Impact of transcatheter edge-to-edge mitral valve repair on central sleep apnoea.

AIMS: Sleep-disordered breathing (SDB) and its subtype central sleep apnoea (CSA) are highly prevalent in patients with heart failure and associated with worse prognosis. Whereas pharmacological therapy of heart failure has been shown to ameliorate CSA, results from previous studies on the effect of mitral regurgitation therapy on SDB are contradicting. The aim of this study was to assess the impact of transcatheter edge-to-edge mitral valve repair (TEER) on prevalence and severity of CSA. METHODS AND RESULTS: We enrolled 47 patients undergoing TEER for symptomatic mitral regurgitation in a prospective study. Secondary mitral regurgitation and left ventricular ejection fraction < 50% were present in 79% and 68% of patients, respectively. Respiratory polygraphy was performed before TEER in a compensated condition and four weeks after the procedure. 34 patients completed the follow-up. At baseline, 19 (56%) patients showed moderate-to-severe SDB, of whom 13 (68%) were classified as CSA. Both apnoea-hypopnoea index and percentage of recorded time spent in Cheyne-Stokes respiration strongly decreased from baseline to follow-up (median [IQR] 16 [7-30] vs. 7 [4-15] /h, p = 0.007; 6 [0-34] vs. 0 [0-8] %, p = 0.008). Median relative reduction of central apnoea index was 75% (p = 0.023), while obstructive apnoea index did not change significantly. Increase in stroke volume after TEER and high systolic pulmonary artery pressure at baseline predicted a > 50% reduction of both Apnoea-hypopnoea index and Cheyne-Stokes respiration. CONCLUSION: TEER is associated with a significant short-term reduction of CSA and Cheyne-Stokes respiration in high-risk patients, strengthening its value as an effective treatment option for advanced heart failure.

Tachycardiomyopathy entails a dysfunctional pattern of interrelated mitochondrial functions.

Tachycardiomyopathy is characterised by reversible left ventricular dysfunction, provoked by rapid ventricular rate. While the knowledge of mitochondria advanced in most cardiomyopathies, mitochondrial functions await elucidation in tachycardiomyopathy. Pacemakers were implanted in 61 rabbits. Tachypacing was performed with 330 bpm for 10 days (n = 11, early left ventricular dysfunction) or with up to 380 bpm over 30 days (n = 24, tachycardiomyopathy, TCM). In n = 26, pacemakers remained inactive (SHAM). Left ventricular tissue was subjected to respirometry, metabolomics and acetylomics. Results were assessed for translational relevance using a human-based model: induced pluripotent stem cell derived cardiomyocytes underwent field stimulation for 7 days (TACH-iPSC-CM). TCM animals showed systolic dysfunction compared to SHAM (fractional shortening 37.8 ± 1.0% vs. 21.9 ± 1.2%, SHAM vs. TCM, p < 0.0001). Histology revealed cardiomyocyte hypertrophy (cross-sectional area 393.2 ± 14.5 µm2 vs. 538.9 ± 23.8 µm2, p < 0.001) without fibrosis. Mitochondria were shifted to the intercalated discs and enlarged. Mitochondrial membrane potential remained stable in TCM. The metabolite profiles of ELVD and TCM were characterised by profound depletion of tricarboxylic acid cycle intermediates. Redox balance was shifted towards a more oxidised state (ratio of reduced to oxidised nicotinamide adenine dinucleotide 10.5 ± 2.1 vs. 4.0 ± 0.8, p < 0.01). The mitochondrial acetylome remained largely unchanged. Neither TCM nor TACH-iPSC-CM showed relevantly increased levels of reactive oxygen species. Oxidative phosphorylation capacity of TCM decreased modestly in skinned fibres (168.9 ± 11.2 vs. 124.6 ± 11.45 pmol·O2·s-1·mg-1 tissue, p < 0.05), but it did not in isolated mitochondria. The pattern of mitochondrial dysfunctions detected in two models of tachycardiomyopathy diverges from previously published characteristic signs of other heart failure aetiologies.

Travelling with heart failure: risk assessment and practical recommendations.

Patients with heart failure are at a higher risk of cardiovascular events compared with the general population, particularly during domestic or international travel. Patients with heart failure should adhere to specific recommendations during travel to lower their risk of developing heart failure symptoms. In this Review, we aim to provide clinicians with a set of guidelines for patients with heart failure embarking on national or international travel. Considerations when choosing a travel destination include travel distance and time, the season upon arrival, air pollution levels, jet lag and altitude level because all these factors can increase the risk of symptom development in patients with heart failure. In particular, volume depletion is of major concern while travelling given that it can contribute to worsening heart failure symptoms. Pre-travel risk assessment should be performed by a clinician 4-6 weeks before departure, and patients should receive advice on potential travel-related illness and on strategies to prevent volume depletion. Oxygen supplementation might be useful for patients who are very symptomatic. Upon arrival at the destination, potential drug-induced photosensitivity (particularly in tropical destinations) and risks associated with the local cuisine require consideration. Special recommendations are needed for patients with cardiac implantable electronic devices or left ventricular assist devices as well as for those who have undergone major cardiac surgery.

Reduction of radiation exposure during transcatheter edge-to-edge mitral valve repair.

BACKGROUND: Transcatheter mitral valve repair is an increasingly used therapy for mitral regurgitation which requires fluoroscopic guidance. Limiting radiation exposure during lengthy procedures is important for both patient and operator safety. This study aimed to investigate radiation dose during contemporary use of MitraClip implantation and the effects of a dose reduction program. METHODS: A total of 115 patients who underwent MitraClip implantation were prospectively enrolled in a single-center observational study. During the inclusion period, our institution adopted a radiation dose reduction program, comprising lowering of fluoroscopy pulse rate and image target dose. The first 58 patients were treated with conventional fluoroscopy settings, while the following 57 patients underwent the procedure with the newly implemented low dose protocol. RESULTS: Radiation dose area product significantly decreased after introduction of the low dose protocol (693 [366-1231] vs. 2265 [1517-3914] cGy·cm2 , p < 0.001). After correcting for fluoroscopy time, gender and body mass index, the low dose protocol emerged as a strong negative predictor of radiation dose (p < 0.001), reducing dose area product by 64% (95% confidence interval [57-70]). Device time, device success, and procedural safety did not differ between the normal dose and low dose group. Furthermore, the low dose protocol was not associated with an increased incidence of a combined endpoint consisting of death, repeat intervention, or heart surgery during 12 months follow-up. CONCLUSION: Reduction of radiation exposure during transcatheter mitral valve repair by 64% is feasible without affecting procedural success or safety.

N-acetyl-ß-D-glucosaminidase is predictive of mortality in chronic heart failure: a 10-year follow-up.

Aim: The study focused on biomarkers of kidney injury as predictors of mortality in patients with chronic heart failure (CHF) in a long-term follow-up (median 104 months). Methods/results: KIM-1, NAG and NGAL were assessed from urine, NT-proBNP from blood samples. 149 patients (age 62 ± 12 years) with CHF (mean EF 30% [IQR 24-40%]) were enrolled. 79 (53%) patients died. Cox regression analysis revealed Log2NAG (HR: 1.46, CI: 1.12-1.89), Log2KIM-1 (HR: 1.23, CI: 1.02-1.49) and Log2NT-proBNP (HR: 1.50, CI: 1.32-1.72) as significant predictors of all-cause mortality as opposed to Log2NGAL (HR: 1.04, CI: 0.90-1.20). Log2NAG remained a significant predictor of all-cause mortality in a multivariate Cox regression model but lost its predictive value in combination with Log2NT-proBNP. Conclusion: The 10-year follow-up suggests NAG as a predictive tubular marker in CHF patients.

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

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

Acquired von Willebrand syndrome and factor VIII in patients with moderate to severe mitral regurgitation undergoing transcatheter mitral valve repair.

BACKGROUND AND HYPOTHESIS: The acquired von Willebrand syndrome (AvWS), which predisposes to bleeding events, is often related to valvular heart diseases. We investigated possible implications of AvWS and factor VIII levels in patients with moderate to severe mitral regurgitation (MR) undergoing transcatheter mitral valve repair (TMVR). METHODS AND RESULTS: 123 patients with moderate to severe MR were prospectively enrolled. Complete measurements of von Willebrand Factor activity (vWFAct), von Willebrand Factor antigen (vWFAg), and factor VIII expression before and 4 weeks after TMVR were available in 85 patients. At baseline, seven patients had a history of gastrointestinal bleeding, two patients suffered bleeding events during their hospital stay, and one patient had a bleeding 4 weeks after TMVR. Even though vWFAct, vWFAct/vWFAg ratio and vWFAg values did not change after TMVR, we observed a significantly lower vWFAct/vWFAg ratio in patients with primary MR as compared to patients with secondary MR both at baseline (p = 0.022) and 4 weeks following the TMVR procedure (p = 0.003). Additionally, patients with a mean mitral valve gradient ≥4 mmHg after TMVR had significantly lower vWFAct/vWFAg ratios as compared to patients with a mean mitral valve gradient <4 mmHg (p = 0.001). CONCLUSIONS: MR of primary etiology was associated with lower vWFAct/vWFAg ratio, hinting toward HMWM loss due to shear stress caused by eccentric regurgitation jets. In addition, morphological changes leading to postprocedural transmitral gradients ≥4 mmHg were related to lower vWFAct/vWFAg ratio 4 weeks after the procedure. Alterations of the vWFAct/vWFAg ratio in turn did not translate into a greater risk for bleeding events.

Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker treatment and haemodynamic factors are associated with increased cardiac mRNA expression of angiotensin-converting enzyme 2 in patients with cardiovascular disease.

AIMS: Coronavirus disease 2019 (COVID-19) is a widespread pandemic with an increased morbidity and mortality, especially for patients with cardiovascular diseases. Angiotensin-converting enzyme 2 (ACE2) has been identified as necessary cell entry point for SARS-CoV-2. Previous animal studies have demonstrated an increased ACE2 expression following treatment with either angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) that have led to a massive precariousness regarding the optimal cardiovascular therapy during this pandemic. METHODS AND RESULTS: We have measured ACE2 mRNA expression using real-time quantitative polymerase chain reaction in atrial biopsies of 81 patients undergoing coronary artery bypass grafting and we compared 62 patients that received ACEi/ARB vs. 19 patients that were not ACEi/ARB-treated. We found atrial ACE2 mRNA expression to be significantly increased in patients treated with an ACEi or an ARB, independent of potential confounding comorbidities. Interestingly, the cardiac ACE2 mRNA expression correlated significantly with the expression in white blood cells of 22 patients encouraging further evaluation if the latter may be used as a surrogate for the former. Similarly, analysis of 18 ventricular biopsies revealed a significant and independent increase in ACE2 mRNA expression in patients with end-stage heart failure that were treated with ACEi/ARB. On the other hand, cardiac unloading with a left ventricular assist device significantly reduced ventricular ACE2 mRNA expression. CONCLUSION: Treatment with ACEi/ARB is independently associated with an increased myocardial ACE2 mRNA expression in patients with coronary artery disease and in patients with end-stage heart failure. Further trials are needed to test whether this association is deleterious for patients with COVID-19, or possibly protective. Nevertheless, haemodynamic factors seem to be equally important for regulation of cardiac ACE2 mRNA expression.

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

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

Predictors of functional improvement in the short term after MitraClip implantation in patients with secondary mitral regurgitation.

BACKGROUND AND OBJECTIVES: MitraClip implantation is an established therapy for secondary mitral regurgitation (MR) in high-risk patients and has shown to improve several important outcome parameters such as functional capacity. Patient selection is both challenging and crucial for achieving therapeutic success. This study investigated baseline predictors of functional improvement as it was quantified by the six-minute walk distance (6MWD) after transcatheter mitral valve repair. METHODS AND RESULTS: We retrospectively analyzed 79 patients with secondary MR treated with MitraClip implantation at an academic tertiary care center. Before and four weeks after the procedure, all patients underwent comprehensive clinical assessment, six-minute walk tests and echocardiography. 6MWD significantly improved after MitraClip therapy (295 m vs. 265 m, p < 0.001). A linear regression model including seven clinical baseline variables significantly predicted the change in 6MWD (p = 0.002, R2 = 0.387). Female gender, diabetes mellitus and arterial hypertension were found to be significant negative predictors of 6MWD improvement. At baseline, female patients had significant higher left ventricular ejection fraction (49% vs. 42%, p = 0.019) and lower 6MWD (240 m vs. 288 m, p = 0.034) than male patients. CONCLUSION: MitraClip implantation in secondary MR significantly improves functional capacity in high-risk patients even in the short term of four weeks after the procedure. Female gender, diabetes mellitus and arterial hypertension are baseline predictors of a less favourable functional outcome. While further validation in a larger cohort is recommended, these parameters may improve patient selection for MitraClip therapy.

Skeletal muscle alterations in tachycardia-induced heart failure are linked to deficient natriuretic peptide signalling and are attenuated by RAS-/NEP-inhibition.

BACKGROUND: Heart failure induced cachexia is highly prevalent. Insights into disease progression are lacking. METHODS: Early state of left ventricular dysfunction (ELVD) and symptomatic systolic heart failure (HF) were both induced in rabbits by tachypacing. Tissue of limb muscle (LM) was subjected to histologic assessment. For unbiased characterisation of early and late myopathy, a proteomic approach followed by computational pathway-analyses was performed and combined with pathway-focused gene expression analyses. Specimen of thoracic diaphragm (TD) served as control for inactivity-induced skeletal muscle alterations. In a subsequent study, inhibition of the renin-angiotensin-system and neprilysin (RAS-/NEP) was compared to placebo. RESULTS: HF was accompanied by loss of protein content (8.7±0.4% vs. 7.0±0.5%, mean±SEM, control vs. HF, p<0.01) and a slow-to-fast fibre type switch, establishing hallmarks of cachexia. In ELVD, the enzymatic set-up of LM and TD shifted to a catabolic state. A disturbed malate-aspartate shuttle went well with increased enzymes of glycolysis, forming the enzymatic basis for enforced anoxic energy regeneration. The histological findings and the pathway analysis of metabolic results drew the picture of suppressed PGC-1α signalling, linked to the natriuretic peptide system. In HF, natriuretic peptide signalling was desensitised, as confirmed by an increase in the ratio of serum BNP to tissue cGMP (57.0±18.6pg/ml/nM/ml vs. 165.8±16.76pg/ml/nM/ml, p<0.05) and a reduced expression of natriuretic peptide receptor-A. In HF, combined RAS-/NEP-inhibition prevented from loss in protein content (8.7±0.3% vs. 6.0±0.6% vs. 8.3±0.9%, Baseline vs. HF-Placebo vs. HF-RAS/NEP, p<0.05 Baseline vs. HF-Placebo, p = 0.7 Baseline vs. HF-RAS/NEP). CONCLUSIONS: Tachypacing-induced heart failure entails a generalised myopathy, preceding systolic dysfunction. The characterisation of "pre-cachectic" state and its progression is feasible. Early enzymatic alterations of LM depict a catabolic state, rendering LM prone to futile substrate metabolism. A combined RAS-/NEP-inhibition ameliorates cardiac-induced myopathy independent of systolic function, which could be linked to stabilised natriuretic peptide/cGMP/PGC-1α signalling.

The role of the tubular biomarkers NAG, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in patients with chest pain before contrast media exposition.

Aim: We evaluated the role of the tubular biomarkers N-acetyl-ß-D-glucosaminidase (NAG), kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in patients with chest pain. Methods: Serum and urine samples were collected of 223 patients and 47 healthy controls. None of them was exposed to contrast media. Results: NAG showed among others significant correlation with N-terminal pro brain natriuretic peptide (NTproBNP), troponin I and creatinine. KIM-1 and NGAL showed weaker correlations. NAG was significantly elevated in all subgroups of acute coronary syndrome (ACS) compared with chest wall syndrome and controls. NAG was an independent predictor for the diagnosis of myocardial infarction. Conclusion: NAG may demonstrate the presence of acute tubular injury due to cardiac impairment already in the emergency department. NAG should be evaluated as marker of acute cardiorenal syndrome in patients with chest pain.

A novel technique to establish hemodynamic monitoring in patients supported with extracorporeal life support systems (ECLS) for cardiopulmonary resuscitation (ECPR).

PURPOSE: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used to support conventional unsuccessful resuscitation and it is mandatory to rapidly initiate invasive hemodynamic monitoring, as soon as ECPR therapy is commenced. Commonly, this is achieved by establishing an additional arterial line via the right radial artery for invasive blood pressure measurement, but this can be challenging and risky on the one hand and might lead to erroneous measurements on the other hand. Therefore, a faster, easier, safer and more valid method for hemodynamic monitoring is pressingly needed. METHODS AND RESULTS: We exemplarily describe one in four clinical cases, where hemodynamic monitoring was rapidly established in an ECPR supported patient by modification of the usual VA-ECMO setup: as previously described, a Y connector was implemented in the arterial cannula and equipped with a hemostatic valve at its blind end. Then, a 5 F pigtail catheter was introduced, pushed forward, and connected with a pressure transducer. This approach allows for a rapid and safe measurement of central blood pressure without need for a potentially hazardous additional arterial line. CONCLUSION: Invasive hemodynamic monitoring in critically ill patients with VA-ECMO support is easily and rapidly achievable by introducing a pigtail catheter through a modified arterial ECMO cannula. Validation of this method in larger clinical trials is warranted.

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

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

3D vena contracta area after MitraClip© procedure: precise quantification of residual mitral regurgitation and identification of prognostic information.

BACKGROUND: Percutaneous mitral valve repair (PMVR) is increasingly performed in patients with severe mitral regurgitation (MR). Post-procedural MR grading is challenging and an unsettled issue. We hypothesised that the direct planimetry of vena contracta area (VCA) by 3D-transoesophageal echocardiography allows quantifying post-procedural MR and implies further prognostic relevance missed by the usual ordinal scale (grade I-IV). METHODS: Based on a single-centre PMVR registry containing 102 patients, the association of VCA reduction and patients' functional capacity measured as six-minute walk distance (6 MW) was evaluated. 3D-colour-Doppler datasets were available before, during and 4 weeks after PMVR. RESULTS: Twenty nine patients (age 77.0 ± 5.8 years) with advanced heart failure (75.9% NYHA III/IV) and severe degenerative (34%) or functional (66%) MR were eligible. VCA was reduced in all patients by PMVR (0.99 ± 0.46 cm2 vs. 0.22 ± 0.15 cm2, p < 0.0001). It remained stable after median time of 33 days (p = 0.999). 6 MW improved after the procedure (257.5 ± 82.5 m vs. 295.7 ± 96.3 m, p < 0.01). Patients with a decrease in VCA less than the median VCA reduction showed a more distinct improvement in 6 MW than patients with better technical result (p < 0.05). This paradoxical finding was driven by inferior results in very large functional MR. CONCLUSIONS: VCA improves the evaluation of small residual MR. Its post-procedural values remain stable during a short-term follow-up and imply prognostic information for the patients' physical improvement. VCA might contribute to a more substantiated estimation of treatment success in the heterogeneous functional MR group.

Heart failure with preserved ejection fraction: current management and future strategies : Expert opinion on the behalf of the Nucleus of the "Heart Failure Working Group" of the German Society of Cardiology (DKG).

About 50% of all patients suffering from heart failure (HF) exhibit a reduced ejection fraction (EF ≤ 40%), termed HFrEF. The others may be classified into HF with midrange EF (HFmrEF 40-50%) or preserved ejection fraction (HFpEF, EF ≥ 50%). Presentation and pathophysiology of HFpEF is heterogeneous and its management remains a challenge since evidence of therapeutic benefits on outcome is scarce. Up to now, there are no therapies improving survival in patients with HFpEF. Thus, the treatment targets symptom relief, quality of life and reduction of cardiac decompensations by controlling fluid retention and managing risk factors and comorbidities. As such, renin-angiotensin-aldosterone inhibitors, diuretics, calcium channel blockers (CBB) and beta-blockers, diet and exercise recommendations are still important in HFpEF, although these interventions are not proven to reduce mortality in large randomized controlled trials. Recently, numerous new treatment targets have been identified, which are further investigated in studies using, e.g. soluble guanylate cyclase stimulators, inorganic nitrates, the angiotensin receptor neprilysin inhibitor LCZ 696, and SGLT2 inhibitors. In addition, several devices such as the CardioMEMS, interatrial septal devices (IASD), cardiac contractility modulation (CCM), renal denervation, and baroreflex activation therapy (BAT) were investigated in different forms of HFpEF populations and some of them have the potency to offer new hopes for patients suffering from HFpEF. On the basic research field side, lot of new disease-modifying strategies are under development including anti-inflammatory drugs, mitochondrial-targeted antioxidants, new anti-fibrotic and microRNA-guided interventions are under investigation and showed already promising results. This review addresses available data of current best clinical practice and management approaches based on expert experiences and summarizes novel approaches towards HFpEF.

Acute Renal Graft-Versus-Host Disease in a Murine Model of Allogeneic Bone Marrow Transplantation.

Acute kidney injury (AKI) is a very common complication after allogeneic bone marrow transplantation (BMT) and is associated with a poor prognosis. Generally, the kidneys are assumed to not be no direct targets of graft-versus-host disease (GvHD), and renal impairment is often attributed to several other factors occurring in the early phase after BMT. Our study aimed to prove the existence of renal GvHD in a fully major histocompatibility complex (MHC)-mismatched model of BALB/c mice conditioned and transplanted according to 2 different intensity protocols. Syngeneically transplanted and untreated animals served as controls. Four weeks after transplantation, allogeneic animals developed acute GvHD that was more pronounced in the high-intensity protocol (HIP) group than in the low-intensity protocol (LIP) group. Urea and creatinine as classic serum markers of renal function could not verify renal impairment 4 weeks after BMT. Creatinine levels were even reduced as a result of catabolic metabolism and loss of muscle mass due to acute GvHD. Proteinuria, albuminuria, and urinary N-acetyl-beta-d-glucosaminidase (NAG) levels were measured as additional renal markers before and after transplantation. Albuminuria and NAG were only significantly increased after allogeneic transplantation, correlating with disease severity between HIP and LIP animals. Histological investigations of the kidneys showed renal infiltration of T cells and macrophages with endarteriitis, interstitial nephritis, tubulitis, and glomerulitis. T cells consisted of CD4+, CD8+, and FoxP3+ cells. Renal expression analysis of allogeneic animals showed increases in indoleamine-2,3 dioxygenase (IDO), different cytokines (tumor necrosis factor α, interferon-γ, interleukin 1 α [IL-1α], IL-2, IL-6, and IL-10), and adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1), resembling findings from other tissues in acute GvHD. In summary, our study supports the entity of renal GvHD with histological features suggestive of cell-mediated renal injury. Albuminuria and urinary NAG levels may serve as early markers of renal impairment.

Combined Inhibition of the Renin-Angiotensin System and Neprilysin Positively Influences Complex Mitochondrial Adaptations in Progressive Experimental Heart Failure.

BACKGROUND: Inhibitors of the renin angiotensin system and neprilysin (RAS-/NEP-inhibitors) proved to be extraordinarily beneficial in systolic heart failure. Furthermore, compelling evidence exists that impaired mitochondrial pathways are causatively involved in progressive left ventricular (LV) dysfunction. Consequently, we aimed to assess whether RAS-/NEP-inhibition can attenuate mitochondrial adaptations in experimental heart failure (HF). METHODS AND RESULTS: By progressive right ventricular pacing, distinct HF stages were induced in 15 rabbits, and 6 animals served as controls (CTRL). Six animals with manifest HF (CHF) were treated with the RAS-/NEP-inhibitor omapatrilat. Echocardiographic studies and invasive blood pressure measurements were undertaken during HF progression. Mitochondria were isolated from LV tissue, respectively, and further worked up for proteomic analysis using the SWATH technique. Enzymatic activities of citrate synthase and the electron transfer chain (ETC) complexes I, II, and IV were assessed. Ultrastructural analyses were performed by transmission electron microscopy. During progression to overt HF, intricate expression changes were mainly detected for proteins belonging to the tricarboxylic acid cycle, glucose and fat metabolism, and the ETC complexes, even though ETC complex I, II, or IV enzymatic activities were not significantly influenced. Treatment with a RAS-/NEP-inhibitor then reversed some maladaptive metabolic adaptations, positively influenced the decline of citrate synthase activity, and altered the composition of each respiratory chain complex, even though this was again not accompanied by altered ETC complex enzymatic activities. Finally, ultrastructural evidence pointed to a reduction of autophagolytic and degenerative processes with omapatrilat-treatment. CONCLUSIONS: This study describes complex adaptations of the mitochondrial proteome in experimental tachycardia-induced heart failure and shows that a combined RAS-/NEP-inhibition can beneficially influence mitochondrial key pathways.

NT-proBNP Predicts Cardiovascular Death in the General Population Independent of Left Ventricular Mass and Function: Insights from a Large Population-Based Study with Long-Term Follow-Up.

AIMS: B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) predict cardiovascular endpoints in patients and all-cause death in the general population. This was assigned to their association with clinical cardiac remodelling defined as changes in size, shape and function of the heart. The aim of this study was to evaluate whether NT-proBNP and BNP were associated with cardiovascular and overall death independent of clinical cardiac remodelling measured by echocardiography as left ventricular hypertrophy (LVH), diastolic dysfunction and left ventricular ejection fraction (EF). METHODS AND RESULTS: In a general population-based cohort study from Germany (KORA-S3) with subjects' baseline age ranging from 25 to 74 years, cardiac morphology and function were assessed as left ventricular mass (LVM), diastolic dysfunction and EF by echocardiography and circulating NT-proBNP and BNP were measured at baseline. In 1,223 subjects with mortality follow-up information, we examined the association of baseline NT-proBNP and BNP with cardiovascular mortality (number of deaths = 52, median follow-up time = 12.9years) using Cox regression without and with adjustment for cardiovascular risk factors, LVM, diastolic dysfunction and EF. The risk of cardiovascular mortality increased with higher NT-proBNP levels measured at baseline (hazard ratio HR = 1.67 per unit increment in logNT-proBNP, p = 2.78*10-4, adjusted for age and sex). This increased risk persisted after adjustment for cardiovascular risk factors, LVM, diastolic dysfunction and EF (HR = 1.73; p = 0.047). When excluding subjects with relevant LVH (LVM to body surface area > 149g/m2 in men / 122g/m2 in women), the NT-proBNP association with mortality was still significant (n = 1,138; number of deaths = 35; HR = 1.48; p = 0.04). We found similar results for BNP. CONCLUSION: Our data confirms NT-proBNP and BNP as predictor of cardiovascular mortality in a large general population-based study with long-term follow-up. Our study extends previously published population-based studies to younger and potentially healthier individuals without relevant LVH, diastolic dysfunction or LVD.