Where Genome Meets Phenome: Rationale for Integrating Genetic and Protein Biomarkers in the Diagnosis and Management of Dilated Cardiomyopathy and Heart Failure


The following are 10 points to consider from this review:

1. Family history alone is insensitive for detection of familial dilated cardiomyopathy (DCM), even when ischemic and other detectable etiologies have been ruled out.

2. The age of onset for DCM ranged from 0 to 75 years in one familial cohort study. In addition, systolic dysfunction may precede symptoms for many years.

3. A combination of approaches involving family history, clinical screening of relatives, and echocardiography is helpful to identify patients with familial DCM.

4. Rare mutations from over 30 genes have been reported to cause familial DCM. Because most mutations are rare or novel and usually specific to one family, it is difficult to determine the true contribution of newly identified variants to disease.

5. No large systematic studies have been performed to examine the genetic basis of sporadic (nonfamilial) idiopathic dilated cardiomyopathy. The extent to which this is a genomic disease remains unclear.

6. Even though genetic mutations (i.e., sarcomeric protein) may predispose subjects to DCM, progression to heart failure involves subsequent complex molecular cascades leading to contractile inefficiencies, metabolic dysregulation, progressive cell death, remodeling, inflammatory activation, and fibrosis.

7. Diagnosis and management of DCM patients may be greatly facilitated by utilizing both genomic information and biomarkers reflecting activation of pathways involved in myocardial dysfunction.

8. Potentially useful protein biomarkers in DCM include those that reflect myocardial stress (i.e., natriuretic peptides, interleukin-1 receptor family member ST2), cell death or turnover (i.e., high-sensitivity troponin), collagen turnover (PIIINP, CITP), matrix dynamics (sMMPs, galectin-3).

9. As we learn more about relevant pathways involved in DCM, panels of protein biomarkers, which appear at different time points in the natural history of DCM progressing to heart failure, may assist in early detection, prognostication, and therapeutic targeting.

10. Characterization of different types of CM in the advanced state is problematic since end-stage ischemic and nonischemic CMs share many molecular and cellular perturbations with only small differences in the transcriptome. Efforts focused on early diagnosis and intervention are therefore most likely to ultimately affect long-term prognosis and be cost-effective.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Genetic Arrhythmic Conditions, Lipid Metabolism, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound

Keywords: Genomics, Galectin 3, Procollagen, Transcriptome, Heart Diseases, Natriuretic Peptides, Prognosis, Genetic Therapy, Annexin A2, Biological Markers, Cardiomyopathies, Collagen, Fibrosis, Cardiomyopathy, Dilated, Echocardiography, Troponin

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