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Review ArticleGenomic Medicine

Cardiovascular Disease

List of authors.
  • Elizabeth G. Nabel, M.D.

Introduction

Cardiovascular disease, including stroke, is the leading cause of illness and death in the United States. There are an estimated 62 million people with cardiovascular disease and 50 million people with hypertension in this country.1 In 2000, approximately 946,000 deaths were attributable to cardiovascular disease, accounting for 39 percent of all deaths in the United States.2 Epidemiologic studies and randomized clinical trials have provided compelling evidence that coronary heart disease is largely preventable.3 However, there is also reason to believe that there is a heritable component to the disease. In this review, I highlight what we know now about genetic factors in cardiovascular disease. As future genomic discoveries are translated to the care of patients with cardiovascular disease, it is likely that what we can do will change.

Lessons Learned from Monogenic Cardiovascular Disorders

Our understanding of the mechanism by which single genes can cause disease, even though such mechanisms are uncommon, has led to an understanding of the pathophysiological basis of more common cardiovascular diseases, which clearly are genetically complex. This point can be illustrated by a description of the genetic basis of specific diseases.

Elevated Levels of Low-Density Lipoprotein Cholesterol and Coronary Artery Disease

Figure 1. Figure 1. The Basic Components of Cholesterol Synthesis and Excretion.

Low-density lipoprotein (LDL) molecules are composed of a cholesteryl ester core surrounded by a coat made up of phospholipid and apolipoprotein B-100. The liver secretes LDLs as larger precursor particles called very-low-density lipoproteins, which contain triglycerides and cholesterol esters. Capillaries in muscle and adipose tissue remove the triglycerides, and the lipid particle is modified into an LDL, with its cholesteryl ester core and apolipoprotein B-100 coat. LDLs circulate in the plasma, and the apolipoprotein B-100 component binds to LDL receptors on the surface of hepatocytes. Through receptor-mediated endocytosis, receptor-bound LDLs enter hepatocytes and undergo degradation in lysosomes, and the cholesterol remnants enter a cellular cholesterol pool. A negative-feedback loop regulates the number of LDL receptors. A rise in the hepatocyte cholesterol level suppresses the transcription of LDL-receptor genes, and LDL is retained in the plasma. Conversely, a decrease in hepatic cholesterol stimulates the transcription of LDL-receptor genes, removing LDL from the plasma. This mechanism accounts for the LDL-lowering action of the statins, which inhibit an enzymatic step in hepatic cholesterol synthesis. Four monogenetic diseases that elevate plasma LDL are highlighted in yellow. ABC denotes ATP-binding cassette.

Table 1. Table 1. Monogenic Diseases That Elevate Plasma Levels of Low-Density Lipoprotein (LDL) Cholesterol.

Low-density lipoprotein (LDL) is the major cholesterol-carrying lipoprotein in plasma and is the causal agent in many forms of coronary heart disease (Figure 1). Four monogenic diseases elevate plasma levels of LDL by impairing the activity of hepatic LDL receptors, which normally clear LDL from the plasma (Table 1). Familial hypercholesterolemia was the first monogenic disorder shown to cause elevated plasma cholesterol levels. The primary defect in familial hypercholesterolemia is a deficit of LDL receptors, and more than 600 mutations in the LDLR gene have been identified in patients with this disorder.5 One in 500 people is heterozygous for at least one such mutation, whereas only 1 in a million is homozygous at a single locus. Those who are heterozygous produce half the normal number of LDL receptors, leading to an increase in plasma LDL levels by a factor of 2 or 3, whereas LDL levels in those who are homozygous are 6 to 10 times normal levels. Homozygous persons have severe coronary atherosclerosis and usually die in childhood from myocardial infarction.

Deficiency of lipoprotein transport abolishes transporter activity, resulting in elevated cholesterol absorption and LDL synthesis. For example, mutations in the APOB-100 gene, which encodes apolipoprotein B-100, reduce the binding of apolipoprotein B-100 to LDL receptors and slow the clearance of plasma LDL, causing a disorder known as familial ligand-defective apolipoprotein B-100.6 One in 1000 people is heterozygous for one of these mutations; lipid profiles and clinical disease in such persons are similar to those of persons heterozygous for a mutation causing familial hypercholesterolemia.

Sitosterolemia, a rare autosomal disorder, results from loss-of-function mutations in genes encoding two ATP-binding cassette (ABC) transporters, ABC G5 and ABC G8,7,8 which act in concert to export cholesterol into the intestinal lumen, thereby diminishing cholesterol absorption. Autosomal recessive hypercholesterolemia is extremely rare (prevalence, <1 case per 10 million persons). The molecular cause is the presence of defects in a putative hepatic adaptor protein, which then fails to clear plasma LDL with LDL receptors.9 Mutations in the gene encoding that protein (ARH) elevate plasma LDL to levels similar to those seen in homozygous familial hypercholesterolemia.

In the majority of people with hypercholesterolemia in the general public, the condition is attributable to high-fat diets and poorly understood susceptibility and modifier genes. Study of the monogenic disorders, noted above, that disrupt LDL-receptor pathways has clarified the importance of cholesterol synthesis and excretion pathways in the liver and has highlighted molecular targets for regulating plasma cholesterol levels. For example, statin therapy for hypercholesterolemia is based on an understanding of the molecular basis of that disorder.

Hypertension

Table 2. Table 2. Monogenic Diseases That Elevate or Lower Blood Pressure. Figure 2. Figure 2. Molecular Mechanisms Mediating Salt Reabsorption in the Kidney and Associated Monogenic Hypertensive Diseases.

The kidney filters more than 180 liters of plasma (containing 23 moles of salt) daily and reabsorbs more than 99 percent of the filtered sodium. The proximal tubule of the nephron reabsorbs about 60 percent of the filtered sodium, primarily by sodium–hydrogen ion exchange. The thick ascending loop of Henle absorbs about 30 percent by sodium–potassium–chloride (Na+–K+–2Cl) cotransporters. The distal convoluted tubule reabsorbs about 7 percent by sodium–chloride cotransporters, and the remaining 3 percent of the filtered sodium is handled by epithelial sodium channels in the cortical collecting tubule. The renin–angiotensin system tightly regulates the activity of the epithelial sodium channels. Decreased delivery of sodium to the loop of Henle leads to renin secretion by the juxtaglomerular apparatus of the kidney. Renin acts on the circulating precursor angiotensinogen to generate angiotensin I, which is converted in the lungs to angiotensin II by angiotensin-converting enzyme. Angiotensin II binds to its specific receptor in the adrenal glomerulosa, stimulating aldosterone secretion. Aldosterone binds to its receptor in the distal nephron, leading to increased activity of the epithelial sodium channels and sodium reabsorption. Monogenetic diseases that alter blood pressure are shown in yellow. (Adapted from Lifton et al.,11 with the permission of the publisher.)

Hypertension is the most common disease in industrialized nations, with a prevalence above 20 percent in the general population. It imparts an increased risk of stroke, myocardial infarction, heart failure, and renal failure; many clinical trials have shown that reductions in blood pressure reduce the incidence of stroke and myocardial infarction.10 Multiple environmental and genetic determinants complicate the study of blood-pressure variations in the general population. In contrast, the investigation of rare mendelian forms of blood-pressure variation in which mutations in single genes cause marked extremes in blood pressure has been very informative (Table 2). These mutations, which impair renal salt handling, provide a molecular basis for understanding the pathogenesis of hypertension (Figure 2).11

Investigation of families with severe hypertension or hypotension has identified mutations in genes that regulate these pathways. Pseudohypoaldosteronism type II is an autosomal dominant disorder characterized by hypertension, hyperkalemia, increased renal salt reabsorption, and impaired potassium- and hydrogen-ion excretion. Wilson and colleagues identified two genes causing pseudohypoaldosteronism type II; both encode proteins in the WNK family of serine–threonine kinases.12 Mutations in WNK1 are intronic deletions on chromosome 12p. Missense mutations in hWNK4, on chromosome 17, also cause pseudohypoaldosteronism type II. Immunofluorescence assays have shown that the proteins localize to distal nephrons and may serve to increase transcellular chloride conductance in the collecting ducts, leading to salt reabsorption, increased intravascular volume, and diminished secretion of potassium and hydrogen ions.

Abnormalities in the activity of aldosterone synthase produce hypertension or hypotension. Glucocorticoid-remediable aldosteronism is an autosomal dominant trait featuring early-onset hypertension with suppressed renin activity and normal or elevated aldosterone levels. This form of aldosteronism is caused by gene duplication arising from an unequal crossover between two genes that encode enzymes in the adrenal-steroid biosynthesis pathway (aldosterone synthase and 11β-hydroxylase).13,14 The chimeric gene encodes a protein with aldosterone synthase activity that is ectopically expressed in the adrenal fasciculata under the control of corticotropin rather than angiotensin II. Normal cortisol production leads to constitutive aldosterone secretion, plasma-volume expansion, hypertension, and suppressed renin levels. Mutations that cause a loss of aldosterone synthase activity impair renal salt retention and the secretion of potassium and hydrogen ions in the distal nephrons and lead to severe hypotension as a result of reduced intravascular volume.15

Mutations that alter renal ion channels and transporters give rise to Liddle's, Gitelman's, and Bartter's syndromes. Liddle's syndrome is an autosomal dominant trait characterized by early-onset hypertension, hypokalemic alkalosis, suppressed renin activity, and low plasma aldosterone levels due to mutations in the epithelial sodium channel.16,17 Loss-of-function mutations in the gene encoding the thiazide-sensitive sodium–chloride cotransporter in the distal convoluted tubules cause Gitelman's syndrome.18 Patients present in adolescence or early adulthood with neuromuscular signs and symptoms, a lower than normal blood pressure, a low serum magnesium level, and a low urinary calcium level. Bartter's syndrome can be produced by mutations in any of three genes required for normal salt reabsorption in the thick ascending loop of Henle; it can be distinguished from Gitelman's syndrome because it features increased urinary calcium levels and normal or reduced magnesium levels.19 In these inherited disorders, the net salt balance consistently predicts the blood pressure. As a result, new targets for antihypertensive therapy, including the epithelial sodium channel, other ion channels, and the WNK kinases, have been identified.

Thrombosis and Hemostasis

The blood-clotting system requires precise control of factors within and outside the coagulation cascade to prevent fatal bleeding or unwanted thrombosis. A common variant in the factor V gene, one encoding the substitution of glutamine for arginine at position 506 (Arg506Gln), prevents the degradation of factor V and promotes clot formation. This substitution, also known as factor V Leiden, has an allele frequency of 2 to 7 percent in European populations and has been observed in 20 to 50 percent of patients with venous thromboembolic disease.20-22 Factor V Leiden has incomplete penetrance and variable expression. Approximately 80 percent of persons who are homozygous for the mutation and 10 percent of those who are heterozygous will have thrombosis at some point in their lifetime.23,24 Factor V Leiden increases the risk of myocardial infarction, stroke, and venous thrombosis in men.25 In a subgroup of patients, thrombosis is associated with coinheritance of gene mutations that modify the factor V Leiden phenotype.26-29 Identification of gene modifiers is an area of active research and is essential for distinguishing, among persons who are heterozygous for factor V Leiden, the 10 percent in whom serious thrombosis will develop from the 90 percent who will have no symptoms.

Hypertrophic Cardiomyopathy

Figure 3. Figure 3. Mutations in Cardiac Sarcomeric Proteins That Cause Hypertrophic Cardiomyopathy.

Sarcomeric proteins that constitute the thick and thin filaments are shown. Sarcomere proteins that cause hypertrophic cardiomyopathy are labeled in yellow. (Adapted from Kamisago et al.32)

Hypertrophic cardiomyopathy is the most common monogenic cardiac disorder and the most frequent cause of sudden death from cardiac causes in children and adolescents.30 On the basis of the evaluation of echocardiograms from a large population of young persons, the incidence of hypertrophic cardiomyopathy has been estimated at approximately 1 in 500 persons.31 Hypertrophic cardiomyopathy is transmitted in an autosomal dominant pattern. Mutations in the genes encoding proteins of the myocardial-contractile apparatus cause the disease (Figure 3).32 Investigators have found multiple causative mutations in at least 10 different sarcomeric proteins,33 including cardiac β-myosin heavy chain, cardiac myosin-binding protein, cardiac troponin T, cardiac troponin I, α-tropomyosin, essential and regulatory light chains, and cardiac actin.

The pathologic features of hypertrophic cardiomyopathy consist of marked left ventricular hypertrophy, a thickened ventricular septum, atrial enlargement, and a small left ventricular cavity. Hypertrophy and disarray of the myocytes and interstitial fibrosis are present throughout the myocardium. The cardiac phenotype and clinical course of patients with hypertrophic cardiomyopathy are highly variable with regard to the pattern and degree of hypertrophy, the age at onset, and the clinical outcome. This variability is due partly to the different functions performed by mutant sarcomeric proteins. For example, a mutation in the gene encoding β-myosin heavy chain was the first mutation identified as a cause of familial hypertrophic cardiomyopathy,34 and more than 100 disease-causing mutations have since been detected.35

Many of the mutations affecting β-myosin heavy chain involve the head and head–rod junction of the heavy chain (Figure 3); some of these lead to pathologic changes early in life and produce severe hypertrophy. The clinical course varies even among persons with these mutations; an arginine-to-glutamine substitution at position 403 (Arg403Gln) and an arginine-to-tryptophan substitution at position 719 (Arg719Trp) predispose persons to sudden death and heart failure, whereas a phenylalanine-to-cysteine substitution at position 513 (Phe513Cys), a leucine-to-valine substitution at position 908 (Leu908Val), and a glycine-to-glutamic acid substitution at position 256 (Gly256Glu) cause less severe clinical disease.30,36 In contrast, mutations affecting cardiac myosin-binding protein produce late-onset hypertrophic cardiomyopathy and are associated with a more favorable prognosis.37

Numerous factors other than sarcomere mutations determine the pathologic features and clinical course of hypertrophic cardiomyopathy. The identical sarcomere mutation can cause different hypertrophic changes and clinical outcomes among kindreds, even within the same pedigree.38,39 Gene modifiers, the environment, sex, and acquired conditions (such as ischemic or valvular heart disease) may account for these differences. Studies examining polymorphisms in the genes encoding angiotensin II, aldosterone, and endothelin that may modify the phenotype of hypertrophic cardiomyopathy have not yielded consistent results.40-43 Interestingly, clinically affected persons with two mutations in the same gene or different genes (compound heterozygotes) have also been described.44

Cardiac Arrhythmias

Table 3. Table 3. Monogenic Diseases That Cause Susceptibility to Arrhythmias.

In 2001, about 450,000 people in the United States died suddenly from cardiac arrhythmias.1,2 Genetic factors may modify the risk of arrhythmia in the setting of common environmental risks. Arrhythmia-susceptibility genes have been identified and provide insight into the molecular pathogenesis of lethal and nonlethal arrhythmias (Table 3).45 The SCN5A gene encodes α subunits that form the sodium channels responsible for initiating cardiac action potentials.46 Mutations in SCN5A cause several familial forms of arrhythmias, including the long-QT syndrome, idiopathic ventricular fibrillation, and cardiac-conduction disease.47-51 A recently identified variant of the SCN5A gene, one with a transversion of cytosine to adenine in codon 1102, causing a serine-to-tyrosine substitution at position 1102 (S1102Y), has been associated with arrhythmia in black Americans.52 The variant allele (Y1102) accelerates sodium-channel activation and increases the likelihood of abnormal cardiac repolarization and arrhythmia. About 13 percent of blacks carry one Y1102 allele,52 which does not cause arrhythmia in most carriers. However, studies such as this point to the usefulness of molecular markers for the prediction of susceptibility to arrhythmia in persons with acquired or other genetic risk factors.

The HERG gene encodes α subunits that assemble with β subunits of minK-related peptide 1 (MiRP-1) to form cardiac IKr potassium channels, which facilitate a repolarizing potassium current.53,54 In turn, KVLQT1 α subunits assemble with minK β subunits to form cardiac IKs potassium channels, which facilitate a second repolarizing potassium current.55,56 These channels terminate the plateau phase of the action potential, causing myocyte repolarization. KVLQT1, HERG, minK, and MiRP-1 mutations result in a loss of function in the potassium channel that leads to the long-QT syndrome by reducing the repolarizing current. RyR2 encodes the ryanodine-receptor calcium-release channel required for excitation–contraction coupling. Gain-of-function mutations in SCN5A cause the long-QT syndrome, whereas loss-of-function mutations in the cardiac sodium channel cause idiopathic ventricular fibrillation. RyR2 mutations cause catecholaminergic ventricular tachycardia. Thus, inherited arrhythmia-susceptibility genes encode cardiac ion channels. Polymorphisms associated with inherited forms of the long-QT syndrome also increase the risk of acquired arrhythmias, such as drug-induced arrhythmias.57

Analysis of Complex Cardiovascular Traits

Although many single genes have been identified as the basis of monogenic cardiovascular disorders, fewer genes underlying common complex cardiovascular diseases have been identified.58 Multiple risk factors, gene–environment interactions, and an absence of rough estimates of the number of genes that influence a single trait all complicate study design. Current research on complex cardiovascular traits focuses on the identification of genetic variants that enhance the susceptibility to given conditions.

Gene Polymorphisms

Association studies provide a powerful approach to identifying DNA variants underlying complex cardiovascular traits and are very useful for narrowing a candidate interval identified by linkage analysis. Improved genotyping techniques, such as genome-wide scanning of single-nucleotide polymorphisms59-61 and mapping of single-nucleotide polymorphisms identifying common haplotypes in the human genome, are facilitating association studies of loci spanning the entire genome. This point can be illustrated by recent examples of case–control studies that used high-throughput genomic techniques to investigate genetic variants in a large number of candidate genes for myocardial infarction, premature coronary artery disease, and heart failure.

Polymorphism-association studies compare the prevalence of a genetic marker in unrelated people with a given disease to the prevalence in a control population. Polymorphism-association studies of cardiovascular disease should be interpreted with caution when biologic plausibility has not been determined or is not known. Single-nucleotide polymorphisms in linkage disequilibrium may be functionally important, or alternatively, the polymorphism may just be a marker for another, yet to be identified, disease-causing sequence variant.

To determine genetic variants in myocardial infarction, Yamada and colleagues examined the prevalence of 112 polymorphisms in 71 candidate genes in patients with myocardial infarction and control patients in Japan.62 The analysis revealed one statistically significant association in men (a cytosine-to-thymine polymorphism at nucleotide 1019 in the connexin 37 gene) and two in women (the replacement of four guanines with five guanines at position –668 [4G–668/5G] in the plasminogen-activator inhibitor type 1 gene and the replacement of five adenines with six adenines at position –1171 [5A–1171/6A] in the stromelysin-1 gene), suggesting that these single-nucleotide polymorphisms may confer susceptibility to myocardial infarction in this population.

The GeneQuest study investigated 62 candidate genes in patients and their siblings with premature myocardial infarction (men <45 years old and women <50 years old).63 In this study, a case–control approach comparing genomic sequences in 72 single-nucleotide polymorphisms between persons with premature coronary artery disease and members of a control population identified three variants in the genes encoding thrombospondin-4, thrombospondin-2, and thrombospondin-1 that showed a statistical association with premature coronary artery disease. The biologic mechanisms by which these variants in thrombospondin proteins may lead to early myocardial infarction have yet to be identified.

Small and colleagues described an association between two polymorphisms in adrenergic-receptor genes and the risk of congestive heart failure in black Americans.64 Genotyping at two loci — one encoding a variant α2c-adrenergic receptor (involving the deletion of four amino acids [α2cDel322–325]) and the other encoding a variant β1-adrenergic receptor (with a glycine at amino acid position 389 [β1Arg389]) — was performed in patients with heart failure and in controls. The α2cDel322–325 variant, when present alone, conferred some degree of risk, whereas the β1Arg389 variant alone did not. However, black patients who were homozygous for both variants had a markedly increased incidence of heart failure. The presence of the α2cDel322–325 variant is associated with norepinephrine release at cardiac sympathetic-nerve synapses, and the presence of the β1Arg389 variant may increase the sensitivity of cardiomyocytes to norepinephrine. The findings of this study suggest that the α2cDel322–325 and β1Arg389 receptors act synergistically in blacks to increase the risk of heart failure. Genotyping at these two loci may identify persons at risk for the development or progression of heart failure and may predict their response to therapy.

Table 4. Table 4. Examples of Polymorphisms in Genes That Alter Cardiovascular Function and Responses to Drugs.

These studies highlight the importance of cardiovascular genotyping to establish a molecular diagnosis, to stratify patients according to risk, and especially to guide therapy. The field of pharmacogenetics — that is, the use of genome-wide approaches to determine the role of genetic variants in individual responses to drugs — has provided data showing that genetic polymorphisms of proteins involved in drug metabolism, transporters, and targets have important effects on the efficacy of cardiovascular drugs65,66 (Table 4). For example, sequence variants in the ADRB2 gene, which encodes the β2-adrenergic receptor, influence the response to β2-agonist drugs.79,87 Two common polymorphisms of the receptor, an arginine-to-glycine substitution at codon 16 (Gly16) and a glycine-to-glutamine substitution at codon 27 (Glu27), are associated with increased agonist-induced desensitization and increased resistance to desensitization, respectively. There is marked linkage disequilibrium between the polymorphisms at codons 16 and 27, with the result that persons who are homozygous for Glu27 are also likely to be homozygous for Gly16, whereas those who are homozygous for Gly16 may be homozygous for Gln27 or Glu27 or heterozygous at codon 27.

In a study that examined the effects of agonist-induced desensitization in the vasculature mediated by these polymorphisms, the investigators found that persons who were homozygous for Arg16 had nearly complete desensitization, as determined by measures of venodilation in response to isoproterenol, in contrast to persons homozygous for Gly16 and regardless of the codon 27 status.79 Similarly, persons homozygous for Gln27 had higher maximal venodilation in response to isoproterenol than those homozygous for Glu27, regardless of their codon 16 status. These data demonstrate that polymorphisms of the β2-adrenergic receptor are important determinants of vascular function. This study also highlights the importance of taking into account haplotypes, rather than a single polymorphism, when defining biologic function.

Gene-Expression Profiling

Functional genomics, which is the study of gene function by means of parallel measurements of expression within control and experimental genomes, commonly involves the use of microarrays and serial analysis of gene expression. Microarrays are artificially constructed grids of DNA in which each element of the grid acts as a probe for a specific RNA sequence; each grid holds a DNA sequence that is a reverse complement to the target RNA sequence. Measurements of gene expression by means of microarrays are useful tools to establish molecular diagnoses, dissect the pathophysiologic features of a disease, and predict patients' response to therapy.88 Microarray analyses have been used to define a role for proliferative and inflammatory genes in the development of restenosis after the placement of coronary-artery stents. Zohlnhöfer and colleagues identified clusters of differentially expressed genes from coronary-artery neointima and peripheral-blood cells from patients with restenosis, as compared with samples of normal coronary arteries.89,90 The up-regulation of genes with functions in cell proliferation, the synthesis of extracellular matrix, cell adhesion, and inflammatory responses were more abundant in the samples of neointima from the patients with restenosis than in the samples of normal coronary artery. Many genes were expressed to a similar extent in the neointimal tissues and the peripheral-blood cells from patients with restenosis, suggesting the possible use of peripheral-blood cells as a substitute in microarray studies when cardiovascular tissue is not available.

Considerations for Molecular and Clinical Diagnosis

Genetic diagnosis — that is, primary classification on the basis of the presence of a mutation, with subsequent stratification according to risk — is not widely available for the diagnosis of monogenic cardiovascular disorders. Today, physical examination and routine testing, such as echocardiography to detect hypertrophic cardiomyopathy or electrocardiographic analysis of the long-QT syndrome, establish clinical diagnoses.91 Genetic diagnoses are then made by research-oriented genotyping of selected pedigrees. Current initiatives focus on the natural history of monogenic disorders in large numbers of patients with specific mutations, in order to identify persons at high risk for cardiovascular events, asymptomatic carriers in whom pharmacologic interventions will retard or prevent disease, and nonaffected family members whose concern about their health can be addressed. With regard to complex traits in more common cardiovascular diseases, current research is identifying functionally significant variations in DNA sequences that can establish a molecular diagnosis and influence patients' outcome.

Funding and Disclosures

I am indebted to the members of my laboratory for their helpful comments.

Author Affiliations

From the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.

Address reprint requests to Dr. Nabel at the National Heart, Lung, and Blood Institute, Bldg. 10/8C103, 10 Center Dr., Bethesda, MD 20892, or at .

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Citing Articles (288)

    Letters

    Figures/Media

    1. Figure 1. The Basic Components of Cholesterol Synthesis and Excretion.
      Figure 1. The Basic Components of Cholesterol Synthesis and Excretion.

      Low-density lipoprotein (LDL) molecules are composed of a cholesteryl ester core surrounded by a coat made up of phospholipid and apolipoprotein B-100. The liver secretes LDLs as larger precursor particles called very-low-density lipoproteins, which contain triglycerides and cholesterol esters. Capillaries in muscle and adipose tissue remove the triglycerides, and the lipid particle is modified into an LDL, with its cholesteryl ester core and apolipoprotein B-100 coat. LDLs circulate in the plasma, and the apolipoprotein B-100 component binds to LDL receptors on the surface of hepatocytes. Through receptor-mediated endocytosis, receptor-bound LDLs enter hepatocytes and undergo degradation in lysosomes, and the cholesterol remnants enter a cellular cholesterol pool. A negative-feedback loop regulates the number of LDL receptors. A rise in the hepatocyte cholesterol level suppresses the transcription of LDL-receptor genes, and LDL is retained in the plasma. Conversely, a decrease in hepatic cholesterol stimulates the transcription of LDL-receptor genes, removing LDL from the plasma. This mechanism accounts for the LDL-lowering action of the statins, which inhibit an enzymatic step in hepatic cholesterol synthesis. Four monogenetic diseases that elevate plasma LDL are highlighted in yellow. ABC denotes ATP-binding cassette.

    2. Table 1. Monogenic Diseases That Elevate Plasma Levels of Low-Density Lipoprotein (LDL) Cholesterol.
      Table 1. Monogenic Diseases That Elevate Plasma Levels of Low-Density Lipoprotein (LDL) Cholesterol.
    3. Table 2. Monogenic Diseases That Elevate or Lower Blood Pressure.
      Table 2. Monogenic Diseases That Elevate or Lower Blood Pressure.
    4. Figure 2. Molecular Mechanisms Mediating Salt Reabsorption in the Kidney and Associated Monogenic Hypertensive Diseases.
      Figure 2. Molecular Mechanisms Mediating Salt Reabsorption in the Kidney and Associated Monogenic Hypertensive Diseases.

      The kidney filters more than 180 liters of plasma (containing 23 moles of salt) daily and reabsorbs more than 99 percent of the filtered sodium. The proximal tubule of the nephron reabsorbs about 60 percent of the filtered sodium, primarily by sodium–hydrogen ion exchange. The thick ascending loop of Henle absorbs about 30 percent by sodium–potassium–chloride (Na+–K+–2Cl) cotransporters. The distal convoluted tubule reabsorbs about 7 percent by sodium–chloride cotransporters, and the remaining 3 percent of the filtered sodium is handled by epithelial sodium channels in the cortical collecting tubule. The renin–angiotensin system tightly regulates the activity of the epithelial sodium channels. Decreased delivery of sodium to the loop of Henle leads to renin secretion by the juxtaglomerular apparatus of the kidney. Renin acts on the circulating precursor angiotensinogen to generate angiotensin I, which is converted in the lungs to angiotensin II by angiotensin-converting enzyme. Angiotensin II binds to its specific receptor in the adrenal glomerulosa, stimulating aldosterone secretion. Aldosterone binds to its receptor in the distal nephron, leading to increased activity of the epithelial sodium channels and sodium reabsorption. Monogenetic diseases that alter blood pressure are shown in yellow. (Adapted from Lifton et al.,11 with the permission of the publisher.)

    5. Figure 3. Mutations in Cardiac Sarcomeric Proteins That Cause Hypertrophic Cardiomyopathy.
      Figure 3. Mutations in Cardiac Sarcomeric Proteins That Cause Hypertrophic Cardiomyopathy.

      Sarcomeric proteins that constitute the thick and thin filaments are shown. Sarcomere proteins that cause hypertrophic cardiomyopathy are labeled in yellow. (Adapted from Kamisago et al.32)

    6. Table 3. Monogenic Diseases That Cause Susceptibility to Arrhythmias.
      Table 3. Monogenic Diseases That Cause Susceptibility to Arrhythmias.
    7. Table 4. Examples of Polymorphisms in Genes That Alter Cardiovascular Function and Responses to Drugs.
      Table 4. Examples of Polymorphisms in Genes That Alter Cardiovascular Function and Responses to Drugs.

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