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Background: Heart failure with preserved ejection fraction (HFPEF) is a common, globally recognised, form of heart failure for which no treatment has yet been shown to improve symptoms or prognosis. The pathophysiology of HFPEF is complex but characterised by increased left atrial pressure, especially during exertion, which might be a key therapeutic target. The rationale for the present study was that a mechanical approach to reducing left atrial pressure might be effective in HFPEF.Methods: The REDUCe Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF) study was an open-label, single-arm, phase 1 study designed to assess the performance and safety of a transcatheter interatrial shunt device (IASD, Corvia Medical, Tewkesbury, MA, USA) in patients older than 40 years of age with symptoms of HFPEF despite pharmacological therapy, left ventricular ejection fraction higher than 40%, and a raised pulmonary capillary wedge pressure at rest (>15 mm Hg) or during exercise (>25 mm Hg). The study was done at 21 centres (all departments of cardiology in the UK, Netherlands, Belgium, France, Germany, Austria, Denmark, Australia, and New Zealand). The co-primary endpoints were the safety and performance of the IASD at 6 months, together with measures of clinical efficacy, including functional capacity and clinical status, analysed per protocol. This study is registered with ClinicalTrials.gov, number NCT01913613.Findings: Between Feb 8, 2014, and June 10, 2015, 68 eligible patients were entered into the study. IASD placement was successful in 64 patients and seemed to be safe and well tolerated; no patient had a peri-procedural or major adverse cardiac or cerebrovascular event or need for cardiac surgical intervention for device-related complications during 6 months of follow-up. At 6 months, 31 (52%) of 60 patients had a reduction in pulmonary capillary wedge pressure at rest, 34 (58%) of 59 had a lower pulmonary capillary wedge pressure during exertion, and 23 (39%) of 59 fulfilled both these criteria. Mean exercise pulmonary capillary wedge pressure was lower at 6 months than at baseline, both at 20 watts workload (mean 32 mm Hg [SD 8] at baseline vs 29 mm Hg [9] at 6 months, p=0·0124) and at peak exercise (34 mm Hg [8] vs 32 [8], p=0·0255), despite increased mean exercise duration (baseline vs 6 months: 7·3 min [SD 3·1] vs 8·2 min [3·4], p=0·03). Sustained device patency at 6 months was confirmed by left-to-right shunting (pulmonary/systemic flow ratio: 1·06 [SD 0·32] at baseline vs 1·27 [0·20] at 6 months, p=0·0004).Interpretation: Implantation of an interatrial shunt device is feasible, seems to be safe, reduces left atrial pressure during exercise, and could be a new strategy for the management of HFPEF. The effectiveness of IASD compared with existing treatment for patients with HFPEF requires validation in a randomised controlled trial.Funding: Corvia Medical Inc. [ABSTRACT FROM AUTHOR]

Aim Activation of the kinase RAF and its downstream targets leads to cardiomyocyte hypertrophy. It has been hypothesized that B-RAF might be the main activator of MEK in various cell types. Therefore, the aim of this study was to investigate the role of B-RAF and its modulating factors in cardiomyocyte hypertrophy. Methods and results Neonatal rat cardiomyocytes were pre-treated with and without the specific B-RAF inhibitor SB590885 and then stimulated with phenylephrine to induce hypertrophy. Inhibition of B-RAF completely impeded the hypertrophic response and led to a significant reduction of MEK1/2 phosphorylation. By applying a eukaryotic cDNA expression screen, based on a dual-luciferase reporter assay for B-RAF activity measurement, we identified RCN1 as a new negative modulator of B-RAF activity. Adenovirus-mediated overexpression of reticulocalbin 1 (RCN1) completely impeded phenylephrine-induced hypertrophy and led to significantly reduced MEK1/2 phosphorylation. Conversely, adenoviral knockdown of RCN1 with a specific synthetic miRNA induced cardiomyocyte hypertrophy and significantly increased MEK1/2 phosphorylation. Conclusions In summary, our results show that the inhibition of B-RAF abolishes cardiomyocyte hypertrophy and we identified RCN1 as novel negative modulator of cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signalling cascade. Our results show that B-RAF kinase activity is essential for cardiac hypertrophy and RCN1, its newly identified negative regulator, abolishes hypertrophic response of cardiomyocytes in vitro. [ABSTRACT FROM PUBLISHER]

Nitric oxide (NO) has influence on various cellular functions. Little is known of the influence of NO on myocardial energetics. In the present study oxygen consumption and mechanical parameters of isometrically contracting rabbit papillary muscles (1 Hz stimulation frequency) were investigated at varying interventions while maintaining physiological conditions (37°C; 2.5 mM Ca2+) to study the effects of NO on energetics. The NO donor sodium nitroprusside (SNP) showed a negative inotropic effect. SNP decreased the maximal force in normal rabbit muscle strips by 30%, the force time integral (FTI) by 40% and the relaxation time by 20%. In addition the oxygen consumption decreased by 60%, a notably disproportional decrease compared to the mechanical parameters. Consequently, the economy as a ratio of FTI and oxygen consumption is significantly increased by SNP. In contrast the negative inotropic effect due to a reduction in extracellular Calcium (Ca2+) from 2.5 to 1.25 mM reduced FTI and oxygen consumption proportionally by 40% and did not change economy. The effect of NO on force and oxygen consumption could be reproduced by the application of the cyclic guanosine monophosphate (cGMP) analogue 8-bromo-cGMP. In summary, NO increased the economy of isometrically contracting papillary muscles. The improvement in contraction economy under NO seems to be mediated by cGMP as the secondary messenger and maybe due to alterations of the crossbridge cycle. [ABSTRACT FROM AUTHOR]

Abstract: Chronic congestive heart failure (CHF) is a common consequence of heart muscle or valve damage and remains a major cause of morbidity and mortality worldwide. There are increasing interests to treat cardiac failure by stem cell-based therapy. Many types of stem cells or progenitor cells have been suggested for cellular therapy of heart failure. While stem cell-based therapy was initially thought to be achieved by transdifferentiation of stem cells into myocardial cells including cardiomyocytes it has become clear that this may be rather an infrequent event. Instead cardiac regeneration may result from vascular differentiation of stem cells or even from stem cell-mediated reverse remodelling. Thus the term stem cell-mediated cardiac regeneration covers the spectrum from stem cell transdifferentiation into cardiomyocytes to cell-mediated pharmacotherapy. In this review we revise stem cell-based cardiac regeneration both in experimental models and in clinical application. We have limited our discussion on some selected types of stem cells, with particular emphasis on their differentiation potential, current status and perspectives on their future applications. [Copyright &y& Elsevier]

G. Hasenfuss and B. Pieske. Calcium Cycling in Congestive Heart Failure. Journal of Molecular and Cellular Cardiology (2002) 34, 951–969. [Copyright &y& Elsevier]

The sodium channel NaV1.8, encoded by the SCN10A gene, has recently emerged as a potential regulator of cardiac electrophysiology. We have previously shown that NaV1.8 contributes to arrhythmogenesis by inducing a persistent Na+ current (late Na+ current, INaL) in human atrial and ventricular cardiomyocytes (CM). We now aim to further investigate the contribution of NaV1.8 to human ventricular arrhythmogenesis at the CM-specific level using pharmacological inhibition as well as a genetic knockout (KO) of SCN10A in induced pluripotent stem cell CM (iPSC-CM). In functional voltage-clamp experiments, we demonstrate that INaL was significantly reduced in ventricular SCN10A-KO iPSC-CM and in control CM after a specific pharmacological inhibition of NaV1.8. In contrast, we did not find any effects on ventricular APD90. The frequency of spontaneous sarcoplasmic reticulum Ca2+ sparks and waves were reduced in SCN10A-KO iPSC-CM and control cells following the pharmacological inhibition of NaV1.8. We further analyzed potential triggers of arrhythmias and found reduced delayed afterdepolarizations (DAD) in SCN10A-KO iPSC-CM and after the specific inhibition of NaV1.8 in control cells. In conclusion, we show that NaV1.8-induced INaL primarily impacts arrhythmogenesis at a subcellular level, with minimal effects on systolic cellular Ca2+ release. The inhibition or knockout of NaV1.8 diminishes proarrhythmic triggers in ventricular CM. In conjunction with our previously published results, this work confirms NaV1.8 as a proarrhythmic target that may be useful in an anti-arrhythmic therapeutic strategy. [ABSTRACT FROM AUTHOR]

Background: Data comparing remote magnetic catheter navigation (RMN) with manual catheter navigation in combination with contact force sensing (MCN-CF) ablation of atrial fibrillation (AF) is lacking. The primary aim of the present retrospective comparative study was to compare the outcome of RMN versus (vs.) MCN-CF ablation of AF with regards to AF recurrence. Secondary aim was to analyze periprocedural risk, ablation characteristics and repeat procedures. Methods: We retrospectively analyzed 452 patients undergoing a total of 605 ablations of AF: 180 patients were ablated using RMN, 272 using MCN-CF. Results: Except body mass index there was no significant difference between groups at baseline. After a mean 1.6 ± 1.6 years of follow-up and 1.3 ± 0.4 procedures, 81% of the patients in the MCN-CF group remained free of AF recurrence compared to 53% in the RMN group (P < 0.001). After analysis of 153 repeat ablations (83 MCN-RF vs. 70 RMN; P = 0.18), there was a significantly higher reconnection rate of pulmonary veins after RMN ablation (P < 0.001). In multivariable Cox-regression analysis, RMN ablation (P < 0.001) and left atrial diameter (P = 0.013) was an independent risk factor for AF recurrence. Procedure time, radiofrequency application time and total fluoroscopy time and fluoroscopy dose were higher in the RMN group without difference in total number of ablation points. Complication rates did not differ significantly between groups (P = 0.722). Conclusions: In our retrospective comparative study, the AF recurrence rate and pulmonary vein reconnection rate is significantly lower with more favorable procedural characteristics and similar complication rate utilizing MCN-CF compared to RMN. [ABSTRACT FROM AUTHOR]

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]

Patient-derived induced pluripotent stem cells (iPSCs) can be differentiated into atrial and ventricular cardiomyocytes to allow for personalized drug screening. A hallmark of differentiation is the manifestation of spontaneous beating in a two-dimensional (2-D) cell culture. However, an outstanding observation is the high variability in this maturation process. We valued that contractile parameters change during differentiation serving as an indicator of maturation. Consequently, we recorded noninvasively spontaneous motion activity during the differentiation of male iPSC toward iPSC cardiomyocytes (iPSC-CMs) to further analyze similar maturated iPSC-CMs. Surprisingly, our results show that identical differentiations into ventricular iPSC-CMs are variable with respect to contractile parameters resulting in two distinct subpopulations of ventricular-like cells. In contrast, differentiation into atrial iPSC-CMs resulted in only one phenotype. We propose that the noninvasive and cost-effective recording of contractile activity during maturation using a smartphone device may help to reduce the variability in results frequently reported in studies on ventricular iPSC-CMs. [ABSTRACT FROM AUTHOR]

Distinct patterns of circulating microRNAs (miRNAs) were found to be involved in misguided thrombus resolution. Thus, we aimed to investigate dysregulated miRNA signatures during the acute phase of pulmonary embolism (PE) and test their diagnostic and predictive value for future diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH). Microarray screening and subsequent validation in a large patient cohort (n = 177) identified three dysregulated miRNAs as potential biomarkers: circulating miR-29a and miR-720 were significantly upregulated and miR-let7a was significantly downregulated in plasma of patients with PE. In a second validation study equal expression patterns for miR-29a and miR-let7a regarding an acute event of recurrent venous thromboembolism (VTE) or deaths were found. MiR-let7a concentrations significantly correlated with echocardiographic and laboratory parameters indicating right ventricular (RV) dysfunction. Additionally, circulating miR-let7a levels were associated with diagnosis of CTEPH during follow-up. Regarding CTEPH diagnosis, ROC analysis illustrated an AUC of 0.767 (95% CI 0.54–0.99) for miR-let7a. Using logistic regression analysis, a calculated patient-cohort optimized miR-let7a cut-off value derived from ROC analysis of ≥ 11.92 was associated with a 12.8-fold increased risk for CTEPH. Therefore, miR-let7a might serve as a novel biomarker to identify patients with haemodynamic impairment and as a novel predictor for patients at risk for CTEPH. [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]

Cardiovascular magnetic resonance (CMR)-derived hemodynamic force (HDF) analyses have been introduced recently enabling more in-depth cardiac function evaluation. Inter-study reproducibility is important for a widespread clinical use but has not been quantified for this novel CMR post-processing tool yet. Serial CMR imaging was performed in 11 healthy participants in a median interval of 63 days (range 49–87). HDF assessment included left ventricular (LV) longitudinal, systolic peak and impulse, systolic/diastolic transition, diastolic deceleration as well as atrial thrust acceleration forces. Inter-study reproducibility and study sample sizes required to demonstrate 10%, 15% or 20% relative changes of HDF measurements were calculated. In addition, intra- and inter-observer analyses were performed. Intra- and inter-observer reproducibility was excellent for all HDF parameters according to intraclass correlation coefficient (ICC) values (> 0.80 for all). Inter-study reproducibility of all HDF parameters was excellent (ICC ≥ 0.80 for all) with systolic parameters showing lower coeffients of variation (CoV) than diastolic measurements (CoV 15.2% for systolic impulse vs. CoV 30.9% for atrial thrust). Calculated sample sizes to detect relative changes ranged from n = 12 for the detection of a 20% relative change in systolic impulse to n = 200 for the detection of 10% relative change in atrial thrust. Overall inter-study reproducibility of CMR-derived HDF assessments was sufficient with systolic HDF measurements showing lower inter-study variation than diastolic HDF analyses. [ABSTRACT FROM AUTHOR]

Background: Aortic stenosis (AS) is one of the most common cardiac diseases and major cause of morbidity and mortality in the elderly. Transcatheter aortic valve implantation (TAVI) is performed in such patients with symptomatic severe AS and reduces mortality for the majority of these patients. However, a significant percentage dies within the first two years after TAVI, such that there is an interest to identify parameters, which predict outcome and could guide pre-TAVI patient selection. High levels of cardiac fibrosis have been identified as such independent predictor of cardiovascular mortality after TAVI. Promoter hypermethylation commonly leads to gene downregulation, and the Iroquois homeobox 3 (IRX3) gene was identified in a genome-wide transcriptome and methylome to be hypermethylated and downregulated in AS patients. In a well-described cohort of 100 TAVI patients in which cardiac fibrosis levels were quantified histologically in cardiac biopsies, and which had a follow-up of up to two years, we investigated if circulating methylated DNA of IRX3 in the peripheral blood is associated with cardiac fibrosis and/or mortality in AS patients undergoing TAVI and thus could serve as a biomarker to add information on outcome after TAVI. Results: Patients with high levels of methylation in circulating IRX3 show a significantly increased survival as compared to patients with low levels of IRX3 methylation indicating that high peripheral IRX3 methylation is associated with an improved outcome. In the multivariable setting, peripheral IRX3 methylation acts as an independent predictor of all-cause mortality. While there is no significant correlation of levels of IRX3 methylation with cardiac death, there is a significant but very weak inverse correlation between circulating IRX3 promoter methylation level and the amount of cardiac fibrosis. Higher levels of peripheral IRX3 methylation further correlated with decreased cardiac IRX3 expression and vice versa. Conclusions: High levels of IRX3 methylation in the blood of AS patients at the time of TAVI are associated with better overall survival after TAVI and at least partially reflect myocardial IRX3 expression. Circulating methylated IRX3 might aid as a potential biomarker to help guide both pre-TAVI patient selection and post-TAVI monitoring. [ABSTRACT FROM AUTHOR]

Maintaining cancer patients' exercise capacity and therefore patients' ability to live a self-determined life is of huge importance, but little is known about major determinants. We sought to identify determinants of exercise capacity in patients with a broad spectrum of cancer types, who were already receiving cancer treatment or about to commence such therapy. Exercise capacity was assessed in 253 consecutive patients mostly suffering from advanced cancer using the 6-min walk test (6-MWT). All patients underwent echocardiography, physical examination, resting electrocardiogram, hand grip strength (HGS) measurement, and laboratory assessments. Patients were divided into two groups according to the median distance in the 6-MWT (459 m). Patients with lower exercise capacity were older, had significantly lower HGS and haemoglobin and higher values of high sensitive (hs) Troponin T and NT-proBNP (all p < 0.05). Whilst the co-morbidity burden was significantly higher in this group, no differences were detected for sex, body mass index, tumor type, or cachexia (all p > 0.2). Using multivariable logistic regression, we found that the presence of anaemia (odds ratio (OR) 6.172, 95% confidence interval (CI) 1.401–27.201, p = 0.016) as well as an increase in hs Troponin T (OR 3.077, 95% CI 1.202–5.301, p = 0.019) remained independent predictors of impaired exercise capacity. Increasing HGS was associated with a reduced risk of a lower exercise capacity (OR 0.896, 95% CI 0.813–0.987, p = 0.026). Screening patients for elevated hs troponin levels as well as reduced HGS may help to identify patients at risk of lower exercise capacity during cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated the efficacy of rehabilitation after a cardiovascular procedure. Especially older and multimorbid patients benefit from rehabilitation after a cardiac procedure. Prehabilitation prior to cardiac procedures may also have positive effects on patients' pre- and postoperative outcomes. Results of a current meta-analysis show that prehabilitation prior to cardiac procedures can improve perioperative outcomes and alleviate adverse effects. Germany currently lacks a structured cardiac prehabilitation program for older patients, which is coordinated across healthcare sectors. Methods: In a randomized, controlled, two-arm parallel group, assessor-blinded multicenter intervention trial (PRECOVERY), we will randomize 422 patients aged 75 years or older scheduled for an elective cardiac procedure (e.g., coronary artery bypass graft surgery or transcatheter aortic valve replacement). In PRECOVERY, patients randomized to the intervention group participate in a 2-week multimodal prehabilitation intervention conducted in selected cardiac-specific rehabilitation facilities. The multimodal prehabilitation includes seven modules: exercise therapy, occupational therapy, cognitive training, psychosocial intervention, disease-specific education, education with relatives, and nutritional intervention. Participants in the control group receive standard medical care. The co-primary outcomes are quality of life (QoL) and mortality after 12 months. QoL will be measured by the EuroQol 5-dimensional questionnaire (EQ-5D-5L). A health economic evaluation using health insurance data will measure cost-effectiveness. A mixed-methods process evaluation will accompany the randomized, controlled trial to evaluate dose, reach, fidelity and adaptions of the intervention. Discussion: In this study, we investigate whether a tailored prehabilitation program can improve long-term survival, QoL and functional capacity. Additionally, we will analyze whether the intervention is cost-effective. This is the largest cardiac prehabilitation trial targeting the wide implementation of a new form of care for geriatric cardiac patients. Trial registration: German Clinical Trials Register (DRKS; http://www.drks.de; DRKS00030526). Registered on 30 January 2023. [ABSTRACT FROM AUTHOR]

In heart failure and atrial fibrillation, a persistent Na+ current (INaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that NaV1.8 contributes to arrhythmogenesis by inducing a INaL. Genome-wide association studies indicate that mutations in the SCN10A gene (NaV1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these NaV1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrial SCN10A-KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the INaL and action potential duration. Ca2+ measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca2+ leak. The INaL was significantly reduced in atrial SCN10A KO CMs as well as after specific pharmacological inhibition of NaV1.8. No effects on atrial APD90 were detected in any groups. Both SCN10A KO and specific blockers of NaV1.8 led to decreased Ca2+ spark frequency and a significant reduction of arrhythmogenic Ca2+ waves. Our experiments demonstrate that NaV1.8 contributes to INaL formation in human atrial CMs and that NaV1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore NaV1.8 could be a new target for antiarrhythmic strategies. [ABSTRACT FROM AUTHOR]

Although infections are frequent in patients with pulmonary embolism (PE), its effect on adverse outcome risk remains unclear. We investigated the incidence and prognostic impact of infections requiring antibiotic treatment and of inflammatory biomarkers (C-reactive protein [CRP] and procalcitonin [PCT]) on in-hospital adverse outcomes (all-cause mortality or hemodynamic insufficiency) in 749 consecutive PE patients enrolled in a single-centre registry. Adverse outcomes occurred in 65 patients. Clinically relevant infections were observed in 46.3% of patients and there was an increased adverse outcome risk with an odds ratio (OR) of 3.12 (95% confidence interval [CI] 1.70–5.74), comparable to an increase in one risk class of the European Society of Cardiology (ESC) risk stratification algorithm (OR 3.45 [95% CI 2.24–5.30]). CRP > 124 mg/dL and PCT > 0.25 µg/L predicted patient outcome independent of other risk factors and were associated with respective ORs for an adverse outcome of 4.87 (95% CI 2.55–9.33) and 5.91 (95% CI 2.74–12.76). In conclusion, clinically relevant infections requiring antibiotic treatment were observed in almost half of patients with acute PE and carried a similar prognostic effect to an increase in one risk class of the ESC risk stratification algorithm. Furthermore, elevated levels of CRP and PCT seemed to be independent predictors of adverse outcome. [ABSTRACT FROM AUTHOR]

Left atrial and ventricular (LA/LV) dysfunction are interlinked in heart failure with preserved ejection fraction (HFpEF); however, little is known about their interplay and relation to cardiac decompensation. We hypothesized that cardiovascular magnetic resonance (CMR) left atrioventricular coupling index (LACI) would identify pathophysiological alterations in HFpEF and be amenable to rest and ergometer-stress CMR. Patients with exertional dyspnoea, signs of diastolic dysfunction (E/e' ≥ 8), and preserved ejection fraction (EF; ≥ 50%) on echocardiography were prospectively recruited and classified as HFpEF (n = 34) or noncardiac dyspnoea (NCD, n = 34) according to pulmonary capillary wedge pressure (PCWP) on right-heart catheterization (rest/stress ≥ 15/25 mmHg). LA and LV volumes were assessed on short-axis real-time cine sequences at rest and during exercise stress. LACI was defined as the ratio of the LA-to-LV end-diastolic volume. Cardiovascular hospitalization (CVH) was assessed after 24 mo. Volume-derived LA (P ≥ 0.008) but not LV (P ≥ 0.347) morphology and function at rest and during exercise stress detected significant differences comparing HFpEF and NCD. There was impaired atrioventricular coupling in HFpEF at rest (LACI, 45.7% vs. 31.6%, P < 0.001) and during exercise stress (45.7% vs. 27.9%, P < 0.001). LACI correlated with PCWP at rest (r = 0.48, P < 0.001) and during exercise stress (r = 0.55, P < 0.001). At rest, LACI was the only volumetry-derived parameter to differentiate patients with NCD from patients with HFpEF, which were identified using exercise-stress thresholds (P = 0.001). Resting and exercise-stress LACI dichotomized at their medians were associated with CVH (P ≤ 0.005). Assessment of LACI is a simple approach for LA/LV coupling quantification and allows easy and fast identification of heart failure with preserved ejection fraction (HFpEF). [ABSTRACT FROM AUTHOR]

Background: Recently, a novel left atrioventricular coupling index (LACI) has been introduced providing prognostic value to predict cardiovascular events beyond common risk factors in patients without cardiovascular disease. Since data on cardiovascular magnetic resonance (CMR)-derived LACI in patients following acute myocardial infarction (AMI) are scarce, we aimed to assess the diagnostic and prognostic implications of LACI in a large AMI patient cohort. Methods: In total, 1046 patients following AMI were included. After primary percutaneous coronary intervention CMR imaging and subsequent functional analyses were performed. LACI was defined by the ratio of the left atrial end-diastolic volume divided by the left ventricular (LV) end-diastolic volume. Major adverse cardiac events (MACE) including death, reinfarction or heart failure within 12 months after the index event were defined as primary clinical endpoint. Results: LACI was significantly higher in patients with MACE compared to those without MACE (p < 0.001). Youden Index identified an optimal LACI cut-off at 34.7% to classify patients at high-risk (p < 0.001 on log-rank testing). Greater LACI was associated with MACE on univariate regression modeling (HR 8.1, 95% CI 3.4–14.9, p < 0.001) and after adjusting for baseline confounders and LV ejection fraction (LVEF) on multivariate regression analyses (HR 3.1 95% CI 1.0–9, p = 0.049). Furthermore, LACI assessment enabled further risk stratification in high-risk patients with impaired LV systolic function (LVEF ≤ 35%; p < 0.001 on log-rank testing). Conclusion: Atrial-ventricular interaction using CMR-derived LACI is a superior measure of outcome beyond LVEF especially in high-risk patients following AMI. Trial registration ClinicalTrials.gov, NCT00712101 and NCT01612312 [ABSTRACT FROM AUTHOR]

Left ventricular (LV) dilatation, a prominent risk factor for heart failure (HF), precedes functional deterioration and is used to stratify patients at risk for arrhythmias and cardiac mortality. Aberrant DNA methylation contributes to maladaptive cardiac remodeling and HF progression following pressure overload and ischemic cardiac insults. However, no study has examined cardiac DNA methylation upon exposure to volume overload (VO) despite being relatively common among HF patients. We carried out global methylome analysis of LV harvested at a decompensated HF stage following exposure to VO induced by aortocaval shunt. VO resulted in pathological cardiac remodeling, characterized by massive LV dilatation and contractile dysfunction at 16 weeks after shunt. Although methylated DNA was not markedly altered globally, 25 differentially methylated promoter regions (DMRs) were identified in shunt vs. sham hearts (20 hypermethylated and 5 hypomethylated regions). The validated hypermethylated loci in Junctophilin-2 (Jph2), Signal peptidase complex subunit 3 (Spcs3), Vesicle-associated membrane protein-associated protein B (Vapb), and Inositol polyphosphate multikinase (Ipmk) were associated with the respective downregulated expression and were consistently observed in dilated LV early after shunt at 1 week after shunt, before functional deterioration starts to manifest. These hypermethylated loci were also detected peripherally in the blood of the shunt mice. Altogether, we have identified conserved DMRs that could be novel epigenetic biomarkers in dilated LV upon VO exposure. [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]

Heart failure (HF) is a major health-care problem and the prognosis of affected patients is poor. HF often coexists with a number of comorbidities of which declining renal function is of particular importance. A loss of glomerular filtration rate, as in acute kidney injury (AKI) or chronic kidney disease (CKD), independently predicts mortality and accelerates the overall progression of cardiovascular disease and HF. Importantly, cardiac and renal diseases interact in a complex bidirectional and interdependent manner in both acute and chronic settings. From a pathophysiological perspective, cardiac and renal diseases share a number of common pathways, including inflammatory and direct, cellular immune-mediated mechanisms; stress-mediated and (neuro)hormonal responses; metabolic and nutritional changes including bone and mineral disorder, altered haemodynamic and acid-base or fluid status; and the development of anaemia. In an effort to better understand the important crosstalk between the two organs, classifications such as the cardio-renal syndromes were developed. This classification might lead to a more precise understanding of the complex interdependent pathophysiology of cardiac and renal diseases. In light of exceptionally high mortality associated with coexisting HF and kidney disease, this Review describes important crosstalk between the heart and kidney, with a focus on HF and kidney disease in the acute and chronic settings. Underlying molecular and cellular pathomechanisms in HF, AKI and CKD are discussed in addition to current and future therapeutic approaches. [ABSTRACT FROM AUTHOR]

Severe aortic stenosis (AS) is a common pathological condition in an ageing population imposing significant morbidity and mortality. Based on distinct hemodynamic features, i.e., ejection fraction (EF), transvalvular gradient and stroke volume, four different AS subtypes can be distinguished: (i) normal EF and high gradient, (ii) reduced EF and high gradient, (iii) reduced EF and low gradient, and (iv) normal EF and low gradient. These subtypes differ with respect to pathophysiological mechanisms, cardiac remodeling, and prognosis. However, little is known about metabolic changes in these different hemodynamic conditions of AS. Thus, we carried out metabolomic analyses in serum samples of 40 AS patients (n = 10 per subtype) and 10 healthy blood donors (controls) using ultrahigh-performance liquid chromatography–tandem mass spectroscopy. A total of 1293 biochemicals could be identified. Principal component analysis revealed different metabolic profiles in all of the subgroups of AS (All-AS) vs. controls. Out of the determined biochemicals, 48% (n = 620) were altered in All-AS vs. controls (p < 0.05). In this regard, levels of various acylcarnitines (e.g., myristoylcarnitine, fold-change 1.85, p < 0.05), ketone bodies (e.g., 3-hydroxybutyrate, fold-change 11.14, p < 0.05) as well as sugar metabolites (e.g., glucose, fold-change 1.22, p < 0.05) were predominantly increased, whereas amino acids (e.g., leucine, fold-change 0.8, p < 0.05) were mainly reduced in All-AS. Interestingly, these changes appeared to be consistent amongst all AS subtypes. Distinct differences between AS subtypes were found for metabolites belonging to hemoglobin metabolism, diacylglycerols, and dihydrosphingomyelins. These findings indicate that relevant changes in substrate utilization appear to be consistent for different hemodynamic subtypes of AS and may therefore reflect common mechanisms during AS-induced heart failure. Additionally, distinct metabolites could be identified to significantly differ between certain AS subtypes. Future studies need to define their pathophysiological implications. [ABSTRACT FROM AUTHOR]

Transcatheter aortic valve replacement (TAVR) has become the standard treatment for aortic stenosis in older patients. It increasingly relies on accurate pre-procedural planning using multidetector computed tomography (MDCT). Since little is known about the required competence levels for MDCT analyses, we comprehensively assessed MDCT TAVR planning reproducibility and accuracy with regard to valve selection in various healthcare workers. 20 randomly selected MDCT of TAVR patients were analyzed using dedicated software by healthcare professionals with varying backgrounds and experience (two structural interventionalists, one imaging specialist, one cardiac surgeon, one general physician, and one medical student). Following the analysis, the most appropriate Edwards SAPIEN 3™ and Medtronic CoreValve valve size was selected. Intra- and inter-observer variability were assessed. The first structural interventionalist was considered as reference standard for inter-observer comparison. Excellent intra- and inter-observer variability was found for the entire group in regard to the MDCT measurements. The best intra-observer agreement and reproducibility were found for the structural interventionalist, while the medical student had the lowest reproducibility. The highest inter-observer agreement was between both structural interventionalists, followed by the imaging specialist. As to valve size selection, the structural interventionalist showed the highest intra-observer reproducibility, independent of the brand of valve used. Compared to the reference structural interventionalist, the second structural interventionalist showed the highest inter-observer agreement for valve size selection [ICC 0.984, 95% CI 0.969–0.991] followed by the cardiac surgeon [ICC 0.947, 95%CI 0.900–0.972]. The lowest inter-observer agreement was found for the medical student [ICC 0.507, 95%CI 0.067–0.739]. While current state-of-the-art MDCT analysis software provides excellent reproducibility for anatomical measurements, the highest levels of confidence in terms of valve size selection were achieved by the performing interventional physicians. This was most likely attributable to observer experience. [ABSTRACT FROM AUTHOR]

The incidence of aortic valve stenosis (AS), the most common reason for aortic valve replacement (AVR), increases with population ageing. While untreated AS is associated with high mortality, different hemodynamic subtypes range from normal left-ventricular function to severe heart failure. However, the molecular nature underlying four different AS subclasses, suggesting vastly different myocardial fates, is unknown. Here, we used direct proteomic analysis of small left-ventricular biopsies to identify unique protein expression profiles and subtype-specific AS mechanisms. Left-ventricular endomyocardial biopsies were harvested from patients during transcatheter AVR, and inclusion criteria were based on echocardiographic diagnosis of severe AS and guideline-defined AS-subtype classification: 1) normal ejection fraction (EF)/high-gradient; 2) low EF/high-gradient; 3) low EF/low-gradient; and 4) paradoxical low-flow/low-gradient AS. Samples from non-failing donor hearts served as control. We analyzed 25 individual left-ventricular biopsies by data-independent acquisition mass spectrometry (DIA-MS), and 26 biopsies by histomorphology and cardiomyocytes by STimulated Emission Depletion (STED) superresolution microscopy. Notably, DIA-MS reliably detected 2273 proteins throughout each individual left-ventricular biopsy, of which 160 proteins showed significant abundance changes between AS-subtype and non-failing samples including the cardiac ryanodine receptor (RyR2). Hierarchical clustering segregated unique proteotypes that identified three hemodynamic AS-subtypes. Additionally, distinct proteotypes were linked with AS-subtype specific differences in cardiomyocyte hypertrophy. Furthermore, superresolution microscopy of immunolabeled biopsy sections showed subcellular RyR2-cluster fragmentation and disruption of the functionally important association with transverse tubules, which occurred specifically in patients with systolic dysfunction and may hence contribute to depressed left-ventricular function in AS. (A) In this study, patients with severe aortic valve stenosis (AS) underwent pre-interventional diagnostic phenotyping including echocardiography prior to (B) transcatheter aortic valve replacement (TAVR), and followed by (C) clinical follow-up. Following the TAVR intervention, LV endomyocardial biopsies were collected for (1) quantitative label-free data-independent acquisition mass spectrometry (DIA-MS) (D-F) and (2) (immuno-)fluorescence labeling (G), confocal microscopy (H), and superresolution stimulated emission depletion (STED) microscopy (I) to identify unique protein expression profiles and subtype-specific AS mechanisms. Proteomic readouts informed about proteins of interest for detailed imaging studies (dashed arrow). (J) Patients with severe AS (aortic valve area (AVA) ≤ 1.0 cm2) were subclassified into one of four hemodynamic subtypes following current guidelines [ 1 , 2 ]: NEF-HG , normal/preserved ejection fraction, high-gradient AS. LEF-HG , low/reduced ejection fraction, high-gradient AS. LEF-LG , low/reduced ejection fraction, low-gradient AS. PLF-LG , paradoxical low-flow, low-gradient AS. Non-failing (NF) donor heart endomyocardial biopsies served as control samples. LVEF, LV ejection fraction; Vmax, aortic valve maximal flow velocity; ΔPm, aortic valve pressure gradient. [Display omitted] • LV biopsies were obtained from patients undergoing TAVR to study hemodynamic subtypes in severe aortic stenosis (AS). • DIA-MS detected 2273 proteins throughout individual LV biopsies and showed 160 myocardial protein abundance changes. • Proteomic profiling segregated AS proteotypes correlating with three hemodynamic subtypes in AS. • Histomorphology showed AS subtype-specific differences in cardiomyocyte hypertrophy. • Superresolution STED imaging revealed RyR2 cluster fragmentation in AS subtypes with reduced systolic LV function. [ABSTRACT FROM AUTHOR]

With emerging therapies, early diagnosis of heart failure with preserved ejection fraction (HFpEF) comes to the fore. Whilst the reference standard of exercise-stress right heart catheterisation is well established, the clinical routine struggles between feasibility of exercise-stress and diagnostic accuracy of available tests. The HFpEF Stress Trial (DZHK-17) prospectively enrolled 75 patients with exertional dyspnoea and echocardiographic signs of diastolic dysfunction (E/e' > 8) who underwent simultaneous rest and exercise-stress echocardiography and right heart catheterisation (RHC). HFpEF was defined according to pulmonary capillary wedge pressure (HFpEF: PCWP rest: ≥15 mmHg stress: ≥25 mmHg). Patients were classified as non-cardiac dyspnoea (NCD) in the absence of HFpEF and cardiovascular disease. LA compliance was defined as reservoir strain (Es)/(E/e'). Follow-up was conducted after 4 years to evaluate cardiovascular hospitalisation (CVH). The final study population included 68 patients (HFpEF n = 34 and NCD n = 34) of which 23 reached the clinical endpoint, 1 patient was lost to follow-up. Patients with HFpEF according to the HFA-PEFF score (≥5 points) had significantly lower LA compliance at rest (p < 0.001) compared to patients with a score ≤ 4. LA compliance at rest outperformed E/e' (AUC 0.78 vs 0.87, p = 0.024) and showed a statistical trend to outperform Es (AUC 0.79 vs 0.87, p = 0.090) for the diagnosis of HFpEF. LA compliance at rest predicted CVH (HR 2.83, 95% CI 1.70–4.74, p < 0.001) irrespective of concomitant atrial fibrillation. LA compliance at rest can be obtained from clinical routine imaging and bears strong diagnostic and prognostic accuracy. Addition of LA compliance can improve the role of echocardiography as the primary test and gatekeeper. Left atrial (LA) compliance is calculated by dividing LA reservoir strain obtained from 2 and 4 chamber view speckle-tracking echocardiography (STE) by E/e' obtained from pulse-wave and tissue doppler. LA compliance shows high diagnostic and prognostic impact in heart failure with preserved ejection fraction (HFpEF) diagnosed according to right heart catheterisation. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Since cardiovascular magnetic resonance (CMR) imaging allows comprehensive quantification of both myocardial function and structure we aimed to assess myocardial remodeling processes in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Methods: CMR imaging was performed in 40 patients with severe AS before and 1 year after TAVR. Image analyses comprised assessments of myocardial volumes, CMR-feature-tracking based atrial and ventricular strain, myocardial T1 mapping, extracellular volume fraction-based calculation of left ventricular (LV) cellular and matrix volumes, as well as ischemic and non-ischemic late gadolinium enhancement analyses. Moreover, biomarkers including NT-proBNP as well as functional and clinical status were documented. Results: Myocardial function improved 1 year after TAVR: LV ejection fraction (57.9 ± 16.9% to 65.4 ± 14.5%, p = 0.002); LV global longitudinal (− 21.4 ± 8.0% to -25.0 ± 6.4%, p < 0.001) and circumferential strain (− 36.9 ± 14.3% to − 42.6 ± 11.8%, p = 0.001); left atrial reservoir (13.3 ± 6.3% to 17.8 ± 6.7%, p = 0.001), conduit (5.5 ± 3.2% to 8.4 ± 4.6%, p = 0.001) and boosterpump strain (8.2 ± 4.6% to 9.9 ± 4.2%, p = 0.027). This was paralleled by regression of total myocardial volume (90.3 ± 21.0 ml/m2 to 73.5 ± 17.0 ml/m2, p < 0.001) including cellular (55.2 ± 13.2 ml/m2 to 45.3 ± 11.1 ml/m2, p < 0.001) and matrix volumes (20.7 ± 6.1 ml/m2 to 18.8 ± 5.3 ml/m2, p = 0.036). These changes were paralleled by recovery from heart failure (decrease of NYHA class: p < 0.001; declining NT-proBNP levels: 2456 ± 3002 ng/L to 988 ± 1222 ng/L, p = 0.001). Conclusion: CMR imaging enables comprehensive detection of myocardial remodeling in patients undergoing TAVR. Regression of LV matrix volume as a surrogate for reversible diffuse myocardial fibrosis is accompanied by increase of myocardial function and recovery from heart failure. Further data are required to define the value of these parameters as therapeutic targets for optimized management of TAVR patients. Trial registration DRKS, DRKS00024479. Registered 10 December 2021—Retrospectively registered, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00024479 [ABSTRACT FROM AUTHOR]

Background: Since cardiovascular magnetic resonance (CMR) imaging allows comprehensive quantification of both myocardial function and structure we aimed to assess myocardial remodeling processes in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Methods: CMR imaging was performed in 40 patients with severe AS before and 1 year after TAVR. Image analyses comprised assessments of myocardial volumes, CMR-feature-tracking based atrial and ventricular strain, myocardial T1 mapping, extracellular volume fraction-based calculation of left ventricular (LV) cellular and matrix volumes, as well as ischemic and non-ischemic late gadolinium enhancement analyses. Moreover, biomarkers including NT-proBNP as well as functional and clinical status were documented. Results: Myocardial function improved 1 year after TAVR: LV ejection fraction (57.9 ± 16.9% to 65.4 ± 14.5%, p = 0.002); LV global longitudinal (− 21.4 ± 8.0% to -25.0 ± 6.4%, p < 0.001) and circumferential strain (− 36.9 ± 14.3% to − 42.6 ± 11.8%, p = 0.001); left atrial reservoir (13.3 ± 6.3% to 17.8 ± 6.7%, p = 0.001), conduit (5.5 ± 3.2% to 8.4 ± 4.6%, p = 0.001) and boosterpump strain (8.2 ± 4.6% to 9.9 ± 4.2%, p = 0.027). This was paralleled by regression of total myocardial volume (90.3 ± 21.0 ml/m2 to 73.5 ± 17.0 ml/m2, p < 0.001) including cellular (55.2 ± 13.2 ml/m2 to 45.3 ± 11.1 ml/m2, p < 0.001) and matrix volumes (20.7 ± 6.1 ml/m2 to 18.8 ± 5.3 ml/m2, p = 0.036). These changes were paralleled by recovery from heart failure (decrease of NYHA class: p < 0.001; declining NT-proBNP levels: 2456 ± 3002 ng/L to 988 ± 1222 ng/L, p = 0.001). Conclusion: CMR imaging enables comprehensive detection of myocardial remodeling in patients undergoing TAVR. Regression of LV matrix volume as a surrogate for reversible diffuse myocardial fibrosis is accompanied by increase of myocardial function and recovery from heart failure. Further data are required to define the value of these parameters as therapeutic targets for optimized management of TAVR patients. Trial registration DRKS, DRKS00024479. Registered 10 December 2021—Retrospectively registered, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00024479 [ABSTRACT FROM AUTHOR]

Feasibility of automated volume-derived cardiac functional evaluation has successfully been demonstrated using cardiovascular magnetic resonance (CMR) imaging. Notwithstanding, strain assessment has proven incremental value for cardiovascular risk stratification. Since introduction of deformation imaging to clinical practice has been complicated by time-consuming post-processing, we sought to investigate automation respectively. CMR data (n = 1095 patients) from two prospectively recruited acute myocardial infarction (AMI) populations with ST-elevation (STEMI) (AIDA STEMI n = 759) and non-STEMI (TATORT-NSTEMI n = 336) were analysed fully automated and manually on conventional cine sequences. LV function assessment included global longitudinal, circumferential, and radial strains (GLS/GCS/GRS). Agreements were assessed between automated and manual strain assessments. The former were assessed for major adverse cardiac event (MACE) prediction within 12 months following AMI. Manually and automated derived GLS showed the best and excellent agreement with an intraclass correlation coefficient (ICC) of 0.81. Agreement was good for GCS and poor for GRS. Amongst automated analyses, GLS (HR 1.12, 95% CI 1.08–1.16, p < 0.001) and GCS (HR 1.07, 95% CI 1.05–1.10, p < 0.001) best predicted MACE with similar diagnostic accuracy compared to manual analyses; area under the curve (AUC) for GLS (auto 0.691 vs. manual 0.693, p = 0.801) and GCS (auto 0.668 vs. manual 0.686, p = 0.425). Amongst automated functional analyses, GLS was the only independent predictor of MACE in multivariate analyses (HR 1.10, 95% CI 1.04–1.15, p < 0.001). Considering high agreement of automated GLS and equally high accuracy for risk prediction compared to the reference standard of manual analyses, automation may improve efficiency and aid in clinical routine implementation. Trial registration: ClinicalTrials.gov, NCT00712101 and NCT01612312. [ABSTRACT FROM AUTHOR]

Background: In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit.Methods: REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance <3.5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome-a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status-was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization.Results: Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; P=0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; P=0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; P=0.004).Conclusions: In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular magnetic resonance imaging is considered the reference standard for assessing cardiac morphology and function and has demonstrated prognostic utility in patients undergoing transcatheter aortic valve replacement (TAVR). Novel fully automated analyses may facilitate data analyses but have not yet been compared against conventional manual data acquisition in patients with severe aortic stenosis (AS).Methods: Fully automated and manual biventricular assessments were performed in 139 AS patients scheduled for TAVR using commercially available software (suiteHEART®, Neosoft; QMass®, Medis Medical Imaging Systems). Volumetric assessment included left ventricular (LV) mass, LV/right ventricular (RV) end-diastolic/end-systolic volume, LV/RV stroke volume, and LV/RV ejection fraction (EF). Results of fully automated and manual analyses were compared. Regression analyses and receiver operator characteristics including area under the curve (AUC) calculation for prediction of the primary study endpoint cardiovascular (CV) death were performed.Results: Fully automated and manual assessment of LVEF revealed similar prediction of CV mortality in univariable (manual: hazard ratio (HR) 0.970 (95% CI 0.943-0.997) p=0.032; automated: HR 0.967 (95% CI 0.939-0.995) p=0.022) and multivariable analyses (model 1: (including significant univariable parameters) manual: HR 0.968 (95% CI 0.938-0.999) p=0.043; automated: HR 0.963 [95% CI 0.933-0.995] p=0.024; model 2: (including CV risk factors) manual: HR 0.962 (95% CI 0.920-0.996) p=0.027; automated: HR 0.954 (95% CI 0.920-0.989) p=0.011). There were no differences in AUC (LVEF fully automated: 0.686; manual: 0.661; p=0.21). Absolute values of LV volumes differed significantly between automated and manual approaches (p < 0.001 for all). Fully automated quantification resulted in a time saving of 10 minutes per patient.Conclusion: Fully automated biventricular volumetric assessments enable efficient and equal risk prediction compared to conventional manual approaches. In addition to significant time saving, this may provide the tools for optimized clinical management and stratification of patients with severe AS undergoing TAVR. [ABSTRACT FROM AUTHOR]

Axial tubule junctions with the sarcoplasmic reticulum control the rapid intracellular Ca2+-induced Ca2+ release that initiates atrial contraction. In atrial myocytes we previously identified a constitutively increased ryanodine receptor (RyR2) phosphorylation at junctional Ca2+ release sites, whereas non-junctional RyR2 clusters were phosphorylated acutely following β-adrenergic stimulation. Here, we hypothesized that the baseline synthesis of 3′,5′-cyclic adenosine monophosphate (cAMP) is constitutively augmented in the axial tubule junctional compartments of atrial myocytes. Confocal immunofluorescence imaging of atrial myocytes revealed that junctin, binding to RyR2 in the sarcoplasmic reticulum, was densely clustered at axial tubule junctions. Interestingly, a new transgenic junctin-targeted FRET cAMP biosensor was exclusively co-clustered in the junctional compartment, and hence allowed to monitor cAMP selectively in the vicinity of junctional RyR2 channels. To dissect local cAMP levels at axial tubule junctions versus subsurface Ca2+ release sites, we developed a confocal FRET imaging technique for living atrial myocytes. A constitutively high adenylyl cyclase activity sustained increased local cAMP levels at axial tubule junctions, whereas β-adrenergic stimulation overcame this cAMP compartmentation resulting in additional phosphorylation of non-junctional RyR2 clusters. Adenylyl cyclase inhibition, however, abolished the junctional RyR2 phosphorylation and decreased L-type Ca2+ channel currents, while FRET imaging showed a rapid cAMP decrease. In conclusion, FRET biosensor imaging identified compartmentalized, constitutively augmented cAMP levels in junctional dyads, driving both the locally increased phosphorylation of RyR2 clusters and larger L-type Ca2+ current density in atrial myocytes. This cell-specific cAMP nanodomain is maintained by a constitutively increased adenylyl cyclase activity, contributing to the rapid junctional Ca2+-induced Ca2+ release, whereas β-adrenergic stimulation overcomes the junctional cAMP compartmentation through cell-wide activation of non-junctional RyR2 clusters. Schematic representation of constitutively increased local cAMP synthesis and Ca2+ fluxes in the junctional compartment of atrial myocytes. A Epac1-based FRET cAMP biosensor fused to the cytosolic junctin N-terminus (Epac1-JNC), expressed in transgenic mice, demonstrates for the first time constitutively augmented cAMP pools in the dyadic cleft of atrial myocytes. (A) At baseline, adenylyl cyclase (AC) activity is constitutively high inside the dyadic cleft, sustaining increased local cAMP levels (FRET decreased) and activating the holoenzyme protein kinase A (PKA holo). The atria-specific cAMP-rich junctional compartment promotes the local PKA phosphorylation of RyR2 channel clusters, priming the rapid baseline Ca2+ release flux. Additionally, the augmented junctional cAMP sustains the local PKA phosphorylation and dissociation of the small G-protein Rad, presumably increasing L-type Ca2+ channel (LTCC) currents and increased Ca2+ influx. Together, both the increased LTCC currents and RyR2 Ca2+ release flux thus synergize the rapid activation of Ca2+-induced Ca2+ release predominantly at axial tubule junctions in atrial myocytes. Indeed, confocal FRET measurements revealed augmented local junctional cAMP levels, explaining the sustained PKA phosphorylation exclusively of junctional but not non-junctional RyR2 channel clusters together with increased LTCC currents under baseline non-stimulated conditions in atrial myocytes. (B) Pharmacological inhibition of sustained adenylyl cyclase activity by MDL-12,330A (MDL) in unstimulated atrial myocytes acutely decreased the junctional cAMP synthesis (FRET increased), the constitutively sustained RyR2 channel phosphorylation at baseline, and the LTCC Ca2+ currents presumably through Rad binding and inhibition of the channel β 2 -subunit. These MDL inhibitory actions thus decrease junctional Ca2+ influx and SR Ca2+ release as indicated by thin arrows. CSQ2, calsequestrin-2; JNC, junctin; JP2, junctophilin-2; LTCC, L-type Ca2+ channel; N, nucleus; RyR2, ryanodine receptor type 2; SR, sarcoplasmic reticulum; TRDN, triadin. [Display omitted] • In atrial myocytes, the SR protein junctin co-localizes with RyR2 channel clusters at voluminous axial tubule junctions. • A junctin-targeted FRET biosensor allows high-resolution monitoring of local cAMP changes at junctional RyR2 clusters. • A constitutively increased adenylyl cyclase activity sustains high junctional cAMP levels in atrial myocytes. • High local cAMP levels augment junctional activitory RyR2 phosphorylation and may disinhibit Rad-dependent LTCC activity. [ABSTRACT FROM AUTHOR]

Placement of an interatrial shunt device reduces pulmonary capillary wedge pressure during exercise in patients with heart failure and preserved or mildly reduced ejection fraction. We aimed to investigate whether an interatrial shunt can reduce heart failure events or improve health status in these patients. In this randomised, international, blinded, sham-controlled trial performed at 89 health-care centres, we included patients (aged ≥40 years) with symptomatic heart failure, an ejection fraction of at least 40%, and pulmonary capillary wedge pressure during exercise of at least 25 mm Hg while exceeding right atrial pressure by at least 5 mm Hg. Patients were randomly assigned (1:1) to receive either a shunt device or sham procedure. Patients and outcome assessors were masked to randomisation. The primary endpoint was a hierarchical composite of cardiovascular death or non-fatal ischemic stroke at 12 months, rate of total heart failure events up to 24 months, and change in Kansas City Cardiomyopathy Questionnaire overall summary score at 12 months. Pre-specified subgroup analyses were conducted for the heart failure event endpoint. Analysis of the primary endpoint, all other efficacy endpoints, and safety endpoints was conducted in the modified intention-to-treat population, defined as all patients randomly allocated to receive treatment, excluding those found to be ineligible after randomisation and therefore not treated. This study is registered with ClinicalTrials.gov , NCT03088033. Between May 25, 2017, and July 24, 2020, 1072 participants were enrolled, of whom 626 were randomly assigned to either the atrial shunt device (n=314) or sham procedure (n=312). There were no differences between groups in the primary composite endpoint (win ratio 1·0 [95% CI 0·8–1·2]; p=0·85) or in the individual components of the primary endpoint. The prespecified subgroups demonstrating a differential effect of atrial shunt device treatment on heart failure events were pulmonary artery systolic pressure at 20W of exercise (p interaction =0·002 [>70 mm Hg associated with worse outcomes]), right atrial volume index (p interaction =0·012 [≥29·7 mL/m2, worse outcomes]), and sex (p interaction =0·02 [men, worse outcomes]). There were no differences in the composite safety endpoint between the two groups (n=116 [38%] for shunt device vs n=97 [31%] for sham procedure; p=0·11). Placement of an atrial shunt device did not reduce the total rate of heart failure events or improve health status in the overall population of patients with heart failure and ejection fraction of greater than or equal to 40%. Corvia Medical. [ABSTRACT FROM AUTHOR]

A large body of evidence suggest an impact of thyroid function on outcomes of cardiovascular diseases, but results for acute pulmonary embolism (PE) are sparse. We analysed the impact of hypothyroidism as well as hyperthyroidism on the short and long-term outcomes of patients with acute PE. The impact was compared to the group of euthyroid PE patients as reference group. Overall, 831 PE patients (median age 69 [IQR 56–77] years; 52.2% females) were analysed. Among these, 734 patients (88.3%) were classified as euthyroid, 40 (4.8%) as hypothyroid and 57 (6.9%) as hyperthyroid. PE patients with hypothyroidism had higher rates of adverse in-hospital outcomes (37.5% vs. 11.6%, P < 0.001), PE-related (22.5% vs. 4.8%, P < 0.001) and all-cause in-hospital death (25.0% vs. 6.8%, P < 0.001), whereas hyperthyroidism did not affect in-hospital outcomes. Long-term mortality was higher in hypothyroidism (52.5% vs. 28.9%, P = 0.002) and hyperthyroidism (43.9% vs. 28.9%, P = 0.018) compared to euthyroid function. In the 750 normotensive PE patients, hyperthyroidism affected adverse in-hospital outcome (OR 2.58 [95%CI 1.12–5.97], P = 0.026) and PE-related in-hospital mortality (OR 3.50 [95%CI 1.10–11.17], P = 0.035) in comparison to euthyroid PE patients, while hypothyroidism showed no influence. Elevated fT4 (HR 1.75 [95%CI 1.16–2.63], P = 0.007) and reduced fT3 values (HR 2.51 [95%CI 1.48–4.28], P = 0.001) were associated with increased long-term mortality. Thyroid dysfunction had a substantial impact on short and long-term outcomes of patients with acute PE. Elevated fT4 and reduced fT3 values were significantly associated with increased long-term mortality in normotensive PE patients. • Thyroid dysfunction had a substantial impact on short and long-term outcomes of patients with PE. • Hyperthyroidism affected adverse in-hospital outcome in normotensive PE patients. • Hypothyroidism showed no influence on in-hospital outcomes in normotensive PE. • Elevated fT4 and reduced fT3 were associated with increased long-term mortality in normotensive PE. [ABSTRACT FROM AUTHOR]

Myocardial deformation assessment by cardiovascular magnetic resonance-feature tracking (CMR-FT) has incremental prognostic value over volumetric analyses. Recently, atrial functional analyses have come to the fore. However, to date recommendations for optimal resolution parameters for accurate atrial functional analyses are still lacking. CMR-FT was performed in 12 healthy volunteers and 9 ischemic heart failure (HF) patients. Cine sequences were acquired using different temporal (20, 30, 40 and 50 frames/cardiac cycle) and spatial resolution parameters (high 1.5 × 1.5 mm in plane and 5 mm slice thickness, standard 1.8 × 1.8 × 8 mm and low 3.0 × 3.0 × 10 mm). Inter- and intra-observer reproducibility were calculated. Increasing temporal resolution is associated with higher absolute strain and strain rate (SR) values. Significant changes in strain assessment for left atrial (LA) total strain occurred between 20 and 30 frames/cycle amounting to 2,5–4,4% in absolute changes depending on spatial resolution settings. From 30 frames/cycle onward, absolute strain values remained unchanged. Significant changes of LA strain rate assessment were observed up to the highest temporal resolution of 50 frames/cycle. Effects of spatial resolution on strain assessment were smaller. For LA total strain a general trend emerged for a mild decrease in strain values obtained comparing the lowest to the highest spatial resolution at temporal resolutions of 20, 40 and 50 frames/cycle (p = 0.006–0.046) but not at 30 frames/cycle (p = 0.140). Temporal and to a smaller extent spatial resolution affect atrial functional assessment. Consistent strain assessment requires a standard spatial resolution and a temporal resolution of 30 frames/cycle, whilst SR assessment requires even higher settings of at least 50 frames/cycle. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Data comparing remote magnetic catheter navigation (RMN) with manual catheter navigation (MCN) ablation of atrial fibrillation (AF) is lacking. The aim of the present prospective observational study was to compare the outcome of RMN versus (vs.) MCN ablation of AF with regards to AF recurrence. Methods: The study comprised 667 consecutive patients with a total of 939 procedures: 287 patients were ablated using RMN, 380 using MCN. Results: There was no significant difference between the groups at baseline. After 2.3 ± 2.3 years of follow‐up, 23% of the patients in the MCN group remained free of AF recurrence compared to 13% in the RMN group (p <.001). After analysis of 299 repeat ablations (133 MCN, 166 RMN) there was a significantly higher reconnection rate of pulmonary veins after RMN ablation p <.001). In multivariable Cox‐regression analysis, RMN ablation was an independent risk factor for AF recurrence besides age, persistent AF, number of isolated pulmonary veins, and left atrial diameter. Procedure time, radiofrequency application time and total number of ablation points were higher in the RMN group. Total fluoroscopy time and total fluoroscopy dose were significantly lower for RMN. Complication rates did not differ between groups (p =.842), although the incidence of significant pericardial effusion was higher in the MCN group (seven cases vs. three in RMN group). Conclusions: In our study the AF recurrence rate and pulmonary vein reconnection rate is higher after RMN ablation with a similar complication rate but reduced probability of pericardial effusion when compared to MCN. [ABSTRACT FROM AUTHOR]

We developed an integrated platform for analysis of parameterized data from human disease models. We report a non‐negative blind deconvolution (NNBD) approach to quantify calcium (Ca2+) handling, beating force and contractility in human‐induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) at the single‐cell level. We employed CRISPR/Cas gene editing to introduce a dilated cardiomyopathy (DCM)‐causing mutation in troponin T (TnT), TnT‐R141W, into wild‐type control iPSCs (MUT). The NNDB‐based method enabled data parametrization, fitting and analysis in wild‐type controls versus isogenic MUT iPSC‐CMs. Of note, Cas9‐edited TnT‐R141W iPSC‐CMs revealed significantly reduced beating force and prolonged contractile event duration. The NNBD‐based platform provides an alternative framework for improved quantitation of molecular disease phenotypes and may contribute to the development of novel diagnostic tools. [ABSTRACT FROM AUTHOR]

Presents a study that measured force, force-time integral, force length area and myocardial oxygen consumption in several isometrically contracting rabbit right ventricular papillary muscles. Methods for papillary muscle isolation; Experimental protocol; Measurement of mechanical parameters and oxygen consumption; Results and discussion.

Cardiovascular magnetic resonance (CMR) imaging provides reliable assessments of biventricular morphology and function. Since manual post-processing is time-consuming and prone to observer variability, efforts have been directed towards novel artificial intelligence-based fully automated analyses. Hence, we sought to investigate the impact of artificial intelligence-based fully automated assessments on the inter-study variability of biventricular volumes and function. Eighteen participants (11 with normal, 3 with heart failure and preserved and 4 with reduced ejection fraction (EF)) underwent serial CMR imaging at in median 63 days (range 49–87) interval. Short axis cine stacks were acquired for the evaluation of left ventricular (LV) mass, LV and right ventricular (RV) end-diastolic, end-systolic and stroke volumes as well as EF. Assessments were performed manually (QMass, Medis Medical Imaging Systems, Leiden, Netherlands) by an experienced (3 years) and inexperienced reader (no active reporting, 45 min of training with five cases from the SCMR consensus data) as well as fully automated (suiteHEART, Neosoft, Pewaukee, WI, USA) without any manual corrections. Inter-study reproducibility was overall excellent with respect to LV volumetric indices, best for the experienced observer (intraclass correlation coefficient (ICC) > 0.98, coefficient of variation (CoV, < 9.6%) closely followed by automated analyses (ICC > 0.93, CoV < 12.4%) and lowest for the inexperienced observer (ICC > 0.86, CoV < 18.8%). Inter-study reproducibility of RV volumes was excellent for the experienced observer (ICC > 0.88, CoV < 10.7%) but considerably lower for automated and inexperienced manual analyses (ICC > 0.69 and > 0.46, CoV < 22.8% and < 28.7% respectively). In this cohort, fully automated analyses allowed reliable serial investigations of LV volumes with comparable inter-study reproducibility to manual analyses performed by an experienced CMR observer. In contrast, RV automated quantification with current algorithms still relied on manual post-processing for reliability. [ABSTRACT FROM AUTHOR]

Background: Myocardial deformation analyses using cardiovascular magnetic resonance (CMR) feature tracking (CMR-FT) have incremental value in the assessment of cardiac function beyond volumetric analyses. Since guidelines do not recommend specifc imaging parameters, we aimed to defne optimal spatial and temporal resolutions for CMR cine images to enable reliable post-processing. Methods: Intra- and inter-observer reproducibility was assessed in 12 healthy subjects and 9 heart failure (HF) patients. Cine images were acquired with diferent temporal (20, 30, 40 and 50 frames/cardiac cycle) and spatial reso‑ lutions (high in-plane 1.5×1.5 mm through-plane 5 mm, standard 1.8×1.8 x 8mm and low 3.0×3.0 x 10mm). CMR-FT comprised left ventricular (LV) global and segmental longitudinal/circumferential strain (GLS/GCS) and associated systolic strain rates (SR), and right ventricular (RV) GLS. Results: Temporal but not spatial resolution did impact absolute strain and SR. Maximum absolute changes between lowest and highest temporal resolution were as follows: 1.8% and 0.3%/s for LV GLS and SR, 2.5% and 0.6%/s for GCS and SR as well as 1.4% for RV GLS. Changes of strain values occurred comparing 20 and 30 frames/cardiac cycle including LV and RV GLS and GCS (p<0.001–0.046). In contrast, SR values (LV GLS/GCS SR) changed signifcantly com‑ paring all successive temporal resolutions (p<0.001–0.013). LV strain and SR reproducibility was not afected by either temporal or spatial resolution, whilst RV strain variability decreased with augmentation of temporal resolution. Conclusion: Temporal but not spatial resolution signifcantly afects strain and SR in CMR-FT deformation analyses. Strain analyses require lower temporal resolution and 30 frames/cardiac cycle ofer consistent strain assessments, whilst SR measurements gain from further increases in temporal resolution. [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]