Hypertrophic cardiomyopathy in purpose-bred cats with the A31P mutation in cardiac myosin binding protein-C

Figures

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  Figure 1. Extended A31P cat colony pedigree. Pedigree representing a family of 74 cats (35 males, 30 females, and 9 cats of unknown sex) derived from single male founder cat heterozygous for the A31P mutation. Squares = males, circles = females, and diamonds = kittens of unknown sex that were either stillborn or died secondary to failure to thrive. Open symbols are wildtype cats, half-filled symbols are heterozygous A31P cats, and filled symbols are homozygous A31P cats. Green symbols are cats of unknown genotype. Forty-four cats were phenotyped via echocardiography for HCM. Red squares indicate HCM-affected cats; HCM affection status was strictly defined as the following: (1) a diastolic LV wall segment ≥ 6 mm identified in at least two separate echocardiographic examinations in the absence of any other systemic or metabolic disease, or (2) a diastolic LV wall segment ≥ 6 mm identified on a single echocardiographic examination in conjunction with a serum NT-proBNP concentration of > 100 pmol/L20 in the absence of any other systemic or metabolic disease. Gray squares indicate cats that were not phenotyped or that have an unknown affected status. Blue symbols are cats that were adopted and…

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  Figure 2. Proportion of HCM-affected status by genotype. The proportion of unaffected and affected cats for each genotype is shown. Of the seven wildtype (WT) cats, five were unaffected and two were affected. Fifteen were heterozygous (HT) for the A31P variant, of which six were unaffected and nine were affected. Of the 22 cats homozygous (HO) for the A31P variant, one cat was unaffected and 21 were affected. HCM: hypertrophic cardiomyopathy; WT: wildtype, HT: heterozygous, HO: homozygous.

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  Figure 3. Plasma NT-proBNP values in A31P cat colony. (A) Highest single measurement of plasma NT-proBNP concentration by genotype. (B) Highest measured plasma NT-proBNP concentration in HCM-unaffected and -affected cats. Dotted line represents 100 pM, the clinically accepted cut off value for high NT-proBNP concentration. ** P < 0.008, *** P < 0.0001. NTproBNP: N-terminal pro-brain natriuretic peptide; HCM: hypertrophic cardiomyopathy.

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  Figure 4. Echocardiography and gross pathology of a severe HCM-affected cat homozygous for the MYBPC3 A31P mutation (cat #2011-14). (A) M-mode image of the LV taken from the right parasternal short axis imaging plane documenting severe LV hypertrophy in a female cat at 3.5 years of age. (B) A coin-cut gross pathology image of LV showing severe wall thickening and prominent papillary muscles; white bar = 1 cm. (C) Longitudinal echocardiographic data of the LVPWd from the right parasternal short axis imaging plane over sequential evaluations. (D) Longitudinal echocardiographic data of LA/Ao in 2D from the right parasternal short axis imaging plane over sequential evaluations. The final evaluation in C and D was completed at ~ 3.5 years of age, immediately prior to euthanasia for new onset left-sided congestive heart failure. Dotted red lines (C) & (D) represent the threshold for LVPWd measures consistent with HCM and LA/Ao consistent with LA enlargement. HCM: hypertrophic cardiomyopathy; MYBPC3: myosin-binding protein-C; LV: left ventricle; LVPWd: left ventricle posterior wall in diastole; LA/Ao: left atrium to aortic root ratio; LA: left atrium.

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  Figure 5. Echocardiography and gross pathology of a severe, early onset, HCM-affected female cat (cat #2011-48) homozygous for the MYBPC3 A31P mutation. (A) 2D echocardiographic image of the LV from the right parasternal short axis imaging plane documenting severe LV hypertrophy at ~ 5 months of age. (B) 2D and color Doppler echocardiographic image of the LVOT from the right parasternal long-axis imaging plane showing turbulence in the LVOT secondary to SAM and associated mild mitral valve regurgitation. Severe LV hypertrophy is again shown in this imaging plane. (C) Gross pathology image of the intact heart showing a prominent LV and dilated LA and LA appendage; white bar = 1 cm. (D) Longitudinal echocardiographic data of the LVPWd from the right parasternal short axis imaging plane over 2 sequential evaluations. (E) Longitudinal echocardiographic data of LA/Ao in 2D from the right parasternal short axis imaging plane over sequential evaluations. The final evaluation in (D) and (E) was completed at ~ 7.5 months of age, just prior to euthanasia for new onset left-sided congestive heart failure. Dotted red lines (D & E) represent the threshold for LVPWd measures consistent with HCM and…