Publications by authors named "Albrecht Schmidt"

65 Publications

The Real-World CONSEQUENT ALL COMERS Study: Predictors for Target Lesion Revascularization and Mortality in an Unselected Patient Population.

Angiology 2021 Mar 29:3319721997314. Epub 2021 Mar 29.

GRN Academic Teaching Hospital Weinheim, Germany.

We evaluated the safety and efficacy of a resveratrol-paclitaxel-coated peripheral balloon catheter in an all-comer patient cohort undergoing endovascular treatment of above-the-knee and below-the-knee peripheral artery disease. CONSEQUENT ALL COMERS (Clinical Post-Market Clinical Follow-up [PMCF] on Peripheral Arteries treated with SeQuent Please OTW [Over-the Wire]) is a prospective, single-arm, multicenter observational study (ClinicalTrials Identifier: NCT02460042). The primary end point was the 12-month target lesion revascularization (TLR) rate. Secondary end points included vessel patency, target vessel revascularization, and all-cause mortality. A total of 879 lesions in 784 consecutive patients (71.3 ± 10.4 years old, 57.7% male) were analyzed; 53.3% had claudication, whereas the remaining 46.7% exhibited critical limb ischemia (CLI). Substantial comorbidities were present, including diabetes mellitus (41.2%), smoking (66.1%), and coronary artery disease (33.9%). Lesion length (879 lesions) was 12.0 ± 9.3 cm and 31.8% were Transatlantic Inter-Society Consensus II C/D lesions. The overall technical success rate of the 1269 drug-coated balloon (DCB)'s used was 99.6% (1.60 ± 0.79 DCB's/patient). At 12 months, the TLR rates were 6.3% in patients with CLI and 9.6% in claudicants, with a primary patency rate of 89.9% and 87.1%, respectively. All-cause mortality was 4.3% (28/658). Predictors for TLR were in-stent restenosis at baseline, vessel diameters ≤ 4.5 mm, lesion length, and post-DCB bailout stenting.
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http://dx.doi.org/10.1177/0003319721997314DOI Listing
March 2021

2020 update of the Austrian Society of Cardiology (ÖKG) and the Austrian Society of Cardiac Surgery (ÖGHTG) on the position statement of the ÖKG and ÖGHTG for transcatheter aortic valve implantation 2011.

Wien Klin Wochenschr 2021 Mar 23. Epub 2021 Mar 23.

3. Medizinische Abteilung mit Kardiologie, Wilhelminenspital der Stadt Wien, Vienna, Austria.

This position statement is an update to the 2011 consensus statement of the Austrian Society of Cardiology (ÖKG) and the Austrian Society of Cardiac Surgery (ÖGTHG) for transfemoral transcatheter aortic valve implantation.Due to a number of recently published studies, broadening of indications and recommendations of medical societies and our own national developments, the ÖKG and the ÖGHTG wish to combine the 2017 ESC/EACTS guidelines for the management of valvular heart disease with a national position paper and to focus on certain details for the application in Austria. Thus, this position statement serves as a supplement and further interpretation of the international guidelines.
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http://dx.doi.org/10.1007/s00508-021-01820-3DOI Listing
March 2021

Nicotinamide for the treatment of heart failure with preserved ejection fraction.

Sci Transl Med 2021 Feb;13(580)

Department of Cardiology, Medical University of Graz, Graz 8036, Austria.

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD). Elevating NAD by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans.
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http://dx.doi.org/10.1126/scitranslmed.abd7064DOI Listing
February 2021

Impact of the Choice of Native T in Pixelwise Myocardial Blood Flow Quantification.

J Magn Reson Imaging 2021 03 8;53(3):755-765. Epub 2020 Oct 8.

Division of General Radiology, Department of Radiology, Medical University of Graz, Graz, Austria.

Background: Quantification of myocardial blood flow (MBF) from dynamic contrast-enhanced (DCE) MRI can be performed using a signal intensity model that incorporates T values of blood and myocardium.

Purpose: To assess the impact of T values on pixelwise MBF quantification, specifically to evaluate the influence of 1) study population-averaged vs. subject-specific, 2) diastolic vs. systolic, and 3) regional vs. global myocardial T values.

Study Type: Prospective.

Subjects: Fifteen patients with chronic coronary heart disease.

Field Strength/sequence: 3T; modified Look-Locker inversion recovery for T mapping and saturation recovery gradient echo for DCE imaging, both acquired in a mid-ventricular short-axis slice in systole and diastole.

Assessment: MBF was estimated using Fermi modeling and signal intensity nonlinearity correction with different T values: study population-averaged blood and myocardial, subject-specific systolic and diastolic, and segmental T values. Myocardial segments with perfusion deficits were identified visually from DCE series.

Statistical Tests: The relationships between MBF parameters derived by different methods were analyzed by Bland-Altman analysis; corresponding mean values were compared by t-test.

Results: Using subject-specific diastolic T values, global diastolic MBF was 0.61 ± 0.13 mL/(min·g). It did not differ from global MBF derived from the study population-averaged T (P = 0.88), but the standard deviation of differences was large (0.07 mL/(min·g), 11% of mean MBF). Global diastolic and systolic MBF did not differ (P = 0.12), whereas global diastolic MBF using systolic (0.62 ± 0.13 mL/(min·g)) and diastolic T values differed (P < 0.05). If regional instead of global T values were used, segmental MBF was lower in segments with perfusion deficits (bias = -0.03 mL/(min·g), -7% of mean MBF, P < 0.05) but higher in segments without perfusion deficits (bias = 0.01 mL/(min·g), 1% of mean MBF, P < 0.05).

Data Conclusion: Whereas cardiac phase-specific T values have a minor impact on MBF estimates, subject-specific and myocardial segment-specific T values substantially affect MBF quantification.

Level Of Evidence: 3 TECHNICAL EFFICACY STAGE: 3.
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http://dx.doi.org/10.1002/jmri.27375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891429PMC
March 2021

Automated mitral valve vortex ring extraction from 4D-flow MRI.

Magn Reson Med 2020 12 18;84(6):3396-3408. Epub 2020 Jun 18.

Division of General Radiology, Department of Radiology, Medical University of Graz, Graz, Austria.

Purpose: To present and validate a method for automated extraction and analysis of the temporal evolution of the mitral valve (MV) vortex ring from MR 4D-flow data.

Methods: The proposed algorithm uses the divergence-free part of the velocity vector field for Q criterion-based identification and tracking of MV vortex ring core and region within the left ventricle (LV). The 4D-flow data of 20 subjects (10 healthy controls, 10 patients with ischemic heart disease) were used to validate the algorithm against visual analysis as well as to assess the method's sensitivity to manual LV segmentation. Quantitative MV vortex ring parameters were analyzed with respect to both their differences between healthy subjects and patients and their correlation with transmitral peak velocities.

Results: The algorithm successfully extracted MV vortex rings throughout the entire cardiac cycle, which agreed substantially with visual analysis (Cohen's kappa = 0.77). Furthermore, vortex cores and regions were robustly detected even if a static end-diastolic LV segmentation mask was applied to all frames (Dice coefficients 0.82 ± 0.08 and 0.94 ± 0.02 for core and region, respectively). Early diastolic MV vortex ring vorticity, kinetic energy and circularity index differed significantly between healthy controls and patients. In contrast to vortex shape parameters, vorticity and kinetic energy correlated strongly with transmitral peak velocities.

Conclusion: An automated method for temporal MV vortex ring extraction demonstrating robustness with respect to LV segmentation strategies is introduced. Quantitative vortex parameter analysis indicates importance of the MV vortex ring for LV diastolic (dys)function.
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http://dx.doi.org/10.1002/mrm.28361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540523PMC
December 2020

Empagliflozin protects heart from inflammation and energy depletion via AMPK activation.

Pharmacol Res 2020 08 17;158:104870. Epub 2020 May 17.

Division of Cardiology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria. Electronic address:

Aims: Sodium-glucose co-transporter 2 (SGLT2) were originally developed as kidney-targeting anti-diabetic drugs. However, due to their beneficial cardiac off-target effects (as SGLT2 is not expressed in the heart), these antagonists currently receive intense clinical interest in the context of heart failure (HF) in patients with or without diabetes mellitus (DM). Since the mechanisms by which these beneficial effects are mediated are still unclear yet, inflammation that is present in DM and HF has been proposed as a potential pharmacological intervention strategy. Therefore, we tested the hypothesis that the SGLT2 inhibitor, empagliflozin, displays anti-inflammatory potential along with its glucose-lowering property.

Methods And Results: Lipopolysaccharide (LPS) was used to induce inflammation in vitro and in vivo. In cardiomyocytes and macrophages empagliflozin attenuated LPS-induced TNFα and iNOS expression. Analysis of intracellular signalling pathways suggested that empagliflozin activates AMP kinase (AMPK) in both cell types with or without LPS-treatment. Moreover, the SGLT2 inhibitor increased the expression of anti-inflammatory M2 marker proteins in LPS-treated macrophages. Additionally, empagliflozin-mediated AMPK activation prevented LPS-induced ATP/ADP depletion. In vivo administration of LPS in mice impaired cardiac contractility and aortic endothelial relaxation in response to acetylcholine, whereby co-administration of empagliflozin preserved cardiovascular function. These findings were accompanied by improved cardiac AMPK phosphorylation and ATP/ADP, reduced cardiac iNOS, plasma TNFα and creatine kinase MB levels.

Conclusion: Our data identify a novel cardio protective mechanism of SGLT2 inhibitor, empagliflozin, suggesting that AMPK activation-mediated energy repletion and reduced inflammation contribute to the observed cardiovascular benefits of the drug in HF.
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http://dx.doi.org/10.1016/j.phrs.2020.104870DOI Listing
August 2020

Impact of Predilatation Prior to Transcatheter Aortic Valve Implantation With the Self-Expanding Acurate neo Device (from the Multicenter NEOPRO Registry).

Am J Cardiol 2020 05 8;125(9):1369-1377. Epub 2020 Feb 8.

Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil.

Safety and feasibility of transfemoral Acurate neo implantation without systematic predilatation are not fully investigated. Our aim was to evaluate the use and impact of pre-implantation balloon aortic valvuloplasty (pre-BAV) before transcatheter aortic valve implantation (TAVI) with Acurate neo. The NEOPRO Registry retrospectively included 1,263 patients who underwent transfemoral TAVI with Acurate neo at 18 centers between January 2012 and March 2018. Information on pre-BAV was available for 1,262 patients (99.9%). Primary end points were pre-discharge moderate-to-severe paravalvular aortic regurgitation (PAR II+), 30-day new permanent pacemaker implantation, and 30-day all-cause mortality or stroke. A total of 1,262 patients who underwent TAVI with (n = 1,051) or without predilatation (n = 211) were included. A reduction in the pre-BAV rate was observed during the study period (from 95.7% in the first date quintile to 78.4% in the last date quintile). Patients who underwent pre-BAV had higher degrees of aortic valve (AV) and left ventricular outflow tract (LVOT) calcification. Primary endpoints were similar between pre-BAV and no pre-BAV groups (PAR II+ 5.5% vs 3.4%, p = 0.214; 30-day permanent pacemaker implantation 9.0% vs 8.0%, p = 0.660; 30-day death or stroke 4.9% vs 4.4%, p = 0.743). The need for postdilatation and other procedural outcomes were comparable between groups. Predilatation did not have a significant impact on primary endpoints across AV and LVOT calcification subgroups (subgroup analyses) and was not independently associated with primary endpoints (multivariate analyses). In conclusion, transfemoral Acurate neo implantation without predilatation appears to be feasible and safe, especially in patients with milder degrees of AV and LVOT calcification.
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http://dx.doi.org/10.1016/j.amjcard.2020.02.003DOI Listing
May 2020

Dataset on the prognostic value of cardiac biomarkers used in clinical routine in patients with severe aortic stenosis undergoing valve replacement.

Data Brief 2020 Apr 9;29:105111. Epub 2020 Jan 9.

University Clinic of Internal Medicine III, Medical University Innsbruck, Innsbruck, Austria.

Hereby, the supplemental data of the research article "Long-Term Prognostic Value of High-Sensitivity Troponin T added to N-Terminal Pro Brain Natriuretic Peptide Plasma Levels before Valve Replacement for Severe Aortic Stenosis" are presented [1]. It offers enhanced input on the predictive value of these biomarkers considering the influence of the presence of concomitant coronary artery disease (CAD) in various severities as well as an additional cox proportional hazard model on cardiovascular mortality. Furthermore, the receiver operating characteristic (ROC) curves are shown as figures. The material described increases therefore the understanding of the predictive value of these already routinely available biomarkers and reduces the risk of potential bias due to possible confounding factors. It also underlines the urge for a multi-factorial approach in diagnostics to detect the optimal point for referral to valve replacement other than just symptomatic status, an observed reduction in left ventricular ejection fraction or the presence of CAD with the necessity for coronary artery bypass grafting (CABG) [2]. The data of the 3595 patients were gathered retrospectively at a consortium of four university hospital centers in Austria and combined with prospectively collected data on cardiovascular and all-cause mortality.
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http://dx.doi.org/10.1016/j.dib.2020.105111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971345PMC
April 2020

Anti-αLβ2 antibodies reveal novel endocytotic cross-modulatory functionality.

Br J Pharmacol 2020 06 9;177(12):2696-2711. Epub 2020 Mar 9.

Division of Clinical Pharmacology & Toxicology, University Hospital Basel, Basel, Switzerland.

Background And Purpose: Antibodies targeting cell surface receptors are considered to enable highly selective therapeutic interventions for immune disorders and cancer. Their biological profiles are found, generally, to represent the net effects of antibody-target interactions. The former therapeutic anti-integrin αLβ2 antibody efalizumab seems to defeat this paradigm by eliciting, via mechanisms currently unknown, much broader effects than would be predicted based on its target specificity.

Experimental Approach: To elucidate the mechanisms behind these broad effects, we investigated in primary human lymphocytes in vitro the effects of anti-αLβ2 antibodies on the expression of αLβ2 as well as unrelated α4 integrins, in comparison to Fab fragments and small-molecule inhibitors.

Key Results: We demonstrate that anti-αLβ2 mAbs directly induce the internalization of α4 integrins. The endocytotic phenomenon is a direct consequence of their antibody nature. It is inhibited when monovalent Fab fragments or small-molecule inhibitors are used. It is independent of crosslinking via anti-Fc mAbs and of αLβ2 activation. The cross-modulatory effect is unidirectional and not observed in a similar fashion with the α4 integrin antibody natalizumab.

Conclusion And Implications: The present study identifies endocytotic cross-modulation as a hitherto unknown non-canonical functionality of anti-αLβ2 antibodies. This cross-modulation has the potential to fundamentally alter an antibody's benefit risk profile, as evident with efalizumab. The newly described phenomenon may be of relevance to other therapeutic antibodies targeting cluster-forming receptors. Thus, pharmacologists should be cognizant of this action when investigating such antibodies.
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http://dx.doi.org/10.1111/bph.14996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236072PMC
June 2020

Long-Term Prognostic Value of High-Sensitivity Troponin T Added to N-Terminal Pro Brain Natriuretic Peptide Plasma Levels Before Valve Replacement for Severe Aortic Stenosis.

Am J Cardiol 2019 12 26;124(12):1932-1939. Epub 2019 Sep 26.

University Clinic of Internal Medicine III, Medical University Innsbruck, Innsbruck, Austria. Electronic address:

Natriuretic peptide plasma levels help to manage patients with severe aortic stenosis (AS). The role of troponin plasma levels in this patient cohort remains speculative. A consortium of 4 university hospital centers in Austria analyzed retrospectively 3,595 patients admitted for valve replacement because of severe AS since 2007. The aim was to compare the additive preprocedural value of high-sensitivity troponin T (hsTnT) to N-terminal pro brain natriuretic peptide (NT-proBNP) plasma levels in predicting postoperative long-term survival in a large cohort undergoing either surgical (57.8%) or transcatheter (42.2%) aortic valve replacement. During a median follow-up of 2.93 (1.91 to 4.92) years, 919 patients (25.6%) died, in them 556 (15.5%) due to cardiovascular causes. Both normal hsTnT (<14 ng/l) and NT-proBNP (within age- and sex-corrected normal range) plasma levels were found in 481 patients (14.3%, group 1). Normal hsTnT but elevated NT-proBNP plasma levels were found in 748 patients (22.3%, group 2). Elevated hsTnT but normal NT-proBNP plasma levels were found in 258 patients (7.7%, group 3). Both elevated hsTnT and elevated NT-proBNP plasma levels were found in 1,869 patients (55.7%, group 4). Using Log Rank tests for comparison there was a highly significant difference in both cardiovascular mortality (p <0.0001) and all-cause mortality (p <0.0001). All-cause mortality rates after 1, 3, and 5 years were 2.1%, 5.4%, 7.7% in group 1; 4.0%, 7.5%, 11.5% in group 2; 5.8%, 8.9%, 14.0% in group 3; and 12.3%, 22.6%, 28.4% in group 4. In conclusion, hsTnT adds additional impact to NT-proBNP as a routinely available biomarker for risk stratification concerning postoperative survival in patients with severe AS admitted for valve replacement. The present study supports the concept to integrate hsTnT plasma levels in the management of severe AS.
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http://dx.doi.org/10.1016/j.amjcard.2019.09.014DOI Listing
December 2019

Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans.

Cell Metab 2019 09 27;30(3):462-476.e6. Epub 2019 Aug 27.

Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Austria; Center for Biomarker Research in Medicine (CBmed), Graz, Austria; HEALTH Institute for Biomedicine and Health Sciences, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Neue Stiftingtalstraße 2, Graz, Austria.

Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study (ClinicalTrials.gov identifier: NCT02673515), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased β-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.
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http://dx.doi.org/10.1016/j.cmet.2019.07.016DOI Listing
September 2019

Control of p21Cip by BRCA1-associated protein is critical for cardiomyocyte cell cycle progression and survival.

Cardiovasc Res 2020 03;116(3):592-604

Department of Cardiology and Pulmonology, Georg-August University, Robert-Koch Str. 40, 37075 Göttingen, Germany.

Aims: Identifying the key components in cardiomyocyte cell cycle regulation is of relevance for the understanding of cardiac development and adaptive and maladaptive processes in the adult myocardium. BRCA1-associated protein (BRAP) has been suggested as a cytoplasmic retention factor for several proteins including Cyclin-dependent-kinase inhibitor p21Cip. We observed profound expressional changes of BRAP in early postnatal myocardium and investigated the impact of BRAP on cardiomyocyte cell cycle regulation.

Methods And Results: General knockout of Brap in mice evoked embryonic lethality associated with reduced myocardial wall thickness and lethal cardiac congestion suggesting a prominent role for BRAP in cardiomyocyte proliferation. αMHC-Cre driven cardiomyocyte-specific knockout of Brap also evoked lethal cardiac failure shortly after birth. Likewise, conditional cardiomyocyte-specific Brap deletion using tamoxifen-induced knockout in adult mice resulted in marked ventricular dilatation and heart failure 3 weeks after induction. Several lines of evidence suggest that Brap deletion evoked marked inhibition of DNA synthesis and cell cycle progression. In cardiomyocytes with proliferative capacity, this causes developmental arrest, whereas in adult hearts loss of BRAP-induced apoptosis. This is explained by altered signalling through p21Cip which we identify as the link between BRAP and cell cycle/apoptosis. BRAP deletion enhanced p21Cip expression, while BRAP overexpression in cardiomyocyte-specific transgenic mice impeded p21Cip expression. That was paralleled by enhanced nuclear Ki-67 expression and DNA synthesis.

Conclusion: By controlling p21Cip activity BRAP expression controls cell cycle activity and prevents developmental arrest in developing cardiomyocytes and apoptosis in adult cardiomyocytes.
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http://dx.doi.org/10.1093/cvr/cvz177DOI Listing
March 2020

Transcatheter Aortic Valve Replacement With Next-Generation Self-Expanding Devices: A Multicenter, Retrospective, Propensity-Matched Comparison of Evolut PRO Versus Acurate neo Transcatheter Heart Valves.

JACC Cardiovasc Interv 2019 03;12(5):433-443

Cardio Center, Humanitas Research Hospital, Rozzano-Milan, Italy.

Objectives: The aim of this study was to compare transcatheter aortic valve replacement (TAVR) with the Acurate neo (NEO) and Evolut PRO (PRO) devices.

Background: The NEO and PRO bioprostheses are 2 next-generation self-expanding devices developed for TAVR.

Methods: The NEOPRO (A Multicenter Comparison of Acurate NEO Versus Evolut PRO Transcatheter Heart Valves) registry retrospectively included patients who underwent transfemoral TAVR with either NEO or PRO valves at 24 centers between January 2012 and March 2018. One-to-one propensity score matching resulted in 251 pairs. Pre-discharge and 30-day Valve Academic Research Consortium (VARC)-2 defined outcomes were evaluated. Binary logistic regression was performed to adjust the treatment effect for propensity score quintiles.

Results: A total of 1,551 patients (n = 1,263 NEO; n = 288 PRO) were included. The mean age was 82 years, and the mean Society of Thoracic Surgeons score was 5.1%. After propensity score matching (n = 502), VARC-2 device success (90.6% vs. 91.6%; p = 0.751) and pre-discharge moderate to severe (II+) paravalvular aortic regurgitation (7.3% vs. 5.7%; p = 0.584) were comparable between the NEO and PRO groups. Furthermore, there were no significant differences in any 30-day clinical outcome between matched NEO and PRO pairs, including all-cause mortality (3.2% vs. 1.2%; p = 0.221), stroke (2.4% vs. 2.8%; p = 1.000), new permanent pacemaker implantation (11.0% vs. 12.8%; p = 0.565), and VARC-2 early safety endpoint (10.6% vs. 10.4%; p = 1.000). Logistic regression on the unmatched cohort confirmed a similar risk of VARC-2 device success, paravalvular aortic regurgitation II+, and 30-day clinical outcomes after NEO and PRO implantation.

Conclusions: In this multicenter registry, transfemoral TAVR with the NEO and PRO bioprostheses was associated with high device success, acceptable rates of paravalvular aortic regurgitation II+, and good 30-day clinical outcomes. After adjusting for potential confounders, short-term outcomes were similar between the devices.
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http://dx.doi.org/10.1016/j.jcin.2018.11.036DOI Listing
March 2019

Diastolic stress test echocardiography in patients with suspected heart failure with preserved ejection fraction: a pilot study.

ESC Heart Fail 2019 02 19;6(1):146-153. Epub 2018 Nov 19.

Department of Internal Medicine and Cardiology, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.

Aims: The purpose of this pilot study was to assess the potential usefulness of diastolic stress test (DST) echocardiography in patients with suspected heart failure with preserved ejection fraction (HFpEF).

Methods And Results: Patients with suspected HFpEF (left ventricular ejection fraction ≥ 50%, exertional dyspnoea, septal E/e' at rest 9-14, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at rest < 220 pg/mL; n = 13) and a control group constituted from asymptomatic patients with arterial hypertension (n = 19) and healthy subjects (n = 18) were included. All patients were analysed by two-dimensional and Doppler echocardiography at rest and during exercise (DST) and underwent cardiopulmonary exercise testing and NT-proBNP analysis during exercise. HFpEF during exercise was defined as exertional dyspnoea and peak VO  ≤ 20.0 mL/min/kg. In patients with suspected HFpEF at rest, 84.6% of these patients developed HFpEF during exercise, whereas in the group of asymptomatic patients with hypertension and healthy subjects, the rate of developed HFpEF during exercise was 0%. Regarding the diagnostic performance of DST to detect HFpEF during exercise, an E/e' ratio >15 during exercise was the most accurate parameter to detect HFpEF (accuracy 86%), albeit a low sensitivity (45.5%). Nonetheless, combining E/e' with tricuspid regurgitation (TR) velocity > 2.8 m/s during exercise provided a significant increase in the sensitivity to detect patients with HFpEF during exercise (sensitivity 72.7%, specificity 79.5%, and accuracy 78%). Consistent with these findings, an increase of E/e' was significantly linked to worse peak VO , and the combination of an increase of both E/e' and TR velocity was associated with elevated NT-proBNP values during exercise.

Conclusions: The findings of this pilot study suggest that DST using E/e' ratio and TR velocity could be of potential usefulness to diagnose HFpEF during exercise in patients with suspected HFpEF at rest.
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http://dx.doi.org/10.1002/ehf2.12375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352885PMC
February 2019

Impact of On-Site Cardiac Surgery on Clinical Outcomes After Transfemoral Transcatheter Aortic Valve Replacement.

JACC Cardiovasc Interv 2018 11;11(21):2160-2167

3(rd) Medical Department, Cardiology, Intensive Care Medicine and Chest Pain Unit, Wilhelminenhospital, Vienna, Austria; Medical School Sigmund Freud University, Vienna, Austria.

Objectives: This study sought to investigate the outcome of high-risk and inoperable patients with severe symptomatic aortic stenosis undergoing transfemoral transcatheter aortic valve replacement (TAVR) in hospitals with (iOSCS) versus without institutional on-site cardiac surgery (no-iOSCS).

Background: Current guidelines recommend the use of TAVR only in institutions with a department for cardiac surgery on site.

Methods: In this analysis of the prospective multicenter Austrian TAVI registry, 1,822 consecutive high-risk patients with severe symptomatic aortic stenosis undergoing transfemoral TAVR were evaluated. A total of 290 (15.9%) underwent TAVR at no-iOSCS centers (no-iOSCS group), whereas the remaining 1,532 patients (84.1%) were treated in iOSCS centers (iOSCS group).

Results: Patients of the no-iOSCS group had a higher perioperative risk defined by the logistic EuroSCORE (20.9% vs. 14.2%; p < 0.001) compared with patients treated in hospitals with iOSCS. Procedural survival was 96.9% in no-iOSCS centers and 98.6% in iOSCS centers (p = 0.034), whereas 30-day survival was 93.1% versus 96.0% (p = 0.039) and 1-year survival was 80.9% versus 86.1% (p = 0.017), respectively. After propensity score matching for confounders procedural survival was 96.9% versus 98.6% (p = 0.162), 93.1% versus 93.8% (p = 0.719) at 30 days, and 80.9% versus 83.4% (p = 0.402) at 1 year.

Conclusions: Patients undergoing transfemoral TAVR in hospitals without iOSCS had a significantly higher baseline risk profile. After propensity score matching short- and long-term mortality was similar between centers with and without iOSCS.
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http://dx.doi.org/10.1016/j.jcin.2018.07.015DOI Listing
November 2018

Intermittent Fasting (Alternate Day Fasting) in Healthy, Non-obese Adults: Protocol for a Cohort Trial with an Embedded Randomized Controlled Pilot Trial.

Adv Ther 2018 Aug 25;35(8):1265-1283. Epub 2018 Jul 25.

Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Background/objectives: Alternate day fasting (ADF) is a subtype of intermittent fasting and is defined as a continuous sequence of a fast day (100% energy restriction, zero calories) and a feed day (ad libitum food consumption), resulting in roughly 36-h fasting periods. Previous studies demonstrated weight reductions and improvements of cardiovascular risk factors with ADF in obese subjects. However, rigorous data on potential endocrine, metabolic and cardiovascular effects, besides weight loss, are lacking. Therefore we aim to investigate the short- and mid- to long-term clinical and molecular effects of ADF in healthy non-obese subjects.

Methods: We will perform a prospective cohort study with an embedded randomized controlled trial (RCT) including 90 healthy subjects. Thirty of them will have performed ADF for at least 6 months (mid-term group). Sixty healthy subjects without a particular diet before enrolment will serve as the control group. These subjects will be 1:1 randomized to either continuing their current diet or performing ADF for 4 weeks. All subjects will undergo study procedures that will be repeated in RCT participants after 4 weeks. These procedures will include assessment of outcome parameters, dual-energy X-ray absorptiometry, measurement of endothelial function, an oral glucose tolerance test, 24-h blood pressure measurement, retinal vessel analysis, echocardiography and physical activity measurement by an accelerometer. Blood, sputum, buccal mucosa and faeces will be collected for laboratory analyses. Participants in the RCT will wear a continuous glucose monitor to verify adherence to the study intervention.

Planned Outcomes: The aim of this project is to investigate the effects of ADF on human physiology and molecular cellular processes. This investigation should gain in-depth mechanistic insights into the concept of ADF and form the basis for larger subsequent cohort recruitment and consecutive intervention studies.

Trial Registration: NCT02673515; registered 24 November 2015. Current protocol date/version: 7 February 2017/version 1.8.
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http://dx.doi.org/10.1007/s12325-018-0746-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096974PMC
August 2018

Heart rate-reducing therapy with add-on ivabradine and bisoprolol before coronary computed tomographic angiography in a fast-track ambulatory setting.

J Int Med Res 2018 Jun 3;46(6):2249-2257. Epub 2018 Apr 3.

1 Department of Cardiology, Medical University Graz, Austria.

Objective This study was performed to determine whether add-on oral ivabradine in patients treated with beta blockers 1 hour before coronary computed tomographic angiography (CCTA) is effective in lowering the heart rate and thus improving CCTA quality. Methods In this single-center cohort study, the data of 294 patients referred for ambulant CCTA were retrospectively screened. Patients with an initial heart rate of ≥75 bpm (n = 112) were pretreated with either a combination of bisoprolol and ivabradine or with bisoprolol alone. Results During the scan, there was no difference in heart rate between the two groups Likewise, there was no significant difference in additionally administered intravenous bradycardic agents, the number of motion artifacts, or the radiation dose. Both drug regimens were tolerated well. Conclusion Additive oral ivabradine 1 hour before CCTA does not result in a further reduction of the heart rate. Consequently, neither movement artifacts nor radiation dose can be reduced. Therefore, pretreatment with ivabradine does not seem reasonably appropriate in an outpatient clinical setting with short patient contact.
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http://dx.doi.org/10.1177/0300060518761302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023055PMC
June 2018

A New Murine Model of Chronic Kidney Disease-Mineral and Bone Disorder.

Int J Endocrinol 2017 14;2017:1659071. Epub 2017 Dec 14.

Clinical Division of Nephrology, Medical University of Graz, Graz, Austria.

Chronic kidney disease (CKD) is associated with mineral and bone disorder (MBD), which is the main cause of the extensively increased cardiovascular mortality in the CKD population. We now aimed to establish a new murine experimental CKD-MBD model. Dilute brown non-Agouti (DBA/2) mice were fed with high-phosphate diet for 4 (HPD4) or 7 (HPD7) days, then with standard chow diet (SCD) and subsequently followed until day 84. They were compared to DBA/2 mice maintained on SCD during the whole study period. Both 4 and 7 days HPD-fed mice developed phosphate nephropathy with tubular atrophy, interstitial fibrosis, decreased glomerular filtration rate, and increased serum urea levels. The abdominal aorta of HPD-treated mice showed signs of media calcification. Histomorphometric analysis of HPD-treated mice showed decreased bone volume/tissue volume, low mineral apposition rate, and low bone formation rate as compared to SCD-fed mice, despite increased parathyroid hormone levels. Overall, the observed phenotype was more pronounced in the HPD7 group. In summary, we established a new, noninvasive, and therefore easy to perform reproducible CKD-MBD model, which showed media calcification, secondary hyperparathyroidism, and low-turnover bone disease.
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http://dx.doi.org/10.1155/2017/1659071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745741PMC
December 2017

ST2 predicts survival in patients undergoing transcatheter aortic valve implantation.

Int J Cardiol 2017 Oct 19;244:87-92. Epub 2017 Jun 19.

Division of Cardiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. Electronic address:

Objective: To assess soluble suppression of tumorigenicity 2 (sST2) serum concentrations and predict mortality in patients undergoing transcatheter aortic valve implantation (TAVI).

Methods: We prospectively enrolled 74 patients with severe aortic stenosis (AS) who underwent TAVI and matched them to patients without aortic valve disease (n=74). AS patients underwent comprehensive echocardiographic and cardiac magnetic resonance imaging and laboratory examinations. sST2 levels were determined by enzyme-linked immunosorbent assay (ELISA), their association with post procedural mortality was investigated using logistic and Cox regression analyses, and the prognostic performance compared to established risk scores.

Results: AS patients had substantially higher sST2 levels than controls (39.5 vs. 17.8ng/mL, p<0.001). sST2 significantly correlated with left and right atrial sizes (r=0.25, p=0.033 and r=0.38, p=0.001). At one and two years, 10 (13.9%) and 18 (25%) patients had died, respectively. sST2 significantly predicted survival in uni- and multivariate Cox regression analyses in our cohort (p=0.005 and p=0.025). sST2 also predicted major adverse cardiovascular events (MACE, p=0.046). Adding sST2 to the established STS score improved prediction of two-year mortality in our cohort (ΔAUC=0.108; 95% CI -0.066-0.281; continuous NRI=0.778; 95% CI: 0.277-1.278 and IDI=0.141; 95% CI: 0.031-0.251), and a model containing both sST2 and the STS score had a negative predictive value of 96.1% and 86.3% regarding one and two-year mortality, respectively.

Conclusions: sST2 is elevated in AS patients and a prognostic marker of survival after TAVI. Implementation of this marker in routine pre-TAVI workup may improve risk prediction and patient selection.
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http://dx.doi.org/10.1016/j.ijcard.2017.06.066DOI Listing
October 2017

Atrial fibrillation in transcatheter aortic valve implantation patients: Incidence, outcome and predictors of new onset.

J Electrocardiol 2017 Jul - Aug;50(4):402-409. Epub 2017 Feb 20.

Division of Cardiology, Medical University of Graz, Graz, Austria.

Background: There is controversial evidence if atrial fibrillation (AF) alters outcome after transcatheter aortic valve implantation (TAVI). TAVI itself may promote new-onset AF (NOAF).

Methods: We performed a single-center study including 398 consecutive patients undergoing TAVI. Before TAVI, patients were divided into a sinus rhythm (SR) group (n=226, 57%) and baseline AF group (n=172, 43%) according to clinical records and electrocardiograms. Furthermore, incidence and predictors of NOAF were recorded.

Results: Baseline AF patients had a significantly higher 1-year mortality than the baseline SR group (19.8% vs. 11.5%, p=0.02). NOAF occurred in 7.1% of patients with prior SR. Previous valve surgery was the only significant predictor of NOAF (HR 5.86 [1.04-32.94], p<0.05). NOAF was associated with higher rehospitalization rate (62.5 vs. 34.8%, p=0.04), whereas mortality was unaffected.

Conclusions: This study shows that NOAF is associated with higher rates of rehospitalization but not mortality after TAVI. Overall, patients with pre-existing AF have higher mortality.
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http://dx.doi.org/10.1016/j.jelectrocard.2017.02.013DOI Listing
May 2018

Dietary spermidine for lowering high blood pressure.

Autophagy 2017 Apr 24;13(4):767-769. Epub 2017 Jan 24.

a Institute of Molecular Biosciences, NAWI Graz, University of Graz , Graz , Austria.

Loss of cardiac macroautophagy/autophagy impairs heart function, and evidence accumulates that an increased autophagic flux may protect against cardiovascular disease. We therefore tested the protective capacity of the natural autophagy inducer spermidine in animal models of aging and hypertension, which both represent major risk factors for the development of cardiovascular disease. Dietary spermidine elicits cardioprotective effects in aged mice through enhancing cardiac autophagy and mitophagy. In salt-sensitive rats, spermidine supplementation also delays the development of hypertensive heart disease, coinciding with reduced arterial blood pressure. The high blood pressure-lowering effect likely results from improved global arginine bioavailability and protection from hypertension-associated renal damage. The polyamine spermidine is naturally present in human diets, though to a varying amount depending on food type and preparation. In humans, high dietary spermidine intake correlates with reduced blood pressure and decreased risk of cardiovascular disease and related death. Altogether, spermidine represents a cardio- and vascular-protective autophagy inducer that can be readily integrated in common diets.
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http://dx.doi.org/10.1080/15548627.2017.1280225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381711PMC
April 2017

Cardioprotection and lifespan extension by the natural polyamine spermidine.

Nat Med 2016 12 14;22(12):1428-1438. Epub 2016 Nov 14.

Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.

Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.
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http://dx.doi.org/10.1038/nm.4222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806691PMC
December 2016

Functional and molecular factors associated with TAPSE in hypoxic pulmonary hypertension.

Am J Physiol Lung Cell Mol Physiol 2016 07 22;311(1):L59-73. Epub 2016 Apr 22.

Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Department of Experimental Anaesthesiology, Medical University of Graz, Graz, Austria.

Adaptation of the right ventricle (RV) to increased afterload is crucial for survival in pulmonary hypertension (PH), but it is challenging to assess RV function and identify associated molecular mechanisms. The aim of the current study was to analyze the relationship between invasive and noninvasive parameters of RV morphology and function and associated molecular changes. The response of mice to normobaric hypoxia was assessed by hechocardiography, invasive hemodynamics, and histological and molecular analyses. Plasma levels of possibly novel markers of RV remodeling were measured by ELISA in patients with idiopathic pulmonary arterial hypertension (IPAH) and matched healthy controls. Chronic hypoxia-induced PH was accompanied by significantly decreased tricuspid annular plane systolic excursion (TAPSE) and unchanged RV contractility index and tau. RV hypertrophy was present without an increase in fibrosis. There was no change in α- and β-major histocompatibility class or natriuretic peptides expression. Comparative microarray analysis identified two soluble factors, fibroblast growth factor-5 (FGF5) and interleukin-22 receptor alpha-2 (IL22RA2), as being possibly associated with RV remodeling. We observed significantly higher plasma levels of IL22RA2, but not FGF5, in patients with IPAH. Hypoxic pulmonary hypertension in a stage of RV remodeling with preserved systolic function is associated with decreased pulmonary vascular compliance, mild diastolic RV dysfunction, and significant decrease in TAPSE. Subtle gene expression changes in the RV vs. the left ventricle upon chronic hypoxia suggest that the majority of changes are due to hypoxia and not due to changes in afterload. Increased IL22RA2 levels might represent a novel RV adaptive mechanism.
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http://dx.doi.org/10.1152/ajplung.00381.2015DOI Listing
July 2016

G0/G1 Switch Gene 2 Regulates Cardiac Lipolysis.

J Biol Chem 2015 Oct 8;290(43):26141-50. Epub 2015 Sep 8.

From the Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria,

The anabolism and catabolism of myocardial triacylglycerol (TAG) stores are important processes for normal cardiac function. TAG synthesis detoxifies and stockpiles fatty acids to prevent lipotoxicity, whereas TAG hydrolysis (lipolysis) remobilizes fatty acids from endogenous storage pools as energy substrates, signaling molecules, or precursors for complex lipids. This study focused on the role of G0/G1 switch 2 (G0S2) protein, which was previously shown to inhibit the principal TAG hydrolase adipose triglyceride lipase (ATGL), in the regulation of cardiac lipolysis. Using wild-type and mutant mice, we show the following: (i) G0S2 is expressed in the heart and regulated by the nutritional status with highest expression levels after re-feeding. (ii) Cardiac-specific overexpression of G0S2 inhibits cardiac lipolysis by direct protein-protein interaction with ATGL. This leads to severe cardiac steatosis. The steatotic hearts caused by G0S2 overexpression are less prone to fibrotic remodeling or cardiac dysfunction than hearts with a lipolytic defect due to ATGL deficiency. (iii) Conversely to the phenotype of transgenic mice, G0S2 deficiency results in a de-repression of cardiac lipolysis and decreased cardiac TAG content. We conclude that G0S2 acts as a potent ATGL inhibitor in the heart modulating cardiac substrate utilization by regulating cardiac lipolysis.
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http://dx.doi.org/10.1074/jbc.M115.671842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646265PMC
October 2015

ZBTB17 (MIZ1) Is Important for the Cardiac Stress Response and a Novel Candidate Gene for Cardiomyopathy and Heart Failure.

Circ Cardiovasc Genet 2015 Oct 14;8(5):643-52. Epub 2015 Jul 14.

Background: Mutations in sarcomeric and cytoskeletal proteins are a major cause of hereditary cardiomyopathies, but our knowledge remains incomplete as to how the genetic defects execute their effects.

Methods And Results: We used cysteine and glycine-rich protein 3, a known cardiomyopathy gene, in a yeast 2-hybrid screen and identified zinc-finger and BTB domain-containing protein 17 (ZBTB17) as a novel interacting partner. ZBTB17 is a transcription factor that contains the peak association signal (rs10927875) at the replicated 1p36 cardiomyopathy locus. ZBTB17 expression protected cardiac myocytes from apoptosis in vitro and in a mouse model with cardiac myocyte-specific deletion of Zbtb17, which develops cardiomyopathy and fibrosis after biomechanical stress. ZBTB17 also regulated cardiac myocyte hypertrophy in vitro and in vivo in a calcineurin-dependent manner.

Conclusions: We revealed new functions for ZBTB17 in the heart, a transcription factor that may play a role as a novel cardiomyopathy gene.
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http://dx.doi.org/10.1161/CIRCGENETICS.113.000690DOI Listing
October 2015

Pressure Overload Creates Right Ventricular Diastolic Dysfunction in a Mouse Model: Assessment by Echocardiography.

J Am Soc Echocardiogr 2015 Jul 1;28(7):828-43. Epub 2015 Apr 1.

Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.

Background: Noninvasive diagnostic tools for right ventricular (RV) dysfunction measurements are increasingly being used, although their association with the pathologic mechanisms of dysfunction is poorly understood. Although investigations have focused mainly on RV systolic function, RV diastolic function remains mostly neglected. The aim of this study was to test which echocardiographic parameters best reflect RV diastolic function in mice.

Methods: Pulmonary artery banding (PAB) was used to induce RV pressure overload in mice. Transthoracic echocardiography and invasive hemodynamic measurements were performed after 3 weeks in PAB and sham-operated mice. Subsequently, the hearts were investigated by histology and analyzed for gene expression.

Results: PAB-induced pressure overload (RV systolic pressure PAB 52.6 ± 11.8 mm Hg vs sham 27.0 ± 2.7 mm Hg) resulted in RV hypertrophy and remodeling, as reflected by increased Fulton index (PAB 0.37 ± 0.05 vs sham 0.25 ± 0.02, P = .001). Masson's trichrome staining revealed increased interstitial fibrosis (PAB 12.25 ± 3.12% vs sham 3.97 ± 1.58%, P = .002). This was associated with significant systolic RV dysfunction as demonstrated by reduced contractility index and diastolic dysfunction as demonstrated by end-diastolic pressure (PAB 2.66 ± 0.83 mm Hg vs sham 1.49 ± 0.50 mm Hg, P < .001) and τ (PAB 40.0 ± 16.1 msec vs sham 13.0 ± 3.5 msec, P < .001). Messenger ribonucleic acid expression of β-myosin heavy chain, atrial and brain natriuretic peptides, collagen family members was elevated, and the sarco/endoplasmic reticulum Ca(2+)-ATPase was decreased. Echocardiography revealed significant increases in RV free wall thickness and isovolumic relaxation time and a decrease in left ventricular eccentricity index, E', and tricuspid annular plane systolic excursion. Isovolumic relaxation time and E' were significantly correlated with end-diastolic pressure (rs = 0.511 and -0.451) and τ (rs = 0.739 and -0.445, respectively). Moreover, E' was negatively correlated with the degree of RV fibrosis (rs = -0.717).

Conclusions: Within 3 weeks, PAB causes pressure overload-induced RV hypertrophy and remodeling with compensated systolic and diastolic dysfunction in mice. RV free wall thickness, tricuspid annular plane systolic excursion, E', E/E' ratio, and isovolumic relaxation time appear to be the most reliable echocardiographic parameters for the assessment of RV dysfunction.
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http://dx.doi.org/10.1016/j.echo.2015.02.014DOI Listing
July 2015

Homoarginine in patients with primary hyperparathyroidism.

Am J Med Sci 2015 Apr;349(4):306-11

Department of Cardiology (AT, NV, BP, EK-K, CC, AS, EB), Medical University of Graz, Graz, Austria; Specialist Clinic for Rehabilitation PV Bad Aussee (AT, JR-M), Bad Aussee, Austria; Medizinische Klinik mit Schwerpunkt Kardiologie (AT, BP, EK-K), Campus Virchow-Klinikum, Charité-Universitaetsmedizin Berlin, Berlin, Germany; Division of Endocrinology and Metabolism, Department of Internal Medicine (MG, CS, KA, AF-P, SP), Medical University of Graz, Graz, Austria; Clinical Institute of Medical and Chemical Laboratory Diagnostics (AM, WM), Medical University of Graz, Graz, Austria; Synlab-Academy (WM), Synlab services LLC, Mannheim, Germany; Medical Clinic V (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology) (WM), Ruperto Carola University Heidelberg, Medical Faculty Mannheim, Mannheim, Germany; Department of Epidemiology and Biostatistics (AJvB) and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands; and Department of Medicine, Division of Nephrology (ER), University Hospital Heidelberg, Heidelberg, Germany.

Background: Low levels of the amino acid homoarginine and parathyroid hormone (PTH) excess are both independently related to an increased risk of cardiovascular morbidity and mortality. Accumulating evidence points to a mutual interplay between homoarginine and PTH. The authors therefore aimed to investigate circulating homoarginine levels in patients with and without primary hyperparathyroidism (PHPT).

Methods: The authors performed a cross-sectional analysis of serum homoarginine levels in 59 patients with mild and severe PHPT and in 92 control persons matched for age, sex and estimated glomerular filtration rate.

Results: Median PTH and serum homoarginine concentrations were 99.1 (79.7-120.2) pg/mL and 1.16 (0.95-1.66) µmol/L in patients with PHPT (79.7% female; 42.4% with normocalcemia) as compared with 45.8 (36.4-53.9) pg/mL and 1.62 (1.33-2.04) µmol/L in the control group (P < 0.001 for both), respectively. The authors observed no statistically differences between cases and controls for 25-hydroxyvitamin D [25(OH)D], serum albumin, hemoglobin, waist-to-hip ratio, C-reactive protein and NT-pBNP values. Multivariate analysis of covariance revealed that patients with PHPT had significantly lower homoarginine levels than controls (P < 0.001). This difference remained significant after adjusting for multiple confounders such as 25(OH)D, body mass index, LDL cholesterol, albumin, calcium, hemoglobin, smoking status and current antihypertensive medication. The differences of homoarginine levels persisted even after exclusion of patients with estimated glomerular filtration rate <60 mL/min (P = 0.003) and 25(OH)D levels <30 ng/mL (P = 0.001), respectively.

Conclusions: Patients with PHPT have lower homoarginine levels compared with matched controls irrespective of age, sex, kidney function and 25(OH)D status. Further studies are needed to evaluate whether low homoarginine accounts for higher cardiovascular risk conferred by PTH excess.
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http://dx.doi.org/10.1097/MAJ.0000000000000419DOI Listing
April 2015

Galectin-3 in patients with heart failure with preserved ejection fraction: results from the Aldo-DHF trial.

Eur J Heart Fail 2015 Feb 24;17(2):214-23. Epub 2014 Nov 24.

Department of Cardiology and Pneumology, Heart Center, University of Göttingen, Göttingen, Germany; German Center for Cardiovascular Research (DZHK), University of Göttingen, Göttingen, Germany.

Aims: Galectin-3 is a marker of myocardial fibrosis and mediates aldosterone-induced cardiovascular inflammation and fibrosis. Characteristics of galectin-3 and its response to spironolactone have not been evaluated in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to determine the association between galectin-3 levels and patient characteristics in HFpEF; to evaluate the interaction between spironolactone and galectin-3 levels; and to assess the association between galectin-3 and clinical outcomes.

Methods And Results: Aldo-DHF investigated spironolactone 25 mg once daily vs. placebo for 12 months in patients with NYHA class II-III, LVEF ≥50%, grade ≥ I diastolic dysfunction, and peakVO2  ≤ 25 mL/kg/min. Galectin-3 levels were obtained at baseline, and at 6 and 12 months. The association between baseline galectin-3, change in galectin-3, and all-cause death or hospitalization was evaluated, and the interaction between galectin-3 and treatment was assessed. Median baseline galectin-3 was 12.1 ng/mL. After multivariable adjustment, baseline galectin-3 inversely correlated with peak VO2 (P = 0.021), 6 min walk distance (P = 0.002), and Short Form 36 (SF-36) physical functioning (P = 0.001), and directly correlated with NYHA class (P = 0.007). Baseline NT-proBNP correlated with E/e' velocity ratio (P ≤ 0.001), left atrial volume index (P < 0.001), and LV mass index (P = 0.009). Increasing galectin-3 at 6 or 12 months was associated with all-cause death or hospitalization independent of treatment arm [hazard ratio (HR) 3.319, 95% confidence interval (CI) 1.214-9.07, P = 0.019] and NT-proBNP (HR 3.127, 95% CI 1.144-8.549, P = 0.026). Spironolactone did not influence galectin-3 levels.

Conclusion: Galectin-3 levels are modestly elevated in patients with stable HFpEF and relate to functional performance and quality of life. Increasing galectin-3 was associated with worse outcome, independent of treatment or NT-proBNP.
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http://dx.doi.org/10.1002/ejhf.203DOI Listing
February 2015

Associations of methylarginines and homoarginine with diastolic dysfunction and cardiovascular risk factors in patients with preserved left ventricular ejection fraction.

J Card Fail 2014 Dec 16;20(12):923-30. Epub 2014 Sep 16.

Department of Cardiology, Medical University of Graz, Austria.

Background: Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and homoarginine are considered to modulate nitric oxide synthesis. We evaluated whether ADMA, SDMA, and homoarginine are associated with diastolic dysfunction.

Methods And Results: We investigated primary care patients at cardiovascular risk with preserved left ventricular ejection fraction from the multicenter DIAST-CHF study. We measured serum concentrations of ADMA, SDMA, and homoarginine and performed standardized echocardiographic examinations. Among 1,396 patients (mean age 65.3 ± 8.3 y, 54.6% women), diastolic dysfunction was ruled out in 261 patients (18.7%). Mild and moderate/severe grades of diastolic dysfunction were present in 900 (64.5%) and 235 (16.8%) study participants, respectively. After adjustments for cardiovascular risk factors, ADMA and SDMA were positively and homoarginine negatively associated with N-terminal pro-B-type natriuretic peptide and midregional pro-adrenomedullin (P < .05 for all). Lower homoarginine levels were associated with diastolic dysfunction, and higher ADMA and SDMA levels were associated with the severity of diastolic dysfunction (P < .05 for all).

Conclusions: Higher levels of ADMA and SDMA and lower levels of homoarginine are associated with an adverse cardiovascular risk profile and diastolic dysfunction. Further studies should clarify the potential of these amino acid derivatives for the therapy of cardiovascular diseases.
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http://dx.doi.org/10.1016/j.cardfail.2014.09.004DOI Listing
December 2014