corpus.ulaval.ca€¦ · Web viewBiomarkers in Mitral regurgitation. Magnus Bäck, MD, PhD1,2,...

Biomarkers in Mitral regurgitation

Magnus Bäck, MD, PhD1,2, Rodolfo Pizarro, MD3, Marie-Annick Clavel’ DVM, PhD4,5

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]

Word count: 3,012

Keywords: Biomarkers, Natriuretic peptide, Proteomic, miRNA, Mitral regurgitation

Disclosures: None.

Bäck et al. Biomarkers in MR

ABSTRACT

Mitral regurgitation (MR) is a common cause of heart failure but may also remain silent

without either symptoms or altered cardiac function. In the latter case, management is

still controversial and biomarkers could be an important means to solving remaining

issues in MR management. As objective markers of myocardial stress and early left

ventricular dysfunction, biomarkers may for example facilitate the identification of

patients with benefit from early surgery of degenerative MR. The most studied

biomarkers are the natriuretic peptides, especially brain natriuretic peptide, as well as its

N terminal prohormone. In addition, other biologically relevant biomarkers have been

recently proposed based in “omic” approaches. Finally, the large family of microRNA,

that are the most abundant non-coding RNA, may also be of future interest. In this

review, we will summarize the current knowledge about natriuretic peptides in

degenerative and functional MR, and general “omic” discoveries and microRNAs.

2


ABBREVIATION LIST

ANP: Atrial Natriuretic Peptide

BNP: B-type Natriuretic Peptide

DMR: Degenerative Mitral Regurgitation

FMR: Functional Mitral Regurgitation

HR: Hazard Ratio

LA: Left Atrial

LV: Left ventricle/ventricular

miR: MicroRNAs

MR: Mitral Regurgitation

MVP: Mitral Valve Prolapse

NPs: Natriuretic Peptides

NT proBNP: N-terminal pro b-type natriuretic peptide

3


INTRODUCTION

Mitral regurgitation (MR) is a common valvular heart disease separated into two different

entities according to etiology. In degenerative mitral regurgitation (DMR) the mitral

valve is intrinsically diseased, whereas in functional mitral regurgitation (FMR) the

mitral valve is globally normal and the regurgitation is secondary to left ventricular (LV)

dysfunction and/or dilatation. Current guidelines for the management of MR rely on

determining the severity of regurgitation in relation to symptoms and/or LV dimensions

and function (1,2). However, most of these recommendations are made based on a low

level of evidence, and guideline indications for interventions have been questioned (3). In

particular, the optimal timing for surgical intervention in asymptomatic patients with

severe DMR may require further objective predictors of LV remodeling, adverse

outcomes and indicators of probable surgical success to optimize clinical decision

making.

Circulating biomarkers could potentially represent objective measures, which are easily

accessible and can be serially evaluated. Adding one or several biomarkers to the

algorithms of clinical decision making in MR could potentially allow to more closely

follow disease progression as well as its impact on LV geometry and function. The

present article aims to review possible biomarkers studied in MR, with focus on DMR

and with emphasis natriuretic peptides (NPs), and also to bring up some novel potential

biomarkers in MR.

4


CORRELATION OF NPS WITH THE SEVERITY AND CONSEQUENCES OF DEGENERATIVE

MITRAL REGURGITATION

Increased LV wall stress is the main stimulus for the release of NPs, which are widely

used in heart failure. Increased NP levels in patients with MR could indicate an initial

subclinical LV dysfunction (4). In the pathophysiological cascade of DMR progression,

volume overload and dilatation of the left cardiac chambers are associated with, or even

preceded by, an increased wall tension (5), raising the possibility that NPs may increase

in DMR before either the onset of symptoms or occurrence of LV dysfunction/dilatation.

Indeed, atrial (ANP) and brain (BNP) natriuretic peptides are increased in patients with

DMR (6) and associated with increased end-systolic volumes, irrespective of symptoms

and etiology of MR (7). In addition, BNP levels increase with worsening of symptoms,

LV and left atrial (LA) remodeling, presence of atrial fibrillation and increase in

pulmonary systolic pressure (7,8). In contrast, NPs are either not or only weakly

associated with DMR severity (7,8), suggesting that NPs primarily are a measure of the

consequences of MR rather than of the disease itself. In other studies, however, both LV

remodeling and MR severity were associated with elevation of NPs (9,10), illustrating the

complex interaction between MR severity, LV remodeling, and NP release.

The clinical importance of NPs is underscored by their capacity to predict ventricular

remodeling as a consequence of MR, appearing before either symptoms or objective

measures of LV function and size. The increase in wall stress, together with regional

remodeling, leads to subclinical LV dysfunction and abnormal longitudinal strain (11).

Interestingly, BNP and LV longitudinal strain are independently associated in MR

5


patients (11). Importantly, signs of impaired diastolic function, such as impaired LV

relaxation, are also associated with BNP levels in patients with MR (11).

Finally, it should be mentioned that in addition to the associations of elevated NPs with

an increase in wall stress at an early stage, the progression of NP levels may be more

sensitive for the detection of early ventricular dysfunction rather than an isolated value

(12). Repeated measures of NPs may therefore be considered during follow-up of patients

with MR.

PROGNOSTIC VALUE OF NPS IN DMR ADDED TO THAT OF CLASSIC VARIABLES

The events associated with BNP elevation in the preoperative stage of MR include death,

congestive heart failure, incident atrial fibrillation, decrease in functional class and the

need for mitral surgery (Table 1) (10-16). In a study of patients with DMR (31%

symptomatic), BNP was an independent predictor of mortality in multivariate analysis,

with 23% increased risk for every 10 pg/ml of BNP and a 10% increased risk for a

combined endpoint of death and heart failure (7). Likewise, in asymptomatic patients

with severe DMR, BNP predicted the combined endpoint of death and heart failure

and/or LV dysfunction, with BNP ≥ 105 pg/ml marking a more than 4-fold higher risk of

events, irrespective of clinical/echocardiographic variables and implemented medical

treatment (10). The addition of BNP to a model, which included end systolic diameter,

MR severity and atrial volume, also improved the discrimination of events (10),

suggesting that an additive value of BNP measures to other recommended parameters in

asymptomatic DMR assessment. This is further supported by a study of asymptomatic

patients with severe DMR and preserved ventricular function, in which patients with

BNP > 40 pg/ml exhibited a four-fold higher risk of major adverse events, irrespective of

6


age, sex, MR severity, LV size and function, LA volume and LV filling pressures (11).

Finally, in a study assessing BNP elevation during and after exercise in MR patients, the

BNP levels at exercise emerged as a marker of increased risk of cardiac events

independently of baseline BNP values and clinical/echocardiographic characteristics (15).

In line with the association between longitudinal LV strain and BNP in patients with MR

discussed above (11,13), these two measures may synergistically favor risk stratification,

since also LV strain is an independent predictor of events in MR patients (11).

Furthermore, the addition of longitudinal LV strain to BNP improves discrimination of

risk in asymptomatic patients with severe MR and preserved LV function (13). Patients

with a reduced longitudinal strain and increased BNP exhibit a marked increase in the

risk of the composite of cardiovascular-related death, mitral valve surgery (as indicated

by symptoms and/or LV dysfunction) and hospitalization for acute pulmonary edema or

congestive heart failure, using < - 20.7 % (median) and BNP ≥ ln 4.04 (median) as cut-

off values. Also, in this study, a cut-off level of BNP at 60 pg/ml was a predictor of death

irrespective of other clinical and echocardiographic variables and risk scoring.

One major issue to resolve before implementing BNP in the clinical management of

patients with DMR, and probably one reason why there is no clear recommendation on

using BNP in current guidelines (1,2) is that the cut-off values vary depending on the

population studied. An interesting finding is also that BNP levels associated with the

consequences of MR are lower as compared to those found in other disorders. For

example, in heart failure with both reduced and preserved LV ejection fraction, the BNP

levels are much higher (17). Indeed, it should also be considered that BNP is sex and age

dependent. The following BNP threshold values identified either adverse remodeling or

7


adverse outcome in studies of patients with MR: Detaint (31 pg/ml),(7) Detaint (70

pg/ml),(18) Pizarro (105 pg/ml),(10) Magne (40 pg/ml)(11) and Mentias (60 pg/ml).(14)

To overcome this issue, Clavel et al, assessed the prognostic value of BNP expressed as

the BNP ratio (measured BNP/maximal expected normal BNP value) in a multicenter

study of 1331 patients with severe DMR (16). Patients with a BNP ratio > 4 had an

increased risk of death under medical management compared with other subgroups (HR

1.62, p=0.02 vs. patients with BNP ratio comprised between 1 and 4; HR 3.71, p<0.0001

vs. patients with BNP ratio < 1) adjusted for age, comorbidities, sex, atrial fibrillation,

dyspnea, MR severity, ejection fraction, creatinine and systolic blood pressure (Figure 1).

(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

8


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)

9


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).

10


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

11


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

12


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

13


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

14


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.

15


REFERENCES

1. Nishimura RA, Otto CM, Bonow RO et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:e57-185.

2. Baumgartner H, Falk V, Bax J et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease: The Task Force for the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). European Heart Journal 2017;In Press.

3. Enriquez-Sarano M, Suri RM, Clavel MA et al. Is there an outcome penalty linked to guideline-based indications for valvular surgery? Early and long-term analysis of patients with organic mitral regurgitation. J Thorac Cardiovasc Surg 2015;150:50-58.

4. Bergler-Klein J, Gyongyosi M, Maurer G. The role of biomarkers in valvular heart disease: Focus on natriuretic peptides. Can J Cardiol 2014;30:1027-1034.

5. Enriquez-Sarano M, Akins CW, Vahanian A. Mitral regurgitation. Lancet 2009;373:1382-1394.

6. Sutton TM, Stewart RA, Gerber IL et al. Plasma natriuretic peptide levels increase with symptoms and severity of mitral regurgitation. J Am Coll Cardiol 2003;41:2280-2287.

7. Detaint D, Messika-Zeitoun D, Avierinos JF et al. B-type natriuretic peptide in organic mitral regurgitation: determinants and impact on outcome. Circulation 2005;111:2391-2397.

8. Potocki M, Mair J, Weber M et al. Relation of N-terminal pro-B-type natriuretic peptide to symptoms, severity, and left ventricular remodeling in patients with organic mitral regurgitation. Am J Cardiol 2009;104:559-564.

9. Yusoff R, Clayton N, Keevil B, Morris J, Ray S. Utility of plasma N-terminal brain natriuretic peptide as a marker of functional capacity in patients with chronic severe mitral regurgitation. Am J Cardiol 2006;97:1498-501. Epub 2006 Mar 29.

10. Pizarro R, Bazzino OO, Oberti PF et al. Prospective validation of the prognostic usefulness of brain natriuretic peptide in asymptomatic patients with chronic severe mitral regurgitation. J Am Coll Cardiol 2009;54:1099-1106.

11. Magne J, Mahjoub H, Piérard LA et al. Prognostic importance of brain natriuretic peptide and left ventricular longitudinal function in asymptomatic degenerative mitral regurgitation. Heart 2012;98:584-591.

12. Klaar U, Gabriel H, Bergler-Klein J et al. Prognostic value of serial B-type natriuretic peptide measurement in asymptomatic organic mitral regurgitation. Eur J Heart Fail 2011;13:163-9. doi: 10.1093/eurjhf/hfq189. Epub 2010 Nov 4.

13. Alashi A, Mentias A, Patel K et al. Synergistic Utility of Brain Natriuretic Peptide and Left Ventricular Global Longitudinal Strain in Asymptomatic Patients With Significant Primary Mitral Regurgitation and Preserved Systolic Function Undergoing Mitral Valve Surgery. Circ Cardiovasc Imaging 2016;9(7).e004451. doi: 10.1161/CIRCIMAGING.115.004451.

14. Mentias A, Patel K, Patel H et al. Prognostic utility of brain natriuretic peptide in asymptomatic patients with significant mitral regurgitation and preserved left ventricular ejection fraction. Am J Cardiol 2016;117:258-63.

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.

16


16. Clavel MA, Tribouilloy C, Vanoverschelde JL et al. Association of B-Type natriuretic peptide with survival in patients with degenerative mitral regurgitation. J Am Coll Cardiol 2016;68:1297-307.

17. van Veldhuisen DJ, Linssen GC, Jaarsma T et al. Brain natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol 2013;61:1498-1506.

18. Detaint D, Messika-Zeitoun D, Chen HH et al. Association of B-type natriuretic Peptide activation to left ventricular end-systolic remodeling in organic and functional mitral regurgitation. Am J Cardiol 2006;97:1029-1034.

19. Krishnaswami A, Jang JJ, Berkheimer S, Pompili M, Lee H. No change in B-type natriuretic peptide levels assessed in the late postoperative period in patients with severe mitral regurgitation after mitral valve surgery. Interact Cardiovasc Thorac Surg 2011;12:768-71. doi: 10.1510/icvts.2010.263251. Epub 2011 Feb 21.

20. Wei T, Zeng C, Chen Q et al. Plasma BNP levels are determined by the severity of left ventricular systolic dysfunction but not the types of underlying heart disease. Acta Cardiol 2005;60:303-6.

21. Mayer SA, De Lemos JA, Murphy SA, Brooks S, Roberts BJ, Grayburn PA. Comparison of B-type natriuretic peptide levels in patients with heart failure with versus without mitral regurgitation. Am J Cardiol 2004;93:1002-1006.

22. Dini FL, Fontanive P, Conti U, Andreini D, Cabani E, De Tommasi SM. Plasma N-terminal protype-B natriuretic peptide levels in risk assessment of patients with mitral regurgitation secondary to ischemic and nonischemic dilated cardiomyopathy. Am Heart J 2008;155:1121-1127.

23. Brenyo A, Barsheshet A, Rao M et al. Brain natriuretic peptide and cardiac resynchronization therapy in patients with mildly symptomatic heart failure. Circ Heart Fail 2013;6:998-1004. doi: 10.1161/CIRCHEARTFAILURE.112.000174. Epub 2013 Jun 25.

24. Kainuma S, Taniguchi K, Toda K et al. B-type natriuretic peptide response and reverse left ventricular remodeling after surgical correction of functional mitral regurgitation in patients with advanced cardiomyopathy. J Cardiol 2015;66:279-85. doi: 10.1016/j.jjcc.2015.02.015. Epub 2015 Apr 4.

25. Berardini A, Biagini E, Saia F et al. Percutaneous mitral valve repair: The last chance for symptoms improvement in advanced refractory chronic heart failure? Int J Cardiol 2017;228:191-197.:10.1016/j.ijcard.2016.11.241. Epub 2016 Nov 12.

26. Taramasso M, Maisano F, Latib A et al. Clinical outcomes of MitraClip for the treatment of functional mitral regurgitation. EuroIntervention 2014;10:746-52. doi: 10.4244/EIJV10I6A128.

27. Hoefer IE, Steffens S, Ala-Korpela M et al. Novel methodologies for biomarker discovery in atherosclerosis. Eur Heart J 2015;36:2635-42.

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.

17


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.

18


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.,

BNPratio #1; blue curve), moderately elevated BNPratio (i.e., 1 < BNPratio #4; orange

curve) and severely elevated BNPratio (i.e., BNPratio >4; gray curve). *Adjusted for age-

weighted Charlson score index, sex, body surface area, atrial fibrillation, dyspnea,

creatinine level, systolic blood pressure, DMR severity, and left ventricular ejection

fraction. BNP: B-type natriuretic peptide; HR: hazard ratio

Figure 2: Kaplan-Meier Survival Curves in Patients Without Class I or IIa Indication for

Mitral Valve Surgery and Followed Medically(16)

Overall survival in the medical treatment group for asymptomatic patients with no atrial

fibrillation, no heart failure, no pulmonary hypertension, LV ejection fraction $60% and

LV end-systolic diameter #40 mm, and with normal BNPratio (i.e., BNPratio #1; blue

curve) or activated BNP (i.e., BNPratio >1; orange curve). *Adjusted for age-weighted

Charlson score index, sex, body surface area, creatinine level, systolic blood pressure,

and degenerative MR severity. BNP: B-type natriuretic peptide; HR: hazard ratio

Figure 3: List of clinical implications of elevation of natriuretic peptides in mitral

regurgitation

19


Table 1: Studies that assessed the prognostic value of BNP in organic MR

Author Population Natriuretic Peptide

Basal Value

Cutoff point assessed

Main Findings Follow up

Detaint et al (7)

Chronic, isolated MR, mild to severe: 31% symptomatic p(n=124)

63 ± 13 years; 60% male; EF: 69 ± 8%

BNP

54 ± 67 pg/ml (0.10- 410 pg/ml)

Cutoff point: 31 pg/ml (median)

Mortality: HR for every 10 pg/ml: 1.23, p=0.004

Death /CHF: HR for every 10 pg/ml: 1.09, p=0.04

5 years

Pizarro et al (10)

Chronic, isolated, severe MR; Asymptomatic p (n=269)

64 ± 5 years; 62% male; AF: 9% EF: 66 ± 4 %PSAP: 31 ±7 mmHg

BNP

Median 21 pg/ml, IQR (9-247)

Cutoff point105 pg/ml

Death, CHF and/or LV Dysfunction

Derivation set

BNP > 105 pg/ml

OR: 4.6 (2.7-11-6), p<0.001

Derivation Set

36 ± 8 months

Klaar et al (12)

Organic, isolated, severe MR Asymptomatic p (n=87)

54 ± 15 yearsEF: 64.4 ± 5.5%AF: 0% PSAP: 36.1 ± 10.3 mmHg

BNP Median 33.5 pg/ml, IQR (16.8-82)

Cutoff point

Log BNP= 4.5 ± 0.6 pg/ml

Symptoms and/or LV Dysfunction

Log BNP= 1.94, p<0.0309 786 ± 454 days

Magne et al (15)

Organic, isolated, moderate to severe MR Asymptomatic p (n=113)

60 ± 14 years; 59% male EF: 69 ± 6%

BNP

Baseline BNP: 57 ± 67 pg/mlExercise BNP: 67 ± 73 pg/ml

Cutoff point BNP peak exercise: 64 pg/ml

Cardiovascular death, mitral surgery (indicated for symptoms or LV dysfunction) and/or hospitalization due to CHF

Exercise BNP > 64 pg/ml

HR: 2.4 (1.2-4.7), p=0.013

23 ± 19 months

Magne et al Organic, isolated moderate to BNP Cardiovascular death, mitral surgery 23 ± 19 months

20


(11) severe MR Asymptomatic no AFib(n=135)

60.4 ± 14 years, 56% male EF: 69 ± 6%

Baseline BNP: 61 ± 70 pg/ml (median: 41)

Cutoff point 40 pg/ml

(indicated for symptoms or LV dysfunction) and/or hospitalization due to CHF

BNP > 40 pg/ml

HR: 4.0 (1.8-8.9), p< 0.001Mentías et al (14)

Organic, isolated, moderate to severe MR Asymptomatic p (n=548)

62 ± 13 years; 62% male EF: 62 ± 4 %

BNP

Ln BNP: 4.2 ± 1.2 (median BNP: 60 pg/ml)

Death

ln BNP >4.1 (BNP > 60 pg/ml) HR: 2.51 (1.86-3.39), p<0.001

7.4 ± 2 years

Alashi et al (13)

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.

21


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-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-21-5p 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)

22


controls

miR-125b ValveConserved in valve tissue across species (31)

Abbreviations: FED: fibroelastic deficiency, miR: microRNA, MMVP: myxomatous mitral valve prolapse MR: mitral regurgitation; MCTR: mitral chordae tendineae rupture.

23


Figure 1

Figure 2

24


Figure 3

25

NPs are associated with LV remodeling, LA overload, and increased pulmonary

systolic pressure.

The prognostic value of NPs in DMR has been established in numerous studies.

Given their high negative and positive predictive value when added to the

classic variables in the follow up of asymptomatic patients, the incorporation of

NPs to the risk stratification of these patients should be anticipated.

The lack of a clear cutoff value applicable to different populations and different

assays currently limit the clinical implementation of NPs.

The BNP ratio, which allows to harmonize for discrepancies and adjusting for

age and sex may be one possible approach.

As an alternative to a single isolated value when measuring NPs, considering

their longitudinal variation may have an additive value.

The clinical value of NPs and their kinetics during the postoperative stage of

valve surgery may discriminate a subpopulation with adverse ventricular

remodeling and a higher risk during medium- and long-term follow up.

corpus.ulaval.ca€¦ · Web viewBiomarkers in Mitral regurgitation. Magnus Bäck, MD, PhD1,2,...

Documents

Transcript of corpus.ulaval.ca€¦ · Web viewBiomarkers in Mitral regurgitation. Magnus Bäck, MD, PhD1,2,...