomarker described in various inflammatory diseases and in MI patients. Here we evaluate the potential of MRP-8/14 and high-sensitivity troponin I (hs-cTnI) to differentiate T2MI from T1MI. Patients with final diagnosis NSTEMI (n = 254; 33.1% female) enrolled in a prospective biomarker registry between 08/2011 and 10/2016 were analysed. Median baseline MRP-8/14 levels were higher in T2MI (n = 55; 3.37(1.88–6.48)μg/mL) than in T1MI (n = 199; 2.4 [1.4–3.79]μg/mL) (p = .013) patients, in contrast to hs-cTnI (T2MI:52[11.65–321.4]ng/L vs. T1MI:436.5 [61.25–1973.8]ng/L; p To detect the strength of this association odds ratios(OR) were calculated with MRP-8/14 yielding 2.13(1.16–3.92; p = .015) to predict T2MI and 0.47(0.26–0.87; p = .015) for T1MI. As expected, hs-cTnI yielded an OR of to predict T2MI 0.34(0.17–0.65; p = .001) and 2.98(1.53–5.81; p = .001) for T1MI. Both markers show comparable and independent results if adjust to hs-cTnI/MRP-8/14, TIMI risk score and CRP. T2MI is associated with higher MRP-8/14 and lower hs-cTnI concentrations than T1MI. Our data suggest that MRP-8/14 as a marker of inflammation might provide usable discriminatory information complementing hs-cTnI in a diagnostic procedure evaluating the type of MI directly upon hospital admission.

The main aim of this study was to assess the prognostic utility of TAPSE/PASP as an echocardiographic parameter of maladaptive RV remodeling in cardiomyopathy patients using cardiac magnetic resonance (CMR) imaging. Furthermore, we sought to compare TAPSE/PASP to TAPSE. The association of the echocardiographic parameters TAPSE/PASP and TAPSE with CMR parameters of RV and LV remodeling was evaluated in 111 patients with ischemic and non-ischemic cardiomyopathy and cut-off values for maladaptive RV remodeling were defined. In a second step, the prognostic value of TAPSE/PASP and its cut-off value were analyzed regarding mortality in a validation cohort consisting of 221 patients with ischemic and non-ischemic cardiomyopathy. A low TAPSE/PASP (

Background: Percutaneous mitral valve repair (PMVR) in high-risk patients is currently controversial, especially in those with secondary mitral regurgitation (MR). Exercise pulmonary hemodynamics may help to unmask cardiac dysfunction as well as the dynamic impact of MR. The present study sought to explore the clinical impact of preprocedural exercise right heart catheterization (RHC) for the selection of patients who could most benefit from PMVR. Methods: Sixty-eight patients with symptomatic primary and secondary MR and exercise RHC before PMVR were included in this retrospective analysis of the association of exercise RHC parameters with survival and improvement in New York Heart Association class within 12 months. Results: Median patient age was 77 years (±8.5), 37% were female, and 81% presented with New York Heart Association class III. A total of 65% of the patients had left ventricular ejection fraction P P Conclusions: In our cohort of patients with indication for PMVR, preprocedural exercise RHC was able to identify patients with an unfavorable outcome. Further studies with larger patient numbers are warranted before this approach can be implemented in a structured diagnostic workup of patients under evaluation for PMVR.

Recent guidelines recommend a risk-adjusted, non-invasive work-up in patients presenting with chest discomfort to exclude coronary artery disease (CAD). However, a risk-adjusted diagnostic approach remains challenging in clinical practice. An acoustic detection device for analyzing micro-bruits induced by stenosis-generated turbulence in the coronary circulation has shown potential for ruling out CAD in patients with low-to-intermediate likelihood. We examined the diagnostic value of this acoustic detection system in a high-prevalence cohort. In total, 226 patients scheduled for clinically indicated invasive coronary angiography (ICA) were prospectively enrolled at two centers and examined using a portable, acoustic detection system. The acoustic analysis was performed in double-blinded fashion prior to quantitative ICA and following percutaneous coronary intervention (PCI). An acoustic detection result (CAD score) was obtained in 94% of all patients. The mean baseline CAD score was 41.2 ± 11.9 in patients with obstructive CAD and 33.8 ± 13.4 in patients without obstructive CAD (p < 0.001). ROC analysis revealed an AUC of 0.661 (95% CI 0.584–0.737). Sensitivity was 97.6% (95% confidence interval (CI) 91.5–99.7%), specificity was 14.5% (CI 9.0–21.7%), negative predictive value was 90.5% (CI 69.6–98.8%), and positive predictive value was 41.7% (CI 34.6–49.0%). Following PCI, the mean CAD score decreased from 40.5 ± 11.2 to 38.3 ± 13.7 (p = 0.039). Using an acoustic detection device identified individuals with CAD in a high-prevalence cohort with high sensitivity but relatively low specificity. The negative predictive value was within the predicted range and may be of value for a fast rule-out of obstructive CAD even in a high-prevalence population.

Aim: This study assessed the utility of osteopontin (OPN) and galectin-3 (Gal-3) as biomarkers of maladaptive right ventricular remodeling in pulmonary hypertension (PH). Materials & methods: We examined plasma levels of OPN and Gal-3 in patients with PH (n = 62), dilated cardiomyopathy (n = 34), left ventricular hypertrophy (LVH; n = 47), and controls without right ventricle (RV) or LV abnormalities (n = 38). Results: OPN and Gal-3 levels were higher in PH, dilated cardiomyopathy and LVH than in the controls. OPN concentrations in PH patients with maladaptive RV were significantly higher than in those with adaptive RV. Gal-3 did not differentiate between adaptive and maladaptive RV remodeling in PH. OPN and Gal-3 levels did not correlate with parameters of LV remodeling. Conclusion: OPN is a potential biomarker of RV maladaptation.

Left ventricular (LV) longitudinal, circumferential, and radial motion can be measured using feature tracking of cardiac magnetic resonance (CMR) images. The aim of our study was to detect differences in LV mechanics between patients with dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) who were matched using a propensity score-based model. Between April 2017 and October 2019, 1224 patients were included in our CMR registry, among them 141 with ICM and 77 with DCM. Propensity score matching was used to pair patients based on their indexed end-diastolic volume (EDVi), ejection fraction (EF), and septal T1 relaxation time (psmatch2 module L Feature tracking provided six parameters for global longitudinal, circumferential, and radial strain with corresponding strain rates in each group. Strain parameters were compared between matched pairs of ICM and DCM patients using paired t tests. Propensity score matching yielded 72 patients in each group (DCM mean age 58.6 ± 11.6 years, 15 females; ICM mean age 62.6 ± 13.2 years, 11 females, p = 0.084 and 0.44 respectively; LV-EF 32.2 ± 13.5% vs. 33.8 ± 12.1%, p = 0.356; EDVi 127.2 ± 30.7 ml/m2 vs. 121.1 ± 41.8 ml/m2, p = 0.251; native T1 values 1165 ± 58 ms vs. 1167 ± 70 ms, p = 0.862). There was no difference in global longitudinal strain between DCM and ICM patients (− 10.9 ± 5.5% vs. − 11.2 ± 4.7%, p = 0.72), whereas in DCM patients there was a significant reduction in global circumferential strain (− 10.0 ± 4.5% vs. − 12.2 ± 4.7%, p = 0.002) and radial strain (17.1 ± 8.51 vs. 21.2 ± 9.7%, p = 0.039). Our data suggest that ICM and DCM patients have inherently different myocardial mechanics, even if phenotypes are similar. Our data show that GCS is significantly more impaired in DCM patients. This feature may help in more thoroughly characterizing cardiomyopathy patients.

To examine the clinical experience and practical use of the PASCAL transcatheter valve repair system (Edwards Lifesciences, Irvine, CA, USA) and to report some of the first clinical results. A total of 18 consecutive patients with severe, symptomatic mitral regurgitation (MR) were included in this German multicentre registry. All patients underwent clinical, echocardiographic, and laboratory assessment prior to the PASCAL procedure and before hospital discharge. MR was classified as functional in 6 patients, degenerative in 2, and combined in 10. All except one received a single PASCAL implant. The preprocedural severe MR present in all patients was reduced: grade 0 in 4 (22.2%), grade I in 11 (61.1%), grade II in 3 (16.7%). The v-wave was significantly reduced from 31.7 ± 9.5 to 18 ± 7.7 mmHg (p

Balloon pulmonary angioplasty (BPA), for chronic thromboembolic pulmonary hypertension, improves pulmonary and systemic hemodynamics. The kidney might benefit from this effect. However, staged BPA therapy comes along with repetitive administration of contrast agent. This study examined the overall effect of BPA therapy on renal function. This study included consecutive patients who underwent BPA treatment and completed a 6-month follow-up between March 2014 and March 2017. Biomarker-based evaluation of renal function was performed at baseline, consecutively prior to and after each BPA and at 6-month follow-up. The 51 patients underwent an average of 5 (±2) BPA sessions. In this course, patients received 133 (±48; 21-300) mL of contrast agent per session and 691 (±24; 240-1410) mL during the whole sequence. Acute kidney injury occurred after 6 (2.3%) procedures. The creatinine [80.1 (IQR 67.8-96.8) µmol/L vs. 77.4 (IQR 66.9-91.5) µmol/L, p = .02] and urea level [13.7 (IQR10.7-16.6) mmol/L vs. 12.5 (IQR 10.0-15.5) mmol/L, p = .02] decreased from baseline to the 6-month follow-up. The estimated glomerular filtration rate (eGFR) [79 (IQR 59-94) mL/min/m

Introduction Copeptin is the C-terminal fragment of the precursor protein of vasopressin. In acute pulmonary embolism, copeptin has been suggested to be a strong predictor of outcome and to provide additional predictive value to the established cardiac biomarkers high-sensitivity cardiac troponin and N-terminal pro-brain natriuretic peptide (NT-proBNP). Chronic thromboembolic pulmonary hypertension (CTEPH) is diagnosed in about 5% of patients who survive acute pulmonary embolism. Individualized risk stratification remains a challenge in the work-up of CTEPH patients. Purpose The current study investigated whether copeptin has the potential to aid the stratification of patients who have experienced pulmonary embolism and CTEPH patients. We examined the baseline (BL) levels and dynamics of copeptin during therapy in CTEPH patients who underwent balloon pulmonary angioplasty (BPA) or pulmonary endarterectomy (PEA). Moreover, the study compared copeptin levels between patients with or without therapy response. Methods The study included a total of 125 CTEPH patients scheduled for treatment. A total of 78 underwent staged BPA and 64 underwent PEA. In accordance with recent studies from our group, therapy success was defined as a decrease in meanPAP ≥25% and PVR ≥35% or a normalization below the thresholds defining pulmonary hypertension. Blood samples were collected at BL, prior to each BPA session in the BPA cohort, and at follow-up (FU) 6 months after BPA or 12 months after PEA. Copeptin was measured in thawed serum aliquots by an immunochemical method. Results The 78 patients in the BPA cohort underwent a mean of 6 BPA procedures each; there were a total of 413 interventions. The hemodynamic clinical and functional status the CTEPH patients improved after BPA and PEA therapy: meanPAP (BL: 43±9 mmHg vs. FU: 27±9 mmHg; p The median serum levels of copeptin [BL 7.7 (4.6–14.2) pmol/L vs. FU 6.3 (3.9–12.5); p=0.009] and NT-proBNP [BL: 811 (157–1857) ng/L vs. FU: 142 (72–335) ng/L p Conclusions Copeptin levels are elevated in CTEPH patients compared with normal values in the literature. Although copeptin is known to provide additional value in the context of risk stratification in acute pulmonary embolism, it failed to provide additional diagnostic benefit in CTEPH in the current study. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): SFB 1213 area CP01

Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a sub group of pulmonary hypertension (PH). CTEPH is characterized by the existence of thromboemboli and vascular remodeling in pulmonary vessels. The effect of increase in pulmonary artery pressures causes right ventricle (RV) hypertrophy and dilatation and finally leads to right heart failure and death. Surgical intervention in operable patients makes the CTEPH as an only curable and unique form of ph. Pulmonary endarterectomy (PEA) is the surgical procedure to remove the thromboembolic clots from the pulmonary vasculature, which restores RV function back to normal with significant improvements in cardiovascular magnetic resonance. Purpose The aim of this study is to use transcriptomic profiling to identify signaling pathways, master regulators, and potentially new biomarkers that specifically indicate the effect of PEA on the RV of patients with chronic thromboembolic pulmonary hypertension. Results RNA -sequencing (RNA-seq) was performed on RV biopsies obtained from CTEPH patients at PEA baseline (before PEA surgery) and the results were compared with those from RV biopsies obtained during follow-up evaluation. Bioinformatic analysis of RNA-seq data identified 2799 genes (n=14, −0.585 ≤ Log2 fold change ≥0.585, FDR ≤0.05) differentially regulated between the PEA baseline and follow-up sample groups. The great number of genes (2799) differentially expressed after PEA surgery in CTEPH patients confirms a major shift in the transcriptional landscape of RV in these patients. To further identify potential biomarker candidates from the large pool of 2799 differentially expressed genes (DEGs), extensive bioinformatic analysis of different data sets shortlisted 250 DEGs that were functionally associated with cardiovascular development or disease. The findings of this study reveal prominent transcriptional changes that occur in response to PEA. Gene ontology enrichment and pathway analysis confirmed altered regulation of hypoxia-inducible factor 1 (HIF-1) signaling, advanced glycation end products and their receptors (AGE-RAGE), mitogen-activated protein kinase (MAPK) signaling, hippo signaling, the Janus kinase/ signal transducers and activators of transcription (Jak-STAT) signaling pathway, and proteoglycans after PEA compared with before PEA. Conclusion Comparison of the results of RNA-seq analysis of RV biopsies of CTEPH patients, pre and post PEA, revealed a major shift in the transcriptional landscape of these patients after reducing the pressure overload of the RV by PEA. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): German Research Foundation (DFG)

Background Cardiac troponins have become the gold standard for appropriate and rapid diagnosis of an acute myocardial infarction (AMI). However, elevated cardiac troponins levels can be observed in the absence of AMI in elderly patients and therefore a loss of specificity is seen in the diagnosis of AMI in elderly patients. Purpose This study aims to define old age in suspected AMI and to evaluate the effect of older age on the diagnostic specificity of a high sensitivity troponin I (hs-cTnI) and high sensitivity troponin T (hs-cTnT) assay in elderly women and men. Methods This study used data from patients with suspected AMI who were enrolled between 08–2011 and 10–2016 to a multicentre biomarker registry and an University Hospital and with available hs-cTnI and hs-cTnT upon admission (n=564 patients). First, we investigated the effect of age on the specificity of both hs-cTnI and hs-cTnT to detect AMI continuously. We then classified over seventy-year-olds as elderly (n=281; 49,8%) and compared the specificity of hs-cTnI and hs-cTnT between elderly and younger patients. Results In the group of older patients, 62.6% (n=176) were diagnosed with AMI compared with 50.9% (n=144) in younger age patients (p Conclusions The specificity of both, hs-cTnI and hs-cTnT is significantly reduced in elderly patients due to higher hs-cTnT and hs-cTnI levels in elderly patients at admission irrespective of the final diagnosis. A relevant loss in diagnostic specificity is observed at 70 years of age starting already at 60 years. Use of assay-specific adjusted cut-offs for hs-cTnI and hs-cTnT for elderly patients regains diagnostic specificity that leads to a more accurate decision-making concerning “rule-in” for older patients with suspected AMI. Funding Acknowledgement Type of funding source: None

Background Chronic thromboembolic pulmonary hypertension (CTEPH) leads to right heart failure. Pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA) restore pulmonary haemodynamics and allow cardiac recovery. This study examined the relationship of copeptin and mid-regional pro-atrial natriuretic peptide (MR-proANP) levels to disease severity and therapy response. Methods This observational cohort study included 125 patients (55 PEA/70 BPA) who underwent treatment and completed a 6-/12-month follow-up. Biomarkers, measured at baseline, prior to every BPA and at follow-up, were compared to 1) severe disease at baseline (right atrial pressure (RAP) ≥8 mmHg and cardiac index ≤2.4 L·min−1·m−2) and 2) optimal therapy response (no persistent pulmonary hypertension combined with a normalised RAP (mean PAP ≤25 mmHg, pulmonary vascular resistance (PVR) ≤3 WU and RAP ≤6 mmHg) or a reduction in mean PAP ≥25%, PVR ≥35% and RAP ≥25%). Results Severely diseased patients had higher levels of MR-proANP (320 (246–527) pmol·L−1 versus 133 (82–215) pmol·L−1; p=0.001) and copeptin (12.7 (7.3–20.6) pmol·L−1 versus 6.8 (4.4–12.8) pmol·L−1; p=0.015) at baseline than the rest of the cohort. At baseline, MR-proANP (area under the curve (AUC) 0.91; cut-off value 227 pmol·L−1; OR 56, 95% CI 6.9–454.3) and copeptin (AUC 0.70; cut-off value 10.9 pmol·L−1; OR 1.5, 95% CI 1.2–1.9) identified severely diseased patients. After PEA/BPA, levels of MR-proANP (99 (58–145) pmol·L−1; p, The assessment of cardiac stress and impact of therapy is crucial in CTEPH. Serum levels of MR-proANP are associated with haemodynamic disease severity and therapy response, and might thus support individualised patient management. https://bit.ly/2QKwb7x

Background * These authors contributed equally as last authors. Balloon pulmonary angioplasty is an evolving, interventional treatment option for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary hypertension at rest as well as exercise capacity is considered to be relevant outcome parameters. The aim of the present study was to determine whether measurement of pulmonary hemodynamics during exercise before and six months after balloon pulmonary angioplasty have an added value. Methods From March 2014 to July 2018, 172 consecutive patients underwent balloon pulmonary angioplasty. Of these, 64 consecutive patients with inoperable CTEPH underwent a comprehensive diagnostic workup that included right heart catheterization at rest and during exercise before balloon pulmonary angioplasty treatments and six months after the last intervention. Results Improvements in pulmonary hemodynamics at rest and during exercise, in quality of life, and in exercise capacity were observed six months after balloon pulmonary angioplasty: WHO functional class improved in 78% of patients. The mean pulmonary arterial pressure (mPAP) at rest was reduced from 41 ± 9 to 31 ± 9 mmHg (p

Background In chronic thromboembolic pulmonary hypertension (CTEPH) impaired pulmonary hemodynamics lead to right heart failure. Natriuretic peptides reflect hemodynamic disease severity. Pregnancy-associated plasma protein-A (PAPP-A) might address another aspect of CTEPH - chronic tissue injury and inflammation. This study assessed dynamics of PAPP-A in CTEPH patients who undergo therapy with pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA). Methods The study included a total of 125 CTEPH patients scheduled for treatment (55 PEA/ 70 BPA) and a control group of 58 patients with pulmonary hypertension other than CTEPH. Biomarker measurement was performed at baseline and follow-up in the CTEPH cohort, prior to each BPA in the BPA cohort and once in the control group. Results The median PAPP-A level was slightly higher (p = 0.05) in CTEPH patients [13.8 (11.0–18.6) mU/L], than in the control group [12.6 (8.6–16.5) mU/L], without a difference between the BPA and PEA group (p = 0.437) and without a correlation to mean pulmonary artery pressure (p = 0.188), pulmonary vascular resistance (p = 0.893), cardiac index (p = 0.821) and right atrial pressure (p = 0.596). PEA and BPA therapy decreased the mean pulmonary artery pressure (p p p = 0.003) and BPA treatment [14.3 (11.2–18.9) vs. 11.1 (9.7–13.3) mU/L; p Conclusion PAPP-A is overexpressed in CTEPH and decrease significantly after surgical or interventional therapy, however without association to hemodynamics. Further investigation is needed to define the underlying mechanism of PAPP-A expression and changes after therapy in CTEPH.

Aim: This study assessed the utility of SPARC-like protein 1 (SPARCL1) as a biomarker of maladaptive right ventricular (RV) function in patients with pulmonary hypertension (PH). Methods: In this prospective study, we examined SPARCL1 levels in 105 patients with adaptive (n = 34) and maladaptive RV (n = 32) pressure overload caused by PH, dilated cardiomyopathy (DCM, n = 18) with LVEF < 35% and preserved RV function and controls without LV or RV abnormalities (n = 21). Results: The median SPARCL1 concentration in patients with maladaptive RV function was higher than in those with adaptive RV function (p p p p p Conclusion: SPARCL1 shows potential as novel biomarker of RV pathological remodelling and is associated with RV maladaptation and ventriculoarterial uncoupling in PH.

Background In chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary artery obstruction leads to impaired pulmonary hemodynamics and secondary right heart failure, which is highly predictive of outcome. Thus, the extent of myocardial -especially right heart- remodelling is an indicator of disease severity. Purpose The aim of the present study was to assess growth differentiation factor-15 (GDF-15), galectin-3, and suppression of tumorigenicity 2 (ST2) as non-invasive biomarkers of myocardial remodelling in patients suffering from CTEPH. Methods We analysed the serum levels of GDF-15, galectin-3 and ST2 in a cohort of 64 CTEPH patients and in a control group of 25 patients without cardiovascular disease. The biomarker levels were further correlated with clinical, laboratory, and hemodynamic data, including 6-minute walking distance (6-MWD), N-terminal pro-brain natriuretic peptide (NT-proBNP), mean pulmonary artery pressure (meanPAP), pulmonary vascular resistance (PVR), and right atrial pressure (RAP). Results The biomarker levels in the control group were: galectin-3: 3.5 ng/l (IQR 2.7–4.0), GDF-15: 92.6 pg/ml (IQR 78.5–129.1), and ST2: 48.65 ng/l (IQR 35.5–57.0). CTEPH patients had higher levels of GDF-15 (196.7 pg/ml; IQR 128.4–302.8; p35 mmHg (GDF-15: p=0.01; ST2: p=0.04) and patients with a PVR >500 dyn sec cm–5 (GDF-15: p=0.004; ST2: p=0.002) had significantly increased biomarker levels. For the detection of a meanPAP >35mmHg, ROC analysis revealed an AUC of 0.71 for GDF-15 and 0.67 for ST2. The level of GDF-15 correlated with the level of NT-proBNP (rrs=0.69; p≤0.001) and the RAP (rrs=0.54; p≤0.001) and inversely with the 6-MWD (rrs=−0.47; p≤0.001). The level of ST2 correlated with the level of NT-proBNP (rrs=0.67; p≤0.001) and the RAP (rrs=0.54; p≤0.001) and inversely with the 6-MWD (rrs=-0.31; p=0.02). Conclusion Our results demonstrate that GDF-15 and ST2, non-invasive biomarkers of myocardial remodelling, are significantly elevated in patients suffering from CTEPH. The correlation of biomarker levels with established outcome predictors suggests a use as indicators of disease severity.

Background Acute myocardial infarction (MI) is associated with high morbidity and mortality. A robust differentiation between type 1 and type 2 MI (T1/T2MI) has prognostic and therapeutic implications. We investigated whether serial high-sensitivity cardiac troponin I measurements could reliably discriminate T1MI from T2MI in patients presenting with a non-ST elevation myocardial infarction (NSTEMI). Methods We used data from a prospective acute coronary syndrome biomarker registry of patients with suspected MI that presented at or were transferred to one of two study centres. Here, we analysed an unselected group of 265 NSTEMI patients (67.2% males). Blood was drawn on admission and after 3 hours. High-sensitivity troponin I (hs-cTnI) was measured in frozen samples by a technician blinded to patient characteristics. T1MI or T2MI was defined as the gold-standard study diagnosis by two independent cardiologists based on all available data according to the Third Universal Definition of MI. Results A diagnosis of T2MI was made in 55 patients (20.8%) in the NSTEMI cohort. T2MI patients did not differ from T1MI patients regarding age, gender, traditional risk factors, or percentage of those with a history of coronary artery disease. Median baseline hs-cTnI levels were higher in T1MI (436.25; IQR 63.7–1918.8 ng/L) than in T2MI patients (48.4; IQR 11.7–305.9 ng/L; p Conclusion Our data show that hs-cTnI concentrations differ between patients presenting with T1 and T2MI. The concentration of hs-cTnI and its change over time has the potential to rule out T2MI and therefore to identify patients who might benefit from an early invasive management. The differentiation between T1MI and T2MI by using hs-cTnI is nevertheless challenging, and further research on specific algorithms is needed. Acknowledgement/Funding 3German Center for Cardiovascular Research (DZHK), Partnersite Rhein Main, Bad Nauheim, Germany

Background There are several tools for primary prevention (e.g. Framingham, ESC) that can be used to predict mortality risk in healthy individuals. However, only a few scores have been validated to predict outcome in patients with cardiovascular disease. One of these instruments is the REACH (REduction of Atherothrombosis for Continued Health) score. The ESC guideline for stable coronary artery disease (CAD) places a clear emphasis on carrying out risk stratification before using invasive treatment. Recent studies have revealed a prognostic value of serum hs-cTnI in patients with stable CAD. Purpose The aim of this study was to evaluate the prognostic information provided by hs-cTnI in stable high-risk CAD patients. Methods Between 2011 and 2014, consecutive stable patients with suspected CAD undergoing coronary angiography were included in the study. Data from a 4-year follow-up was obtained; the study endpoint was defined as all-cause mortality. Serum hs-cTnI was measured before angiography using a high-sensitivity assay. Results A total of 3,742 patients were included, of whom 2,274 (60.1%) had confirmed CAD. Patients with an estimated annual mortality rate above 3% using the REACH score were defined as having high risk (n=996 in the low-risk group, n=1,278 in the high-risk cohort). Patients with higher risk were more often male (81.5% vs. 69.2%, p Conclusion Hs-cTnI was found to be an independent risk factor in low- as well as high-risk patients. Hs-cTnI levels correlate with the REACH risk score. Moreover, it was possible to separate patients at very high and very low risk by combining REACH score and hs-cTnI.

Background Adult heart failure in industrialized nations is primarily due to dilated (DCM) and ischemic cardiomyopathy (ICM). Both diseases are characterized by different pathological pathways. While ICM is predominantly caused by local, subendocardial myocyte necrosis, DCM is characterized by a general myocyte apoptosis involving all myocardial layers. Using feature tracking, longitudinal, circumferential, and radial motion of the left ventricle (LV) can be measured, which allows the function of subendocardial, mostly longitudinal orientated, and subepicardial, mostly circumferential orientated fibers to be assessed independently. Purpose It was the aim of our study to detect differences of LV motion between DCM and ICM patients in a propensity score-matched cohort. Methods Between April 2017 and December 2018 we included 845 patients with a clinical indication for CMR in our tertiary care center registry. Out of this cohort we identified 273 patients with ICM and 126 with DCM. Propensity score matching was used to pair patients in each group based on their indexed enddiastolic volume (EDVi), ejection fraction (EF), septal T1. Feature tracking technique was used for strain analyses quantified on steady state free precession cine CMR images yielding six strain parameters. Results Propensity score matching yielded 59 patients in each group (ICM mean age 59.4±13.0 years, 11 females; DCM mean age 66.5±10.6 years, 15 females; LV-EF 32.6±11.4% vs. 33.0±14.2%, p=0.8178; EDVi 124.2±36 ml/m2 vs. 132.9±42 ml/m2, p=0.0909; native T1 values 1161±66 ms vs. 1164±59 ms, p=0.7049). There was no difference in global longitudinal strain between ICM and DCM patients (−10.9±4.4% vs. −10.6±5.8%, p=0.686), whereas global circumferential strain and radial strain were reduced in DCM patients (−12.0±4.3% vs. −10.31±4.8%, p=0.0190 and 21.1±8.9% vs. 18.0±15.5%, p=0.0386). Conclusion Our data confirm the inherently different mechanics of ICM and DCM patients. While myocardial fibres are globally affected in DCM, myocardial damage is predominantly confined to subendocardial layers in ICM despite equally reduced EF.

Background Balloon pulmonary angioplasty (BPA) is an evolving treatment option for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). The main indicator for success is improvement in pulmonary hemodynamics, but outcome data are heterogeneous. Purpose The aim of the present study was to evaluate pulmonary hemodynamics not only at rest, but also during exercise before and 6 months after BPA. Methods We report a prospective series of 64 consecutive patients with inoperable CTEPH who were treated interventionally with BPA. All patients underwent standardized assessment prior to the first BPA and 6 months after the last intervention. Assessment included WHO FC, Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR), 6-minute walking distance (6MWD), serum levels of the N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP), and exercise RHC. Results The mean number of sessions per patient was 5.6 (± 1.3) and the mean number of pulmonary segments targeted in all interventions was 11 (± 3). BPA treatment led to improvements in pulmonary hemodynamics and exercise capacity (6MWD: 416±94 m vs. 463±96 m; p Conclusion Significant improvements in pulmonary hemodynamics at rest and during exercise were observed 6 months after BPA. Exercise right heart catheterization offers a more discriminating evaluation of the changes in pulmonary hemodynamics after BPA.

The aim of our study was to analyse the protein expression of cartilage intermediate layer protein (CILP)1 in a mouse model of right ventricular (RV) pressure overload and to evaluate CILP1 as a biomarker of cardiac remodelling and maladaptive RV function in patients with pulmonary hypertension (PH).Pulmonary artery banding was performed in 14 mice; another nine mice underwent sham surgery. CILP1 protein expression was analysed in all hearts using Western blotting and immunostaining. CILP1 serum concentrations were measured in 161 patients (97 with adaptive and maladaptive RV pressure overload caused by PH; 25 with left ventricular (LV) hypertrophy; 20 with dilative cardiomyopathy (DCM); 19 controls without LV or RV abnormalities)In mice, the amount of RV CILP1 was markedly higher after banding than after sham. Control patients had lower CILP1 serum levels than all other groups (p−1) was associated with lower tricuspid annular plane excursion/pulmonary artery systolic pressure ratios (pCILP1 is a novel biomarker of RV and LV pathological remodelling that is associated with RV maladaptation and ventriculoarterial uncoupling in patients with PH.

Aims Balloon pulmonary angioplasty (BPA) is an interventional treatment modality for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Therapy monitoring, based on non-invasive biomarkers, is a clinical challenge. This post-hoc study aimed to assess dynamics of high-sensitivity cardiac troponin T (hs-cTnT) as a marker for myocardial damage and its relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels as a marker for cardiac wall stress. Methods and results This study included 51 consecutive patients who underwent BPA treatment and completed a 6-month follow-up (6-MFU) between 3/2014 and 3/2017. Biomarker measurement was performed consecutively prior to each BPA and at 6-MFU. In total, the 51 patients underwent an average of 5 BPA procedures. The 6-month survival rate was 96.1%. The baseline (BL) meanPAP (39.5±12.1mmHg) and PVR (515.8±219.2dyn×sec×cm-5) decreased significantly within the 6-MFU (meanPAP: 32.6±12.6mmHg, P

Riociguat is the treatment of choice for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). We addressed here whether additional balloon pulmonary angioplasty (BPA) provides further benefits. A prospective series of 36 consecutive patients with inoperable CTEPH were treated with riociguat at least three months before BPA. All patients underwent diagnostic workup at baseline, before BPA treatments, and six months after final intervention. The main outcome measures were pulmonary hemodynamic parameters and World Health Organization (WHO) functional class (FC). Significant improvements in pulmonary hemodynamics and physical capacity were observed for riociguat treatment, and subsequent BPA interventions yielded further benefits. With targeted medication, WHO FC improved by at least one class in 13 (36.1%) patients ( P = 0.01). Hemodynamic assessment showed significant improvements in mean pulmonary arterial pressure (mPAP) (49 ± 12 mmHg vs. 43 ± 12 mmHg; P = 0.003) and PVR (956 ± 501 dyn·s·cm –5 vs. 517 ± 279 dyn·s·cm –5 ; P = 0.0001). Treatment with a combination of targeted medication and BPA resulted in WHO FC improvement in 34 (94.4%) patients. Hemodynamic assessment showed significant improvement in mPAP (43 ± 12 mmHg vs. 34 ± 14 mmHg; P = 0.0001) and PVR (517 ± 279 dyn·s·cm –5 vs. 360 ± 175 dyn·s·cm –5 ; P = 0.0001). These findings provide, for the first time, support for the therapeutic strategy recommended by current guidelines.

The aim of this study was to assess native T1 mapping in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) before and 6 months after balloon pulmonary angioplasty (BPA) and compare the results with right heart function and pulmonary haemodynamics. Magnetic resonance imaging at 1.5 T and right heart catheterisation were performed in 21 consecutive inoperable CTEPH patients before and 6 months after BPA. T1 values were measured within the septal myocardium, the upper and lower right ventricular insertion points, and the lateral wall at the basal short-axis section. In addition, the area-adjusted septal native T1 time (AA-T1) was calculated and compared with right ventricular function (RVEF), mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR). The mean AA-T1 value decreased significantly after BPA (1,045.8 ± 44.3 ms to 1,012.5 ± 50.4 ms; p < 0.001). Before BPA, native T1 values showed a moderate negative correlation with RVEF (r = -0.61; p = 0.0036) and moderate positive correlations with mPAP (r = 0.59; p < 0.01) and PVR (r = 0.53; p < 0.05); after BPA correlation trends were present (r = -0.21, r = 0.30 and r = 0.35, respectively). Native T1 values in patients with inoperable CTEPH were significantly lower after BPA and showed significant correlations with RVEF and pulmonary haemodynamics before BPA. Native T1 mapping seems to be indicative of reverse myocardial tissue remodelling after BPA and might therefore have good potential for pre-procedural patient selection, non-invasive therapy monitoring and establishing a prognosis. • BPA is a promising treatment option for patients with inoperable CTEPH • Native septal T1 values significantly decrease after BPA and show good correlations with right ventricular function and haemodynamics before BPA • Prognosis and non-invasive therapy monitoring might be supported in the future by native T1 mapping

The use of thrombus aspiration (TA) prior to primary percutaneous coronary intervention (PPCI) has undergone a radical change in intervention guidelines. The clinical implications, however, are still under scrutiny. This study investigated the clinical effects and outcome of TA before PPCI in patients with ST-segment elevation myocardial infarction (STEMI). Overall 1027 patients with STEMI were analyzed in this retrospective, propensity score-adjusted, multicenter study. The primary endpoints were in-hospital and long-term mortality. There were 418 patients in the TA group and 609 in the conventional PPCI group. The in-hospital mortality rate was significantly higher in the TA group (8.7 vs. 5.0%; P = 0.03). During long-term follow-up [median follow-up duration 689 days (IQR 405–959)] the mortality rates were similar (TA 14.3%, conventional PPCI 15.0%; P = 0.85). Survival analysis for the complete observation period revealed no significant benefit of TA [hazard ratio (HR) 1.12; 97.5% CI 0.90–0.71; P = 0.63]. There were also no significant differences between the groups in the following secondary endpoints: composite of cardiovascular death and non-fatal reinfarction at discharge (P = 0.39), post-PPCI thrombolysis in myocardial infarction flow-grade-3 (P = 0.14), left ventricular ejection fraction (P = 0.47), and non-fatal reinfarction during follow-up (P = 0.17). Rehospitalization rate (1.82 vs. 10.3%; P

In patients with refractory cardiogenic shock (CS) mechanical assistance by venous-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy may be considered to reach haemodynamic stabilization. In this first-in-man study, we analysed the applicability of the new i-cor VA-ECMO assist device equipped with a diagonal pump system.In total, 15 patients with refractory CS were treated with the i-cor assist device in three tertiary care centres. In 71%, CS was due to acute myocardial infarction (AMI). At baseline, patients were hypotensive (systolic/diastolic blood pressure 97 ± 4/62 ± 4 mm Hg) despite high doses of catecholamines. Under ECMO therapy, a significant reduction in vasopressor therapy and serum lactate levels was observed (norepinephrine: 0.69 ± 0.1 µg/kg/min at baseline vs 0.21 ± 0.08 µg/kg/min on the last day of treatment, p0.0001; serum lactate: 6.7 ± 1.4 mmol/l at baseline versus 1.3 ± 0.1 mmol/l on the last day, p0.001). Inspiratory oxygen concentration was significantly reduced during the course of VA-ECMO support (80.4 ± 7.0% at baseline vs 42.7 ± 2.4% on final day; p0.001). At baseline, three patients (20%) were on continuous haemodialysis treatment. Of the 12 patients without haemodialysis at baseline, only one patient required haemodialysis during the course of ECMO treatment. Glomerular filtration rate (GFR) significantly increased with treatment (41.2 ± 7.4 at baseline vs 69.0 ± 10.8 on last day; p=0.006). Bleeding at the insertion site was recorded in two patients (13.3%). Overall, 11 patients (73.3%) needed blood transfusion. Three patients (20%) developed signs of limb ischaemia that were fully reversible. Haemolysis was recorded in five patients (33%). None of the complications required the interruption of ECMO therapy. Overall mortality was 33.3% (five patients); two patients died during, and three patients after, ECMO therapy.This first-in-man analysis suggests that the i-cor ECMO device is successfully applicable in humans. The data set the stage for further evaluation of this novel system and provide the necessary basis to design randomised evaluations.

Background N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) levels correlate with higher peri-procedural mortality after transcatheter aortic valve replacement (TAVR). The long-term prognostic value of NT-proBNP within the first days after TAVR, however, remains unclear. This study examined early changes in NT-proBNP prior to and within 6 days after TAVR, the diagnostic value of this biomarker regarding aortic regurgitation (AR), and its prognostic value regarding one-year mortality. Methods and results NT-proBNP concentrations were measured in 504 consecutive patients undergoing transapical (TA) or transfemoral (TF) TAVR before and directly after TAVR as well as 4 h and 1, 2, 3, and 6 days after TAVR. The follow-up period was 1 year. NT-proBNP was elevated in all patients at baseline (median 2141 ng/L [IQR 1021–5319 ng/L]). NT-proBNP changes in the first 6 days after TAVR showed significant differences depending on the approach, with a greater and more prolonged rise evident in TA-TAVR patients. NT-proBNP was an independent predictor of mortality in TA patients with AR, with an AUC of 0.794 (95% CI 0.663–0.925; P = 0.003) when measured on day 3 after TAVR. For TF patients with AR and reduced left ventricular systolic function, the AUC for prediction of mortality was 0.897 (95% CI 0.778–1.0; P = 0.004) on day 2. Conclusions The prognostic information of early post-procedural NT-proBNP concentrations is superior to pre-procedural values regarding all-cause mortality within 1 year. Post-procedural NT-proBNP must be interpreted in relation to the TAVR approach. NT-proBNP predicts mortality in TF-TAVR patients with AR and reduced left ventricular function.

BACKGROUND Balloon pulmonary angioplasty (BPA) is an emerging interventional treatment option for chronic thromboembolic pulmonary hypertension (CTEPH). The non-invasive monitoring of CTEPH patients is a clinical challenge. In this study we examined changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients undergoing BPA for inoperable CTEPH and related them to peri-procedural success. METHODS In this study we analyzed a total of 51 consecutive patients who underwent BPA treatment and completed a 6-month follow-up (6-MFU) between March 2014 and March 2017. Serum samples for NT-proBNP measurement were collected before every BPA and at 6-MFU. RESULTS The 51 patients underwent 265 interventions involving angioplasty of a total of 410 vessels. The 6-month survival rate was 96.1%. The baseline (BL) mean pulmonary artery pressure (PAP) was 39.5 ± 12.1 mm Hg, pulmonary vascular resistance (PVR) was 515.8 ± 219.2 dynes/s/cm5 and the median NT-proBNP level was 820 (153 to 1,871.5) ng/liter. At BL, World Health Organization functional class (FC) was ≥III in 96.1% of the patients, whereas, at 6-MFU, 11.8% were in WHO FC ≥III. At 6-MFU, mean PAP (32.6 ± 12.6 mm Hg; p < 0.001), PVR (396.9 ± 182.6 dynes/s/cm5; p < 0.001) and NT-proBNP (159.3 [84.4 to 464.3] ng/liter; p < 0.001) levels were reduced. The decrease in NT-proBNP levels correlated with the decrease in mean PAP (rrs = 0.43, p = 0.002) and PVR (rrs = 0.50, p = 0.001). A reduction in the NT-proBNP level of 46% indicated a decrease in mean PAP of ≥25% (area under the curve [AUC] = 0.71) and a reduction of 61% indicated a decrease in PVR of ≥35% (AUC 0.77). CONCLUSIONS Our results demonstrate that NT-proBNP levels decrease after BPA, providing valuable evidence of procedural success. NT-proBNP measurement allows identification of patients who are BPA non-responders and may thus be a valuable adjunct in therapy monitoring.

Angiopoietin-2 (Ang-2) impairs endothelial integrity. The association of Ang-2 in the presence of oedema and outcome of patients with acute decompensated heart failure (ADHF) has not been investigated.Angiopoietin-2 was measured in 132 ADHF patients, which were included in a monocentric, prospective trial (Clinicaltrials.gov: NCT01429857). Primary endpoint was all-cause death at 6-months. 20 healthy persons served as control group (HC). In ADHF patients, mean Ang-2 concentration at admission was significantly increased compared to HC (2,111 ± 117 vs. 971 ± 46 pg/ml, p = 0.0002). Ang-2 was increased in patients with compared to those without peripheral oedema (2,294 ± 140 vs. 1,540 ± 170 pg/ml; p = 0.009) and in patients with NYHA class III or IV symptoms compared to those with NYHA class II symptoms (2,256 ± 132 vs. 1,341 ± 380 pg/ml, p = 0.023). During the 6-month follow-up, 10 patients died. In survivors, Ang-2 significantly decreased at discharge compared to admission (2,046 ± 118 vs. 1,431 ± 93 pg/ml; p0.0001). Non-survivors showed no difference between Ang-2 concentration at admission and discharge (3,296 ± 594 vs. 2,909 ± 536 pg/ml). Ang-2 concentrations at discharge above 2,500 pg/ml were associated with an increased risk of death compared to Ang-2 concentrations below this threshold (Hazard ratio 8.8; 95 % confidence interval; 2.48-31.16, p0.001).In ADHF patients, Ang-2 is significantly increased compared to healthy controls, shows a relationship in the presence of oedema and is a predictor of poor outcome.

Background Chronic thromboembolic pulmonary hypertension (CTEPH) is associated with poor outcome if untreated, although it is a curable form of pulmonary hypertension (PH). Successful treatment requires an optimized diagnostic work-up. Purpose The aim of this study was to identify non-invasive biomarkers that might serve as new diagnostic parameters in the multifaceted pathophysiology of CTEPH. Methods The biomarker profile of 64 CTEPH patients who underwent balloon pulmonary angioplasty (BPA) was analyzed prior to and after therapy and compared with that of a healthy control group (CG1, n=25) at baseline. Proteomes were analyzed by semiquantitative screening based on a proximity extension assay of three high-throughput, multiplex immunoassay panels. Serum levels of a subset of biomarkers identified in the screening were additionally measured by immunochemical methods. Results Fifty protein biomarkers were found to differ between CTEPH patients and CG1. Eight biomarkers changed significantly after therapy. The overlap of these two groups revealed six targets that were all upregulated in CTEPH at baseline and modifiable by treatment. In this group of biomarkers, the levels of DCN (decorin), HGF (hepatocyte growth factor), BNP (B-type natriuretic peptide), and PAPP-A (papalysin-1) decreased after therapy, whereas SPON-1 (spondin-1) and MEPE (matrix extracellular phosphoglycoprotein) further increased at follow-up. The differences in these biomarkers in CTEPH as well as the dynamics after therapy were confirmed and quantified in enzyme-linked immunosorbent assays. Conclusions This study identified 6 biomarkers that might serve as new diagnostic parameters or constitute new therapeutic targets in CTEPH. Further prospective studies will be necessary to determine the specific pathophysiological role of each marker. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): SFB 1213 area CP01