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Aims: The safety and effectiveness of the MitraClip device to treat functional mitral regurgitation (FMR) has been tested in previous clinical trials yielding somewhat heterogeneous results in heart failure (HF) patients. Over time, the MitraClip device system has been modified and clinical practice evolved to consider also less severely diseased HF patients with FMR for this therapeutic option. The RESHAPE‐HF2 trial aims to assess the safety and effectiveness of the MitraClip device system on top of medical therapy considered optimal in the treatment of clinically significant FMR in symptomatic patients with chronic HF. Methods: The RESHAPE‐HF2 is an investigator‐initiated, prospective, randomized, parallel‐controlled, multicentre trial designed to evaluate the use of the MitraClip device (used in the most up‐to‐date version as available at sites) plus optimal standard of care therapy (device group) compared to optimal standard of care therapy alone (control group). Eligible subjects have signs and symptoms of HF (New York Heart Association [NYHA] class II–IV despite optimal therapy), and have moderate‐to‐severe or severe FMR, as confirmed by a central echocardiography core laboratory; have an ejection fraction between ≥20% and ≤50% (initially 15–35% for NYHA class II patients, and 15–45% for NYHA class III/IV patients); have been adequately treated per applicable standards, and have received appropriate revascularization and cardiac resynchronization therapy, if eligible; had a HF hospitalization or elevated natriuretic peptides (B‐type natriuretic peptide [BNP] ≥300 pg/ml or N‐terminal proBNP ≥1000 pg/ml) in the last 90 days; and in whom isolated mitral valve surgery is not a recommended treatment option. The trial has three primary endpoints, which are these: (i) the composite rate of total (first and recurrent) HF hospitalizations and cardiovascular death during 24 months of follow‐up, (ii) the rate of total (i.e. first and recurrent) HF hospitalizations within 24 months, and (iii) the change from baseline to 12 months in the Kansas City Cardiomyopathy Questionnaire overall score. The three primary endpoints will be analysed using the Hochberg procedure to control the familywise type I error rate across the three hypotheses. Conclusions: The RESHAPE‐HF2 trial will provide sound evidence on the MitraClip device and its effects in HF patients with FMR. The recruitment was recently completed with 506 randomized patients. [ABSTRACT FROM AUTHOR]

Implantable devices form an integral part of the management of patients with heart failure (HF) and provide adjunctive therapies in addition to cornerstone drug treatment. Although the number of these devices is growing, only few are supported by robust evidence. Current devices aim to improve haemodynamics, improve reverse remodelling, or provide electrical therapy. A number of these devices have guideline recommendations and some have been shown to improve outcomes such as cardiac resynchronization therapy, implantable cardioverter‐defibrillators and long‐term mechanical support. For others, more evidence is still needed before large‐scale implementation can be strongly advised. Of note, devices and drugs can work synergistically in HF as improved disease control with devices can allow for further optimization of drug therapy. Therefore, some devices might already be considered early in the disease trajectory of HF patients, while others might only be reserved for advanced HF. As such, device therapy should be integrated into HF care programmes. Unfortunately, implementation of devices, including those with the greatest evidence, in clinical care pathways is still suboptimal. This clinical consensus document of the Heart Failure Association (HFA) and European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC) describes the physiological rationale behind device‐provided therapy and also device‐guided management, offers an overview of current implantable device options recommended by the guidelines and proposes a new integrated model of device therapy as a part of HF care. [ABSTRACT FROM AUTHOR]

Aims: The REDUCE‐LAP II trial demonstrated adverse outcomes after interatrial shunt device (IASD) placement in heart failure with preserved ejection fraction (HFpEF) attributed to latent pulmonary vascular disease (PVD). We hypothesized that exercise stress cardiovascular magnetic resonance (CMR) imaging could provide non‐invasive characterization of cardiac and pulmonary physiology for improved patient selection. Methods and results: The HFpEF‐Stress trial prospectively enrolled 75 patients with exertional dyspnoea and diastolic dysfunction. Patients underwent rest and exercise stress right heart catheterization, echocardiography and CMR imaging. Pulmonary artery and capillary wedge pressures, cardiac index (CI) and pulmonary vascular resistance (PVR) were calculated. Latent PVD was defined as increased PVR ≥ 1.74 Wood units during exercise stress. CMR assessed long‐axis strains (LAS) and filling volumes of all cardiac chambers. Right ventricular (RV) function was further quantified by stroke and peak flow volumes. Patients with latent PVD (n = 24) showed lower RV function (rest tricuspid annular plane systolic excursion, p = 0.010; stress RV LAS, p < 0.001) compared to patients without (n = 43). During exercise stress, RV stroke and peak flow volumes (p < 0.001) were reduced and led to impaired left atrial filling (p = 0.040) with a strong statistical trend to impaired ventricular (LV) filling (p = 0.098). This subsequently resulted in reduced LV‐CI (p < 0.001) despite preserved LV systolic function (LV LAS p ≥ 0.255). The degree of RV dysfunction during exercise stress best predicted latent PVD (RV peak flow, area under the curve at rest 0.73 vs. stress 0.89, p = 0.004). Conclusions: Latent PVD is a feature of HFpEF and is associated with impaired RV functional reserve, global diastolic filling and LV‐CI. This can be quantified by CMR and used to identify patients likely to benefit from IASD implantation. [ABSTRACT FROM AUTHOR]

Aims: A hallmark of heart failure with preserved ejection fraction (HFpEF) is impaired exercise capacity of varying severity. The main determinant of exercise capacity is cardiac output (CO), however little information is available about the relation between the constituents of CO – heart rate and stroke volume – and exercise capacity in HFpEF. We sought to determine if a heterogeneity in heart rate and stroke volume response to exercise exists in patients with HFpEF and describe possible clinical phenotypes associated with differences in these responses. Methods and results: Data from two prospective trials of HFpEF (n = 108) and a study of healthy participants (n = 42) with invasive haemodynamic measurements during exercise were utilized. Differences in central haemodynamic responses were analysed with regression models. Chronotropic incompetence was present in 39–56% of patients with HFpEF and 3–56% of healthy participants depending on the definition used, but some (n = 47, 44%) had an increase in heart rate similar to that of healthy controls. Patients with HFpEF had a smaller increase in their stroke volume index (SVI) (HFpEF: +4 ± 10 mL/m2, healthy participants: +24 ± 12 mL/m2, P < 0.0001), indeed, SVI fell in 28% of patients at peak exercise. Higher body mass index and lower SVI at rest were associated with smaller increases in heart rate during exercise, whereas higher resting heart rate, and angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker use were associated with a greater increase in SVI in patients with HFpEF. Conclusion: The haemodynamic response to exercise was very heterogeneous among patients with HFpEF, with chronotropic incompetence observed in up to 56%, and 28% had impaired increase in SVI. This suggests that haemodynamic exercise testing may be useful to identify which HFpEF patients may benefit from interventions targeting stroke volume and chronotropic response. [ABSTRACT FROM AUTHOR]

Endpoints of large‐scale trials in chronic heart failure have mostly been defined to evaluate treatments with regard to hospitalizations and mortality. However, patients with heart failure are also affected by very severe reductions in exercise capacity and quality of life. We aimed to evaluate the effects of heart failure treatments on these endpoints using available evidence from randomized trials. Interventions with evidence for improvements in exercise capacity include physical exercise, intravenous iron supplementation in patients with iron deficiency, and – with less certainty – testosterone in highly selected patients. Erythropoiesis‐stimulating agents have been reported to improve exercise capacity in anaemic patients with heart failure. Sinus rhythm may have some advantage when compared with atrial fibrillation, particularly in patients undergoing pulmonary vein isolation. Studies assessing treatments for heart failure co‐morbidities such as sleep‐disordered breathing, diabetes mellitus, chronic kidney disease and depression have reported improvements of exercise capacity and quality of life; however, the available data are limited and not always consistent. The available evidence for positive effects of pharmacologic interventions using angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, beta‐blockers, and mineralocorticoid receptor antagonists on exercise capacity and quality of life is limited. Studies with ivabradine and with sacubitril/valsartan suggest beneficial effects at improving quality of life; however, the evidence base is limited in particular for exercise capacity. The data for heart failure with preserved ejection fraction are even less positive, only sacubitril/valsartan and spironolactone have shown some effectiveness at improving quality of life. In conclusion, the evidence for state‐of‐the‐art heart failure treatments with regard to exercise capacity and quality of life is limited and appears not robust enough to permit recommendations for heart failure. The treatment of co‐morbidities may be important for these patient‐related outcomes. Additional studies on functional capacity and quality of life in heart failure are required. [ABSTRACT FROM AUTHOR]

The last several years have seen increasing interest in understanding cachexia, muscle wasting, and physical frailty across the broad spectrum of patients with cardiovascular illnesses. This interest originally started in the field of heart failure, but has recently been extended to other areas such as atrial fibrillation, coronary artery disease, peripheral artery disease as well as to patients after cardiac surgery or transcatheter aortic valve implantation. Tissue wasting and frailty are prevalent among many of the affected patients. The ageing process itself and concomitant cardiovascular illness decrease lean mass while fat mass is relatively preserved, making elderly patients particularly prone to develop wasting syndromes and frailty. The aim of this review is to provide an overview of the available knowledge of body wasting and physical frailty in patients with cardiovascular illness, particularly focussing on patients with heart failure in whom most of the available data have been gathered. In addition, mechanisms of wasting and possible therapeutic targets are discussed. [ABSTRACT FROM AUTHOR]

Aims: Deregulation of epigenetic processes and aberrant gene expression are important mechanisms in heart failure. Here we studied the potential relevance of m6A RNA methylation in heart failure development.Methods and Results: We analysed m6A RNA methylation via next-generation sequencing. We found that approximately one quarter of the transcripts in the healthy mouse and human heart exhibit m6A RNA methylation. During progression to heart failure we observed that changes in m6A RNA methylation exceed changes in gene expression both in mouse and human. RNAs with altered m6A RNA methylation were mainly linked to metabolic and regulatory pathways, while changes in RNA expression level mainly represented changes in structural plasticity. Mechanistically, we could link m6A RNA methylation to altered RNA translation and protein production. Interestingly, differentially methylated but not differentially expressed RNAs showed differential polysomal occupancy, indicating transcription-independent modulation of translation. Furthermore, mice with a cardiomyocyte restricted knockout of the RNA demethylase Fto exhibited an impaired cardiac function compared to control mice.Conclusions: We could show that m6A landscape is altered in heart hypertrophy and heart failure. m6A RNA methylation changes lead to changes in protein abundance, unconnected to mRNA levels. This uncovers a new transcription-independent mechanisms of translation regulation. Therefore, our data suggest that modulation of epitranscriptomic processes such as m6A methylation might be an interesting target for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Aims: Cardiac contractility modulation (CCM) improves symptoms and exercise tolerance and reduces heart failure (HF) hospitalizations over 6-month follow-up in patients with New York Heart Association (NYHA) class III or IV symptoms, QRS < 130 ms and 25% ≤ left ventricular ejection fraction (LVEF) ≤ 45% (FIX-HF-5C study). The current prospective registry study (CCM-REG) aimed to assess the longer-term impact of CCM on hospitalizations and mortality in real-world experience in this same population.Methods and Results: A total of 140 patients with 25% ≤ LVEF ≤ 45% receiving CCM therapy (CCM-REG25-45 ) for clinical indications were included. Cardiovascular and HF hospitalizations, Minnesota Living with Heart Failure Questionnaire (MLHFQ) and NYHA class were assessed over 2 years. Mortality was tracked through 3 years and compared with predictions by the Seattle Heart Failure Model (SHFM). A separate analysis was performed on patients with 35% ≤ LVEF ≤ 45% (CCM-REG35-45 ) and 25% ≤ LVEF < 35% (CCM-REG25-34 ). Hospitalizations decreased by 75% (from 1.2/patient-year the year before, to 0.35/patient-year during the 2 years following CCM, P < 0.0001) in CCM-REG25-45 and by a similar amount in CCM-REG35-45 (P < 0.0001) and CCM-REG25-34 . MLHFQ and NYHA class improved in all three cohorts, with progressive improvements over time (P < 0.002). Three-year survival in CCM-REG25-45 (82.8%) and CCM-REG24-34 (79.4%) were similar to those predicted by SHFM (76.7%, P = 0.16; 78.0%, P = 0.81, respectively) and was better than predicted in CCM-REG35-45 (88.0% vs. 74.7%, P = 0.046).Conclusion: In real-world experience, CCM produces results similar to those of previous studies in subjects with 25% ≤ LVEF ≤ 45% and QRS < 130 ms; cardiovascular and HF hospitalizations are reduced and MLHFQ and NYHA class are improved. Overall mortality was comparable to that predicted by the SHFM but was lower than predicted in patients with 35% ≤ LVEF ≤ 45%. [ABSTRACT FROM AUTHOR]

Aims: Empagliflozin, a clinically used oral antidiabetic drug that inhibits the sodium-dependent glucose co-transporter 2, has recently been evaluated for its cardiovascular safety. Surprisingly, empagliflozin reduced mortality and hospitalization for heart failure (HF) compared to placebo. However, the underlying mechanisms remain unclear. Therefore, our study aims to investigate whether empagliflozin may cause direct pleiotropic effects on the myocardium.Methods and Results: In order to assess possible direct myocardial effects of empagliflozin, we performed contractility experiments with in toto-isolated human systolic end-stage HF ventricular trabeculae. Empagliflozin significantly reduced diastolic tension, whereas systolic force was not changed. These results were confirmed in murine myocardium from diabetic and non-diabetic mice, suggesting independent effects from diabetic conditions. In human HF cardiomyocytes, empagliflozin did not influence calcium transient amplitude or diastolic calcium level. The mechanisms underlying the improved diastolic function were further elucidated by studying myocardial fibres from patients and rats with diastolic HF (HF with preserved ejection fraction, HFpEF). Empagliflozin beneficially reduced myofilament passive stiffness by enhancing phosphorylation levels of myofilament regulatory proteins. Intravenous injection of empagliflozin in anaesthetized HFpEF rats significantly improved diastolic function measured by echocardiography, while systolic contractility was unaffected.Conclusion: Empagliflozin causes direct pleiotropic effects on the myocardium by improving diastolic stiffness and hence diastolic function. These effects were independent of diabetic conditions. Since pharmacological therapy of diastolic dysfunction and HF is an unmet need, our results provide a rationale for new translational studies and might also contribute to the understanding of the EMPA-REG OUTCOME trial. [ABSTRACT FROM AUTHOR]

Background: Disruption of Ca2+ homeostasis is a key pathomechanism in heart failure. CaMKII-dependent hyperphosphorylation of ryanodine receptors in the sarcoplasmic reticulum (SR) increases the arrhythmogenic SR Ca2+ leak and depletes SR Ca2+ stores. The contribution of conversely acting serine/threonine phosphatases [protein phosphatase 1 (PP1) and 2A (PP2A)] is largely unknown.Methods and Results: Human myocardium from three groups of patients was investigated: (i) healthy controls (non-failing, NF, n = 8), (ii) compensated hypertrophy (Hy, n = 16), and (iii) end-stage heart failure (HF, n = 52). Expression of PP1 was unchanged in Hy but greater in HF compared to NF while its endogenous inhibitor-1 (I-1) was markedly lower expressed in both compared to NF, suggesting increased total PP1 activity. In contrast, PP2A expression was lower in Hy and HF compared to NF. Ca2+ homeostasis was severely disturbed in HF compared to Hy signified by a higher SR Ca2+ leak, lower systolic Ca2+ transients as well as a decreased SR Ca2+ load. Inhibition of PP1/PP2A by okadaic acid increased SR Ca2+ load and systolic Ca2+ transients but severely aggravated diastolic SR Ca2+ leak and cellular arrhythmias in Hy. Conversely, selective activation of PP1 by a PP1-disrupting peptide (PDP3) in HF potently reduced SR Ca2+ leak as well as cellular arrhythmias and, importantly, did not compromise systolic Ca2+ release and SR Ca2+ load.Conclusion: This study is the first to functionally investigate the role of PP1/PP2A for Ca2+ homeostasis in diseased human myocardium. Our data indicate that a modulation of phosphatase activity potently impacts Ca2+ cycling properties. An activation of PP1 counteracts increased kinase activity in heart failure and successfully seals the arrhythmogenic SR Ca2+ leak. It may thus represent a promising future antiarrhythmic therapeutic approach. [ABSTRACT FROM AUTHOR]

Aims: Changes in heart failure (HF) patients' body composition may be associated with reduced exercise capacity. The aim of the present study was to determine the overlap in wasting syndromes in HF (cachexia and sarcopenia) and to compare their functional impact.Methods and Results: We prospectively enrolled 207 ambulatory male patients with clinically stable chronic HF. All patients underwent a standardized protocol examining functional capacity, body composition, and quality of life (QoL). Cachexia was present in 39 (18.8%) of 207 patients, 14 of whom also fulfilled the characteristics of sarcopenia (sarcopenia + cachexia group, 6.7%), whereas 25 did not (cachectic HF group, 12.1%). Sarcopenia without cachexia was present in 30 patients (sarcopenic HF group, 14.4%). A total of 44 patients (21.3%) presented with sarcopenia; however, 138 patients showed no signs of wasting (no wasting group, 66%). Patients with sarcopenia had lower strength and exercise capacity than both the no wasting and the cachectic HF group. Handgrip strength, quadriceps strength, peak oxygen uptake (VO2 ), distance in the 6-minute walk test (6MWT), and QoL results were lowest in the sarcopenia + cachexia group vs. the no wasting group (P < 0.05 for all). Likewise, the sarcopenic HF group showed lower handgrip strength, quadriceps strength, 6MWT, peak VO2 , and QoL results vs. the no wasting group (P < 0.05 for all).Conclusion: Losing muscle with or without weight loss appears to have a more pronounced role than weight loss alone with regard to functional capacity and QoL among male patients with chronic HF.Clinical Trial Registration: ClinicalTrials.gov Identifier NCT01872299. [ABSTRACT FROM AUTHOR]

Background: Myocardial fibrosis is characterized by excessive cross-linking and deposition of collagen type I and is involved in left ventricular stiffening and left ventricular diastolic dysfunction (LVDD). We investigated whether the effect of spironolactone on LVDD in patients with heart failure with preserved ejection fraction (HFpEF) depends on its effects on collagen cross-linking and/or deposition.Methods and Results: We investigated 381 HFpEF patients from the multicentre, randomized, placebo-controlled Aldo-DHF trial with measures of the E:e' ratio. The ratio of serum carboxy-terminal telopeptide of collagen type I to serum matrix metalloproteinase-1 (CITP:MMP-1, an inverse index of myocardial collagen cross-linking) and serum carboxy-terminal propeptide of procollagen type I (PICP, a direct index of myocardial collagen deposition) were determined at baseline and after 1-year treatment with spironolactone 25 mg once daily or placebo. Patients were classified by CITP:MMP-1 and PICP tertiles at baseline. While CITP:MMP-1 tertiles at baseline interacted (P < 0.05) with spironolactone effect on E:e', PICP tertiles did not. In fact, while spironolactone treatment did not modify E:e' in patients with lower CITP:MMP-1 levels, this ratio was significantly reduced in the remaining spironolactone-treated patients. In addition, PICP was unchanged in patients with lower CITP:MMP-1 levels but was reduced in the remaining spironolactone-treated patients.Conclusions: A biochemical phenotype of high collagen cross-linking identifies HFpEF patients resistant to the beneficial effects of spironolactone on LVDD. It is suggested that excessive collagen cross-linking, which stabilizes collagen type I fibres, diminishes the ability of spironolactone to reduce collagen deposition in these patients. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction ( HFpEF) is a common disease with high incidence and increasing prevalence. Patients suffer from functional limitation, poor health-related quality of life, and reduced prognosis. A pilot study in a smaller group of HFpEF patients showed that structured, supervised exercise training ( ET) improves maximal exercise capacity, diastolic function, and physical quality of life. However, the long-term effects of ET on patient-related outcomes remain unclear in HFpEF. The primary objective of the Exercise training in Diastolic Heart Failure (Ex-DHF) trial is to investigate whether a 12 month supervised ET can improve a clinically meaningful composite outcome score in HFpEF patients. Components of the outcome score are all-cause mortality, hospitalizations, NYHA functional class, global self-rated health, maximal exercise capacity, and diastolic function. After undergoing baseline assessments to determine whether ET can be performed safely, 320 patients at 11 trial sites with stable HFpEF are randomized 1:1 to supervised ET in addition to usual care or to usual care alone. Patients randomized to ET perform supervised endurance/resistance ET (3 times/week at a certified training centre) for 12 months. At baseline and during follow-up, anthropometry, echocardiography, cardiopulmonary exercise testing, and health-related quality of life evaluation are performed. Blood samples are collected to examine various biomarkers. Overall physical activity, training sessions, and adherence are monitored and documented throughout the study using patient diaries, heart rate monitors, and accelerometers. The Ex- DHF trial is the first multicentre trial to assess the long-term effects of a supervised ET programme on different outcome measures in patients with HFpEF. [ABSTRACT FROM AUTHOR]

Aim: We have previously reported that early phase (1 week) of experimental volume overload (VO) has an adaptive phenotype while wall stress-matched pressure overload (PO) is maladaptive. Here we investigate the transition from adaptation to heart failure (HF) in long-term VO.Methods and Results: FVB/N wild-type mice were subjected to VO induced by aortocaval shunt, and were followed by serial echocardiography until in vivo left ventricular ejection fraction was below <50% (135 ± 35 days). Heart failure was evident from increased lung and liver weight and increased mortality compared with sham. Maladaptive remodelling resulted in significantly reduced sarcomeric titin phosphorylation (causing increased sarcomeric stiffness), whereas interstitial fibrosis was not increased. This was paralleled by re-expression of the fetal gene program, activation of calcium/calmodulin-dependent protein kinase II (CaMKII), decreased protein kinase B (Akt) phosphorylation, high oxidative stress, and increased apoptosis. Consistently, development of HF and mortality were significantly aggravated in Akt-deficient mice.Conclusion: Transition to HF in VO is associated with decreased Akt and increased CaMKII signalling pathways together with increased oxidative stress and apoptosis. Lack of interstitial fibrosis together with sarcomeric titin hypophosphorylation indicates an increased stiffness at the sarcomeric but not matrix level in VO-induced HF (in contrast to PO). Transition to HF may result from myocyte loss and myocyte dysfunction owing to increased stiffness. [ABSTRACT FROM AUTHOR]

Aims Galectin-3 is a marker of myocardial fibrosis and mediates aldosterone-induced cardiovascular inflammation and fibrosis. Characteristics of galectin-3 and its response to spironolactone have not been evaluated in heart failure with preserved ejection fraction ( HFpEF). The aim of this study was to determine the association between galectin-3 levels and patient characteristics in HFpEF; to evaluate the interaction between spironolactone and galectin-3 levels; and to assess the association between galectin-3 and clinical outcomes. Methods and results Aldo- DHF investigated spironolactone 25 mg once daily vs. placebo for 12 months in patients with NYHA class II-III, LVEF ≥50%, grade ≥ I diastolic dysfunction, and peakVO2 ≤ 25 mL/kg/min. Galectin-3 levels were obtained at baseline, and at 6 and 12 months. The association between baseline galectin-3, change in galectin-3, and all-cause death or hospitalization was evaluated, and the interaction between galectin-3 and treatment was assessed. Median baseline galectin-3 was 12.1 ng/ mL. After multivariable adjustment, baseline galectin-3 inversely correlated with peak VO2 ( P = 0.021), 6 min walk distance ( P = 0.002), and Short Form 36 ( SF-36) physical functioning ( P = 0.001), and directly correlated with NYHA class ( P = 0.007). Baseline NT-proBNP correlated with E/e' velocity ratio ( P ≤ 0.001), left atrial volume index ( P < 0.001), and LV mass index ( P = 0.009). Increasing galectin-3 at 6 or 12 months was associated with all-cause death or hospitalization independent of treatment arm [hazard ratio ( HR) 3.319, 95% confidence interval ( CI) 1.214-9.07, P = 0.019] and NT-proBNP ( HR 3.127, 95% CI 1.144-8.549, P = 0.026). Spironolactone did not influence galectin-3 levels. Conclusion Galectin-3 levels are modestly elevated in patients with stable HFpEF and relate to functional performance and quality of life. Increasing galectin-3 was associated with worse outcome, independent of treatment or NT-proBNP. [ABSTRACT FROM AUTHOR]

Aims: Galectin-3 is a marker of myocardial fibrosis and mediates aldosterone-induced cardiovascular inflammation and fibrosis. Characteristics of galectin-3 and its response to spironolactone have not been evaluated in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to determine the association between galectin-3 levels and patient characteristics in HFpEF; to evaluate the interaction between spironolactone and galectin-3 levels; and to assess the association between galectin-3 and clinical outcomes.Methods and Results: Aldo-DHF investigated spironolactone 25 mg once daily vs. placebo for 12 months in patients with NYHA class II-III, LVEF ≥50%, grade ≥ I diastolic dysfunction, and peakVO2  ≤ 25 mL/kg/min. Galectin-3 levels were obtained at baseline, and at 6 and 12 months. The association between baseline galectin-3, change in galectin-3, and all-cause death or hospitalization was evaluated, and the interaction between galectin-3 and treatment was assessed. Median baseline galectin-3 was 12.1 ng/mL. After multivariable adjustment, baseline galectin-3 inversely correlated with peak VO2 (P = 0.021), 6 min walk distance (P = 0.002), and Short Form 36 (SF-36) physical functioning (P = 0.001), and directly correlated with NYHA class (P = 0.007). Baseline NT-proBNP correlated with E/e' velocity ratio (P ≤ 0.001), left atrial volume index (P < 0.001), and LV mass index (P = 0.009). Increasing galectin-3 at 6 or 12 months was associated with all-cause death or hospitalization independent of treatment arm [hazard ratio (HR) 3.319, 95% confidence interval (CI) 1.214-9.07, P = 0.019] and NT-proBNP (HR 3.127, 95% CI 1.144-8.549, P = 0.026). Spironolactone did not influence galectin-3 levels.Conclusion: Galectin-3 levels are modestly elevated in patients with stable HFpEF and relate to functional performance and quality of life. Increasing galectin-3 was associated with worse outcome, independent of treatment or NT-proBNP. [ABSTRACT FROM AUTHOR]

Aims The sarcoplasmic reticulum ( SR) Ca2+ leak is an important pathomechanism in heart failure ( HF). It has been suggested that Ca2+/calmodulin-dependent protein kinase II ( CaMKII) is only relevant for the induction of the SR Ca2+ leak in non-ischaemic but not in ischaemic HF. Therefore, we investigated CaMKII and its targets as well as the functional effects of CaMKII inhibition in human ischaemic cardiomyopathy ( ICM, n = 37) and dilated cardiomyopathy ( DCM, n = 40). Methods and results Western blots showed a significantly increased expression (by 54 ± 9%) and autophosphorylation at Thr286 (by 129 ± 29%, P < 0.05 each) of CaMKII in HF compared with healthy myocardium. However, no significant difference could be detected in ICM compared with DCM as to the expression and autophosphorylation of CaMKII nor the phosphorylation of the target sites ryanodine receptor 2 ( RyR2)- S2809, RyR2-S2815, and phospholamban-Thr17. Isolated human cardiomyocytes ( CMs) of patients with DCM and ICM showed a similar frequency of diastolic Ca2+ sparks (confocal microscopy) as well as of major arrhythmic events (Ca2+ waves, spontaneous Ca2+ transients). Despite a slightly smaller size of Ca2+ sparks in DCM ( P < 0.01), the calculated SR Ca2+ leak [Ca2+ spark frequecy ( CaSpF) × amplitude × width × duration] did not differ between CMs of ICM vs. DCM. Importantly, CaMKII inhibition by autocamide-2-related inhibitory peptide ( AIP, 1 µmol/L) reduced the SR Ca2+ leak by ∼80% in both aetiologies ( P < 0.05 each) and effectively decreased the ratio of arrhythmic cells ( P < 0.05). Conclusion Functional and molecular measures of the SR Ca2+ leak are comparable in human ICM and DCM. CaMKII is equally responsible for the induction of the ' RyR2 leakiness' in both pathologies. Thus, CaMKII inhibition as a therapeutic measure may not be restricted to patients suffering from DCM but rather may be beneficial for the majority of HF 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]

Aims Mitral valve regurgitation plays a significant role in the aetiology and course of heart failure. We investigated the impact of the learning curve on outcomes after percutaneous mitral valve repair with MitraClip. Methods and results Outcomes of the first 75 consecutive patients treated with MitraClip at our centre were stratified by subsequent treatment periods (25 patients each). Median total procedure time and device time decreased from 180 and 105 min in period 1 to 95 and 55 min in period 3 (P < 0.005 each). There was an excess of total safety events in period 1 (n = 16) that decreased in periods 2 and 3 (n = 6 and 3, P = 0.0003). Acute procedural success [APS; clip successfully placed and mitral regurgitation (MR) grade ≤2+ at discharge] was 80% in periods 1 and 2, but 92% in period 3 (P = 0.46). At 6 months, improvement in durability and completeness of mitral valve repair was evident: 89.4% of patients in period 3 and 65.0% in period 1 had MR ≤2+ at 6 months (P = 0.03). Within 30 days, no patient sustained myocardial infarction or stroke, and mortality was 2.7% for all patients without significant differences regarding periods. Furthermore, while treatment period did not affect mid-term survival and hospitalization for heart failure, failure of APS, STS (Society of Thoracic Surgeons) score ≥15%, and overt right heart failure at baseline predicted increased mortality. Conclusion MitraClip showed a learning curve regarding mid-term durability and completeness of mitral valve repair, and APS predicted mortality. Recently published studies should be interpreted in consideration of these findings. [ABSTRACT FROM AUTHOR]

Aims Heart failure with normal ejection fraction (HFnEF) is an important clinical entity that remains incompletely understood. The novel biomarker growth differentiation factor 15 (GDF-15) is elevated in systolic heart failure (HFrEF) and is predictive of an adverse outcome. We investigated the clinical relevance of GDF-15 plasma levels in HFnEF. Methods and results A subgroup of patients from the ongoing DIAST-CHF observational trial, with a history of chronic heart failure (CHF) or positive Framingham criteria at presentation, was selected. Patients were classified as having either HFrEF (n = 86) or HFnEF (n = 142) and compared with healthy elderly controls (n = 188) from the same cohort. Growth differentiation factor 15 levels in HFnEF were significantly higher than in controls and similar to those in HFrEF. In multivariate analysis, factors significantly associated with GDF-15 levels were age, sex, estimated glomerular filtration rate (eGFR), presence of HFrEF and HFnEF. Growth differentiation factor 15 correlated with multiple echocardiographic markers of diastolic function and was associated with 6 min walk test performance and SF-36 physical score on multivariate analysis in all patients. When using a classification for HFnEF that did not employ N-terminal pro brain natriuretic peptide (NT-proBNP) as a diagnostic criterion, the diagnostic properties of GDF-15 for detecting HFnEF tended to be superior to those of NT-proBNP, and a combination significantly improved diagnostic accuracy. Conclusion Growth differentiation factor 15 is elevated in HFnEF to a similar degree as in HFrEF. It is independently associated with impairment in exercise capacity and in physical components of quality of life. Diagnostic precision of GDF-15 is at least as good as that of NT-proBNP and combining both markers improves diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Aims: Increasing evidence suggests that enhanced aldosterone signalling plays a key role in the onset and progression of diastolic heart failure (DHF). Aldo-DHF will test the hypothesis that aldosterone receptor blockade by spironolactone will improve exercise capacity and diastolic function in patients with DHF. Methods: Aldo-DHF is a randomized, placebo-controlled, double-blinded, two-armed, multicentre, parallel group study. Four hundred and twenty patients with DHF will be randomly assigned to receive spironolactone 25 mg per day or placebo. The main inclusion criteria are: age > or = 50 years, New York Heart Association II/III, preserved left ventricular ejection fraction (> or =50%), and echocardiographic evidence of diastolic dysfunction. The two primary endpoints are changes in exercise capacity (peak VO(2), spiroergometry) and in diastolic function (E/é, echocardiography) after 12 months. Secondary endpoints include effects of spironolactone on additional parameters of exercise performance and diastolic as well as systolic function, neurohumoral activation, and quality of life. Morbidity and mortality as well as safety aspects will also be assessed. Conclusion: Aldo-DHF is the first large-scale clinical trial to evaluate the effects of aldosterone receptor blockade on exercise capacity and diastolic function in patients with DHF. Aldo-DHF will provide important information about the clinical course of this condition and may have significant impact on treatment strategies and future trials in these patients. [ABSTRACT FROM AUTHOR]

Aims: Increasing evidence suggests that enhanced aldosterone signalling plays a key role in the onset and progression of diastolic heart failure (DHF). Aldo-DHF will test the hypothesis that aldosterone receptor blockade by spironolactone will improve exercise capacity and diastolic function in patients with DHF. [ABSTRACT FROM PUBLISHER]

Aims: The combined therapeutic impact of atrial overdrive pacing (AOP) and cardiac resynchronization therapy (CRT) on central sleep apnoea (CSA) in chronic heart failure (CHF) so far has not been investigated. We aimed to evaluate the effect of CRT alone and CRT + AOP on CSA in CHF patients and to compare the influence of CRT on CHF between CSA positive and CSA negative patients. [ABSTRACT FROM PUBLISHER]

Abstract: Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. Indirect evidence from clinical trials demonstrates that chronic inhibition of the renin–angiotensin-system (RAS) significantly reduces the incidence of AF. Since mechanisms of this protective effect of RAS-blockade are poorly understood, we directly tested proarrhythmic effects of angiotensin II (Ang II) in human atrial myocardium. Methods: Isolated trabeculae from human atrial appendages (n =80) were electrically stimulated. We assessed isometric force and incidence of arrhythmic extra contractions (AECs) with and without increasing concentrations of Ang II (1–1000 nmol/L) in the absence or presence of receptor-blockade by saralasin (non-specific ATR-antagonist), irbesartan (AT1R-antagonist) or PD123319 (AT2R-antagonist). Results: Twitch force and AECs concentration-dependently increased with Ang II. Effects became significant at concentrations >1 nmol/L Ang II and were maximal at 1000 nmol/L (increase in twitch force to 157±14% and AECs from 0 to 80%) saralasin and irbesartan partially prevented the inotropic effect of 100 nmol/L Ang II (by 45±12% and 68±6%; p <0.05), and completely prevented the occurrence of AECs. Conclusion: Ang II exerts direct pro-arrhythmic effects in human atrial myocardium. These effects are mediated by AT1-receptors and can be prevented by AT1R-blockade. This mechanism may contribute to the beneficial effects of RAS-blockade on AF in clinical trials. [Copyright &y& Elsevier]

Abstract: 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 μmol/L) inhibited the insulin-induced increase in phosphorylation of Akt and its downstream targets, GSK-3β 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 (50 mg∙kg−1∙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. [Copyright &y& Elsevier]

Background and Aim: The clinical use of doxorubicin (DOX) and other anthracyclines is limited by a dosage-dependent cardiotoxicity, which can lead to cardiomyopathy. The role of the individual genetic makeup in this disorder is poorly understood. Alterations in genes encoding cardiac cytoskeleton or sarcolemma proteins may increase the susceptibility to doxorubicin-related cardiotoxicity. Methods: Female dystrophin-deficient mice (MDX) and age-matched wild-type mice underwent chronic treatment with doxorubicin. Cardiac function and tissue damage were assessed by echocardiography and histopathology, respectively. Gene expression changes were investigated using microarrays. Results: DOX treatment resulted in mortality, cardiac insufficiency, and cardiac interstitial fibrosis. These alterations were more pronounced in DOX-treated MDX mice than in DOX-treated wild-type mice. Changes in gene expression were more numerous in MDX mice, including genes involved in cell adhesion, oxidative stress, cytoskeleton organization, inflammatory and immune response and cell death. Conclusions: Dystrophin deficiency facilitates the development and progression of doxorubicin-induced cardiac injury. The underlying mechanisms may involve changes in cell adhesion, in cytoskeleton, as well as in inflammatory and immune responses. Genetic variants of cytoskeletal proteins in humans may affect the individual susceptibility to doxorubicin. Cardiotoxic drugs may accelerate the manifestation of pre-clinical cardiomyopathies caused by deficiencies in cytoskeletal or sarcolemma proteins. [ABSTRACT FROM AUTHOR]

Abstract: α1-adrenergic stimulation and mechanical load are considered crucial for the expression of sarcolemmal Na+/Ca2+ exchanger (NCX1). However, the interaction between these processes is unknown. We investigated electrically stimulated (1 Hz, 1.75 mmol/L Ca2+) rabbit ventricular trabeculae at physiological preload under stimulation by the selective α1-agonist phenylephrine (PE, 10 μmol/L). Using quantitative real-time PCR, downregulation of mRNA to 76.5% (p <0.05) was found, while B-type natriuretic peptide (BNP) was increased to 569.5% (p <0.05) compared to control. These changes were abolished in the presence of both the α1-blocker prazosin (13 μmol/L) and the PKC inhibitor GF109203X (1 μmol/L). Furthermore, no changes in NCX mRNA levels under the influence of PE were found in unstretched trabeculae or in unstretched isolated rabbit myocytes (24 h), while BNP was increased in both preparations. In addition, since the α1-adrenergic effect could be Ca2+-dependent we tested increased extracellular Ca2+ (3.0 mmol/L) in stretched trabeculae and found downregulation of NCX1 to 75.2% (p <0.05). α1-stimulation decreases NCX1 mRNA in rabbit myocardium via PKC. This is critically load-dependent and may be mediated by changes in [Ca2+]. In hypertrophy and heart failure, distinct phenotypes with respect to NCX1 expression may result from the interaction between mechanical load and α1-adrenergic stimulation. [Copyright &y& Elsevier]

Abstract: We investigated the hypothesis that increased intracellular [Na+]i in heart failure contributes to preservation of SR Ca2+ load which may become particularly evident at slow heart rates. [Na+]i in SBFI-loaded myocytes from rabbits with pacing-induced heart failure (PHF) was significantly higher at each frequency as compared to Sham-operated animals. Furthermore, PHF rabbits demonstrated reduced SR Ca2+-ATPase protein levels (−37%, p <0.04) but unchanged Na+/Ca2+ exchanger protein levels. At 0.25 Hz, isometric force was similar in cardiac trabeculae from PHF rabbits as compared to control (PHF, 3.6±1.3; Sham, 4.4±0.6 mN/mm2). Rapid cooling contractures (RCCs) were unchanged indicating preserved SR Ca2+ load at this frequency. In Sham, isometric twitch force increased with rising frequencies to 29.0±2.8 mN/mm2 at 3.0Hz (p <0.05) as compared to 0.25 Hz. RCCs showed a parallel increase by 186±47% (p <0.01). In PHF, frequency-dependent increase in force (15.8±4.7 mN/mm2 at 3.0 Hz) and RCCs (increase by 70±40%) were significantly blunted. Thus, in PHF in rabbits SR Ca2+ load is preserved at low frequencies despite decreased SR Ca2+-ATPase expression. This may result from [Na+]i-dependent changes in Na+/Ca2+ exchanger activity. [Copyright &y& Elsevier]

Background: Pyruvate increases myocardial performance in isolated myocardium and improves hemodynamics in patients with congestive heart failure. Aims: To investigate the influence of pyruvate on detailed parameters of systolic and diastolic left ventricular (LV) function. Methods and Results: In patients with heart failure due to dilated cardiomyopathy (LVEF 30±4%, n=9) pyruvate was infused intracoronarily. LV function was analysed before, during and after application of different pyruvate concentrations using a LV-micromanometer catheter. LV volumes were determined using cine ventriculography. Pyruvate increased maximum rate of LV isovolumic pressure rise (Peak +dP/dt) from 802±106 to 1125±103 mmHg/s (P<0.05). Left ventricular end-diastolic pressure declined in parallel from 17±2 to 12±2 mmHg (P<0.05) and heart rate decreased from 79±4 to 72±5 min−1 (P<0.05). Stroke volume index increased from 34±4 to 43±6 ml/m2 (P<0.05), end-diastolic LV volume remained unchanged, thus left ventricular ejection fraction increased with pyruvate from 30±4 to 39±4% (P<0.05). Maximum rate of LV isovolumic pressure decline (Peak −dP/dt) was significantly increased with pyruvate (from 794±94 to 980±108 mmHg/s; P<0.05) and mean arterial pressure increased from 80±5 to 88±4 mmHg (P<0.05). Discontinuation of pyruvate resulted in immediate reversibility of its effects. Conclusion: Intracoronary pyruvate improves systolic and diastolic myocardial function and increases ejection fraction without increasing heart rate. Pyruvate thus exhibits the profile of a favourable inotropic agent, however, further investigation for the treatment of patients with acute heart failure is mandatory. [Copyright &y& Elsevier]