Gerd Hasenfuß

Acute outcomes after MitraClip therapy in highly aged patients: results from the German TRAnscatheter Mitral valve Interventions (TRAMI) Registry.

AIMS The influence of age on baseline demographics and outcomes of patients selected for MitraClip has not been previously investigated. METHODS AND RESULTS Baseline demographics and acute outcomes in 1,064 patients from the German TRAMI registry were stratified by age (525 patients ≥76 years and 539 patients <76 years). In elderly patients, logistic EuroSCORE was higher (25[15-40]% vs. 18[10-31]%, p<0.0001) and the proportion of women was greater (47.2% vs. 29.3%, p<0.0001). Elderly patients were more likely to have preserved left ventricular ejection fraction >50% (40.1% vs. 21.8%, p<0.0001) and degenerative mitral regurgitation (DMR, 35.3% vs. 25.6%, p<0.01). Age was the most frequent reason for non-surgical treatment in the elderly (69.4% vs. 36.1%, p<0.0001). The intrahospital MACCE (death, myocardial infarction, stroke) was low in both groups (3.5% vs. 3.4%, p=0.93) and the proportion of non-severe mitral regurgitation at discharge was similar (95.8% vs. 96.4%, p=0.73). A logistic regression model did not reveal any significant impact of age on acute efficacy and safety of MitraClip therapy. In both groups, the majority of patients were discharged home (81.8% vs. 86.2%, p=0.06). CONCLUSIONS Elderly and younger patients have similar benefits from MitraClip therapy. Age was the most frequent cause for denying surgery in elderly patients.

Slow breathing reduces sympathoexcitation in COPD.

Neurohumoral activation has been shown to be present in hypoxic patients with chronic obstructive pulmonary disease (COPD). The aims of the present study were to investigate whether there is sympathetic activation in COPD patients in the absence of hypoxia and whether slow breathing has an impact on sympathoexcitation and baroreflex sensitivity. Efferent muscle sympathetic nerve activity, blood pressure, cardiac frequency and respiratory movements were continuously measured in 15 COPD patients and 15 healthy control subjects. Baroreflex sensitivity was analysed by autoregressive spectral analysis and the alpha-angle method. At baseline, sympathetic nerve activity was significantly elevated in COPD patients and baroreflex sensitivity was decreased (5.0±0.6 versus 8.9±0.8 ms·mmHg−1). Breathing at a rate of 6 breaths·min−1 caused sympathetic activity to drop significantly in COPD patients (from 61.3±4.6 to 53.0±4.3 bursts per 100 heartbeats) but not in control subjects (39.2±3.2 versus 37.5±3.3 bursts per 100 heartbeats). In both groups, slow breathing significantly enhanced baroreflex sensitivity. In conclusion, sympathovagal imbalance is present in normoxic chronic obstructive pulmonary disease patients. The possibility of modifying these changes by slow breathing may help to better understand and influence this systemic disease.

Blunted frequency-dependent upregulation of cardiac output is related to impaired relaxation in diastolic heart failure

Aims We tested the hypothesis that, in heart failure with normal ejection fraction (HFNEF), diastolic dysfunction is accentuated at increasing heart rates, and this contributes to impaired frequency-dependent augmentation of cardiac output. Methods and results In 17 patients with HFNEF (median age 69 years, 13 female) and seven age-matched control patients, systolic and diastolic function was analysed by pressure–volume loops at baseline heart rate and during atrial pacing to 100 and 120 min−1. At baseline, relaxation was prolonged and end-diastolic left ventricular stiffness was higher in HFNEF, whereas all parameters of systolic function were not different from control patients. This resulted in smaller end-diastolic volumes, higher end-diastolic pressure, and a lower stroke volume and cardiac index in HFNEF vs. control patients. During pacing, frequency-dependent upregulation of contractility indices (+dP/dtmax and Ees) occurred similarly in HFNEF and control patients, but frequency-dependent acceleration of relaxation (dP/dtmin) was blunted in HFNEF. In HFNEF, end-diastolic volume and stroke volume decreased with higher heart rates while both remained unchanged in control patients. Conclusion In HFNEF, frequency-dependent upregulation of cardiac output is blunted. This results from progressive volume unloading of the left ventricle due to limited relaxation reserve in combination with increased LV passive stiffness, despite preserved force–frequency relation.

The novel biomarker growth differentiation factor 15 in heart failure with normal ejection fraction

Heart failure with normal ejection fraction (HFnEF) is an important clinical entity that remains incompletely understood. The novel biomarker growth differentiation factor 15 (GDF‐15) is elevated in systolic heart failure (HFrEF) and is predictive of an adverse outcome. We investigated the clinical relevance of GDF‐15 plasma levels in HFnEF.

A transcatheter intracardiac shunt device for heart failure with preserved ejection fraction (REDUCE LAP-HF): a multicentre, open-label, single-arm, phase 1 trial

BACKGROUND Heart failure with preserved ejection fraction (HFPEF) is a common, globally recognised, form of heart failure for which no treatment has yet been shown to improve symptoms or prognosis. The pathophysiology of HFPEF is complex but characterised by increased left atrial pressure, especially during exertion, which might be a key therapeutic target. The rationale for the present study was that a mechanical approach to reducing left atrial pressure might be effective in HFPEF. METHODS The REDUCe Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF) study was an open-label, single-arm, phase 1 study designed to assess the performance and safety of a transcatheter interatrial shunt device (IASD, Corvia Medical, Tewkesbury, MA, USA) in patients older than 40 years of age with symptoms of HFPEF despite pharmacological therapy, left ventricular ejection fraction higher than 40%, and a raised pulmonary capillary wedge pressure at rest (>15 mm Hg) or during exercise (>25 mm Hg). The study was done at 21 centres (all departments of cardiology in the UK, Netherlands, Belgium, France, Germany, Austria, Denmark, Australia, and New Zealand). The co-primary endpoints were the safety and performance of the IASD at 6 months, together with measures of clinical efficacy, including functional capacity and clinical status, analysed per protocol. This study is registered with ClinicalTrials.gov, number NCT01913613. FINDINGS Between Feb 8, 2014, and June 10, 2015, 68 eligible patients were entered into the study. IASD placement was successful in 64 patients and seemed to be safe and well tolerated; no patient had a peri-procedural or major adverse cardiac or cerebrovascular event or need for cardiac surgical intervention for device-related complications during 6 months of follow-up. At 6 months, 31 (52%) of 60 patients had a reduction in pulmonary capillary wedge pressure at rest, 34 (58%) of 59 had a lower pulmonary capillary wedge pressure during exertion, and 23 (39%) of 59 fulfilled both these criteria. Mean exercise pulmonary capillary wedge pressure was lower at 6 months than at baseline, both at 20 watts workload (mean 32 mm Hg [SD 8] at baseline vs 29 mm Hg [9] at 6 months, p=0·0124) and at peak exercise (34 mm Hg [8] vs 32 [8], p=0·0255), despite increased mean exercise duration (baseline vs 6 months: 7·3 min [SD 3·1] vs 8·2 min [3·4], p=0·03). Sustained device patency at 6 months was confirmed by left-to-right shunting (pulmonary/systemic flow ratio: 1·06 [SD 0·32] at baseline vs 1·27 [0·20] at 6 months, p=0·0004). INTERPRETATION Implantation of an interatrial shunt device is feasible, seems to be safe, reduces left atrial pressure during exercise, and could be a new strategy for the management of HFPEF. The effectiveness of IASD compared with existing treatment for patients with HFPEF requires validation in a randomised controlled trial. FUNDING Corvia Medical Inc.

A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy

AIMS Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM. METHODS AND RESULTS Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 × 10(-9)) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors. CONCLUSION The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.

Validation of N-terminal pro-brain natriuretic peptide cut-off values for risk stratification of pulmonary embolism

The optimal N-terminal pro-brain natriuretic peptide (NT-proBNP) cut-off value for risk stratification of pulmonary embolism remains controversial. In this study we validated and compared different proposed NT-proBNP cut-off values in 688 normotensive patients with pulmonary embolism. During the first 30 days, 28 (4.1%) patients reached the primary outcome (pulmonary embolism-related death or complications) and 29 (4.2%) patients died. Receiver operating characteristic analysis yielded an area under the curve of 0.70 (0.60–0.80) for NT-proBNP. A cut-off value of 600 pg·mL−1 was associated with the best prognostic performance (sensitivity 86% and specificity 50%) and the highest odds ratio (6.04 (95% CI 2.07–17.59), p=0.001) compared to the cut-off values of 1000, 500 or 300 pg·mL−1. Using multivariable logistic regression analysis, NT-proBNP ≥600 pg·mL−1 had a prognostic impact on top of that of the simplified Pulmonary Embolism Severity Index and right ventricular dysfunction on echocardiography (OR 4.27 (95% CI 1.22–15.01); p=0.024, c-index 0.741). The use of a stepwise approach based on the simplified Pulmonary Embolism Severity Index, NT-proBNP ≥600 pg·mL−1 and echocardiography helped optimise risk assessment. Our findings confirm the prognostic value of NT-proBNP and suggest that a cut-off value of 600 pg·mL−1 is most appropriate for risk stratification of normotensive patients with pulmonary embolism. NT-proBNP should be used in combination with a clinical score and an imaging procedure for detecting right ventricular dysfunction. Stepwise approach based on sPESI, NT-proBNP and echocardiography for pulmonary embolism risk stratification http://ow.ly/tsMud

Impact of frailty on short- and long-term morbidity and mortality after transcatheter aortic valve implantation: risk assessment by Katz Index of activities of daily living.

AIMS Transcatheter aortic valve implantation (TAVI) represents a less invasive treatment option for elderly patients. Therefore, we aimed to determine the impact of frailty measured by the Katz Index of activities of daily living (ADL) on short- and long-term mortality after TAVI. METHODS AND RESULTS Our study included 300 consecutive patients (mean age, 82±5 years) who had undergone TAVI at our institution (158 transapical, 142 transfemoral procedures). At baseline, 144 patients were impaired in at least one ADL and therefore defined as frail (Katz Index <6). Regarding in-hospital outcome, all serious complications except for stage 3 acute kidney injury were equally distributed in both groups, but early mortality was significantly higher in frail persons (5.5% vs. 1.3%, p=0.04 for immediate procedural mortality; 17% vs. 5.8%, p=0.002 for 30-day mortality; and 23% vs. 6.4%, p<0.0001 for procedural mortality). The risk-score-based 30-day mortality estimates (29% vs. 24% for log. EuroSCORE I, 9.5% vs. 7.5% for EuroSCORE II, and 8.8% vs. 5.9% for STS score) reflected neither the observed 30-day mortality in both groups nor the threefold risk elevation in frail patients. In contrast, the Katz Index <6 was identified as a significant independent predictor of long-term all-cause mortality by multivariate analysis (HR 2.67 [95% CI: 1.7-4.3], p<0.0001). During follow-up (median observation period 537 days) 56% of frail vs. 24% of non-frail patients died. CONCLUSIONS Frailty status measured by the Katz Index represents a powerful predictor of adverse early and late outcome after TAVI, whereas commonly used risk scores lack calibration and discrimination in a TAVI-specific patient cohort. Therefore, we propose the incorporation of this simple and reproducible measure into pre-TAVI risk assessment.

Cardiovascular magnetic resonance feature-tracking assessment of myocardial mechanics: Intervendor agreement and considerations regarding reproducibility

Aim To assess intervendor agreement of cardiovascular magnetic resonance feature tracking (CMR-FT) and to study the impact of repeated measures on reproducibility. Materials and methods Ten healthy volunteers underwent cine imaging in short-axis orientation at rest and with dobutamine stimulation (10 and 20 μg/kg/min). All images were analysed three times using two types of software (TomTec, Unterschleissheim, Germany and Circle, cvi42, Calgary, Canada) to assess global left ventricular circumferential (Ecc) and radial (Err) strains and torsion. Differences in intra- and interobserver variability within and between software types were assessed based on single and averaged measurements (two and three repetitions with subsequent averaging of results, respectively) as determined by Bland–Altman analysis, intraclass correlation coefficients (ICC), and coefficient of variation (CoV). Results Myocardial strains and torsion significantly increased on dobutamine stimulation with both types of software (p<0.05). Resting Ecc and torsion as well as Ecc values during dobutamine stimulation were lower measured with Circle (p<0.05). Intra- and interobserver variability between software types was lowest for Ecc (ICC 0.81 [0.63–0.91], 0.87 [0.72–0.94] and CoV 12.47% and 14.3%, respectively) irrespective of the number of analysis repetitions. Err and torsion showed higher variability that markedly improved for torsion with repeated analyses and to a lesser extent for Err. On an intravendor level TomTec showed better reproducibility for Ecc and torsion and Circle for Err. Conclusions CMR-FT strain and torsion measurements are subject to considerable intervendor variability, which can be reduced using three analysis repetitions. For both vendors, Ecc qualifies as the most robust parameter with the best agreement, albeit lower Ecc values obtained using Circle, and warrants further investigation of incremental clinical merit.

Quantification of left atrial strain and strain rate using Cardiovascular Magnetic Resonance myocardial feature tracking: a feasibility study

BackgroundCardiovascular Magnetic Resonance myocardial feature tracking (CMR-FT) is a quantitative technique tracking tissue voxel motion on standard steady-state free precession (SSFP) cine images to assess ventricular myocardial deformation. The importance of left atrial (LA) deformation assessment is increasingly recognized and can be assessed with echocardiographic speckle tracking. However atrial deformation quantification has never previously been demonstrated with CMR. We sought to determine the feasibility and reproducibility of CMR-FT for quantitative derivation of LA strain and strain rate (SR) myocardial mechanics.Methods10 healthy volunteers, 10 patients with hypertrophic cardiomyopathy (HCM) and 10 patients with heart failure and preserved ejection fraction (HFpEF) were studied at 1.5 Tesla. LA longitudinal strain and SR parameters were derived from SSFP cine images using dedicated CMR-FT software (2D CPA MR, TomTec, Germany). LA performance was analyzed using 4- and 2-chamber views including LA reservoir function (total strain [εs], peak positive SR [SRs]), LA conduit function (passive strain [εe], peak early negative SR [SRe]) and LA booster pump function (active strain [εa], late peak negative SR [SRa]).ResultsIn all subjects LA strain and SR parameters could be derived from SSFP images. There was impaired LA reservoir function in HCM and HFpEF (εs [%]: HCM 22.1 ± 5.5, HFpEF 16.3 ± 5.8, Controls 29.1 ± 5.3, p < 0.01; SRs [s-1]: HCM 0.9 ± 0.2, HFpEF 0.8 ± 0.3, Controls 1.1 ± 0.2, p < 0.05) and impaired LA conduit function as compared to healthy controls (εe [%]: HCM 10.4 ± 3.9, HFpEF 11.9 ± 4.0, Controls 21.3 ± 5.1, p < 0.001; SRe [s-1]: HCM -0.5 ± 0.2, HFpEF -0.6 ± 0.1, Controls -1.0 ± 0.3, p < 0.01). LA booster pump function was increased in HCM while decreased in HFpEF (εa [%]: HCM 11.7 ± 4.0, HFpEF 4.5 ± 2.9, Controls 7.8 ± 2.5, p < 0.01; SRa [s-1]: HCM -1.2 ± 0.4, HFpEF -0.5 ± 0.2, Controls -0.9 ± 0.3, p < 0.01). Observer variability was excellent for all strain and SR parameters on an intra- and inter-observer level as determined by Bland-Altman, coefficient of variation and intraclass correlation coefficient analyses.ConclusionsCMR-FT based atrial performance analysis reliably quantifies LA longitudinal strain and SR from standard SSFP cine images and discriminates between patients with impaired left ventricular relaxation and healthy controls. CMR-FT derived atrial deformation quantification seems a promising novel approach for the study of atrial performance and physiology in health and disease states.