Circulation: Heart Failure最新文献

Background: Cardiorenal dysfunction with impaired cyclic GMP (cGMP) response is common in patients presenting with acute heart failure (HF). Type V phosphodiesterase (PDEV) is known to be upregulated in HF and may explain the dysfunction of renal response. The aim of this study was to determine whether B-type natriuretic peptide (BNP) alone or in combination with PDEV inhibition improves renal function and increases urinary sodium and cGMP excretion in acute HF.

Methods: This open-label study included 67 patients hospitalized with acute HF and renal dysfunction. Patients were randomized to standard care, low-dose intravenous BNP (0.005 µg/kg per minute), or combination BNP/PDEV inhibition with sildenafil (25 mg q12 hours) for 48 hours. The coprimary end points were the percent change in estimated glomerular filtration rate and blood urea nitrogen from baseline to 48 hours.

Results: Treatment with BNP and BNP/PDEV inhibitor significantly increased plasma cGMP at 24 hours (+25.6% [+9.8%, +84.7%] and +60.8% [+32.3%, +103.8%] for BNP and BNP/PDEV versus -13.5% [-29.1%, +14.2%] with standard care; P=0.001). However, there was no significant change in estimated glomerular filtration rate 0 (-10.8%, +12.7%) for standard care versus 0 (-15.3%, +11.8%) for the BNP group versus -8.8% (-14.3%, +8.3%) for the BNP/PDEV group (P=0.60) or blood urea nitrogen -1.4% (-10.7%, +12.0%) for standard care versus -5.9% (-14.6%, +9.4%) for the BNP group versus +6.9% (-5.3%, +18.8%) for the BNP/PDEV group (P=0.38) between groups. Hypotension was more common in the BNP/PDEV inhibitor group.

Conclusions: BNP and combination BNP/PDEV inhibition increased plasma cGMP in patients with acute HF but did not improve renal function or urinary sodium/cGMP excretion. Our study does not support the use of intravenous low-dose BNP with or without PDEV inhibition to enhance renal function in patients admitted with acute HF.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00972569.

Background: Pregnancy imposes significant cardiovascular adaptations, including progressive increases in plasma volume and cardiac output. For most women, this physiological adaptation resolves at the end of pregnancy, but some women develop pathological dilatation and ultimately heart failure late in pregnancy or in the postpartum period, manifesting as peripartum cardiomyopathy (PPCM). Despite the mortality risk of this form of heart failure, the molecular mechanisms underlying PPCM have not been extensively examined in human hearts.

Methods: Protein and metabolite profiles from left ventricular tissue of end-stage PPCM patients (N=6-7) were compared with dilated cardiomyopathy (DCM; N=5-6) and nonfailing donors (N=7-18) using unbiased quantitative mass spectrometry. All samples were derived from the Sydney Heart Bank. Data are available via ProteomeXchange with identifier PXD055986. Differential protein expression and metabolite abundance and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed.

Results: Proteomic analysis identified 2 proteins, SBSPON (somatomedin B and thrombospondin type 1 domain-containing protein precursor) and TNS3 (tensin 3), that were uniquely downregulated in PPCM. SBSPON, an extracellular matrix protein, and TNS3, involved in actin remodeling and cell signaling, may contribute to impaired tissue remodeling and fibrosis in PPCM. Metabolomic analysis revealed elevated levels of homogentisate and deoxycholate and reduced levels of lactate and alanine in PPCM, indicating disrupted metabolic pathways and glucose utilization. Both PPCM and DCM shared pathways related to inflammation, immune responses, and signal transduction. However, thyroid hormone signaling was notably reduced in PPCM, affecting contractility and calcium handling through altered expression of PLN (phospholamban) and Sarcoendoplasmic Reticulum Calcium ATPase (SERCA). Enhanced endoplasmic reticulum stress and altered endocytosis pathways in PPCM suggested additional mechanisms of energy metabolism disruption.

Conclusions: The present study reveals unique posttranslational molecular features of the PPCM myocardium, which mediates cellular and metabolic remodeling, and holds promise as potential targets for therapeutic intervention.

Background: Currently, there are no therapies targeting specific pathogenic pathways in myocarditis. IL (interleukin)-1 blockade has shown promise in preclinical studies and case reports. We hypothesized that blockade of IL1RAP (IL-1 receptor accessory protein), a shared subunit of the IL-1, IL-33, and IL-36 receptors, could be more efficient than IL-1 blockade alone.

Methods: We induced coxsackievirus B3 (CVB3)-mediated or experimental autoimmune myocarditis (EAM) in BALB/c mice, followed by treatment with an Fc (fragment crystallizable)-modified mIgG2a mouse anti-mouse IL1RAP monoclonal antibody (mCAN10). Myocarditis severity and immune infiltration were assessed by histology and flow cytometry. Cardiac function was measured by echocardiography. We used spatial transcriptomics (Visium 10× Genomics) to compare the gene expression landscape in the hearts of mCAN10-treated versus control mice.

Results: IL1RAP blockade reduced CVB3 and EAM severity. In EAM, the treatment prevented deterioration of cardiac function, measured on day 42 post-disease induction (left ventricular ejection fraction: 56.5% versus 51.0% in isotype controls [P=0.002] and versus 51.4% in mice treated with anti-IL-1β antibodies alone [P=0.003]; n=10-11 mice per group). In the CVB3 model, mCAN10 did not impede viral clearance from the heart and significantly lowered the numbers of CD4⁺ (cluster of differentiation 4) T cells (P=0.025), inflammatory Ly6C⁺CCR2⁺ (lymphocyte antigen 6 complex, locus C/C-C motif chemokine receptor 2) monocytes (P=0.038), neutrophils (P=0.001) and eosinophils (P<0.001) infiltrating the myocardium. The spatial transcriptomic analysis revealed reduced canonical IL-1 signaling and chemokine expression in cardiac immune foci in CVB3-infected mice treated with IL1RAP blockade.

Conclusions: Blocking IL1RAP reduces acute CVB3 myocarditis and EAM severity and preserves cardiac function in EAM. We conclude that IL1RAP blockade is a potential therapeutic strategy in viral and autoimmune myocarditis.

Background: Hypertrophic cardiomyopathy (HCM) is a heterogeneous condition that can lead to atrial fibrillation, heart failure, and sudden cardiac death in many individuals but mild clinical impact in others. The mechanisms underlying this phenotypic heterogeneity are not well defined. The aim of this study was to use plasma proteomic profiling to help illuminate biomarkers that reflect or inform the heterogeneity observed in HCM.

Methods: The Olink antibody-based proteomic platform was used to measure plasma proteins in patients with genotype positive (sarcomeric) HCM participating in the HCM Registry. We assessed associations between plasma protein levels with clinical features, cardiac magnetic resonance imaging metrics, and the development of atrial fibrillation.

Results: We measured 275 proteins in 701 patients with sarcomeric HCM. There were associations between late gadolinium enhancement with proteins reflecting neurohormonal activation (NT-proBNP [N-terminal pro-B-type natriuretic peptide] and ACE2 [angiotensin-converting enzyme 2]). Metrics of left ventricular remodeling had novel associations with proteins involved in vascular development and homeostasis (vascular endothelial growth factor-D and TM [thrombomodulin]). Assessing clinical features, the European Society of Cardiology sudden cardiac death risk score was inversely associated with SCF (stem cell factor). Incident atrial fibrillation was associated with mediators of inflammation and fibrosis (MMP2 [matrix metalloproteinase 2] and SPON1 [spondin 1]).

Conclusions: Proteomic profiling of sarcomeric HCM identified biomarkers associated with adverse imaging and clinical phenotypes. These circulating proteins are part of both established pathways, including neurohormonal activation and fibrosis, and less familiar pathways, including endothelial function and inflammatory proteins less well characterized in HCM. These findings highlight the value of plasma profiling to identify biomarkers of risk and to gain further insights into the pathophysiology of HCM.

Background: Invasive exercise right heart catheterization is a gold standard in diagnosing heart failure with preserved ejection fraction (HFpEF). Body positions during the test influence hemodynamics. However, the discrepancy in HFpEF diagnosis between exercise testing in supine versus upright position is unknown.

Methods: We conducted a 2-center prospective study enrolling patients referred for exercise right heart catheterization for HFpEF. We performed a Supright protocol integrating submaximal supine bicycle ergometry (20 W) followed by maximal upright bicycle ergometry with a breath-by-breath oxygen analyzer. HFpEF hemodynamic criteria specific to testing positions were applied. Patients were considered to have concordant HFpEF if they met criteria in both positions or discordant HFpEF if they met criteria only in the supine position.

Results: Of 36 patients who met HFpEF criteria in supine position, 18 (50%) did not meet criteria in upright position (discordant HFpEF). Discordant HFpEF had less atrial fibrillation (0% versus 55%; P<0.001), lower left atrial volume (60±14 versus 77±21 mL; P=0.010), and lower H₂FPEF score (2.1±1.3 versus 5.1±2.3; P<0.001). In supine position, pulmonary arterial wedge pressure was lower in discordant HFpEF at rest (15±4 versus 19±7 mm Hg; P=0.040). In upright position, pulmonary arterial wedge pressure was lower in discordant HFpEF both at rest (8±4 versus 14±6 mm Hg; P=0.002) and at peak exercise (14±4 versus 27±7 mm Hg; P<0.001). Pulmonary arterial wedge pressure/cardiac output slope was lower in discordant HFpEF (1.6±1.7 versus 3.6±2.9; P<0.001). Maximal workload (46±18 versus 49±24 W; P=0.59) or peak oxygen consumption (11.4±2.8 versus 12.9±3.4 mL/[kg·min]; P=0.15) was similar between groups.

Conclusions: Half of patients who met HFpEF criteria in the supine position did not meet the criteria in the upright position. Patients with a discordant HFpEF phenotype had less structural and hemodynamic abnormalities compared with those with concordant HFpEF. A Supright exercise right heart catheterization approach is feasible and merits further investigation to determine the clinical implications of discordant exercise hemodynamic findings in supine and upright positions.

Spironolactone, a steroidal mineralocorticoid receptor antagonist (MRA), has been used to treat patients with heart failure (HF) for more than half a century. Spironolactone improved outcomes in patients with severely symptomatic HF with reduced ejection fraction, and later, eplerenone expanded the benefits to patients with mildly symptomatic HF with reduced ejection fraction and myocardial infarction complicated by HF. Spironolactone reduced HF events in some patients with HF with preserved ejection fraction, but the results were not generalizable to all patients with HF with preserved ejection fraction. More recently, the nonsteroidal MRA finerenone improved the HF outcomes of patients with HF with preserved ejection fraction, expanding the benefits previously seen among patients with diabetes and albuminuric chronic kidney disease. The use of MRAs has been limited due to excessive concern about hyperkalemia. Education about the limited true risk associated with hyperkalemia, and about how to predict, prevent, and manage hyperkalemia, may lead to wider acceptability and use of these agents. Several ongoing trials are testing steroidal and nonsteroidal MRAs in HF populations. In this review, we perform a critical appraisal of MRA use in HF populations and point toward future directions.