Endocrinology Vol. 143, No. 6 2045-2050
Copyright © 2002 by The Endocrine Society
Perspective: Cardiovascular Disease in the Postgenomic Era—Lessons Learned and Challenges Ahead
Jonathan A. Epstein,
Daniel J. Rader and
Michael S. Parmacek
Department of Medicine (J.A.E., D.J.R., M.S.P.) and, Center for Experimental Therapeutics (D.J.R.), University of Pennsylvania, Philadelphia, Pennsylvania 19104
Address all correspondence and requests for reprints to: Jonathan A. Epstein, University of Pennsylvania School of Medicine, Basic Research Building II/III, Curie Boulevard, Philadelphia, Pennsylvania 19104. E-mail: . epsteinj{at}mail.med.upenn.edu
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Abstract
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SUMMARY: Despite remarkable advances in medical therapeutics and technology over the last 40 yr, cardiovascular disease remains the leading cause of mortality in the United States. Elucidation of the human genome and the application of gene mapping techniques to kindreds harboring rare monogenic cardiovascular syndromes have provided fundamental insights into the pathogenesis of common cardiovascular diseases including hypertension, hypercholesterolemia, cardiomyopathy with and without conduction system disease, cardiac arrhythmias, and most recently congenital heart disease. These findings led to the unanticipated conclusion that common cardiovascular pathologies (e.g. cardiomyopathy, congenital heart disease, hypertension, cardiac arrhythmias) are united by association with distinct subsets of genes. In this review, the impact of these data on the molecular pathogenesis and development of future therapies for cardiomyopathy, congenital heart disease, and atherosclerosis are highlighted. In addition, the application and limitations of evolving genetic and genomic technologies to acquired and/or multigenic cardiovascular states including atherosclerosis and high density lipoprotein (HDL) metabolism is discussed.
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Introduction
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Over the last 40 yr, the age-adjusted mortality of cardiovascular disease has decreased significantly in the United States (1). This decrease in mortality resulted from many factors including the identification of cardiovascular risk factors, development of new classes of pharmacological agents that modify cardiovascular risk factors and treat acute coronary syndromes, and the development and application of new medical technologies (1). However, despite these advances, cardiovascular disease remains the number one cause of morbidity and mortality in the United States and the prevalence of cardiovascular disease on a worldwide basis is projected to increase over the next 20 yr (1). Moreover, certain common diseases, including diabetic vascular disease, are increasing in prevalence, often prove to be medically refractory, and not surprisingly, remain poorly understood at a molecular level.
The application of molecular biology and medical genetics has profoundly impacted the practice of cardiovascular medicine over the last 20 yr. In a series of seminal studies, Brown and Goldstein (2) studied patients suffering from a rare genetic disease, familial hypercholesterolemia, and elucidated the molecular basis of cholesterol regulation and homeostasis. These research studies ultimately led to development of a new class of drugs, the 3-hydroxy-3-methylglutasyl coenzyme A reductase inhibitors or statins, which reduce circulating low density lipoprotein (LDL) cholesterol levels and reduce cardiovascular morbidity and mortality in patients at risk for cardiovascular disease (3). Over the past 10 yr, elucidation of the genetic basis of rare monogenic diseases affecting the cardiovascular system has provided fundamental insights into the molecular pathogenesis of hypertension, hypertrophic and dilated cardiomyopathies, cardiac rhythm disturbances and, most recently, some forms of congenital heart disease. In this review, we will discuss how identification of genes responsible for rare monogenic disorders has been translated to increase understanding of relatively common multigenic and/or acquired cardiovascular diseases and how these studies may impact future therapies.
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Congestive heart failure
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Hypertrophic cardiomyopathy and sarcomere function.
Familial hypertrophic cardiomyopathy (HCM) is a relatively common congenital form of cardiomyopathy characterized by unique pathophysiology including thickened left ventricular wall dimensions (classically asymmetric septal hypertrophy), enhanced contractile function with poor ventricular relaxation, and outflow tract obstruction (4). At the cellular level, cardiac myocyte hypertrophy and myofibrillar disarray are observed. HCM follows a variable clinical course (5, 6). While many patients experience no clinical sequelae, others experience debilitating symptoms related to diastolic dysfunction, outflow tract obstruction, or life-threatening cardiac arrhythmias. HCM and is one of the most common causes of sudden death in young athletes (7). HCM is inherited as an autosomal dominant trait though sporadic cases are frequently observed. Gene mapping studies have reinforced the general hypothesis that HCM is a disease of the cardiac sarcomere or myofibrillar apparatus (8). As shown in Table 1
, mutations in eight different components of the sarcomere, including ß-myosin heavy chain, myosin essential light chain, myosin regulatory light chain, myosin binding protein C, 
-tropomyosin, troponin T, and troponin I, have been identified in patients diagnosed with autosomal dominant familial HCM.
Dilated cardiomyopathy (DCM) and the cytoskeletal and sarcolemmal apparatus.
DCM is the most common form of congestive heart failure (4, 9). Idiopathic DCM is the most commonly diagnosed form of the disease though DCM is also associated with infection, toxins including alcohol and the peripartum state (for review see Ref. 10). It is now recognized that up to 40% of patients with DCM have one or more affected family members suggesting that genetics may predispose to this frequently observed condition (11). DCM is characterized by poor systolic function and ventricular dilatation without a significant increase in wall thickness (10). At the cellular level, myocyte hypertrophy is observed with myocyte loss and accumulation of extracellular matrix (12). Autosomal dominant DCM is the most common familial form with ten loci mapped for pure DCM and an additional five loci mapped for families with DCM and cardiac conduction system disease. An X-linked form of DCM associated with Duchenne/Becker muscular dystrophy has also been described (13). The genes associated with DCM are associated with the cytoskeleton, though mutations in genes encoding muscle cell membrane or sarcolemmal proteins and myofibrillar proteins at sites of attachment to the cytoskeleton have also been described (9, 13). Specific mutations have been identified in the genes encoding desmin, 
-sarcoglycan, ß-sarcoglycan, -cardiac actin, and titin (14) (9). Animal studies suggest that these mutations cause DCM by decreasing force transmission across cardiac myocytes.
Calcium-activated signaling pathways and cardiomyopathies.
Accumulating evidence suggests that common molecular pathways may contribute to cardiac myocyte hypertrophy observed in hypertrophic and dilated cardiomyopathies. Though the initiating events in this pathway remain to be elucidated, transgenic and gene knockout studies strongly suggest that intracellular calcium-regulated signaling pathways including calcium activation of the protein phosphatase calcineurin and calmodulin may play a central role in the pathogenesis of cardiac myocyte hypertrophy (15, 16). As shown in Fig. 1, activated calcineurin dephosphorylates nuclear factor of activated T cells, a transcription factor, that when activated translocates to the nucleus to activate a set of genes associated with cardiac myocyte hypertrophy. A second calcium-mediated pathway involves activation of calcium and calmodulin-activated protein kinase (CaMK), or a related kinase, that activates the MADS box transcription factor, myocyte enhancer factor-2 (MEF2) (17). MEF2 in turn recruits histone deacetylases (HDACs) that function to repress the hypertrophic genetic program. This repression is relieved by CaMK phosphorylation of HDACs, which results in nuclear export and concomitant activation of MEF2 targets (18). Animal studies support the argument that these pathways are contributory in the development of cardiac hypertrophy in man, and several animal models with defects in specific components of these pathways produce dramatic cardiac hypertrophy. The development of new therapeutic agents for the treatment of cardiac hypertrophy and heart failure are based on these results and include agents related to cyclosporin and FK506 that inhibit calcineurin activity. Elucidation of these and other calcium-dependent and -independent pathways will provide insights into other potential therapeutic targets.
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Figure 1. Proposed molecular pathways responsible for cardiac hypertrophy. Calcium signaling results in activation of the phosphatase calcineurin and the kinase CaMK. Calcineurin dephosphorylates nuclear factor of activated T cells, which results in its nuclear translocation, association with GATA4, and transcription of the hypertrophic gene program. Calcium activation of CaMK results in phosphorylation of HDAC, which causes it to dissociate from MEF2 and to exit the nucleus, thus relieving HDAC inhibition of MEF2-mediated gene transcription. These pathways offer potential for novel therapeutic interventions related to the treatment of hypertrophy and heart failure.
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Molecular insights into congenital heart disease
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Transcription factors and congenital heart disease.
Congenital heart disease is the most common birth defect in humans occurring as frequently as 1 in 150 live births. Most forms of congenital heart defects relate to abnormal morphogenesis and patterning during development. Environmental and dietary influences on heart formation are well established and will not be reviewed here. Genetic etiologies of several classes of congenital heart disease have recently been described in detail (19, 20, 21, 22). To date, most genetic causes of structural heart disease in children have been attributed to mutations in transcription factor genes that govern critical aspects of patterning and morphogenesis. Table 1
shows a summary of transcription factor gene mutations implicated in congenital heart disease.
NKX2.5 encodes a transcription factor that is found in the nucleus of cardiac myocytes and regulates transcription of downstream cardiac-specific genes. An important conceptual advance related to NKX2.5 function in humans arose from the convergence of independent investigations. While developmental studies in murine, Xenopus, and Drosophila models were elucidating functions for Nkx2.5 in the embryonic heart, human genetic studies revealed that mutations in NKX2.5 cause atrial septal defects and conduction abnormalities (23). Subsequently, a wide array of mutations have been identified in other patients with congenital heart defects ranging from AV conduction abnormalities to ventricular septal defects and Tetralogy of Fallot (24, 25). Cardiac disorders associated with NKX2.5 mutations have either been sporadic or inherited in an autosomal dominant pattern.
Congenital heart disease and the cardiac neural crest.
DiGeorge syndrome is the most common chromosome deletion syndrome and is characterized by congenital heart disease and other neural crest-related abnormalities (14, 26, 27). These include deficiency of parathyroid function due to decreased calcitonin-containing C cells, and newborns with DiGeorge syndrome often present with hypocalcemia. Thymus and thyroid defects can also occur. Most affected individuals have deletions on chromosome 22q11 that commonly include a 1.5-megabase region termed the DiGeorge critical region. It remains unclear whether all aspects of DiGeorge syndrome in man can be attributed to deficiency of a single gene, or whether deficiency of multiple genes in this region is required to produce the entire syndrome. Interestingly, many patients with congenital heart defects, but without other characteristics of DiGeorge syndrome, also have deletions on chromosome 22q11 (28, 29).
Significant advances toward identification of the genetic etiology of this syndrome have come from studies in mice. Hemizygous deletion of a region of murine chromosome 16 homologous to the DiGeorge critical region recapitulates many of the characteristics of DiGeorge syndrome including cardiac, thymus, and parathyroid defects (30, 31, 32). A series of transgenic rescue experiments identified a single gene, Tbx1, as a critical contributor to these defects (31, 32, 33). Heterozygous Tbx1 deficiency in mice produces congenital heart disease. Nevertheless, missense mutations in TBX1 have not yet been identified in patients with DiGeorge syndrome or in patients with isolated congenital heart disease (31, 34).
Nkx2.5 and Tbx1 are both transcription factors that play a role in embryonic patterning by regulating sets of cardiac-specific genes. Other members of the T-box family have also been implicated in cardiac development and in congenital heart disease. Mutations in TBX5 cause Holt-Oram syndrome (35), which includes cardiac and limb defects, and mutations in a closely related gene, TBX3, cause ulnar- mammary syndrome (36). Interestingly, Tbx5 is able to heterodimerize with Nkx2.5, suggesting a close relationship between genetic pathways regulating cardiac morphogenesis (37). Similarly, mutation of the human GATA4 gene, which encodes a zinc finger transcription factor controlling cardiac-restricted myofibrillar genes, is associated with congenital heart defects in humans (38). Together, these data are consistent with the unifying hypothesis that mutations in transcription factor genes account for most forms of structural congenital heart disease in humans.
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Lipid metabolism and atherosclerosis
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HDL and coronary heart disease (CHD).
Premature CHD often clusters in families (39). Some of the heritability of CHD can be explained by mutations in genes regulating LDL metabolism and by other traditional risk factors that have a genetic component, such as dyslipidemia, hypertension, and diabetes mellitus. However, much of the inherited risk cannot be explained, indicating that there must be additional genetic factors that predispose to premature CHD (40). The search for additional genetic factors that predispose to premature (and mature) CHD is well underway, and the reader is referred to an excellent recent review on this subject (41). The remainder of this review will focus on the genetics and biology of HDL as an example of how applied genetics and genomics has already provided novel insights into a complex disease process such as atherosclerosis.
Plasma levels of HDL cholesterol are strongly inversely associated with cardiovascular risk (42). Inherited low levels of HDL cholesterol (HDL-C) are frequently found in patients with premature CHD (43), and genetic syndromes of high HDL-C are often associated with longevity and decreased CHD (44). Genes involved in the metabolism of HDL represent potential targets for the development of drug therapies. As shown in Fig. 2, the structure and metabolism of HDL is complex. HDL is composed of lipids as well as apolipoproteins, the major one of which is ApoA-I (45, 46). ApoA-I is synthesized and secreted by both the intestine and the liver. HDL is thought to protect against atherosclerosis primarily by promoting efflux of excess cholesterol from cells in the arterial wall and returning that cholesterol to the liver for excretion into the bile, a process known as "reverse cholesterol transport" (47, 48). Lipid-poor ApoA-I interacts with peripheral cells and acquires cholesterol through a transport process facilitated by the cellular protein ATP-binding cassette protein A1 (ABCA1). Unesterified cholesterol is esterified to cholesteryl ester within the HDL particle by the enzyme lecithin:cholesterol acyltransferase (LCAT). Cholesteryl ester is either selective taken up by the liver through the HDL receptor scavenger receptor BI or transferred to ApoB-containing lipoproteins through the action of the cholesteryl ester transfer protein (CETP). Conversely, the phospholipid transfer protein mediates transfer of phospholipids from ApoB-containing lipoproteins to HDL. Hydrolysis of triglycerides (TGs) in TG-rich lipoproteins by lipoprotein lipase (LPL) results in transfer of lipids and apolipoproteins to HDL. Hepatic lipase (HL) and probably endothelial lipase hydrolyze HDL triglyceride and phospholipids, generating smaller lipid-depleted HDL particles. A great deal of our knowledge about the importance of several of these genes in human biology is based on the study of rare genetic deficiency disorders.
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Figure 2. A schematic diagram depicting HDL metabolism. Lipid-poor ApoA-I acquires free cholesterol from peripheral cells through an efflux process facilitated by the cellular protein ABCA1. Free cholesterol is converted to cholesteryl ester within the HDL particle by the enzyme LCAT. HDL-CE can be taken up selectively by the liver through the action of the scavenger receptor class BI and targeted for excretion in the bile. HDL-CE can also be selectively transferred to ApoB-containing lipoproteins in exchange for TG through the action of CETP. This cholesteryl ester can then be returned to the liver via the LDL receptor. The phospholipid transfer protein transfers phospholipids from ApoB-containing lipoproteins to HDL. HL hydrolyzes HDL triglyceride and phospholipid, generating smaller HDL particles. Endothelial lipase also participates in the remodeling of HDL to smaller particles. Lipid-poor ApoA-I is rapidly catabolized via the kidneys.
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Single gene disorders causing low HDL cholesterol levels.
Genetic absence of ApoA-I due to deletions is associated with markedly reduced HDL-C levels and premature CHD (49). Tangier disease is a rare genetic disease caused by mutations in ABCA1, resulting in impaired removal of excess cholesterol from cells and rapid catabolism of poorly lipidated ApoA-I. It is characterized by extremely low HDL-C (<5 mg/dl) and cholesterol accumulation in the reticuloendothelial system resulting in hepatosplenomegaly, intestinal mucosal abnormalities, and enlarged orange tonsils (49). Heterozygotes for ABCA1 mutations have low levels of HDL-C (15–35 mg/dl), suggesting that this may be a relatively common cause of low HDL (50). Patients with ABCA1 mutations appear to have an increased risk of premature CHD (50). The ABCA1 knockout mouse has phenotypic features that resemble the human disease (51). Based on the phenotype of this rare genetic disease, up-regulation of ABCA1 is a pharmacologic approach that is under active investigation. LCAT deficiency in humans is also rare and results in markedly diminished formation of HDL cholesteryl esters and reduced levels of both HDL-C and ApoA-I (52); LCAT knockout mice have similar features (53). However, LCAT deficiency does not appear to be associated with premature CHD in humans.
Single gene disorders causing high HDL cholesterol levels.
As noted above, CETP mediates transfer of cholesteryl ester from HDL to ApoB-containing lipoproteins (46). In humans, genetic homozygous CETP deficiency is associated with markedly increased HDL-C levels (54) and is limited primarily to Japan. The relationship between CETP deficiency and CHD is not firmly established. However, because CETP deficiency is associated with high HDL-C in humans, inhibition of CETP is a pharmacologic approach that is under active clinical development. HL is a lipolytic enzyme that is known to influence HDL metabolism as well as the metabolism of remnant ApoB-containing lipoproteins (55). Hepatic lipase deficiency in humans is rare and associated with modestly elevated HDL-C levels as well as elevated levels of remnant lipoproteins (56). Hepatic lipase deficiency in mice is associated with modestly elevated HDL-C and reduced atherosclerosis (57). Most subjects with inherited high HDL-C levels do not yet have a defined molecular etiology.
Genomic approaches to the study of HDL metabolism.
Because HDL-C is a quantitative trait, approaches to the genetics that underlie its variation are not limited to case-control studies of patients with low or high HDL-C levels, but can also be approached in large randomly selected populations. Single nucleotide polymorphisms in candidate genes such as those known to be associated with HDL metabolism can be assessed in large populations and the HDL-C levels in groups of different genotypes can be compared. If a specific gene locus contributes to variation in HDL-C (even if it doesn’t cause an extreme phenotype of low or high HDL-C), it may be uncovered with this type of approach. Furthermore, HDL-C can be used as a quantitative trait for linkage studies using a quantitative trait locus approach. A recent publication used this approach in a cohort of Mexican-Americans to identify a locus on chromosome 9p that is linked to a quantitative trait locus for HDL-C (58). Ultimately, it is likely that we will find that many genes have minor contributions to variation in HDL-C levels. The identification of these genes may lead to the development of new therapies, just as the discovery of ABCA1 deficiency (Tangier disease) and CETP deficiency have already done.
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Future application of genomic technologies to cardiovascular diseases
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Over the past decade, the application of molecular genetic and genomic technologies has led to fundamentally important advances in understanding the pathogenesis of cardiovascular diseases. Many of the advances have come through the identification and characterization of genes responsible for rare cardiovascular syndromes. This generally involved the application of gene mapping technologies developed in the 1980s to DNA samples collected from syndromic family members with monogenic patterns of inheritance. Identification of the genes responsible for these rare familial forms of cardiovascular disease proved to be relevant to nonsyndromic patients with common pathologies. These findings have led to the unanticipated conclusion that common cardiovascular pathologies (e.g. cardiomyopathy, congenital heart disease, hypertension, cardiac arrhythmias) are united by association with distinct subsets of genes. These include genes encoding subcellular structures (e.g. sarcomere, cytoskeleton, channels), metabolic regulatory enzymes (e.g. renin-angiotensin system, cholesterol metabolic pathway), or intracellular signaling pathways (e.g. calcineurin, CaMK). Indeed, in cases where pharmacological agents directed toward these pathways are available, they have generally proven to be efficacious in patient populations with common cardiovascular diseases including hypertension (e.g. the angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists) and coronary artery disease (i.e. the statins).
Yet despite these advances, cardiovascular disease remains the leading cause of death in the United States, and morbidity from cardiovascular disease will become the leading cause of death on a worldwide basis within 20 yr (1). Moreover, the pathogenetic bases of many common cardiovascular diseases, including diabetic vascular disease, remain poorly understood and therapies are limited. In the near term, drugs and bioactive molecules are in development that directly activate or inhibit the molecular pathways responsible for monogenic cardiovascular syndromes. For example, compounds are currently being tested that sensitize the sarcomere to calcium in patients with end-stage heart failure and cardiomyopathy or raise HDL in patients at risk for CHD. It is noteworthy that these therapeutic interventions have lagged 10–20 yr behind the discovery of gene mapping technologies and elucidation of the human genome. Therefore, we anticipate that within 10–20 yr advances in bioinformatic and genomic technologies will make it possible to identify novel genes (and molecular pathways) that play important roles in the pathogenesis of multigenic acquired and/or heritable diseases, including atherosclerosis and diabetic vascular disease. These postgenomic era studies, in turn, will lead to novel therapeutic targets and primary cardiovascular disease prevention.
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Footnotes
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Abbreviations: ABCA1, ATP-binding cassette protein A1; Apo, apoliprotein; CaMK, calmodulin-activated protein kinase; CETP, cholesteryl ester transfer protein; CHD, coronary heart disease; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HDAC, histone deacetylases; HDL, high density lipoprotein; HDL-C, HDL cholesterol; HL, hepatic lipase; LCAT, lecithin cholesterol acyltransferase; LDL, low density lipoprotein; MEF2, myocyte enhancer factor-2; TG, triglyceride.
Received March 29, 2002.
Accepted for publication March 29, 2002.
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Abstract
Introduction