Hypertrophic cardiomyopathy is a myocardial disorder characterised by autosomal dominant inheritance patterns resulting from genetic mutations affecting the cardiac sarcomere genes. Reference Elliott, Anastasakis and Borger1 This condition exhibits clinical variability in the paediatric population, spanning from asymptomatic incidental findings to progression to end-stage congestive heart failure, or sudden cardiac death. Reference Ali, Marrone and Martins2 It stands as a leading cause of sudden cardiac death among paediatric population, with an estimated annual risk ranging from 1 to 7%. Reference Thakkar, Karajgi and Kallamvalappil3 Histologically, hypertrophic cardiomyopathy is distinguished by the presence of myocardial fibrosis, myocardial hypertrophy, and disarrayed myocytes. Reference Varnava, Elliott, Sharma, McKenna and Davies4 These changes are primarily attributable to an increased extracellular collagen content resulting from mutations in sarcomere genes. Reference Varnava, Elliott, Sharma, McKenna and Davies4 Patients with hypertrophy cardiomyopathy often manifest coronary microvascular dysfunction, which results in a diminished coronary flow reserve and ultimately predisposing them to a spectrum of adverse cardiac complications. Reference Ismail, Hsu and Greve5
Cardiac MRI with delayed contrast is a standard non-invasive imaging for detection, quantification, and differentiation of interstitial myocardial fibrosis in cardiomyopathies, while also enabling the evaluation of left ventricular thickness and mass. Reference Almaas, Haugaa and Strøm6,Reference Puntmann, Yap, McKenna and Camm7 Furthermore, cardiac MRI with gadolinium contrast facilitates the assessment of myocardial hypertrophy and changes, aiding in the differentiation from alternative diagnoses involving left ventricular hypertrophy. Reference Rubinshtein, Glockner and Ommen8 Late gadolinium enhancement effectively reveals macroscopic myocardial scarring in patients with hypertrophic cardiomyopathy, serving as a predictive indicator for poor cardiac outcomes. Reference Green, Berger, Kramer and Salerno9 The presence of myocardial scarring in hypertrophic cardiomyopathy patients is associated with diastolic dysfunction leading to heart failure and arrhythmias. Reference Ellims, Iles, Ling, Hare, Kaye and Taylor10 Late gadolinium enhancement is detected in approximately 60% of adult populations with overt hypertrophic cardiomyopathy with its prevalence and progression showing a propensity to increase with time. Reference Green, Berger, Kramer and Salerno9,Reference Moon, Reed and Sheppard11,Reference Todiere, Aquaro and Piaggi12 Similarly, the presence of late gadolinium enhancement is also reported in paediatric patients and this presence tends to progress with time. Reference Ali, Marrone and Martins2,Reference Axelsson Raja, Farhad and Valente13
The extent of myocardial fibrosis detected through late gadolinium enhancement in cardiac MRI has been identified in adult population as a significant risk factor for adverse cardiac events, which include ventricular fibrillation, ventricular tachycardia, implantable cardioverter-defibrillator discharges, hospitalisations, and sudden cardiac death. Reference Moon, Reed and Sheppard11,Reference O’Hanlon, Grasso and Roughton14 The demographic profiles, clinical presentations, and risk factors for mortality in paediatric hypertrophic cardiomyopathy differ from those observed in the adult population, underscoring the distinct and unique characteristics of this cardiac condition in the younger age group. Reference Moak and Kaski15 However, there is a paucity of data regarding the prevalence of late gadolinium enhancement in paediatric cases and its predictors for cardiac complications. Reference Chaowu, Shihua, Jian, Li and Wei16 Therefore, this study aims to investigate the prevalence of late gadolinium enhancement in paediatric hypertrophic cardiomyopathy and its clinical significance.
Materials and methods
Search strategies
A systematic literature search was conducted via PubMed, SCOPUS, and Ovid SP through September 2023 using the following search strategy: ((hypertrophic cardiomyopathy) OR (HCM)) AND ((pediatric) OR (paediatric) OR (children) OR (adolescent) OR (young adult)) AND ((late gadolinium enhancement) OR (late gadolinium enhancement) OR LGE). The authors also retrieved additional papers of interest from the reference lists of selected articles and reviews to optimise the search. The literature search was limited to studies published in English language and peer-reviewed journals. Abstracts and case reports were excluded from the search strategy.
Eligibility criteria
The criteria for inclusion for this meta-analysis include (i) observational cohort studies (prospective or retrospective), (ii) studies involving paediatric patients, (iii) diagnosis of hypertrophic cardiomyopathy, (iv) evaluation of myocardial fibrosis using cardiac MRI, and (v) reporting the presence or absence of late gadolinium enhancement. The criteria for exclusion for this meta-analysis include (i) studies involving adult patients, (ii) studies related to other forms of cardiomyopathy such as dilated cardiomyopathy, ischaemic cardiomyopathy, infiltrative cardiomyopathy or acute myocarditis, and (iii) studies that did not report relevant data, outcomes, and variables between late gadolinium enhancement positive and negative groups.
Study selection and data extraction
The authors independently screened all the titles and abstracts of the articles for eligibility to be included in the meta-analysis. When the eligibility for inclusion based on titles and abstracts was inconclusive, full-text of the article was used for review. Any discrepancies or disagreements regarding the inclusion criteria were resolved through consensus and discussion between both authors. Relevant data from the included studies were independently extracted by both authors into a standardised electronic form created in Excel. The following data were extracted from the included studies: name of first author, year of publication, country of the study, study design, age, prevalence of late gadolinium enhancement, late gadolinium extent, prevalence of adverse event, left ventricular ejection fraction, and left ventricular mass index.
Quality assessment
The methodological quality and the risk of bias of the included studies were evaluated according to the Newcastle–Ottawa Scale. Reference Wells, Shea and O’Connell17 The quality of the selected observational studies was determined based on study selection (representativeness of the exposed cohort, selection of the non-exposed cohort, ascertainment of exposure, demonstration that outcome of interest was not present at start of study), comparability (comparability of cohorts on the basis of the design and analysis), and outcome (assessment of outcome, was follow-up long enough for outcomes to occur, adequacy of follow-up of cohorts). Each study was allocated a score of one for each criterion, with a potential maximum score of two for comparability when the studies fulfilled the decision rule for each criterion, culminating in a possible maximum total score of nine.
Data analysis
The primary endpoints of this study were the prevalence and extent of late gadolinium enhancement. The secondary endpoints of this study were the prevalence and odds ratio of adverse events in patients with late gadolinium enhancement, left ventricular ejection fraction, and left ventricular mass index in both late gadolinium enhancement positive and negative groups. Pooled estimates with a 95% confidence interval were calculated using the random-effects generic inverse variance model. Reference DerSimonian and Laird18 Prevalence was expressed as percentage. The standard error for prevalence was calculated using the formula of standard error = √ p (1-p)/ n, 95% confidence interval = p ± 1.96 × standard error; where, p = prevalence and n = sample size. Standardised mean differences were used for continuous variables presented as mean ± standard deviation. Heterogeneity between studies was determined using the chi-squared test, with the degree of heterogeneity quantified by I 2. Reference Higgins, Altman and Gøtzsche19 I 2 values of 25, 50, and 75% correspond to low, moderate, and high heterogeneity effects, respectively. Reference Higgins, Altman and Gøtzsche19 Begg’s funnel plot and Egger’s test were used to assess the possibility of publication bias. Reference Sterne and Egger20 Publication bias was considered significant if the Begg’s funnel plot was asymmetric and Egger’s test had a P < 0.05. Statistical analysis was conducted using the Cochrane Review Manager v5.4 21 and R programming language 22 with metafor package. Reference Viechtbauer23 The findings of this meta-analysis were reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Reference Moher, Liberati, Tetzlaff and Altman24
Results
Search results and eligible studies
The systematic literature search identified a total of 480 articles, with an additional two articles were identified through the reference list of the included articles. After eliminating duplicates, 130 articles were screened based on title and abstract. A comprehensive assessment was conducted on 20 studies for eligibility based on a full-text review. Out of the 20 articles reviewed in detail, three were excluded: two did not provide data regarding the prevalence of late gadolinium enhancement, and one did not specify the type of cardiomyopathy. Consequently, 17 eligible studies were included in this meta-analysis. A detailed flow chart illustrating the study selection process details following Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram is depicted in Figure 1. All 17 studies were included in the analysis of prevalence of late gadolinium enhancement. Prevalence and odds ratio for adverse cardiac events were based on the analysis of four and five studies, respectively. Finally, seven studies were included for the calculations of standardised mean differences of left ventricular ejection fraction and left ventricular mass index.
Figure 1. PRISMA flow chart of study selection. LGE, late gadolinium enhancement.
Study characteristics
A total of 778 patients derived from 17 studies were included in this meta-analysis. Reference Axelsson Raja, Farhad and Valente13,Reference Chaowu, Shihua, Jian, Li and Wei16,Reference Smith, Dorfman and Yu25–Reference Mukhtar, Sasidharan and Krishnamoorthy39 The sample size of the included studies ranged from 13 to 152 participants. All studies included in this analysis were retrospective cohort studies. The average age of the population under study was approximately 14.3 ± 2.3. Sixteen of the studies reported male participants as the majority, whereas only one study reported a majority of female participants. A majority of the studies were conducted in North America with a total of 11 studies (eight United States and three Canada). Four studies were conducted in Asian countries (China, Egypt, Turkey, and India) and two in European nations (Sweden and Poland). An overview of the characteristics of the included studies is summarised in Table 1.
Table 1. Description of the included studies
FWHM = full width at half maximum; NR = not reported; SI = signal intensity.
Critical appraisal of studies
The study quality according to the Newcastle-Ottawa Scale is shown in Table 2. The scores of the studies ranged from five to nine. The majority of the studies achieved scores of six or higher, and four studies obtained the maximum score of nine. In total, only six studies were classified as high quality. Eleven studies did not report on the duration of the follow-up and therefore adequacy of follow-up was unable to be assessed. The average score of the studies included was 6.9 ± 1.39.
Table 2. Newcastle-Ottawa-scale scores for the quality assessment of including studies
Prevalence of late gadolinium enhancement
The prevalence of late gadolinium enhancement in paediatric hypertrophic cardiomyopathy displayed significant variability, ranging from 18 to 92%. The overall pooled prevalence of late gadolinium enhancement was 51% (95% CI, 40–62%) (Fig. 2). Furthermore, eight studies reported the extent of late gadolinium enhancement as a percentage of left ventricular mass, which ranged from 2.18% to 11.5%. The overall pooled extent of late gadolinium enhancement was 4.70% (95% confidence interval, 2.11–7.30%) (Fig. 3). Among these, seven reported septal hypertrophy as the most common pattern for late gadolinium enhancement, four studies reported myocardial hypertrophy, and one study reported mid-wall hypertrophy.
Figure 2. Prevalence of late gadolinium enhancement in paediatric patients with hypertrophic cardiomyopathy.
Figure 3. Late gadolinium enhancement extent expressed in percentage of left ventricular mass.
Adverse cardiac events in late gadolinium enhancement-positive patients
Adverse cardiac events reported in these studies include ventricular arrhythmias, atrial fibrillation, congestive heart failure, implantable cardioverter-defibrillator discharges, heart transplantation, and aborted sudden cardiac death. The prevalence of adverse cardiac events ranged from 20% to 35.3%. The overall prevalence of adverse cardiac events was 22% (95% confidence interval, 15–29%) (Fig. 4). Furthermore, the presence of late gadolinium enhancement was associated with an increased risk of adverse cardiac events compared to patients without late gadolinium enhancement (pooled odds ratio 3.49, 95% confidence interval 1.10–11.09) (Fig. 5).
Figure 4. Prevalence of adverse cardiac events in late gadolinium enhancement-positive patients.
Figure 5. Pooled odds ratio for adverse cardiac events.
Left ventricular ejection fraction and mass index
Seven studies reported data on the left ventricular ejection fraction and left ventricular mass index. The analysis indicated no significant difference in left ventricular ejection fraction between the late gadolinium positive and negative groups (standardised mean difference –0.53, 95% confidence interval −3.68, 2.62) (Fig. 6). However, the left ventricular mass index of late gadolinium enhancement-positive group was slightly higher than the negative group, with a standardised mean difference of 0.91 (95% confidence interval, 0.42–1.41) (Fig. 7).
Figure 6. Standardised mean difference for left ventricular ejection fraction.
Figure 7. Standardised mean difference for left ventricular mass index.
Publication bias
The publication bias of the meta-analysis was assessed using Begg’s funnel plot and Egger’s test. Visual assessment of Begg’s funnel plot for prevalence of late gadolinium enhancement showed a symmetrical distribution of studies around the overall estimate (Fig. 8). However, Egger’s test indicated the presence of publication bias (P = 0.0003). Regarding the odds ratio of adverse cardiac events, the visual assessment of Begg’s funnel plot displayed a symmetrical distribution (Fig. 9). Furthermore, Egger’s test also suggested the absence of publication bias (P = 0.05142).
Figure 8. Begg’s funnel plot for prevalence of late gadolinium enhancement.
Figure 9. Begg’s funnel plot for odds ratio for adverse cardiac events.
Discussion
Studies have reported that late gadolinium enhancement is present in 55–67% of adult patients with hypertrophic cardiomyopathy. Reference Green, Berger, Kramer and Salerno9 This meta-analysis found that the prevalence of late gadolinium enhancement in paediatric hypertrophic cardiomyopathy was 51%, which is similar to the adult population. However, assessing late gadolinium enhancement in paediatric patients can be challenging due to potential patient cooperation issues, leading to motion artefacts or respiration interference. Reference Smith, Dorfman and Yu25 Furthermore, the extent of late gadolinium enhancement tends to increase over time in both paediatric and adult populations as hypertrophic cardiomyopathy is a progressive condition. Reference Windram, Benson and Dragelescu26,Reference Gebker, Neuss, Paetsch and Nagel40,Reference Choi, Kim and Lee41 On average, studies have shown an increase of approximately 6–7 grams of late gadolinium enhancement in adult and paediatric populations over a span of about 2 years of follow-up. Reference Todiere, Aquaro and Piaggi12,Reference Axelsson Raja, Farhad and Valente13 Late gadolinium enhancement has a strong correlation with hypertrophy, as individuals without late gadolinium enhancement generally have normal wall thickness. Reference Smith, Dorfman and Yu25 The presence of late gadolinium enhancement in patients with hypertrophic cardiomyopathy is influenced by several factors including connective tissue deposition and fibrosis of the myocardium, microvascular ischaemia and left ventricular wall thickness, and mass. Reference Kwon, Smedira and Rodriguez42,Reference Kitamura, Shimizu and Ino43 In hypertrophic cardiomyopathy, diastolic dysfunction is an early manifestation attributed to elevated myocardial stiffness resulting from increased fibrosis. Reference Bonura, Bos and Abdelsalam34 Studies have linked late gadolinium enhancement, an indicative of fibrosis, with increased left ventricular filling pressures and abnormal myocardial relaxation, leading to diastolic remodelling. Reference Bonura, Bos and Abdelsalam34
Cardiac MRI offers high-resolution spatial images for assessing wall thickness and identifying localised pattern of hypertrophy, being particularly valuable in detecting challenging-to-visualise apical wall and basal anteroseptal thickening when compared to echocardiography. Reference Rickers, Wilke and Jerosch-Herold44,Reference Moon, Fisher, McKenna and Pennell45 Late gadolinium enhancement in adults often displays a mid-wall and midmyocardial pattern. Reference Elliott, Anastasakis and Borger1,Reference Popović, Kwon and Mishra46,Reference Choudhury, Mahrholdt and Wagner47 However, the majority of studies included in this meta-analysis demonstrated that the late gadolinium enhancement in paediatric population has a septal hypertrophy pattern. Majority of children with positive late gadolinium enhancement exhibited myocardial scarring and pronounced hypertrophic involvement in the interventricular septum. Reference Windram, Benson and Dragelescu26,Reference Bogarapu, Puchalski, Everitt, Williams, Weng and Menon29 The extent, severity, and distribution of hypertrophy may serve as the primary substrates for adverse outcomes, including ventricular arrhythmias or sudden cardiac death. Reference Nazarian, Bluemke and Lardo48 The extent of late gadolinium enhancement has been shown to be associated with an increased risk of ventricular tachycardia and sudden cardiac death in both adult and paediatric populations. Reference Smith, Dorfman and Yu25,Reference Spinner, Noel and Denfield28 Left ventricular apical aneurysms are more frequently observed in older children, although they remain rare, yet they carry a substantial annual risk of adverse clinical outcomes, estimated at around 11%. Reference Chaowu, Shihua, Jian, Li and Wei16,Reference Maron, Finley and Bos49,Reference Matsubara, Nakamura, Kuribayashi, Azuma and Nakagawa50 Furthermore, paediatric patients with a concentric hypertrophy pattern demonstrate a higher prevalence compared to adults and are also associated with poor outcomes such as end-stage hypertrophic cardiomyopathy, congestive heart failure, and heart transplantation. Reference Chaowu, Shihua, Jian, Li and Wei16 In cases where paediatric patients exhibit extensive left ventricular hypertrophy extending beyond the interventricular septum, this condition could potentially worsen myocardial ischaemia, potentially leading to the progression to end-stage hypertrophic cardiomyopathy. Reference Harris, Spirito and Maron51
Hypertrophic cardiomyopathy represents a primary contributing factor to the occurrence of sudden cardiac death among adolescents, primarily attributed to ventricular tachycardia or ventricular fibrillation, resulting in haemodynamic instability. Reference Thakkar, Karajgi and Kallamvalappil3,Reference Maron, Finley and Bos49 Studies have shown that late gadolinium enhancement in adult populations is an independent risk factor for ventricular arrhythmias, implantable cardioverter-defibrillator discharge, and an increased relative risk of all-cause and cardiovascular mortality. Reference Kamp, Chery and Kosinski52 The findings of this meta-analysis also indicated that the presence of late gadolinium enhancement was associated with a higher risk of adverse cardiac events in paediatric population. Furthermore, studies also suggested that the presence of late gadolinium enhancement in paediatric hypertrophic cardiomyopathy increases the likelihood of requiring an implantable cardioverter-defibrillator. Reference Smith, Dorfman and Yu25 However, the role of late gadolinium enhancement as an indicator for implantable cardioverter-defibrillator placement in the paediatric population is limited due to the high incidence of complications, ranging from 32 to 41% during follow-up. Reference Maron, Spirito and Ackerman53,Reference Kamp, Von Bergen and Henrikson54 In paediatric hypertrophic cardiomyopathy, left ventricular hypertrophy generally becomes apparent during late childhood or adolescence and earlier presentation in childhood is often associated with complex syndromes and a less favourable prognosis. Reference Bonura, Bos and Abdelsalam34
The findings of this meta-analysis suggested that there was no significant difference in left ventricular ejection fraction between those with and without late gadolinium enhancement. Therefore, the role of late gadolinium enhancement as an indicator of left ventricular functional decline remains uncertain. Reference Windram, Benson and Dragelescu26 Peak strain analysis has been suggested as a more sensitive indicator of systolic dysfunction, especially when compared to ejection fraction, which can be paradoxically increased in patients with hypertrophic cardiomyopathy. Reference Kato, Noda and Izawa55–Reference Nagakura, Takeuchi and Yoshitani57 Additionally, T1 mapping of cardiac MRI, which quantifies diffuse interstitial fibrosis, emerges as a more useful indicator for left ventricular functional decline. Reference Windram, Benson and Dragelescu26,Reference Hussain, Dragulescu and Benson58 Study by Sunthankar et al demonstrated that patient patients with hypertrophic cardiomyopathy demonstrated increased native T1 but not synthetic extracellular volume. Reference Sunthankar, Parra and George-Durrett32 Furthermore, the global native T1 is inversely proportional to the left ventricular ejection fraction. Reference Sunthankar, Parra and George-Durrett32 Moreover, this meta-analysis showed a slight increase in the left ventricular mass index in patients with late gadolinium enhancement. However, some studies suggest that there is no direct correlation between left ventricular mass and left atrial function. Reference Kowallick, Silva Vieira and Kutty59 Nevertheless, an increased left ventricular mass may disrupt the electrophysiological processes of the myocardium leading to initiation of fatal arrhythmias. Reference Lang, Bierig and Devereux60 Thus, in turn, establishes that increase in left ventricular mass in patients with hypertrophic cardiomyopathy is an independent risk factor for sudden cardiac death. Reference Laukkanen, Khan and Kurl61
There were several limitations of this meta-analysis. Some studies were excluded from this meta-analysis due to the absence of raw data regarding the presence of late gadolinium enhancement. Furthermore, many studies relied on binary classification for presence of late gadolinium enhancement and did not provide data regarding its extent and quantification, which are known to be more informative for prognostication. Furthermore, we are unable to analyse the association between quantified late gadolinium enhancement and left ventricular mass index or ejection fraction. The studies did not report incidence of life-threatening and non-life-threatening cardiac adverse effects separately given the distinct management strategies required for each category. Subgroup analysis across various age cohorts was unfeasible due to the predominant absence of patient categorisation into distinct age groups within the majority of studies. In addition, the meta-analysis of prevalence of late gadolinium enhancement revealed a highly significant heterogeneity possibly attributed to variations in methodology, low sample sizes, lack of population representativeness, and incomplete reporting of results. Nevertheless, the use of random-effect models aimed to minimise the influence of heterogeneity on the outcomes. Additionally, all the studies included in this meta-analysis were retrospective observational studies, and the pooled prevalence was not adjusted for potential confounding variables.
Conclusion
In conclusion, this meta-analysis reveals important insights into late gadolinium enhancement in children and adolescents with hypertrophic cardiomyopathy. The prevalence of late gadolinium enhancement in this population is found to be similar to what is observed in adults. Furthermore, this meta-analysis highlights that the presence and extent of late gadolinium enhancement serve as independent predictors for adverse cardiac events, underlining its significance as a valuable tool for prognostication. This implies that children and adolescents with late gadolinium enhancement-positive hypertrophic cardiomyopathy should undergo regular follow-up assessments, including electrocardiograms, echocardiograms, or cardiac MRIs, to monitor their condition. Further large-scale prospective and longitudinal studies should be conducted to further assess the prognostic value of late gadolinium enhancement in paediatric hypertrophic cardiomyopathy. Such studies will provide a more comprehensive understanding of this condition in the younger population and help refine treatment and management strategies.
Acknowledgements
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Financial support
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Competing interests
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