Discussion

In response to cardiac stress, myocytes release N-terminal pro-brain natriuretic peptide, a physiologically inactive metabolite, along with biologically active brain natriuretic peptide.^{Reference Zhang, Wang and Xiao8} N-terminal pro-brain natriuretic peptide is a breakdown product of brain natriuretic peptide and has more stable properties in vivo and is often used as a biological marker of active hormones. Under normal circumstances, the atria are the main source of secretion of this peptide and the ventricles.^{Reference Hall9} The stimulus for brain natriuretic peptide release is mainly due to myocyte stretching. In severe chronic mitral regurgitation conditions, increased left ventricular volume causes compensatory dilatation and eccentric hypertrophy.^{Reference Steadman, Ray, L. and McCann10} Chronic stretching of myocytes, such as in heart failure conditions, leads to upregulation of peptide production, which predominantly occurs in the ventricular.^{Reference Hall11} In individuals with rheumatic heart disease, the N-terminal pro-brain natriuretic peptide biomarker has potential to help determine the severity of mitral regurgitation.

The subjects’ average age was 11.32 years, and 58.3% of them were male. This is by the study conducted at Harapan Kita Hospital Jakarta. The study found that the average age of children with rheumatic heart disease was 12 years old.^{Reference Lilyasari, Prakoso and Kurniawati12} The peak incidence of tonsillopharyngitis occurring at this age period may be the cause of the high prevalence of rheumatic heart disease in children and adolescents aged 5–15.^{Reference Tobing, Ontoseno, Rahayuningsih, Ganie and Siregar13} Most of the subjects in this study had severe mitral regurgitation (52.8%). Similar findings were attained by Sulaiman et al. in a study conducted in Uganda. Mitral valve dysfunction was the most common valve abnormality (98.9%), and most subjects had severe mitral regurgitation when first diagnosed (73.1%).^{Reference Lubega, Aliku and Lwabi14} This similar result may be because both studies were conducted in tertiary health facilities where most patients with rheumatic heart disease were referred with severe symptoms.

This study found a positive correlation between N-terminal pro-brain natriuretic peptide levels and the severity of mitral regurgitation only or accompanied by mild aortic valve dysfunction in patients with rheumatic heart disease based on the parameters of vena contracta width, regurgitant jet area, and regurgitation volume. We did not find any confounding factors that could affect N-terminal pro-brain natriuretic peptide levels in subjects such as pneumonia, bronchiolitis, CHD, acute coronary syndrome, renal failure, pulmonary embolism, atrial fibrillation, and subclinical cardiac dysfunction. The correlation result was not affected by confounding factors because the confounding factors were excluded.

N-terminal pro-brain natriuretic peptide levels had a moderately positive correlation with regurgitant jet area and vena contracta width. N-terminal pro-brain natriuretic peptide levels showed weakly positive correlation with regurgitation volume. This is the first study including regurgitant jet area for rheumatic heart disease severity evaluation. This result was also obtained by Elif et al. Elif et al. study showed a weak positive correlation between N-terminal pro-brain natriuretic peptide levels and vena contracta width/body surface area (r = 0.46; P value = 0.003) and a very weak positive correlation with regurgitation volume/body surface area (BSA) (r = 0.32; P value = 0.04). These different results may be due to differences in exclusion criteria. Elif et al.’s study excluded patients with acute rheumatic fever who recovered in the last 6 months. The sensitivity and specificity of N-terminal pro-brain natriuretic peptide for the presence of mitral regurgitation (MR) in Elif study were 89.2% and 59.5%, respectively.^{Reference Erolu and Akalin15}

The levels of N-terminal pro-brain natriuretic peptide and effective regurgitation orifice area were not significantly correlated in our study. This result was consistent with Elif et al.’s results that N-terminal pro-brain natriuretic peptide levels did not correlate with effective regurgitation orifice area/BSA (r = 0.47; P value = 0.002). The prolapse factor in the mitral could affect the effective regurgitation orifice area to be lower when measured during the systolic phase. Mitral valve prolapse was found in 3 subjects with effective regurgitation orifice area values indicating moderate mitral regurgitation. As mitral regurgitation is influenced by its duration, particularly in situations when the mitral valve is prolapsed, effective regurgitation orifice area also could not accurately predict the volume of regurgitation in mitral regurgitation. Assessment of mitral regurgitation severity based on effective regurgitation orifice area could be greater in measurement during the late systolic phase despite a small regurgitation volume. The proximal isovelocity surface area measurement method used for effective regurgitation orifice area is based on a single frame. The effect of mitral regurgitation duration needs to be considered in the proximal iso velocity surface area method if there is a difference in regurgitation severity based on effective regurgitation orifice area and regurgitation volume. The calculation of regurgitation volume involves the components of effective regurgitation orifice area and velocity time integral, i.e. RgV = EROA x VT. Velocity time integral is mathematically identical to the square root of the systolic mean pressure gradient multiplied by the duration (T), i.e. √MPGxT. This equation shows that the time component can affect the regurgitation volume but not the effective regurgitation orifice area value.^{Reference Grayburn, Weissman and Zamorano16} Sample size can also affect the difference in the results of our study and Elif et al. Elif et al.’s study included more subjects (45 subjects).^{Reference Erolu and Akalin15}

The non-normal distribution of N-terminal pro-brain natriuretic peptide levels in this study could be due to extreme differences in N-terminal pro-brain natriuretic peptide levels from the lowest levels of 30 pg/ml to the highest level of 9939 pg/ml. This result was different from the results of Elif et al. Elif et al. obtained a lower mean N-terminal pro-brain natriuretic peptide level of 140.4 (15.7) pg/ml. These considerable results might be due to differences in the subjects’ mitral regurgitation severity. Most of our study subjects had severe mitral regurgitation (52.8%), while 60% of the subjects in Elif et al.’s study showed mild mitral regurgitation. Elif et al. only included patients with chronic mitral regurgitation. Long-term secondary prophylaxis might lead to an improvement in mitral regurgitation severity.^{Reference Erolu and Akalin15}

Most of our subjects showed normal left ventricular dimensions. Similar results were obtained in a study by Faris et al. that compared the profiles of children with heart disease accompanied by mitral regurgitation who received angiotensin-converting enzyme inhibitor treatment at Dr Saiful Anwar Hospital in Malang. In this study, both groups using captopril and not using captopril showed almost the same left ventricular dimensions.^{Reference Nugroho, Rohman, Rizal, Martini, Prasetya and Makhmud17}

The median ejection fraction of our study subjects was within the normal range of 66 (30.381.5) %. This outcome is consistent with a 2016 study by Anurag et al. performed at the Cardiology Clinic of the All India Institute of Medical Sciences. The subjects’ mean left ventricular systolic function was 60.1 (5.1) %.^{Reference Mehta, Saxena, Juneja, Ramakrishnan, Gupta and Kothari18} The compensatory phase is indicated by normal left ventricular dimensions and ejection fraction. The ventricle has not yet undergone structural or functional changes during the compensatory phase of mitral regurgitation.^{Reference Gaasch and Meyer19}

Mitral valve annulus dilatation was found in 50% of the subjects in this study. This may be because most subjects had severe mitral regurgitation (52.8%). The severity of mitral regurgitation is known to be correlated with the annulus area. Michael et al. found that the anterior and posterior leaflets were significantly larger in severe mitral regurgitation. The putative mechanisms underlying annulus dysfunction, including mitral valve annulus dilatation, are most likely associated with papillary muscle shift due to ventricular dilatation resulting from mitral regurgitation.^{Reference Yeong, Silbery, Finucane, Wilson and Gentles20}

The limitation of our study was that this study only showed a positive correlation between N-terminal pro-brain natriuretic peptide levels and echocardiography parameters to assess the mitral regurgitation severity. The cut-off N-terminal pro-brain natriuretic peptide levels to determine the mitral regurgitation severity cannot be determined. This study also included rheumatic heart disease patients with mitral regurgitation and mild aortic valve problems. Future studies are expected to increase internal validity by involving patients with single mitral regurgitation and not receiving any therapy yet. The discrepancy between the mitral regurgitation severity based on effective regurgitation orifice area and regurgitation volume was found in this study. Future studies are expected to use three-dimensional echocardiography and zoom to overcome study limitation. This study is anticipated to encourage further investigation into the optimal cut-off value for N-terminal pro-brain natriuretic peptide levels.

In conclusion, our study found moderate positive correlation between N-terminal pro-brain natriuretic peptide levels and the regurgitation severity based on echocardiography parameters of regurgitant jet area, a moderate positive correlation with vena contracta width, and a weak positive correlation with regurgitation volume in patients with rheumatic heart disease. No correlation was found between N-terminal pro-brain natriuretic peptide levels and effective regurgitation orifice area. Most children with rheumatic heart disease with single mitral regurgitation or mild aortic regurgitation/stenosis showed severe mitral regurgitation with normal left ventricular function and left ventricular dimensions.