B i o m a r k e r s i n A d u l t Co n g e n i t a l H e a r t Di s e a s e H e a r t Fa i l u re Hideo Ohuchi, MD, PhDa,b,*, Gerhard-Paul Diller, MD, PhD, MScc KEYWORDS  Adult congenital heart disease  Biomarker  Natriuretic peptide  Heart failure  Ventricular dysfunction  Mortality

KEY POINTS  Most adults with congenital heart disease (ACHD) show high levels of natriuretic peptides (NP) when compared with normal controls although the magnitude of elevation is less pronounced in patients with ACHD when compared with non-ACHD cardiac patients.  Norepinephrine and NP levels were strongly related to outcome in studies that included many symptomatic patients, especially those with unrepaired ACHD, Eisenmenger syndrome, and pulmonary hypertension.  Limited data are available regarding serial assessment of biomarkers, and such information could provide additional important information to help identify patients at risk, as demonstrated during patient follow-up and pregnancy. We provide an overview over the literature of biomarkers in ACHD, including possible associations with symptoms, ventricular function and outcome.

Major causes of heart failure (HF) in adults with acquired heart disease are myocardial ischemia, systemic hypertension, valvular disease and cardiomyopathies for left-sided HF, and idiopathic and thromboembolic pulmonary hypertension (PH) for right-sided HF. On the other hand, the cause of HF in adult congenital heart disease (ACHD) is different from that of non-ACHD, and the specific causes include single-ventricle physiology, such as Fontan circulation, non–left ventricular (LV) type morphology of the systemic ventricle, and various residual hemodynamic abnormalities, such as valve stenosis and/or regurgitation. In addition, cyanotic patients without definitive repair and those with Eisenmenger syndrome present with unique pathophysiology.

ASSESSMENT OF PATHOPHYSIOLOGY IN ACHD The first step in managing ACHD HF patients is to understand their pathophysiology and to select the appropriate modalities for assessment. In addition to cardiac echocardiography, magnetic resonance imaging (MRI), and computed tomography (CT) for assessment of the cardiac structure and function, one should not forget that noncardiac global assessment of HF severity is also important for the prognosis and management strategy in both ACHD and non-ACHD HF patients. The major nonspecific assessment modalities include biomarkers and cardiopulmonary exercise testing, such information having become more relevant and established in daily practice in adult cardiac patients with non-ACHD. However,

a Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan; b Department of Adult Congenital Heart Disease, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan; c Division of Adult Congenital and Valvular Heart Disease, Department of Cardiovascular Medicine, University Hospital Muenster, Albert-Schweitzer-Str. 33, Mu¨nster 48149, Germany * Corresponding author. Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. E-mail address: [email protected]

Heart Failure Clin 10 (2014) 43–56 http://dx.doi.org/10.1016/j.hfc.2013.09.020 1551-7136/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.

heartfailure.theclinics.com

SPECIFIC PATHOPHYSIOLOGY IN ACHD

44

Ohuchi & Diller there are limited data regarding these parameters, and the clinical significance of biomarkers remains largely unknown in ACHD.

assessment; and third, knowledge of the measured level should aid in medical decision making.2

EVIDENCE OF BIOMARKERS IN ACHD CRITERIA FOR BIOMARKERS Biomarkers of HF may be subdivided into 7 categories (Box 1),1 and 3 criteria for biomarkers have been proposed. First, accurate, repeated measurements must be available to the clinician at a reasonable cost and with short turnaround times; second, the biomarker must provide information that is not already available from a careful clinical

Box 1 Definitions and categorization of biomarkers in heart failure Definition 1. Available to clinicians 2. The biomarker adds new information 3. The biomarker helps the clinician to manage patients Category 1. Inflammation C-reactive protein, tumor necrosis factor-a, interleukin-6, etc 2. Oxidative stress Oxidized low-density lipoproteins, myeloperoxidase, etc 3. Extracellular-matrix remodeling Matrix metalloproteinases, plasma procollagen type III, etc 4. Neurohormones Norepinephrine, endothelin-1, etc

renin,

aldosterone,

5. Myocyte injury Troponins I and T, creatinine kinase MB fraction, etc 6. Myocyte stress Atrial and brain natriuretic peptides, NT-proBNP, etc 7. New biomarkers Adiponectin, asymmetric demethylarginine, etc Data from Braunwald E. Biomarkers in heart failure. N Engl J Med 2008;358:2149, with permission; and Morrow DA, de Lemos JA. Benchmarks for the assessment of novel cardiovascular biomarkers. Circulation 2007;115:950.

There has been large number of studies on circulating biomarkers in adult HF patients without ACHD. However, this evidence may not be always applicable to unique ACHD HF pathophysiology. This article subdivides documented studies into 6 categories, as follows: (1) studies of heterogeneous ACHD cohorts with various kinds of systemic ventricle (SV) (mixed group); (2) studies of ACHD patients with biventricular physiology with a morphologic right ventricle (RV) as a pulmonary ventricle (PV) (PRV group); (3) studies of ACHD with an RV as an SV (SRV group); (4) studies of adult patients with Fontan physiology (Fontan group); (5) studies of hypoxic ACHD without definitive repair, including Eisenmenger syndrome (Unrepaired group); and (6) studies of female ACHD patients during pregnancy and delivery (Pregnancy group) (Table 1). Correlations between biomarkers and clinical variables and predictive and/or prognostic values of biomarkers in ACHD are summarized in Tables 2 and 3, respectively.

Mixed Group Patients’ characteristics Heterogeneous ACHD patients with and without definitive repair were included in this category.3–10 These studies consisted of 7 to 94 clinically stable patients with a mean age of 26.6 to 39.4 years, and a relatively large percentage of symptomatic ACHD patients, that is, New York Heart Association (NYHA) functional class II or higher (although those with NYHA class IV were rare). Ventricular function was assessed by echocardiography in all studies except 1,3 and subjective visual assessment of SV function was used because of the difficulty in the measurement of SV volume. Several exclusion criteria were also applied variably, such as acute HF,4,7 liver and/or renal dysfunction,3,4,8 infection,4 NYHA class IV,10 and LV dysfunction.3 Biomarkers All studies measured brain natriuretic peptide(s) (BNP), including one study of N-terminal proBNP (NT-proBNP),10 and 3 studies measured atrial natriuretic peptide (ANP).3,4,9 Catecholamines, hormones of the renin-angiotensin-aldosterone system (RAS) and asymmetric dimethylarginine were measured in 1 study each.4,10 ACHD patients showed significantly higher levels of natriuretic peptides (NPs) compared with controls, and the

Table 1 Biomarkers in heart failure in adults with congenital heart disease Biomarkers

Natriuretic Peptides

S.No

SV-Type Category

1

Mixed

Authors,

Ref.

Tulevski et al,3 2001 Bolger et al,4 2002 Book et al,5 2005 Law et al,6 2005 Perlowski et al,7 2007 Trojnarska et al,8 2010 Giannakoulas et al,9 2010 Tutarel et al,10 2012

ANP

NTproANP

RAS System

Others

Ventricular Function

Cases

Total

Female

Age (y)

NYHA I/II/III/IV

21

9

26.6  8.6

13/8/0/0

53

29

33.5  1.5

B

8

3

B

7

B

PVEDVI (mL/m2)

PVEF/(Tei) (%)/—

MRI/Echo

68.1  11.0

65.3  23.3

58.0  12.0

Echo

[36/7/3]

27.3  5.3

11/31/10/ 1 2.4  0.9









54

31

39  13



Echo

B

53

32

39.4  14.3

4/36/13/0

Echo

B

49

26

34  11

11/28/10/ 0

94

39

30.2  10.6

56/21/17/ 0

B

B

B

NTproBNP

PVO2 (mL/kg/ min)

SVEF/(Tei) [Visual EF]

BNP

B

B

Catecholamines

Patients

NE

B

B

E

B

PRA

B

PAC

B

ET-1

Others

B

B

Modality

SVEDVI (mL/m2)

Echo

15.5  4.9

[26.9  14.8]

Echo

[21/19/9]

Echo

[52/33/7]

(continued on next page)

45

46

Table 1 (continued) Biomarkers

Natriuretic Peptides

S.No 2

SV-Type Category Pulmonary RV

Authors,

Ref.

ANP

NTproANP

BNP

NTproBNP

Catecholamines

NE

E

Patients RAS System

PRA

PAC

Others

ET-1

Others

Ventricular Function

Cases

Total

Female

Age (y)

NYHA I/II/III/IV

PVO2 (mL/kg/ min)

Modality

Nagaya et al,12 1998

B

B

41

25

44 (20–68)

Nagaya et al,13 1998 Nagaya et al,14 2000 Brili et al,15 2005 Norozi et al,16 2005

B

B

31

19

46 (19–72)

10/20/1/0

B

B

60

42

38 (15–69)

0/6/42/12

Echo

25



50

26

27.8  1.7

46/4/0/0

Echo

B

59

29

30  8

32/25/2/0

B

20

12

43  13

12/5/3/0

70

26

21  1

53/17/0/0

B

130

53

16.1  7.1

105/25/0/0

Echo

B

42

17

30 (17–57)



MRI

27

15

23.6  2.9

1.9  0.5 1.56  0.5 (PVR)

Norozi et al,17 2006 Schoen et al,18 2007 Festa et al,19 2007 Koch et al,20 2010 Oosterhof et al,21 2006 WesthoffBleck et al,22 2011

B

B

B B

B

B

B

B

B

B

B

B

B

B

B

B

CT

25  6

SVEDVI (mL/m2)

SVEF/(Tei) [Visual EF]

PVEDVI (mL/m2)

56  4 (ASD) 63  4 (PH)

56  3 (ASD) 57  2 (PH)

165  14 (ASD) 104  6 (PH)

33  1.4 (m)/34  1 (f) (0.50  0.09)

Echo MRI/ Echo

18.4  1.6

26.6  7.5

MRI

MRI

PVEF/(Tei) (%)/—

127  17

(0.37  0.1) 37  9

76  2

63  1

140  5

53  1

74.9  15.8 83.1  32.5 (PVR)

52.8  8.2 59.2  11.5 (PVR)

150.7  27.7

47.6  8.7

3

Systemic RV (Fontan)

B

Norozi et al,23 2005 Dore et al,24 2005 Chow et al,25 2008 Vogt et al,26 2009 Schaefer et al,27 2010 Plymen et al,28 2010  ski Szyman et al,29 2011 Winter et al,30 2008 Koch et al,31 2008 Garg et al,32 2008

Fontan

Inai et al,35 2005 Motoki et al,36 2009

5

23.4  7.4

Echo

29

8

Echo

B

44



30.3  10.9 19.7  4.0

37/6/1/1

Echo

B

16

25.6  3.7

7/4/5/0

Echo

B

B

B

B

14

29  4



MRI/ Echo

77  20

48  8

B

35

11

29 (18–40)

23/12/0/0

MRI

107  27

51  8

42

11

20.8  3.7

27/15 (II–IV)

Echo

47

17

35 (21–69)



B

48

14

41/7/0/0

B

24

8

61

19

19  5 (9.6– 37.7) 24.6 (11.4– 36.5) 26  8

40

24

28.8  9.5

27/12/1/0

50

24

22.7  7.0

41/9/0/0

Cath

68

28

25–53

1.7–2.6

Cath

B

B

B

B

B

(0.48  0.16)

43

B

B

(0.63  0.17) 41.6  9.3

B

B

Larsson et al,33 2007 Trojnarska et al,34 2010 4

33

B B

B

B

B

B

B

14/6/4/0a

(78.5%  23.9%)

20/42 (FAC 40%) 36.8  7.8

MRI/CT/ Echo Echo

28.1  7.5

36/26 (II–IV)

MRI/RI

98.8  27.8

Echo

21.7  5.9

49.1  11.0

60.3  8.4

[23/12/26 (m-s)]



56  5 80.6– 170.6

57.1–63.3

(continued on next page)

47

48

Table 1 (continued) Biomarkers

Natriuretic Peptides

S.No 5

6

SV-Type Category Unrepaired ( Eisenmenger)

Pregnancy

Authors,Ref. Hopkins & Hall,37 1997 Hopkins et al,38 2004 Reardon et al,39 2012

ANP

NTproANP

BNP

NTproBNP

Catecholamines

NE

E

Patients RAS System

PRA

PAC

Others

ET-1

Others

B

B

B

B

Diller et al,40 2012 Schuuring et al,41 2012 Saab & Aboulhosn,42 2013

B

Tanous et al,48 2010 Kamiya et al,49 2012

Ventricular Function

Cases

Total

Female

Age (y)

26

12

30  8

9

6

33  12

53

23

44  11.2

NYHA I/II/III/IV

PVO2 (mL/kg/ min)

Modality

Cath/ Echo



36.9  12.1 45  12

19/48/ 111/3 I–II (9)/III– IV (22)

13

8

38  14

2.46

Cath/ Echo

B

66

66

31  5

54/10/ 2 III

Echo

B

25

25

31.3  3.3 (event1)

23/1/1/0

Echo

181

116

31

B

B

B

SVEDVI (mL/m2)

SVEF/(Tei) [Visual EF]

PVEDVI (mL/m2)

PVEF/(Tei) (%)/—

54  9 (event )

44  9 (event )

51  10 (event1)

38  13 (event1)

Echo

55

30.0  5.3 (event ) Visual EF consists of 3 categories (preserved/reduced/severely reduced). The symbol “B” indicates biomarkers that are assessed in the corresponding study. Abbrebiations: ANP, atrial natriuretic peptide; ASD, atrial septal defect; BNP, brain natriuretic peptide; Cath, cardiac catheterization; CT, computed tomography; E, epinephrine; Echo, echocardiogram; ET-1, endothelin-1; FAC, fractional area change; MRI, magnetic resonance imaging; NE, norepinephrine; NYHA, New York Heart Association functional class; PAC, plasma aldosterone; PRA, plasma renin activity; PVEDVI, pulmonary ventricular end-diastolic volume index; PVEF, pulmonary ventricular ejection fraction; PVO2, peak oxygen uptake; PVR, pulmonary valve replacement; RAS, renin-angiotensin-aldosterone; RI, radionuclide imaging; RV, morphologic right ventricle; SVEDVI, systemic ventricular enddiastolic volume index; SVEF, systemic ventricular ejection fraction.

Biomarkers in ACHD Heart Failure NP levels were positively correlated with NYHA class4,9,10 and inversely correlated with peak oxygen uptake (PVO2) in some studies.4,8 Regarding the associations with ventricular function, NP levels were inversely correlated with the systolic function of the PV or SV.3,4,9,10 Echocardiographic variables, such as Tei-index7 and tissue Doppler findings,6 were also associated with NP levels. In terms of the noncardiac variables, the NP level was correlated positively with age and inversely with arterial oxygen saturation (SpO2).8 Pulmonary function and PVO2 were also inversely correlated with the NP levels.8 The norepinephrine level was higher in ACHD than in controls, and correlated with the NYHA classes and cardiothoracic ratio as well as the NP level.4 The endothelin-1 level was also higher in the ACHD group and correlated with NYHA class, PVO2, cardiac size, and SV function, and these associations with clinical variables were the second strongest after the NP levels.4 On the other hand, although the hormone levels of RAS were higher in the ACHD, there was a weak association with cardiopulmonary function.4 Regarding the other biomarkers, one study demonstrated that asymmetric dimethylarginine level reflected the HF severity as did the NT-proBNP level, although it was not associated with ventricular function.10 Regarding the diagnostic value, a BNP level of greater than 40 pg/mL predicted SV dysfunction,6 and high levels of ANP and BNP predicted mortality in ACHD, with the statistically optimal cutoff values being 78 and 146 pg/mL, respectively.9 Note Even if functional class was comparable, BNP level was lower in ACHD patients than in nonACHD HF patients,6 and similar findings were also demonstrated in pediatric and adolescent postoperative patients with CHD,11 implying a unique HF pathophysiology in CHD patients regardless of age.

PRV Group Patients’ characteristics This category includes patients with ventricular volume and/or pressure overload caused by atrial septal defect (ASD), those with idiopathic PH, and those with postoperative tetralogy of Fallot (TOF).12–22 These studies consisted of 20 to 130 clinically stable patients. Ages at the time of study were lower in TOF patients, with a mean of 16 to 30 years, when compared with age in patients with an ASD and idiopathic PH, with a mean age of 38 to 46 years. Most patients with ASD12,13,18 and TOF15–17,20 were in NYHA

class I or II, and NYHA class III or higher was rare. On the other hand, most patients were symptomatic in studies of idiopathic PH patients, including NYHA class IV patients.12,14 In more than half of the studies, ventricular function was assessed by CT12 or MRI18,19,21,22 as well as echocardiography. Several exclusion criteria were also applied in some studies, such as acute HF, liver and/or renal dysfunction, arrhythmia, and LV dysfunction.12–14,16–19 Biomarkers NP levels were measured in all studies, catecholamine levels in 3,14,16,19 and RAS hormones in 2.16,19 Higher levels of NP were found in the ACHD groups in general,12,13,16,17,19 with even higher levels in those with PH,13 whereas the catecholamine and RAS hormone levels did not differ from those in controls.16,19 The NP and norepinephrine levels were correlated with NYHA class and PVO214,16,18–20 but the epinephrine and RAS hormone levels were not.16 Regarding associations with ventricular function, despite a lack of association between LV function and biomarkers in all studies except 1,21 a greater RV volume and a reduced RV systolic function were associated with higher levels of biomarkers.12,15,16,18–21 As a result, the magnitude of pulmonary regurgitation was also positively correlated with NP levels.16,20,21 NP levels were inversely correlated with the systolic function of the PV or SV.3,4,9,10 Echocardiographic variables, such as the Tei-index7 and tissue Doppler findings,6 were also associated with NP levels. In particular, relatively strong correlations were observed between impaired hemodynamics and high levels of biomarkers in PH patients.12–14,18 Regarding the diagnostic value, NP and norepinephrine levels were able to predict mortality in PH patients,14 although there have been no studies as to whether biomarker(s) could predict the mortality of TOF patients. Apart from prognosis, a ratio of BNP to ANP of greater than 1.0,13 NT-proBNP greater than 200 ng/L, and NT-proBNP greater than 105 to 148 ng/L was associated with the presence of PH, RV volume overload, and impaired exercise capacity, respectively.17,19 Device ASD closure18 and pulmonary valve replacement significantly decreased NP levels,20,22 and the reduction in NP level was associated with the corresponding reduction in RV volume.22 ANP level sensitively reflected an acute efficacy of PH treatment by nitric oxide, and long-term benefits resulted in decreases in both NP levels.12 A cutoff BNP value of 150 pg/mL and the increase during follow-up predicted the mortality.14

49

50

Table 2 Correlations between biomarkers and clinical variables in heart failure in adults with congenital heart disease

S.No 1

SV-Type Category Mixed

Demographics Ref.

Biomarker

Unit

n

Value

3

ANP BNP ANP BNP NE BNP BNP

pmol/L pmol/L pmol/L pmol/L nmol/L pg/mL pg/mL

21

54 53

9

BNP

pg/mL

49

10

NT-proBNP

pg/mL

94

7.3  4.5 5.3  3.5 56.6  17.8 35.8  7.7 2.19  0.09 — 122.4  106.7 52.7 (39.1– 115.4) —

12

ANP BNP ANP BNP ANP BNP NE BNP NT-proANP NT-proBNP

pg/mL pg/mL pg/mL pg/mL pg/mL pg/mL pg/mL pg/mL pg/mL pg/mL

41

NE NT-proBNP NT-proBNP NT-proBNP BNP

ng/L pg/mL ng/L ng/L pg/mL

59 20 70 130

BNP

pg/mL

42

4

7 8

2

Pulmonary RV

13

14

15 16

17 18 19 20

21

53

31 60

25 50

— — 27  4 31  5 — — — 85.0  87.0 704  62 147  28 (m)/150  23 (f) 452  36 150  141 240  93 218  30 16 (11–30) (m)/37 (21–57) (f) —

Age

Gender

Functional Capacity NYHA

0 0 0 0

PVO2

EDV

EF/(Tei)   0 0 B /(B)

0 B  0

0

 

B B B  0

 B 0

B

EDV/Dd

EF/(Tei)

 

0 0

Hemodynamics RAP

PVSP

PAP

CI

SpO2

PR

Qp/Qs

 

/(0)

0

0  



AVVR

B

0

 

Pulmonary Ventricle

Systemic Ventricle

B 0 

 

 









0

 

0 0

0  B

0 0

0 0

B B

0 0 

0 0 0 

0 0 B

B

 

0



 B

 B 0 0



B

0

B

3

Systemic RV (Fontan)

23

NT-proBNP NT-proBNP

pg/mL pg/mL

33 29

BNP BNP NT-proBNP NT-proBNP

pg/mL pg/mL ng/L pmol/L

44 16 43 35

30

NT-proBNP

ng/L

47

31

BNP ANP BNP BNP NT-proBNP

pg/mL pg/mL pg/mL pmol/L ng/L

48 24

34

BNP

pg/mL

40

35

ANP BNP NE BNP

pg/mL pg/mL pg/mL pg/mL

50

NT-proANP NT-proANP NT-proBNP BNP

pmol/L pmol/L pmol/L pg/mL

26 9

BNP

pg/mL

181

24

25 26 27 28

32

33

4

Fontan

36

5

Unrepaired (Eisenmenger)

37 38

39

40

61

68

53

240  230 257.7  243.4 19 (6–522) 67  12 200  148 25 (5–135, 38  34) 269 (34– 4476) — 61.8  43.3 15.4  18.2 13 (1–52) 340 (49– 1959) 71.8  74.4



 

D

B 0/(0)

B

B 0

 B

0

B

 B

 

0 0



0

76  10 90.9  14.3 380  30 32.9–227.2 1828  1147 1817  1553 122  140 100  157 (noevent)/ 322  347 (event)a 97.6  150.3

B

B  

0 0

0 B 

   

0 0 0

   

B

0 

B

 0

0

B

B

0

0 B B



Significance: , not significant; D, P

Biomarkers in adult congenital heart disease heart failure.

Most adults with congenital heart disease show high levels of natriuretic peptide (NP) when compared with normal controls. Levels of norepinephrine an...
324KB Sizes 0 Downloads 0 Views