Page 107 - Feline Cardiology

106 Section D: Cardiomyopathies

binding to myosin and/or actin (Meurs et al. 2005). In
and compensatory mechanisms to lead to the final an experimental model of interrupted MBPC and
phenotype of concentric hypertrophy, myofiber disarray, myosin interaction in ventricular myocytes, there were
and myocardial fibrosis. increased calcium sensitivity, force of contraction, and
• Environmental influences, including nutrition and air- or time to half-relaxation (Calaghan et al. 2000). Similarly,
waterborne factors, are not known to cause HCM in in a knock-in mouse HCM model missing the linker
cats, but have only been sparsely investigated.
between motifs C 0 –C 1 , there was an increased calcium
sensitivity to force production (Witt et al. 2001). These
experimental findings of diastolic impairment closely
parallel those seen in cats with naturally occurring HCM
Familial Hypertrophic Cardiomyopathy in Cats
Cardiomyopathies HCM is a heritable disease in Maine coon cats, Ragdoll nisms of familial HCM in cats with mutations of MBPC
and may help identify possible pathophysiologic mecha-
cats, and American shorthair cats, and many other pure-
(Bright et al. 1999). The pathway that links a defective,
bred cats are predisposed (Meurs et al. 1997, 2005, 2007).
dysfunctional sarcomere to development of the final
Although heritable, it is not a congenital disease that is
phenotype of concentric hypertrophy involves many
present at birth. Rather, it is a developmental disease that
occurs as the cat ages, at any time during its life span factors that increase the cell’s machinery to synthesize
more muscle cells that compensate for the dysfunctional
ranging from adolescent to geriatric. ones, at the expense of increased muscle stiffness and
HCM is an autosomal dominant inherited disease decreased ventricular diastolic relaxation.
with incomplete penetrance in Maine coon cats A family of American shorthair cats has also been
(Kittleson et al. 1999). A missense mutation in the found to have an autosomal dominant heritable form of
myosin binding protein C gene (MYBPC3) has been HCM, consisting mostly of systolic anterior motion of
identified in some Maine coon cats, which results in a the mitral valve (Meurs et al. 1997). Anecdotal evidence
change from the conserved amino acid alanine to suggests that other purebred cats may have an inherited
proline, thus altering protein conformation (Meurs et al. form of HCM, including British shorthair, Norwegian
2005). A second mutation of MYBPC3 has been found forest cat, Turkish van, Scottish fold, Bengal, Siberian,
in Ragdoll cats with familial HCM (Meurs et al. 2007). Sphynx, and Rex. A heritable form of HCM was sus-
This missense mutation results in a change in the con- pected in a family of mixed-breed domestic shorthair
served amino acid from arginine to tryptophan, which cats, which also appears to be observed in clinical prac-
alters the structure of myosin binding protein C (MBPC). tice (Nakagawa et al. 2002; see also Chapter 10). Aside
The acronym MBPC indicates the sarcomeric protein, from the familial heritable forms of HCM, the remain-
and the acronym MYBPC3 represents the actual genetic ing cases of spontaneously developing HCM are possibly
mutation of the myosin binding protein C that alters the due to de novo sarcomeric mutations, as they are in
structure of the protein. MBPC is a sarcomeric protein approximately 1/3 of humans with HCM (Marian et al.
located at the transverse band within the A band of the 2001). Since these “unknown cause” cases do not have
sarcomere and attaches to titin and β-myosin heavy mutations in the genes found to cause HCM in people,
chain (see Figure 11.1). Its role is believed to be both little is known about their etiology, and there may be
structural and regulatory (Marian et al. 2001; Harris et environmental or other influences, or just unrecognized
al. 2002). The axial alignment of MBPC along the beta familial mutations, underlying them. An individual that
myosin heavy chain (β-MHC) backbone and the inter- develops a “spontaneous” de novo sarcomeric mutation
action of MBPC with titin are necessary for ordered, may then pass on that mutation to offspring as a heri-
stabilized arrangement of the sarcomere. Consequently, table trait. This process likely occurs in cats, because one
absence of MBPC in transgenic MBPC knockout mice Maine coon cat (with severe HCM but without the
results in malignment of sarcomeric striations, a classic MYBPC3 mutation) from a colony of familial HCM
histopathologic abnormality seen in HCM (Harris et al. sired many progeny affected with HCM without the
2002). MBPC also interacts with the β-MHC head, and MYBPC3 mutation (K. MacDonald, personal observation).
acts as a braking mechanism between the interaction of
actin and β-MHC. When MBPC is phosphorylated, it Etiology of HCM in Humans and Molecular
undergoes a conformational change in the C 0 –C 1 linker Mechanisms of Disease
region that releases the myosin head to be in a favorable To help understand etiology and pathophysiology of
position to bind with actin (Weisberg and Winegrad feline HCM, it is helpful to examine the pertinent genetic
1996). The mutation of MBPC in Maine coon cats is and molecular mechanisms of disease in humans and
localized to the C 0 and C 0 –C 1 linker region involved with other animal species with familial HCM. The sarcomere