severe aortic stenosis, including evaluation focused on hemodynamic subtypes. .... measure in particular at 2 mechanically active regions within the titin springs ...
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CLINICAL RESEARCH
Alterations in Titin Properties and Myocardial Fibrosis Correlate With Clinical Phenotypes in Hemodynamic Subgroups of Severe Aortic Stenosis Michael Gotzmann, MD,a Susanne Grabbe,b Dominik Schöne,b Marion von Frieling-Salewsky,c Cristobal G. dos Remedios, PHD,d Justus Strauch, MD,e Matthias Bechtel, MD,e Johannes W. Dietrich, MD,f Andrea Tannapfel, MD, PHD,g Andreas Mügge, MD,b Wolfgang A. Linke, PHDc
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by following the instructions given at the conclusion of the activity. CME/MOC Objective for This Article: Upon completion of this paper, the reader should be able to: 1) understand the different patterns of myocardial fibrosis and the degree of isoform-expression and phosphorylation changes in cardiomyocyte titin in the different hemodynamic subgroups of
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aortic stenosis; 2) examine the extent of myocardial remodeling in para-
Issue Date: June 2018
doxical aortic stenosis to help better understand the poor prognosis of
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From the aDepartment of Cardiology, Marien Hospital Witten, Ruhr University Bochum, Bochum, Germany; bCardiology and Angiology, Bergmannsheil, Ruhr University Bochum, Bochum, Germany; cInstitute of Physiology II, University of Münster, Münster, Germany; dDepartment of Anatomy & Histology, Bosch Institute, University of Sydney, Sydney, Australia; eDepartment of Cardiac and Thoracic Surgery, Bergmannsheil, Ruhr University Bochum, Bochum, Germany; fDepartment of Internal Medicine, Bergmannsheil, Ruhr University Bochum, Bochum, Germany; and the gInstitute of Pathology, Ruhr University Bochum, Bochum, Germany. This work was supported by the German Heart Foundation/German Foundation of Heart Research. Dr. Dietrich has received funding from Sanofi-Henning, Hexal AG, Bristol-Myers Squibb, and Pfizer; and is co-owner of the intellectual property rights for the patent “System and Method for Deriving Parameters for Homeostatic Feedback Control of an Individual” (Singapore
ISSN 2452-302X
https://doi.org/10.1016/j.jacbts.2018.02.002
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Gotzmann et al.
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 3, NO. 3, 2018 JUNE 2018:335–46
Titin and Fibrosis in Aortic Stenosis
Alterations in Titin Properties and Myocardial Fibrosis Correlate With Clinical Phenotypes in Hemodynamic Subgroups of Severe Aortic Stenosis Michael Gotzmann, MD,a Susanne Grabbe,b Dominik Schöne,b Marion von Frieling-Salewsky,c Cristobal G. dos Remedios, PHD,d Justus Strauch, MD,e Matthias Bechtel, MD,e Johannes W. Dietrich, MD,f Andrea Tannapfel, MD, PHD,g Andreas Mügge, MD,b Wolfgang A. Linke, PHDc
VISUAL ABSTRACT
HIGHLIGHTS The extent of myocardial fibrosis and the degree of isoform-expression and phosphorylation changes in cardiomyocyte titin were unknown in different hemodynamic subgroups of AS, including “paradoxical” low-flow, low-gradient AS with preserved ejection fraction. Hemodynamic subtypes of AS were found to exhibit increased cardiac fibrosis, titinisoform transition toward more compliant N2BA variants, and both total and sitespecific titin (N2Bus) hypophosphorylation compared with donor heart controls. A significant shift toward N2BA titin appeared in “paradoxical” AS, whereas alterations in total-titin phosphorylation and cardiac fibrosis were similar in all hemodynamic subtypes of AS, suggesting increased myocardial passive stiffness. The unfavorable prognosis of “paradoxical” AS could be explained by the pronounced myocardial remodeling, which is no less severe than in other AS subtypes.
Gotzmann, M. et al. J Am Coll Cardiol Basic Trans Science. 2018;3(3):335–46.
Institute for Clinical Sciences, Biomedical Sciences Institutes, Application Number 201208940-5, WIPO number WO/2014/088516). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page. Manuscript received September 18, 2017; revised manuscript received February 12, 2018, accepted February 13, 2018.
Gotzmann et al.
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 3, NO. 3, 2018 JUNE 2018:335–46
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Titin and Fibrosis in Aortic Stenosis
ABBREVIATIONS
SUMMARY
AND ACRONYMS
Titin-isoform expression, titin phosphorylation, and myocardial fibrosis were studied in 30 patients with severe
AS = aortic stenosis
symptomatic aortic stenosis (AS). Patients were grouped into “classical” high-gradient, normal-flow AS with
AVA = aortic valve area
preserved ejection fraction (EF); “paradoxical” low-flow, low-gradient AS with preserved EF; and AS with
BNP = B-type
reduced EF. Nonfailing donor hearts served as controls. AS was associated with increased fibrosis, titin-isoform
natriuretic peptide
switch toward compliant N2BA, and both total and site-specific titin hypophosphorylation compared with
EF = ejection fraction
control hearts. All AS subtypes revealed titin and matrix alterations. The extent of myocardial remodeling in
LV = left ventricular
“paradoxical” AS was no less severe than in other AS subtypes, thus explaining the unfavorable prognosis.
MHC = myosin heavy chain
(J Am Coll Cardiol Basic Trans Science 2018;3:335–46) © 2018 The Authors. Published by Elsevier on behalf of the
N2Bus = unique sequence
American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license
within the cardiac-specific N2B
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
titin domain
NYHA = New York Heart Association
Z = valvuloarterial impedance
S
evere symptomatic aortic stenosis (AS) is a
emerged as a main contributor to myocardial relaxa-
common cardiac disease associated with poor
tion and stiffness (14). Titin properties can be
prognosis in the absence of heart valve replace-
severely altered in heart failure, including AS (14).
ment (1). In AS, chronically elevated afterload induces
Titin is expressed in 2 major isoforms in adult hearts:
left ventricular (LV) hypertrophy, increased myocar-
stiff N2B and compliant N2BA isoforms (15). In recent
dial stiffness, and impaired relaxation (2,3). This
years, there has been growing evidence for a titin
myocardial remodeling is associated with progressive
isoform switch toward the more compliant N2BA
dyspnea, the most common symptom of AS, and poor
isoform in various cardiac diseases, for example,
prognosis (1).
heart failure with reduced or preserved EF (14). This isoform transition may be compensatory, to counSEE PAGE 347
teract the increased stiffening from myocardial fibrosis. In contrast, for AS patients, it is not clear
Patients with severe, high-gradient, normal-flow
whether titin isoforms switch toward N2BA, N2B, or
AS with preserved ejection fraction (“classical” AS)
not at all (16–18). In addition, there are no studies of
benefit with a high probability from aortic valve
titin isoform expression in different hemodynamic
replacement (1). However, there are other hemody-
subtypes of AS. Phosphorylation of titin is another
namic types of AS, such as low-flow, low-gradient
parameter that determines myocardial passive stiff-
severe AS with preserved ejection fraction (EF)
ness (14), but likewise, has not been studied in
(“paradoxical” AS) and aortic stenosis with reduced
hemodynamic subtypes of AS. To our knowledge,
ejection fraction (ASrEF), which occur in more than
site-specific titin phosphorylation has never been
30% of all cases (4,5). Probably due to advanced
investigated in human AS, but would be important to
myocardial
of
measure in particular at 2 mechanically active regions
aortic valve replacement is more uncertain in these
within the titin springs present in both the N2B and
patients (1,5).
N2BA isoforms, the N2B-unique sequence (N2Bus)
remodeling,
the
positive
effect
In particular, the pathophysiology of “paradoxical”
and the proline/glutamate/valine/lysine-rich (PEVK)
AS is not fully understood. There is controversy about
region, because the stiffness of these segments is
whether it is merely a moderate form of AS with
altered when they become phosphorylated (14) or
favorable prognosis or an advanced form of AS. It
dephosphorylated (19).
could be a pseudo-severe AS due to inaccuracies in
In the present study, we investigated titin-isoform
the measurements or inconsistencies in the guide-
expression, total-titin and site-specific N2Bus/PEVK
lines (6–8), or it could be a true AS associated with
phosphorylation, and the degree of fibrosis in
pronounced myocardial stiffening, severe intrinsic
endomyocardial biopsy samples from AS patients
myocardial damage, impaired relaxation, and there-
compared with nonfailing donor heart samples. We
fore, worse prognosis than “classical” AS (5,9,10).
examined these properties in 3 hemodynamic sub-
Pathological myocardial relaxation and stiffness in
groups of AS: “paradoxical” AS, “classical” AS, and
AS are determined, in part, by fibrosis (11–13). More
ASrEF. We aimed to establish whether such indexes
recently, the giant sarcomere protein titin has
of structural and functional cardiac remodeling with
338
Gotzmann et al.
JACC: BASIC TO TRANSLATIONAL SCIENCE VOL. 3, NO. 3, 2018 JUNE 2018:335–46
Titin and Fibrosis in Aortic Stenosis
relevance for myocardial passive stiffness are similar
Z (Z ¼ SAP $ MG/SVI, where SAP is the systolic arterial
or different among those patients and compared with
pressure, MG is the mean gradient, and SVI is the
the nonfailing control hearts.
stroke volume index) was calculated. Measurements of global longitudinal strain were performed by
METHODS
speckle tracking. Quantification of valve regurgitation was performed according to current recommen-
PATIENT COHORT. In this prospective study, we
dations (21). The volume of the left atrium was
examined patients with severe AS and an indication
measured and related to the body surface. LV dia-
for surgical aortic valve replacement. Inclusion
stolic dysfunction with abnormal relaxation and
criteria were: aortic valve area (AVA)