Left Atrium in Heart Failure With Preserved Ejection Fraction
2014; Lippincott Williams & Wilkins; Volume: 7; Issue: 6 Linguagem: Inglês
10.1161/circheartfailure.114.001276
ISSN1941-3297
AutoresAndrea Rossi, Mihai Gheorghiade, Filippos Triposkiadis, Scott D. Solomon, Burkert Pieske, Javed Butler,
Tópico(s)Cardiac pacing and defibrillation studies
ResumoHomeCirculation: Heart FailureVol. 7, No. 6Left Atrium in Heart Failure With Preserved Ejection Fraction Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBLeft Atrium in Heart Failure With Preserved Ejection FractionStructure, Function, and Significance Andrea Rossi, MD, Mihai Gheorghiade, MD, Filippos Triposkiadis, MD, Scott D. Solomon, MD, Burkert Pieske, MD and Javed Butler, MD MPH Andrea RossiAndrea Rossi From the Section of Cardiology, Department of Medicine, University of Verona, Verona, Italy (A.R.); Center for Cardiovascular Innovation, Northwestern Feinberg School of Medicine, Chicago, IL (M.G.); Department of Medicine, Cardiology Division, University of Larissa, Larissa, Greece (F.T.); Department of Medicine, Cardiology Division, Brigham and Womens Hospital, Harvard Medicine School, Boston, MA (S.D.S.); Department of Cardiology, Medical University Graz, Graz, Austria (B.P.); and Department of Medicine, Cardiology Division, Emory University, Atlanta, GA (J.B.). , Mihai GheorghiadeMihai Gheorghiade From the Section of Cardiology, Department of Medicine, University of Verona, Verona, Italy (A.R.); Center for Cardiovascular Innovation, Northwestern Feinberg School of Medicine, Chicago, IL (M.G.); Department of Medicine, Cardiology Division, University of Larissa, Larissa, Greece (F.T.); Department of Medicine, Cardiology Division, Brigham and Womens Hospital, Harvard Medicine School, Boston, MA (S.D.S.); Department of Cardiology, Medical University Graz, Graz, Austria (B.P.); and Department of Medicine, Cardiology Division, Emory University, Atlanta, GA (J.B.). , Filippos TriposkiadisFilippos Triposkiadis From the Section of Cardiology, Department of Medicine, University of Verona, Verona, Italy (A.R.); Center for Cardiovascular Innovation, Northwestern Feinberg School of Medicine, Chicago, IL (M.G.); Department of Medicine, Cardiology Division, University of Larissa, Larissa, Greece (F.T.); Department of Medicine, Cardiology Division, Brigham and Womens Hospital, Harvard Medicine School, Boston, MA (S.D.S.); Department of Cardiology, Medical University Graz, Graz, Austria (B.P.); and Department of Medicine, Cardiology Division, Emory University, Atlanta, GA (J.B.). , Scott D. SolomonScott D. Solomon From the Section of Cardiology, Department of Medicine, University of Verona, Verona, Italy (A.R.); Center for Cardiovascular Innovation, Northwestern Feinberg School of Medicine, Chicago, IL (M.G.); Department of Medicine, Cardiology Division, University of Larissa, Larissa, Greece (F.T.); Department of Medicine, Cardiology Division, Brigham and Womens Hospital, Harvard Medicine School, Boston, MA (S.D.S.); Department of Cardiology, Medical University Graz, Graz, Austria (B.P.); and Department of Medicine, Cardiology Division, Emory University, Atlanta, GA (J.B.). , Burkert PieskeBurkert Pieske From the Section of Cardiology, Department of Medicine, University of Verona, Verona, Italy (A.R.); Center for Cardiovascular Innovation, Northwestern Feinberg School of Medicine, Chicago, IL (M.G.); Department of Medicine, Cardiology Division, University of Larissa, Larissa, Greece (F.T.); Department of Medicine, Cardiology Division, Brigham and Womens Hospital, Harvard Medicine School, Boston, MA (S.D.S.); Department of Cardiology, Medical University Graz, Graz, Austria (B.P.); and Department of Medicine, Cardiology Division, Emory University, Atlanta, GA (J.B.). and Javed ButlerJaved Butler From the Section of Cardiology, Department of Medicine, University of Verona, Verona, Italy (A.R.); Center for Cardiovascular Innovation, Northwestern Feinberg School of Medicine, Chicago, IL (M.G.); Department of Medicine, Cardiology Division, University of Larissa, Larissa, Greece (F.T.); Department of Medicine, Cardiology Division, Brigham and Womens Hospital, Harvard Medicine School, Boston, MA (S.D.S.); Department of Cardiology, Medical University Graz, Graz, Austria (B.P.); and Department of Medicine, Cardiology Division, Emory University, Atlanta, GA (J.B.). Originally published1 Nov 2014https://doi.org/10.1161/CIRCHEARTFAILURE.114.001276Circulation: Heart Failure. 2014;7:1042–1049Cardiac remodeling is a fundamental part of the heart failure (HF) syndrome, representing a common response to various pathological stimuli that result in changes in the structural and functional properties of the heart. To date, most studies in HF have focused on ventricular remodeling, and much less emphasis has been placed on atrial structural and functional changes. Specifically, in the context of HF with preserved ejection fraction (HFpEF), more attention has recently been placed on the left atrial (LA) remodeling, which is now considered a potential therapeutic target and an end point for evaluation of novel therapies. In this review, we discuss the pathophysiologic and clinical implication of LA remodeling in HFpEF.AnatomyLeft atrium is a thin-walled structure located in the inflow path from the pulmonary veins to the left ventricle (LV) and is characterized by (a) main body with smooth walls that embryologically is developed from the outgrowth of the pulmonary veins and (b) by a finger-like trabeculated appendage, which is a remnant of the original embryonic left atrium.1 Distribution of atrial myocyte fibers is highly variable, but some components are relatively constant. In particular, the Bachmann's bundle is the most superficial group of circumferential myofibers located close to the atrioventricular groove. In this bundle, the electric conduction from right to LA preferentially occurs. Other myocardial longitudinal fibres are likely responsible for upward motion of mitral annulus during atrial contraction.FunctionMechanical FunctionThe mechanical function of LA is usually defined by 3 phases of LA volume variations during the cardiac cycle. The reservoir phase takes place during ventricular systole when the LA collects blood coming from the pulmonary veins. This phase is mechanistically determined by LA relaxation and by LV contraction, which moves the mitral annulus toward the apex, resulting in increased LA volume.2 Atrial compliance allows chamber volume to increase during the reservoir phase, maintaining filling pressures within normal limits. A reduction in atrial compliance increases LA pressure, particularly at the end-ventricular systole (v-wave). In the early diastole, blood stored in LA during the reservoir phase is driven into LV by the high early diastolic atrial–ventricular pressure gradient. Subsequently, direct flow from the pulmonary vein through the atrium into the ventricle takes place (atrial conduit volume). At end-diastole, atrial contraction occurs, forcing blood to fill the LV3 (Figure 1). Thus, LA contributes importantly to cardiac function, and altered LA diastolic and systolic properties may influence cardiac filling and output.Download figureDownload PowerPointFigure 1. Phases of left atrial function. Left atrial chamber serves as a reservoir storing blood coming from pulmonary vein during ventricular systole and acts as a conduit that empties into the ventricle after mitral valve opening and passively transfers pulmonary vein flow during ventricular diastasis. Left atrium finally contracts and actively empties during ventricular end diastole, completing ventricular filling. LA indicates left atrial; LV, left ventricle; Vp, left atrial volume before atrial contraction; Vmax, maximal volume (as defined at left ventricular end-systolic phase); and Vmin, left atrial minimal volume (as defined at left ventricular end-diastolic phase). Reprinted from Karayannis et al3 with permission of the publisher. Copyright © 2007, Springer Science + Business Media. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.Neurohormonal FunctionMyocytes produce and store natriuretic peptides in intracellular granules as prohormone. Atrial natriuretic peptide is mainly produced in atria and is secreted in the blood stream, exerting many of its actions through the A-type natriuretic peptide receptor, resulting principally in diuresis and vasodilation. Increased atrial volume and stretch are mainly responsible for its release.4 Natriuretic peptide secretion is also stimulated by paracrine factors, such as endothelin, nitric oxide, angiotensin II, vasopressin, and adrenergic agonists; all systems typically activated in HF.5 Consequently, atrial endocrine function might be a crucial mechanism to compensate the hemodynamic and neurohormonal disturbances seen in HF.Regulatory FunctionLA is crucial for the volume receptor reflex through its mechanoreceptors located in the venous–atrial junctions.6 An optimal volume control is essential for cardiovascular function and might be vital in conditions like hemorrhages and HF. This system is regulated on a moment-by-moment basis and works in parallel with other endocrine systems, such as natriuretic peptide, and angiotensin–aldosterone signals for more long-term regulation. The atrial mechanoreceptors are highly efficient, and fluctuation in venous volume of 32 mL/m2 is associated with 6.5-fold increase risk of postoperative AF.49 In elderly patients, an enlarged LA is associated with a 2-fold increased risk of incident HF.50DiagnosisThe European Society of Cardiology51 recommend that 3 conditions must be met for HFpEF diagnosis: (1) HF symptoms or sign, (2) normal or near-normal ejection fraction, and (3) evidence of elevated filling pressure (wedge pressure or Doppler E/E′ ratio or natriuretic peptide level). In the majority of HFpEF studies, LA size is mild to moderate enlargement (Table 2). LA volume is determined mainly by LV diastolic dysfunction.63 The relatively load-independency of a dilated LA provides an important advantage over Doppler parameters that are related to filling pressures. Also, LA volume is a long-term marker of ventricular pressure.64 This is crucial as patients with HFpEF may have normal filling pressure at rest with disproportionate increase during effort. Thus, LA imaging may provide important clue for HFpEF diagnosis.Table 2. Left Atrial Remodeling in Heart Failure With Preserved Ejection Fraction StudiesPatientsEchocardiographic Inclusion CriteriaLA Volume, mL/m2LA Area, cm2LA Diameter, cmLA Classification (ASE/EAE)TOPCAT52935EF>4529.8±12.51PARAMOUNT53292EF>4535.9±13.52Aldo-DHF54422EF>50 and DD or AF28±8NRELAX55216EF>5044 (35, 59)3CHARM56312EF>4041.3±14.73I-PRESERVE25745EF>4523±61PEP-CHF578502 over: EF>40 or LAD >40 or IVT≥12 mm or E/A 553.9±0.51Gupta/ARIC5985EF>503.4 (3.1, 3.8)NTribouilloy60368EF>504.1±0.71Northwestern61402EF>50 and DD grade ≥234±142Kaneko36301EF>554.13±1.01Yamamoto62245EF>404.4±0.82Rossi26183EF>454.1±1.01LA classification used cut off value for left atrial size identified by American (ASE) and European (EAE) Society of Echocardiography: N, normal (left atrial diameter, ≤2.3 cm/m2; area, ≤20 cm2/m2; volume, ≤28 mL/m2); 1, mildly enlarged (left atrial diameter, ≤2.6 cm/m2; area, ≤30 cm2/m2; volume, ≤33 mL/m2); 2, moderately enlarged (left atrial diameter, ≤2.9 cm/m2; area, ≤40 cm2/m2; volume, ≤39 mL/m2); 3, severely enlarged (left atrial diameter, ≥3.0 cm/m2; area, >40 cm2/m2; volume, ≥40 mL/m2). AF indicates atrial fibrillation; Aldo-DHF, aldosterone receptor blockade in diastolic heart failure; ARIC, Atherosclerosis Risk In Communities; CHARM, Candesartan in Heart failure: Assessment of reduction in mortality and morbidity; DD, diastolic dysfunction; EF, ejection fraction; I-PRESERVED, the Irbesartan in Heart Failure with Preserved Ejection Fraction trial; IVT, interventricular septum thickness; LA, left atrial; LAD, left atrial diameter; PARAMOUNT, Prospective Comparison of ARNI With ARB Management of Heart Failure With Preserved Ejection Fraction; PEP-CHF, The Perindopril in Elderly People with Chronic Heart Failure; RELAX, the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction; and TOPCAT, Treatment Of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist.PrognosisLA volume is a marker of increased morbidity and mortality for various cardiac diseases, including HF.44 A large meta-analysis showed that LA dilation was associated with 2.4-fold increase risk of mortality, independent of ejection fraction, restrictive mitral filling, functional class, and age.65 LA size is modified in HFpEF, and the degree of atrial dilation is associated with increased mortality25,26,36,62 (Figure 5).Download figureDownload PowerPointFigure 5. Prognostic significance of left atrial remodeling. The associations between hazard ratios (HR; y-axis) for mortality in previous studies by left atrial size (blue boxes) and ejection fraction (green boxes) are shown over a wide range of ventricular systolic function as defined by ejection fraction (EF; x-axis). Left atrial size maintained a significant association with mortality independently of the mechanisms underlying ventricular dysfunction. Note that the hazard ratios cannot be compared across studies because different methodologies were used to quantify left atrial size.Reverse Atrial RemodelingAs recently pointed out by a consensus article on HFpEF, another potential application of LA volume is as a therapeutic target.66 LA remodeling may identify patients who might improve with, and aid in monitoring the response to, novel pharmacological and nonpharmacological therapies. In patients with end-stage renal disease, a progressive increase of LA volume is associated with incident cardiovascular events.67 LA reversal remodeling is possible and has been described after surgery for mitral valve diseases68 and in hypertensive patients with ACE-inhibitors.69 In hypertensive patients with LV hypertrophy, both an increase and a decrease of LA size during follow-up were associated with onset of AF.70 In patients with HF undergoing resynchronization therapy, LA improvement is associated with decreased risk for atrial arrhythmias and improved survival.71 In HFpEF, benefit with carvedilol was amplified in patients with dilated LA, suggesting that LA might be used to select HFpEF patients who might have more benefit from therapy.62 Recently, the Prospective Comparison of ARNI With ARB Management of Heart Failure With Preserved Ejection Fraction trial showed that angiotensin receptor naprilysin inhibitor compared with valsartan significantly reduced both natriuretic peptide levels and LA volume.53 The ongoing Safety and Efficacy Study of Four Dose Regiments of BAY1021189 in Patients With Heart Failure and Preserved Ejection Fraction Suffering From Worsening Chronic Heart Failure trial also includes changes in natriuretic peptide levels and LA volume as primary outcome measures in patients treated with vericiguat versus placebo.72 Finally, based on these data, the Efficacy and Safety of LCZ696 Compared to Valsartan on Morbidity and Mortality in Heart Failure With Preserved Ejection Fraction trial will use LA enlargement as an eligibility criteria for enrolment (http://clinicaltrials.gov/ct2/show/study/NCT01920711).ConclusionsLA structure and function is easily assessable and holds promise to provide incremental value to existing parameters for diagnosis, management, and research for patients with HFpEF. With the growing burden of HFpEF, a projected increase over time with aging population, and with no known therapy with proven efficacy, new prevention and treatment strategies for HFpEF are needed. LA might be useful both for identifying patients with and those at risk for HFpEF and may be a marker for target for novel therapies. Further research on the importance and clinical utility of LA in patients with HFpEF is needed.DisclosuresDrs Rossi, Triposkiadis, Solomon, and Pieske have no relevant conflict of interests. Dr Gheorghiade reports following relationships: Abbott Laboratories, Astellas, AstraZeneca, Bayer Schering Pharma AG, Cardiorentis Ltd, CorThera, Cytokinetics, CytoPherx, Inc, DebioPharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, INC, Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Ono Pharmaceuticals USA, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda Pharmaceuticals, and Trevena Therapeutics, and has received significant support from Bayer Schering Pharma AG, DebioPharm S.A., Medtronic,Novartis Pharma AG, Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, and Takeda Pharmaceuticals. Dr Butler reports research support from the National Institutes of Health, European Union, and Health Resources Service Administration and is a consultant to Amgen, Bayer, BG Medicine, Cardiocell, Celladon, Gambro, GE Healthcare, Medtronic, Novartis, Ono Pharma, Takeda, Trevena, and Zensun.FootnotesCorrespondence to Javed Butler, MD, MPH, Emory Clinical Cardiovascular Research Institute, 1462 Clifton Road, NE, Suite 504, Atlanta, GA 30322. E-mail: [email protected]References1. Corradi D, Maestri R, Macchi E, Callegari S. The atria: from morphology to function.J Cardiovasc Electrophysiol. 2011; 22:223–235.MedlineGoogle Scholar2. Barbier P, Solomon SB, Schiller NB, Glantz SA. Left atrial relaxation and left ventricular systolic function determine left atrial reservoir function.Circulation. 1999; 100:427–436.LinkGoogle Scholar3. Karayannis G, Kitsios G, Kotidis H, Triposkiadis F. Left atrial remodelling contributes to the progression of asymptomatic left ventricular systolic dysfunction to chronic symptomatic heart failure.Heart Fail Rev. 2008; 13:91–98.CrossrefMedlineGoogle Scholar4. Levin ER, Gardner DG, Samson WK. Natriuretic peptides.N Engl J Med. 1998; 339:321–328.CrossrefMedlineGoogle Scholar5. Dietz JR. M
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