Titolo della tesi: Outcome of Genetic and Non-Genetic Pediatric Cardiomyopathies. Local Center Experience
Introduction
Pediatric cardiomyopathies are rare diseases with an annual incidence of up to 1.5 per 100 000. Dilated and hypertrophic cardiomyopathies are the most common types. Other types occur infrequently and include restrictive, noncompaction, mixed cardiomyopathies, and Arrhythmogenic right ventricular cardiomyopathy. Pediatric cardiomyopathies can be familial or idiopathic, with genetic or non-genetic causes. They can result from coronary artery abnormalities, tachyarrhythmia, exposure to infection or toxins, or secondary to other underlying disorders. Pediatric cardiomyopathies often occur in the absence of comorbidities Increasingly, the importance of genetic mutations in the pathogenesis of isolated or syndromic pediatric cardiomyopathies is becoming apparent.
Methodology
A Retrospective single-center review of all patients with a diagnosis of cardiomyopathy admitted / or seen in our OPD during the period from January 2011 to May 2020. The data was collected from the inpatient and outpatient database from the time of initial presentation till the last follow-up. The demographic, clinical, and echocardiographic variables collected also include hospital course and management /treatment received. Results of the genetic and metabolic study, as well as the outcome (improvement, static, alive/died, heart transplantation), were reported. Patients were divided according to the EF at presentation (those with DCM) as those with EF of 20% or more or those with EF less than 20%. They were divided also according to the age of presentation (especially those with HCM) into those presented at an age of 6 months or less and those who present at more than 6 months of age. Comparison between the groups as well as the creation of the ROC curve to look at the prediction for mortality based on the age of presentation and the EF at presentation. The results of genetic and metabolic studies were recorded, with the association between the genetic/metabolic abnormality and the type of CMP as well as the outcome.
Results
During the study period, 229 pediatric patients were diagnosed to have cardiomyopathy. The commonest type of cardiomyopathy was dilated CMP (160 patients 70%) followed by HCM (60 patients, 26.2%), RCM (4 cases, 1.7%), and isolated LV non-compaction (5 cases, 2.2%).
The male to female ratio was almost 1:1 (51 to 49 % respectively). Almost 52% of cases presented at 6 months of age or less ((118 cases, (51.5%). The mean age of presentation for all cases was 16.8 months (+/- 28.7 months) (minimum 1 week and maximum 13 years). The commonest mode of presentation was signs and symptoms of heart failure (170 cases,74.2%) and cardiogenic shock (30 patients,13.1%). Most of the cases were admitted to the ICU (119 cases,52%) at the initial presentation. The genetic and or metabolic disorder was confirmed in 21.4% of all cases, most commonly VLCAD defect in 16 cases (7%) and ELAC2 gene defect in 10 cases (4.4%).
Eighty-eight patients (38.4%) with DCM and 38 patients with HCM (65%) died during the follow-up period, mostly in the first and second years after the diagnosis in HCM and DCM respectively.
In patients with DCM, an EF of 20% or less at presentation carries a risk for mortality with a relative risk of 3.88 when compared with those who had an EF > 20% (Odds Ratio of 11.09).
Patients with HCM presentation at 6 months or less carries a risk for mortality with a relative risk of 2.06 when compared with those who present at more than 6 months of age, (Odds Ratio of 4.35).
A genetic study was confirmed in 49 patients (20 with DCM (13.1% of DCM cases),27 with HCM (45% of HCM cases), and 2 with LVNC.
Conclusion
Cardiomyopathy is a heterogeneous group of myocardial disorders with multifactorial etiologies. It is a frequent cause of heart failure and the most common cause of heart transplantation in children older than 1 year of age. The commonest forms are dilated cardiomyopathy and HCM. Diagnosis confirmation is based on echocardiographic findings. A genetic study using Whole-Exome/whole-genome sequencing is advised for all cases with CMP and at-risk family members. The mortality for CMP in children reaches up to 40%, with a mortality rate for patients with DCM of 30% and HCM of 65%. Mortality was more in those with HCM, DCM with EF of 20% or less and HCM presented at 6 months of age or less. The predictors of poor prognosis (Death and/or heart transplantation) differ according to the type of CMP. Patients with HCM presented in the first year of life and those with DCM with EF at presentation 20% or less have a poor prognosis. The Presence of abnormal genetic abnormality carries a poor prognosis in HCM compared with DCM cases with abnormal genetic testing (have a better prognosis).
Multivariate Survival Analysis, All Cases:
Kaplan Meyer survival for all cases was created with univariate and m multivariable survival analysis (figures 1 to 7). The results of multivariate survival analysis for all cases are
1. Patients with HCM have a higher mortality rate and die at an earlier age when compared with DCM and other types of CMP. No mortality among patients with isolated LVNC.
2. Patients Presented at 6 months of age or less had a higher mortality rate and die at an earlier age.
3. Patients with a positive family history of CMP have a higher mortality rate and die at an earlier age when compared with those with negative F/H of CMP.
4. No difference in the mortality rate and time of death among males and females with CMP.
5. Patients admitted to the hospital in the initial presentation, have a higher risk for mortality.
6. Patients admitted to the ICU in the initial presentation, have a higher risk for mortality.
7. Patients who required inotropic support have a higher survival rate. Inotropic support was used more in patients with DCM, especially those with high suspicion of viral myocarditis.
8. Patients who required ventilatory support have a higher survival rate. ventilatory support was used more in patients with DCM, especially those with high suspicion of viral myocarditis.
Multivariate Survival Analysis for patients with DCM: (Figures to 9 to 16)
Kaplan Meyer survival for patients with DCM was created with univariate and m multivariable survival analysis (figures 9 to 16). The results of multivariate survival analysis for patients with DCM are:
1. The mortality rate among DCM patients was 30% with most deaths occurring in the first 2 years after the diagnosis.
2. EF at the presentation of 20% or less had a significant risk for a bad outcome (p-value < 0.001).
3. No change in the mortality rate among males and females.
4. No significant difference in mortality rate according to the age of presentation (Less or more than 6 months of age).
5. Admission at first presentation increases the risk for mortality (P-value 0.002).
6. Consanguineous parents increase the risk for mortality, (p-value 0.002).
7. Family history of CMP increases the risk for mortality, (p-value 0.005).
8. The use of Digoxin didn't change the outcome ( p-value 0.503
9. Patients admitted to the ICU had a higher mortality rate (p-value 0.047).
10. Patients who received Inotropic medications had a lower mortality rate (p-value 0.022). 0.074
11. IVIG administration had no significant effect on reducing mortalities (p-value 0.074).
Multivariate Survival Analysis for patients with HCM: (Figures to 17 to 20)
Kaplan Meyer survival for patients with HCM was created with univariate and m multivariable survival analysis (figures 17 to 20). The results of multivariate survival analysis for patients with HCM are:
1. The mortality rate among patients with HCM was 65%, with 35 patients died, most of them in the same year of diagnosis (First year of life).
2. Presentation with HCM at 6 months or less was a risk for mortality in our cohort.
3. The requirement for ICU admission on presentation with HCM was a risk for mortality in our cohort.
4. No effect of the genetic results on the survival rate (mortality among patients with negative genetic analysis have higher mortality). There might be other undetected or unidentified genetic anomalies related to HCM.
5. No change in survival rate concerning consanguinity and positive family history of CMP