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      Relationship of Transmural Variations in Myofiber Contractility to Left Ventricular Ejection Fraction: Implications for Modeling Heart Failure Phenotype With Preserved Ejection Fraction

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          Abstract

          The pathophysiological mechanisms underlying preserved left ventricular (LV) ejection fraction (EF) in patients with heart failure and preserved ejection fraction (HFpEF) remain incompletely understood. We hypothesized that transmural variations in myofiber contractility with existence of subendocardial dysfunction and compensatory increased subepicardial contractility may underlie preservation of LVEF in patients with HFpEF. We quantified alterations in myocardial function in a mathematical model of the human LV that is based on the finite element method. The fiber-reinforced material formulation of the myocardium included passive and active properties. The passive material properties were determined such that the diastolic pressure-volume behavior of the LV was similar to that shown in published clinical studies of pressure-volume curves. To examine changes in active properties, we considered six scenarios: (1) normal properties throughout the LV wall; (2) decreased myocardial contractility in the subendocardium; (3) increased myocardial contractility in the subepicardium; (4) myocardial contractility decreased equally in all layers, (5) myocardial contractility decreased in the midmyocardium and subepicardium, (6) myocardial contractility decreased in the subepicardium. Our results indicate that decreased subendocardial contractility reduced LVEF from 53.2 to 40.5%. Increased contractility in the subepicardium recovered LVEF from 40.5 to 53.2%. Decreased contractility transmurally reduced LVEF and could not be recovered if subepicardial and midmyocardial contractility remained depressed. The computational results simulating the effects of transmural alterations in the ventricular tissue replicate the phenotypic patterns of LV dysfunction observed in clinical practice. In particular, data for LVEF, strain and displacement are consistent with previous clinical observations in patients with HFpEF, and substantiate the hypothesis that increased subepicardial contractility may compensate for subendocardial dysfunction and play a vital role in maintaining LVEF.

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          Trends in patients hospitalized with heart failure and preserved left ventricular ejection fraction: prevalence, therapies, and outcomes.

          Benjamin Steinberg, Xin Zhao, Paul A Heidenreich … (2012)
          Heart failure with preserved ejection fraction (EF) is a common syndrome, but trends in treatments and outcomes are lacking. We analyzed data from 275 hospitals in Get With the Guidelines-Heart Failure from January 2005 to October 2010. Patients were stratified by EF as reduced EF (EF <40% [HF-reduced EF]), borderline EF (40%≤EF<50% [HF-borderline EF]), or preserved (EF ≥50% [HF-preserved EF]). Using multivariable models, we examined trends in therapies and outcomes. Among 110 621 patients, 50% (55 083) had HF-reduced EF, 14% (15 184) had HF-borderline EF, and 36% (40 354) had HF-preserved EF. From 2005 to 2010, the proportion of hospitalizations for HF-preserved EF increased from 33% to 39% (P<0.0001). In multivariable analyses, use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers at discharge decreased in all EF groups, and β-blocker use increased. Patients with HF-preserved EF less frequently achieved blood pressure control (adjusted odds ratio, 0.44 versus HF-reduced EF; P<0.001) and were more likely discharged to skilled nursing (adjusted odds ratio, 1.16 versus HF-reduced EF; P<0.001). In-hospital mortality for HF-preserved EF decreased from 3.32% in 2005 to 2.35% in 2010 (adjusted odds ratio, 0.89 per year; P=0.01) but was stable for patients with HF-reduced EF (3.03%-2.83%; adjusted odds ratio, 0.93 per year; P=0.10). Hospitalization for HF-preserved EF is increasing relative to HF-reduced EF. Although in-hospital mortality for patients with HF-preserved EF declined over the study period, an important opportunity remains for identifying evidence-based therapies in patients with HF-preserved EF.
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            Noninvasive single-beat determination of left ventricular end-systolic elastance in humans.

            Chen-Huan Chen, Barry J Fetics, Erez Nevo … (2001)
            The goal of this study was to develop and validate a method to estimate left ventricular end-systolic elastance (E(es)) in humans from noninvasive single-beat parameters. Left ventricular end-systolic elastance is a major determinant of cardiac systolic function and ventricular-arterial interaction. However, its use in heart failure assessment and management is limited by lack of a simple means to measure it noninvasively. This study presents a new noninvasive method and validates it against invasively measured E(es). Left ventricular end-systolic elastance was calculated by a modified single-beat method employing systolic (P(s)) and diastolic (P(d)) arm-cuff pressures, echo-Doppler stroke volume (SV), echo-derived ejection fraction (EF) and an estimated normalized ventricular elastance at arterial end-diastole (E(Nd)): E(es(sb)) = [P(d) - (E(Nd(est)) x P(s) x 0.9)[/(E(Nd(est)) x SV). The E(Nd) was estimated from a group-averaged value adjusted for individual contractile/loading effects; E(es(sb)) estimates were compared with invasively measured values in 43 patients with varying cardiovascular disorders, with additional data recorded after inotropic stimulation (n = 18, dobutamine 5 to 10 microg/kg per min). Investigators performing noninvasive analysis were blinded to the invasive results. Combined baseline and dobutamine-stimulated E(es) ranged 0.4 to 8.4 mm Hg/ml and was well predicted by E(es(sb)) over the full range: E(es) = 0.86 x E(es(sb)) + 0.40 (r = 0.91, SEE = 0.64, p < 0.00001, n = 72). Absolute change in E(es(sb)) before and after dobutamine also correlated well with invasive measures: E(es(sb)): DeltaE(es) = 0.86 x DeltaE(es(sb)) + 0.67 (r = 0.88, p < 0.00001). Repeated measures of E(es(sb)) over two months in a separate group of patients (n = 7) yielded a coefficient of variation of 20.3 +/- 6%. The E(es) can be reliably estimated from simple noninvasive measurements. This approach should broaden the clinical applicability of this useful parameter for assessing systolic function, therapeutic response and ventricular-arterial interaction.
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              Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort.

              R Vasan, Phillip Levy, C Reiss … (1999)
              The purpose of this study was to assess the relative proportions of normal versus impaired left ventricular (LV) systolic function among persons with congestive heart failure (CHF) in the community and to compare their long-term mortality during follow-up. Several hospital-based investigations have reported that a high proportion of subjects with CHF have normal LV systolic function. The prevalence and prognosis of CHF with normal LV systolic function in the community are not known. We evaluated the echocardiograms of 73 Framingham Heart Study subjects with CHF (33 women, 40 men, mean age 73 years) and 146 age- and gender-matched control subjects (nested case-control study). Impaired LV systolic function was defined as an LV ejection fraction (LVEF) <0.50. Thirty-seven CHF cases (51%) had a normal LVEF; 36 (49%) had a reduced LVEF. Women predominated in the former group (65%), whereas men constituted 75% of the latter group. During a median follow-up of 6.2 years, CHF cases with normal LVEF experienced an annual mortality of 8.7% versus 3.0% for matched control subjects (adjusted hazards ratio = 4.06, 95% confidence interval 1.61 to 10.26). Congestive heart failure cases with reduced LVEF had an annual mortality of 18.9% versus 4.1% for matched control subjects (adjusted hazards ratio = 4.31, 95% confidence interval 1.98 to 9.36). Normal LV systolic function is often found in persons with CHF in the community and is more common in women than in men. Although CHF cases with normal LVEF have a lower mortality risk than cases with reduced LVEF, they have a fourfold mortality risk compared with control subjects who are free of CHF.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Physiol
                Journal ID (iso-abbrev): Front Physiol
                Journal ID (publisher-id): Front. Physiol.
                Title: Frontiers in Physiology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-042X
                Publication date (Electronic): 24 August 2018
                Publication date Collection: 2018
                Volume: 9
                Electronic Location Identifier: 1003
                Affiliations
                [1] 1Department of Surgery, University of California, San Francisco , San Francisco, CA, United States
                [2] 2Section of Cardiology, West Virginia University Heart and Vascular Institute, West Virginia University , Morgantown, WV, United States
                Author notes

                Edited by: Massimo Pagani, Università degli Studi di Milano, Italy

                Reviewed by: Peter L. Kerkhof, VU University Medical Center, Netherlands; Maxime Sermesant, Institut National de Recherche en Informatique et en Automatique (INRIA), France

                *Correspondence: Julius M. Guccione julius.guccione@ 123456ucsf.edu

                This article was submitted to Computational Physiology and Medicine, a section of the journal Frontiers in Physiology

                Article
                DOI: 10.3389/fphys.2018.01003
                PMC ID: 6117406
                PubMed ID: 30197595
                SO-VID: 26ad7d71-2926-4a61-81a5-f318bc6d5e0c
                Copyright © Copyright © 2018 Dabiri, Sack, Shaul, Sengupta and Guccione.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 13 January 2018
                Date accepted : 09 July 2018
                Page count
                Figures: 9, Tables: 2, Equations: 7, References: 72, Pages: 11, Words: 7842
                Categories
                Subject: Physiology
                Subject: Methods

                ScienceOpen disciplines: Anatomy & Physiology
                Keywords: heart failure and preserved ejection fraction,left ventricle,myocardial contractility,finite element method,simulation
                Data availability:
                ScienceOpen disciplines: Anatomy & Physiology
                Keywords: heart failure and preserved ejection fraction, left ventricle, myocardial contractility, finite element method, simulation

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