Publications by authors named "Jan-Christian Reil"

56 Publications

Response by Marquetand and Reil to Letter Regarding Article, "Invasive and Echocardiographic Characteristics of a Patient With Severe Pulmonary Valve Regurgitation Pretending Severe Pulmonary Stenosis".

Circ Heart Fail 2021 May 6:CIRCHEARTFAILURE121008618. Epub 2021 May 6.

Department of Cardiology, Angiology and Intensive Care, Medicine Medical Clinic II, University Heart Center Lübeck, Germany.

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.121.008618DOI Listing
May 2021

Effects of selective heart rate reduction with ivabradine on LV function and central hemodynamics in patients with chronic coronary syndrome.

Int J Cardiol Heart Vasc 2021 Jun 23;34:100757. Epub 2021 Mar 23.

Department of Internal Medicine III, Saarland University Medical Center, Saarland University, Homburg/Saar, Germany.

Objectives: We assessed left ventricular (LV) function and central hemodynamic effects in patients with a heart rate (HR) at rest of ≥70 beats per minute (bpm) and chronic coronary syndrome (CCS) after long-term treatment with ivabradine compared to placebo by cardiac magnetic resonance (CMR) imaging.

Methods And Results: In a randomized, double-blinded, prospective cross-over design, 23 patients (18 male, 5 female) were treated with ivabradine (7.5 mg bid) or placebo for 6 months. CMR imaging was performed at baseline and after 6 and 12 months to determine LV functional parameters.Mean resting HR on treatment with ivabradine was 58 ± 8.2 bpm and 70.2 ± 8.3 bpm during placebo (p < 0.0001).There was no difference in systolic LV ejection fraction (ivabradine 57.4 ± 11.2% vs placebo 53.0 ± 10.9%, p = 0.18), indexed end-diastolic (EDVi) or end-systolic volumes (ESVi). Indexed stroke volume (SVi) (ml/m) remained unchanged after treatment with ivabradine. Volume time curve parameters reflecting systolic LV function (peak ejection rate and time) were unaffected by ivabradine, while both peak filling rate (PFR) and PFR/EDV were significantly increased. Mean aortic velocity (cm/s) was significantly reduced during treatment with ivabradine (ivabradine 6.7 ± 2.7 vs placebo 9.0 ± 3.4, p = 0.01). Aortic flow parameters were correlated to parameters of vascular stiffness. The strongest correlation was revealed for mean aortic velocity with aortic distensibility (AD) (r = -0.86 [-0.90 to -0.85], p < 0.0001).

Conclusion: Long-term reduction of HR with ivabradine in patients with CCS improved diastolic function and reduced mean aortic flow velocity.
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http://dx.doi.org/10.1016/j.ijcha.2021.100757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024658PMC
June 2021

Long-Term Outcomes of Patients Undergoing the Ross Procedure.

J Am Coll Cardiol 2021 Mar;77(11):1412-1422

Department of Cardiac and Thoracic Vascular Surgery, University Heart Center Lübeck, University Hospital Schleswig-Holstein, Lübeck Campus, Lübeck, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Lübeck, Lübeck, Germany.

Background: Treatment of aortic-valve disease in young patients still poses challenges. The Ross procedure offers several potential advantages that may translate to improved long-term outcomes.

Objectives: This study reports long-term outcomes after the Ross procedure.

Methods: Adult patients who were included in the Ross Registry between 1988 and 2018 were analyzed. Endpoints were overall survival, reintervention, and major adverse events at maximum follow-up. Multivariable regression analyses were performed to identify risk factors for survival and the need of Ross-related reintervention.

Results: There were 2,444 adult patients with a mean age of 44.1 ± 11.7 years identified. Early mortality was 1.0%. Estimated survival after 25 years was 75.8% and did not statistically differ from the general population (p = 0.189). The risk for autograft reintervention was 0.69% per patient-year and 0.62% per patient-year for right-ventricular outflow tract (RVOT) reintervention. Larger aortic annulus diameter (hazard ratio [HR]: 1.12/mm; 95% confidence interval [CI]: 1.05 to 1.19/mm; p < 0.001) and pre-operative presence of pure aortic insufficiency (HR: 1.74; 95% CI: 1.13 to 2.68; p = 0.01) were independent predictors for autograft reintervention, whereas the use of a biological valve (HR: 8.09; 95% CI: 5.01 to 13.08; p < 0.001) and patient age (HR: 0.97 per year; 95% CI: 0.96 to 0.99; p = 0.001) were independent predictors for RVOT reintervention. Major bleeding, valve thrombosis, permanent stroke, and endocarditis occurred with an incidence of 0.15% per patient-year, 0.07% per patient-year, 0.13%, and 0.36% per patient-year, respectively.

Conclusions: The Ross procedure provides excellent survival over a follow-up period of up to 25 years. The rates of reintervention, anticoagulation-related morbidity, and endocarditis were very low. This procedure should therefore be considered as a very suitable treatment option in young patients suffering from aortic-valve disease. (Long-Term Follow-up After the Autograft Aortic Valve Procedure [Ross Operation]; NCT00708409).
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http://dx.doi.org/10.1016/j.jacc.2021.01.034DOI Listing
March 2021

Echocardiographic evidence of an intrapulmonary shunt in a patient with severe liver cirrhosis.

Clin Res Cardiol 2021 Feb 23. Epub 2021 Feb 23.

Klinik Für Innere Medizin II, Kardiologie, Angiologie Und Internistische Intensivmedizin, Universitäres Herzzentrum Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, Lübeck, Germany.

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http://dx.doi.org/10.1007/s00392-021-01817-yDOI Listing
February 2021

Invasive and Echocardiographic Characteristics of a Patient With Severe Pulmonary Valve Regurgitation Pretending Severe Pulmonary Stenosis.

Circ Heart Fail 2021 Jan 28;14(1):e007486. Epub 2020 Dec 28.

Department of Cardiology, Angiology and Intensive Care Medicine, University Heart Center Lübeck, Germany (C.M., I.E., J.-C. R.).

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007486DOI Listing
January 2021

Reduced left ventricular contractility, increased diastolic operant stiffness and high energetic expenditure in patients with severe aortic regurgitation without indication for surgery.

Interact Cardiovasc Thorac Surg 2021 Jan;32(1):29-38

Klinik für Herzchirurgie, Universitäres Herzzentrum Lübeck, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany.

Objectives: Recent mortality studies showed worse prognosis in patients (ARNS) with severe aortic regurgitation and preserved ejection fraction (EF) not fulfilling the criteria of current guidelines for surgery. The aim of our study was to analyse left ventricular (LV) systolic and diastolic function and mechanical energetics to find haemodynamic explanations for the reduced prognosis of these patients and to seek a new concept for surgery.

Methods: Global longitudinal strain (GLS) and echo-based single-beat pressure-volume analyses were performed in patients with ARNS (LV end-diastolic diameter <70 mm, EF >50%, GLS > -19% n = 41), with indication for surgery (ARS; n = 19) and in mild hypertensive controls (C; n = 20). Additionally, end-systolic elastance (LV contractility), stroke work and total energy (pressure-volume area) were calculated.

Results: ARNS demonstrated significantly depressed LV contractility versus C: end-systolic elastance (1.58 ± 0.7 vs 2.54 ± 0.8 mmHg/ml; P < 0.001), despite identical EF (EF: 59 ± 6% vs 59 ± 7%). Accordingly, GLS was decreased [-15.7 ± 2.7% (n = 31) vs -21.2 ± 2.4%; P < 0.001], end-diastolic volume (236 ± 90 vs 136 ± 30 ml; P < 0.001) and diastolic operant stiffness were markedly enlarged, as were pressure-volume area and stroke work, indicating waste of energy. The correlation of GLS versus end-systolic elastance was good (r = -0.66; P < 0.001). ARNS and ARS patients demonstrated similar haemodynamic disorders, whereas only GLS was worse in ARS.

Conclusions: ARNS patients almost matched the ARS patients in their haemodynamic and energetic deterioration, thereby explaining poor prognosis reported in literature. GLS has been shown to be a reliable surrogate for LV contractility, possibly overestimating contractility due to exhausted preload reserve in aortic regurgitation patients. GLS may outperform conventional echo parameters to predict more precisely the timing of surgery.
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http://dx.doi.org/10.1093/icvts/ivaa232DOI Listing
January 2021

Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice.

J Biol Chem 2020 09 9;295(36):12605-12617. Epub 2020 Jul 9.

Klinik für Innere Medizin III, Universität des Saarlandes, Homburg/Saar, Germany

In the heart, the serine carboxypeptidase cathepsin A (CatA) is distributed between lysosomes and the extracellular matrix (ECM). CatA-mediated degradation of extracellular peptides may contribute to ECM remodeling and left ventricular (LV) dysfunction. Here, we aimed to evaluate the effects of CatA overexpression on LV remodeling. A proteomic analysis of the secretome of adult mouse cardiac fibroblasts upon digestion by CatA identified the extracellular antioxidant enzyme superoxide dismutase (EC-SOD) as a novel substrate of CatA, which decreased EC-SOD abundance 5-fold. , both cardiomyocytes and cardiac fibroblasts expressed and secreted CatA protein, and only cardiac fibroblasts expressed and secreted EC-SOD protein. Cardiomyocyte-specific CatA overexpression and increased CatA activity in the LV of transgenic mice (CatA-TG) reduced EC-SOD protein levels by 43%. Loss of EC-SOD-mediated antioxidative activity resulted in significant accumulation of superoxide radicals (WT, 4.54 μmol/mg tissue/min; CatA-TG, 8.62 μmol/mg tissue/min), increased inflammation, myocyte hypertrophy (WT, 19.8 μm; CatA-TG, 21.9 μm), cellular apoptosis, and elevated mRNA expression of hypertrophy-related and profibrotic marker genes, without affecting intracellular detoxifying proteins. In CatA-TG mice, LV interstitial fibrosis formation was enhanced by 19%, and the type I/type III collagen ratio was shifted toward higher abundance of collagen I fibers. Cardiac remodeling in CatA-TG was accompanied by an increased LV weight/body weight ratio and LV end diastolic volume (WT, 50.8 μl; CatA-TG, 61.9 μl). In conclusion, CatA-mediated EC-SOD reduction in the heart contributes to increased oxidative stress, myocyte hypertrophy, ECM remodeling, and inflammation, implicating CatA as a potential therapeutic target to prevent ventricular remodeling.
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http://dx.doi.org/10.1074/jbc.RA120.013488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476717PMC
September 2020

CaMKII activity contributes to homeometric autoregulation of the heart: A novel mechanism for the Anrep effect.

J Physiol 2020 08 14;598(15):3129-3153. Epub 2020 Jun 14.

Institute of Physiology, Ruhr University Bochum, Bochum, Germany.

Key Points: The Anrep effect represents the alteration of left ventricular (LV) contractility to acutely enhanced afterload in a few seconds, thereby preserving stroke volume (SV) at constant preload. As a result of the missing preload stretch in our model, the Anrep effect differs from the slow force response and has a different mechanism. The Anrep effect demonstrated two different phases. First, the sudden increased afterload was momentary equilibrated by the enhanced LV contractility as a result of higher power strokes of strongly-bound myosin cross-bridges. Second, the slightly delayed recovery of SV is perhaps dependent on Ca /calmodulin-dependent protein kinase II activation caused by oxidation and myofilament phosphorylation (cardiac myosin-binding protein-C, myosin light chain 2), maximizing the recruitment of available strongly-bound myosin cross-bridges. Short-lived oxidative stress might present a new facet of subcellular signalling with respect to cardiovascular regulation. Relevance for human physiology was demonstrated by echocardiography disclosing the Anrep effect in humans during handgrip exercise.

Abstract: The present study investigated whether oxidative stress and Ca /calmodulin-dependent protein kinase II (CaMKII) activity are involved in triggering the Anrep effect. LV pressure-volume (PV) analyses of isolated, preload controlled working hearts were performed at two afterload levels (60 and 100 mmHg) in C57BL/6N wild-type (WT) and CaMKII-double knockout mice (DKO ). In snap-frozen WT hearts, force-pCa relationship, H O generation, CaMKII oxidation and phosphorylation of myofilament and Ca handling proteins were assessed. Acutely raised afterload showed significantly increased wall stress, H O generation and LV contractility in the PV diagram with an initial decrease and recovery of stroke volume, whereas end-diastolic pressure and volume, as well as heart rate, remained constant. Afterload induced increase in LV contractility was blunted in DKO -hearts. Force development of single WT cardiomyocytes was greater with elevated afterload at submaximal Ca concentration and associated with increases in CaMKII oxidation and phosphorylation of cardiac-myosin binding protein-C, myosin light chain and Ca handling proteins. CaMKII activity is involved in the regulation of the Anrep effect and associates with stimulation of oxidative stress, presumably starting a cascade of CaMKII oxidation with downstream phosphorylation of myofilament and Ca handling proteins. These mechanisms improve LV inotropy and preserve stroke volume within few seconds.
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http://dx.doi.org/10.1113/JP279607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657994PMC
August 2020

Disturbed ventricular-arterial coupling and increased left atrial stiffness in a patient with heart failure with preserved ejection fraction and hyperaldosteronism: a case report.

Eur Heart J Case Rep 2019 Dec 28;3(4):1-6. Epub 2019 Sep 28.

Department of Internal Medicine 2, Cardiology, Angiology and Intensive Care Medicine, University Heart Center Lübeck, Ratzeburger Allee 160, 23552 Lübeck, Germany.

Background: Aldosterone is involved in almost all parts of the cardiovascular system. Hyperaldosteronism causes arterial hypertension and might predispose to stroke, atrial fibrillation, and heart failure.

Case Summary: A 60-year-old obese woman with long-standing hypertension, hypokalaemia, and shortness of breath was admitted to our hospital. Hypertension was caused by primary hyperaldosteronism due to an adenoma of the adrenal gland. Detailed transthoracic echocardiography revealed diastolic dysfunction, disturbed ventricular-arterial interaction, and atrial compliance resulting in heart failure with preserved ejection fraction (HFPEF). Three months of aldosterone antagonist treatment improved ventricular-arterial coupling, while left ventricular diastolic and atrial dysfunction remained unchanged.

Discussion: Presumably, hyperaldosteronism is the reason for HFPEF in this case. Standard criteria to diagnose HFPEF include clinical symptoms of heart failure and an ejection fraction (EF) >50% as well as echocardiographically or invasively assessed elevated filling pressures. Single beat pressure-volume analysis gives insights on the pathophysiology of increased filling pressures, showing in our case diastolic dysfunction as well as disturbed ventricular-arterial interaction. Three months of aldosterone antagonist treatment reduced blood pressure with concomitant improvement of ventricular-arterial interaction, thereby reducing stroke work while stroke volume remained nearly unchanged. Diastolic dysfunction and increased atrial stiffness were unaltered.
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http://dx.doi.org/10.1093/ehjcr/ytz156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939786PMC
December 2019

Treatment of Recurrent MR by MitraClip XTR in a Patient With a PASCAL Device.

JACC Cardiovasc Interv 2019 12 27;12(24):e219-e221. Epub 2019 Nov 27.

Department of Cardiology, Angiology and Intensive Care Medicine, University Hospital, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany; German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jcin.2019.09.043DOI Listing
December 2019

Conventional echocardiographic parameters or three-dimensional echocardiography to evaluate right ventricular function in percutaneous edge-to-edge mitral valve repair (PMVR).

Int J Cardiol Heart Vasc 2019 Sep 30;24:100413. Epub 2019 Aug 30.

University Hospital, Department of Anaesthesiology and Intensive Care Medicine, Eberhard Karls University Tuebingen, 72076 Tuebingen, Germany.

Introduction: In this study, we evaluated right ventricular (RV) function before and after percutaneous mitral valve repair (PMVR) using conventional echocardiographic parameters and novel 3DE data sets acquired prior to and directly after the procedure.

Patients And Methods: Observational study on 45 patients undergoing PMVR at an university hospital.

Results: In the overall collective, the 3D RV-EF before and after PMVR showed no significant change (p = 0.16). While there was a significant increase of the fractional area change (FAC, from 23 [19-29] % to 28 [24-33] %, p = 0.001), no significant change of the tricuspid annular plane systolic excursion (TAPSE, from 17 ± 6 mm to 18 ± 5 mm (standard deviation), p = 0.33) was observed. Regarding patients with a reduced RV-EF (< 35%), a significant RV-EF improvement was observed (from 27 [23-34] % to 32.5 [30-39] % (p = 0.001). 71.4% of patients had an improved clinical outcome (improvement in 6-minute walk test and/or improvement in NYHA class of more than one grade), whereas clinical outcome did not improve in 28.6% of patients. Using univariate logistic regression analysis, the post-PMVR RV-EF (OR 1.15: 95% CI 1.02-1.29; p = 0.02) and the change in RV-EF (OR 1.13: 95% CI 1.02-1.25; p = 0.02) were significant predictors for improved clinical outcome at 6 months follow up.

Conclusion: Thus, RV function may be an important non-invasive parameter to add to the predictive parameters indicating a potential clinical benefit from treatment of severe mitral regurgitation using PMVR.
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http://dx.doi.org/10.1016/j.ijcha.2019.100413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723083PMC
September 2019

Defibrillator-Heart Pump: An Implantable Ventricular Assist Device With Integrated Defibrillator Component-The First In Vitro Testing.

Surg Innov 2019 Dec 27;26(6):720-724. Epub 2019 Jul 27.

Ruhr-University Bochum, Bad Oeynhausen, Germany.

Left ventricular assist devices (LVADs) are an important therapeutic option for patients with end-stage heart failure waiting for heart transplantation or in older patients as definite therapy for heart failure. Interestingly, about 62% of patients receiving LVADs do not have an automatic implantable cardioverter-defibrillator (AICD) at the time of implantation, although these patients have increased risk of being confronted with dangerous arrhythmia. Therefore, an LVAD system including AICD function is a reasonable alternative for such heart failure patients thereby avoiding a second surgical intervention for AICD implantation. In this article, a newly developed system including LVAD and AICD function is introduced, and we also report its first in vitro testing.
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http://dx.doi.org/10.1177/1553350619862994DOI Listing
December 2019

Anaphylatoxin Receptor C3aR Contributes to Platelet Function, Thrombus Formation and In Vivo Haemostasis.

Thromb Haemost 2019 Jan 31;119(1):179-182. Epub 2018 Dec 31.

Department of Cardiology and Cardiovascular Medicine, University Clinic, Eberhard Karls University of Tübingen, Tübingen, Germany.

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http://dx.doi.org/10.1055/s-0038-1676349DOI Listing
January 2019

Long-Term Hemodynamic Improvement after Transcatheter Mitral Valve Repair.

J Am Soc Echocardiogr 2018 09;31(9):1013-1020

Universität Leipzig, Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Leipzig, Germany.

Background: Correction of mitral regurgitation (MR) alters the load on the left ventricle. There are few data on the long-term hemodynamic adaptations of the cardiovascular system after transcatheter mitral valve repair (TMVR). The aim of this study was to determine a comprehensive hemodynamic status using noninvasive pressure-volume analysis.

Methods: Pressure-volume parameters were calculated from echocardiography with simultaneous arm-cuff blood pressure measurements at baseline before TMVR and 12 months after TMVR. Eighty-eight consecutive patients undergoing edge-to-edge mitral clip implantation because of grade 3+ or 4+, symptomatic (79.5% in New York Heart Association functional class ≥III) MR were prospectively enrolled. The mean left ventricular (LV) ejection fraction was 42 ± 14%. Sixty-seven percent of the patients had secondary MR.

Results: Twelve months after TMVR, 17.7% of patients had died, and 19.0% were rehospitalized because of decompensated heart failure. MR grade was ≤2+ in 90% of surviving patients, and 77% were in New York Heart Association functional class ≤II. LV end-diastolic volume index decreased from 87 ± 38 to 77 ± 40 mL/m (P < .0001), end-systolic volume index changed from 54 ± 34 to 50 ± 36 mL/m (P = .018), hence total stroke volume index was reduced (from 34 ± 11 to 28 ± 7 ml/m, P < .0001). Ejection fraction and global longitudinal peak systolic strain remained unchanged. Increased forward ejection fraction (30 ± 14% vs 41 ± 20%, P < .0001), cardiac index (from 1.7 ± 0.4 to 1.9 ± 0.5 mL/min/m, P = .003), and peak power index (214 ± 114 vs 280 ± 149 mm Hg/sec, P = .0001) as well as similar end-systolic elastance at reduced LV volumes indicated improved LV performance. Cardiac efficiency, measured as cardiac index relative to myocardial energy, was improved (0.012 ± 0.008 vs 0.019 ± 0.010 mm Hg, P = .002). Logistic regression analysis revealed baseline values of total ejection fraction and diastolic pulmonary pressure gradient as predictors of clinical improvement (odds ratios, 1.076 [P = .009] and 0.812 [P = .015], respectively) after TMVR.

Conclusions: One year after TMVR, patients showed reverse remodeling and improved LV performance that was associated with improved symptom status. This hemodynamic improvement supports TMVR as long-term effective therapy for patients with symptomatic MR.
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http://dx.doi.org/10.1016/j.echo.2018.05.010DOI Listing
September 2018

Cor triatriatum sinister.

Clin Res Cardiol 2018 May 23;107(5):447-448. Epub 2018 Feb 23.

Medical Clinic II (Cardiology/Angiology/Intensive Care Medicine), University Heart Center Lübeck, University Hospital Schleswig-Holstein, Ratzeburger Allee 160, 23538, Lübeck, Germany.

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http://dx.doi.org/10.1007/s00392-017-1197-8DOI Listing
May 2018

Prognostic Significance of Remote Myocardium Alterations Assessed by Quantitative Noncontrast T1 Mapping in ST-Segment Elevation Myocardial Infarction.

JACC Cardiovasc Imaging 2018 03 14;11(3):411-419. Epub 2017 Jun 14.

University Heart Center Lübeck, Medical Clinic II, Department of Cardiology, Angiology and Intensive Care Medicine, University of Lübeck, Lübeck, Germany; German Center for Cardiovascular Research (DZHK), partner site Hamburg/Kiel/Lübeck, Lübeck, Germany. Electronic address:

Objectives: This study assessed the prognostic significance of remote zone native T1 alterations for the prediction of clinical events in a population with ST-segment elevation myocardial infarction (STEMI) who were treated by primary percutaneous coronary intervention (PPCI) and compared it with conventional markers of infarct severity.

Background: The exact role and incremental prognostic relevance of remote myocardium native T1 mapping alterations assessed by cardiac magnetic resonance (CMR) after STEMI remains unclear.

Methods: We included 255 consecutive patients with STEMI who were reperfused within 12 h after symptom onset. CMR core laboratory analysis was performed to assess left ventricular (LV) function, standard infarct characteristics, and native T1 values of the remote, noninfarcted myocardium. The primary endpoint was a composite of death, reinfarction, and new congestive heart failure within 6 months (major adverse cardiac events [MACE]).

Results: Patients with increased remote zone native T1 values (>1,129 ms) had significantly larger infarcts (p = 0.012), less myocardial salvage (p = 0.002), and more pronounced LV dysfunction (p = 0.011). In multivariable analysis, remote zone native T1 was independently associated with MACE after adjusting for clinical risk factors (p = 0.001) or other CMR variables (p = 0.007). In C-statistics, native T1 of remote myocardium provided incremental prognostic information beyond clinical risk factors, LV ejection fraction, and other markers of infarct severity (all p < 0.05). The addition of remote zone native T1 to a model of prognostic CMR parameters (ejection fraction, infarct size, and myocardial salvage index) led to net reclassification improvement of 0.82 (95% confidence interval: 0.46 to 1.17; p < 0.001) and to an integrated discrimination improvement of 0.07 (95% confidence interval: 0.02 to 0.13; p = 0.01).

Conclusions: In STEMI patients treated by PPCI, evaluation of remote zone alterations by quantitative noncontrast T1 mapping provided independent and incremental prognostic information in addition to clinical risk factors and traditional CMR outcome markers. Remote zone alterations may thus represent a novel therapeutic target and a useful parameter for optimized risk stratification. (Effect of Conditioning on Myocardial Damage in STEMI [LIPSIA-COND]; NCT02158468).
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http://dx.doi.org/10.1016/j.jcmg.2017.03.015DOI Listing
March 2018

Hyperaldosteronism induces left atrial systolic and diastolic dysfunction.

Am J Physiol Heart Circ Physiol 2016 10 9;311(4):H1014-H1023. Epub 2016 Sep 9.

Institute for Molecular Cell Biology and Research Centre for Molecular Imaging and Screening, Saarland University, Homburg/Saar, Germany.

Patients with hypertension and hyperaldosteronism show an increased risk of stroke compared with patients with essential hypertension. Aim of the study was to assess the effects of aldosterone on left atrial function in rats as a potential contributor to thromboembolism. Osmotic mini-pumps delivering 1.5 μg aldosterone/h were implanted in rats subcutaneously (Aldo, n = 39; controls, n = 38). After 8 wk, left ventricular pressure-volume analysis of isolated working hearts was performed, and left atrial systolic and diastolic function was also assessed by atrial pressure-diameter loops. Moreover, left atrial myocytes were isolated to investigate their global and local Ca handling and contractility. At similar heart rates, pressure-volume analysis of isolated hearts and in vivo hemodynamic measurements revealed neither systolic nor diastolic left ventricular dysfunction in Aldo. In particular, atrial filling pressures and atrial size were not increased in Aldo. Aldo rats showed a significant reduction of atrial late diastolic A wave, atrial active work index, and increased V waves. Consistently, in Aldo rats, sarcomere shortening and the amplitude of electrically evoked global Ca transients were substantially reduced. Sarcoplasmic reticulum-Ca content and fractional Ca release were decreased, substantiated by a reduced sarcoplasmic reticulum calcium ATPase activity, resulting from a reduced CAMKII-evoked phosphorylation of phospholamban. Hyperaldosteronism induced atrial systolic and diastolic dysfunction, while atrial size and left ventricular hemodynamics, including filling pressures, were unaffected in rats. The described model suggests a direct causal link between hyperaldosteronism and decreased atrial contractility and diastolic compliance.
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http://dx.doi.org/10.1152/ajpheart.00261.2016DOI Listing
October 2016

Early Hemodynamic Improvement after Percutaneous Mitral Valve Repair Evaluated by Noninvasive Pressure-Volume Analysis.

J Am Soc Echocardiogr 2016 09 29;29(9):888-98. Epub 2016 Jun 29.

Universität des Saarlandes, Medizinische Fakultät, Klinik für Innere Medizin III - Kardiologie, Angiologie und internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.

Background: Mitral regurgitation represents a volume load on the left ventricle leading to congestion and symptoms of heart failure. The aim of this study was to characterize early hemodynamic adaptions after percutaneous mitral valve (MV) repair.

Methods: Forty-six consecutive patients with symptomatic high-grade MV insufficiency (mean age, 72 years; 54% men) were prospectively included in the study and examined before and after successful catheter-based clip implantation. Seventy percent of patients had secondary mitral regurgitation. Noninvasive pressure-volume loops were reconstructed from echocardiography with simultaneous blood pressure measurements.

Results: MV repair reduced left ventricular end-diastolic volume index from 87 ± 41 to 80 ± 40 mL/m(2) (P < .0001). End-systolic volume index was 55 ± 37 mL/m(2) before versus 54 ± 37 mL/m(2) after repair (P = .52). Hence, total stroke volume decreased from 60 ± 23 to 49 ± 16 mL (P < .0001), as did total ejection fraction (from 41 ± 14% to 37 ± 13%, P = .002) and global longitudinal strain (from -11 ± 4.9% to -9.1 ± 4.4%, P = .0001). Forward stroke volume, forward ejection fraction, and forward cardiac output remained constant (43 ± 12 mL vs 42 ± 11 mL, 33 ± 17% vs 35 ± 18%, and 3.2 ± 0.9 L/min vs 3.4 ± 0.8 L/min, respectively). Parameters of left ventricular contractility (end-systolic elastance and peak power index) and measurements of afterload (arterial elastance, end-systolic wall stress, and total peripheral resistance) were similar before and after MV repair. Forward ejection fraction correlated more strongly with end-systolic elastance (r = 0.61, P < .0001) than did total ejection fraction (r = 0.35, P = .0007) or global longitudinal strain (r = -0.38, P = .0002). Total mechanical energy (pressure-volume area) decreased from 10,903 ± 4,410 to 9,124 ± 2,968 mm Hg × mL (P = .0007) because of reduced stroke work (5,546 ± 2,241 mm Hg × mL vs 4,414 ± 1,412 mm Hg × mL, P < .0001). At 3 months, symptom status had improved (76% of patients in New York Heart Association classes I and II), and 97% of patients had mitral regurgitation grade ≤2+.

Conclusions: Left ventricular contractility and forward cardiac output remained unchanged after percutaneous MV repair despite decreases in total ejection fraction and global longitudinal strain. The left ventricle was unloaded through reduced end-diastolic volume. Thus, MV repair is associated with an improved hemodynamic state in noninvasive pressure-volume analysis.
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http://dx.doi.org/10.1016/j.echo.2016.05.012DOI Listing
September 2016

Cathepsin A mediates susceptibility to atrial tachyarrhythmia and impairment of atrial emptying function in Zucker diabetic fatty rats.

Cardiovasc Res 2016 06 31;110(3):371-80. Epub 2016 Mar 31.

Department of Physiology, University Maastricht, Maastricht, The Netherlands.

Aims: Type 2 diabetes (T2D) is an independent risk factor for atrial fibrillation (AF) and stroke. The serine protease cathepsin A (CatA) is up-regulated in diabetes and plays an important role in the degradation of extracellular peptides. This study sought to delineate the role of CatA for the development of atrial remodelling under diabetic conditions.

Methods And Results: Zucker Diabetic Fatty rats (ZDF) were treated with vehicle (n = 20) or CatA-inhibitor (SAR; 50 mg/kg; n = 20), and compared with age-matched non-diabetic littermates (Ctr, n = 20). Left-atrial (LA) emptying function [magnetic resonance imaging (MRI)] and atrial electrophysiological parameters were measured before sacrifice for histological and biochemical analysis. The impact of enhanced cardiac CatA expression on atrial remodelling was determined using CatA-transgenic mice. At the age of 9.5 months, atrial tissues of ZDF rats showed increased CatA gene expression and CatA-activity, along with increased AF-susceptibility and impaired LA-emptying function. CatA-inhibition reduced CatA-activity in ZDF comparable to Ctr values and decreased LA-fibrosis formation and connexin 43 lateralization. This was associated with shorter median duration of LA-tachyarrhythmia (12.0 ± 1.7 vs. 1.2 ± 0.47 s, P < 0.01) induced by burst pacing and diminished regions of slow conduction. Cardiac MRI revealed better LA-emptying function parameters (active per cent emptying: 29 ± 1 vs. 23 ± 2%, P < 0.01) after CatA-inhibition. CatA-inhibition reduced LA bradykinin-degrading activity in ZDF. Transgenic mice overexpressing CatA demonstrated enhanced atrial fibrosis formation and increased AF-susceptibility.

Conclusion: T2D leads to arrhythmogenic atrial remodelling in ZDF rats. CatA-inhibition reduces LA bradykinin-degrading activity in ZDF and suppresses the development of atrial structural changes and AF-promotion, implicating CatA as an important mediator for AF-substrate in T2D.
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http://dx.doi.org/10.1093/cvr/cvw071DOI Listing
June 2016

Inhibition of NHE3-mediated Sodium Absorption in the Gut Reduced Cardiac End-organ Damage Without Deteriorating Renal Function in Obese Spontaneously Hypertensive Rats.

J Cardiovasc Pharmacol 2016 Mar;67(3):225-31

Department of Cardiology, Universitätsklinikum des Saarlandes, Homburg, Germany.

Increased sodium absorption in the gut is one mechanism contributing to hypertensive blood pressure values. The sodium-proton-exchanger subtype 3 (NHE3) is an important mediator of intestinal sodium absorption. The compound SAR is a new specific NHE3 inhibitor with extremely low oral absorbability leading to decreased sodium absorption in the gut and substantial systolic blood pressure reduction. The effects of intestinal NHE3 inhibition on cardiac and renal hypertensive end-organ damage are unknown. The effects of SAR (1 mg·kg⁻¹·d⁻¹ in chow) on left ventricular (LV) and renal remodeling processes were studied by magnetic resonance imaging and biochemical and histological analysis in obese spontaneously hypertensive rats (SHR-ob SAR) compared with placebo-treated SHR-ob (SHR-ob PLAC). Inhibition of intestinal NHE3 by SAR lowered blood pressure and reduced LV end-diastolic pressure from 21 ± 3.0 to 15 ± 2.0 mm Hg (P = 0.0016), whereas heart rate kept unchanged. LV mass indices, LV myocyte diameters, and LV fibrosis formation were lower in SHR-ob SAR compared with SHR-ob PLAC. SAR did not influence urinary albumin to creatinine ratio or glomerular filtration rate. Renal interstitial fibrosis formation, as well as podocyte damage and glomerulosclerosis remained unchanged. Reduction of intestinal sodium absorption by selective NHE3 inhibition in the gut lowered high blood pressure and reduced LV remodeling without deteriorating renal functional and structural parameters in SHR-ob.
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http://dx.doi.org/10.1097/FJC.0000000000000336DOI Listing
March 2016

Cardiac remodeling in Gαq and Gα11 knockout mice.

Int J Cardiol 2016 Jan 9;202:836-45. Epub 2015 Oct 9.

Institute for Molecular Cell Biology and Research Centre for Molecular Imaging and Screening, Saarland University, 66421 Homburg/Saar, Germany. Electronic address:

Background: Although both Gαq- and Gα11-protein signaling are believed to be involved in the regulation of cardiac hypertrophy, their detailed contribution to myocardial function remains elusive.

Methods And Results: We studied remodeling processes in healthy transgenic mice with genetically altered Gαq/Gα11-expression, in particular a global Gα11-knockout and a novel inducible cardiac specific Gαq-knockout, as well as a combined double knockout (dKO) mouse line. Echocardiography and telemetric ECG recordings revealed that compared with wild type mice, hearts of dKO mice showed an increased ejection fraction and a decreased heart rate, irrespective of age resulting in a maintained cardiac output. We attributed these findings to the lack of Gα11, which the absence was associated with a decreased afterload. Histological analysis of the extracellular matrix in the heart depicted a diminished presence of collagen in aging hearts of dKO mice compared to wild-type mice. The results of a transcriptome analysis on isolated ventricular cardiac myocytes revealed alterations of the activity of genes involved in the Gαq/Gα11-dependent regulation of the extracellular matrix, such as the matricellular protein Cyr61.

Conclusions: From our data we conclude that Gαq/Gα11 signaling pathways play a pivotal role in maintaining gene activity patterns. For the heart we revealed their importance in modulating the properties of the extracellular matrix, a mechanism that might be an important contributor and mechanistic basis for the development of pressure-overload induced cardiac hypertrophy.
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http://dx.doi.org/10.1016/j.ijcard.2015.10.069DOI Listing
January 2016

Reversal of Mitochondrial Transhydrogenase Causes Oxidative Stress in Heart Failure.

Cell Metab 2015 Sep 6;22(3):472-84. Epub 2015 Aug 6.

Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421 Homburg, Germany. Electronic address:

Mitochondrial reactive oxygen species (ROS) play a central role in most aging-related diseases. ROS are produced at the respiratory chain that demands NADH for electron transport and are eliminated by enzymes that require NADPH. The nicotinamide nucleotide transhydrogenase (Nnt) is considered a key antioxidative enzyme based on its ability to regenerate NADPH from NADH. Here, we show that pathological metabolic demand reverses the direction of the Nnt, consuming NADPH to support NADH and ATP production, but at the cost of NADPH-linked antioxidative capacity. In heart, reverse-mode Nnt is the dominant source for ROS during pressure overload. Due to a mutation of the Nnt gene, the inbred mouse strain C57BL/6J is protected from oxidative stress, heart failure, and death, making its use in cardiovascular research problematic. Targeting Nnt-mediated ROS with the tetrapeptide SS-31 rescued mortality in pressure overload-induced heart failure and could therefore have therapeutic potential in patients with this syndrome.
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http://dx.doi.org/10.1016/j.cmet.2015.07.008DOI Listing
September 2015

Atrial Remodeling Following Catheter-Based Renal Denervation Occurs in a Blood Pressure- and Heart Rate-Independent Manner.

JACC Cardiovasc Interv 2015 Jun 20;8(7):972-80. Epub 2015 May 20.

Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.

Objectives: This study sought to investigate left atrial (LA) remodeling in relation to blood pressure (BP) and heart rate (HR) after renal sympathetic denervation (RDN).

Background: In addition to reducing BP and HR in certain patients with hypertension, RDN can decrease left ventricular (LV) mass and ameliorate LV diastolic dysfunction.

Methods: Before and 6 months after RDN, BP, HR, LV mass, left atrial volume index (LAVI), diastolic function (echocardiography), and premature atrial contractions (PAC) (Holter electrocardiogram) were assessed in 66 patients with resistant hypertension.

Results: RDN reduced office BP by 21.6 ± 3.0/10.1 ± 2.0 mm Hg (p < 0.001), and HR by 8.0 ± 1.3 beats/min (p < 0.001). At baseline, LA size correlated with LV mass, diastolic function, and pro-brain natriuretic peptide, but not with BP or HR. Six months after RDN, LAVI was reduced by 4.0 ± 0.7 ml/kg/m(2) (p < 0.001). LA size decrease was stronger when LAVI at baseline was higher. In contrast, the decrease in LAVI was not dependent on LV mass or diastolic function (E/E' or E/A) at baseline. Furthermore, LAVI decreased without relation to decrease in systolic BP or HR. Additionally, occurrence of PAC (median of >153 PAC/24 h) was reduced (to 68 PAC/24 h) by RDN, independently of changes in LA size.

Conclusions: In patients with resistant hypertension, LA volume and occurrence of PAC decreased 6 months after RDN. This decrease was independent of BP and HR at baseline or the reduction in BP and HR reached by renal denervation. These data suggest that there is a direct, partly BP-independent effect of RDN on cardiac remodeling and occurrence of premature atrial contractions.
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http://dx.doi.org/10.1016/j.jcin.2015.02.014DOI Listing
June 2015

Twenty-four-hour heart rate lowering with ivabradine in chronic heart failure: insights from the SHIFT Holter substudy.

Eur J Heart Fail 2015 May 20;17(5):518-26. Epub 2015 Mar 20.

Universitätsklinikum des Saarlandes, Klinik für Innere Medizin III, Homburg/Saar, Germany.

Aims: Analysis of 24-h Holter recordings was a pre-specified substudy of SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial) for exploring the heart rhythm safety of ivabradine and to determine effects of ivabradine on 24-h, daytime, and night-time heart rate (HR) compared with resting office HR.

Methods And Results: The 24-h Holter monitoring was performed at baseline and 8 months after randomization to ivabradine (n = 298) or matching placebo (n = 304) titrated maximally to 7.5 mg b.i.d. in patients with baseline HR ≥70 b.p.m. Patients received guideline-based optimized heart failure therapy including ACE inhibitors and/or ARBs in 93% and beta-blockers at maximally tolerated doses in 93%. After 8 months, HR over 24 h decreased by 9.5 ± 10.0 b.p.m. with ivabradine, from 75.4 ± 10.3 b.p.m. (P < 0.0001), and by 1.2 ± 8.9 b.p.m. with placebo, from 74.8 ± 9.7 b.p.m. (P < 0.0001 for difference vs. ivabradine). HR reduction with ivabradine was similar in resting office and in 24-h, awake, and asleep recordings, with beneficial effects on HR variability and no meaningful increases in supraventricular or ventricular arrhythmias. At 8 months, 21.3% on ivabradine vs. 8.5% on placebo had ≥1 episode of HR <40 b.p.m. (P < 0.0001). No episode of HR <30 b.p.m. was recorded; 3 (1.2%) patients had RR intervals >2.5 s on ivabradine vs. 4 (1.6%) patients on placebo. No RR intervals >3 s were identified in patients taking ivabradine.

Conclusion: Ivabradine safely and significantly lowers HR and improves HR variability in patients with systolic heart failure, without inducing significant bradycardia, ventricular arrhythmias, or supraventricular arrhythmias.
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http://dx.doi.org/10.1002/ejhf.258DOI Listing
May 2015

Resting heart rate: risk indicator and emerging risk factor in cardiovascular disease.

Am J Med 2015 Mar 15;128(3):219-28. Epub 2014 Oct 15.

Weill Medical College of Cornell University, New York, NY.

Resting heart rate is central to cardiac output and is influenced by changes occurring in numerous diseases. It predicts longevity and cardiovascular diseases, and current evidence suggests that it is also an important marker of outcome in cardiovascular disease, including heart failure. Beta-blockers improve outcomes in heart failure; however, they have effects outside reducing heart rate. Ivabradine has demonstrated efficacy in reducing rehospitalizations and mortality in heart failure and in improving exercise tolerance and reducing angina attacks in patients with coronary artery disease, whereas selective heart rate reduction may also prove to be beneficial in therapeutic areas outside those in which ivabradine has already demonstrated clinical efficacy. This review provides an update on the associations between heart rate and cardiovascular outcomes in various conditions, the experimental effects of heart rate reduction with ivabradine, and the potential new indications in cardiovascular disease.
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http://dx.doi.org/10.1016/j.amjmed.2014.09.016DOI Listing
March 2015

Cardiac CaM Kinase II genes δ and γ contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy.

Circulation 2014 Oct 14;130(15):1262-73. Epub 2014 Aug 14.

From the Research Unit Cardiac Epigenetics, Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (M.M.K., L.H.L., S.K., M.-O.H., U.O., J.B.); Department of Cardiology, Saarland University, Homburg, Germany (M.K., J.-C.R., C.M.); Department of Internal Medicine II, University of Regensburg, Germany (K.N., L.S.M.); British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, United Kingdom (M.D.S.); Department of Internal Medicine, University of Southwestern Texas Medical Center, Dallas (J.A.H.); Institute of Pharmacology, University of Duisburg-Essen, Germany (D.D.); Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany (H.-J.G.); Department of Cardiology, University of Heidelberg, and DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (H.A.K.); and the Department of Molecular Biology, University of Southwestern Texas Medical Center, Dallas (E.N.O.).

Background: Ca(2+)-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear.

Methods And Results: We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca(2+) handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling.

Conclusions: We established a mouse model in which CaMKII's activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.114.006185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4316667PMC
October 2014

Stiff by stress: operant LV diastolic stiffness assessed with pre-load stress echocardiography.

JACC Cardiovasc Imaging 2014 Jul;7(7):650-2

Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jcmg.2014.05.001DOI Listing
July 2014

Improvements in left ventricular hypertrophy and diastolic function following renal denervation: effects beyond blood pressure and heart rate reduction.

J Am Coll Cardiol 2014 May 4;63(18):1916-23. Epub 2013 Dec 4.

Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.

Objectives: This study sought to investigate the interaction between blood pressure (BP) and heart rate (HR) reduction and changes in left ventricular (LV) structure and function following renal sympathetic denervation (RDN).

Background: Hypertension results in structural and functional cardiac changes. RDN reduces BP, HR, and LV mass and improves diastolic dysfunction.

Methods: We evaluated LV size, mass, and function before and 6 months after RDN in 66 patients with resistant hypertension and analyzed results in relation to systolic BP (SBP) and HR.

Results: SBP decreased by 11 ± 3 mm Hg in the first, 18 ± 5 mm Hg in the second, and 36 ± 7 mm Hg in the third tertile of SBP at baseline (p < 0.001). HR decreased by 13 ± 4 beats/min, 8 ± 3 beats/min, and 11 ± 6 beats/min in tertiles of SBP (p for interaction between tertiles = 0.314). In all SBP tertiles, LV mass index (LVMI) decreased similarly (LVMI -6.3 ± 2.2 g/m(2.7), -8.3 ± 2.1 g/m(2.7), and -9.6 ± 1.9 g/m(2.7); p for interaction = 0.639). LVMI decreased unrelated to HR at baseline (p for interaction = 0.471). The diastolic parameters E-wave deceleration time, isovolumetric relaxation time, and E'-wave velocity improved similarly in all tertiles of SBP and HR. Changes in LV mass and function were also unrelated to reduction in SBP or HR. Vascular compliance improved dependently on BP but independently of HR reduction.

Conclusions: In patients with resistant hypertension, LV hypertrophy and diastolic function improved 6 months after RDN, without significant relation to SBP and HR. These findings suggest a direct effect of altered sympathetic activity in addition to unloading on cardiac hypertrophy and function.
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http://dx.doi.org/10.1016/j.jacc.2013.10.073DOI Listing
May 2014

Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients.

J Am Coll Cardiol 2013 Nov 7;62(21):1977-1985. Epub 2013 Aug 7.

Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.

Objectives: The study aimed to determine whether isolated heart rate (HR) reduction with ivabradine reduces afterload of patients with systolic heart failure.

Background: The effective arterial elastance (Ea) represents resistive and pulsatile afterload of the heart derived from the pressure volume relation. HR modulates Ea, and, therefore, afterload burden.

Methods: Among the patients with systolic heart failure (ejection fraction ≤35%) randomized to either placebo or ivabradine in the SHIFT (Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial), 275 patients (n = 132, placebo; n = 143, ivabradine 7.5 mg twice a day) were included in the echocardiographic substudy. Ea, total arterial compliance (TAC), and end-systolic elastance (Ees) were calculated at baseline and after 8 months of treatment. Blood pressure was measured by arm cuff; stroke volume (SV), ejection fraction, and end-diastolic volume were assessed by echocardiography.

Results: At baseline Ea, TAC, HR, and Ees did not differ significantly between ivabradine- and placebo-treated patients. After 8 months of treatment, HR was significantly reduced in the ivabradine group (p < 0.0001) and was accompanied by marked reduction in Ea (p < 0.0001) and improved TAC (p = 0.004) compared with placebo. Although contractility remained unchanged, ventricular-arterial coupling was markedly improved (p = 0.002), resulting in a higher SV (p < 0.0001) in the ivabradine-treated patients.

Conclusions: Isolated HR reduction by ivabradine improves TAC, thus reducing Ea. Because Ees is unaltered, improved ventricular-arterial coupling is responsible for increased SV. Therefore, unloading of the heart may contribute to the beneficial effect of isolated HR reduction in patients with systolic heart failure.
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http://dx.doi.org/10.1016/j.jacc.2013.07.027DOI Listing
November 2013