Search

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., (© 2022. The Author(s).)

Aims: Transcatheter mitral valve implantation (TMVI) is a new treatment option for patients with symptomatic mitral valve (MV) disease. Real-world data have not yet been reported. This study aimed to assess procedural and 30-day outcomes of TMVI in a real-world patient cohort., Method and Results: All consecutive patients undergoing implantation of a transapically delivered self-expanding valve at 26 European centres from January 2020 to April 2021 were included in this retrospective observational registry. Among 108 surgical high-risk patients included (43% female, mean age 75 ± 7 years, mean STS-PROM 7.2 ± 5.3%), 25% was treated for an off-label indication (e.g. previous MV intervention or surgery, mitral stenosis, mitral annular calcification). Patients were highly symptomatic (New York Heart Association [NYHA] functional class III/IV in 86%) and mitral regurgitation (MR) was graded 3+/4+ in 95% (38% primary, 37% secondary, and 25% mixed aetiology). Technical success rate was 96%, and MR reduction to ≤1+ was achieved in all patients with successful implantation. There were two procedural deaths and 30-day all-cause mortality was 12%. At early clinical follow-up, MR reduction was sustained and there were significant reductions of pulmonary pressure (systolic pulmonary artery pressure 52 vs. 42 mmHg, p < 0.001), and tricuspid regurgitation severity (p = 0.013). Heart failure symptoms improved significantly (73% in NYHA class I/II, p < 0.001). Procedural success rate according to MVARC criteria was 80% and was not different in patients treated for an off-label indication (74% vs. 81% for off- vs. on-label, p = 0.41)., Conclusion: In a real-world patient population, TMVI has a high technical and procedural success rate with efficient and durable MR reduction and symptomatic improvement., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

[Figure: see text].

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., Competing Interests: The authors have declared that no competing interests exist.

Aims: Identifying the key components in cardiomyocyte cell cycle regulation is of relevance for the understanding of cardiac development and adaptive and maladaptive processes in the adult myocardium. BRCA1-associated protein (BRAP) has been suggested as a cytoplasmic retention factor for several proteins including Cyclin-dependent-kinase inhibitor p21Cip. We observed profound expressional changes of BRAP in early postnatal myocardium and investigated the impact of BRAP on cardiomyocyte cell cycle regulation., Methods and Results: General knockout of Brap in mice evoked embryonic lethality associated with reduced myocardial wall thickness and lethal cardiac congestion suggesting a prominent role for BRAP in cardiomyocyte proliferation. αMHC-Cre driven cardiomyocyte-specific knockout of Brap also evoked lethal cardiac failure shortly after birth. Likewise, conditional cardiomyocyte-specific Brap deletion using tamoxifen-induced knockout in adult mice resulted in marked ventricular dilatation and heart failure 3 weeks after induction. Several lines of evidence suggest that Brap deletion evoked marked inhibition of DNA synthesis and cell cycle progression. In cardiomyocytes with proliferative capacity, this causes developmental arrest, whereas in adult hearts loss of BRAP-induced apoptosis. This is explained by altered signalling through p21Cip which we identify as the link between BRAP and cell cycle/apoptosis. BRAP deletion enhanced p21Cip expression, while BRAP overexpression in cardiomyocyte-specific transgenic mice impeded p21Cip expression. That was paralleled by enhanced nuclear Ki-67 expression and DNA synthesis., Conclusion: By controlling p21Cip activity BRAP expression controls cell cycle activity and prevents developmental arrest in developing cardiomyocytes and apoptosis in adult cardiomyocytes., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: Pantoprazole has been shown to exert a negative inotropic effect in isolated myocardium. The purpose of this study was to evaluate the hemodynamic effects of pantoprazole in vivo in healthy myocardium and in the setting of heart failure., Methods and Results: Healthy mice and mice with heart failure 4 weeks after myocardial infarction induced by permanent LAD ligation were instrumented with a Millar Mikrotip conductance catheter to record pressure-volume loops. Pantoprazole was infused at rates of 3 and 10 mg/kg/min intravenously, and hemodynamic parameters were recorded. Infusion of pantoprazole at increasing rates lead to a significant decline of end systolic LV pressure by decreasing heart rate, myocardial contractility and arterial elastance. These effects were quick, beginning immediately with the infusion and usually reaching a plateau after 2 or 3 min of infusion. The effects on blood pressure and heart rate were of comparable size in healthy mice and mice with MI. However, in sham-operated mice, there was a compensatory increase in stroke volume that sufficed to maintain cardiac output at a constant level, which was missing in mice with MI. In 4 of 13 mice with MI infusion of 10 mg/kg/min pantoprazole lead to pump failure, which was lethal in 2 of these animals., Conclusion: At higher infusion rates, pantoprazole is able to induce negative hemodynamic responses. In particular, in the setting of heart failure, these effects can lead to significant impairment of cardiac function. Therefore, high infusion rates of pantoprazole should be avoided especially in heart failure patients., (© 2014 John Wiley & Sons Ltd.)

Giant-cell myocarditis (GCM) is known as a rare, rapidly progressive, and frequently fatal myocardial disease in young and middle-aged adults. We report about a 76 year old male patient who underwent implantation with a biventricular Berlin Heart Excor system at the age of 74 due to acute biventricular heart failure caused by giant-cell myocarditis. The implantation was without any surgical problems; however, a difficulty was the immunosuppressive therapy after implantation. Meanwhile the patient is 76 years old and lives with circulatory support for about 3 years without major adverse events. Also, in terms of mobility in old age there are no major limitations. It seems that in even selected elderly patients an implantation of a long term support with the biventricular Berlin Heart Excor is a useful therapeutic option with an acceptable outcome.

Rationale: Telethonin (also known as titin-cap or t-cap) is a 19-kDa Z-disk protein with a unique β-sheet structure, hypothesized to assemble in a palindromic way with the N-terminal portion of titin and to constitute a signalosome participating in the process of cardiomechanosensing. In addition, a variety of telethonin mutations are associated with the development of several different diseases; however, little is known about the underlying molecular mechanisms and telethonin's in vivo function., Objective: Here we aim to investigate the role of telethonin in vivo and to identify molecular mechanisms underlying disease as a result of its mutation., Methods and Results: By using a variety of different genetically altered animal models and biophysical experiments we show that contrary to previous views, telethonin is not an indispensable component of the titin-anchoring system, nor is deletion of the gene or cardiac specific overexpression associated with a spontaneous cardiac phenotype. Rather, additional titin-anchorage sites, such as actin-titin cross-links via α-actinin, are sufficient to maintain Z-disk stability despite the loss of telethonin. We demonstrate that a main novel function of telethonin is to modulate the turnover of the proapoptotic tumor suppressor p53 after biomechanical stress in the nuclear compartment, thus linking telethonin, a protein well known to be present at the Z-disk, directly to apoptosis ("mechanoptosis"). In addition, loss of telethonin mRNA and nuclear accumulation of this protein is associated with human heart failure, an effect that may contribute to enhanced rates of apoptosis found in these hearts., Conclusions: Telethonin knockout mice do not reveal defective heart development or heart function under basal conditions, but develop heart failure following biomechanical stress, owing at least in part to apoptosis of cardiomyocytes, an effect that may also play a role in human heart failure.

Sarcoplasmic reticulum (SR) calcium (Ca) leak can be reduced by enhancing FKBP12.6 binding to SR Ca release channels (RyR2) and expression of a "sticky" FKBP12.6(D37S) mutant may correct reduced binding stoichiometry in RyR2 from failing hearts. Both calcium/calmodulin-dependent protein kinase IIδc (CaMKIIδc) and protein kinase A (PKA) are activated in heart failure and promote SR Ca leak at RyR2. It is possible that FKBP12.6 dissociation from RyR2 may promote remodeling and that interventions to reassociate FKBP12.6 with RyR2 reflect a future therapeutic strategy. We created transgenic (TG) mice expressing FKBP12.6(D37S) and tested their capacity to improve intracellular Ca handling and pathological remodeling in vivo. FKBP12.6(D37S) TG mice were cross-bred with CaMKIIδc TG mice, which are known to exhibit pronounced RyR2 dysfunction and heart failure. We observed a significant improvement of post-rest Ca transients and a higher SR Ca content in FKBP12.6(D37S) TG mice. In double-TG mice, a marked reduction of SR Ca spark frequency indicated reduced SR Ca leak but neither SR Ca transient amplitude, SR Ca content nor morphological or functional parameters improved in vivo. Likewise, FKBP12.6(D37S) TG mice subjected to increased afterload after aortic banding exhibited higher SR Ca load but did not exhibit any improvement in hypertrophic growth or functional decline. Enhancement of FKBP12.6-RyR2 binding markedly reduced RyR2 Ca leak in CaMKIIδc-induced heart failure and in pressure overload. Our data suggest that activation of CaMKIIδc and pressure overload confer significant resistance towards approaches aiming at FKBP12.6-RyR2 reconstitution in heart failure and maladaptive remodeling, although RyR2 Ca leak can be reduced., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Heart failure is characterised by reduced expression of sarcoplasmic reticulum calcium-ATPase (SERCA) and increased expression of B-type natriuretic peptide (BNP). The present study was performed to investigate causality of this inverse relationship under in vivo conditions in the transversal aortic constriction mouse model (TAC). Left ventricular SERCA-mRNA expression was significantly upregulated in TAC by 32% after 6 h, but not different from sham after 24 h. Serum proANP and BNP levels were increased in TAC after 24 h (BNP +274%, p < 0.01; proANP +60%, p < 0.05), but only proANP levels were increased after 6 h (+182%, p < 0.01). cGMP levels were only increased 24 h after TAC (+307%, p < 0.01), but not 6 h after TAC. BNP infusion inhibited the increase in SERCA expression 6 h after TAC. In BNP-receptor-knockout animals (GC-A), the expression of SERCA was still significantly increased 24 h after TAC at the mRNA level by 35% (p < 0.05), as well as at the protein level by 25% (p < 0.05). MCIP expression as an indicator of calcineurin activity was regulated in parallel to SERCA after 6 and 24 h. MCIP-mRNA was increased by 333% 6 h after TAC, but not significantly different from sham after 24 h. In the GC-A-KO mice, MCIP-mRNA was significantly increased in TAC compared to WT after 24 h. In mice with BNP infusion, MCIP was significantly lower 6 h after TAC compared to control animals. In conclusion, mechanical load leads to an upregulation of SERCA expression. This is followed by upregulation of natriuretic peptides with subsequent suppression of SERCA upregulation. Elevated natriuretic peptides may suppress SERCA expression by inhibition of calcineurin activity via activation of GC-A.

Background: Hemodynamic load regulates myocardial function and gene expression. We tested the hypothesis that afterload and preload, despite similar average load, result in different phenotypes., Methods and Results: Afterload and preload were compared in mice with transverse aortic constriction (TAC) and aortocaval shunt (shunt). Compared with sham mice, 6 hours after surgery, systolic wall stress (afterload) was increased in TAC mice (+40%; P<0.05), diastolic wall stress (preload) was increased in shunt (+277%; P<0.05) and TAC mice (+74%; P<0.05), and mean total wall stress was similarly increased in TAC (69%) and shunt mice (67%) (P=NS, TAC versus shunt; each P<0.05 versus sham). At 1 week, left ventricular weight/tibia length was significantly increased by 22% in TAC and 29% in shunt mice (P=NS, TAC versus shunt). After 24 hours and 1 week, calcium/calmodulin-dependent protein kinase II signaling was increased in TAC. This resulted in altered calcium cycling, including increased L-type calcium current, calcium transients, fractional sarcoplasmic reticulum calcium release, and calcium spark frequency. In shunt mice, Akt phosphorylation was increased. TAC was associated with inflammation, fibrosis, and cardiomyocyte apoptosis. The latter was significantly reduced in calcium/calmodulin-dependent protein kinase IIdelta-knockout TAC mice. A total of 157 mRNAs and 13 microRNAs were differentially regulated in TAC versus shunt mice. After 8 weeks, fractional shortening was lower and mortality was higher in TAC versus shunt mice., Conclusions: Afterload results in maladaptive fibrotic hypertrophy with calcium/calmodulin-dependent protein kinase II-dependent altered calcium cycling and apoptosis. Preload is associated with Akt activation without fibrosis, little apoptosis, better function, and lower mortality. This indicates that different loads result in distinct phenotype differences that may require specific pharmacological interventions.

In human hearts, the transition from cardiac hypertrophy to advanced heart failure (HF) is accompanied by a tremendous increase in Akt phosphorylation. In non-myocardial tissue, the cyclooxygenase (COX)-2 inhibitor celecoxib has been shown to COX-independently inhibit Akt signalling. We studied the effects of celecoxib on Akt signalling and hypertrophic response in myocardium. In rabbit isolated cardiac myocytes celecoxib concentration-dependently (10-100 micromol/L) inhibited the insulin-induced increase in phosphorylation of Akt and its downstream targets, GSK-3beta and p70 S6 kinase, by reducing the phosphorylation level of the upstream regulator PTEN. Inhibition of Akt signalling was accompanied by a significant suppression of characteristic features of cardiac hypertrophy: Celecoxib concentration-dependently suppressed the agonist-induced enhancement of total protein synthesis and BNP mRNA expression. In mice (C57BL/6NCrl) subjected to left ventricular (LV) pressure overload by aortic banding, celecoxib treatment (50mg x kg-1 x d-1) significantly attenuated LV dilation and contractile dysfunction compared with placebo-treated mice. Moreover, celecoxib significantly reduced mortality 8 weeks after banding. Thus, celecoxib can be used to titrate Akt signalling and hypertrophic response in myocardium. It reduces load-induced LV dilation, contractile dysfunction and mortality in vivo. This may have clinical implications for the prevention and treatment of maladaptive hypertrophy and its progression to HF in humans.

Background The aim of this retrospective study was to evaluate our experience with the surgical pericardiectomy procedure for patients suffering from isolated severe constrictive pericarditis. Methods From 1995 to 2016, 39 patients underwent isolated pericardiectomy for constrictive pericarditis. Fifteen patients were excluded because of concomitant surgery. There were 31 male (79.5%) patients and 8 female (20.5%) patients, 28 to 76 years old (mean, 56.6±13.6 years). The underlying etiologies were idiopathic pericarditis (74.5%), infection (10%), rheumatic disorders (8%), status post cardiac surgery (2.5%), tuberculosis (2.5%), and status post mediastinal irradiation (2.5%). Results Pericardiectomy was performed through midline sternotomy in all cases. Sixteen patients (41%) underwent pericardiectomy electively employing cardiopulmonary bypass with the heart beating, and 23 patients (59%) had surgery without extracorporeal circulation (ECC). The overall 30-day mortality rate was 50% if cardiopulmonary bypass was used (13.8% since 2007). If surgery was performed without a heart-lung machine, mortality was 0%. On-pump patients had a significantly longer intensive care unit (ICU) stay (12±9 vs. 4±4 days, p=0.013). Likewise, the duration of mechanical ventilation was much longer (171±246 vs. 21±40 hours, p=0.04). The hospital stay was comparable with 28±10 and 24±18 days (p=0.21). Conclusion The present study demonstrates that pericardiectomy, without the use of cardiopulmonary bypass as treatment for constrictive pericarditis, is a safe procedure with an excellent outcome in critically ill patients. [ABSTRACT FROM AUTHOR]

Aims Muscle LIM protein (MLP) null mice are often used as a model for human dilated cardiomyopathy. So far, little is known about the time course and pathomechanisms leading to the development of the adult phenotype. Methods and results We systematically analysed the contractile phenotype, myofilament calcium (Ca2+) responsiveness, passive myocardial mechanics, histology, and mRNA expression in mice aged 4 and 12 weeks. In 4-week-old animals, there was no significant difference in the force–frequency relationship (FFR) and catecholamine response of intact isolated papillary muscles between wild-type (WT) and MLP null myocardium. In 12-week-old animals, WT myocardium exhibited a significantly positive FFR, while that of MLP null mice was significantly negative, and the inotropic response to catecholamines was significantly reduced in MLP null mice. This time course of decline in contractile function was confirmed in vivo by echocardiography. Whereas at 4 weeks of age MLP null mice and WT littermates showed similar levels of SERCA2a (sarcoplasmic reticulum Ca2+ ATPase) expression, the expression was significantly lower in 12-week-old MLP null mice compared with littermate controls. Myofilament Ca2+ responsiveness was not affected by the lack of MLP, irrespective of age. Whereas in 4-week-old animals MLP null myocardium showed a trend to an increased compliance compared with the WT, myocardium of 12-week-old MLP null mice was significantly less compliant than WT myocardium. Parallel to the decrease in compliance there was an increase in fibrosis in the MLP null animals. Conclusion Our data suggest that MLP deficiency does not primarily influence myocardial contractility. A lack of MLP leads to an age-dependent impairment of excitation–contraction coupling with resulting contractile dysfunction and secondary fibrosis. [ABSTRACT FROM PUBLISHER]

Objective Enhanced late Na current (late I Na ) induces Na-dependent Ca overload as well as proarrhythmogenic events on the cellular level that include spatio-temporally uncoordinated diastolic Ca release from the sarcoplasmic reticulum (SR) and delayed afterdepolarizations (DADs). The Ca/calmodulin-dependent protein kinase II (CaMKII) gets activated upon increases in [Ca] i and mediates diastolic SR Ca leak as well as DADs. Rationale We hypothesized that increased late I Na (in disease-comparable ranges) exerts proarrhythmogenic events in isolated ventricular mouse myocytes in a manner depending on CaMKII-dependent SR Ca leak. We further tested whether inhibition of disease-related late I Na may reduce proarrhythmogenic SR Ca leak in myocytes from failing human hearts. Methods Ventricular myocytes were isolated from healthy wildtype (WT), failing CaMKIIδ C transgenic (TG) mouse, and failing human hearts. ATX-II (0.25–10 nmol/L) was used to enhance late I Na . Spontaneous Ca loss from the SR during diastole (Ca sparks), DADs, non-triggered diastolic Ca transients in myocytes and premature beats of isometrically twitching papillary muscles were used as readouts for proarrhythmogenic events. CaMKII autophosphorylation was assessed by immunoblots. Late I Na was inhibited using ranolazine (Ran, 10 μmol/L) or TTX (2 μmol/L), and CaMKII by KN-93 (1 μmol/L) or AIP (1 μmol/L). Results In WT myocytes, sub-nanomolar ATX-II exposure (0.5 nmol/L) enhanced late I Na by ~ 60%, which resulted in increased diastolic SR Ca loss despite unaltered SR Ca content. In parallel, DADs and non-triggered diastolic Ca transients arose. Inhibition of enhanced late I Na by RAN or TTX significantly attenuated diastolic SR Ca loss and suppressed DADs as well as mechanical alternans in mouse and diastolic SR Ca loss in failing human myocytes. ATX-II caused Ca-dependent CaMKII-activation without changes in protein expression, which was reversible by Ran or AIP. Conversely, CaMKII-inhibition decreased diastolic SR Ca loss, DADs and non-triggered diastolic Ca transients despite ATX-II-exposure. Finally, failing mouse myocytes with increased CaMKII activity (TG CaMKIIδ C ) showed an even aggravated diastolic SR Ca loss that was associated with an increased frequency of non-triggered diastolic Ca transients upon enhanced late I Na. Conclusions Increased late I Na (in disease-comparable ranges) induces proarrhythmogenic events during diastole in healthy and failing mouse myocytes, which are mediated via CaMKII-dependent SR Ca loss. Inhibition of late I Na not only attenuated these cellular arrhythmias in mouse myocytes but also in failing human myocytes indicating some antiarrhythmic potential for an inhibition of the elevated late I Na /CaMKII signaling pathway in this setting. [ABSTRACT FROM AUTHOR]