Microaxial Flow Pump or Standard Care in Infarct-Related Cardiogenic Shock.

BACKGROUND: The effects of temporary mechanical circulatory support with a microaxial flow pump on mortality among patients with ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock remains unclear. METHODS: In an international, multicenter, randomized trial, we assigned patients with STEMI and cardiogenic shock to receive a microaxial flow pump (Impella CP) plus standard care or standard care alone. The primary end point was death from any cause at 180 days. A composite safety end point was severe bleeding, limb ischemia, hemolysis, device failure, or worsening aortic regurgitation. RESULTS: A total of 360 patients underwent randomization, of whom 355 were included in the final analysis (179 in the microaxial-flow-pump group and 176 in the standard-care group). The median age of the patients was 67 years, and 79.2% were men. Death from any cause occurred in 82 of 179 patients (45.8%) in the microaxial-flow-pump group and in 103 of 176 patients (58.5%) in the standard-care group (hazard ratio, 0.74; 95% confidence interval [CI], 0.55 to 0.99; P = 0.04). A composite safety end-point event occurred in 43 patients (24.0%) in the microaxial-flow-pump group and in 11 (6.2%) in the standard-care group (relative risk, 4.74; 95% CI, 2.36 to 9.55). Renal-replacement therapy was administered to 75 patients (41.9%) in the microaxial-flow-pump group and to 47 patients (26.7%) in the standard-care group (relative risk, 1.98; 95% CI, 1.27 to 3.09). CONCLUSIONS: The routine use of a microaxial flow pump with standard care in the treatment of patients with STEMI-related cardiogenic shock led to a lower risk of death from any cause at 180 days than standard care alone. The incidence of a composite of adverse events was higher with the use of the microaxial flow pump. (Funded by the Danish Heart Foundation and Abiomed; DanGer Shock ClinicalTrials.gov number, NCT01633502.).

Mitral Valve Transcatheter Edge-to-Edge Repair: 1-Year Outcomes From the MiCLASP Study.

BACKGROUND: Mitral transcatheter edge-to-edge repair (M-TEER) is a guideline-recommended treatment option for patients with severe symptomatic mitral regurgitation (MR). Outcomes with the PASCAL system in a post-market setting have not been established. OBJECTIVES: The authors report 30-day and 1-year outcomes from the MiCLASP (Transcatheter Repair of Mitral Regurgitation with Edwards PASCAL Transcatheter Valve Repair System) European post-market clinical follow-up study. METHODS: Patients with symptomatic, clinically significant MR were prospectively enrolled. The primary safety endpoint was clinical events committee-adjudicated 30-day composite major adverse event rate and the primary effectiveness endpoint was echocardiographic core laboratory-assessed MR severity at discharge compared with baseline. Clinical, echocardiographic, functional, and quality-of-life outcomes were assessed at 1 year. RESULTS: A total of 544 patients were enrolled (59% functional MR, 30% degenerative MR). The 30-day composite major adverse event rate was 6.8%. MR reduction was significant from baseline to discharge and sustained at 1 year with 98% of patients achieving MR ≤2+ and 82.6% MR ≤1+ (all P < 0.001 vs baseline). One-year Kaplan-Meier estimate for survival was 87.3%, and freedom from heart failure hospitalization was 84.3%. Significant functional and quality-of-life improvements were observed at 1 year, including 71.6% in NYHA functional class I/II, 14.4-point increase in Kansas City Cardiomyopathy Questionnaire score, and 24.2-m improvement in 6-minute walk distance (all P < 0.001 vs baseline). CONCLUSIONS: One-year outcomes of this large cohort from the MiCLASP study demonstrate continued safety and effectiveness of M-TEER with the PASCAL system in a post-market setting. Results demonstrate high survival and freedom from heart failure hospitalization, significant and sustained MR reduction, and improvements in symptoms, functional capacity, and quality of life.

Baseline NT-proBNP predicts acute kidney injury following transcatheter aortic valve implantation.

BACKGROUND/PURPOSE: Acute kidney injury (AKI) after transcatheter aortic valve implantation (TAVI) increases morbidity and mortality. Our study aimed to investigate the role of baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) as a predictor of AKI following TAVI. METHODS: All consecutive TAVI patients were included in the analysis, except patients with dialysis and those with a GFR < 15 ml/min/1.73 m2 at baseline. Rates of AKI after TAVI were assessed according to the updated valve academic research consortium definitions using AKIN classification in three stages. NT-proBNP was measured at baseline. One-year mortality rates were assessed. RESULTS: We included 1973 patients treated with TAVI between January 2006 and December 2016. Median [IQR] age was 81.0 [77.0;84.0] years, the STS score was 6.2 [3.9;9.0], and the logEuroScore was 14.5 [9.0;23.0]. 30-day and one-year mortality was 5.1 % and 16.1 % for all patients, respectively. Multivariate analysis revealed that patients with NT-proBNP levels higher than two times above the upper level of normal (ULN) had an increased risk for AKI after TAVI compared to patients with NT-proBNP levels < 2× ULN (OR 1.40 [1.03-1.91]). CONCLUSIONS: Routine assessment of baseline NT-proBNP levels might be an additional tool to identify patients at increased risk for AKI after TAVI.

Transcatheter or Surgical Treatment of Aortic-Valve Stenosis.

BACKGROUND: Among low-risk patients with severe, symptomatic aortic stenosis who are eligible for both transcatheter aortic-valve implantation (TAVI) and surgical aortic-valve replacement (SAVR), data are lacking on the appropriate treatment strategy in routine clinical practice. METHODS: In this randomized noninferiority trial conducted at 38 sites in Germany, we assigned patients with severe aortic stenosis who were at low or intermediate surgical risk to undergo either TAVI or SAVR. Percutaneous- and surgical-valve prostheses were selected according to operator discretion. The primary outcome was a composite of death from any cause or fatal or nonfatal stroke at 1 year. RESULTS: A total of 1414 patients underwent randomization (701 to the TAVI group and 713 to the SAVR group). The mean (±SD) age of the patients was 74±4 years; 57% were men, and the median Society of Thoracic Surgeons risk score was 1.8% (low surgical risk). The Kaplan-Meier estimate of the primary outcome at 1 year was 5.4% in the TAVI group and 10.0% in the SAVR group (hazard ratio for death or stroke, 0.53; 95% confidence interval [CI], 0.35 to 0.79; P<0.001 for noninferiority). The incidence of death from any cause was 2.6% in the TAVI group and 6.2% in the SAVR group (hazard ratio, 0.43; 95% CI, 0.24 to 0.73); the incidence of stroke was 2.9% and 4.7%, respectively (hazard ratio, 0.61; 95% CI, 0.35 to 1.06). Procedural complications occurred in 1.5% and 1.0% of patients in the TAVI and SAVR groups, respectively. CONCLUSIONS: Among patients with severe aortic stenosis at low or intermediate surgical risk, TAVI was noninferior to SAVR with respect to death from any cause or stroke at 1 year. (Funded by the German Center for Cardiovascular Research and the German Heart Foundation; DEDICATE-DZHK6 ClinicalTrials.gov number, NCT03112980.).

Leucine Supplementation Prevents the Development of Skeletal Muscle Dysfunction in a Rat Model of HFpEF.

Heart failure with preserved ejection fraction (HFpEF) is associated with exercise intolerance due to alterations in the skeletal muscle (SKM). Leucine supplementation is known to alter the anabolic/catabolic balance and to improve mitochondrial function. Thus, we investigated the effect of leucine supplementation in both a primary and a secondary prevention approach on SKM function and factors modulating muscle function in an established HFpEF rat model. Female ZSF1 obese rats were randomized to an untreated, a primary prevention, and a secondary prevention group. For primary prevention, leucine supplementation was started before the onset of HFpEF (8 weeks of age) and for secondary prevention, leucine supplementation was started after the onset of HFpEF (20 weeks of age). SKM function was assessed at an age of 32 weeks, and SKM tissue was collected for the assessment of mitochondrial function and histological and molecular analyses. Leucine supplementation prevented the development of SKM dysfunction whereas it could not reverse it. In the primary prevention group, mitochondrial function improved and higher expressions of mitofilin, Mfn-2, Fis1, and miCK were evident in SKM. The expression of UCP3 was reduced whereas the mitochondrial content and markers for catabolism (MuRF1, MAFBx), muscle cross-sectional area, and SKM mass did not change. Our data show that leucine supplementation prevented the development of skeletal muscle dysfunction in a rat model of HFpEF, which may be mediated by improving mitochondrial function through modulating energy transfer.

Bioresorbable molybdenum temporary epicardial pacing wires.

Cardiac pacing with temporary epicardial pacing wires (TEPW) is used to treat rhythm disturbances after cardiac surgery. Occasionally, TEPW cannot be mechanically extracted and remain in the thorax, where they may rarely cause serious complications like migration and infection. We aim to develop bioresorbable TEPW that will dissolve over time even if postoperative removal is unsuccessful. In the present study, we demonstrate a completely bioresorbable design using molybdenum (Mo) as electric conductor and the resorbable polymers poly(D, L-lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL) for electrically insulating double-coating. We compared the pacing properties of these Mo TEPW demonstrators to conventional steel TEPW in Langendorff-perfused rat hearts and observed similar functionality. In vitro, static immersion tests in simulated body fluid for up to 28 days elucidated the degradation behaviour of uncoated Mo strands and the influence of polymer coating thereon. Degradation was considerably reduced in double-coated Mo TEPW compared to the uncoated and the PLGA-coated condition. Furthermore, we confirmed good biocompatibility of Mo degradation products in the form of low cytotoxicity in cell cultures of human cardiomyocytes and cardiac fibroblasts. STATEMENT OF SIGNIFICANCE: Temporary pacing wires are routinely implanted on the heart surface to treat rhythm disturbances in the days following cardiac surgery. Subsequently, these wires are to be removed. When removal attempts are unsuccessful, wires are cut at skin level and the remainders are left inside the chest. Retained fragments may migrate within the body or become a centre of infection. These complications may be prevented using resorbable pacing wires. We manufactured completely resorbable temporary pacing wires using molybdenum as electrical conductor and assessed their function, degradation and biological compatibility. Our study represents an important step in the development of a safer approach to the treatment of rhythm disturbances after cardiac surgery.

Sex-related differences in patients presenting with heart failure-related cardiogenic shock.

BACKGROUND: Heart failure-related cardiogenic shock (HF-CS) accounts for a significant proportion of all CS cases. Nevertheless, there is a lack of evidence on sex-related differences in HF-CS, especially regarding use of treatment and mortality risk in women vs. men. This study aimed to investigate potential differences in clinical presentation, use of treatments, and mortality between women and men with HF-CS. METHODS: In this international observational study, patients with HF-CS (without acute myocardial infarction) from 16 tertiary-care centers in five countries were enrolled between 2010 and 2021. Logistic and Cox regression models were used to assess differences in clinical presentation, use of treatments, and 30-day mortality in women vs. men with HF-CS. RESULTS: N = 1030 patients with HF-CS were analyzed, of whom 290 (28.2%) were women. Compared to men, women were more likely to be older, less likely to have a known history of heart failure or cardiovascular risk factors, and lower rates of highly depressed left ventricular ejection fraction and renal dysfunction. Nevertheless, CS severity as well as use of treatments were comparable, and female sex was not independently associated with 30-day mortality (53.0% vs. 50.8%; adjusted HR 0.94, 95% CI 0.75-1.19). CONCLUSIONS: In this large HF-CS registry, sex disparities in risk factors and clinical presentation were observed. Despite these differences, the use of treatments was comparable, and both sexes exhibited similarly high mortality rates. Further research is necessary to evaluate if sex-tailored treatment, accounting for the differences in cardiovascular risk factors and clinical presentation, might improve outcomes in HF-CS.

Exercise training and high-sensitivity cardiac troponin-I in patients with heart failure with reduced ejection fraction.

AIMS: The aims of this sub-study of the SMARTEX trial were (1) to evaluate the effects of a 12-week exercise training programme on serum levels of high sensitivity cardiac troponin I (hs-cTnI) in patients with moderate chronic heart failure (CHF), in New York Heart Association class II-III with reduced ejection fraction (HFrEF) and (2) to explore the associations with left ventricular remodelling, functional capacity and filling pressures measured with N-terminal pro brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS: In this sub-study, 196 patients were randomly assigned to high intensity interval training (HIIT, n = 70), moderate continuous training (MCT, n = 59) or recommendation of regular exercise (RRE), (n = 67) for 12 weeks. To reveal potential difference between structured intervention and control, HIIT and MCT groups were merged and named supervised exercise training (SET) group. The RRE group constituted the control group (CG). To avoid contributing factors to myocardial injury, we also evaluated changes in patients without additional co-morbidities (atrial fibrillation, hypertension, diabetes mellitus, and chronic obstructive pulmonary disease). The relationship between hs-cTnI and left ventricular end-diastolic diameter (LVEDD), VO2peak, and NT-proBNP was analysed by linear mixed models. At 12 weeks, Hs-cTnI levels were modestly but significantly reduced in the SET group from median 11.9 ng/L (interquartile ratio, IQR 7.1-21.8) to 11.5 ng/L (IQR 7.0-20.7), P = 0.030. There was no between-group difference (SET vs. CG, P = 0.116). There was a numerical but not significant reduction in hs-cTnI for the whole population (P = 0.067) after 12 weeks. For the sub-group of patients without additional co-morbidities, there was a significant between-group difference: SET group (delta -1.2 ng/L, IQR -2.7 to 0.1) versus CG (delta -0.1 ng/L, IQR -0.4 to 0.7), P = 0.007. In the SET group, hs-cTnI changed from 10.9 ng/L (IQR 6.0-22.7) to 9.2 ng/L (IQR 5.2-20.5) (P = 0.002), whereas there was no change in the CG (6.4 to 5.8 ng/L, P = 0.64). Changes in hs-cTnI (all patients) were significantly associated with changes in; LVEDD, VO2peak, and NT-proBNP, respectively. CONCLUSIONS: In patients with stable HFrEF, 12 weeks of structured exercise intervention was associated with a modest, but significant reduction of hs-cTnI. There was no significant difference between intervention group and control group. In the sub-group of patients without additional co-morbidities, this difference was highly significant. The alterations in hs-cTnI were associated with reduction of LVEDD and natriuretic peptide concentrations as well as improved functional capacity.

Valve Hemodynamics by Valve Size and 1-Year Survival Following Implantation of the Portico Valve in the Multicenter CONFIDENCE Registry.

Background: The CONtrolled delivery For ImproveD outcomEs with cliNiCal Evidence registry was initiated to characterize the clinical safety and device performance from experienced transcatheter aortic valve implantation (TAVI) centers in Europe and Australia that use the Portico valve to treat patients with severe aortic stenosis. We herein report for the first time the valve performance at 30-day across all implanted valve sizes and the 1-year survival from this registry. Methods: This was a prospective, multicenter, single-arm observational clinical investigation of patients clinically indicated for implantation of a Portico valve in experienced TAVI centers. Patients were treated with a commercially available valve (size 23, 25, 27, or 29 mm) using either the first-generation delivery system (DS) (n = 501) or the second-generation (FlexNav) DS (n = 500). Adverse events were adjudicated by an independent clinical events committee according to Valve Academic Research Consortium-2 criteria. Echocardiographic outcomes were assessed at 30 days by an independent core laboratory, and a survival check was performed at 1 year. Results: We enrolled 1001 patients (82.0 years, 62.5% female, 63.7% New York Heart Association functional class III/IV at baseline) from 27 clinical sites in 8 countries across Europe and one site in Australia. Implantation of a single valve was successful in 97.5% of subjects. Valve hemodynamics at 30 days were substantially improved relative to baseline, with large aortic valve areas and low mean gradients across all implanted valve sizes (aortic valve areas were 1.7 ± 0.4, 1.7 ± 0.5, 1.8 ± 0.5, and 2.0 ± 0.5 cm2, and mean gradients were 7.0 ± 2.7, 7.5 ± 4.7, 7.3 ± 3.3, and 6.4 ± 3.3 mmHg for 23, 25, 27, and 29 mm valve sizes, respectively). Across all implanted valve sizes, most patients (77.1%) had no patient-prosthesis mismatch. Death from any cause within 1 year occurred in 13.7% of the patients in the first-generation DS group as compared with 11.0% in the second-generation DS group (p = 0.2). Conclusions: The Portico valve demonstrated excellent hemodynamic performance across all valve sizes in a large cohort of subjects implanted in experienced TAVI centers. One-year survival rates were favorable when using both the first-generation and second-generation (FlexNav) DSs in this high-risk cohort. ClinicalTrialsgov Identifier: NCT03752866.

Clinical presentation, shock severity and mortality in patients with de novo versus acute-on-chronic heart failure-related cardiogenic shock.

AIMS: Heart failure-related cardiogenic shock (HF-CS) accounts for a significant proportion of CS cases. Whether patients with de novo HF and those with acute-on-chronic HF in CS differ in clinical characteristics and outcome remains unclear. The aim of this study was to evaluate differences in clinical presentation and mortality between patients with de novo and acute-on-chronic HF-CS. METHODS AND RESULTS: In this international observational study, patients with HF-CS from 16 tertiary care centres in five countries were enrolled between 2010 and 2021. To investigate differences in clinical presentation and 30-day mortality, adjusted logistic/Cox regression models were fitted. Patients (n = 1030) with HF-CS were analysed, of whom 486 (47.2%) presented with de novo HF-CS and 544 (52.8%) with acute-on-chronic HF-CS. Traditional markers of CS severity (e.g. blood pressure, heart rate and lactate) as well as use of treatments were comparable between groups. However, patients with acute-on-chronic HF-CS were more likely to have a higher CS severity and also a higher mortality risk, after adjusting for relevant confounders (de novo HF 45.5%, acute-on-chronic HF 55.9%, adjusted hazard ratio 1.38, 95% confidence interval 1.10-1.72, p = 0.005). CONCLUSION: In this large HF-CS cohort, acute-on-chronic HF-CS was associated with more severe CS and higher mortality risk compared to de novo HF-CS, although traditional markers of CS severity and use of treatments were comparable. These findings highlight the vast heterogeneity of patients with HF-CS, emphasize that HF chronicity is a relevant disease modifier in CS, and indicate that future clinical trials should account for this.

Infective Endocarditis After Transcatheter Versus Surgical Aortic Valve Replacement.

BACKGROUND: Scarce data are available comparing infective endocarditis (IE) following surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). This study aimed to compare the clinical presentation, microbiological profile, management, and outcomes of IE after SAVR versus TAVR. METHODS: Data were collected from the "Infectious Endocarditis after TAVR International" (enrollment from 2005 to 2020) and the "International Collaboration on Endocarditis" (enrollment from 2000 to 2012) registries. Only patients with an IE affecting the aortic valve prosthesis were included. A 1:1 paired matching approach was used to compare patients with TAVR and SAVR. RESULTS: A total of 1688 patients were included. Of them, 602 (35.7%) had a surgical bioprosthesis (SB), 666 (39.5%) a mechanical prosthesis, 70 (4.2%) a homograft, and 350 (20.7%) a transcatheter heart valve. In the SAVR versus TAVR matched population, the rate of new moderate or severe aortic regurgitation was higher in the SB group (43.4% vs 13.5%; P < .001), and fewer vegetations were diagnosed in the SB group (62.5% vs 82%; P < .001). Patients with an SB had a higher rate of perivalvular extension (47.9% vs 27%; P < .001) and Staphylococcus aureus was less common in this group (13.4% vs 22%; P = .033). Despite a higher rate of surgery in patients with SB (44.4% vs 27.3%; P < .001), 1-year mortality was similar (SB: 46.5%; TAVR: 44.8%; log-rank P = .697). CONCLUSIONS: Clinical presentation, type of causative microorganism, and treatment differed between patients with an IE located on SB compared with TAVR. Despite these differences, both groups exhibited high and similar mortality at 1-year follow-up.

Association between left ventricular ejection fraction, mortality and use of mechanical circulatory support in patients with non-ischaemic cardiogenic shock.

BACKGROUND: Currently, use of mechanical circulatory support (MCS) in non-ischaemic cardiogenic shock (CS) is predominantly guided by shock-specific markers, and not by markers of cardiac function. We hypothesise that left ventricular ejection fraction (LVEF) can identify patients with a higher likelihood to benefit from MCS and thus help to optimise their expected benefit. METHODS: Patients with non-ischaemic CS and available data on LVEF from 16 tertiary-care centres in five countries were analysed. Cox regression models were fitted to evaluate the association between LVEF and mortality, as well as the interaction between LVEF, MCS use and mortality. RESULTS: N = 807 patients were analysed: mean age 63 [interquartile range (IQR) 51.5-72.0] years, 601 (74.5%) male, lactate 4.9 (IQR 2.6-8.5) mmol/l, LVEF 20 (IQR 15-30) %. Lower LVEF was more frequent amongst patients with more severe CS, and MCS was more likely used in patients with lower LVEF. There was no association between LVEF and 30-day mortality risk in the overall study cohort. However, there was a significant interaction between MCS use and LVEF, indicating a lower 30-day mortality risk with MCS use in patients with LVEF ≤ 20% (hazard ratio 0.72, 95% confidence interval 0.51-1.02 for LVEF ≤ 20% vs. hazard ratio 1.31, 95% confidence interval 0.85-2.01 for LVEF > 20%, interaction-p = 0.017). CONCLUSION: This retrospective study may indicate a lower mortality risk with MCS use only in patients with severely reduced LVEF. This may propose the inclusion of LVEF as an adjunctive parameter for MCS decision-making in non-ischaemic CS, aiming to optimise the benefit-risk ratio.

VARC-3 defined outcome of valve-in-valve transcatheter aortic valve implantation in stentless compared with stented aortic bioprostheses.

BACKGROUND: Valve-in-valve (ViV) transcatheter aortic valve implantation (TAVI) is a viable alternative to redo surgery in selected patients with bioprosthetic valve dysfunction. Most ViV-TAVI procedures have been performed in stented bioprosthetic valves (ST); stentless bioprostheses (SL) lack fluoroscopic markers and could be more challenging for ViV-TAVI. Data on more recent patients applying Valve Academic Research Consortium (VARC)-3 defined outcomes are scarce. We compared patient characteristics, procedural outcomes, and 5-year mortality of patients with SL versus ST aortic bioprosthetic valve failure undergoing ViV-TAVI. METHODS: Patients undergoing ViV-TAVI between 2007 and 2022 (52.5% of cases after 2015) at 3 German centers were included in this analysis. The co-primary outcome measures were technical success, device success, and early safety defined by VARC-3. Mortality was assessed up to 5 years. RESULTS: Overall, 43 (11.8%) SL and 313 (88.2%) ST ViV-TAVI were included. Patients were comparable with regard to age, sex, clinically relevant baseline comorbidities, and surgical risk. Technical success (SL: 83.7% versus ST: 79.9%, p = 0.552), device success (SL: 67.4% versus ST: 54.3%, p = 0.105), and early safety (SL: 74.4% versus ST: 66.5%, p = 0.296) were comparable between groups. The 30-day mortality (SL: 7.0% versus ST: 2.6%, p = 0.136) and 5-year mortality rates (SL: 23.3% versus ST: 24.6%, p = 0.874) were not significantly different between groups. CONCLUSION: SL and ST ViV-TAVI led to comparable short-term outcomes according to VARC-3- defined endpoints and similar mortality rates up to 5 years of follow-up. VARC-3 defined technical success, device success, and early safety as well as 5-year all-cause mortality in patients undergoing valve-in-valve transcatheter aortic valve implantation (ViV-TAVI) into stentless (SL) compared with stented (ST) failed aortic bioprostheses.

Locomotor and respiratory muscle abnormalities in HFrEF and HFpEF.

Heart failure (HF) is a chronic and progressive syndrome affecting worldwide billions of patients. Exercise intolerance and early fatigue are hallmarks of HF patients either with a reduced (HFrEF) or a preserved (HFpEF) ejection fraction. Alterations of the skeletal muscle contribute to exercise intolerance in HF. This review will provide a contemporary summary of the clinical and molecular alterations currently known to occur in the skeletal muscles of both HFrEF and HFpEF, and thereby differentiate the effects on locomotor and respiratory muscles, in particular the diaphragm. Moreover, current and future therapeutic options to address skeletal muscle weakness will be discussed focusing mainly on the effects of exercise training.

Leucine Supplementation Improves Diastolic Function in HFpEF by HDAC4 Inhibition.

Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome associated with a high morbidity and mortality rate. Leucine supplementation has been demonstrated to attenuate cardiac dysfunction in animal models of cachexia and heart failure with reduced ejection fraction (HFrEF). So far, no data exist on leucine supplementation on cardiac function in HFpEF. Thus, the current study aimed to investigate the effect of leucine supplementation on myocardial function and key signaling pathways in an established HFpEF rat model. Female ZSF1 rats were randomized into three groups: Control (untreated lean rats), HFpEF (untreated obese rats), and HFpEF_Leu (obese rats receiving standard chow enriched with 3% leucine). Leucine supplementation started at 20 weeks of age after an established HFpEF was confirmed in obese rats. In all animals, cardiac function was assessed by echocardiography at baseline and throughout the experiment. At the age of 32 weeks, hemodynamics were measured invasively, and myocardial tissue was collected for assessment of mitochondrial function and for histological and molecular analyses. Leucine had already improved diastolic function after 4 weeks of treatment. This was accompanied by improved hemodynamics and reduced stiffness, as well as by reduced left ventricular fibrosis and hypertrophy. Cardiac mitochondrial respiratory function was improved by leucine without alteration of the cardiac mitochondrial content. Lastly, leucine supplementation suppressed the expression and nuclear localization of HDAC4 and was associated with Protein kinase A activation. Our data show that leucine supplementation improves diastolic function and decreases remodeling processes in a rat model of HFpEF. Beneficial effects were associated with HDAC4/TGF-ß1/Collagenase downregulation and indicate a potential use in the treatment of HFpEF.

Impella for the Management of Ventricular Septal Defect Complicating Acute Myocardial Infarction: A European Multicenter Registry.

Ventricular septal defect (VSD) is a rare but severe complication of myocardial infarction (MI). Temporary mechanical circulatory support (MCS) can be used as a bridge to VSD closure, heart transplantation, or ventricular assist device. We describe the use of Impella device in this context based on a multicenter European retrospective registry (17 centers responded). Twenty-eight post-MI VSD patients were included (Impella device were 2.5 for 1 patient, CP for 20, 5.0 for 5, and unknown for 2). All patients were in cardiogenic shock with multiple organ failure (SAPS II 41 [interquantile range {IQR} = 27-53], lactate 4.0 ± 3.5 mmol/L) and catecholamine support (dobutamine 55% and norepinephrine 96%). Additional temporary MCS was used in 14 patients (50%), mainly extracorporeal life support (ECLS) (n = 9, 32%). Severe bleedings were frequent (50%). In-hospital and 1 year mortalities were 75%. Ventricular septal defect management was surgical for 36% of patients, percutaneous for 21%, and conservative for 43%. Only surgically managed patients survived (70% in-hospital survival). Type and combination of temporary MCS used were not associated with mortality (Impella alone or in combination with intra-aortic balloon pump [IABP] or ECLS, p = 0.84). Impella use in patients with post-MI VSD is feasible but larger prospective registries are necessary to further elucidate potential benefits of left ventricular unloading in this setting.

Baroreflex activation therapy in patients with heart failure with reduced ejection fraction: a single-centre experience.

AIMS: Heart failure with reduced ejection fraction (HFrEF) is associated with excessive sympathetic and impaired parasympathetic activity. The Barostim Neo™ device is used for electronical baroreflex activation therapy (BAT) to counteract autonomic nervous system dysbalance. Randomized trials have shown that BAT improves walking distance and reduces N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels at least in patients with only moderate elevation at baseline. Its impact on the risk of heart failure hospitalization (HFH) and death is not yet established, and experience in clinical routine is limited. METHODS AND RESULTS: We report on patient characteristics and clinical outcome in a retrospective, non-randomized single-centre registry of BAT in HFrEF. Patients in the New York Heart Association (NYHA) Classes III and IV with a left ventricular ejection fraction (LVEF) <35% despite guideline-directed medical therapy were eligible. Symptom burden, echocardiography, and laboratory testing were assessed at baseline and after 12 months. Clinical events of HFH and death were recorded at routine clinical follow-up. Data are shown as number (%) or median (inter-quartile range). Between 2014 and 2020, 30 patients were treated with BAT. Median age was 67 (63-77) years, and 27 patients (90%) were male. Most patients (83%) had previous HFH. Device implantation was successful in all patients. At 12 months, six patients had died and three were alive but did not attend follow-up. NYHA class was III/IV in 26 (87%)/4 (13%) patients at baseline, improved in 19 patients, and remained unchanged in 5 patients (P < 0.001). LVEF improved from 25.5 (20.0-30.5) % at baseline to 30.0 (25.0-36.0) % at 12 months (P = 0.014). Left ventricular end-diastolic diameter remained unchanged. A numerical decrease in NT-proBNP [3165 (880-8085) vs. 1001 (599-3820) pg/mL] was not significant (P = 0.526). Median follow-up for clinical events was 16 (10-33) months. Mortality at 1 (n = 6, 20%) and 3 years (n = 10, 33%) was as expected by the Meta-Analysis Global Group in Chronic Heart Failure risk score. Despite BAT, event rate was high in patients with NYHA Class IV, NT-proBNP levels >1600 pg/mL, or estimated glomerular filtration rate (eGFR) <30 mL/min at baseline. NYHA class and eGFR were independent predictors of mortality. CONCLUSIONS: Patients with HFrEF who are selected for BAT are in a stage of worsening or even advanced heart failure. BAT appears to be safe and improves clinical symptoms and-to a modest degree-left ventricular function. The risk of death remains high in advanced disease stages. Patient selection seems to be crucial, and the impact of BAT in earlier disease stages needs to be established.