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Arrhythmogenic inherited heart muscle diseases in children
1Department of Pediatrics (Cardiology), Baylor College of Medicine, Houston, TX 77030, USA. jtowbin@bcm.tmc.edu
Insights
Left ventricular (LV) dysfunction, often leading to heart failure, has genetic and acquired causes. Research is uncovering the molecular genetics, identifying specific genes and pathways involved in LV dysfunction.
Area of Science:
- Cardiology
- Molecular Genetics
- Genetics
Background:
- Left ventricular (LV) dysfunction is a critical condition, often progressing to congestive heart failure.
- Idiopathic dilated cardiomyopathy is a common diagnosis when the cause of LV dysfunction is unknown.
- Therapeutic interventions include medications, mechanical support devices, and cardiac transplantation.
Purpose of the Study:
- To review the molecular genetics of left ventricular dysfunction.
- To explore the genetic basis of familial dilated cardiomyopathy.
- To present evidence for a common molecular pathway in LV dysfunction.
Main Methods:
- Literature review of genetic and molecular studies on LV dysfunction.
- Identification of genes associated with inherited forms of dilated cardiomyopathy.
- Analysis of molecular mechanisms in acquired LV dysfunction, such as inflammatory heart disease.
Main Results:
- Approximately 30-40% of LV dysfunction cases are inherited, with various inheritance patterns.
- Specific genes (e.g., dystrophin, G4.5, actin, desmin, lamin A/C, delta-sarcoglycan) have been linked to familial dilated cardiomyopathy.
- Inflammatory mediators and protein cleavage are implicated in acquired LV dysfunction.
Conclusions:
- The genetic underpinnings of LV dysfunction are increasingly understood.
- A unifying "final common pathway" may explain the diverse origins of LV dysfunction.
- Further research into molecular genetics can inform therapeutic strategies for heart failure.
Abstract:
The left ventricle (LV) plays a central role in the maintenance of health of children and adults due to its role as the major pump of the heart. In cases of LV dysfunction, a significant percentage of affected individuals develop signs and symptoms of congestive heart failure, leading to the need for therapeutic intervention. Therapy for these patients include anticongestive medications and, in some, placement of devices such as aortic balloon pump or left ventricular assist device, or cardiac transplantation. In the majority of patients the origin is unknown, leading to the term idiopathic dilated cardiomyopathy. During the past decade, the basis of LV dysfunction has begun to unravel. In approximately 30% to 40% of cases, the disorder is inherited; autosomal dominant inheritance is most common (although X-linked, autosomal recessive and mitochondrial inheritance occurs). In the remaining patients, the disorder is presumed to be acquired, with inflammatory heart disease playing an important role. In the case of familial dilated cardiomyopathy, the genetic basis is beginning to unfold. To date, 2 genes for X-linked familial dilated cardiomyopathy (dystrophin, G4.5) have been identified and 4 genes for the autosomal dominant form (actin, desmin, lamin A/C, delta-sarcoglycan) have been described. In 1 form of inflammatory heart disease, coxsackievirus myocarditis, inflammatory mediators, and dystrophin cleavage play a role in the development of LV dysfunction. This review describes the molecular genetics of LV dysfunction and provide evidence for a "final common pathway" responsible for the phenotype.