Therapeutic Targeting of Left Atrial Myopathy in Atrial Fibrillation and Heart Failure With Preserved Ejection Fraction.
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SUBMITTER: Patel RB
PROVIDER: S-EPMC7529338 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The aim of this study was to determine whether left atrial ejection fraction (LAEF) quantified with cardiovascular magnetic resonance (CMR) was different between heart failure with preserved ejection fraction (HFpEF) and controls, and its relation to prognosis. As part of our single-centre, prospective, observational study, 188 subjects (HFpEF n?=?140, controls n?=?48) underwent phenotyping with contrast-enhanced CMR, transthoracic echocardiography, blood sampling and six-minute walk testing. LAEF was calculated using the biplane method. Atrial fibrillation (AF) was present in 43 (31%) of HFpEF subjects. Overall, LAEF (%) was lower in HFpEF patients inclusive of AF (32?±?16) or those in sinus rhythm alone (41?±?12) compared to controls (51?±?11), p?<?0.0001. LAEF correlated inversely with maximal and minimal left atrial volumes indexed (r?=??-?0.602, r?=??-?0.762), and plasma N-terminal pro-atrial natriuretic peptide (r?=??-?0.367); p?<?0.0001. During median follow-up (1429 days), there were 67 composite events of all-cause death or hospitalization for heart failure (22 deaths, 45 HF hospitalizations) in HFpEF. Lower LAEF (below median) was associated with an increased risk of composite endpoints (Log-Rank: all p?=?0.028; sinus p?=?0.036). In multivariable Cox regression analysis, LAEF (adjusted hazard ratio [HR] 0.767, 95% confidence interval [CI] 0.591-0.996; p?=?0.047) and indexed extracellular volume (HR 1.422, CI 1.015-1.992; p?=?0.041) were the only parameters that remained significant when added to a base prognostic model comprising age, prior HF hospitalization, diastolic blood pressure, lung disease, NYHA, six-minute-walk-test-distance, haemoglobin, creatinine and B-type natriuretic peptide. CMR-derived LAEF is lower in HFpEF compared to healthy controls and is a strong prognostic biomarker.
| S-EPMC6942575 | biostudies-literature
Project description:Left atrial (LA) enlargement is present in the majority of heart failure with preserved ejection fraction (HFpEF) patients and is a marker of risk. However, the importance of LA function in HFpEF is less well understood.The PARAMOUNT trial enrolled HFpEF patients (LVEF ?45%, NT-proBNP >400?pg/mL). We assessed LA reservoir, conduit, and pump function using two-dimensional volume indices and speckle tracking echocardiography in 135 HFpEF patients in sinus rhythm at the time of echocardiography and 40 healthy controls of similar age and gender. Systolic LA strain was related to clinical characteristics and measures of cardiac structure and function. Compared with controls, HFpEF patients had worse LA reservoir, conduit, and pump function. The differences in systolic LA strain (controls 39.2?±?6.6% vs. HFpEF 24.6?±?7.3%) between groups remained significant after adjustments and even in the subsets of HFpEF patients with normal LA size or without a history of AF. Among HFpEF patients, lower systolic LA strain was associated with higher prevalence of prior HF hospitalization and history of AF, as well as worse LV systolic function, and higher LV mass and LA volume. However, NT-proBNP and E/E' were similar across the quartiles of LA function.In this HFpEF cohort, we observed impairment in all phases of LA function, and systolic LA strain was decreased independent of LA size or history of AF. LA dysfunction may be a marker of severity and play a pathophysiological role in HFpEF.NCT00887588.
| S-EPMC5535768 | biostudies-literature
Project description:BackgroundAlthough left atrial (LA) mechanical dysfunction in heart failure with preserved ejection fraction (HFpEF) is associated with poor clinical outcomes, the influence of LA myopathy on temporal changes in cardiovascular biomarkers is unclear.Methods and resultsWe evaluated biomarker correlates of LA myopathy, as defined by reduced LA strain, and the associations of LA strain with longitudinal changes in biomarkers among participants in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial. LA speckle-tracking was performed on baseline echocardiograms of RELAX participants to measure LA reservoir and LA contractile strain. Of the 216 RELAX participants, 169 (78%) had measurable LA strain and biomarker data. Participants with LA reservoir strain below median (13.5%, interquartile range: 10%-22.5%) were older, more likely to have atrial fibrillation, and had higher jugular venous pressure (P < .05 for all). At baseline, higher levels of endothelin-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin I were independently associated with lower LA reservoir and contractile strain (Padjusted < .05 for all comparisons). Higher LA reservoir strain (? coefficient per 1-unit increase: -21.2, 95% CI: -38.8, -3.7; P?=?.02) was independently associated with reduction in NT-proBNP at 24 weeks.ConclusionIn HFpEF, LA myopathy is characterized by elevation in biomarkers of neurohormonal activation and myocardial necrosis. Lower LA function is associated with continued elevation in NT-proBNP over time, suggesting that LA myopathy is associated with persistent congestion in HFpEF.
| S-EPMC7078046 | biostudies-literature
Project description:Impaired left atrial (LA) function in heart failure with preserved ejection fraction (HFpEF) is associated with adverse outcomes. A subgroup of HFpEF may have LA myopathy out of proportion to left ventricular (LV) dysfunction; therefore, we sought to characterize HFpEF patients with disproportionate LA myopathy. In the prospective, multicenter, Prevalence of Microvascular Dysfunction in HFpEF study, we defined disproportionate LA myopathy based on degree of LA reservoir strain abnormality in relation to LV myopathy (LV global longitudinal strain [GLS]) by calculating the residuals from a linear regression of LA reservoir strain and LV GLS. We evaluated associations of disproportionate LA myopathy with hemodynamics and performed a plasma proteomic analysis to identify proteins associated with disproportionate LA myopathy; proteins were validated in an independent sample. Disproportionate LA myopathy correlated with better LV diastolic function but was associated with lower stroke volume reserve after passive leg raise independent of atrial fibrillation (AF). Additionally, disproportionate LA myopathy was associated with higher pulmonary artery systolic pressure, higher pulmonary vascular resistance, and lower coronary flow reserve. Of 248 proteins, we identified and validated 5 proteins (involved in cardiomyocyte stretch, extracellular matrix remodeling, and inflammation) that were associated with disproportionate LA myopathy independent of AF. In HFpEF, LA myopathy may exist out of proportion to LV myopathy. Disproportionate LA myopathy is a distinct HFpEF subtype associated with worse hemodynamics and a distinct proteomic signature, independent of AF.
| S-EPMC7921666 | biostudies-literature
Project description:BackgroundMany patients with heart failure and preserved ejection fraction have no overt volume overload and normal resting left atrial (LA) pressure.ObjectivesThis study sought to characterize patients with normal resting LA pressure (pulmonary capillary wedge pressure [PCWP] <15 mm Hg) but exercise-induced left atrial hypertension (EILAH).MethodsThe 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) trial randomized 626 patients with ejection fraction ≥40% and exercise PCWP ≥25 mm Hg to atrial shunt or sham procedure. The primary trial outcome, a hierarchical composite of death, heart failure hospitalization, intensification of diuretics, and change in health status was compared between patients with EILAH and those with heart failure and resting left atrial hypertension (RELAH).ResultsPatients with EILAH (29%) had similar symptom severity, but lower natriuretic peptide levels, higher 6-minute walk distance, less atrial fibrillation, lower left ventricular mass, smaller LA volumes, lower E/e', and better LA strain. PCWP was lower at rest, but had a larger increase with exercise in EILAH. Neither group as a whole had a significant effect from shunt therapy vs sham. Patients with EILAH were more likely to have characteristics associated with atrial shunt responsiveness (peak exercise pulmonary vascular resistance <1.74 WU) and no pacemaker (63% vs 46%; P < 0.001). The win ratio for the primary outcome was 1.56 (P = 0.08) in patients with EILAH and 1.51 (P = 0.04) in those with RELAH when responder characteristics were present.ConclusionsPatients with EILAH had similar symptom severity but less advanced myocardial and pulmonary vascular disease. This important subgroup may be difficult to diagnose without invasive exercise hemodynamics, but it has characteristics associated with favorable response to atrial shunt therapy. (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 TRIAL II]; NCT03088033).
| S-EPMC11185159 | biostudies-literature
Project description:BackgroundParoxysmal and permanent atrial fibrillation (AF) are common in heart failure with preserved ejection fraction (HFpEF).ObjectivesThis study sought to determine the implications of left atrial (LA) myopathy and dysrhythmia across the spectrum of AF burden in HFpEF.MethodsConsecutive patients with HFpEF (n = 285) and control subjects (n = 146) underwent invasive exercise testing and echocardiographic assessment of cardiac structure, function, and pericardial restraint.ResultsPatients with HFpEF were categorized into stages of AF progression: 181 (65%) had no history of AF, 49 (18%) had paroxysmal AF, and 48 (17%) had permanent AF. Patients with permanent AF were more congested with greater pulmonary vascular disease and lower cardiac output. LA volumes increased, while LA compliance, LA reservoir strain, and right ventricular function decreased with increasing AF burden. The presence of permanent AF was characterized by a distinct pathophysiology, with greater total heart volume caused by atrial dilatation, leading to elevated filling pressures through heightened pericardial restraint. Survival decreased with increasing AF burden. Ten-year progression to permanent AF was common, particularly in paroxysmal AF (52%), and the likelihood of AF progression increased with higher AF stage, poorer LA compliance, and lower LA strain.ConclusionsLA compliance and mechanics progressively decline with increasing AF burden in HFpEF, increasing risk for new onset AF and progressive AF. These changes promote development of a unique phenotype of HFpEF characterized by heightened ventricular interaction, right heart failure, and worsening pulmonary vascular disease. Further study is required to identify therapeutic interventions targeting LA myopathy to improve outcomes in HFpEF.
| S-EPMC7455760 | biostudies-literature
Project description:AimsUnderstanding of the pathophysiology of progressive heart failure (HF) in patients with heart failure with preserved ejection fraction (HFpEF) is incomplete. We sought to identify factors differentially associated with risk of progressive HF death and hospitalization in patients with HFpEF compared with patients with HF and reduced ejection fraction (HFrEF).Methods and resultsProspective cohort study of patients newly referred to secondary care with suspicion of HF, based on symptoms and signs of HF and elevated natriuretic peptides (NP), followed up for a minimum of 6 years. HFpEF and HFrEF were diagnosed according to the 2016 European Society of Cardiology guidelines. Of 960 patients referred, 467 had HFpEF (49%), 311 had HFrEF (32%), and 182 (19%) had neither. Atrial fibrillation (AF) was found in 37% of patients with HFpEF and 34% with HFrEF. During 6 years follow-up, 19% of HFrEF and 14% of HFpEF patients were hospitalized or died due to progressive HF, hazard ratio (HR) 0.67 (95% CI: 0.47-0.96; P = 0.028). AF was the only marker that was differentially associated with progressive HF death or hospitalization in patients with HFpEF HR 2.58 (95% CI: 1.59-4.21; P < 0.001) versus HFrEF HR 1.11 (95% CI: 0.65-1.89; P = 0.7).ConclusionsDe novo patients diagnosed with HFrEF have greater risk of death or hospitalization due to progressive HF than patients with HFpEF. AF is associated with increased risk of progressive HF death or hospitalization in HFpEF but not HFrEF, raising the intriguing possibility that this may be a novel therapeutic target in this growing population.
| S-EPMC9715884 | biostudies-literature
Project description:AimsWe sought to determine the prognostic impact of left atrial (LA) size and function in patients with heart failure with preserved ejection fraction (HFpEF) in sinus rhythm (SR) vs. atrial fibrillation (AF).Methods and resultsWe enrolled consecutive HFpEF patients and assessed indexed LA volumes and emptying fractions (LA-EF) on cardiac magnetic resonance imaging. In addition, all patients underwent right and left heart catheterization, 6 min walk test, and N-terminal prohormone of brain natriuretic peptide evaluation. We prospectively followed patients and used Cox regression models to determine the association of LA size and function with a composite endpoint of heart failure hospitalization and cardiovascular death. A total of 188 patients (71% female patients, 70 ± 8 years old) were included of whom 92 (49%) were in persistent AF. Sixty-five patients reached the combined endpoint during a follow-up of 31 (9-57) months. Multivariate Cox regression adjusted for established risk factors revealed that LA-EF was significantly associated with outcome in patients in SR [adjusted hazard ratio 2.14; 95% confidence interval (1.32-3.47) per 1-SD decline, P = 0.002]. In persistent AF, no LA imaging parameter was related to outcome. By receiver operating characteristic and restricted cubic spline analyses, we identified an LA-EF ≥ 40% as best indicator for favourable outcomes in patients with HFpEF and SR. Persistent AF carried a similar risk for adverse outcome compared with impaired LA-EF (<40%) in SR (log-rank, P = 0.340).ConclusionsIn HFpEF patients in SR, impaired LA-EF is independently associated with worse cardiovascular outcome, which is similar to persistent AF. In persistent AF, LA parameters lose their prognostic ability.
| S-EPMC8787979 | biostudies-literature
Project description:BackgroundLeft atrial (LA) size is an established marker of risk for adverse outcomes in heart failure with preserved ejection fraction (HFpEF). However, the independent prognostic importance of LA function in HFpEF is not known.Methods and resultsWe assessed LA function measured by speckle-tracking echocardiography in 357 patients with HFpEF enrolled in the Treatment Of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial who were in sinus rhythm at the time of echocardiography. Lower peak LA strain, indicating LA dysfunction, was associated with older age, higher prevalence of atrial fibrillation and left ventricular (LV) hypertrophy, worse LV and right ventricular systolic function, and worse LV diastolic function. At a mean follow-up of 31 months (interquartile range, 18-43months), 91 patients (25.5%) experienced the primary composite end point of cardiovascular death, HF hospitalization, and aborted sudden death. Lower peak LA strain was associated with a higher risk of the composite end point (hazard ratio, 0.96 per unit of reduction in strain; 95% confidence interval, 0.94-0.99; P=0.009) and of HF hospitalization alone (hazard ratio, 0.95 per unit of reduction in strain; 95% confidence interval, 0.92-0.98; P=0.003). The association of LA strain with incident HF hospitalization remained significant after adjustment for clinical confounders, but not after further adjustment for LV global longitudinal strain and the E/E' ratio, parameters of LV systolic and diastolic function, respectively.ConclusionsLA dysfunction in HFpEF is associated with a higher risk of HF hospitalization independent of potential clinical confounders, but not independent of LV strain and filling pressure. Impairment in LV systolic and diastolic function largely explains the association between impaired LA function and higher risk of HF hospitalization in HFpEF.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00094302.
| S-EPMC4826720 | biostudies-literature
Project description:BackgroundAlthough ∼20% of the elderly population develops atrial fibrillation (AF), little is known about the mechanisms. Heart failure with preserved ejection fraction (HFpEF), which is associated with AF, is more common in aged women than in men.ObjectiveThe purpose of this study was to identify potential mechanisms of AF in an age-related HFpEF model.MethodsIn aged female Fischer F344 rats (21- to 24-month-old), which are prone to HFpEF, we induced AF by atrial pacing. Young Fischer F344 female rats (3- to 4-month-old) and age-matched Sprague Dawley female rats (27-month-old) served as controls. Phenotyping included echocardiography to assess left ventricular structure/function; in vivo electrophysiology and ex vivo high-resolution optical mapping to assess AF vulnerability; systemic and atrial inflammatory profiling; atrial histology; and expression of inflammasome signaling proteins.ResultsAged rats developed left ventricular hypertrophy, left atrial enlargement, diastolic dysfunction, and pulmonary congestion, without ejection fraction impairment, thus meeting the criteria for HFpEF. Increased serum inflammatory markers, hypertension, and obesity further characterize aged females. Sinoatrial and atrioventricular node dysfunction was associated with the high inducibility of AF in aged rats. Ex vivo electrical activation mapping revealed abnormal β-adrenergic responsiveness and slowed conduction velocity. Atrial inflammasome signaling was enhanced in aged rats, which may contribute to fibrotic remodeling and high AF susceptibility.ConclusionTogether, our data demonstrate that aging-related atrial remodeling and HFpEF are associated with atrial enlargement, fibrosis, conduction abnormalities, and nodal dysfunction, favoring a substrate conducive to AF.
| S-EPMC7802887 | biostudies-literature