Patients with paradoxical low-flow, low-gradient aortic stenosis gain the least benefit from TAVI among all hemodynamic subtypes.

BACKGROUND: Substantial controversy exists regarding the clinical benefit of patients with severe paradoxical low-flow, low-gradient aortic stenosis (PLF-LG AS) from TAVI. Therefore, we compared post-TAVI benefit by long-term mortality (all-cause, CV and SCD), clinical improvement of heart failure symptoms, and cardiac reverse remodelling in guideline-defined AS subtypes. METHODS: We prospectively included 250 consecutive TAVI patients. TTE, 6mwt, MLHFQ, NYHA status and NT-proBNP were recorded at baseline and 6 months. Long-term mortality and causes of death were assessed. RESULTS: 107 individuals suffered from normal EF, high gradient AS (NEF-HG AS), 36 from low EF, high gradient AS (LEF-HG), 52 from "classic" low-flow, low-gradient AS (LEF-LG AS), and 38 from paradoxical low-flow, low-gradient AS (PLF-LG AS). TAVI lead to a significant decrease in MLHFQ score and NT-proBNP levels in all subtypes except for PLF-LG. Regarding reverse remodelling, a significant increase in EF and decrease in LVEDV was present only in subtypes with reduced baseline EF, whereas a significant decrease in LVMI and LAVI could be observed in all subtypes except for PLF-LG. During a follow-up of 3-5 years, PLF-LG patients exhibited the poorest survival among all subtypes (HR 4.2, P = 0.0002 for CV mortality; HR 7.3, P = 0.004 for SCD, in comparison with NEF-HG). Importantly, PLF-LG was independently predictive for CV mortality (HR 2.9 [1.3-6.9], P = 0.009). CONCLUSIONS: PLF-LG patients exhibit the highest mortality (particularly CV and SCD), the poorest symptomatic benefit and the least reverse cardiac remodelling after TAVI among all subtypes. Thus, this cohort seems to gain the least benefit.

Next-generation atrial fibrillation ablation: clinical performance of pulsed-field ablation and very high-power short-duration radiofrequency.

INTRODUCTION: Pulsed-field energy (PFA) and very high-power short-duration radiofrequency (vHPSD-RF) are two novel ablation methods for pulmonary vein isolation (PVI). Both PFA and vHPSD-RF show promise for improving efficacy, safety, and reducing procedure durations. However, direct comparisons between these two techniques are scarce. METHODS AND RESULTS: Retrospective analysis of 82 patients with symptomatic AF. Of these, 52 patients received PFA and 30 received vHPSD-RF (90 W, 4 s) as index procedure. At the 6-month follow-up, AF recurrence occurred in 4 patients following PFA and 5 patients following vHPSD-RF (p-value = 0.138). Significant improvements in the EHRA and NYHA stages were evident in both PFA (p < 0.001 and p = 0.047, respectively) and vHPSD-RF groups (p = 0.007 and p = 0.012, respectively). The total procedure duration and the left atrial dwell time were significantly shorter in the PFA group (64 ± 19 min vs. 99 ± 32 min, p < 0.001 and 41 ± 12 min vs. 62 ± 29 min, p < 0.001, respectively). The fluoroscopy time and dose area product were significantly higher in PFA (14 ± 6 vs. 9 ± 5 min, p < 0.001 and 14 ± 9 vs. 11 ± 9 Gy cm2, p = 0.046, respectively). One patient in the vHPSD-RF group suffered a stroke, not directly linked to the procedure (0 vs. 1 major complication, p = 0.366). CONCLUSION: Based on this retrospective single-center study, PFA and vHPSD-RF were associated with similar effectiveness and safety profiles. PFA was linked to shorter procedure times and higher radiation exposure compared to vHPSD-RF.

Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome.

Noonan syndrome patients harboring causative variants in LZTR1 are particularly at risk to develop severe and early-onset hypertrophic cardiomyopathy. In this study, we investigate the mechanistic consequences of a homozygous variant LZTR1L580P by using patient-specific and CRISPR-Cas9-corrected induced pluripotent stem cell (iPSC) cardiomyocytes. Molecular, cellular, and functional phenotyping in combination with in silico prediction identify an LZTR1L580P-specific disease mechanism provoking cardiac hypertrophy. The variant is predicted to alter the binding affinity of the dimerization domains facilitating the formation of linear LZTR1 polymers. LZTR1 complex dysfunction results in the accumulation of RAS GTPases, thereby provoking global pathological changes of the proteomic landscape ultimately leading to cellular hypertrophy. Furthermore, our data show that cardiomyocyte-specific MRAS degradation is mediated by LZTR1 via non-proteasomal pathways, whereas RIT1 degradation is mediated by both LZTR1-dependent and LZTR1-independent pathways. Uni- or biallelic genetic correction of the LZTR1L580P missense variant rescues the molecular and cellular disease phenotype, providing proof of concept for CRISPR-based therapies.

Dysferlin Enables Tubular Membrane Proliferation in Cardiac Hypertrophy.

BACKGROUND: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies but can result in cardiac failure if left untreated. We hypothesized that the tail-anchored protein dysferlin with multiple Ca2+-binding C2-domains is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy. OBJECTIVE: To reveal the impact of the membrane fusion and repair protein dysferlin on TAT network stabilization and proliferation necessary for the hypertrophic growth of cardiomyocytes. METHODS AND RESULTS: Super-resolution light and electron microscopy of mouse cardiomyocytes identified a specific localization of dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum, a.k.a. junctional complexes for Ca2+-induced Ca2+ release. Mass spectrometry was used to characterize the cardiac dysferlin interactome, thereby identifying a novel protein interaction with the membrane-tethering sarcoplasmic reticulum protein juncophilin-2, a putative interactor of L-type Ca2+ channels and ryanodine receptor Ca2+ release channels in junctional complexes. While the dysferlin knockout caused a mild progressive phenotype of dilated cardiomyopathy in the mouse heart, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction, dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while dysferlin knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging demonstrated a profound reorganization of the TAT network in wild-type left-ventricular myocytes post-transverse aortic constriction with robust proliferation of axial tubules, which critically depended on the increased expression of dysferlin within newly emerging tubule components. CONCLUSIONS: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-sarcoplasmic reticulum junctional complexes for regulated excitation-contraction coupling and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure overload.

Left Atrial Roof Enlargement Is a Distinct Feature of Heart Failure With Preserved Ejection Fraction.

BACKGROUND: It remains unknown to what extent intrinsic atrial cardiomyopathy or left ventricular diastolic dysfunction drive atrial remodeling and functional failure in heart failure with preserved ejection fraction (HFpEF). Computational 3-dimensional (3D) models fitted to cardiovascular magnetic resonance allow state-of-the-art anatomic and functional assessment, and we hypothesized to identify a phenotype linked to HFpEF. METHODS: Patients with exertional dyspnea and diastolic dysfunction on echocardiography (E/e', >8) were prospectively recruited and classified as HFpEF or noncardiac dyspnea based on right heart catheterization. All patients underwent rest and exercise-stress right heart catheterization and cardiovascular magnetic resonance. Computational 3D anatomic left atrial (LA) models were generated based on short-axis cine sequences. A fully automated pipeline was developed to segment cardiovascular magnetic resonance images and build 3D statistical models of LA shape and find the 3D patterns discriminant between HFpEF and noncardiac dyspnea. In addition, atrial morphology and function were quantified by conventional volumetric analyses and deformation imaging. A clinical follow-up was conducted after 24 months for the evaluation of cardiovascular hospitalization. RESULTS: Beyond atrial size, the 3D LA models revealed roof dilation as the main feature found in masked HFpEF (diagnosed during exercise-stress only) preceding a pattern shift to overall atrial size in overt HFpEF (diagnosed at rest). Characteristics of the 3D model were integrated into the LA HFpEF shape score, a biomarker to characterize the gradual remodeling between noncardiac dyspnea and HFpEF. The LA HFpEF shape score was able to discriminate HFpEF (n=34) to noncardiac dyspnea (n=34; area under the curve, 0.81) and was associated with a risk for atrial fibrillation occurrence (hazard ratio, 1.02 [95% CI, 1.01-1.04]; P=0.003), as well as cardiovascular hospitalization (hazard ratio, 1.02 [95% CI, 1.00-1.04]; P=0.043). CONCLUSIONS: LA roof dilation is an early remodeling pattern in masked HFpEF advancing to overall LA enlargement in overt HFpEF. These distinct features predict the occurrence of atrial fibrillation and cardiovascular hospitalization. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03260621.

2-Year Outcomes of an Atrial Shunt Device in HFpEF/HFmrEF: Results From REDUCE LAP-HF II.

BACKGROUND: The REDUCE LAP-HF II (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II) trial found that, compared with a sham procedure, the Corvia Atrial Shunt did not improve outcomes in heart failure with preserved or mildly reduced ejection fraction. However, after 12-month follow-up, "responders" (peak-exercise pulmonary vascular resistance <1.74 WU and absence of a cardiac rhythm management device) were identified. OBJECTIVES: This study sought to determine: 1) the overall efficacy and safety of the atrial shunt vs sham control after 2 years of follow-up; and 2) whether the benefits of atrial shunting are sustained in responders during longer-term follow-up or are offset by adverse effects of the shunt. METHODS: The study analyzed 2-year outcomes in the overall REDUCE LAP-HF II trial, as well as in responder and nonresponder subgroups. The primary endpoint was a hierarchical composite of cardiovascular death or nonfatal ischemic/embolic stroke, total heart failure events, and change in health status. RESULTS: In 621 randomized patients, there was no difference between the shunt (n = 309) and sham (n = 312) groups in the primary endpoint (win ratio: 1.01 [95% CI: 0.82-1.24]) or its individual components at 2 years. Shunt patency at 24 months was 98% in shunt-treated patients. Cardiovascular mortality and nonfatal ischemic stroke were not different between the groups; however, major adverse cardiac events were more common in those patients assigned to the shunt compared with sham (6.9% vs 2.7%; P = 0.018). More patients randomized to the shunt had an increase in right ventricular volume of ≥30% compared with the sham control (39% vs 28%, respectively; P < 0.001), but right ventricular dysfunction was uncommon and not different between the treatment groups. In responders (n = 313), the shunt was superior to sham (win ratio: 1.36 [95% CI: 1.02-1.83]; P = 0.037, with 51% fewer HF events [incidence rate ratio: 0.49 [95% CI: 0.25-0.95]; P = 0.034]). In nonresponders (n = 265), atrial shunting was inferior to sham (win ratio: 0.73 [95% CI: 0.54-0.98]). CONCLUSIONS: At 2 years of follow-up in REDUCE LAP-HF II, there was no difference in efficacy between the atrial shunt and sham groups in the overall trial group. The potential clinical benefit identified in the responder group after 1 and 2 years of follow-up is currently being evaluated in the RESPONDER-HF (Re-Evaluation of the Corvia Atrial Shunt Device in a Precision Medicine Trial to Determine Efficacy in Mildly Reduced or Preserved Ejection Fraction Heart Failure) trial. (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II [REDUCE LAP-HF II]; NCT03088033).

Cardiac fibrosis as a predictor for sudden cardiac death after transcatheter aortic valve implantation.

BACKGROUND: Cardiac fibrosis plays a major pathophysiological role in any form of chronic heart disease, and high levels are associated with poor outcome. Diffuse and focal cardiac fibrosis are different subtypes, which have different pathomechanisms and prognostic implications. The total fibrosis burden in endomyocardial biopsy tissue was recently proved to play an independent prognostic role in aortic stenosis patients after transcatheter aortic valve implantation (TAVI). AIMS: Here, for the first time, we aim to assess the specific impact of different fibrosis subtypes on sudden cardiac death (SCD) as a primary reason for cardiovascular mortality after TAVI. METHODS: The fibrosis pattern was assessed histologically in the left ventricular biopsies obtained during TAVI interventions in 161 patients, who received a structured follow-up thereafter. RESULTS: Receiver operating characteristic analyses, performed 6, 12, 24 and 48 months after TAVI, showed diffuse, but not focal, fibrosis as a significant predictor for SCD at all timepoints, with the highest area under the curve at the first time point and a decrease in its SCD predictivity over time. In both multivariate Cox proportional hazards and Fine-Gray competing risk models, including both fibrosis subtypes, as well as age, sex and ejection fraction, high diffuse fibrosis remained statistically significant. Accordingly, it represents an independent SCD predictor, most importantly for the occurrence of early events. CONCLUSIONS: The burden of diffuse cardiac fibrosis plays an important and independent prognostic role regarding SCD early after TAVI. Therefore, the histological evaluation of fibrosis topography has value as a prognostic tool for TAVI patients and may help to tailor individualised approaches to optimise their postinterventional management.

NaV1.8 as Proarrhythmic Target in a Ventricular Cardiac Stem Cell Model.

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.

CMR-based cardiac phenotyping in different forms of heart failure.

Heart failure (HF) is a heterogenous disease requiring precise diagnostics and knowledge of pathophysiological processes. Since structural and functional imaging data are scarce we hypothesized that cardiac magnetic resonance (CMR)-based analyses would provide accurate characterization and mechanistic insights into different HF groups comprising preserved (HFpEF), mid-range (HFmrEF) and reduced ejection fraction (HFrEF). 22 HFpEF, 17 HFmrEF and 15 HFrEF patients as well as 19 healthy volunteers were included. CMR image assessment contained left atrial (LA) and left ventricular (LV) volumetric evaluation as well as left atrioventricular coupling index (LACI). Furthermore, CMR feature-tracking included LV and LA strain in terms of reservoir (Es), conduit (Ee) and active boosterpump (Ea) function. CMR-based tissue characterization comprised T1 mapping as well as late-gadolinium enhancement (LGE) analyses. HFpEF patients showed predominant atrial impairment (Es 20.8%vs.25.4%, p = 0.02 and Ee 8.3%vs.13.5%, p = 0.001) and increased LACI compared to healthy controls (14.5%vs.23.3%, p = 0.004). Patients with HFmrEF showed LV enlargement but mostly preserved LA function with a compensatory increase in LA boosterpump (LA Ea: 15.0%, p = 0.049). In HFrEF LA and LV functional impairment was documented (Es: 14.2%, Ee: 5.4% p < 0.001 respectively; Ea: 8.8%, p = 0.02). This was paralleled by non-invasively assessed progressive fibrosis (T1 mapping and LGE; HFrEF > HFmrEF > HFpEF). CMR-imaging reveals insights into HF phenotypes with mainly atrial affection in HFpEF, ventricular affection with atrial compensation in HFmrEF and global impairment in HFrEF paralleled by progressive LV fibrosis. These data suggest a necessity for a personalized HF management based on imaging findings for future optimized patient management.

Heart failure with preserved ejection fraction: diagnosis, risk assessment, and treatment.

The aetiology of heart failure with preserved ejection fraction (HFpEF) is heterogenous and overlaps with that of several comorbidities like atrial fibrillation, diabetes mellitus, chronic kidney disease, valvular heart disease, iron deficiency, or sarcopenia. The diagnosis of HFpEF involves evaluating cardiac dysfunction through imaging techniques and assessing increased left ventricular filling pressure, which can be measured directly or estimated through various proxies including natriuretic peptides. To better narrow down the differential diagnosis of HFpEF, European and American heart failure guidelines advocate the use of different algorithms including comorbidities that require diagnosis and rigorous treatment during the evaluation process. Therapeutic recommendations differ between guidelines. Whilst sodium glucose transporter 2 inhibitors have a solid evidence base, the recommendations differ with regard to the use of inhibitors of the renin-angiotensin-aldosterone axis. Unless indicated for specific comorbidities, the use of beta-blockers should be discouraged in HFpEF. The aim of this article is to provide an overview of the current state of the art in HFpEF diagnosis, clinical evaluation, and treatment.

Transition from asymptomatic to symptomatic systolic chronic heart failure: rationale and design of TransitionCHF.

AIMS: Chronic systolic heart failure (CHF) is a major health burden. A relevant number of patients shows asymptomatic left ventricular dysfunction (ALVSD) before symptomatic CHF or becomes asymptomatic after initiating heart failure therapy. Clinical course, prognosis, and response to pharmacological and device-based treatment are largely unknown in these two distinct groups of patients. Current pharmacological and interventional therapies do neither properly address the underlying pathophysiology nor prevent malignant loss of function. New therapeutic paradigms are needed to stop the progression from asymptomatic to symptomatic heart failure. Key questions are what causes progression of clinically asymptomatic New York Heart Association (NYHA) I heart failure to overt heart failure (>NYHA I) in some but not all patients and the underlying reasons for this transition. This requires the identification of disease mechanisms and biomarkers that predict outcome in well-defined cohorts for innovative preclinical and clinical trials. METHODS AND RESULTS: TransitionCHF is a prospective, multicentre, longitudinal pathophysiological evaluation cohort study in patients with asymptomatic systolic dysfunction NYHA I and left ventricular ejection fraction ≤40%. The cohort comprises both incidental findings and patients who had become asymptomatic after a previous symptomatic event. TransitionCHF has recruited 1000 patients with ALVSD caused by various aetiologies in 20 university heart failure clinics across Germany. Both patients with and without comorbidities at study entry will be recruited. Patients will be systematically investigated and followed up annually over the course of the study. The primary composite endpoint is time to hospitalization for heart failure and cardiovascular death. The secondary endpoints assess time to all-cause mortality, to cardiovascular mortality, to heart failure mortality, to all-cause hospitalization, to heart failure hospitalization, and to recurrent heart failure hospitalizations, as well as time to assist device implantation/transplantation. Additional investigations focusing on biomarkers, comorbidities, gender aspects, nutrition, and functional parameters including quality of life will be performed. CONCLUSIONS: TransitionCHF will provide a more thorough pathophysiological understanding of the progression of asymptomatic systolic dysfunction into symptomatic heart failure that will help develop therapies tailored to prevent progressive heart failure.

Randomized investigation of the MitraClip device in heart failure: Design and rationale of the RESHAPE-HF2 trial design.

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.

Atrial Shunt Device Effects on Cardiac Structure and Function in Heart Failure With Preserved Ejection Fraction: The REDUCE LAP-HF II Randomized Clinical Trial.

Importance: Although the results of A Study to Evaluate the Corvia Medical Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF II) trial were neutral overall, atrial shunt therapy demonstrated potential efficacy in responders (no latent pulmonary vascular disease and no cardiac rhythm management device). Post hoc analyses were conducted to evaluate the effect of shunt vs sham stratified by responder status. Objective: To evaluate the effect of atrial shunt vs sham control on cardiac structure/function in the overall study and stratified by responder status. Design, Setting, and Participants: This was a sham-controlled randomized clinical trial of an atrial shunt device in heart failure with preserved ejection fraction (HFpEF)/HF with mildly reduced EF (HFmrEF). Trial participants with evaluable echocardiography scans were recruited from 89 international medical centers. Data were analyzed from April 2023 to January 2024. Interventions: Atrial shunt device or sham control. Main Outcome Measures: Changes in echocardiographic measures from baseline to 1, 6, 12, and 24 months after index procedure. Results: The modified intention-to-treat analysis of the REDUCE LAP-HF II trial included 621 randomized patients (median [IQR] age, 72.0 [66.0-77.0] years; 382 female [61.5%]; shunt arm, 309 [49.8%]; sham control arm, 312 [50.2%]). Through 24 months, 212 of 217 patients (98%) in the shunt arm with evaluable echocardiograms had patent shunts. In the overall trial population, the shunt reduced left ventricular (LV) end-diastolic volume (mean difference, -5.65 mL; P <.001), left atrial (LA) minimal volume (mean difference, -2.8 mL; P =.01), and improved LV systolic tissue Doppler velocity (mean difference, 0.69 cm/s; P <.001) and LA emptying fraction (mean difference, 1.88 percentage units; P =.02) compared with sham. Shunt treatment also increased right ventricular (RV; mean difference, 9.58 mL; P <.001) and right atrial (RA; mean difference, 9.71 mL; P <.001) volumes but had no effect on RV systolic function, pulmonary artery pressure, or RA pressure compared with sham. In the shunt arm, responders had smaller increases in RV end-diastolic volume (mean difference, 5.71 mL vs 15.18 mL; interaction P =.01), RV end-systolic volume (mean difference, 1.58 mL vs 7.89 mL; interaction P =.002), and RV/LV ratio (mean difference, 0.07 vs 0.20; interaction P <.001) and larger increases in transmitral A wave velocity (mean difference, 5.08 cm/s vs -1.97 cm/s; interaction P =.02) compared with nonresponders randomized to the shunt, suggesting greater ability to accommodate shunted blood through the pulmonary circulation enabling LA unloading. Conclusions and Relevance: In this post hoc analysis of the REDUCE LAP-HF II trial, over 2 years of follow-up, atrial shunting led to reverse remodeling of left-sided chambers and increases in volume of right-sided chambers consistent with the shunt flow but no change in RV systolic function compared with sham. Changes in cardiac structure/function were more favorable in responders compared with nonresponders treated with the shunt, supporting the previously identified responder group hypothesis and mechanism, although further evaluation with longer follow-up is needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03088033.

Prognostic and diagnostic implications of impaired rest and exercise-stress left atrial compliance in heart failure with preserved ejection fraction: Insights from the HFpEF stress trial.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Impact of epicardial adipose tissue on cardiac function and morphology in patients with diastolic dysfunction.

AIMS: This study aimed to identify the impact of increased epicardial adipose tissue (EAT) and its regional distribution on cardiac function in patients with diastolic dysfunction. METHODS AND RESULTS: Sixty-eight patients with exertional dyspnoea (New York Heart Association ≥II), preserved ejection fraction (≥50%), and diastolic dysfunction (E/e' ≥ 8) underwent rest and stress right heart catheterization, transthoracic echocardiography, and cardiovascular magnetic resonance (CMR). EAT volumes were depicted from CMR short-axis stacks. First, the impact of increased EAT above the median was investigated. Second, the association of ventricular and atrial EAT with myocardial deformation at rest and during exercise stress was analysed in a multivariable regression analysis. Patients with high EAT had higher HFA-PEFF and H2FPEFF scores as well as N-terminal prohormone of brain natriuretic peptide levels (all P < 0.048). They were diagnosed with manifest heart failure with preserved ejection fraction (HFpEF) more frequently (low EAT: 37% vs. high EAT: 64%; P = 0.029) and had signs of adverse remodelling indicated by higher T1 times (P < 0.001). No differences in biventricular volumetry and left ventricular mass (all P > 0.074) were observed. Patients with high EAT had impaired atrial strain at rest and during exercise stress, and impaired ventricular strain during exercise stress. Regionally increased EAT was independently associated with functional impairment of the adjacent chambers. CONCLUSIONS: Patients with diastolic dysfunction and increased EAT show more pronounced signs of diastolic functional failure and adverse structural remodelling. Despite similar morphological characteristics, patients with high EAT show significant cardiac functional impairment, in particular in the atria. Our results indicate that regionally increased EAT directly induces atrial functional failure, which represents a distinct pathophysiological feature in HFpEF.

Rest and exercise-stress estimated pulmonary capillary wedge pressure using real-time free-breathing cardiovascular magnetic resonance imaging.

BACKGROUND: Identification of increased pulmonary capillary wedge pressure (PCWP) by right heart catheterization (RHC) is the reference standard for the diagnosis of heart failure with preserved ejection fraction (HFpEF). Recently, cardiovascular magnetic resonance (CMR) imaging estimation of PCWP at rest was introduced as a non-invasive alternative. Since many patients are only identified during physiological exercise-stress, we hypothesized that novel exercise-stress CMR-derived PCWP emerges superior compared to its assessment at rest. METHODS: The HFpEF-Stress Trial prospectively recruited 75 patients with exertional dyspnea and diastolic dysfunction who then underwent rest and exercise-stress RHC and CMR. HFpEF was defined according to PCWP (overt HFpEF ≥15 mmHg at rest, masked HFpEF ≥25 mmHg during exercise-stress). CMR-derived PCWP was calculated based on previously published formula using left ventricular mass and either biplane left atrial volume (LAV) or monoplane left atrial area (LAA). RESULTS: LAV (rest/stress: r = 0.50/r = 0.55, p < 0.001) and LAA PCWP (rest/stress: r = 0.50/r = 0.48, p < 0.001) correlated significantly with RHC-derived PCWP while numerically overestimating PCWP at rest and underestimating PCWP during exercise-stress. LAV and LAA PCWP showed good diagnostic accuracy to detect HFpEF (area under the receiver operating characteristic curve (AUC) LAV rest 0.73, stress 0.81; LAA rest 0.72, stress 0.77) with incremental diagnostic value for the detection of masked HFpEF using exercise-stress (AUC LAV rest 0.54 vs stress 0.67, p = 0.019, LAA rest 0.52 vs stress 0.66, p = 0.012). LAV but not LAA PCWP during exercise-stress was a predictor for 24 months hospitalization independent of a medical history for atrial fibrillation (hazard ratio (HR) 1.26, 95% confidence interval 1.02-1.55, p = 0.032). CONCLUSION: Non-invasive PCWP correlates well with the invasive reference at rest and during exercise stress. There is overall good diagnostic accuracy for HFpEF assessment using CMR-derived estimated PCWP despite deviations in absolute agreement. Non-invasive exercise derived PCWP may particularly facilitate detection of masked HFpEF in the future.

Epicardial adipose tissue as an independent predictor of long-term outcome in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.

BACKGROUND: Accurate risk stratification is important to improve patient selection and outcome of patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). As epicardial adipose tissue (EAT) is discussed to be involved in cardiovascular disease, it could be useful as a marker of poor prognosis in patients with severe AS undergoing TAVR. METHODS: A total of 416 patients diagnosed with severe AS by transthoracic echocardiography were assigned for TAVR and enrolled for systematic assessment. Patients underwent clinical surveys and 5-year long-term follow-up, with all-cause mortality as the primary endpoint. EAT volume was quantified on pre-TAVR planning CTs. Patients were retrospectively dichotomized at the median of 74 cm3 of EAT into groups with low EAT and high EAT volumes. Mortality rates were compared using Kaplan-Meyer plots and uni- and multivariable cox regression analyses. RESULTS: A total number of 341 of 416 patients (median age 80.9 years, 45% female) were included in the final analysis. Patients with high EAT volumes had similar short-term outcome (p = 0.794) but significantly worse long-term prognosis (p = 0.023) compared to patients with low EAT volumes. Increased EAT volumes were associated with worse long-term outcome (HR1.59; p = 0.031) independently from concomitant cardiovascular risk factors, general type of AS, and functional echocardiography parameters of AS severity (HR1.69; p = 0.013). CONCLUSION: Increased EAT volume is an independent predictor of all-cause mortality in patients with severe AS undergoing TAVR. It can be easily obtained from pre-TAVR planning CTs and may thus qualify as a novel marker to improve prognostication and management of patient with severe AS. TRIAL REGISTRATION: DRKS, DRKS00024479.