Echocardiographic-determined septal morphology in Z-disc hypertrophic cardiomyopathy

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Abstract

Hypertrophic cardiomyopathy (HCM) can be classified into at least four major anatomic subsets based upon the septal contour, and the location and extent of hypertrophy: reverse curvature-, sigmoidal-, apical-, and neutral contour-HCM. Here, we sought to identify genetic determinants for sigmoidal-HCM and hypothesized that Z-disc-HCM may be associated preferentially with a sigmoidal phenotype. Utilizing PCR, DHPLC, and direct DNA sequencing, we performed mutational analysis of five genes encoding cardiomyopathy-associated Z-disc proteins. The study cohort consisted of 239 unrelated patients with HCM previously determined to be negative for mutations in the eight genes associated with myofilament-HCM. Blinded to the Z-disc genotype status, the septal contour was graded qualitatively using standard transthoracic echocardiography. Thirteen of the 239 patients (5.4%) had one of 13 distinct HCM-associated Z-disc mutations involving residues highly conserved across species and absent in 600 reference alleles: LDB3 (6), ACTN2 (3), TCAP (1), CSRP3 (1), and VCL (2). For this subset with Z-disc-associated HCM, the septal contour was sigmoidal in 11 (85%) and apical in 2 (15%). While Z-disc-HCM is uncommon, it is equal in prevalence to thin filament-HCM. In contrast to myofilament-HCM, Z-disc-HCM is associated preferentially with sigmoidal morphology.

Section snippets

Methods

Between April 1997 and December 2001, a total of 382 unrelated patients (210 male, mean maximum left ventricular wall thickness (MLVWT) 21.5 ± 6 mm) had both comprehensive echocardiographic examination and evaluation in Mayo Clinic’s HCM clinic, and genetic testing. HCM was diagnosed according to WHO criteria as unexplained cardiac hypertrophy (>13 mm) in the absence of hypertrophy inciting factors such as aortic stenosis. Following written informed consent for this IRB-approved research protocol,

Results

The demographics of the myofilament genotype negative cohort are shown in Table 1. As indicated in the study design exclusion criteria, no mutations in the eight genes underlying myofilament-HCM (β-myosin heavy chain, myosin binding protein C, etc.) were present in this cohort. This cohort consisted of 239 patients (131 male) with an average age at diagnosis of 45.1 years and a mean LVWT of 20.7 mm. Fifty-six percent of patients presented with cardiac symptoms, 24% had a family history of HCM in

Discussion

Due to the hundreds of mutations scattered throughout the genes which encode proteins of the myofilament, HCM has long been considered a disease of the sarcomere, more specifically, a disease of the myofilament. With the recent discovery of HCM-associated mutations in genes encoding for proteins of the Z-disc [9], [10], [11], [12], [14] and the distinction whereby HCM-associated mutations in PRKAG2 and LAMP2 have categorized certain cases of glycogen storage disease [27], [28], the spectrum of

Conclusions

Thus far, examination of the five established cardiomyopathy-susceptibility genes, encoding key components of the Z-disc, demonstrates that perturbations in the Z-disc are a much less common cause for HCM compared to the two most common HCM-associated genotypes of myosin binding protein C- and β-myosin heavy chain-HCM. Nevertheless, Z-disc-HCM is as common as thin filament-HCM (i.e. troponin T-, troponin I-, tropomyosin-, or actin-HCM). However, unlike myofilament-HCM, Z-disc-HCM is

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    J.L.T. and J.M.B. are co-equal first authors.

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