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The Journal of Clinical Hypertension logoLink to The Journal of Clinical Hypertension
. 2007 May 25;6(Suppl 4):11–18. doi: 10.1111/j.1524-6175.2004.03562.x

Physiology, Genetics, and Cardiovascular Disease: Focus on African Americans

Gary H Gibbons 1
PMCID: PMC8109610  PMID: 15073462

Abstract

The disproportionate impact of cardiovascular disease in African Americans is well recognized. Not only do risk factors such as obesity occur at a higher rate in the African‐American community, but this population experiences a greater mortality from cardiovascular disease than their white counterparts. The cardiovascular system is regulated in part by two opposing mediators linking the risk factors of obesity, vascular dysfunction, and diabetes. One of these mediators—angiotensin II–increases blood pressure, impairs endothelial function, decreases peroxisome proliferator activated‐receptor γ, and is proinflammatory, growth stimulating, profibrotic, and proatherogenic. The other mediator, peroxisome proliferator activated‐receptor γ, lowers blood pressure, improves endothelial function, decreases angiotensin II type 1 receptor function, and is anti‐inflammatory, growth‐inhibiting, antifibrotic, and antiatherogenic. Genotypic variants have been discovered that affect the functioning of both of these important systems. Some of these variants—like some genotypic variants discovered in the adrenergic system—occur with different frequencies in African Americans than in Americans of European descent and may help to explain racial/ethnic differences in susceptibility to cardiovascular disease and aspects of the response to treatment. Recognition of these genotypic differences may permit the development of therapies tailored to individual patients.

Cardiovascular disease (CVD) is a continuum beginning with risk factors, such as obesity and hypertension, that have an impact on the cardiovascular tree at a subclinical level. These risk factors lead to subclinical changes in vascular function and structure that result in vascular dysfunction and overt vascular disease. This is followed by tissue injury/wall stress that causes pathological remodeling that may in turn progress to target organ dysfunction, end‐stage heart failure, and finally death. This process is mediated by several substances, including angiotensin II, aldosterone, and norepinephrine, and takes place in the context of a person's genetic make‐up, which may influence both susceptibility to CVD and response to therapy. This article examines the cardiovascular continuum from the perspective of factors of particular relevance to the development and treatment of CVD in African Americans.

RISK FACTORS

Of the risk factors for CVD, obesity is perhaps the most important contributor to the growing incidence of these disorders in the United States. Obesity has long been associated with both left ventricular hypertrophy and dilation, 1 , 2 two recognized precursors of heart failure, and is a risk factor for conditions such as hypertension, diabetes mellitus, and dyslipidemia that, in turn, augment the risk of heart failure. 3 , 4 , 5 In addition to its role in the development of other cardiovascular risk factors, obesity alone is responsible for 11% of cases of heart failure among men and 14% of cases among women. 2 The effect of excess weight on CVD is not limited to the extremely obese; it is seen in moderately overweight persons as well. As demonstrated in a recent study, each 1 unit increment in body mass index (BMI) may increase the risk of heart failure by 5% in men and 7% in women, with the risk of heart failure in obese subjects double that of persons with normal BMIs. 2

The current epidemic of obesity in this country has particular relevance for the development of CVD in African Americans. Forty‐five percent of African‐American women older than 40 years of age are obese, compared with 17.9% of the US adult population in general. 6 In this regard, E. Ofili, MD, communicated in a personal conversation (January 2002) that a direct relationship has been found between BMI and decreased vasodilatory ability in normotensive African‐American women, illustrating an early subclinical effect of obesity on the cardiovascular system in this highly at‐risk population (Figure 1).

Figure 1.

Figure 1

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Endothelial dysfunction in African Americans: influence of obesity in normotensive African‐American females with forearm hyperemia Source: Personal communication with E. Ofili, MD; January 2002.

Equally disturbing is the fact that African Americans are becoming obese at a very young age. According to the 1999‐2000 National Health and Nutrition Examination Survey, the prevalence of overweight among African‐American adolescents increased from 13.4% in 1988–1994 to 23.6% in 1999–2000 (Figure 2). Twenty percent of African‐American females between the ages of 12 and 19 exceeded the adult definition of obesity, compared with 16% of Mexican‐American females and 10% of white females. 7

Figure 2.

Figure 2

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Overweight prevalence in American adolescents. Error bars represent standard errors. Adapted with permission from JAMA. 2002;288:1728—1732.

The increase in childhood obesity contributes to the development of CVD in several ways. Many of these children can be expected to continue being overweight as adults, and thus to suffer all of the possible consequences of adult obesity, including CVD. In addition, childhood obesity has more immediate effects. Until recently, type 2 diabetes was rarely seen in children; however, an increase in these cases has been noted recently, especially among minority populations. 8 Obesity in childhood also has early effects on the vascular tree. Severely obese children have been shown to have increased stiffness of the common carotid artery compared with normal‐weight children. Endothelium‐dependent and independent functions were also lower in obese children than in their control counterparts. 9 The cardiovascular effects of childhood obesity may be permanent, even if overweight children do not go on to become overweight adults. A 55‐year follow‐up study indicates that adults who were overweight in adolescence had an increased risk of morbidity and mortality from CVD, independent of their current adult weight. 10

MEDIATORS

A variety of mediators—including norepinephrine, angiotensin II, aldosterone, endothelin, tumor necrosis factor, and interleukin‐6—have been identified as causative factors in the development of CVD. 11 , 12 Of these, the renin angiotensin‐aldosterone system (RAAS) has a particularly important role in linking obesity, vascular dysfunction, and vascular disease.

There are considerable differences between African Americans and European Americans in regard to the role of the RAAS in the development of CVD. Unlike whites, African Americans with hypertension tend to have low plasma renin activity (PRA). 13 , 14 , 15 Not only does this difference have important implications for understanding the etiology of CVD in this population, but it has also led to the mistaken belief that angiotensin‐converting enzyme (ACE) inhibitors (which help prevent the generation of angiotensin II) have little to offer in this group of patients. To the contrary, research has shown that a low circulating PRA need not mean that the RAAS is inactive in African Americans. Rather, this may be a physiologic response to high dietary salt intake coupled with increased salt sensitivity. Although African Americans on a high‐salt diet reach lower PRA values than do whites, during sodium restriction the increase in PRA is actually greater than that observed in whites. 15 Moreover, controlling salt intake or using a diuretic diminishes race‐related differences in the effectiveness of ACE inhibitors. 15

In contrast to the proinflammatory and proatherogenic effects of the RAAS, the nuclear receptor peroxisome proliferator‐activated receptor γ (PPARγ) has an anti‐inflammatory, antiatherogenic role in CVD. Increased understanding of the mechanisms of action and genetic determinants of these and other mediators of CVD may provide further explanations for some of the variability in responsiveness to treatment observed in African‐American patients and an opportunity to develop more pathophysiologically targeted therapies.

RAAS

RAAS is both a circulating neuroendocrine system acting on target organs such as blood vessels, adrenal glands, and kidneys and an autocrine/paracrine system produced at various tissue sites where it exerts relevant local effects. 16 , 17 Circulating RAAS is activated during episodes of cardiovascular decompensation (e.g., hemorrhage, heart failure) to maintain blood pressure and is then just as quickly turned off when homeostasis balance is restored. In contrast, tissue RAAS operates over a longer time frame, affecting cardiovascular function and structure and playing a pathophysiologic role in hypertension, glomerular hyperplasia, vascular/myocardial hypertrophy, and congestive heart failure. 16 , 18 The relative activity of these two forms of the RAAS is evidenced by the fact that 90%–99% of ACE is found in tissue, whereas only 1%–10% is found in the systemic circulation. 16 One of the features linking cardiovascular risk factors—including hypertension, diabetes, obesity, left ventricular hypertrophy, myocardial infarction, oxidatively modified low‐density lipoprotein, and C‐reactive protein—is an increased activation of the local tissue RAAS. Because of the central role of tissue RAAS in the pathogenesis of cardiovascular remodeling, it has become a major target in the effort to prevent or slow the progression of CVD.

Angiotensin II, a primary mediator of RAAS activity resulting from the activity of the ACE helping convert inactive angiotensin I to angiotensin II, acts through a variety of mechanisms to ultimately alter cardiovascular function and structure. Angiotensin II is a potent vasoconstrictor, the effect of which is to decrease myocardial oxygen supply. 19 In addition to its vasoconstrictor activity, angiotensin II promotes the degradation of bradykinin, a peptide that facilitates the release of the vasodilator nitric oxide. 20 , 21 Angiotensin II also increases the production of oxygen free radicals, promoting oxidative stress. 22 Increased production of oxygen free radicals counteracts the effects of the vasodilating properties of nitric oxide, stimulates expression of adhesion molecules, and promotes adhesion of leukocytes to the endothelium. 18 These actions trigger an acute inflammatory response, proliferation of smooth muscle cells, and production of extracellular matrix, all of which contribute to the pathogenesis of CVD. 23

Initiation and Progression of Atherosclerosis

Angiotensin II induces adhesion molecule expression in endothelial cells and activates human monocytes, resulting in increased adhesion to endothelial cells. 24 It is also chemotactic for T lymphocytes and stimulates growth, migration, and matrix production in smooth muscle cells, which may contribute to plaque expansion. In addition, angiotensin II may promote atherosclerotic plaque growth through its induction of superoxide production in vascular smooth muscle cells, 25 which in turn may induce growth of vascular smooth muscle cells, lipid peroxidation, inactivation of nitric oxide, and stimulation of adhesion molecule expression. 26

ACE expression in macrophages is induced by oxidatively modified low‐density lipoprotein. 26 There is a marked accumulation of ACE, an important element in the generation of angiotensin II, in the vulnerable region of atherosclerotic plaques in association with the localized presence of inflammatory cells, especially in clusters of macrophages and T lymphocytes. 26 Moreover, neovasculature within the plaque exhibits enhanced ACE immunoreactivity. 26

Myocardium

In the myocardium, angiotensin II acts as a positive inotrope in addition to its impairing of diastolic relaxation. It also directly stimulates cardiac myocyte hypertrophy and serves an important role in myocardial remodeling. The level of myocardial aldosterone is associated with the degree of myocardial fibrosis and left ventricular dysfunction, 27 while increased cardiac formation of angiotensin II is directly associated with heart failure. 28 Angiotensin II can also enhance the development of arrhythmias in patients with ischemia or advanced heart failure and may contribute to subendocardial ischemia through its vasoconstrictor effect on coronary circulation. 16

Insulin Resistance

Leukocytes produce angiotensin II. Levels of leukocyte angiotensin II correlate strongly with steady‐state plasma glucose concentration, as well as with BMI and plasma insulin, suggesting that angiotensin II may be directly associated with insulin resistance. 29 It is important to note that distinct differences have been observed between African Americans and whites in the relationship between renin and insulin resistance. In a study of children, whites had higher PRA values, and renin activity correlated with blood pressure and insulin resistance in whites only, suggesting that renin may be a component of the insulin resistance syndrome early in life only in whites. 30

Angiotensin Blockade

ACE inhibitors and angiotensin‐receptor blockers reduce oxidative stress in the vessel wall, thereby increasing the bioavailability of nitric oxide and reversing vascular dysfunction. 31 Treatment with ACE inhibitors also significantly reduces carotid intimal medial thickness. 32 Interestingly, the beneficial effects of angiotensin blockade are associated with an increase in the levels of the body's own antioxidants. 32 In contrast, vitamin‐based antioxidant therapies have little effect on the progression of atherosclerosis. 32 Therefore, the success of therapeutic agents such as ACE inhibitors and angiotensin‐receptor blockers may be due at least in part to a resulting increase in the cardioprotective actions of the body's own antioxidants.

Organ Damage. Relative to whites, African Americans are at greatly increased risk of hypertensive end‐stage renal disease. 33 However, because of the typically low renin status of hypertensive African Americans, ACE inhibitors and angiotensin‐receptor blockers as monotherapy have traditionally not been considered useful in these patients. 34 However, recent clinical trial evidence in both diabetics and patients with proteinuric nondiabetic kidney disease indicate that these agents may have an important role in controlling blood pressure and slowing progressive renal failure in African Americans when their use is accompanied by sufficient amounts of additional hypertensive agents, especially diuretics, to achieve per protocol goal blood pressure. 15 , 34 , 35

Obesity

Fat is more than a simple storage depot. In many respects, it functions as an endocrine organ, producing mediators such as interleukin‐6, growth factors, and C‐reactive protein and maintaining a certain level of activity of its own local tissue RAAS. In the aggregate these factors promote the generation of free radicals, which are then associated with accelerated aging and damage to tissues, as well as endothelial dysfunction, and may also predispose persons to insulin resistance and diabetes. Thus, the recognition that angiotensin may have an important role in the progression from obesity to cardiovascular complications and diabetes provides an opportunity to interrupt or modulate this cycle. In fact, studies indicate that blocking RAAS reduces the development of new onset diabetes in at‐risk persons. 36

Although obesity‐related hypertension and essential hypertension share many similarities, obesity‐related hypertension has unique features, some of which may be especially relevant in understanding the unique CVD risk in the African‐American population. Although glomerular filtration rate and renal plasma flow are normal in obese persons, there is an increased tubular reabsorption of sodium, and the accompanying hemodynamic changes associated with this sodium and water retention are the hallmark finding of obesity‐associated hypertension. 37

It has been suggested that compression of renal medullary tubules and blood vessels from obesity‐related pressure on the renal medulla may contribute to this increased tubular sodium reabsorption. 37

Although there is a clear linear relationship between increased body weight and increased blood pressure/CVD mortality in Asians and whites, this relationship has not been clearly demonstrated in African Americans. 37 African Americans have higher blood pressures at lower weights than do other groups and, in at least one study, this relationship was flat at lower body weights, suggesting a threshold effect. 37 , 38 One possible explanation for these racial differences may be that the much higher incidence of low birth weight in the African American community acts as a confounding variable in the development of excess morbidity and mortality from hypertension. Several studies have documented a relationship between low birth weight and the later development of hypertension. 39 Lower birth weight seems to be associated with both a smaller nephron mass that extends into adulthood and a lower β‐cell mass, which in turn leads to the earlier development of hypertension, diabetes mellitus, and end‐stage renal disease. 37 Therefore, African Americans with lower body weights may have a higher risk for hypertension than other racial groups because of the increased occurrence of low birth weight in this population. The impact of low birth weight may also explain why body weight is less predictive for CVD mortality in African Americans than is the case in whites. 37

PPARγ

The nuclear receptor PPARγ is a key regulator of fat cell (adipocyte) differentiation 40 and is expressed in endothelial and vascular smooth muscle cells, as well as adipose tissue. 41 Evidence from several sources points to the importance of the PPARγ system in mediating cardiovascular function and structure. Activation of PPARγ with thiazolidinediones lowers blood pressure in humans, 42 blocks calcium channel activity in smooth muscle cells, 43 inhibits the release of the vasoconstrictor substance endothelin‐1, 44 and promotes the secretion of the vasodilator C‐type natriuretic peptide. 45 PPARγ expression is downregulated in genetically hypertensive rats, 46 and administration of a PPARγ agonist inhibits vascular remodeling in these animals through a reduction of fibrosis in the blood vessels. 47

The recent discovery of dominant negative mutations in PPARγ, which result in a syndrome of severe insulin resistance and the development of diabetes and hypertension at an unusually early age, 48 provides strong evidence at the genetic level of the critical importance of this mediator in determining cardiovascular structure and function.

GENETIC FACTORS

Genetic factors influence susceptibility to disease, as well as the efficacy of drugs and, in certain instances, the probability of an adverse drug reaction. 49 Most of the genetic variability in humans is due to differences between persons within a population; however, 10%–15% is attributable to differences between population groups. These genetic differences can result in important ethnic/racial discrepancies in disease characteristics and treatment outcome, 50 , 51 differences that may be of more importance for the treatment of African Americans than for Americans of European descent. In a recent study of commonly encountered single‐nucleotide polymorphisms in these two groups, 22% were restricted to African‐American subjects, whereas only 5% were restricted to European Americans. Moreover, 36% of the common single‐nucleotide polymorphisms that were present in both populations occurred at significantly different frequencies in the two groups; 185 of these were common in African Americans but not European Americans, compared with 72 that were common in European Americans but not African Americans. 53

Disease Susceptibility

An example of the way in which these genetic differences may increase the risk of CVD can be seen in genotypic variations in adrenergic receptors (ARs). A synergistic interaction between specific variants of β1‐and α2c‐AR has been found to dramatically increase the risk of heart failure, particularly in African Americans. People who were homozygous for this α2c‐AR variant had an adjusted odds ratio of heart failure of 5.65 compared with African Americans having other α2c‐AR genotypes. By itself, the β1‐AR variant carried no increased risk. However, the adjusted odds ratio rose dramatically to 10.11 for individuals who were homozygous for both the variant α2c‐AR and the variant β1‐AR. 54 Although there was no indication that the risk of heart failure was different in African‐American and white people having these variants, 54 the frequency at which they occurred differed significantly in the two groups. The α2c‐AR variant was more than 10 times as common among African‐American controls as among white controls, whereas the β1 variant was somewhat less common among African‐Americans than whites, resulting in far fewer whites who were homozygous for both. 54

Genetic polymorphisms are also associated with differences in ACE concentration and blood pressure. Two of these polymorphisms, ACE4 and ACE8, accounted for 6% and 19%, respectively, of the variance in ACE in a Nigerian population and were also associated, through interaction, with differences in systolic and diastolic blood pressure (Figure 3). 55 More recent work in a biracial American population demonstrated a significant association between two individual single‐nucleotide polymorphisms in the genes encoding RAAS and hypertension in African Americans, with consistent but less significant evidence found in European Americans. 56 Different transmission patterns associated with ACE polymorphisms were also noted in these two populations, with haplotype AAAA of the ACE gene—present primarily among African Americans being—overtransmitted to affected offspring. 56

Figure 3.

Figure 3

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Genomic determinants of angiotensin‐converting enzyme (ACE) level: ethnicity and DNA variation. ACE4 and ACE8 are significantly associated with systolic blood pressure (p<.05), with gender, age, and body mass index as covariatesSource: Am J Hum Genet. 2001;68:1139–1148. 55

Genetic determinants linked with venous thromboembolism in whites are uncommon in African Americans, despite the fact that the incidence of venous thromboembolism is at least as great in African Americans as in whites. 57 , 58 , 59 , 60 The frequencies of other genetic variants of RAAS (such as angiotensinogen M235T and A1166C of AT1R), reported in some studies to be associated with hypertension and/or myocardial infarction, also differed significantly in African Americans and whites. 60

Response to Drugs

Inherited variations in drug effects are common, 49 with striking ethnic and population differences in the types and frequencies of genes determining these effects. 49 The variability in drug effects studied so far has stemmed primarily from differences in drug metabolism and involves a wide range of medications, including major agents used in the treatment of CVD. 61 Due to inherited CYP2D6 genes that encode an enzyme with little or no activity, 5%–7% of white subjects have a relative deficiency in their ability to oxidize the antihypertensive drug debrisoquine and to metabolize the antiarrhythmic drug sparteine. 62 , 63 , 64 This deficiency results in excessively high plasma concentrations of CYP2D6 substrates, leading to exaggerated drug effects in affected individuals and placing them at increased risk of side effects. Although multiple CYP2D6 genes are relatively infrequent among northern Europeans, they occur in up to 29% of east African populations. 65

Differences in drug effects may be due to inherited differences in factors other than metabolism. In an in vitro study of four β‐ARs (β1‐AR, variant β1AR‐Arg, β2‐AR, and variant β2AR‐Ile), up to 10 levels of signaling by these receptors could be found based on the combined influences of desensitization and genetic variation, perhaps offering an explanation for the high degree of interperson variability in response to β‐agonists and β‐antagonists that has been observed. 66 ACE polymorphism has also been shown to interact with β‐blocker therapy in determining transplant‐free survival in patients with congestive heart failure. Although ACE inhibitors have failed to eliminate the detrimental effect of the ACE D allele on survival, this genotype‐dependent risk was not observed in patients receiving β blockers. Moreover, among the three ACE genotypes (ACE II, ACE ID, ACE DD), only those patients who were homozygous for the D allele experienced a survival benefit with β blockers, 67 suggesting that ACE polymorphism may play an important role in determining the effectiveness of these agents (Figures  4 and 5).

Finally, the discovery of mutations in PPARγ that are associated with severe insulin resistance, diabetes, and hypertension suggests that this may be a particularly fertile ground for further genetic investigation.

CONCLUSIONS

The structural and functional changes occurring in CVD are the result of a complex interaction between genetic make‐up, risk factors, and cardiovascular modulation by a variety of mediators, including RAAS, α‐ and β‐adrenergic systems, interleukin‐6, tumor necrosis factor, and other cytokines and growth factors. Although the impact of risk factors such as obesity on the growing incidence of CVD in the African‐American community is well known, altering factors that lead to behaviorally based risks is notoriously difficult. Less well understood have been genetic factors that may expose African Americans to a higher risk of heart disease and/or differentially affect their response to treatment.

Although most genetic variants are present across racial/ethnic groups, some variants affecting CVD and its treatment have a greater impact on those of African descent. For example, α‐adrenergic receptor variants conferring a dramatically increased risk of heart failure have been found to be much more common in African Americans than in European Americans. As the common link between obesity, vascular dysfunction/vascular disease, and diabetes, angiotensin II has a central role in the pathophysiology of these disorders and has been a primary target of therapies designed to prevent or reverse the progression of cardiovascular remodeling. Thus, the finding in Nigerians of genetic polymorphisms for ACE that are associated with systolic and diastolic blood pressure may have special relevance for African Americans. ACE polymorphism may also play an important role in determining the effectiveness of β blockers, although no racial differences have been reported in this regard. Clearly, it is time to begin to integrate genetic aspects into our understanding of the CVD continuum and to take into account ethnic/racial differences in the disease and its treatment. This approach may enable us to develop treatments tailored to individual persons, thus improving therapy for all patients, especially those in the African‐American community.

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