Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Blood biomarkers predicting adverse clinical outcomes in congenital heart disease patients, with consideration for pulmonary valve replacement

Blood biomarkers predicting adverse clinical outcomes in congenital heart disease patients, with... Acta Marisiensis - Seria Medica 2023;69(1):11-16 DOI: 10.2478/amma-2023-0009 REVIEW Blood biomarkers predicting adverse clinical outcomes in congenital heart disease patients, with consideration for pulmonary valve replacement 1* 2 Milla Marika Kainlauri , Irina-Bianca Kosovski 1. George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania 2. Department of Pathophysiology, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania Objective: This review aims to make a brief overview of blood biomarkers’ clinical decision limits, possibly aiding in outcome prediction in all-aged Tetralogy of Fallot patients. Potentially, these biomarkers could also assist in necessity and timing of pulmonary valve replacement. Methods: Studies with all-aged patients with Tetralogy or Pentalogy of Fallot and blood biomarkers, BNP, NT-proBNP and hs-cTn, usage in clinical outcome prediction were included. Additionally, pulmonary valve replacement indications were considered. Other congenital heart diseases, biomarkers irrelevant to clinical outcome and associated pathologies or physiological status were the exclusion criteria. Keywords, Tetralogy and Pentalogy of Fallot, pulmonary valve replacement, blood biomarkers, yielded 69 suitable studies from Google Scholar, PubMed and Web-of-Science. 30 studies were selected. Results: Blood biomarkers were increased in TOF patients in comparison to controls; the higher the values, the worse adverse outcomes. Blood biomarkers combined with other biomarkers, imagistic methods or parameters showed promising results in outcome prediction. Conclusions: Blood biomarkers are validated as follow-up predictors in congenital heart disease paediatric patients. Further research is required to establish age-appropriate clinical decision limits. Pulmonary valve replacement timing remains controversial. Keywords: congenital heart disease, tetralogy of Fallot, pentalogy of Fallot, blood biomarkers, pulmonary valve replacement Received 20 October 2022 / Accepted 14 February 2023 Introduction some degree of pulmonary valve incompetence requiring Tetralogy of Fallot (TOF) and Pentalogy of Fallot (POF) reintervention in adulthood [4]. Congenital heart disease (CHD) is the most common Increasing risk of non-cardiac and cardiac complica- congenital malformation and the leading cause of infant tions, such as severe arrhythmias, ventricular dysfunction mortality [1]. TOF is the most common cyanotic CHD and sudden death, is due to longstanding pulmonary re- [2] [3]. It affects up to 10% of CHD patients [4]. TOF gurgitation (PR). PR in turn causes RV overload and in- occurs due to anterior-superior deviation of ventricular creasing RV filling pressures [5]. Symptomatic heart failure septum into the right ventricular (RV) outflow tract. This (HF) is progressively recognised complication in adults results in four anatomical lesions: ventricular septal de- with CHD [4]. With pulmonary valve replacement (PVR) fect, pulmonary stenosis, right ventricle hypertrophy and the end-diastolic and end-systolic volumes can be reduced dextropositioned aorta [1][5]. Deoxygenated blood from by 30-50%, reducing the adverse long-term outcomes [7]. the RV partially bypasses the pulmonary circulation and is Despite the observed benefit, optimal timing of PVR is mixed with oxygenated blood from the left ventricle (LV). challenging [8]. Too early intervention can result in con- Thus, inadequate oxygen delivery to the systemic circula - duit dysfunction, but PVR should occur prior to RV dys- tion results. If aforementioned pathological anomalies are function development, significant RV dilation indicating associated with atrial septal defect, the nomination changes irreversible myocardial changes [3]. from TOF to POF [6]. Blood biomarkers Outcomes and pulmonary valve replacement (PVR) Biomarkers reflect the presence or severity of a disease. Unrepaired TOF has a poor prognosis: only 50% survive Ideally, the markers are easily measurable and are sensitive until 3 years of age. Earlier and improved diagnosis has and specific to the disease stage they are intended for. This enabled appropriate full repair already in infancy [4]. Suc- makes them especially useful in paediatric cardiology since cesses in surgical procedures have enhanced patient sur- many children cannot express their symptoms accurately vival. Thus, adults with rTOF (repaired Tetralogy of Fallot) [9]. outnumber paediatric patients, 30-year survival rate being Cardiac myocytes synthesise and release natriuretic pep- around 90% [5]. Nonetheless, most patients remain with tides (NPs) in response to abnormal ventricular wall stress, such as increased volume and pressure of the heart [10] [11]. The concentrations are confounded by several fac - * Correspondence to: Milla Marika Kainlauri E-mail: milli.k@outlook.com tors: age, sex, renal function and body mass index [12]. 12 Acta Marisiensis - Seria Medica 2023;69(1) Brain natriuretic peptide (BNP) is released primar- Results ily from ventricular myocytes in response to myocardial The literature search yielded in total of 30 potential stud - stretch or stress in pressure or volume overloaded stages ies. Sensitivity indicates the ability of disease detection of [12]. It improves myocardial relaxation through natriure- a test; with high sensitivity tests many individuals who are sis, diuresis and vasodilation [12]. It can be used as a prog- sick, receive a positive result. Specificity describes the abil - nostic marker in paediatric cardiac surgery [13]. BNP val- ity of identification of people without the disease; high ues peak in infancy, decreasing to adult levels by 6 years of sensitivity tests give only a few false positives. age [7]. In healthy adults, the BNP concentration is about 10 pg/mL [12]. BNP in paediatric patients In adults, BNP and N-terminal segment of its pro-hor- Table I summarises the BNP cut-off values and clinical in - mone (NT-proBNP), are considered the first-line biomark - dications in paediatric patients. ers in diagnosis of acute and chronic HF [14]. They can also A review by Nawaytou and Bernstein showed that BNP provide information in evaluation of cardiac functions in ≥40 pg/mL, with an accuracy of 84%, differentiated car - paediatric patients with a suspected CHD [13]. NT-proB- diac from pulmonary disease. BNP levels also correlated NP range of 8-13 pmol/L is normal for adults [15]. with exercise capacity, degree of pulmonary insufficiency Cardiac troponin is released as a consequence of cardiac and RV dimensions [9]. myocyte necrosis as in HF or myocardial ischemia [16]. Hirono et al. stated cut-off of ln BNP 4.1412, with High-sensitivity cardiac troponin (hs-cTn) elevations cor- 66.7% sensitivity and 100.0% specificity, predicting re - relate with cardiovascular morbidity, mortality, and cardio- operation in patients with rTOF. BNP could be utilised vascular events in adults with CHD [17]. in assessing RV load, which in turn could be a potential This systematic review aims to make a brief overview of prognostic indicator of RV condition [18]. potential blood biomarker clinical decision limits. These Cantinotti et al. focused on distinguishing hemody- limits could be then applied to predict adverse clinical out- namically significant cardiovascular disease from other comes in all-aged TOF patients. Also, the necessity and disease processes, specifically in paediatric outpatients with correct timing of PVR is evaluated. chronic LV dysfunction due to cardiomyopathies. BNP levels <300 pg/mL, with 93% sensitivity and 95% specific - Methods ity, had a 0.88 predictive value and a negative predictive Studies with all-aged TOF patients and the usage of blood value of 0.97 for adverse cardiovascular events [13]. biomarkers, BNP, NT-proBNP and hs-cTn, in the clini- cal outcome prediction were included. Thus, in the review BNP in adults it was possible to divide the material into separated ta- Table II summarises the BNP cut-off values and clinical bles and subsections, concerning separately paediatric and indications in adults. adult patients. In addition, indications for PVR were con- Nir et al. predicted death during follow-up at cut-off sidered. Exclusion criteria consisted of other CHDs, us- of >78 pg/mL with 100% sensitivity and 76% specificity age of other biomarkers showing no importance in clinical [19]. outcome or other associated pathological or physiological Villafãne et al., stated a greater increase in BNP was re- conditions. ported in TOF patients compared to controls when evalu- Material was retrieved from Google Scholar, Web-of- ating ventricular function and HF [3]. Science and PubMed. Publication dates were focused on Heng concluded BNP level being a predictor of adverse the past 10 years. For TOF, the studies were searched by outcomes of sustained arrhythmia and mortality. It was using advanced search methods with keywords TOF, PVR also associated with functional capacity, LV dysfunction and blood biomarker. The search yielded approximately and mortality in HF patients. In rTOF patients, elevated 3,860 studies in total. Regarding POF, the keywords, Pen- BNP correlated with RV end-diastolic dimensions and the talogy of Fallot, blood biomarker and pulmonary valve PR severity [6]. replacement, yielded approximately 64 studies. In total, a Heng et al. noted abnormal BNP concentrations in number of 69 applicable studies were retrieved. 79% of rTOF patients, at ≥5.3 pmol/L, and in 70% of Each study title and abstract were screened to identify asymptomatic patients [20]. relevant articles. Language of the publications was restrict- ed to English. The three blood biomarkers included to the NT-proBNP in paediatric patients study, BNP, NT-proBNP and hs-cTn, were the focus when Table III summarises the NT-proBNP cut-off values and selecting the articles. The studies had to include research clinical indications in paediatric patients. about Tetralogy and/or Pentalogy of Fallot and minimum Paolino et al., presented a cut-off value of >133.2 pg/ one of the aforementioned blood biomarkers. PVR was mL indicating dilated RV end-diastolic and end-systolic additional accepted criterion. Out of retrieved studies, 30 volumes over centile 95. It also predicted PVR, based on studies were selected for the final review. RV end diastolic volume, with 75% sensitivity and 55% Acta Marisiensis - Seria Medica 2023;69(1) 13 Table I. brain natriuretic peptide cut-off values and their indications in paediatric patients Studies Patient number and age Cut-off values Clinical outcomes Kapoor et al. [28] 250, <1-year-old to >18-year-old >290 pg/mL Increased probability of adverse outcomes in the intensive care unit Nawaytou and Bernstein [9] 49 infants and children ≥40 pg/mL Differentiation of cardiac from pulmonary disease 42, age 0-7 days 58 of 7 days to 40 pg/mL and ≥170 pg/mL Differentiation of paediatric patients and neonates, respec- 19-year-old tively, with a heart disease from those without 29, 1 month to 7-year-old ≥30 pg/mL Sensitivity and specificity for diagnosing HF Hirono et al. [18] 58 patients, 1-18 years 4.1412 (ln BNP) Reoperation in rTOF patients Cantinotti et al. [13] 53, from 2 months to 21-year-old <300 pg/mL Adverse cardiovascular outcomes in paediatric outpatients with chronic LV dysfunction with 0.97 negative prediction CHD – congenital heart disease, HF - heart failure, RV – right ventricle, rTOF – repaired tetralogy of Fallot, PR – pulmonary regurgitation, LV – left ventricle Table II. brain natriuretic peptide cut-off values and their indications in adult patients and studies combining both patient groups Studies Patient number and age Cut-off values Clinical outcomes Nir et al. [19] 2156, all-aged adult patients >35 pg/mL Chronic HF probable <35 pg/mL Chronic HF improbable <100 pg/mL Acute HF probable >400 pg/mL Acute HF improbable >35 pg/mL Cardiac overload should be considered >78 pg/mL Predictor of death during follow-up Villafãne et al. [3] 130 children and adults 37.6 ± 27.5 pg/ml in rTOF patients 11.3 ± 4.5 pg/mL in controls Heng [6] 90 patients, 32.7 ± 11.3 years ≥15 pmol/L 19% absolute mortality at 5-year follow-up ≤15 pmol/L 3% absolute mortality at 5-year follow-up Heng et al. [20] 90 patients, 32.7 ± 11.3 years ≥5.3 pmol/L In 79% of rTOF patients 15.5 pmol/L and 8.9 pmol/L Increasing trend towards deceased patients compared to survivors ≥15 pmol/L 5-fold increased risk of mortality Eindhoven et al. 770 patients, 4.2 to 30.9 years of age 19-85 pg/mL Increased values compared to age-matched healthy controls Khokhar et al. [29] 530 adults, 42 ± 15 years >100 ng/L Predicting mortality in CHD adults CHD – congenital heart disease, rTOF – repaired tetralogy of Fallot Table III. N-terminal pro BNP cut-off values and their indications in paediatric patients Studies Patient number and age Cut-off values Clinical outcomes Paolino et al. [21] 43 patients, 15.1 years in average >133.2 pg/mL Dilated RV end-diastolic and end-systolic volumes <71.2 pg/mL Excluded presence of significant RV end-diastolic and systolic vol - umes and PR >40% 187.5 pg/mL Statistically in correlation with RV dilation and PR fraction Alborikan et al. [30] 1479 patients, 22.7 ± 8.3 years of 147 pg/mL All-cause mortality age 232 pg/mL Adverse clinical events 349.5 pg/mL HF predictor 145 pg/mL Presence of RV dilatation 115 pg/mL Presence of RV dilatation and/or dysfunction Nawaytou and 21, 12.06 ± 2.30 years of age >115 pg/mL RV dilation and ejection fraction <40% Bernstein [9] Hirono et al. [18] 58 patients, 1-18-years 6.2195 (ln NT-proBNP) Reoperation in rTOF Nir et al. [19] 2156, all-aged adult patients <125 pg/mL Chronic HF improbable >125 pg/mL Chronic HF probable <300 pg/mL Acute HF improbable at <50, >50 and >75 years >450, >900, >1800 pg/mL Acute HF probable at age groups <50, >50 and >75 years, respectively <400 pg/mL Acute HF in adults unlikely >200 pg/mL Acute HF probable 150-200 pg/mL Identification of exercise incapacity and dilated RV in systole >125 pg/mL Cardiac overload RV – right ventricle, PR – pulmonary regurgitation, HF – heart failure, BNP – brain natriuretic peptide, RV – right ventricle, rTOF – repaired tetralogy of Fallot, PVR – pulmonary valve replacement specificity, and systolic volume, with 100% sensitivity and RV end-diastolic pressure. NT-proBNP was also found in 52.5% specificity. 187.5 pg/mL was in correlation with correlation to age and the ratio between the pulmonary RV dilation for end-diastolic and end-systolic volumes and and systemic vascular resistance. However, cardiac magnet- with PR fraction [21]. ic resonance imaging that is often used to evaluate the need Study by Hirono et al., stated ln NT-proBNP cut-off of for PVR, was not found in correlation with biomarker lev- 6.2195, with 88.9% sensitivity and 91.8% specificity, in els [7]. predicting reoperation in patients with rTOF. NT-proBNP was found closely in association with right HF in patients, NT-proBNP in adults being also a good predictor of PVR necessity, with 88.9% Table IV summarises the NT-proBNP cut-off values and sensitivity and 91.8% specificity [18]. clinical indications in adults. Zegelbone et al. notified significant correlation between Eindhoven et al. noted LV ejection fraction to be sig- NT-proBNP and baseline mean right atrial pressure and nificantly lower in patients with increased NT-proBNP. 14 Acta Marisiensis - Seria Medica 2023;69(1) Table IV. N-terminal pro BNP cut-off values and their indications in adult patients and studies combining both patient groups Studies Patient number and age Cut-off values Clinical outcomes Eindhoven et al. [22] 177 patients, 34.6 ± 11.8 years of age 15.6 pmol/L The median value exceeds the normal value in 55% of patients Jabagi et al. [12] 1586 adults 300 pg/mL Greater negative predictive value for acute HF compared to BNP Schoonbeek et al. [23] 306 adult patients ≥125 pg/mL In 44% of PVR patients Westhoff-Bleck et 81 patients, 26.3 ± 7.4 years of age 232-764 pg/mL In cumulative survival curves worse outcomes al. [2] 168 ng/L and ≥232 ng/L Specificity increased with increasing levels: from 75% to 85.3% Baggen et al. [24] 595 patients, median age 33 years <15.2 pmol/L Cumulative proportion of death and HF of 1% >33.3 pmol/L Strongest association with cardiovascular events, death or HF Eindhoven et al. [11] 770 patients, 4.2 to 30.9 years of age 18-231 pg/mL Increased values compared to healthy controls (38-111 pg/mL) HF – heart failure, BNP – brain natriuretic peptide, PVR – pulmonary valve replacement However, in the total study population or in a subgroup Baggen et al. stated adults, with median age of 33, of patients without prior PVR, the severity of PR was not showing hs-cTn levels >14 ng/L faced the highest risk of related to NT-proBNP [22]. cardiovascular events [24]. Schoonbeek et al., stated that 44% of the PVR patients presented with high NT-proBNP levels, ≥125 pg/mL. Ad- PVR ditionally, an association between a higher age at the lat- Yasukawa et al. showed how within 3 years after PVR, BNP est valve replacement and higher NT-proBNP levels was was higher in the subnormal-stroke volume index group established [23]. compared to normal stroke volume index group [26]. Westhoff-Bleck et al. showed significantly worse out - According to Kitagawa et al., BNP cut-off value consid - comes in patients with NT-proBNP levels between 232- ering PVR was 32.15 pg/mL [27]. 764 ng/L in cumulative survival curves. The emphasis was Paolino et al. used a NT-proBNP cut-off value of 133.2 on the diagnostic power and utility of NT-proBNP in pg/mL predicting PVR, based on the RV end-diastolic and prediction of adverse clinical outcomes. Increasing levels end-systolic values [21]. had an association with increasing specificity. Cut-off of In a study by Peng et al., BNP was found to correlate 168 ng/L yielded 84.5% sensitivity and 75% specificity, with PR severity, and decreased significantly following whereas NT-proBNP ≥232 ng/L resulted in 76.9% sen- PVR [10]. sitivity with 85.3% specificity. NT-proBNP levels tended Nir et al. noted a significant increase in BNP levels in to increase with increasing NYHA class. NT-proBNP a small group of patients requiring PVR before the proce- also remained as an independent predictor of all adverse dure. However, both BNP and NT-proBNP diminished in events correlating with LV ejection fraction, mass, and patients with significant PR following PVR [19]. end-diastolic and end-systolic volume indexes. During the follow-up patients receiving PVR tended to have higher Discussion NT-proBNP levels at the baseline [2]. CHDs are widely recognised as causative agents of infant According to Baggen et al., NT-proBNP >14 pmol/L mortality as well as adverse outcomes later in life despite identified those patients with the highest risk for cardio - the early initial correction. Thus, for more precise clini - vascular events, death or HF. The strongest association was cal outcome prediction of TOF, more clinically applicable at >33.3 pmol/L. The risk of patients who presented with a blood biomarker decision limits need to be established, high NT-proBNP level could be further evaluated by com- which this review aimed for. Also, controversies related to bining also hs-cTn to NT-proBNP testing [24]. PVR were under consideration. All blood biomarkers showed increased values in TOF Hs-cTn patients compared to healthy individuals and decreased In a study by Jabagi et al., hs-cTn level increased with in- following PVR throughout the cohort of studies. The creasing RV volume and worsening RV ejection fraction higher the presented cut-off values were, the higher was in adult patients with previous TOF repair. Predictive and the probability and severity of adverse outcome presen- diagnostic utility of this marker, measured in patients un- tation. For the most severe outcome, death, prediction dergoing cardiac surgery, could provide information about BNP cut-off values varied between >78 pg/mL in paediat - the post-operative recovery. [12]. ric patients and >100 ng/L in adults. NT-proBNP >33.3 Rajpal et al. showed in a multivariable analysis how hs- pmol/L had the strongest association with cardiovascular TnT, including hs-cTn, was a predictive of the secondary events, HF or death, in adult patients. All-cause mortal- end point; death or HF in adults. Primary end point, such ity was increased at NT-proBNP levels 147 pg/mL in pae- as death, HF, hospitalisation, or arrhythmia, was no longer diatric patients. Hs-cTn levels >14 ng/L had the highest significant in multivariable adjustment. However, it was risk of cardiovascular events. The data clearly shows the found more common in the highest hs-TnT quartile, with age-dependent variation of these blood biomarkers. NPs >7.7 ng/L, compared to the first quartile, with levels <3 additionally proved to be useful in the paediatric patients ng/L [25]. in diagnosing and differentiation of pathologies. In gen - Acta Marisiensis - Seria Medica 2023;69(1) 15 eral, the acute adverse clinical outcomes, such as acute HF, approach to unique problems faced by CHD patients [19]. showed significantly higher values throughout in compari - The differential gene expression in rTOF is already dem - son with chronic stages like cardiac overload. Notable is onstrated with RNA sequencing, which could be utilised how even relatively small increases above the baseline can in studying genotype-phenotype relationships. This could be clinically significant. Thus, before the occurrence of a be demonstrated by the genotype of patients originally more systematic treatment plan, every patient should be with significant pulmonary stenosis in relation with later periodically evaluated, combining laboratory results with developed PR or gene expression pre-intervention versus imagistic methods. Consequently, declining in the condi- post-intervention in PVR [6]. tion could be recognised, for example by clearly changed blood biomarker values, enabling prompt and correctly Conclusion timed intervention. Advanced surgical repair techniques in infancy have in- Based on literature, blood biomarkers are already rela- creased patient survival into adulthood. Hence, adverse tively extensively utilised for assessing the patients with dif- clinical outcomes concern not only children but also adult ferent cardiac diseases. In case of CHDs, biomarker ranges, patients, enabling the outcome occurrence at any point of which respect different types of pathologies, age and gen - life. Periodical blood biomarker measurements in addition der, need to be outlined for more systematic treatment. to other diagnostic methods should be performed to detect Additionally, more correlations between blood biomark- significant changes in blood biomarker values. This could ers and other clinical evaluation methods, such as cardiac possibly prevent adverse clinical outcomes also in the long- magnetic resonance imaging, should be established. term setting and detect the most suitable timing for PVR This review, as many others, have been greatly limited for each patient individually. To aid in prevention and cor- by the small population size and heterogeneity of the age rectly timed interventions, more standardised guidelines groups in the studies. Physiological BNP level variation considering age-dependency should be established. Also, complicated the interpretation of the results regarding the the possible emergence of new blood biomarkers and thus long-term outcome prediction. Due to these factors, the new combinations with imagistic and other parameters indications and correct timing for PVR remain contro- would create more systematic treatment for these patients. versial, however, with wide range of possibilities. For in- stance, the potential of hs-TnT in CHD patients is clearly Acknowledgements and funding recognised but not yet widely utilised. Additionally, POF This work was supported by the George Emil Palade Uni - presenting lower prevalence compared to TOF, the afore- versity of Medicine, Pharmacy, Sciences and Technology mentioned limitations are even more weighted, requiring of Târgu Mureș, Research Grant number NR. 224/1 / special attention. 10.01.2022 Blood biomarkers are unlikely able to act alone in out- come prediction. However, the results are promising in Conflicts or competing interests combination with imagistic methods, other biomarkers None to declare. and parameters, such as cardiac magnetic resonance im- aging, cardiopulmonary exercise testing and heart volume Authors' contribution and function tests. Certain studies are already establish- MK (Conceptualization; Data curation; Formal analy- ing relationships between echocardiographic findings and sis; Investigation; Methodology; Project administration; natriuretic peptides. With complex multifactorial CHDs Resources; Software; Validation; Visualization; Writing – easily measurable, affordable, sensitive, and specific param - original draft; Writing – review & editing) eters combined are most likely to yield the best possible IBK (Conceptualization; Investigation; Methodology, results. Validation; Visualization, Supervision; Writing – review & The future holds many promising directions concern - editing) ing the clinical outcome prediction. Firstly, deepening the knowledge on already discussed blood biomarkers and es- References 1. Søndergaard Lars. Early Versus Later Re-valving in Tetralogy of Fallot tablishing their relationship with other evaluation methods with Free Pulmonary Regurgitation. 2019 May;(5th Edition). Available is essential. Establishing the trends of biomarker profile as - from: https://www.clinicaltrials.gov/ProvidedDocs/32/NCT04084132/ Prot_SAP_000.pdf sociated with clinical declining could prompt more effec - 2. Westhoff-Bleck M, Kornau F, Haghikia A, Horke A, Bertram H, Treptau tive assessment, yielding an algorithm of NPs in relation J, et al. NT-proBNP Indicates Left Ventricular Impairment and Adverse to the common interventions. Also standardisation of dif- Clinical Outcome in Patients With Tetralogy of Fallot and Pulmonary Regurgitation. Can J Cardiol. 2016 Oct;32(10):1247.e29-1247.e36. ferent commercial assays is needed [16][19]. Additionally, 3. Villafañe J, Feinstein JA, Jenkins KJ, Vincent RN, Walsh EP, Dubin highly sensitive troponins are less used in CHD patients: AM, et al. Hot Topics in Tetralogy of Fallot. J Am Coll Cardiol. 2013 Dec;62(23):2155–66. they could offer information independently from, and ad - 4. Downing TE, Kim YY. Tetralogy of Fallot. Cardiol Clin. 2015 Nov;33(4):531– ditive to NPs in various outcomes. Secondly, the emergence and interpretation of more sensitive early biomarkers, such 5. Bhagra CJ, Hickey EJ, Van De Bruaene A, Roche SL, Horlick EM, Wald RM. Pulmonary Valve Procedures Late After Repair of Tetralogy of Fallot: as copeptin, MR-proANP and GDF-15, may elucidate the 16 Acta Marisiensis - Seria Medica 2023;69(1) Current Perspectives and Contemporary Approaches to Management. adults with congenital heart disease. Biomark Med. 2012 Dec;6(6):827– Can J Cardiol. 2017 Sep;33(9):1138–49. 37. 6. Heng EL. Improved outcome prediction in tetralogy of Fallot. 2016 20. Heng EL, Bolger AP, Kempny A, Davlouros PA, Davidson S, Swan L, et Dec [cited 2022 Jul 12]; Available from: http://spiral.imperial.ac.uk/ al. Neurohormonal activation and its relation to outcomes late after repair handle/10044/1/50676 of tetralogy of Fallot. Heart. 2015 Mar 15;101(6):447–54. 7. Zegelbone PM, Ringel RE, Coulson JD, Nies MK, Stabler ME, Brown JR, 21. Paolino A, Hussain T, Pavon A, Velasco MN, Uribe S, Ordoñez A, et al. NT- et al. Heart failure biomarker levels correlate with invasive haemodynamics proBNP as Marker of Ventricular Dilatation and Pulmonary Regurgitation in pulmonary valve replacement. Cardiol Young. 2020 Jan;30(1):50–4. After Surgical Correction of Tetralogy of Fallot: A MRI Validation Study. Pediatr Cardiol. 2017 Feb;38(2):324–31. 8. van der Ven JPG, van den Bosch E, Bogers AJCC, Helbing WA. 22. Eindhoven JA, Menting ME, van den Bosch AE, Cuypers JAAE, Ruys Current outcomes and treatment of tetralogy of Fallot. F1000Research. TPE, Witsenburg M, et al. Associations between N-terminal pro-B-type 2019;8:F1000 Faculty Rev-1530. natriuretic peptide and cardiac function in adults with corrected tetralogy 9. Nawaytou H, Bernstein HS. Biomarkers in pediatric heart disease. of Fallot. Int J Cardiol. 2014 Jul;174(3):550–6. Biomark Med. 2014 Aug;8(7):943–63. 23. Schoonbeek RC, Pieper PG, van Slooten YJ, Freling HG, Sieswerda GT, 10. Peng EWK, Spooner R, Young D, Danton MHD. Acute B-type natriuretic van Dijk APJ, et al. NT-proBNP and exercise capacity in adult patients peptide response and early postoperative right ventricular physiology with congenital heart disease and a prosthetic valve: a multicentre following tetralogy of Fallot’s repair. Interact Cardiovasc Thorac Surg. PROSTAVA study. Neth Heart J. 2016 Nov;24(11):653–65. 2012 Sep 1;15(3):335–9. 24. Baggen VJM, van den Bosch AE, Eindhoven JA, Schut ARW, Cuypers 11. Eindhoven JA, van den Bosch AE, Jansen PR, Boersma E, Roos- JAAE, Witsenburg M, et al. Prognostic Value of N-Terminal Pro-B-Type Hesselink JW. The Usefulness of Brain Natriuretic Peptide in Complex Natriuretic Peptide, Troponin-T, and Growth-Differentiation Factor 15 in Congenital Heart Disease. J Am Coll Cardiol. 2012 Nov;60(21):2140–9. Adult Congenital Heart Disease. Circulation. 2017 Jan 17;135(3):264–79. 12. Jabagi H, Mielniczuk LM, Liu PP, Ruel M, Sun LY. Biomarkers in the 25. Rajpal S, Alshawabkeh L, Opotowsky AR. Current Role of Blood and Diagnosis, Management, and Prognostication of Perioperative Right Urine Biomarkers in the Clinical Care of Adults with Congenital Heart Ventricular Failure in Cardiac Surgery—Are We There Yet? J Clin Med. Disease. Curr Cardiol Rep. 2017 Jun;19(6):50. 2019 Apr 25;8(4):559. 26. Yasukawa T, Hoashi T, Imai K, Okuda N, Fukuda T, Ohuchi H, et al. 13. Cantinotti M, Law Y, Vittorini S, Crocetti M, Marco M, Murzi B, et al. The The reduced left ventricular stroke volume does not fully recover after potential and limitations of plasma BNP measurement in the diagnosis, pulmonary valve replacement in patients with repaired tetralogy of Fallot. prognosis, and management of children with heart failure due to congenital Eur J Cardiothorac Surg. 2021 Sep 11;60(3):526–33. cardiac disease: an update. Heart Fail Rev. 2014 Nov;19(6):727–42. 27. Kitagawa A, Oka N, Kimura S, Ando H, Honda T, Takanashi M, et al. 14. Cantinotti M, Walters HL, Crocetti M, Marotta M, Murzi B, Clerico A. Clinical Utility of the Plasma Brain Natriuretic Peptide Level in Monitoring BNP in children with congenital cardiac disease: is there now sufficient Tetralogy of Fallot Patients over the Long Term After Initial Intracardiac evidence for its routine use? Cardiol Young. 2015 Mar;25(3):424–37. Repair: Considerations for Pulmonary Valve Replacement. Pediatr 15. S.E. Luijnenburg. Outcome Late After Repair of Tetralogy of Fallot Cardiol. 2015 Apr;36(4):752–8. [Internet]. Available from: https://repub.eur.nl/pub/40677/ 28. Kapoor PM, Subramanian A, Malik V, Kiran U, Velayoudham D. B-type 16. Dobson R, Walker HA, Walker NL. Biomarkers in congenital heart natriuretic peptide as prognostic marker in tetralogy of Fallot surgery. disease. Biomark Med. 2014 Aug;8(7):965–75. Asian Cardiovasc Thorac Ann. 2015 Feb;23(2):146–52. 17. Willinger L, Brudy L, Meyer M, Oberhoffer-Fritz R, Ewert P, Müller J. 29. Khokhar A, Zuhair M, Raj B, Heng EL, Alonso-Gonzalez R, Kempny Prognostic value of non-acute high sensitive troponin-T for cardiovascular A, et al. 2109Predictors of mortality following hospitalisation in adults morbidity and mortality in adults with congenital heart disease: A with congenital heart disease. Eur Heart J [Internet]. 2018 Aug 1 [cited systematic review. J Cardiol. 2021 Sep;78(3):206–12. 2022 Aug 26];39(suppl_1). Available from: https://academic.oup.com/ 18. Hirono K, Sekine M, Shiba N, Hayashi S, Nakaoka H, Ibuki K, et al. eurheartj/article/doi/10.1093/eurheartj/ehy565.2109/5082713 N-terminal pro-Brain Natriuretic Peptide as a Predictor of Reoperation 30. Alborikan S, Von Klemperer K, Bhan A, Walker F, Pandya B, Badiani S, et in Children With Surgically Corrected Tetralogy of Fallot. Circ J. al. Blood biomarkers in patients with repaired Tetralogy of Fallot (rTOF); 2014;78(3):693–700. A systematic review and meta-analysis. Int J Cardiol Congenit Heart Dis. 19. Nir A, Luchner A, Rein AJ. The natriuretic peptides as biomarkers for 2021 Dec;6:100237. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Marisiensis - Seria Medica de Gruyter

Blood biomarkers predicting adverse clinical outcomes in congenital heart disease patients, with consideration for pulmonary valve replacement

Loading next page...
 
/lp/de-gruyter/blood-biomarkers-predicting-adverse-clinical-outcomes-in-congenital-KRQBp77Y0a

References (23)

Publisher
de Gruyter
Copyright
© 2023 Milla Marika Kainlauri et al., published by Sciendo
eISSN
2668-7763
DOI
10.2478/amma-2023-0009
Publisher site
See Article on Publisher Site

Abstract

Acta Marisiensis - Seria Medica 2023;69(1):11-16 DOI: 10.2478/amma-2023-0009 REVIEW Blood biomarkers predicting adverse clinical outcomes in congenital heart disease patients, with consideration for pulmonary valve replacement 1* 2 Milla Marika Kainlauri , Irina-Bianca Kosovski 1. George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania 2. Department of Pathophysiology, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, Romania Objective: This review aims to make a brief overview of blood biomarkers’ clinical decision limits, possibly aiding in outcome prediction in all-aged Tetralogy of Fallot patients. Potentially, these biomarkers could also assist in necessity and timing of pulmonary valve replacement. Methods: Studies with all-aged patients with Tetralogy or Pentalogy of Fallot and blood biomarkers, BNP, NT-proBNP and hs-cTn, usage in clinical outcome prediction were included. Additionally, pulmonary valve replacement indications were considered. Other congenital heart diseases, biomarkers irrelevant to clinical outcome and associated pathologies or physiological status were the exclusion criteria. Keywords, Tetralogy and Pentalogy of Fallot, pulmonary valve replacement, blood biomarkers, yielded 69 suitable studies from Google Scholar, PubMed and Web-of-Science. 30 studies were selected. Results: Blood biomarkers were increased in TOF patients in comparison to controls; the higher the values, the worse adverse outcomes. Blood biomarkers combined with other biomarkers, imagistic methods or parameters showed promising results in outcome prediction. Conclusions: Blood biomarkers are validated as follow-up predictors in congenital heart disease paediatric patients. Further research is required to establish age-appropriate clinical decision limits. Pulmonary valve replacement timing remains controversial. Keywords: congenital heart disease, tetralogy of Fallot, pentalogy of Fallot, blood biomarkers, pulmonary valve replacement Received 20 October 2022 / Accepted 14 February 2023 Introduction some degree of pulmonary valve incompetence requiring Tetralogy of Fallot (TOF) and Pentalogy of Fallot (POF) reintervention in adulthood [4]. Congenital heart disease (CHD) is the most common Increasing risk of non-cardiac and cardiac complica- congenital malformation and the leading cause of infant tions, such as severe arrhythmias, ventricular dysfunction mortality [1]. TOF is the most common cyanotic CHD and sudden death, is due to longstanding pulmonary re- [2] [3]. It affects up to 10% of CHD patients [4]. TOF gurgitation (PR). PR in turn causes RV overload and in- occurs due to anterior-superior deviation of ventricular creasing RV filling pressures [5]. Symptomatic heart failure septum into the right ventricular (RV) outflow tract. This (HF) is progressively recognised complication in adults results in four anatomical lesions: ventricular septal de- with CHD [4]. With pulmonary valve replacement (PVR) fect, pulmonary stenosis, right ventricle hypertrophy and the end-diastolic and end-systolic volumes can be reduced dextropositioned aorta [1][5]. Deoxygenated blood from by 30-50%, reducing the adverse long-term outcomes [7]. the RV partially bypasses the pulmonary circulation and is Despite the observed benefit, optimal timing of PVR is mixed with oxygenated blood from the left ventricle (LV). challenging [8]. Too early intervention can result in con- Thus, inadequate oxygen delivery to the systemic circula - duit dysfunction, but PVR should occur prior to RV dys- tion results. If aforementioned pathological anomalies are function development, significant RV dilation indicating associated with atrial septal defect, the nomination changes irreversible myocardial changes [3]. from TOF to POF [6]. Blood biomarkers Outcomes and pulmonary valve replacement (PVR) Biomarkers reflect the presence or severity of a disease. Unrepaired TOF has a poor prognosis: only 50% survive Ideally, the markers are easily measurable and are sensitive until 3 years of age. Earlier and improved diagnosis has and specific to the disease stage they are intended for. This enabled appropriate full repair already in infancy [4]. Suc- makes them especially useful in paediatric cardiology since cesses in surgical procedures have enhanced patient sur- many children cannot express their symptoms accurately vival. Thus, adults with rTOF (repaired Tetralogy of Fallot) [9]. outnumber paediatric patients, 30-year survival rate being Cardiac myocytes synthesise and release natriuretic pep- around 90% [5]. Nonetheless, most patients remain with tides (NPs) in response to abnormal ventricular wall stress, such as increased volume and pressure of the heart [10] [11]. The concentrations are confounded by several fac - * Correspondence to: Milla Marika Kainlauri E-mail: milli.k@outlook.com tors: age, sex, renal function and body mass index [12]. 12 Acta Marisiensis - Seria Medica 2023;69(1) Brain natriuretic peptide (BNP) is released primar- Results ily from ventricular myocytes in response to myocardial The literature search yielded in total of 30 potential stud - stretch or stress in pressure or volume overloaded stages ies. Sensitivity indicates the ability of disease detection of [12]. It improves myocardial relaxation through natriure- a test; with high sensitivity tests many individuals who are sis, diuresis and vasodilation [12]. It can be used as a prog- sick, receive a positive result. Specificity describes the abil - nostic marker in paediatric cardiac surgery [13]. BNP val- ity of identification of people without the disease; high ues peak in infancy, decreasing to adult levels by 6 years of sensitivity tests give only a few false positives. age [7]. In healthy adults, the BNP concentration is about 10 pg/mL [12]. BNP in paediatric patients In adults, BNP and N-terminal segment of its pro-hor- Table I summarises the BNP cut-off values and clinical in - mone (NT-proBNP), are considered the first-line biomark - dications in paediatric patients. ers in diagnosis of acute and chronic HF [14]. They can also A review by Nawaytou and Bernstein showed that BNP provide information in evaluation of cardiac functions in ≥40 pg/mL, with an accuracy of 84%, differentiated car - paediatric patients with a suspected CHD [13]. NT-proB- diac from pulmonary disease. BNP levels also correlated NP range of 8-13 pmol/L is normal for adults [15]. with exercise capacity, degree of pulmonary insufficiency Cardiac troponin is released as a consequence of cardiac and RV dimensions [9]. myocyte necrosis as in HF or myocardial ischemia [16]. Hirono et al. stated cut-off of ln BNP 4.1412, with High-sensitivity cardiac troponin (hs-cTn) elevations cor- 66.7% sensitivity and 100.0% specificity, predicting re - relate with cardiovascular morbidity, mortality, and cardio- operation in patients with rTOF. BNP could be utilised vascular events in adults with CHD [17]. in assessing RV load, which in turn could be a potential This systematic review aims to make a brief overview of prognostic indicator of RV condition [18]. potential blood biomarker clinical decision limits. These Cantinotti et al. focused on distinguishing hemody- limits could be then applied to predict adverse clinical out- namically significant cardiovascular disease from other comes in all-aged TOF patients. Also, the necessity and disease processes, specifically in paediatric outpatients with correct timing of PVR is evaluated. chronic LV dysfunction due to cardiomyopathies. BNP levels <300 pg/mL, with 93% sensitivity and 95% specific - Methods ity, had a 0.88 predictive value and a negative predictive Studies with all-aged TOF patients and the usage of blood value of 0.97 for adverse cardiovascular events [13]. biomarkers, BNP, NT-proBNP and hs-cTn, in the clini- cal outcome prediction were included. Thus, in the review BNP in adults it was possible to divide the material into separated ta- Table II summarises the BNP cut-off values and clinical bles and subsections, concerning separately paediatric and indications in adults. adult patients. In addition, indications for PVR were con- Nir et al. predicted death during follow-up at cut-off sidered. Exclusion criteria consisted of other CHDs, us- of >78 pg/mL with 100% sensitivity and 76% specificity age of other biomarkers showing no importance in clinical [19]. outcome or other associated pathological or physiological Villafãne et al., stated a greater increase in BNP was re- conditions. ported in TOF patients compared to controls when evalu- Material was retrieved from Google Scholar, Web-of- ating ventricular function and HF [3]. Science and PubMed. Publication dates were focused on Heng concluded BNP level being a predictor of adverse the past 10 years. For TOF, the studies were searched by outcomes of sustained arrhythmia and mortality. It was using advanced search methods with keywords TOF, PVR also associated with functional capacity, LV dysfunction and blood biomarker. The search yielded approximately and mortality in HF patients. In rTOF patients, elevated 3,860 studies in total. Regarding POF, the keywords, Pen- BNP correlated with RV end-diastolic dimensions and the talogy of Fallot, blood biomarker and pulmonary valve PR severity [6]. replacement, yielded approximately 64 studies. In total, a Heng et al. noted abnormal BNP concentrations in number of 69 applicable studies were retrieved. 79% of rTOF patients, at ≥5.3 pmol/L, and in 70% of Each study title and abstract were screened to identify asymptomatic patients [20]. relevant articles. Language of the publications was restrict- ed to English. The three blood biomarkers included to the NT-proBNP in paediatric patients study, BNP, NT-proBNP and hs-cTn, were the focus when Table III summarises the NT-proBNP cut-off values and selecting the articles. The studies had to include research clinical indications in paediatric patients. about Tetralogy and/or Pentalogy of Fallot and minimum Paolino et al., presented a cut-off value of >133.2 pg/ one of the aforementioned blood biomarkers. PVR was mL indicating dilated RV end-diastolic and end-systolic additional accepted criterion. Out of retrieved studies, 30 volumes over centile 95. It also predicted PVR, based on studies were selected for the final review. RV end diastolic volume, with 75% sensitivity and 55% Acta Marisiensis - Seria Medica 2023;69(1) 13 Table I. brain natriuretic peptide cut-off values and their indications in paediatric patients Studies Patient number and age Cut-off values Clinical outcomes Kapoor et al. [28] 250, <1-year-old to >18-year-old >290 pg/mL Increased probability of adverse outcomes in the intensive care unit Nawaytou and Bernstein [9] 49 infants and children ≥40 pg/mL Differentiation of cardiac from pulmonary disease 42, age 0-7 days 58 of 7 days to 40 pg/mL and ≥170 pg/mL Differentiation of paediatric patients and neonates, respec- 19-year-old tively, with a heart disease from those without 29, 1 month to 7-year-old ≥30 pg/mL Sensitivity and specificity for diagnosing HF Hirono et al. [18] 58 patients, 1-18 years 4.1412 (ln BNP) Reoperation in rTOF patients Cantinotti et al. [13] 53, from 2 months to 21-year-old <300 pg/mL Adverse cardiovascular outcomes in paediatric outpatients with chronic LV dysfunction with 0.97 negative prediction CHD – congenital heart disease, HF - heart failure, RV – right ventricle, rTOF – repaired tetralogy of Fallot, PR – pulmonary regurgitation, LV – left ventricle Table II. brain natriuretic peptide cut-off values and their indications in adult patients and studies combining both patient groups Studies Patient number and age Cut-off values Clinical outcomes Nir et al. [19] 2156, all-aged adult patients >35 pg/mL Chronic HF probable <35 pg/mL Chronic HF improbable <100 pg/mL Acute HF probable >400 pg/mL Acute HF improbable >35 pg/mL Cardiac overload should be considered >78 pg/mL Predictor of death during follow-up Villafãne et al. [3] 130 children and adults 37.6 ± 27.5 pg/ml in rTOF patients 11.3 ± 4.5 pg/mL in controls Heng [6] 90 patients, 32.7 ± 11.3 years ≥15 pmol/L 19% absolute mortality at 5-year follow-up ≤15 pmol/L 3% absolute mortality at 5-year follow-up Heng et al. [20] 90 patients, 32.7 ± 11.3 years ≥5.3 pmol/L In 79% of rTOF patients 15.5 pmol/L and 8.9 pmol/L Increasing trend towards deceased patients compared to survivors ≥15 pmol/L 5-fold increased risk of mortality Eindhoven et al. 770 patients, 4.2 to 30.9 years of age 19-85 pg/mL Increased values compared to age-matched healthy controls Khokhar et al. [29] 530 adults, 42 ± 15 years >100 ng/L Predicting mortality in CHD adults CHD – congenital heart disease, rTOF – repaired tetralogy of Fallot Table III. N-terminal pro BNP cut-off values and their indications in paediatric patients Studies Patient number and age Cut-off values Clinical outcomes Paolino et al. [21] 43 patients, 15.1 years in average >133.2 pg/mL Dilated RV end-diastolic and end-systolic volumes <71.2 pg/mL Excluded presence of significant RV end-diastolic and systolic vol - umes and PR >40% 187.5 pg/mL Statistically in correlation with RV dilation and PR fraction Alborikan et al. [30] 1479 patients, 22.7 ± 8.3 years of 147 pg/mL All-cause mortality age 232 pg/mL Adverse clinical events 349.5 pg/mL HF predictor 145 pg/mL Presence of RV dilatation 115 pg/mL Presence of RV dilatation and/or dysfunction Nawaytou and 21, 12.06 ± 2.30 years of age >115 pg/mL RV dilation and ejection fraction <40% Bernstein [9] Hirono et al. [18] 58 patients, 1-18-years 6.2195 (ln NT-proBNP) Reoperation in rTOF Nir et al. [19] 2156, all-aged adult patients <125 pg/mL Chronic HF improbable >125 pg/mL Chronic HF probable <300 pg/mL Acute HF improbable at <50, >50 and >75 years >450, >900, >1800 pg/mL Acute HF probable at age groups <50, >50 and >75 years, respectively <400 pg/mL Acute HF in adults unlikely >200 pg/mL Acute HF probable 150-200 pg/mL Identification of exercise incapacity and dilated RV in systole >125 pg/mL Cardiac overload RV – right ventricle, PR – pulmonary regurgitation, HF – heart failure, BNP – brain natriuretic peptide, RV – right ventricle, rTOF – repaired tetralogy of Fallot, PVR – pulmonary valve replacement specificity, and systolic volume, with 100% sensitivity and RV end-diastolic pressure. NT-proBNP was also found in 52.5% specificity. 187.5 pg/mL was in correlation with correlation to age and the ratio between the pulmonary RV dilation for end-diastolic and end-systolic volumes and and systemic vascular resistance. However, cardiac magnet- with PR fraction [21]. ic resonance imaging that is often used to evaluate the need Study by Hirono et al., stated ln NT-proBNP cut-off of for PVR, was not found in correlation with biomarker lev- 6.2195, with 88.9% sensitivity and 91.8% specificity, in els [7]. predicting reoperation in patients with rTOF. NT-proBNP was found closely in association with right HF in patients, NT-proBNP in adults being also a good predictor of PVR necessity, with 88.9% Table IV summarises the NT-proBNP cut-off values and sensitivity and 91.8% specificity [18]. clinical indications in adults. Zegelbone et al. notified significant correlation between Eindhoven et al. noted LV ejection fraction to be sig- NT-proBNP and baseline mean right atrial pressure and nificantly lower in patients with increased NT-proBNP. 14 Acta Marisiensis - Seria Medica 2023;69(1) Table IV. N-terminal pro BNP cut-off values and their indications in adult patients and studies combining both patient groups Studies Patient number and age Cut-off values Clinical outcomes Eindhoven et al. [22] 177 patients, 34.6 ± 11.8 years of age 15.6 pmol/L The median value exceeds the normal value in 55% of patients Jabagi et al. [12] 1586 adults 300 pg/mL Greater negative predictive value for acute HF compared to BNP Schoonbeek et al. [23] 306 adult patients ≥125 pg/mL In 44% of PVR patients Westhoff-Bleck et 81 patients, 26.3 ± 7.4 years of age 232-764 pg/mL In cumulative survival curves worse outcomes al. [2] 168 ng/L and ≥232 ng/L Specificity increased with increasing levels: from 75% to 85.3% Baggen et al. [24] 595 patients, median age 33 years <15.2 pmol/L Cumulative proportion of death and HF of 1% >33.3 pmol/L Strongest association with cardiovascular events, death or HF Eindhoven et al. [11] 770 patients, 4.2 to 30.9 years of age 18-231 pg/mL Increased values compared to healthy controls (38-111 pg/mL) HF – heart failure, BNP – brain natriuretic peptide, PVR – pulmonary valve replacement However, in the total study population or in a subgroup Baggen et al. stated adults, with median age of 33, of patients without prior PVR, the severity of PR was not showing hs-cTn levels >14 ng/L faced the highest risk of related to NT-proBNP [22]. cardiovascular events [24]. Schoonbeek et al., stated that 44% of the PVR patients presented with high NT-proBNP levels, ≥125 pg/mL. Ad- PVR ditionally, an association between a higher age at the lat- Yasukawa et al. showed how within 3 years after PVR, BNP est valve replacement and higher NT-proBNP levels was was higher in the subnormal-stroke volume index group established [23]. compared to normal stroke volume index group [26]. Westhoff-Bleck et al. showed significantly worse out - According to Kitagawa et al., BNP cut-off value consid - comes in patients with NT-proBNP levels between 232- ering PVR was 32.15 pg/mL [27]. 764 ng/L in cumulative survival curves. The emphasis was Paolino et al. used a NT-proBNP cut-off value of 133.2 on the diagnostic power and utility of NT-proBNP in pg/mL predicting PVR, based on the RV end-diastolic and prediction of adverse clinical outcomes. Increasing levels end-systolic values [21]. had an association with increasing specificity. Cut-off of In a study by Peng et al., BNP was found to correlate 168 ng/L yielded 84.5% sensitivity and 75% specificity, with PR severity, and decreased significantly following whereas NT-proBNP ≥232 ng/L resulted in 76.9% sen- PVR [10]. sitivity with 85.3% specificity. NT-proBNP levels tended Nir et al. noted a significant increase in BNP levels in to increase with increasing NYHA class. NT-proBNP a small group of patients requiring PVR before the proce- also remained as an independent predictor of all adverse dure. However, both BNP and NT-proBNP diminished in events correlating with LV ejection fraction, mass, and patients with significant PR following PVR [19]. end-diastolic and end-systolic volume indexes. During the follow-up patients receiving PVR tended to have higher Discussion NT-proBNP levels at the baseline [2]. CHDs are widely recognised as causative agents of infant According to Baggen et al., NT-proBNP >14 pmol/L mortality as well as adverse outcomes later in life despite identified those patients with the highest risk for cardio - the early initial correction. Thus, for more precise clini - vascular events, death or HF. The strongest association was cal outcome prediction of TOF, more clinically applicable at >33.3 pmol/L. The risk of patients who presented with a blood biomarker decision limits need to be established, high NT-proBNP level could be further evaluated by com- which this review aimed for. Also, controversies related to bining also hs-cTn to NT-proBNP testing [24]. PVR were under consideration. All blood biomarkers showed increased values in TOF Hs-cTn patients compared to healthy individuals and decreased In a study by Jabagi et al., hs-cTn level increased with in- following PVR throughout the cohort of studies. The creasing RV volume and worsening RV ejection fraction higher the presented cut-off values were, the higher was in adult patients with previous TOF repair. Predictive and the probability and severity of adverse outcome presen- diagnostic utility of this marker, measured in patients un- tation. For the most severe outcome, death, prediction dergoing cardiac surgery, could provide information about BNP cut-off values varied between >78 pg/mL in paediat - the post-operative recovery. [12]. ric patients and >100 ng/L in adults. NT-proBNP >33.3 Rajpal et al. showed in a multivariable analysis how hs- pmol/L had the strongest association with cardiovascular TnT, including hs-cTn, was a predictive of the secondary events, HF or death, in adult patients. All-cause mortal- end point; death or HF in adults. Primary end point, such ity was increased at NT-proBNP levels 147 pg/mL in pae- as death, HF, hospitalisation, or arrhythmia, was no longer diatric patients. Hs-cTn levels >14 ng/L had the highest significant in multivariable adjustment. However, it was risk of cardiovascular events. The data clearly shows the found more common in the highest hs-TnT quartile, with age-dependent variation of these blood biomarkers. NPs >7.7 ng/L, compared to the first quartile, with levels <3 additionally proved to be useful in the paediatric patients ng/L [25]. in diagnosing and differentiation of pathologies. In gen - Acta Marisiensis - Seria Medica 2023;69(1) 15 eral, the acute adverse clinical outcomes, such as acute HF, approach to unique problems faced by CHD patients [19]. showed significantly higher values throughout in compari - The differential gene expression in rTOF is already dem - son with chronic stages like cardiac overload. Notable is onstrated with RNA sequencing, which could be utilised how even relatively small increases above the baseline can in studying genotype-phenotype relationships. This could be clinically significant. Thus, before the occurrence of a be demonstrated by the genotype of patients originally more systematic treatment plan, every patient should be with significant pulmonary stenosis in relation with later periodically evaluated, combining laboratory results with developed PR or gene expression pre-intervention versus imagistic methods. Consequently, declining in the condi- post-intervention in PVR [6]. tion could be recognised, for example by clearly changed blood biomarker values, enabling prompt and correctly Conclusion timed intervention. Advanced surgical repair techniques in infancy have in- Based on literature, blood biomarkers are already rela- creased patient survival into adulthood. Hence, adverse tively extensively utilised for assessing the patients with dif- clinical outcomes concern not only children but also adult ferent cardiac diseases. In case of CHDs, biomarker ranges, patients, enabling the outcome occurrence at any point of which respect different types of pathologies, age and gen - life. Periodical blood biomarker measurements in addition der, need to be outlined for more systematic treatment. to other diagnostic methods should be performed to detect Additionally, more correlations between blood biomark- significant changes in blood biomarker values. This could ers and other clinical evaluation methods, such as cardiac possibly prevent adverse clinical outcomes also in the long- magnetic resonance imaging, should be established. term setting and detect the most suitable timing for PVR This review, as many others, have been greatly limited for each patient individually. To aid in prevention and cor- by the small population size and heterogeneity of the age rectly timed interventions, more standardised guidelines groups in the studies. Physiological BNP level variation considering age-dependency should be established. Also, complicated the interpretation of the results regarding the the possible emergence of new blood biomarkers and thus long-term outcome prediction. Due to these factors, the new combinations with imagistic and other parameters indications and correct timing for PVR remain contro- would create more systematic treatment for these patients. versial, however, with wide range of possibilities. For in- stance, the potential of hs-TnT in CHD patients is clearly Acknowledgements and funding recognised but not yet widely utilised. Additionally, POF This work was supported by the George Emil Palade Uni - presenting lower prevalence compared to TOF, the afore- versity of Medicine, Pharmacy, Sciences and Technology mentioned limitations are even more weighted, requiring of Târgu Mureș, Research Grant number NR. 224/1 / special attention. 10.01.2022 Blood biomarkers are unlikely able to act alone in out- come prediction. However, the results are promising in Conflicts or competing interests combination with imagistic methods, other biomarkers None to declare. and parameters, such as cardiac magnetic resonance im- aging, cardiopulmonary exercise testing and heart volume Authors' contribution and function tests. Certain studies are already establish- MK (Conceptualization; Data curation; Formal analy- ing relationships between echocardiographic findings and sis; Investigation; Methodology; Project administration; natriuretic peptides. With complex multifactorial CHDs Resources; Software; Validation; Visualization; Writing – easily measurable, affordable, sensitive, and specific param - original draft; Writing – review & editing) eters combined are most likely to yield the best possible IBK (Conceptualization; Investigation; Methodology, results. Validation; Visualization, Supervision; Writing – review & The future holds many promising directions concern - editing) ing the clinical outcome prediction. Firstly, deepening the knowledge on already discussed blood biomarkers and es- References 1. Søndergaard Lars. Early Versus Later Re-valving in Tetralogy of Fallot tablishing their relationship with other evaluation methods with Free Pulmonary Regurgitation. 2019 May;(5th Edition). Available is essential. Establishing the trends of biomarker profile as - from: https://www.clinicaltrials.gov/ProvidedDocs/32/NCT04084132/ Prot_SAP_000.pdf sociated with clinical declining could prompt more effec - 2. Westhoff-Bleck M, Kornau F, Haghikia A, Horke A, Bertram H, Treptau tive assessment, yielding an algorithm of NPs in relation J, et al. NT-proBNP Indicates Left Ventricular Impairment and Adverse to the common interventions. Also standardisation of dif- Clinical Outcome in Patients With Tetralogy of Fallot and Pulmonary Regurgitation. Can J Cardiol. 2016 Oct;32(10):1247.e29-1247.e36. ferent commercial assays is needed [16][19]. Additionally, 3. Villafañe J, Feinstein JA, Jenkins KJ, Vincent RN, Walsh EP, Dubin highly sensitive troponins are less used in CHD patients: AM, et al. Hot Topics in Tetralogy of Fallot. J Am Coll Cardiol. 2013 Dec;62(23):2155–66. they could offer information independently from, and ad - 4. Downing TE, Kim YY. Tetralogy of Fallot. Cardiol Clin. 2015 Nov;33(4):531– ditive to NPs in various outcomes. Secondly, the emergence and interpretation of more sensitive early biomarkers, such 5. Bhagra CJ, Hickey EJ, Van De Bruaene A, Roche SL, Horlick EM, Wald RM. Pulmonary Valve Procedures Late After Repair of Tetralogy of Fallot: as copeptin, MR-proANP and GDF-15, may elucidate the 16 Acta Marisiensis - Seria Medica 2023;69(1) Current Perspectives and Contemporary Approaches to Management. adults with congenital heart disease. Biomark Med. 2012 Dec;6(6):827– Can J Cardiol. 2017 Sep;33(9):1138–49. 37. 6. Heng EL. Improved outcome prediction in tetralogy of Fallot. 2016 20. Heng EL, Bolger AP, Kempny A, Davlouros PA, Davidson S, Swan L, et Dec [cited 2022 Jul 12]; Available from: http://spiral.imperial.ac.uk/ al. Neurohormonal activation and its relation to outcomes late after repair handle/10044/1/50676 of tetralogy of Fallot. Heart. 2015 Mar 15;101(6):447–54. 7. Zegelbone PM, Ringel RE, Coulson JD, Nies MK, Stabler ME, Brown JR, 21. Paolino A, Hussain T, Pavon A, Velasco MN, Uribe S, Ordoñez A, et al. NT- et al. Heart failure biomarker levels correlate with invasive haemodynamics proBNP as Marker of Ventricular Dilatation and Pulmonary Regurgitation in pulmonary valve replacement. Cardiol Young. 2020 Jan;30(1):50–4. After Surgical Correction of Tetralogy of Fallot: A MRI Validation Study. Pediatr Cardiol. 2017 Feb;38(2):324–31. 8. van der Ven JPG, van den Bosch E, Bogers AJCC, Helbing WA. 22. Eindhoven JA, Menting ME, van den Bosch AE, Cuypers JAAE, Ruys Current outcomes and treatment of tetralogy of Fallot. F1000Research. TPE, Witsenburg M, et al. Associations between N-terminal pro-B-type 2019;8:F1000 Faculty Rev-1530. natriuretic peptide and cardiac function in adults with corrected tetralogy 9. Nawaytou H, Bernstein HS. Biomarkers in pediatric heart disease. of Fallot. Int J Cardiol. 2014 Jul;174(3):550–6. Biomark Med. 2014 Aug;8(7):943–63. 23. Schoonbeek RC, Pieper PG, van Slooten YJ, Freling HG, Sieswerda GT, 10. Peng EWK, Spooner R, Young D, Danton MHD. Acute B-type natriuretic van Dijk APJ, et al. NT-proBNP and exercise capacity in adult patients peptide response and early postoperative right ventricular physiology with congenital heart disease and a prosthetic valve: a multicentre following tetralogy of Fallot’s repair. Interact Cardiovasc Thorac Surg. PROSTAVA study. Neth Heart J. 2016 Nov;24(11):653–65. 2012 Sep 1;15(3):335–9. 24. Baggen VJM, van den Bosch AE, Eindhoven JA, Schut ARW, Cuypers 11. Eindhoven JA, van den Bosch AE, Jansen PR, Boersma E, Roos- JAAE, Witsenburg M, et al. Prognostic Value of N-Terminal Pro-B-Type Hesselink JW. The Usefulness of Brain Natriuretic Peptide in Complex Natriuretic Peptide, Troponin-T, and Growth-Differentiation Factor 15 in Congenital Heart Disease. J Am Coll Cardiol. 2012 Nov;60(21):2140–9. Adult Congenital Heart Disease. Circulation. 2017 Jan 17;135(3):264–79. 12. Jabagi H, Mielniczuk LM, Liu PP, Ruel M, Sun LY. Biomarkers in the 25. Rajpal S, Alshawabkeh L, Opotowsky AR. Current Role of Blood and Diagnosis, Management, and Prognostication of Perioperative Right Urine Biomarkers in the Clinical Care of Adults with Congenital Heart Ventricular Failure in Cardiac Surgery—Are We There Yet? J Clin Med. Disease. Curr Cardiol Rep. 2017 Jun;19(6):50. 2019 Apr 25;8(4):559. 26. Yasukawa T, Hoashi T, Imai K, Okuda N, Fukuda T, Ohuchi H, et al. 13. Cantinotti M, Law Y, Vittorini S, Crocetti M, Marco M, Murzi B, et al. The The reduced left ventricular stroke volume does not fully recover after potential and limitations of plasma BNP measurement in the diagnosis, pulmonary valve replacement in patients with repaired tetralogy of Fallot. prognosis, and management of children with heart failure due to congenital Eur J Cardiothorac Surg. 2021 Sep 11;60(3):526–33. cardiac disease: an update. Heart Fail Rev. 2014 Nov;19(6):727–42. 27. Kitagawa A, Oka N, Kimura S, Ando H, Honda T, Takanashi M, et al. 14. Cantinotti M, Walters HL, Crocetti M, Marotta M, Murzi B, Clerico A. Clinical Utility of the Plasma Brain Natriuretic Peptide Level in Monitoring BNP in children with congenital cardiac disease: is there now sufficient Tetralogy of Fallot Patients over the Long Term After Initial Intracardiac evidence for its routine use? Cardiol Young. 2015 Mar;25(3):424–37. Repair: Considerations for Pulmonary Valve Replacement. Pediatr 15. S.E. Luijnenburg. Outcome Late After Repair of Tetralogy of Fallot Cardiol. 2015 Apr;36(4):752–8. [Internet]. Available from: https://repub.eur.nl/pub/40677/ 28. Kapoor PM, Subramanian A, Malik V, Kiran U, Velayoudham D. B-type 16. Dobson R, Walker HA, Walker NL. Biomarkers in congenital heart natriuretic peptide as prognostic marker in tetralogy of Fallot surgery. disease. Biomark Med. 2014 Aug;8(7):965–75. Asian Cardiovasc Thorac Ann. 2015 Feb;23(2):146–52. 17. Willinger L, Brudy L, Meyer M, Oberhoffer-Fritz R, Ewert P, Müller J. 29. Khokhar A, Zuhair M, Raj B, Heng EL, Alonso-Gonzalez R, Kempny Prognostic value of non-acute high sensitive troponin-T for cardiovascular A, et al. 2109Predictors of mortality following hospitalisation in adults morbidity and mortality in adults with congenital heart disease: A with congenital heart disease. Eur Heart J [Internet]. 2018 Aug 1 [cited systematic review. J Cardiol. 2021 Sep;78(3):206–12. 2022 Aug 26];39(suppl_1). Available from: https://academic.oup.com/ 18. Hirono K, Sekine M, Shiba N, Hayashi S, Nakaoka H, Ibuki K, et al. eurheartj/article/doi/10.1093/eurheartj/ehy565.2109/5082713 N-terminal pro-Brain Natriuretic Peptide as a Predictor of Reoperation 30. Alborikan S, Von Klemperer K, Bhan A, Walker F, Pandya B, Badiani S, et in Children With Surgically Corrected Tetralogy of Fallot. Circ J. al. Blood biomarkers in patients with repaired Tetralogy of Fallot (rTOF); 2014;78(3):693–700. A systematic review and meta-analysis. Int J Cardiol Congenit Heart Dis. 19. Nir A, Luchner A, Rein AJ. The natriuretic peptides as biomarkers for 2021 Dec;6:100237.

Journal

Acta Marisiensis - Seria Medicade Gruyter

Published: Mar 1, 2023

Keywords: congenital heart disease; tetralogy of Fallot; pentalogy of Fallot; blood biomarkers; pulmonary valve replacement

There are no references for this article.