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JACC: BASIC TO TRANSLATIONAL SCIENCE

VOL. 3, NO. 3, 2018

ª 2018 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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

JACC: BASIC TO TRANSLATIONAL SCIENCE CME/MOC This article has been selected as the month’s JACC: Basic to Translational

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severe aortic stenosis, including evaluation focused on hemodynamic

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Author Disclosures: This work was supported by the German Heart

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Foundation/German Foundation of Heart Research. Dr. Dietrich has

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in this issue of the journal. 3. Answer the post-test questions. At least 2 out of the 3 questions provided must be answered correctly to obtain CME/MOC credit.

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 Institute for Clinical

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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

Expiration Date: May 31, 2019

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

336

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

337

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)