Page 109 - Feline Cardiology

108 Section D: Cardiomyopathies

Mutant sarcomeric protein expression

Functional sarcomeric defect Sarcomere dysgenesis

Ca 2+ Calcium Cross-bridge Sarcomeric Myofibrillar
sensitivity uptake cycling structural defect disarray

Cardiomyopathies Cardiomyocyte Impaired cardiomyocyte performance factors

Environmental
Gene polymorphisms
stress
Modifier genes
Myocyte Collagen Myocyte
hypertrophy synthesis disarray

Cardiac systolic & diastolic dysfunction

Figure 11.2. Pathophysiologic mechanisms of hypertrophic cardiomyopathy. The initial sarcomeric defect in HCM leads to cardiomyo-
cyte dysfunction, which activates cell stress responses. Increased cell transcription leads to development of cardiomyocyte hypertrophy,
increased collagen formation, and myofiber disarray. The final phenotype is concentric left ventricular hypertrophy, myocardial fibrosis,
and myofiber disarray, which lead to diastolic and possibly systolic dysfunction.

proteins, which cause a wide range in phenotypic abnor- ative factor. Viral myocarditis has been hypothesized
malities including degree of fibrosis, ventricular to be a factor in development of cardiomyopathy in
hypertrophy, or sudden death. The initial defects are people, and has been investigated in cats with cardiomy-
impossible to clinically recognize as they occur on a cel- opathy. Feline panleukopenia virus was present in the
lular level, and often phenotypic abnormalities are only myocardium of 32% (10/31) of cats with various cardio-
identified much later once left ventricular hypertrophy myopathies (58% had HCM), and 80% of cats with
or global diastolic dysfunction have occurred closer to panleukopenia virus in the myocardium had concurrent
the end-stage of the disease. Likewise, some individuals myocarditis (Meurs et al. 2000). The presence of panleu-
may not ever display phenotypic abnormalities despite kopenia virus and myocarditis does not establish a
being genotypically affected, or they may develop abnor- causal relationship with HCM, but it is possible that it
malities much later in life. This is paralleled by our clini- may contribute to the pathology of HCM or its final
cal experience in cats, where even within families of cats common pathway. Likewise, it is not clear whether the
with HCM, there is great variability in the time of onset panleukopenia virus could be merely present in the
of the disease, the extent of ventricular hypertrophy and myocardium secondary to vaccination with a modified
atrial dilation, and the clinical course where some cats live panleukopenia virus vaccine.
remain asymptomatic yet relatives may decompensate There are several examples of polymorphisms in
over a short time. genes that modify the severity of phenotypic expression
Other factors involved in phenotypic expression in of HCM in people, i.e., the extent of gene penetrance
people with HCM include environmental factors, poly- and ensuing LV hypertrophy are increased or decreased
morphisms in other genes that modify left ventricular by the expression of other genes. For example, tumor
hypertrophy, and concomitant diseases. These factors necrosis factor (TNF-α) is an important modifier of
have been largely neglected in the study of feline HCM. HCM phenotype. The polymorphism that causes the AA
There are no environmental, nutritional, amino acid genotype, which is known to produce greater amounts
deficiencies (i.e., taurine deficiency), infectious, or of TNF-α, is associated with greater LV mass index and
immunologic factors that are implicated to cause HCM clinical diagnosis at an earlier age when compared to the
in cats, nor have vaccinations been implicated as a caus- GA and GG genotypes (Patel et al. 2000). The presence