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Summary: Jonathan Seidman is interested in the molecular causes of left ventricular hypertrophy, or thickening of the heart wall. Two different types of disease-causing mutations have been identified that cause this condition in humans. One involves sarcomere protein genes, and the other involves a gene encoding an AMP kinase subunit. Mice bearing altered genes have been created to model these human conditions, and the pathways by which these mutant genes cause disease are being dissected. These studies may eventually lead to new therapies for left ventricular hypertrophy.

Left ventricular hypertrophy (LVH), or thickening of the heart wall, is diagnosed in humans by echocardiography, a noninvasive technique. Perhaps the most common form of LVH occurs secondary to high blood pressure, although LVH is also relatively common in the absence of hypertension or other causative conditions. LVH is found in 1 person in 500 in the general population. Many of these individuals have LVH because they have an inherited gene defect. Over the past decade we have begun to dissect the genetic mechanisms that lead to LVH.

Familial hypertrophic cardiomyopathy (HCM) is an autosomal-dominant disorder that is caused by defects in cardiac muscle. Over the past several years, we and others have identified mutations in 10 sarcomere protein genes that cause HCM. We have used embryonic stem cell technology to make four murine models of this condition and have studied the effect of known mutations on mouse physiology. These studies help to explain how sarcomere protein gene mutations cause the clinical features associated with HCM and to explain the variation in clinical features that is seen among affected individuals bearing the same mutation. We have begun to define the genetic and/or environmental factors that exacerbate this condition. A better understanding of the pathway from sarcomere protein gene mutation to cardiac hypertrophy will lead to therapeutic approaches to this condition.

HCM is characterized by unexplained myocardial hypertrophy. Clinical manifestations of the disorder can include syncope, arrhythmias, congestive heart failure, and sudden death. Previous studies by our lab have demonstrated that missense mutations in the β-cardiac myosin heavy-chain (MHC) gene cause HCM in about 30 percent of affected individuals. We now know that mutations in cardiac troponin I, actin, essential myosin light chain, regulatory myosin light chain, cardiac troponin T, α-tropomyosin, myosin-binding protein C (MyBP-C), α-cardiac MHC, and titin can also cause this condition. All of the mutations that have been identified to date are dominant-acting mutations. Some mutations cause severe disease, while others cause more-benign forms of the disease.

The first identified HCM mutation alters a highly conserved arginine residue to a glutamine (Arg403Gln). This mutation causes HCM in more than 20 members of a large family from eastern Canada. The disease is as or more severe in these individuals than in individuals with any other HCM-causing mutation. However, a few of these Arg403Gln-bearing individuals have somewhat milder cardiac hypertrophy than other affected individuals in the same family. The average life expectancy of individuals bearing this mutation is about 40 years. By contrast, mutations in the sarcomere protein gene MyBP-C cause a milder form of the disease: many affected individuals do not show clinical signs of HCM until the fourth or fifth decade of life, and their life expectancy is near normal. We have made mice bearing mutations in these two different genes.

Our analyses of the αMHC ^403/+ (bearing the cardiac myosin heavy-chain gene mutation Arg403Gln) and the MyBP-C ^Δ/+ (bearing a truncation mutation in the cardiac MyBP-C gene) mice have defined the effects of these mutations on cardiac development and function. Both strains of mice are viable and have been followed for several years. Their blood pressure and heart rates are normal or near normal. These animals, which have been studied by echocardiography, do not develop significant cardiac hypertrophy until age 30 weeks. Histologic examination of sections from heart walls of 5-, 15-, and 30-week animals demonstrates that both strains have significant myocyte disarray, fibrosis, and myocyte hypertrophy, analogous to the human condition. In mice, as in humans, the Arg403Gln cardiac myosin heavy-chain missense mutation causes more severe disease than truncation of cardiac MyBP-C. All αMHC ^403/+ mice (bred onto the 129SvEv background) develop cardiac hypertrophy by age 30 weeks; however, the MyBP-C ^Δ/+ mice do not develop obvious hypertrophy until they are 2 years old. Furthermore, we have used the murine HCM models to demonstrate that pressure overload (high blood pressure) induces LVH by a different pathway than sarcomere protein gene mutations.

Recently we have demonstrated that there is at least one polymorphic murine modifier gene that determines the hypertrophic response to the Arg403Gln mutation. When this mutation is bred onto the inbred 129SvEv background, 100 percent of the mice develop cardiac hypertrophy by age 30 weeks. When this mutation is bred onto an outbred genetic background (Black Swiss), however, about 50 percent of the mice develop cardiac hypertrophy by age 30 weeks, while 50 percent are spared. We have now bred this mutation onto five other genetic backgrounds (SJL, FVB, Balb/C, C57BL/6, C3H/HeJ). All heterozygous mice derived from mating 129SvEv with these strains develop hypertrophy. The modifier allele(s) from 129SvEv is dominant. Furthermore, we have demonstrated that C57BL/6 mice carrying the Arg403Gln mutation are protected from hypertrophy. The C57BL/6 modifier gene allele protects these mice from the hypertrophic response. We have mapped this modifier gene to murine chromosome 15 and are in the process of trying to identify it.

We have also demonstrated that Ca ²⁺ plays a critical role in transmitting the hypertrophic signal in αMHC ^403/+ myocytes. Much is known about the mechanisms that control Ca ²⁺ concentration in myocytes, because Ca ²⁺ plays a central role in the contractile process. Hence a variety of pharmacologic agents are available that can modulate Ca ²⁺ in these cells. We have screened several of these compounds for their ability to alter the hypertrophic response in the mutant mice. We have recently demonstrated that the hypertrophic response in these mice can be blocked by the drug diltiazem, an L-type Ca ²⁺ channel blocker that regulates the uptake of Ca ²⁺ into the cell. In the near future we hope to test the efficacy of this drug in treating individuals with sarcomere protein gene mutations.

Although sarcomere protein gene mutations are the most common inherited cause of LVH, there are other mechanisms that lead to this condition. More recently, we and others have demonstrated that mutations in PRKAG2 , the gene for the γ2 regulatory subunit of AMP-activated protein kinase, also lead to cardiac hypertrophy as well as conduction system disease. We have demonstrated that these mutations act by causing an accumulation of glycogen in the heart and in the conduction system. Mice that overexpress PRKAG2 cDNA bearing these mutations in the heart have been created. These mutant mice have the same cardiac features as humans expressing PRKAG2 mutations. We are investigating the mechanisms by which glycogen accumulation leads to cardiac hypertrophy and the mechanisms by which glycogen-loaded myocytes cause conduction system disease. In summary, we now know that there are at least two unrelated pathways by which the left ventricle can become hypertrophied. We are investigating the features of each of these pathways.

Recognition that there are independent pathways leading to cardiac hypertrophy has significant implications for patients, physicians, and basic researchers. We anticipate that treatment of LVH will eventually be predicated on the mechanism that causes the disease. We also expect that murine models of LVH will be useful for dissecting these pathways and suggesting therapies for affected individuals. Equally important, we believe that understanding the pathways that lead to cardiac hypertrophy will provide insights into the basic mechanisms that control the cardiac myocyte and the structure of the heart.

These studies were done in collaboration with Christine Seidman (HHMI, Brigham and Women's Hospital, Boston).

Some of this work was also supported by grants from the National Institutes of Health.

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