Page 108 - Feline Cardiology

Chapter 11: Hypertrophic Cardiomyopathy 107

is the basic unit of muscular contraction and relaxation incomplete penetrance pattern (Marian et al. 2001). The
in a muscle cell (myocyte). The primary components are troponin (Tn) complex and tropomyosin behave like a
the myofilaments, actin and myosin, which interact in a calcium switch that regulates the interaction of actin and
ratcheting-type mechanism referred to as cross-bridge β-MHC, which is necessary for cross-bridge cycling and
cycling during muscle contraction. The fibers slide power generation. TnT mutations are a fairly common
against each other, bringing the two ends of the sarco- (20%) cause of familial human HCM cases. Sudden
mere closer to shorten the muscle during contraction. cardiac death with minimal hypertrophy is typical for
Release of myosin from actin allows the sarcomere to mutations in this gene (Marian et al. 2001). Actin muta-
elongate and relax in a resting state. Muscle relaxation is tions involve the region near the β-MHC binding site
not passive but active, and it requires ATP for normal and result in heterogeneous phenotypes ranging from
relaxation. Defects in cellular energetics or calcium han- mild hypertrophy to severe septal hypertrophy and sys-
dling impact both contraction (systole) and relaxation tolic anterior motion (SAM) of the mitral valve (Marian
(diastole) of the muscle. The cardiomyocyte consists of et al. 2001). Mechanical performance (i.e., ability to con- Cardiomyopathies
thousands of sarcomeres that are anchored together by tract) of muscle fibers is reduced when there are muta-
a cytoskeletal framework necessary to maintain coordi- tions in β-MHC, TnT, and tropomyosin (Marian et al.
nated contraction and relaxation. Cardiomyopathies 2001). Most sarcomeric protein mutations also result in
involve defects in sarcomeric proteins (actin, myosin, an enhanced calcium sensitivity of the contractile appa-
etc.), cytoskeletal proteins, nuclear membrane proteins, ratus, which may lead to diastolic dysfunction (Marian
or mitochondrial energetics. et al. 2001). In vitro, the majority of mutant sarcomeric
Molecular techniques have made it possible to iden- proteins assemble into sarcomeres and then myofila-
tify mutations in proteins within the cardiomyocytes of ments, and do not cause immediate sarcomere dysgen-
patients with various cardiomyopathies including HCM, esis or myofibrillar degeneration, but cause systolic and/
dilated cardiomyopathy, or other inherited cardiomy- or diastolic dysfunction at a cellular level (Marian et al.
opathies (Spaendonck-Zwarts et al. 2008). Two-thirds of 2001). If sarcomeric protein mutations are expressed in
people with HCM develop the disorder due to familial a very high concentration, there may be sarcomere dys-
inherited, sarcomeric mutations (see Figure 11.1) genesis and myofibrillar disarray. It is hypothesized that
(Marian et al. 2001). In a large study of a genotyped the initial expression (phenotype) of HCM at the sarco-
population of people with familial HCM, there was meric level is a functional defect, and there are interme-
incomplete, age-related penetrance that was greater in diary pathways that connect the initial defect to the final
males than in females (Charron et al. 1997). This means phenotype of LV hypertrophy, myocardial fibrosis, and
that the severity of ventricular hypertrophy is highly myofiber disarray (Figure 11.2) (Marian et al. 2001). The
variable, occurs more frequently in older people and is mutated sarcomeric proteins are often termed “poison
typically more severe in males. This closely parallels the peptides,” which exert a dominant negative effect follow-
characteristics of feline familial HCM. Mutations in ing incorporation into the myofibrils (Marian et al.
people have been identified in a number of sarcomeric 2001). The impaired mechanical function leads to
protein genes including those for β-MHC, essential and increased myocyte stress and activation of stress respon-
regulatory light chains, α-cardiac actin, α-tropomyosin, sive intracellular signaling kinases, calcium sensitive sig-
troponin I (TnI), troponin T (TnT), MBPC, and titin naling molecules, and trophic factors (Marian et al.
(see Figure 11.1) (Towbin and Bowles 2002). The most 2001). Transcriptional machinery of the myocyte is acti-
common mutations in people involve β-MHC or MBPC vated, which leads to myocyte hypertrophy, collagen
genes. Of the β-MHC mutations identified to date in synthesis, and myocyte disarray (Marian et al. 2001). LV
humans, many are associated with an earlier onset of hypertrophy is a compensatory process occurring later
disease, more extensive hypertrophy, and a higher inci- in the disease (Marian et al. 2001). Gene transfer studies
dence of sudden cardiac death than other mutations. in adult cardiac myocytes document myocyte dysfunc-
β-MHC mutations mostly involve the portion of the tion prior to development of myofibrillar disarray
gene that encodes for the myosin head or head-rod junc- (Marian et al. 1997). Likewise, in humans and transgenic
tion, where the altered protein decreases the ability of animals with sarcomeric mutations for familial HCM
myosin to dislocate from actin (Marian et al. 2001). and no LV hypertrophy, there is reduced velocity of
Mutations in MBPC occur in approximately 20% of myocardial contraction and relaxation, documenting
familial HCM cases in people, and often cause aberrant early systolic and diastolic dysfunction (Nagueh et al.
transcripts that result in truncated peptides that lack the 2000, 2001). Together these findings indicate that
myosin binding domain. MBPC mutations often cause HCM is not a monomorphic disease but is caused
a delayed onset of hypertrophy after age 40, with an by a variety of mutations of different sarcomeric