Reverse Cardiac Remodeling Research Articles

P589Assessment of cardiac reverse remodelling following mitral valve repair and mitral valve replacement in degenerative mitral regurgitation: a cardiovascular magnetic resonance study

Abstract Background Mitral valve (MV) repair is currently recommended over replacement (1). The guidelines suggesting this are however based on historic evidence which compared outdated techniques of MV replacement. Recent data cast doubts on its validity in the current era of chordal-preservation techniques in MV replacement. Purpose Using cardiovascular magnetic resonance (CMR) imaging, this study aimed to assess the impact of MV repair and MV replacement on cardiac left ventricular (LV) reverse remodelling. Methods 65 patients with moderate-severe and severe mitral regurgitation (MR) were prospectively recruited. Of these, 37 patients (59% men, 65±15 years) to date with paired CMR scans at baseline and at 6 months were evaluated. Patients either underwent MV repair (n=9), MV replacement (n=10) or watchful waiting (n=18). The CMR protocol included cines for left ventricle (LV), left atria (LA), and aortic flow assessment. The LA and LV parameters, and MR fraction were analysed. Results At 6 months, both the MV repair and replacement groups exhibited a reduction in LV end-diastolic volume (LVEDV) and LA volumes when compared to the control group. The indexed LVEDV decreased significantly from 129±33ml/m2 to 99±37ml/m2, p<0.001 in the repair group, from 118±24ml/m2 to 90±26ml/m2, p<0.001 in the replacement group and remained unchanged in the control group 115±25ml/m2 to 113±25ml/m2, p=0.53. The absolute reduction in indexed LVEDV was not significantly different between the repair and replacement groups (−30±15ml/m2 vs −29±19ml/m2, repair vs replacement, p=1.00). Similarly, both surgical groups also sustained an equal degree of LA size reduction (−42±26ml/m2 vs −36±23ml/m2, repair vs replacement; p=1.00). There was a decline in the global postoperative LV ejection fraction (Table 1). The degree of reduction in LV ejection fraction however did not differ between the repair and replacement group (−9±6% vs −6±8%, repair vs replacement; p=1.00). Those undergoing surgery experienced a significant reduction in their MR severity, although those with replacement had a more effective reduction in MR severity (MR fraction for repair: 47±9% to 15±10%, p<0.001 vs replacement: 41±13% to 5±4%, p<0.001). Conclusion MV surgery leads to atrial and left ventricular reverse remodelling, and a decline in global LV ejection fraction. In this small series, MV replacement with chordal preservation showed similar cardiac reverse remodelling benefits to MV repair. Although residual MR is often seen following repair, this did not lead to less favourable cardiac reverse remodelling. Acknowledgement/Funding Leeds NIHR infrastructure

P5579Pre-existing depression significantly improves after transcatheter aortic valve implantation (TAVI): analysis of long-term effects and screening for novel biomarkers

Abstract Background and aims Depression negatively affects symptom tolerance as well as clinical endpoints in cardiovascular diseases. For aortic stenosis (AS) patients undergoing Transcatheter Aortic Valve Implantation (TAVI), a reduction of pre-existing depression and anxiety in short term follow-up could be recently shown by our group. The current study was aimed to evaluate these effects in long-term follow-up and to screen for promising biomarkers, e.g., 5-Hydroxytryptamin (5-HT), Endothelin-1 (ET-1), neutrophil gelatinase associated lipocalin (NGAL) and Tenascin-C (Tn-C) variants. These molecules might reflect a pathophysiological link between reverse cardiac remodelling and mental state. Methods The study included 182 out of 226 patients who underwent TAVI at the University Hospital Jena since August 2016. Besides clinical parameters, the EuroQol questionnaire (EQ-5D), the Visual Analog Scale (VAS), the Clinical Frailty Scale (CFS) and, to specifically detect depression and anxiety, the Hospital Anxiety and Depression Scale (HADS-D) were assessed directly before TAVI, at 6-weeks, 6-month as well as 12- months follow-up. Blood samples were withdrawn before TAVI and during 6-weeks and 6-month follow-up. Results Study patients represented a typical moderate- to high-risk TAVI collective (n=182, mean age 78,1±7.9 years, 46,9% male, mean STS-Score 4.6±2,8). Before TAVI, analysis of HADS revealed ≥8 points, defined as pathologic, for depression and/or anxiety in 71 patients (39%) and for depression only in 46 patients (25.3%). In the depressive subgroup, there was a significant improvement after 6 weeks for depression (p<0.001) and anxiety (p=0.006). BNP serum levels were significantly reduced (p=0.007) and 6-minutes' walk distance was significantly increased from a low level (p=0.008), VAS, CFS and 2 out of 5 parameters of the EQ-5D were significantly improved (p<0.05). All observed short-term effects continued at stable levels over time. A pre-existing depression state was not associated with an increased long-term mortality rate, which was 14.8%. Circulating biomarker levels in depressive patients before and 6 weeks after TAVI revealed no significant differences. At the 6 months follow-up, only for C+ Tn-C there was a significant increase compared to both, the timepoint before TAVI (p=0.046) and the 6 weeks follow-up (p=0.033). Conclusions Already in short-term follow-up after successful TAVI, a remarkable decrease in depression could be detected using HADS. Especially in the depressive subgroup, the patients showed benefit also with respect to other surrogate parameters of mental health and functional performance. Interestingly, these effects were completely maintained not only in mid-term but also in long-term follow-up. We could show that the improvement of depression after TAVI is reflected by a delayed decrease of C+ Tn-C serum levels. C+ Tn-C can be suggested as promising biomarker possibly linked to reactive depression in somatic diseases.

Rationale and design of the IRON-CRT trial: effect of intravenous ferric carboxymaltose on reverse remodelling following cardiac resynchronization therapy.

AimsIron deficiency is common in heart failure with reduced ejection fraction (HFrEF). In patients with cardiac resynchronization therapy (CRT), it is associated with a diminished reverse remodelling response and poor functional improvement. The latter is partially related to a loss in contractile force at higher heart rates (negative force–frequency relationship).Methods and resultsThe effect of intravenous ferric carboxymaltose on reverse remodelling following cardiac resynchronization therapy (IRON‐CRT) trial is a multicentre, prospective, randomized, double‐blind controlled trial in HFrEF patients who experienced incomplete reverse remodelling (defined as a left ventricular ejection fraction below <45%) at least 6 months after CRT. Additionally, patients need to have iron deficiency defined as a ferritin below 100 μg/L irrespective of transferrin saturation or a ferritin between 100 and 300 μg/L with a transferrin saturation <20%. Patients will be randomized to either intravenous ferric carboxymaltose (dose based according to Summary of Product Characteristics) or intravenous placebo. The primary objective is to evaluate the effect of ferric carboxymaltose on metrics of cardiac reverse remodelling and contractility, measured by the primary endpoint, change in left ventricular ejection fraction assessed by three‐dimensional (3D) echo from baseline to 3 month follow‐up and the secondary endpoints change in left ventricular end‐systolic and end‐diastolic volume. The secondary objective is to determine if ferric carboxymaltose is capable of improving cardiac contractility in vivo, by assessing the force–frequency relationship through incremental biventricular pacing. A total of 100 patients will be randomized in a 1:1 fashion.ConclusionsThe IRON‐CRT trial will determine the effect of ferric carboxymaltose on cardiac reverse remodelling and rate‐dependent cardiac contractility in HFrEF patients.

TCT-79 Multimodality Assessment of Prosthetic Valve Regurgitation to Predict Reverse Cardiac Remodeling and Long-Term Clinical Outcomes After Transcatheter Aortic Valve Replacement: Results From the Prospective POST-TAVI Registry

Prosthetic valve regurgitation (PVR) is associated with increased early and midterm mortality after transcatheter aortic valve replacement (TAVR); but, its impact on long-term outcomes in not known, and the relevant cutpoints of severity are not adequately validated. We sought to investigate the

Mechanisms of sacubitril-valsartan benefit in HFrEF.

Two studies reveal new details of the mechanisms underlying the benefits of the angiotensin receptor–neprilysin inhibitor sacubitril–valsartan in patients with heart failure and reduced ejection fraction, suggesting that sacubitril–valsartan induces reverse cardiac remodelling but has no effect in reducing central aortic stiffness.

Association of Change in N-Terminal Pro–B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment With Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction

In patients with heart failure and reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan reduces N-terminal pro-b-type natriuretic peptide (NT-proBNP) concentrations. The effect of sacubitril-valsartan on cardiac remodeling is uncertain. To determine whether NT-proBNP changes in patients with HFrEF treated with sacubitril-valsartan correlate with changes in measures of cardiac volume and function. Prospective, 12-month, single-group, open-label study of patients with HFrEF enrolled in 78 outpatient sites in the United States. Sacubitril-valsartan was initiated and the dose adjusted. Enrollment commenced on October 25, 2016, and follow-up was completed on October 22, 2018. NT-proBNP concentrations among patients treated with sacubitril-valsartan. The primary outcome was the correlation between changes in log2-NT-proBNP concentrations and left ventricular (LV) EF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e') at 12 months. Among 794 patients (mean age, 65.1 years; 226 women [28.5%]; mean LVEF = 28.2%), 654 (82.4%) completed the study. The median NT-proBNP concentration at baseline was 816 pg/mL (interquartile range [IQR], 332-1822) and 455 pg/mL (IQR, 153-1090) at 12 months (difference, P < .001). At 12 months, the change in log2-NT-proBNP concentration was correlated with changes in LVEF (r = -0.381 [IQR, -0.448 to -0.310]; P < .001), LVEDVI (r = 0.320 [IQR, 0.246 to 0.391]; P < .001), LVESVI (r = 0.405 [IQR, 0.335 to 0.470]; P < .001), LAVI (r = 0.263 [IQR, 0.186 to 0.338]; P < .001), and E/e' (r = 0.269 [IQR, 0.182 to 0.353]; P < .001). At 12 months, LVEF increased from 28.2% to 37.8% (difference, 9.4% [95% CI, 8.8% to 9.9%]; P < .001), while LVEDVI decreased from 86.93 to 74.15 mL/m2 (difference, -12.25 mL/m2 [IQR, -12.92 to -11.58]; P < .001) and LVESVI decreased from 61.68 to 45.46 mL/m2 (difference, -15.29 mL/m2 [95% CI, -16.03 to -14.55]; P < .001). LAVI and E/e' ratio also decreased significantly. The most frequent adverse events were hypotension (17.6%), dizziness (16.8%), hyperkalemia (13.2%), and worsening kidney function (12.3%). In this exploratory study of patients with HFrEF treated with sacubitril-valsartan, reduction in NT-proBNP concentration was weakly yet significantly correlated with improvements in markers of cardiac volume and function at 12 months. The observedreverse cardiac remodeling may provide a mechanistic explanation for the effectsof sacubitril-valsartan in patients with HFrEF. ClinicalTrials.gov Identifier: NCT02887183.

Abstract 246: Applying a Quantitative, Cell Surface Glycoproteomic Approach to Understanding the Role of Human Cardiac Fibroblasts in Advanced Heart Failure

Heart Failure (HF) is a complex clinical syndrome defined by the heart’s inability to adequately perfuse the human body. The clinical progression of HF has been linked to the pathological activation of CF, which contributes to adverse remodeling and cardiac fibrosis. Previous studies have shown that unloading the failing heart via mechanical circulatory support devices contributes to reverse remodeling, improving both cardiac structure and function. However, despite the importance of CF in biology and disease, little is known regarding CF-specific mechanisms and functions during cardiac remodeling and reverse remodeling. Moreover, most human studies have relied on in vitro culture systems to investigate CF function, despite the fact that extended culturing leads to phenotypic changes in CF. Here, we apply state-of-the-art mass spectrometry approaches to discover and quantify cell surface and extracellular matrix (ECM) proteins to 1) develop an optimized CF culture system that allows for the preservation of their in situ phenotype and 2) study CF isolated from failing hearts, including failing hearts treated with mechanical circulatory support to identify novel targets for tracking and studying disease. To date, we have identified &gt;600 surface N- glycoproteins on primary human CF (n=12), including those with known relevance to CF ( e.g. BGN, BSG, FBN1) and those not previously described within CF ( e.g. HHIP, NFACS, GPNMB). In CF samples that were passaged ex vivo , cell surface and ECM N- glycoproteins that are associated with a phenotype switch ( e.g. COL5A1, ECM1, FBLN5, LAMB2) were detected and changes in their abundance correlated with increased expression of α-SMA. Our studies also identified cell surface and ECM proteins that have not been previously associated with the heart and those with known relevance to HF, cardiac remodeling and fibrosis ( e.g. BGN, GLUT8, ITGA11). Current efforts are underway to quantify surface proteins of interest to determine how their abundance changes during reverse remodeling in the context of HF. Overall, this work allowed for the development of an optimized CF culture system and revealed new cell-type specific molecular targets to study and track reverse remodeling in the context of advanced HF.

CARDIAC CONTRACTILITY MODULATION IN HEART FAILURE PATIENTS. FUNDAMENTAL MECHANISMS AND CLINICAL RESULTS

This review highlights the preclinical and clinical data about a relatively new electrophysiological method for chronic heart failure (CHF) treatment, cardiac contractility modulation (CCM). The review presents efficacy and safety data. An updated information about the capability of CCM to influence the molecular genetic apparatus of the cardiomyocytes is proposed. In addition, the review assesses prospects for application of CCM as a tool for reverse cardiac remodeling in patients with CHF.

Effects of the Angiotensin-Receptor Neprilysin Inhibitor on Cardiac Reverse Remodeling: Meta-Analysis.

BackgroundThe angiotensin‐receptor neprilysin inhibitor (ARNI) sacubitril/valsartan was shown to be superior to the angiotensin‐converting enzyme inhibitor enalapril in terms of reducing cardiovascular mortality in the PARADIGM‐HF (Prospective Comparison of ARNI with angiotensin‐converting enzyme inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) study. However, the impact of ARNI on cardiac reverse remodeling (CRR) has not been established.Methods and ResultsWe conducted a meta‐analysis to compare the effects of ARNI versus angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers on CRR indices. We searched databases for studies published between 2010 and 2019 that reported CRR indices following ARNI administration. Effect size was expressed as mean difference (MD) with 95% CIs. Twenty studies enrolling 10 175 patients were included. ARNI improved functional capacity in patients with heart failure (HF) and a reduced ejection fraction (EF), including increasing New York Heart Association functional class (MD −0.79, 95% CI −0.86, −0.71) and 6‐minute walking distance (MD 27.62 m, 95% CI 15.76, 39.48). ARNI outperformed angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers in terms of CRR indices, with striking changes in left ventricular EF, diameter, and volume. However, there were no significant improvements in indices except left ventricular mass index (MD −3.25 g/m2, 95% CI −3.78, −2.72) and left atrial volume (MD −7.20 mL, 95% CI −14.11, −0.29) in HF patients with preserved EF treated with ARNI. Improvements in CRR indices were observed at 3 months and became more significant with longer follow‐up to 12 months. The regression equation for the relationship between left ventricular EF and end‐diastolic dimension was y=0.041+0.071x+0.045x2+0.006x3.ConclusionsARNI distinctly improved left ventricular size and hypertrophy compared with angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers in HF with reduced EF patients, even after short‐term follow‐up. Patients appeared to benefit more in terms of CRR treated with ARNI as early as possible and for at least 3 months. Further large sample trials are required to determine the effects of ARNI on CRR in HF with preserved EF patients.

A clinical trial of intravenous mesenchymal stem cells for treatment of anthracycline associated cardiomyopathy

Background & Aim Cardiomyopathy and cardiovascular toxicities can occur up to 20 years after anthracycline exposure with an incidence of 20%. Anthracycline cardiotoxicity (AC) is mediated by reactive oxygen species. Despite guideline directed medical therapy (GDMT) 52% of AC patients develop progressive heart failure. Mesenchymal stem cells (MSCs) have been shown to improve left ventricular structure/function by reducing fibrosis and inducing neoangiogenesis in acute myocardial infarction (AMI) and chronic ischemic cardiomyopathy. MSCs home to sites of injury and secrete VEGF in response to hypoxia, encouraging angiogenesis and increased oxygenated blood flow. MSCs create an immunosuppressive microenvironment which mitigates inflammatory response and decreases formation of scar tissue. In the AMI setting others have reported a dose related reduction in both end-systolic and end-diastolic volumes, demonstrating reverse cardiac remodeling. Methods, Results & Conclusion Methods MSCs have not been used in the AC setting. We conducted a phase 2 trial to evaluate safety and efficacy of MSCs in the AC setting. Eligibility required that patients be adults receiving maximal GDMT for heart failure and have a LVEF Conclusion Our results are consistent with prior reports in the AMI setting that the time from injury/exposure to treatment with stem cells is important. We postulate that the first patient, with exposure to anthracycline two decades prior and longstanding heart failure had scar tissue and fibrosis that was not reversible. The last two patients had more recent anthracycline exposure and both had a sustained significant improvement in EF following intravenous treatment with MSCs. No adverse events were noted. Accrual to the trial continues.

Lipoxygenase drives lipidomic and metabolic reprogramming in ischemic heart failure

BackgroundAfter myocardial infarction (MI), delayed progression or reversal of cardiac remodeling is a prime target to limit advanced chronic heart failure (HF). However, the temporal kinetics of lipidomic and systemic metabolic signaling is unclear in HF. There is no consensus on metabolic and lipidomic signatures that influence structure, function, and survival in HF. Here we use genetic knock out model to delineate lipidomic, and metabolic changes to describe the role of lipoxygenase in advancing ischemic HF driven by leukocyte activation with signs of non-resolving inflammation. Bioactive lipids and metabolites are implicated in acute and chronic HF, and the goal of this study was to define the role of lipoxygenase in temporal kinetics of lipidomic and metabolic reprogramming in HF. Materials and methodsTo address this question, we used a permanent coronary ligation mouse model which showed profound metabolic and lipidomic reprogramming in acute HF. Additionally, we defined the lipoxygenase-mediated changes in cardiac pathophysiology in acute and chronic HF. For this, we quantitated systemic metabolic changes and lipidomic profiling in infarcted heart tissue with obvious structural remodeling and cardiac dysfunction progressing from acute to chronic HF in the survival cohort. ResultsAfter MI, lipoxygenase-derived specialized pro-resolving mediators were quantitated and showed lipoxygenase-deficient mice (12/15LOX−/−) biosynthesize epoxyeicosatrienoic acid (EETs; cypoxins) to facilitate cardiac healing. Lipoxygenase-deficient mice reduced diabetes risk biomarker 2-aminoadipic acid with profound alterations of plasma metabolic signaling of hexoses, amino acids, biogenic amines, acylcarnitines, glycerophospholipids, and sphingolipids in acute HF, thereby improved survival. ConclusionSpecific lipoxygenase deletion alters lipidomic and metabolic signatures, with modified leukocyte profiling that delayed HF progression and improved survival. Future studies are warranted to define the molecular network of lipidome and metabolome in acute and chronic HF patients.

Fate and long-term prognostic implications of mitral regurgitation in patients undergoing transcatheter aortic valve replacement

BackgroundThe management of patients with mitral regurgitation (MR) undergoing transcatheter aortic valve replacement (TAVR) is challenging. We sought to investigate the evolution and long-term prognostic impact of residual post-TAVR MR. MethodsThe severity of MR was assessed at baseline and at 30 days and six months post-TAVR. Left ventricular mass and volumes were assessed by magnetic resonance imaging at two weeks and six months post-TAVR. ResultsThe study included 970 patients (age, 80.6 ± 6.2 years; female, 53.2%; Society of Thoracic Surgeons score, 5.2 ± 4.6). Moderate-severe MR at baseline improved at 30-day post-TAVR in 60% of cases, and TAVR with the Medtronic CoreValve (OR: 0.44 [0.23–0.86]) was associated with a lower likelihood of improvement. Further MR improvement continued beyond 30 days post-TAVR especially in patients with a significant improvement of left ventricular volume and mass.Stratified by the severity of MR at 30 days post-TAVR, the 5-year cumulative incidence of the composite of cardiovascular mortality or heart failure hospitalization was 37.5%, 40.0%, and 58.2% in patients with none-mild, moderate, and severe MR, respectively (log rank p < .001; adjusted hazard ratio of severe vs. none-mild MR: 4.83 [2.49–9.38]. ConclusionsMR improves in a majority of patients early after TAVR, and its evolution continues thereafter in line with reverse cardiac remodeling. Residual post-TAVR severe MR is associated with adverse long-term outcome. Therefore, intervention to treat severe MR persisting after TAVR should be considered by the heart team.

Cardiac Reverse Remodeling and Recovery in Dilated Cardiomyopathy Medication-Naive Patients Requiring Durable Left Ventricular Assist Device Support

Purpose Occasionally new onset cardiomyopathy patients (pts) present late, in such advanced disease stage that they cannot tolerate heart failure (HF) drug therapy. We investigated the cardiac recovery (CR) potential following a combination of left ventricular assist device (LVAD) and guideline-directed HF drug therapy in this medication-naive population. Methods Chronic advanced HF pts requiring durable continuous-flow LVAD were prospectively evaluated. Pts with acute HF (myocarditis etc) or post LVAD follow up Results Univariate analysis showed that “med-naive” pts were younger, more likely to be on intravenous vasoactive agents, temporary MCS and with lower INTERMACS profile before LVAD implantation. Interestingly, no differences were seen in HF symptoms duration or other comorbidities. Baseline and follow up hemodynamics were similar in both groups, besides higher right atrial pressure pre-LVAD in the “meds-naive” group (16 vs 11 mmHg; p=0.04). Baseline echocardiographic (including LV dilation) and biochemical parameters revealed no differences between the groups, besides lower LVEF and higher BNP in the “meds-naive” group (14 vs 19 %; p=0.03 and 2352 vs 1270; p=0.03, respectively). CR rates were significantly higher on “meds-naive” versus “meds-failed” group (50.0 vs 13.8 %; p=0.005). Despite higher cardiac recovery rates in the “meds-naive” group the time course and magnitude of the favorable functional and structural response was similar among the CR responders of each of the 2 groups. Conclusion Young pts with new onset dilated cardiomyopathy sometimes present late, with advanced disease stage, unable to tolerate HF medications and requiring durable LVAD support. This patient population appears to have a potential for CR up to 50% and this could be factored in decisions surrounding their long-term therapeutic options.

REVERSE CARDIAC REMODELING IN HEART FAILURE AFTER CARDIAC RESYNCHRONIZATION THERAPY IS ASSOCIATED TO REDUCTION OF RHO KINASE ACTIVATION IN PERIPHERAL MONONUCLEAR BLOOD CELLS

Major challenges in heart failure with reduced ejection fraction (HFrEF) are promotion of reverse cardiac remodeling and development of specific biomarkers. Activation of the Rho kinase (ROCK) signaling pathway in HFrEF patients is associated to myocardial remodeling and LV dysfunction. Besides,

Sacubitril/Valsartan in Real-Life Practice: Experience in Patients with Advanced Heart Failure and Systematic Review.

Sacubitril/valsartan reduced heart failure (HF) admissions and cardiovascular mortality in the PARADIGM-HF trial. However, real-life studies are scarce comparing daily practice patients with those of the trial. The aim of our study was to analyze the efficacy and safety of the drug in an advanced heart failure cohort and to review systematically the previous real-life studies published to date. We performed a retrospective analysis of consecutive patients prescribed sacubitril/valsartan in a single tertiary HF clinic between September 2016 and February 2018. HF admissions before and after the initiation of the drug were assessed in a paired fashion. A systematic review of real-life studies published to date was also conducted. Sacubitril/valsartan was started in 108 patients who were in a more advanced NYHA class and more frequently treated with mineral receptor antagonists, internal cardiac defibrillator, and cardiac resynchronization therapy than in the PARADIGM-HF trial. After a 6-month follow-up, we observed a significant reduction in the HF hospitalizations, median levels of NT-proBNP, and need for levosimendan ambulatory perfusion. Likewise, we found a significant improvement in mean LVEF and end diastolic left ventricle diameter. Regarding safety, sacubitril/valsartan was well-tolerated without any severe adverse effect. Sacubitril/valsartan in real-life is prescribed to a more advanced HF population, which could be responsible for the difficulties in reaching high doses of the drug. However, after a 6-month follow-up, sacubitril/valsartan significantly reduces HF hospitalization and induces cardiac reverse remodeling, without remarkable adverse events.

Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction.

Sacubitril/valsartan reduced the occurrence of sudden cardiac death in the PARADIGM-HF trial. However, limited information is available about the mechanism. Heart failure (HF)-patients receiving sacubitril/valsartan for a class-I indication equipped with an implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) with remote tele-monitoring were retrospectively analyzed. Device-registered arrhythmic-events were determined [ventricular tachycardia/fibrillation (VT/VF), appropriate therapy, non-sustained VT (NsVT; > 4beats and < 30s), hourly premature ventricular contraction (PVC)-burden], following sacubitril/valsartan initiation (incident-analysis) and over an equal time period before initiation (antecedent-analysis). Reverse remodeling to sacubitril/valsartan was defined as an improvement of left ventricular ejection fraction of ≥ 5% between baseline and follow-up. A-total of 151 HF-patients with reduced LVEF (29 ± 9%) were included. Patients were switched from ACE-I or ARB to equal doses of sacubitril/valsartan (expressed as %-target-dose; before = 58 ± 30% vs. after = 56 ± 27%). The mean follow-up of both the incident and antecedent analysis was 364 days. Following the initiation, VT/VF-burden dropped (individual patients with VT/VF pre_n = 19 vs. post_n = 10, total-episodes of VT/VF pre_n = 51 vs. post_n = 14, both p < 0.001), resulting in reduced occurrence of appropriate therapy (pre_n = 16 vs. post_n = 6; p < 0.001). NsVT-burden per patient also dropped (mean episodes pre_n = 7.7 ± 11.8 vs. post_n = 3.7 ± 5.4; p < 0.001). There was no impact on atrial-fibrillation burden. PVC-burden dropped significantly which was associated with an improvement in BiV-pacing in patients with < 90% BiV-pacing at baseline. A higher degree of reverse remodeling was associated with a lower burden of NsVT and PVCs (both p < 0.05). Initiation of sacubitril/valsartan is associated with a lower degree of VT/VF, resulting in less ICD-interventions. This beneficial effect on ventricular arrhythmias might be related to cardiac reverse remodeling.

Noninvasive imaging assessment of rehabilitation therapy in heart failure with preserved and reduced left ventricular ejection fraction (IMAGING-REHAB-HF): design and rationale.

Background:Studies have shown significant benefits of exercise therapy in heart failure (HF) with a reduced ejection fraction (HFrEF) and HF with a preserved ejection fraction (HFpEF). The mechanisms responsible for the beneficial effect of exercise in HFrEF and HFpEF are still unclear. We hypothesized that the effect of exercise on myocardial remodeling may explain its beneficial effect.Methods:IMAGING-REHAB-HF is a single-center, randomized, controlled clinical trial using cardiac magnetic resonance imaging, vasomotor endothelial function, cardiac sympathetic activity imaging and serum biomarkers to compare the effect of exercise therapy in HFpEF (LVEF ≥ 45%) and HFrEF (LVEF < 45%). Subjects will be assessed at baseline and after 4 months. The exercise program will consist of three 60-min exercise sessions/week. The primary endpoints are the effect of exercise on myocardial extracellular volume (ECV), left ventricular (LV) systolic function, LV mass, LV mass-to-volume and LV cardiomyocyte volume. Secondary endpoints include the effect of exercise on vasomotor endothelial function, cardiac sympathetic activity and plasmatic biomarkers. Patients will be allocated in a 2:1 fashion to supervised exercise program or usual care. A total sample size of 90 patients, divided into two groups according to LVEF:HFpEF group (45 patients:30 in the intervention arm and 15 in the control arm) and HFrEF group (45 patients:30 in the intervention arm and 15 in the control arm) – will be necessary to achieve adequate power.Conclusion:This will be the first study to evaluate the benefits of a rehabilitation program on cardiac remodeling in HF patients. The unique design of our study may provide unique data to further elucidate the mechanisms involved in reverse cardiac remodeling after exercise in HFpEF and HFrEF patients.

The Crosstalk between Acetylation and Phosphorylation: Emerging New Roles for HDAC Inhibitors in the Heart.

Approximately five million United States (U.S.) adults are diagnosed with heart failure (HF), with eight million U.S. adults projected to suffer from HF by 2030. With five-year mortality rates following HF diagnosis approximating 50%, novel therapeutic treatments are needed for HF patients. Pre-clinical animal models of HF have highlighted histone deacetylase (HDAC) inhibitors as efficacious therapeutics that can stop and potentially reverse cardiac remodeling and dysfunction linked with HF development. HDACs remove acetyl groups from nucleosomal histones, altering DNA-histone protein electrostatic interactions in the regulation of gene expression. However, HDACs also remove acetyl groups from non-histone proteins in various tissues. Changes in histone and non-histone protein acetylation plays a key role in protein structure and function that can alter other post translational modifications (PTMs), including protein phosphorylation. Protein phosphorylation is a well described PTM that is important for cardiac signal transduction, protein activity and gene expression, yet the functional role for acetylation-phosphorylation cross-talk in the myocardium remains less clear. This review will focus on the regulation and function for acetylation-phosphorylation cross-talk in the heart, with a focus on the role for HDACs and HDAC inhibitors as regulators of acetyl-phosphorylation cross-talk in the control of cardiac function.

SUR2B/Kir6.1 channel openers correct endothelial dysfunction in chronic heart failure via the miR-1-3p/ET-1 pathway

The SUR2B/Kir6.1 channel openers iptakalim and natakalim reverse cardiac remodeling and ameliorate endothelial dysfunction by re-establishing the balance between the nitric oxide and endothelin systems. In this study, we investigated the microRNAs (miRs) involved in the molecular mechanisms of SUR2B/Kir6.1 channel opening in chronic heart failure. Both iptakalim and natakalim significantly upregulated the expression of miR-1-3p, suggesting that this miR is closely associated with the therapeutic effects against chronic heart failure. Bioinformatic analysis showed that many of the 183 target genes of miR-1-3p are involved in cardiovascular diseases, suggesting that miR-1-3p plays a vital role in such diseases and vascular remodeling. Target gene prediction showed that miR-1-3p combines with the 3′ untranslated region (UTR) of endothelin-1 (ET-1) mRNA. Iptakalim and natakalim upregulated miR-1-3p expression and downregulated ET-1 mRNA expression in vitro. The dual luciferase assay confirmed that there is a complementary binding sequence between miR-1-3p and the 3′ UTR 158–165 sequence of ET-1 mRNA. To verify the effect of miR-1-3p on ET-1, lentiviral vectors overexpressing or inhibiting miR-1-3p were constructed for the transduction of rat primary cardiac microvascular endothelial cells. The results showed that natakalim enhanced the miR-1-3p level. miR-1-3p overexpression downregulated the expression of ET-1, whereas miR-1-3p inhibition had the opposite effect. Therefore, we verified that SUR2B/Kir6.1 channel openers could correct endothelial imbalance and ameliorate chronic heart failure through the miR-1-3p/ET-1 pathway in endothelial cells. Our study provides comprehensive insights into the molecular mechanisms behind the SUR2B/Kir6.1 channel’s activity against chronic heart failure.

Long‐term treatment with ivabradine in transgenic atrial fibrillation mice counteracts hyperpolarization‐activated cyclic nucleotide gated channel overexpression

Recent studies have demonstrated that ivabradine (IVA), is a selective inhibitor of funny current (If) and exerts antiarrhythmic effects in the settings of various diseases such as heart failure and myocardial ischemia. However, little is known regarding the effects of long-term IVA treatment on If current and hyperpolarization-activated cyclic nucleotide gated (HCN) channel overexpression. We investigated both the If current and HCN channel expression in wild-type (WT) mice and transgenic (TG) atrial fibrillation (AF) mice (heart-specific overexpressing of (pro) renin receptor TG mice) and examined the effects of IVA on the If current and HCN channel expression, and whether those effects were sufficient to prevent an AF episode. Compared with WT mice, the If current density (at -170 mV: TG, -39.6 ± 4.6 pA/pF; WT, -26.9 ± 3.0 pA/pF; P < 0.001) and activation kinetics (V1/2 : TG, -109.45 ± 1.35 mV; WT, -128.20 ± 1.65 mV), as well as HCN2 and HCN4 messenger RNA expression and HCN4 protein expression were significantly increased in the atrial myocytes of TG mice. After 4 months of IVA treatment (7 mg/kg per day orally) the effects of IVA on TG AF mice were accompanied by the inhibition of upregulation of HCN2 and HCN4 protein expression in atrial tissue, and then resulted in a uniform If loss of function.Furthermore, we observed that ivabradine significantly decreased the incidence of AF in the TG mice (41.2% in TG mice, 16.7% in TG + IVA mice; P < 0.01). IVA reduced the incidence of AF in mice, and the antiarrhythmic effects of IVA are not limited to heart rate reduction, as theypartially counteractHCN overexpression and reverseelectrophysiological cardiac remodeling by attenuating If gain-of-function.