Page 110 - Feline Cardiology

Chapter 11: Hypertrophic Cardiomyopathy 109

of this polymorphism accounts for approximately 6% of familial HCM in humans. Aside from the Maine coon
the variability of LV hypertrophy in humans. TNF-α cat model, the transgenic β-MHC rabbit model most
provokes a dose-dependent increase in hypertrophy by closely approximates human HCM. Transgenic rabbits
increasing synthesis of actin and myosin in the cardio- have myocyte disarray involving 10–20% of the LV, 2–3-
myocyte. TNF-α also interacts with the renin- fold increase in interstitial fibrosis, concentric LV hyper-
angiotensin-aldosterone system (RAAS) and increases trophy, sudden cardiac death, and diastolic dysfunction
expression of angiotensin II receptor type 1. (Marian et al. 1999). This mirrors the same pathologic
There are four polymorphisms in genes that encode abnormalities and clinical correlates described in cats
for proteins in RAAS that are associated with higher with HCM (Fox 2003a; Fox et al. 1995). A spontaneously
activation of RAAS and have been identified as “pro-left developing, moderately heritable model of HCM has
ventricular hypertrophy” genotypes in some familial been identified in pigs from a breeder farm in Taiwan
HCM-related mutations (Ortlepp et al. 2002). These (Huang et al. 1996; Dai et al. 1996). Pigs develop similar
polymorphisms are an insertion/deletion polymor- phenotypic abnormalities to those of Maine coon cats Cardiomyopathies
phism of angiotensin converting enzyme (ACE) gene, a and humans, including concentric LV hypertrophy,
T/C exchange in the angiotensinogen gene, an A/C poly- SAM, and left atrial enlargement (Lin et al. 2002). Like
morphism of the angiotensin II receptor type I gene, and people and cats, these pigs also develop the hallmark
a C/T exchange of the aldosterone synthase gene (Ortlepp histopathologic abnormalities of HCM including myo-
et al. 2002; Kupari et al. 1998). The ACE-DD polymor- fiber disarray, intramural coronary arteriosclerosis, and
phism causes a higher tissue concentration of ACE, and myocardial fibrosis (Dai et al. 1996). Therefore, these
has been associated with more severe LV hypertrophy in pigs may serve as models for feline HCM, and future
patients with β-MHC mutations. Approximately 15% of diagnostic and therapeutic discoveries could possibly be
the variability of LV mass index in humans with familial relevant to cats with HCM.
HCM is due to the type of ACE genotype present in an
individual (Lechin et al. 1995). However, the relation-
ship of the RAAS system and ACE in feline HCM is not Relationship Between HCM and Other
clear, given the lack of any measurable improvement in Cardiomyopathies
left ventricular hypertrophy in asymptomatic Maine Although cardiomyopathies are classified into specific
coon cats with HCM given an ACE inhibitor daily for 1 and very different functional categories (i.e., dilated,
year (MacDonald et al. 2006b). The angiotensinogen CC restricted, hypertrophic), there are many similarities of
polymorphism results in greater production of angio- molecular genetic mechanisms in humans with various
tensinogen, the catalytic enzyme that converts renin to cardiomyopathies. Historically, it was hypothesized that
angiotensin I. The angiotensin II receptor type I CC the different functional classes were manifestations
polymorphism is associated with higher receptor along a continuum of one disease, spanning HCM at
responsiveness. All four prohypertrophic RAAS poly- one extreme, DCM as end-stage myocardial failure at
morphisms are independently related to the degree of the other, and intermediate cardiomyopathy (currently
penetrance and severity of LV hypertrophy in humans recognized as restrictive or unclassified cardiomyopa-
with familial HCM due to a MBPC mutation (Ortlepp thy) as a transitional stage from HCM to DCM (Harpster
et al. 2002). Given the highly variable nature of feline 1977). Continued research (molecular genetic studies,
HCM, it is an intriguing hypothesis that these RAAS clinical observation), however, has not supported this
polymorphisms exist in cats. Given the wide spectrum hypothesis and the different cardiomyopathies are now
of HCM phenotype and clinical course in cats, it is pos- considered distinct entities (Spaendonck-Zwarts et al.
sible that there are different modifiers (gene, environ- 2008; Maron et al. 2006). However, while transition from
ment, etc.) that occur, which makes it impossible to HCM to RCM/UCM to DCM does not represent the
extrapolate results of clinical therapeutic studies in a natural evolution of cardiomyopathy in the cat, muta-
group of cats (maybe within a specific breed or family) tions in many of the same sarcomeric proteins linked
to apply to all cats with HCM. to familial HCM have been shown to cause familial
dilated cardiomyopathy or restrictive cardiomyopathy
Experimental Animal Models of Familial HCM in people (Maron et al. 2006). Since mutations affect
There are several transgenic or knockout mice with some of the same proteins in HCM and DCM – two
mutations in β-MHC, tropomyosin, TnT, TnI, MBPC, clinically distinct diseases with opposite pathophysiol-
and essential light chains, as well as a transgenic TnT ogy – the mutations likely confer different structural and
mutation rat model (Marian et al. 2001). Often there is functional consequences to explain the disparate pheno-
a substantial discrepancy between the phenotype of types. Although previously described as idiopathic,
rodent models compared with the phenotype seen in RCM is now known to be a familial heritable disease in