Biomarkers in Mitral regurgitation Magnus Bäck, MD, PhD 1,2 , Rodolfo Pizarro, MD 3 , Marie-Annick Clavel’ DVM, PhD 4,5 1 Department of Medicine, Center for Molecular Medicine, and Divison of Valvular and Coronary Disease, Karolinska Institutet and University Hospital Stockholm, 17176 Stockholm, Sweden. 2 INSERM U1116, Université de Lorraine, Centre Hospitalier Régional Universitaire de Nancy, 54505 Vandoeuvre les Nancy, France 3 Department of Cardiology, Hospital Italiano, Buenos Aires, Argentina. 4 Institut Universitaire de Cardiologie et de Pneumologie, Québec Heart & Lung Institute, Université Laval, Québec, Canada. 5 Department of Cardiology, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota Address for correspondence: Dr Marie-Annick Clavel, DVM, PhD, Institut Universitaire de Cardiologie et de Pneumologie de Québec (Quebec Heart and Lung Institute), 2725, Chemin Sainte-Foy, #A-2047, Québec, QC, Canada, G1V 4G5. Phone: (1)418-656-8711 ext.: 2678. Fax: (1)418-656-4715 E-mail: [email protected]
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1 Department of Medicine, Center for Molecular Medicine, and Divison of Valvular and Coronary Disease, Karolinska Institutet and University Hospital Stockholm, 17176 Stockholm, Sweden.2 INSERM U1116, Université de Lorraine, Centre Hospitalier Régional Universitaire de Nancy, 54505 Vandoeuvre les Nancy, France
3 Department of Cardiology, Hospital Italiano, Buenos Aires, Argentina.4 Institut Universitaire de Cardiologie et de Pneumologie, Québec Heart & Lung Institute, Université Laval, Québec, Canada.5 Department of Cardiology, Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota
Address for correspondence:
Dr Marie-Annick Clavel, DVM, PhD, Institut Universitaire de Cardiologie et de Pneumologie de Québec (Quebec Heart and Lung Institute), 2725, Chemin Sainte-Foy, #A-2047, Québec, QC, Canada, G1V 4G5. Phone: (1)418-656-8711 ext.: 2678. Fax: (1)418-656-4715
(16) Among the subgroup of patients (n= 287), without class I or IIa indication for valve
surgery, and who were hence treated medically, 66 subjects (23%) had a BNP elevation
(BNP ratio >1) during follow up, with an increased mortality (HR: 2.68, p =0.03),
adjusted for age, sex, comorbidities, systolic blood pressure and creatinine. In this
subgroup of patients, the addition of BNP to other parameters resulted in a 10% net
reclassification index to predict death at one year (Figure 2).(16) Another message of the
latter study was that the prognostic value of BNP is blunted with early valve surgery
(p=0.23). (16)
NPS IN POSTOPERATIVE DMR
Some patients with DMR do not decrease their NP level 6 months after mitral valve
surgery as compared to the preoperative value, which is related to persistent LV
dysfunction, indicating an irreversible LV remodeling. However, a longer postoperative
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observation period may be needed to assess the dynamics of NPs, and to predict HF in
patients who exhibit persistent elevated NP levels (19). In line with these findings, a
mean follow-up of 7 years, in a cohort in which 90% underwent early surgery (92%
valvuloplasty), the preoperative ln BNP (corresponding to a BNP threshold of 60 pg/ml)
was associated with mortality and LV dysfunction during follow up (13), further
supporting that certain patients with LV dysfunction do not improve after surgery.
Finally, a preoperative BNP ≥ 125 pg/ml predict a combined end-point of cardiac death
and/or hospitalization (HR: 5.5) during a mean postoperative follow up of 4.5 years
NATRIURETIC PEPTIDES IN FUNCTIONAL MR
In FMR, activation of NPs is more important than in DMR, reflecting a more severe LV
dysfunction which, at least in part, may be independent of the MR. (7,18,20). However,
in patients with heart failure, those with moderate or severe functional MR exhibit higher
BNP levels compared to those with none or mild MR (21) and BNP levels correlate
strongly with the end-systolic volume (18).
In a group of patients with both ischemic and non-ischemic cardiomyopathy, an LV
ejection fraction ≤ 45% in combination with functional MR, N-terminal proBNP (NT
proBNP) >1941 pg/ml was an independent predictor of death (HR: 2.17, p=0.026) (22).
Although also the end-systolic volume (> 82 ml/m2) was an independent predictor in the
latter study, NT proBNP had greater power to predict the combined end-point of
death/hospitalization (HR: 3.19, p<0.0001). Increase in NT proBNP values and the
presence of moderate to severe MR identified a subgroup of patients who were at higher
risk of cardiac death.(22)
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Cardiac resynchronization therapy is associated with improved clinical outcome in
patients with functional MR and ventricular dysynchrony. Interestingly, in patients with
dilated cardiomyopathy undergoing resynchronization, decreased BNP levels during
follow-up were associated with improved echocardiographic parameters and a lower risk
of heart failure and death (23).
After surgery correcting FMR (mitral annuloplasty), BNP levels are correlated with
positive remodeling of left ventricle, improvement of ejection fraction and especially a
decrease in end-systolic wall stress (24). Also after percutaneous mitral valve repair, BNP
decreases, in association with decreased MR and NYHA functional class in patients with
FMR (25). NT pro-BNP >1600pg/ml before percutaneous mitral valve repair have been
found to be predictor of unfavorable outcome (26) .
Taken together, those studies support that the use of NPs in MR may not be limited to
DMR but also applicable in FMR.
The clinical implication of elevation of NPs in MR are summarized in Figure 3. Despite
being the most studied biomarker and probably the only one ready for prime time in
clinical use, NPs are not the only interesting biomarkers that could be used in MR.
Indeed, numerous biomarkers are under study to assess development of the disease and
time the better timing for intervention given that this is a highly controversial point in
DMR management where objective and reversible markers of worse outcome are needed.
USE OF PROTEOMICS IN DMR PATIENTS
A recent Position Paper from the European Society of Cardiology emphasized the
importance of large-scale “omics” approaches for the discovery of novel biomarkers (27).
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Although the latter position was taken for atherosclerosis, similar arguments could also
apply to biomarker discovery in MR. One such “omics” approach is proteomics, which
allows comparisons of the expression of thousands of proteins in samples derived from
patients with and without MR.
The firstly reported proteomic biomarker study in DMR used pooled samples from 24
patients with asymptomatic isolated moderate to severe (RV≥35 mL) (28). DMR patients,
compared to control subjects with normal echocardiography, had lower plasma levels of
haptoglobin, platelet basic protein (PBP), and complement component C4b. It should
however be noted that DMR patients as expected exhibited significantly larger left
ventricular and left atrial dimensions and higher pulmonary artery pressure, which may
have confounded the results. Nevertheless, that study suggested that hemolysis, platelet
dysfunction, and complement activation may be linked to DMR with potential predictive
value (28). A subsequent study comparing control subjects with patients diagnosed with
different degree of DMR, confirmed the decrease in plasma haptoglobin with DMR
severity, and identified lower plasma levels of HDL and apolipoprotein-A1 as predictors
of MR severity (29).
Taken together, these studies indicate the feasibility of proteomic-based biomarker
discovery in MR, and provide indications for novel biomarkers of DMR. However, their
applicability in terms of predictive and prognostic value remains to be established in
larger cohorts of patients.
MICRORNA IN MR
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MicroRNAs (miR) are the most abundant non-coding RNA species and exert their
function through mRNA target recognition, leading to the inhibition of protein synthesis.
In addition to this cellular localisation, miRs are secreted into the extracellular space and
circulation. Since their discovery in the circulation, the potential use of miRs as serum
biomarkers for diagnosis and prognosis of cardiovascular pathologies has been intensely
studied including valvular heart disease, albeit less in DMR (30).
As an indication of their specificity, certain miRs exhibit a highly conserved expression
pattern in distinct cardiac structures (31). For example, whereas miR-1 and miR-208b are
mainly expressed in the myocardium across different mammalian species (rat, dog,
monkey), preserved valve-enriched miRs include miR-125b-5p and miR-204, with
similar expression patterns in a human cardiac sample (31). Such approach may facilitate
the identification of specific biomarkers that potentially distinguish between mitral
valvular changes and the ventricular and atrial responses to the MR-induced
hemodynamic alterations. To validate such assumption, the proposed valve-specific miRs
must be differentially expressed under pathophysiological conditions and be reliably
detectable in peripheral blood samples with levels that reflect their changes in valvular
expression.
Indeed, local miR levels are altered in DMR, as suggested from a study comparing
human mitral valves derived from ten patients with myxomatous prolapse and ten valves
with fibroelastic deficiency (32), providing a first indication that a specific miR signature
potentially could identified DMR of different origins. One of the few studies that have
specifically analyzed circulating miR levels as biomarkers of DMR identified 22
differentially expressed miRs in 21 patients with mitral chordal rupture compared with
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age- and gender matched controls (33), hence reinforcing the potentials of using
circulating miRs as biomarkers of DMR. In another study, Chen et al. (34) focused on
serum miRs that were differentially expressed in MR patients either with (n=6) or
without (n=5) heart failure as compared to control subjects without valvular heart disease
and heart failure (n=2). Such approach may be useful to separate valvular and myocardial
miR profiles associated with disease for application as biomarkers in MR. Nevertheless,
the proposed candidate miR-409-3p exhibited similar expression patterns in atrial cardiac
tissues and the authors suggested that this miR might serve as biomarker for incident
heart failure in MR patients (34).
There is today a too limited number of studies to firmly suggest which miR has the best
potential as biomarker in MR. Interestingly, some overlap in reported candidate miR exist
between the above-mentioned studies, indicating replicated candidate miRs of interest for
MR, as indicated in Table 2. Of those, the let-7 miR family was among the conserved
valve-enriched miR across species (31), whose serum levels were decreased in MR as
compared with controls (34). Animal studies have however indicated increased serum
levels of this miR family in canine MR (35). Another valve-enriched miR (31) identified
in serum from MR patients (34) is 125b-5p, but it should be pointed out that this miR was
also recently associated also with vascular calcification (36). Other overlapping miRs are
miR-16 being decreased in serum from MR patients compared with controls in two
studies (33,34). Finally, the miR 19 family represent an example of coherent results
locally in the valve (lower in fibroelastic deficient mitral valves;(36)) and serum levels
(lower in MR patients; (34)). As already pointed out, an “omics” approach with further
studies using either array-based or sequencing technology (27) may be the approach of
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choice for the discovery of further miR biomarkers for MR. Also, the combination of
several miRs as a miR signature can be of potential interest. The validation of such
candidate miR and miR signatures would then be needed in larger patient cohorts before
an application of miRs as biomarkers of MR.
Biomarkers with causal involvement can also provide insight into pathophysiological
processes and even be used for testing drug efficacy, and may as such be regarded more
valuable for risk stratification (27). In this context, the miRs identified both in human
mitral valves and in serum from MR patients regulate targets that may be related to
relevant pathophysiological pathways for the development of organic MR. The predictive
mRNA targets of the miRs discussed above may connect the MR signature to
pathophysiologically important pathways distinguishing for example fibroeleastic
deficienicy (e.g. proteoglycan regulation) and genes encoding structural integrity proteins
involved in myoxamtous deposition (32,34)
In summary, although still in its infancy, the implications of miRs as biomarkers of MR
warrant further exploration. The major challenges in this field are presently to distinguish
valvular miRs from ventricular and/or atrial markers of the disesae, to apply a universally
applicable endogenous control, and to identify a pertinent miR signature to be validated
in larger cohort of patients.
CONCLUSION
As objective markers of degradation of geometry and function of the left ventricle and/or
progression of the mitral valve disease, biomarkers have a key role to play in evaluation
and management of patients with mitral regurgitation. Indeed, biomarkers will reveal
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Bäck et al. Biomarkers in MR
subclinical and/or very early damages induced by the volume overload created by the
mitral regurgitation that generally are reversible if mitral regurgitation is repaired. Thus,
by predicting poor outcome under medical management while no increase in adverse
event after repair, biomarkers must be integrated, with other evaluation of mitral disease
and patient’s comorbidities. Albeit not specific for MR, BNP and NT proBNP are
emerging as clinically applicable biomarker with potential to be implemented in the
management of MR.
ACKNOWLEDGEMENTS
Supported by a Karolinska Institutet and Mayo Clinic Collaboration Grant.
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15. Magne J, Mahjoub H, Pibarot P, Pirlet C, Pierard LA, Lancellotti P. Prognostic importance of exercise brain natriuretic peptide in asymptomatic degenerative mitral regurgitation. Eur J Heart Fail 2012;14:1293-1302.
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28. Tan HT, Ling LH, Dolor-Torres MC, Yip JW, Richards AM, Chung MC. Proteomics discovery of biomarkers for mitral regurgitation caused by mitral valve prolapse. J Proteomics 2013;94:337-45.
29. Deroyer C, Magne J, Moonen M et al. New biomarkers for primary mitral regurgitation. Clin Proteomics 2015;12:25.
30. Oury C, Servais L, Bouznad N, Hego A, Nchimi A, Lancellotti P. MicroRNAs in Valvular Heart Diseases: Potential Role as Markers and Actors of Valvular and Cardiac Remodeling. Int J Mol Sci 2016;17.
31. Vacchi-Suzzi C, Hahne F, Scheubel P et al. Heart structure-specific transcriptomic atlas reveals conserved microRNA-mRNA interactions. PLoS One 2013;8:e52442.
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32. Chen YT, Wang J, Wee AS et al. Differential MicroRNA Expression Profile in Myxomatous Mitral Valve Prolapse and Fibroelastic Deficiency Valves. Int J Mol Sci 2016;17.
33. Bulent Vatan M, Kalayci Yigin A, Akdemir R et al. Altered Plasma MicroRNA Expression in Patients with Mitral Chordae Tendineae Rupture. J Heart Valve Dis 2016;25:580-588.
34. Chen MC, Chang TH, Chang JP et al. Circulating miR-148b-3p and miR-409-3p as biomarkers for heart failure in patients with mitral regurgitation. Int J Cardiol 2016;222:148-54.
35. Li Q, Freeman LM, Rush JE, Laflamme DP. Expression Profiling of Circulating MicroRNAs in Canine Myxomatous Mitral Valve Disease. Int J Mol Sci 2015;16:14098-108.
36. Chao CT, Liu YP, Su SF et al. Circulating MicroRNA-125b Predicts the Presence and Progression of Uremic Vascular Calcification. Arterioscler Thromb Vasc Biol 2017.
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Figure 1: Kaplan-Meier Survival Curves in Patients Followed Medically According to
BNPratio(16)
Overall survival in the medical treatment group for patients with normal BNPratio (i.e.,
Organic, isolated, moderate to severe MR Asymptomatic p (n= 448)
61 ± 12 years; 69% male EF: 62 ± 3 %
BNP
Ln BNP: median 4.04(median BNP: 60 pg/ml)
Post op Death
Ln BNP (for every unit increase)
HR: 2.26 (1.67-3.06) p<0.001
7.7 ± 2 years
Clavel et al (16)
Degenerative, isolated, moderate to severe MR (n=1345)57% Dyspnea
65 ± 15 years; 66% maleEF: 64 ± 9 %
BNP
Median: 92 pg/ml IQR (36-250)
BNP Ratio
Median: 1.02 IQR (0.43-2.39)
Cutoff point BNP ratio > 1
Total Mortality
BNP Ratio > 1
HR: 2.00 (1.29-3.17), p=0.002
Ln BNP Ratio
HR: 1.01 (1.78-2.72), p<0.0001
5.1 ± 2.6 years
EF: ejection fraction; AF: atrial fibrillation; CHF : congestive Heart failure; sPAP: systolic pulmonary arterial pressure ; EROA: effective regurgitant orifice area; ESD: end- systolic diameter; IQR: interquartile range ; LVEDVi: left ventricular end – diastolic volume index; LA: left atrial ; GLS : global longitudinal strain ; RVSP: right ventricular systolic pressure; HR : hazard ratio.
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Table 2: Differential serum and valve expression levels of microRNAs reported in different studies of mitral regurgitation (without considering reported fold-change and level of significance).
miRvalve/serum Observation
Reference
miR-let-7e-5p SerumLower levels in MR patients vs controls (34)
miR-let-7c ValveConserved in valve tissue across species (31)
miR-16-5p SerumLower levels in MR patients vs controls (34)
miR-16-5p SerumLower levels in MR patients vs controls (33)
miR-17 Valve Lower in MMVP vs FED (32)
miR-17-5p SerumLower levels in MCTR patients vs controls (33)
miR-203 Valve Lower in MMVP vs FED (32)
miR-203a SerumLower levels in MR patients vs controls (34)
miR-21-3p SerumLower levels in MR patients vs controls (34)
miR-21-5p SerumLower levels in MCTR patients vs controls (33)
miR-92a-3p SerumLower levels in MCTR patients vs controls (33)
miR-92b-3p SerumLower levels in MR patients vs controls (34)
miR-125b-5p Serum Lower levels in MR patients vs (34)
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controls
miR-125b ValveConserved in valve tissue across species (31)