Paediatric Dilated Cardiomyopathy Research Articles

Long-term milrinone therapy in children with dilated cardiomyopathy.

The aim of this study was to assess the safety and efficacy of long-term milrinone therapy in children with acute decompensated heart failure due to dilated cardiomyopathy (DCM). A single-centre retrospective study of all children ≤18 years with acute decompensated heart failure and DCM who received continuous long-term (≥7 consecutive days) intravenous milrinone between January 2008 and January 2022. The 47 patients had a median age of 3.3 months [interquartile range (IQR) 1.0-18.1], weight of 5.7kg [IQR 4.3-10.1] and fractional shortening of 11.9% [±4.7]. Idiopathic DCM (n=19) and myocarditis (n=18) were the most common diagnoses. The median milrinone infusion duration was 27 days [IQR 10-50, range 7-290]. No adverse events necessitated milrinone termination. Nine patients required mechanical circulatory support. Median follow-up was 4.2 years [IQR 2.7-8.6]. On initial admission, four patients died, six were transplanted and 79% [37/47] were discharged home. The 18 readmissions resulted in five more deaths and four transplantations. Cardiac function recovered in 60% [28/47], as measured by normalised fractional shortening. Long-term intravenous milrinone is safe and effective in paediatric acute decompensated DCM. Combined with conventional heart failure therapies, it can act as a bridge to recovery and thereby potentially reduce the need for mechanical support or heart transplantation.

Cardiomyocyte deoxyribonucleic acid damage and cardiac recovery in paediatric dilated cardiomyopathy.

The goal of this study was to identify the clinical significance of the deoxyribonucleic acid (DNA) damage response marker, phosphorylated H2A histone variant X, on the bridge to recovery in low-weight paediatric patients with dilated cardiomyopathy (DCM) after having a Berlin Heart EXCOR implanted. Consecutive paediatric patients with DCM who had an EXCOR implanted for DCM at our hospital between 2013 and 2021 were reviewed. Patients were classified into 2 groups according to the degree of DNA damage in the left ventricular cardiomyocytes-the low DNA damage group and the high DNA damage group-using the median value as the threshold. We examined and compared the preoperative factors and histologic findings associated with cardiac functional recovery following the explant procedure in the 2 groups. Competing outcome analysis of 18 patients (median body weight, 6.1 kg) showed that the incidence of an EXCOR explant was 40% at 1 year after the implant procedure. Serial echocardiography revealed significant left ventricular functional recovery in the low DNA damage group 3 months after the implant. The univariable Cox proportional hazards model revealed that the percentage of phosphorylated H2A histone variant X-positive cardiomyocytes was the significant factor associated with cardiac recovery and the EXCOR explant (hazard ratio, 0.16; 95% confidence interval, 0.027-0.51; P = 0.0096). The degree of DNA damage response to the EXCOR implant may aid in predicting the bridge to recovery with EXCOR among low-weight paediatric patients with DCM.

GUIDELINE-DIRECTED MEDICAL THERAPY IN A SICKKIDS PAEDIATRIC DILATED CARDIOMYOPATHY COHORT: REAL-WORLD UTILIZATION DATA

BACKGROUND Dilated cardiomyopathy (DCM) is the most common cause of pediatric end-stage heart failure (HF). Guideline-directed medical treatment (GDMT) for HF improves outcomes in adults. The effect of being on GDMT is not as well established in children. We aim to determine the utilization and associated outcomes of HF medications in a SickKids DCM cohort. METHODS AND RESULTS The SickKids HF Database identified patients diagnosed between Jan 1, 2001 – July 1, 2018 and included those with idiopathic or genetic/familial DCM. Descriptive statistics and Kaplan-Meier survival curves were used for transplant-free (Tx-free) survival. Angiotensin-converting enzyme inhibitors, beta-blockers, and mineralocorticoid receptor antagonist were at target if achieved 70% of therapeutic dosing (Table 1). Of the 126 patients, 56% were males, the median age at diagnosis was 1.1y (IQR=0.3-10.9) and median follow-up duration was 1.4y (IQR=0.3-5.5). Patients on ≥2 target HF medications (≥2meds) were compared to patients on < 2 HF medications, of which 25% (n=31) were on ≥2meds at 3 months. Patients on ≥2meds had higher left-ventricular end-diastolic dimension at baseline [median 7.9(IQR=3.6-10.2) vs. 4.4(IQR=2.4-7.3) p=0.005] and likely to be on diuretics [(26(84%) vs. 44(46%) p < 0.0003)] or anticoagulation [(21(68%) vs. 41(43%) p=0.02)]. Patients on ≥2meds were more likely to have at least moderately reduced left-ventricular (LV) function [31 (100%) vs. 78 (82%) p=0.01] and at least moderate mitral regurgitation (MR) [22 (71%) vs. 44 (46%) p=0.02] at 3 months. Independent risk factors for death/transplant were lower baseline ejection fraction and the need for cardiopulmonary resuscitation (CPR). Tx-free survival was improved for patients with ≥2meds ever during follow-up versus no medications (Figure 1). CONCLUSION Majority of paediatric DCM patients fail to reach GDMT target dosing. Those able to achieve ≥2meds have improved Tx-free survival, compared to those on less or no medications, despite being more likely to have reduced LV function and MR on echocardiogram. These patients are also more likely to require additional medications to manage their HF. Patients with lower baseline ejection fraction or needing CPR during follow-up have worse Tx-free survival. This study indicates further quality improvement work is needed to improve GDMT for pediatric HF patients. Dilated cardiomyopathy (DCM) is the most common cause of pediatric end-stage heart failure (HF). Guideline-directed medical treatment (GDMT) for HF improves outcomes in adults. The effect of being on GDMT is not as well established in children. We aim to determine the utilization and associated outcomes of HF medications in a SickKids DCM cohort. The SickKids HF Database identified patients diagnosed between Jan 1, 2001 – July 1, 2018 and included those with idiopathic or genetic/familial DCM. Descriptive statistics and Kaplan-Meier survival curves were used for transplant-free (Tx-free) survival. Angiotensin-converting enzyme inhibitors, beta-blockers, and mineralocorticoid receptor antagonist were at target if achieved 70% of therapeutic dosing (Table 1). Of the 126 patients, 56% were males, the median age at diagnosis was 1.1y (IQR=0.3-10.9) and median follow-up duration was 1.4y (IQR=0.3-5.5). Patients on ≥2 target HF medications (≥2meds) were compared to patients on < 2 HF medications, of which 25% (n=31) were on ≥2meds at 3 months. Patients on ≥2meds had higher left-ventricular end-diastolic dimension at baseline [median 7.9(IQR=3.6-10.2) vs. 4.4(IQR=2.4-7.3) p=0.005] and likely to be on diuretics [(26(84%) vs. 44(46%) p < 0.0003)] or anticoagulation [(21(68%) vs. 41(43%) p=0.02)]. Patients on ≥2meds were more likely to have at least moderately reduced left-ventricular (LV) function [31 (100%) vs. 78 (82%) p=0.01] and at least moderate mitral regurgitation (MR) [22 (71%) vs. 44 (46%) p=0.02] at 3 months. Independent risk factors for death/transplant were lower baseline ejection fraction and the need for cardiopulmonary resuscitation (CPR). Tx-free survival was improved for patients with ≥2meds ever during follow-up versus no medications (Figure 1). Majority of paediatric DCM patients fail to reach GDMT target dosing. Those able to achieve ≥2meds have improved Tx-free survival, compared to those on less or no medications, despite being more likely to have reduced LV function and MR on echocardiogram. These patients are also more likely to require additional medications to manage their HF. Patients with lower baseline ejection fraction or needing CPR during follow-up have worse Tx-free survival. This study indicates further quality improvement work is needed to improve GDMT for pediatric HF patients.

Paediatric dilated cardiomyopathy with and without endocardial fibroelastosis - a pathological analysis of 89 explants.

Heart failure due to dilated cardiomyopathy is a major indication for paediatric cardiac transplantation. Endocardial fibroelastosis is a recognised pathological finding of unknown prognostic significance in paediatric dilated cardiomyopathy. To evaluate the nature of the association between left ventricular endocardial fibroelastosis and paediatric dilated cardiomyopathy, we reviewed surgical pathology reports of dilated cardiomyopathy explants (1986-2016) in order to characterise the pathological findings and to compare and contrast their frequency among four age groups: less than 1 year; 1-5 years; 6-10 years; and greater than 11 years. The 89 explants (47 males and 42 females) were all characterised by increased weight and left ventricular chamber dilatation without increased wall thickness. Ninety-five per cent of the specimens in the two youngest subsets had left ventricular endocardial fibroelastosis. Compared to the oldest age group, recipients aged 1-5 years had a 6-fold increase and those younger than 1 year a 19-fold increase in the odds of observing left ventricular endocardial fibroelastosis. Explants with and without endocardial fibroelastosis were otherwise phenotypically similar. In paediatric dilated cardiomyopathy endocardial fibroelastosis is a very common pathological finding, especially in infants and young children. We propose that the descriptive, clinico-pathological designation "Dilated Cardiomyopathy with Endocardial Fibroelastosis" should be adopted to facilitate future investigation into the potential prognostic/therapeutic significance of left ventricular endocardial fibroelastosis.

T1 mapping and conditional survival in paediatric dilated cardiomyopathy with advanced heart failure.

Myocardial fibrosis is associated with adverse events in idiopathic dilated cardiomyopathy. Cardiac MRI with late gadolinium enhancement can detect myocardial fibrosis. We evaluated the conditional survival of children and adolescents based on native T1 mapping (combined proton signal from myocytes and interstitium prior to contrast administration by the measurement of myocardial and blood relaxation time) as a means to assess myocardial fibrosis. This retrospective case-cohort over a 3-year period included all consecutive patients (aged ≤ 21 years) with advanced heart failure from dilated cardiomyopathy (echocardiographic left ventricular ejection fraction ≤ 45% and NYHA class ≥ 2) who underwent cardiac MRI.Conditional survival (follow-up ≥ 6 months after cardiac MRI) was assessed to include NYHA functional class and time to event (death or heart transplantation). A total of 57 patients (mean age 11.7 ± 6.1 years; 58% male) had a median NYHA Class III (31/57) and median left ventricular ejection fraction 25% (20-38%). Survival data were available in 82% patients (46/57) and the crude mortality rate was 24% (11/46) and one patient (2%) underwent heart transplantation. The median native T1 was elevated at 1351 ms (95% CI 1332, 1394) and it showed no difference between the groups who survived to those who died. Performing a multilevel regression analysis on prognosis failed to predict 6-month conditional survival.

Paediatric dilated cardiomyopathy in Khartoum state, Sudan: a prospective study

BackgroundDilated cardiomyopathy (DCM) is a disease of the heart muscle that affects ventricular function; it is a debilitating disease that can lead to heart failure and death in children. There...

Biallelic variants in PPP1R13L cause paediatric dilated cardiomyopathy.

Childhood dilated cardiomyopathy (DCM) is a leading cause of heart failure requiring cardiac transplantation and approximately 5% of cases result in sudden death. Knowledge of the underlying genetic cause can aid prognostication and clinical management and enables accurate recurrence risk counselling for the family. Here we used genomic sequencing to identify the causative genetic variant(s) in families with children affected by severe DCM. In an international collaborative effort facilitated by GeneMatcher, biallelic variants in PPP1R13L were identified in seven children with severe DCM from five unrelated families following exome or genome sequencing and inheritance-based variant filtering. PPP1R13L encodes inhibitor of apoptosis-stimulating protein of p53 protein (iASPP). In addition to roles in apoptosis, iASPP acts as a regulator of desmosomes and has been implicated in inflammatory pathways. DCM presented early (mean: 2 years 10 months; range: 3 months-9 years) and was progressive, resulting in death (n = 3) or transplant (n = 3), with one child currently awaiting transplant. Genomic sequencing technologies are valuable for the identification of novel and emerging candidate genes. Biallelic variants in PPP1R13L were previously reported in a single consanguineous family with paediatric DCM. The identification here of a further five families now provides sufficient evidence to support a robust gene-disease association between PPP1R13L and severe paediatric DCM. The PPP1R13L gene should be included in panel-based genetic testing for paediatric DCM.

Low mutation rate in the TTN gene in paediatric patients with dilated cardiomyopathy \u2013 a pilot study

Idiopathic dilated cardiomyopathy (DCM) is a common cardiomyopathy with the prevalence of 1:250, and at least one-third of all the cases are inherited. Mutations in the TTN gene are considered as the most frequent cause of inherited DCM and cover 10–30% of the cases. The studies were mainly focused on the adult or mixed age group of patients with DCM. The mutation rate in the TTN gene, the characteristics of manifestations and their prognostic significance in childhood have not been studied. To determine TTN mutation rate in children with DCM and the relevance of including this gene in the DNA diagnostic protocol for paediatric DCM, complete clinical and instrumental examination of 36 DCM patients (up to 18 years) with the manifestation of the disease was conducted in specialised cardiology centres. Molecular genetic testing included sequencing of coding and adjacent regulatory regions of the major cardiac TTN isoform N2BA using IonTorrent ™ semiconductor sequencing (for 25 isolated cases) and trio whole exome sequencing (trio WES)on the Illumina platform (for 11 family cases). Our pilot group included 36 probands with DCM diagnosis first established on the basis of the generally accepted criteria at the age of 5 days to 18 years(average age: 6.5 years). The sex ratio (M:F) was 23: 8. There were 25 sporadic DCM cases and 11 cases of familial DCM (at least one of the parents and/or siblings were also diagnosed with DCM). The only likely pathogenic truncating variant p.Arg33703*in the TTN gene (TTNtv) was found in a 16-year-oldmale proband out of 36 (3%). Apparently, TTN-dependent forms of DCMs manifest later at a young (but older than 18 years) or more mature age, and TTN gene cannot be considered as the first-line genetic testing for DCM in the paediatric group, despite several studies have reported a generally high mutation rate in this gene with DCM. Further research is needed to compare the representation of mutations in the TTN gene in different age groups of DCM patients.

Dilated cardiomyopathy in a national paediatric population.

Dilated cardiomyopathy is the most common form of childhood cardiomyopathy and is known to result in significant morbidity and mortality. This study aims to review the aetiology and associated outcomes of DCM. The median age at diagnosis was 6months (0-42months); n = 23 (43.3%) were idiopathic; n = 11 (20.9%) secondary to a viral infection; n = 12 (22.6%) genetic disorders and n = 7 (13.2%) as a result of vitamin D deficiency. There was a significant correlation between aetiology and mortality, r = 0.85, with a lower survival rate in idiopathic and genetic cohorts. Males were significantly less likely to survive to 1year of age, p = 0.035. The age at diagnosis did not alter survival to 1year and the predicted survival beyond 1year was 84.3% (95% CI, 71.3 to 94.5%). Severely impaired left ventricular fractional shortening at presentation (< 15%) was an independent predictor of death, p = 0.002, (95% CI, 11.2 to 14.2%).Conclusion: Paediatric DCM is a heterogeneous disease resulting in significant morbidity. The aetiology alters the age of presentation. Identification of a specific cause is a useful for risk stratification and prognostication. The first year after diagnosis is a critical time period reflected by the significant morbidity and mortality. What is Known: •Paediatric dilated cardiomyopathy (DCM) is the commonest of the childhood cardiomyopathies, with significant associated morbidity and mortality. •DCM is most commonly idiopathic. What is New: •Identifying the aetiology of DCM in the paediatric population aids risk stratification and prognostication. •The first year after diagnosis of DCM is associated with significant mortality.

P15 Paediatric dilated cardiomyopathy: Implications of initial mode of presentation

Background The effect of severity of presentation on transplant-free survival and recovery of function in paediatric dilated cardiomyopathy (DCM) is unknown. Methods and Results We report a large single centre experience of 209 new DCM referrals from 2008–2013 (table 1). 82 children median age 1.0 years (IQR 3.4) required intensive care (ICU) and their survival without death or transplant was 51% to one year and 45% to five years. 127 children presented to the paediatric heart failure clinic. Excluding 58 with neuromuscular disease, median age was 4.1 years (IQR 11.3) and survival without death or transplant 85% to 1 year and 50% to 5 years. NT-proBNP normalised in survivors before echocardiographic parameters (Figure 1). Predictors of recovery included younger age, lower NT-proBNP and higher fractional shortening measurement on echocardiogram at presentation. Conclusion Transplant-free survival to one year is significantly better for patients presenting to clinic, but longer-term survival is better amongst those presenting to ICU due to a late attrition in those with less severe heart failure at presentation (Figure 2). Falling NT- proBNP is the earliest marker of recovery.

Clinical implications of mitral valve geometric alterations in children with dilated cardiomyopathy.

We aimed to elucidate the relationship between severity of secondary mitral regurgitation and mitral valve geometry in children with dilated cardiomyopathy. The medical records of 16 children with dilated cardiomyopathy (median age, 1.2 years; range, 0.4-12.3 years) were reviewed. Mitral valve geometry was evaluated by measuring coaptation depth using echocardiographic apical four-chamber views at the initial presentation. Patients were dichotomised according to the mitral regurgitation severity: patients with moderate or severe secondary mitral regurgitation (n=6) and those with mild secondary mitral regurgitation (n=10). A total of 58 healthy children were considered as normal controls, and a regression equation to predict coaptation depth by body surface area was derived: coaptation depth [mm]=4.37+1.34×ln (body surface area [m2]) (residual standard error, 0.49; adjusted R2, 0.68; p<0.0001). Compared with patients with mild secondary mitral regurgitation, those with moderate or severe secondary mitral regurgitation had significantly larger coaptation depth z-scores (6.4±2.3 versus 1.9±1.4, p<0.005), larger mitral annulus diameter z-scores (3.6±2.6 versus 0.9±1.8, p<0.05), higher left ventricular sphericity index (0.89±0.07 versus 0.79±0.06, p<0.005), and greater left ventricular fraction shortening (0.15±0.05 versus 0.09±0.05, p<0.05). In conclusion, geometric alteration in the mitral valve and the left ventricle is associated with the severity of secondary mitral regurgitation in paediatric dilated cardiomyopathy, which would provide a theoretical background to surgical intervention for secondary mitral regurgitation in paediatric populations.

Paediatric dilated cardiomyopathy: clinical profile and outcome. The experience of a tertiary centre for paediatric cardiology

Dilated cardiomyopathy is the most common form of cardiomyopathy in the paediatric population and an important cause of heart transplantation in children. The clinical profile and course of dilated cardiomyopathy in children have been poorly characterised. A retrospective review of 61 patients (37 female; 24 male) diagnosed with dilated cardiomyopathy from January, 2005 to June, 2012 at a single institution was performed. The median age at diagnosis was 15 months. Heart failure was present in 83.6% of patients and 44.3% required intensive care. The most prevalent causes were idiopathic (47.5%), viral myocarditis (18.0%) and inherited metabolic diseases (11.5%). In viral myocarditis, Parvovirus B19 was the most common identified agent, in concurrence with the increasing incidence documented recently. Inherited metabolic diseases were responsible for 11.5% of dilated cardiomyopathy cases compared with the 4-6% described in the literature, which reinforces the importance of considering this aetiology in differential diagnosis of paediatric dilated cardiomyopathy. The overall mortality rate was 16.1% and five patients underwent heart transplantation. In our series, age at diagnosis and aetiology were the most important prognosis factors. We report no mortality in the five patients who underwent heart transplantation, after 2 years of follow-up.

Procollagen type III amino-terminal propeptide: a serum biomarker of left ventricular remodelling in paediatric dilated cardiomyopathy

Procollagen type III amino-terminal propeptide is a collagen III cleavage product released in blood. The serum levels of this propeptide in adults with dilated cardiomyopathy are associated with cardiac remodelling and prognosis. The utility of procollagen type III amino-terminal propeptide as a biomarker in paediatric dilated cardiomyopathy is unknown. This was a prospective, longitudinal study of children with dilated cardiomyopathy and changes in procollagen type III amino-terminal propeptide. The serum level of propeptide was measured serially, compared with paediatric normal values, and correlated with clinical status and left ventricular size and function on echocardiograms and cardiac magnetic resonance imaging. Procollagen type III amino-terminal propeptide was measured serially in 149 samples from 39 patients, age 9.0±6.4 years, followed up for 16.8±16.3 months. Procollagen type III amino-terminal propeptide in dilated cardiomyopathy was higher than in normal children. On multivariate analyses, procollagen type III amino-terminal propeptide had a positive correlation with left ventricular dilation, left ventricular end-diastolic diameter index (p<0.0001), and left ventricular end-diastolic diameter Z-score (p=0.0003), and a negative correlation with shortening fraction changes over time (p=0.001). Patients with myocarditis (n=12) had higher procollagen type III amino-terminal propeptide values than those with idiopathic dilated cardiomyopathy (n=20). Procollagen type III amino-terminal propeptide increases with left ventricular dilation and decreases with improvement in systolic function in paediatric dilated cardiomyopathy, indicating a role as a biomarker of cardiac remodelling in children. The diagnostic utility of procollagen type III amino-terminal propeptide to differentiate myocarditis from idiopathic dilated cardiomyopathy warrants further investigation.

Beta-adrenergic adaptation in idiopathic dilated cardiomyopathy: differences between children and adults

This editorial refers to ‘Beta-adrenergic adaptation in paediatric idiopathic dilated cardiomyopathy’, by S.D. Miyamoto et al. , doi:10.1093/eurheartj/ehs229 The study of Miyamoto et al .1 found differences in beta-adrenergic adaptation to heart failure (HF) in explanted heart tissue between children and adults with symptomatic dilated cardiomyopathy (DCM). Differences included: (i) down-regulation of beta-1- and beta-2-adrenergic receptors in children but maintained beta-2-adrenergic receptor expression in adults; and (ii), in children, uncoupling of the beta-1-adrenergic receptors and stimulatory G-proteins, among others.1 An important family of cell surface protein receptors, the G-protein-coupled receptors (GPCRs), enable cells to sense and respond to outside signals. For children with cardiomyopathy and heart failure, we need a better understanding of the structure–function relationships and the detailed regulation of GCPRs, as well as the drugs that stimulate or inhibit these relationships. Understanding beta-adrenergic adaptation in children with HF should indicate how cardiomyocytes interact with their extracellular environment and adapt to new situations, such as when epinephrine acts on cells to increase blood pressure and heart rate. Miyamoto and colleagues observed that the GCPR signalling system has become the target of prescription drugs, including beta-blockers, to relieve HF.1 In fact, about half of all medications act on these receptors, so learning about them is key to developing better drugs. The GPCR initiates a cascade of signals into the cell, prompting it to respond appropriately, as well as a secondary cascade in which a feedback signal leads to desensitization. A molecule called beta-arrestin binds to the GPCR and reduces or temporarily stops GPCR's sensitivity. Beta-arrestin, in addition to receptor desensitization, is involved in receptor endocytosis and activating extracellular signal-regulated kinase (ERK) and other …

Determinants of extracellular matrix remodelling are differentially expressed in paediatric and adult dilated cardiomyopathy

The left ventricular phenotype of idiopathic dilated cardiomyopathy (DCM) can appear similar in paediatric and adult patients. However, the aetiology of paediatric DCM is usually idiopathic, and often leads an aggressive clinical course. A structural underpinning of DCM is extracellular matrix changes, which are determined by a balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). This study tested the hypothesis that different MMP/TIMP profiles occur in paediatric and adult DCM patients. Left ventricular samples from paediatric (age 9 ± 5 years; n = 10) and adult (age 62 ± 3 years; n = 20) DCM (at time of transplant) were subjected to an MMP/TIMP multiplex array and immunoassay in order to measure the MMP subclasses; collagenases (MMP-8, -13), gelatinases (MMP-2, -9), stromelysin/matrilysin (MMP-3, -7), membrane type (MT1-MMP), as well as for the four known TIMPs. MMP-8 and -9 levels increased by over 150% (P < 0.05), whereas MMP-3 and -7 levels decreased by over 30% (P < 0.05) in paediatric DCM when compared with adult DCM. TIMP-1 and -2 levels increased two-fold (P < 0.05), but TIMP-3 fell by 41% (P < 0.05) in paediatric DCM. Myocardial levels of specific interleukins (IL-1beta, IL-2, IL-8) were increased by approximately 50% in paediatric DCM. These unique findings demonstrated that a specific MMP/TIMP profile occurs in paediatric DCM when compared with adult DCM, and that local cytokine induction may contribute to this process. These distinct differences in the determinants of myocardial matrix structure and function may contribute to the natural history of DCM in children.

Plasma profiling determinants of matrix homeostasis in paediatric dilated cardiomyopathy

Dilated cardiomyopathy is an important cause of cardiac failure in both children and adults, but is more progressive in children. In adult dilated cardiomyopathy, left ventricular remodelling is associated with changes in the plasma levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases. Plasma matrix metalloproteinases and tissue inhibitors of metalloproteinase changes in paediatric dilated cardiomyopathy have not been examined. This study developed a low blood volume, high-sensitivity assay to test the hypothesis that unique and differential plasma matrix metalloproteinases and tissue inhibitors of metalloproteinase profile exist in patients with paediatric dilated cardiomyopathy. A systemic blood sample (1 millilitre) was obtained from seven children aged 8 plus or minus 7 years with dilated cardiomyopathy and 26 age-matched normal volunteers. Using a high-throughput multiplex suspension immunoassay, plasma levels were quantified for collagenases (matrix metalloproteinase-8), gelatinases (matrix metalloproteinase-2 and -9), lysins (matrix metalloproteinase-3 and -7), and tissue inhibitor of metalloproteinases-1, -2, and -4. The matrix metalloproteinase to tissue inhibitors of metalloproteinases ratios were also calculated. The plasma matrix metalloproteinase-2, -7, -8, and -9 levels were increased by greater than twofold in patients with dilated cardiomyopathy than normal patients (with p less than 0.05). Patients with dilated cardiomyopathy also had significantly higher tissue inhibitors of metalloproteinases-1 and -4 (298% and 230%; with p less than 0.05). These unique findings show that a specific plasma matrix metalloproteinase/tissue inhibitor of metalloproteinase profile occurs in paediatric dilated cardiomyopathy when compared to the cases of normal children. These distinct differences in the determinants of myocardial matrix structure and function may contribute to the natural history of dilated cardiomyopathy in children and may provide a novel biomarker platform in paediatric dilated cardiomyopathy.

Early changes in right ventricular function and their clinical consequences in childhood and adolescent dilated cardiomyopathy

The aim of the paper was to investigate the right ventricle in paediatric dilated cardiomyopathy. We examined 11 patients with dilated cardiomyopathy as well as 12 normal paediatric controls. Cardiac magnetic resonance imaging was performed for ventricular size and function. N-terminal pro-brain natriuretic peptide was collected at this time and the results from the most recent echocardiogram and exercise test were reviewed.We found that patients with dilated cardiomyopathy had significantly faster heart rates, that is, 85 versus 65 beats per minute, lower left ventricular ejection fraction, that is, 42 versus 61%, and right ventricular ejection fraction of 44 versus 54%, lower left and right ventricular stroke volumes, that is, 35.5 versus 49.5 millilitres per square metre and 40.9 versus 56.4 millilitres per square metre, respectively, and lower mitral and tricuspid valve inflow e/a wave velocity ratios of 2.02 versus 2.80 and 1.25 versus 2.58, respectively, than the controls. Tricuspid valve annulus velocity, measured by tissue Doppler echocardiography, correlated with right ventricular ejection fraction (r = 0.60, p = 0.05). Right ventricular ejection fraction and indexed right ventricular end-diastolic volume correlated with N-terminal pro-brain natriuretic peptide (r = -0.67, p = 0.03, r = 0.65, p = 0.04, respectively), and right ventricular ejection fraction correlated with the oxygen uptake at the anaerobic threshold (r = 0.67, p = 0.049). Neither left ventricular ejection fraction nor left ventricular volume correlated with N-terminal pro-brain natriuretic peptide or exercise tolerance. The right ventricular function is decreased in the early stages of dilated cardiomyopathy. Right ventricular size and ejection fraction may be important indicators of sub-clinical cardiac failure and we suggest monitoring them routinely in dilated cardiomyopathy.

Clinical profiles and outcomes for Omani children with dilated cardiomyopathy seen in a regional referral hospital

To provide an account of paediatric dilated cardiomyopathy as seen in a region of Oman, analysing the data from 32 consecutive children who received care in our unit between January, 1999, and August, 2007. The patients, of whom 17 were male, were aged between 5 weeks and 8 years at presentation, with a median of 7 months. The disease was deemed to be myocarditis-induced in one-third, and idiopathic in half. Cardiac failure, seen in almost four-fifths, was the most frequent presenting feature. Correspondingly, the cardiothoracic ratios were increased, to a mean of 68% in 20 infants, and to 65% in 8 older children, and the left ventricular ejection fraction depressed, to a mean of 41%, in the 23 patients in whom it could be evaluated. Patients in cardiac failure received various combinations of diuretics, inotropes, and captopril. In addition, 6 received carvedilol, and 3 intravenous immunoglobulin. Death occurred in 2 patients shortly after admission, one left the hospital against medical advice, and the remaining 29 were followed-up for a mean of 37 months, with a range from 2 to 102 months. Recovery was noted in one-third of the patients, with one-quarter showing improvement but still requiring anti-failure medications. Slightly over two-fifths died. Of those with the idiopathic form, 40% died, with death occurring in 46% of those deemed to have myocarditis-induced disease, in half of those presenting in infancy, and in 57% of those who presented in cardiac failure. Dilated cardiomyopathy was often severe in our patients, albeit that the cause was frequently uncertain, and the response to standard anti-failure treatment unsatisfactory. Efforts should be intensified for unravelling its aetiology and improving medical treatment.