Circulation: Heart Failure最新文献

Contemporary hemodynamic testing intersects with many aspects of cardiovascular disease management. There is a growing understanding that accurate diagnosis, phenotyping, and management of cardiogenic shock, heart failure with preserved ejection fraction, and pulmonary hypertension, and left ventricular assist device support, require both baseline and provocative invasive hemodynamic testing, and often serial measurements. However, there is limited consensus regarding the standardization and interpretation of hemodynamic data. Provocative hemodynamic studies-whether related to volume, drugs, exercise, or device speed-are similarly nonuniform. A frequent limitation to their routine use relates to a lack of concise information regarding provocative study protocols. The aim of this scientific statement is to provide the evidence and rationale underlying best practices for static and provocative right heart catheterization, as well as actionable protocols to standardize their practice. In addition to outlining optimal resting right heart catheterization assessment, indications, and methods for vasodilator challenges to assess pulmonary hypertension reversibility in heart failure, this scientific statement includes discussion on volume challenges, invasive exercise hemodynamic testing, and vasodilator testing for acute pulmonary hypertension. Ramp, reverse-ramp, and exercise studies in patients with left ventricular assist devices are also detailed to help guide care and aid assessment for recovery. The utility and practical application of temporal changes in invasive hemodynamics are covered, from cardiogenic shock to remote patient monitoring. The standardization and advancement of invasive hemodynamic assessment in heart failure represent crucial steps toward optimizing patient outcomes. Continued collaboration across disciplines, enhanced focus on standardization, and investment in emerging technologies are crucial for bridging these gaps and driving innovation.

Background: Left ventricular noncompaction cardiomyopathy (LVNC; OMIM No. 604169) is anatomically characterized by excess trabeculation and deep intertrabecular recesses. It is the third most prevalent pediatric cardiomyopathy. Despite its clinical significance, the pathogenesis of LVNC remains uncertain.

Methods: We examined Numb expression in epicardial cells (EpiCs) and epicardial-derived cells (EPDCs) using a mCherry::Numb knock-in mouse line; used Tbx18^Cre/+ and inducible WT1^CreERT2/+ to generate epicardium-specific Numb and Numblike double knockouts (epicardial Nb;Nl double knockout [EDKO]) and inducible EpiC-specific Nb;Nl knockout, respectively; monitored EpiCs/EPDCs invasion into the myocardium by lineage tracing; assessed LVNC defects via the ratio of noncompact to compact zone thickness/area; utilized single-nuclei mRNA sequencing and biochemical tools to determine the disrupted molecular mechanisms of EDKOs; and used pharmacological approaches to rescue defects in EDKOs. Cardiac structural and functional changes in adult stages were examined using echocardiography and histochemistry. Sample sizes ranged from 3 to 9 hearts across experiments.

Results: Numb is enriched in EpiCs and EPDCs. In EDKO hearts, EPDCs displayed abnormal differentiation, and their migration was arrested at the outer compact zone, resulting in the absence of EPDCs in the inner compact zone and trabeculae. The EDKO hearts displayed LVNC, and inducible EpiC-specific Nb;Nl knockouts (induced at embryonic day 10.5) recapitulated the defects. Single-nuclei mRNA sequencing revealed the upregulation of Fgfr1 (fibroblast growth factor receptor 1) in epicardium and the downregulation of Fgf (fibroblast growth factor) ligands in cardiomyocytes in EDKOs. Exogenous Fgf2 supplementation to pregnant females partially rescued epithelial-mesenchymal transition and compaction defects in EDKO hearts. Female EDKOs survived to adulthood and maintained LVNC.

Conclusions: Ablation of NFPs (Numb family proteins) in EpiCs disrupted the invasion and differentiation of EPDCs and the communication between cardiomyocytes and other cells, and caused LVNC. The epithelial-mesenchymal transition and compaction defects can be partially rescued by exogenous Fgf2 supplementation. Our findings highlight an essential role for the epicardial NFPs-Fgf/Fgfr axis in regulating ventricular compaction.

Background: Patients with heart failure and reduced ejection fraction (HFrEF) have a high residual risk for heart failure hospitalizations and cardiovascular death. We aimed to use multimodality data to identify unique HFrEF subgroups with high residual risk.

Methods: In this VICTORIA substudy (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), clinical, electrocardiographic, echocardiographic, quantitative biomarker, and targeted proteomics data were collected. Agglomerative hierarchical clustering was performed using 105 variables to define HFrEF phenogroups. Cox regression estimated the relationship between the HFrEF phenogroups and the primary composite outcome of cardiovascular death or heart failure hospitalization. External validation of the phenogroups was performed in the BIOSTAT-CHF cohort (Biology Study to Tailored Treatment in Chronic Heart Failure). Multinomial logistic regression identified the most important variables in defining the HFrEF phenogroups.

Results: There were 564 participants; after clustering, the optimal number of HFrEF phenogroups was 3. Phenogroup 1 was young, well-treated with guideline-directed medical therapy, and least likely to have an implantable cardioverter defibrillator. Phenogroup 2 had the highest prevalence of atrial fibrillation and pathological Q-waves on electrocardiography. Phenogroup 3 was older, had more biventricular dysfunction, and had advanced renal disease. A stepwise increase in the risk of the primary composite outcome was observed from HFrEF phenogroup 1 to 3 (hazard ratio, 7.0 [95% CI, 4.1-12.0]; P≤0.01). The phenogroups were externally validated in BIOSTAT-CHF, and phenogroup 3 had similar patient characteristics (eg, older with more significant renal dysfunction) and had the highest event rate at 1 year (41% [95% CI, 38%-45%]). After multinomial regression, GDF-15 (growth differentiation factor 15) was the most important variable in discriminating the 3 HFrEF phenogroups in both VICTORIA and BIOSTAT-CHF.

Conclusions: We identified and externally validated unique HFrEF subpopulations with shared biological characteristics that differentiated residual risk for cardiovascular death or heart failure hospitalization. GDF-15 was the most important protein used to distinguish the 3 HFrEF phenogroups. These findings may inform study entry criteria for future HFrEF trials focused on the development of novel therapeutics.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02861534.

Background: In patients with right ventricular (RV) outflow tract stenosis and pulmonary regurgitation (PR), percutaneous pulmonary valve implantation (PPVI) aims to preserve RV and left ventricular (LV) integrity and function. Our study aimed to assess acute changes in biventricular intrinsic myocardial function occurring with PPVI.

Methods: Twenty patients with RV outflow tract dysfunction (mean±1 SD; age, 23.0±10.9 years; mean peak echocardiographic RV outflow tract gradient, 64±25 mm Hg) underwent PPVI with biventricular assessment of pressure-volume loops using the conductance catheter technique during the same cardiac catheterization. Load-independent parameters of ventricular contractility (ventricular elastance) and ventricular compliance function, as well as pulmonary/systemic arterial elastance and ventriculoarterial coupling, were assessed before and directly after PPVI. Cardiac magnetic resonance for quantification of biventricular volumes, function, and PR was also performed.

Results: After PPVI, both RV ventricular elastance (median [interquartile range], 0.26 [0.16-0.83] to 0.19 [0.13-0.42] mm Hg/mL per m²; P=0.029) and pulmonary systemic arterial elastance (0.32±0.20 to 0.25±0.19 mm Hg/mL per m²; P<0.001) decreased significantly, while right ventriculoarterial coupling (1.14±0.61 to 1.10±0.59; P=0.76) did not change statistically significant. LV ventricular elastance (1.31±0.93 to 1.23±0.72 mm Hg/mL per m²; P=0.68) and left ventriculoarterial coupling (0.75 [0.51-1.23] to 0.82 [0.53-1.10]; P=0.98) were not affected by PPVI although systemic arterial elastance increased significantly (0.83±0.26 to 0.90±0.34 mm Hg/mL per m²; P=0.032). Both RV (P=0.37) and LV (P=0.20) compliance showed no significant change after PPVI. Patients with relevant PR (≥25%; n=10) had lower RV ventricular elastance (P=0.043) before and higher LV compliance (P=0.010) after PPVI compared with patients with minor PR (<25%; n=10), whereas ventriculoarterial coupling was similar between the 2 groups.

Conclusions: Acute reduction of RV overload by PPVI is accompanied by an instantaneous decline in RV contractility with persistent and inefficient ventriculoarterial coupling. The LV adequately adapts to an increase in pre- and post-load with nonsignificant changes in LV intrinsic function and ventriculoarterial coupling. The relevance of these response patterns on long-term biventricular remodeling requires further investigation.

Background: The prevalence and prognostic significance of liver biomarkers in heart failure (HF) with mildly reduced or preserved ejection fraction are uncertain, with both potential hemodynamic and metabolic contributions to liver dysfunction in these patients. We evaluated the prevalence and prognostic value of liver biomarkers and assessed the effects of the nonsteroidal mineralocorticoid receptor antagonist finerenone on these biomarkers and clinical outcomes in FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure).

Methods: FINEARTS-HF was a randomized, double-blind, placebo-controlled trial that enrolled 6001 patients with left ventricular ejection fraction ≥40%, evidence of structural heart disease, and elevated NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Liver biomarkers examined were total bilirubin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase.

Results: Among 5873 patients with available baseline bilirubin measurements, 11.9% had elevated levels (>1.0 mg/dL). Higher bilirubin levels were associated with a greater risk of total worsening HF events and cardiovascular death. Compared with placebo, finerenone rapidly reduced bilirubin and alkaline phosphatase levels (but not transaminase levels), with effects sustained over time. Finerenone reduced the risk of total worsening HF events and cardiovascular death across all bilirubin tertiles (T1 [<0.4 mg/dL], rate ratio 0.94 [95% CI, 0.75-1.17]; T2 [0.5-0.6 mg/dL], 0.83 [0.66-1.05]; T3 [≥0.7 mg/dL], 0.77 [0.62-0.97]), with no significant interaction by bilirubin level (P_interaction=0.43). Consistent effects were observed for the components of the primary outcome, all-cause death, and improvement in the Kansas City Cardiomyopathy Questionnaire total symptom score.

Conclusions: Baseline bilirubin concentration was an independent predictor of worse outcomes but did not modify the benefits of finerenone on morbidity and mortality in HF with mildly reduced or preserved ejection fraction. Finerenone reduced bilirubin and alkaline phosphatase, suggesting a possible decongestive effect in HF with mildly reduced or preserved ejection fraction.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04435626.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) causes a restrictive cardiomyopathy resulting in heart failure (HF). Signaling pathways associated with ATTR-CM are not well defined. The purpose of this study was to identify signaling pathways that are dysregulated in ATTR-CM compared with controls.

Methods: This was a case-control study of cases with ATTR-CM, internal controls with hypertensive left ventricular hypertrophy, and external controls with HF. For model development, ATTR-CM cases were age- and sex-matched with internal controls with hypertensive left ventricular hypertrophy. Plasma proteomics profiling of 7289 proteins was conducted. A sparse partial least squares discriminant analysis was performed to develop a proteomics-based discrimination model from 70% of the data (ie, the training set), and the discriminative ability was tested in the remaining 30% of the data (ie, the internal test set). External validation using HF controls was also conducted. Pathway analysis of significantly (ie, univariable P<10^-6) dysregulated proteins was executed. Signaling pathways with a false discovery rate <0.05 were declared positive.

Results: The analysis included 169 cases and 220 controls. A total of 211 discriminant proteins were identified in the training set from the proteomics-based model developed to distinguish ATTR-CM cases from 170 internal controls with hypertensive left ventricular hypertrophy. The area under the receiver-operating characteristic curve to discriminate ATTR-CM in the test set from 50 external controls with HF was 0.89 (95% CI, 0.82-0.96). The sensitivity was 0.90 (95% CI, 0.75-0.97), and the specificity was 0.86 (95% CI, 0.72-0.96). Pathway analysis revealed the PI3K-Akt (phosphoinositide-3-kinase-protein kinase) pathway and its related pathways (eg, JAK-STAT [Janus kinase-signal transducer and activator of transcription]) were dysregulated. Dysregulation of previously identified pathways, such as the complement and coagulation cascade pathways, was also observed.

Conclusions: This study reveals a distinct proteomic profile of ATTR-CM compared with controls with HF, and elucidates both novel and known signaling pathways that are differentially regulated in ATTR-CM.

Background: Less than 1 in 3 patients in the United States with heart failure (HF) with reduced ejection fraction are receiving guideline-recommended medical therapy. Remote titration programs outside of structured episodes of care may address this issue and improve the implementation of guideline-recommended care.

Methods: AIM-POWER (Artificial Intelligence Mobile Health Trial of a Digital Platform to Optimize Guideline-Directed Heart Failure Therapy Using Wearable Sensors) was a multicenter, open-label, clinical trial of participants with HF with reduced ejection fraction who were not optimized on medical therapy designed to evaluate the safety and efficacy of a digital intervention to guide optimal initiation and titration of pharmacological therapy. Participants were randomized 1:1 to a BiovitalsHF intervention or usual care and followed for 90 days. Participants receiving the intervention assessed their weight daily, and blood pressure and heart rate twice daily. These data were collected remotely and used to create outpatient medication titration recommendations from the BiovitalsHF platform to site clinicians every 2 weeks. The primary outcome was the between-group difference in the change in an HF optimal therapy score.

Results: We randomized 122 participants at 21 sites in the United States. The mean (±SD) age of the participants was 61.6±12.4 years, and 69% were male. The mean left ventricular ejection fraction was 29±6.7%, and the mean baseline HF optimal therapy score was 3.8±1.8 (range, 0-8). At 90 days after randomization, the change in the score was significantly greater in the intervention group than usual care group (1.72 ±1.75 intervention versus 0.44 ±1.18 usual care; P<0.001).

Conclusions: In participants with HF with reduced ejection fraction who were not yet optimized on medical therapy, a digital intervention that focused on the optimization of HF pharmacological therapy resulted in a significantly greater change in an HF optimal therapy score at 90 days than usual care.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04191330.