(Hypertension. 1995;26:858-862.)
© 1995 American Heart Association, Inc.
Articles |
Does Keloid Pathogenesis Hold the Key to Understanding Black/White Differences in Hypertension Severity?
From the University of Vermont, College of Medicine, Burlington.
Correspondence to Harriet P. Dustan, 34 Lang Dr, Essex, VT 05452.
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Abstract |
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 Top Abstract IntroductionBlack/White Differences in the...Black/White Differences in...Keloids as a Corollary...Keloid Pathogenesis and...SummaryReferences |
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Abstract Repeated national surveys have shown that in the United States hypertension is more common and more severe in the black than in the white population. This discussion presents the hypothesis that the racial difference in hypertension severity is because of differences in growth factors (cytokines) affecting vascular smooth muscle cell growth. This hypothesis is derived from studies of keloids, which occur almost exclusively in blacks. Keloid fibroblasts in culture have growth characteristics that differ substantially from those of normal skin. Furthermore, there is evidence that peripheral blood mononuclear cells from patients with keloids produce different amounts of cytokines than do similar preparations from the blood of individuals without keloids. A growing body of evidence indicates that growth factors play a pivotal role in the pathogenesis of atherosclerosis, in experimental forms of hypertension, and in various renal diseases; it may be that they function in clinical hypertension as well.
Key Words: Blacks • keloid • muscle, smooth, vascular • cytokines
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Introduction |
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TopAbstractIntroductionBlack/White Differences in the...Black/White Differences in...Keloids as a Corollary...Keloid Pathogenesis and...SummaryReferences |
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In the United States hypertension occurs more frequently and is more severe in the black than in the white population.1 2 In addition, ESRD from all causes except polycystic renal disease is more frequent in blacks than in whites, and this racial difference is particularly striking for nephrosclerosis.3 Currently, there is no explanation for either the increased prevalence or severity. Theories concerning the greater prevalence have addressed psychosocial stress4 and a genetic predisposition for avid renal salt conservation.5 However, the racial difference in severity has not been considered.
This discussion will focus on that difference in severity. At its core is a hypothesis that differences in growth factors, either in amounts produced or responsiveness of VSMCs or vascular fibroblasts to them, account for racial differences in the severity of hypertension and frequency of nephrosclerotic ESRD.6 This hypothesis derives from evidence that keloid fibroblasts have growth patterns different from those of normal skin7 and that growth factors are central to atherogenesis8 9 and are implicated in the vascular hyperplasia/hypertrophy of vascular smooth muscle in some experimental forms of hypertension.10 11
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Black/White Differences in the Prevalence of Hypertension and ESRD |
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TopAbstractIntroductionBlack/White Differences in the...Black/White Differences in...Keloids as a Corollary...Keloid Pathogenesis and...SummaryReferences |
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More than 30 years ago the first national survey of hypertension prevalence in the United States12 documented the black/white differences that had been found in smaller studies.13 14 This difference has persisted in subsequent surveys. The most recent, the Third National Health and Nutrition Examination Survey (NHANES III), found hypertension in 28.4±1.4% of blacks as opposed to 24.6±1.0% of whites.2
With regard to diastolic hypertension, which is a major
concern for severity, early mortality, and ESRD, specific data are
available from NHANES II.1 The Table gives
information about both diastolic hypertension and isolated
systolic hypertension (ie, systolic BP 
140 mm Hg
when diastolic BP is <90 mm Hg). Of note is the fact that
isolated systolic hypertension occurred with almost equal
frequency in blacks and whites, suggesting that diastolic
and isolated systolic hypertensions have quite different
etiologies. The data presented in the Table show that at the
time of the survey mild hypertension (diastolic BP 90 to
104 mm Hg) was 1.3 times more common in blacks than whites, moderate
hypertension (diastolic BP 105 to 114 mm Hg) was
approximately 2.0 times more common, and severe hypertension
(diastolic BP 115 mm Hg) was increased threefold. Black
men had severe hypertension more often than black women (2.2% versus
0.8%). Although these percentages may seem trivial, the fact is that
severe hypertension was present four times more frequently in black
than in white men and five times more frequently in black than in white
women.
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These racial differences in the severity of hypertension have relevance for the hypothesis relating to differences in vascular smooth muscle biology. For example, two studies have reported more cardiac hypertrophy in blacks than in whites having the same degrees of arterial pressure elevation.15 16 A study of systemic hemodynamics documented the same vascular resistance in blacks and whites when subjects were matched for equivalent levels of arterial pressure,17 but a look at renal hemodynamics revealed that in pressure-matched subjects renal blood flow was slightly but significantly lower and renal vascular resistance was higher in blacks than whites.18 Of interest, renal resistance was positively correlated with systemic BP only in blacks. These studies, although involving relatively few hypertensive patients but carefully matched as to age, sex, and height of arterial pressure, suggest that the VSMCs and cardiac myocytes of blacks have a propensity for hypertrophy/hyperplasia.
There are also marked differences in the occurrence of ESRD between black and white patients. This became obvious shortly after the establishment of the National Dialysis Program of Medicare in 1973. By 1982 Rostand et al3 had found that the Jefferson County, Ala, program had enrolled 66% black patients. Thus, of the total enrollment 196 were black and 98 were white. If census proportions had been met, 200 whites would have needed dialysis versus 94 blacks. This increase in ESRD among blacks was found for all renal diseases except polycystic disease, but it was particularly marked for nephrosclerosis, in which the risk for blacks was 17.7 times greater than for whites. The yearly report of the US Renal Data System supports this racial difference, as does a 1991 review of the overall experience since the beginning of the federally funded Dialysis Program.19 These authors reported that the black-white incidence ratio for nephrosclerosis ranged from 17.7 in Jefferson County, Ala, to 4.4 in Los Angeles, Calif. For type II diabetes that ratio averaged 4.3; ESRD from glomerulonephritis was also increased in blacks, with black-white incidence ratios ranging from 1.5 to 1.3. They concluded that these racial differences could not be explained solely by the difference in hypertension severity and suggested that other race-related factors must be involved.
A case for these other factors can be made from experience with the treatment of hypertension. A number of drug treatment trials have shown that although good BP control protects against the development of heart failure and strikingly reduces the incidence of stroke, it does not always prevent deterioration of renal function. In fact, the possibility of something other than the severity of hypertension itself came as early as 1958 when my colleagues and I reported the life-saving benefit of treating malignant hypertension.20 At that time we suggested that some factors in addition to BP elevation might participate in the progression of nephrosclerosis.20
Several more recent reports provide support for this suggestion. For example, in 1991 Qualheim et al21 published an update of the Jefferson County, Ala, experience. They had expected a decrease in enrollment in the Dialysis Program because of an increased use of antihypertensive drugs; however, they found that the percentage of ESRD attributed to hypertension had not changed (28% versus 24% in the earlier period3 ). They did note, however, that the age incidence of hypertensive ESRD had changed from 40 to 49 years in their original report to 50 to 59 years between 1982 and 1987 (P<.001). This finding is reminiscent of the slow progress in renal failure that occurred in treated malignant hypertension.20
The large-scale Hypertension Detection and Follow-up Program,
which observed 10 940 hypertensive individuals over a 5-year period of
treatment (5485 randomized to Stepped Care and 5455 to Referred Care),
found that a small percentage had significant decreases in renal
function despite good BP control.22 Moreover, most of the
participants who experienced the decrease were black. A similar
experience was reported by Rostand et al,23 who followed
94 essential hypertensive patients during treatment that ranged from 12
to 74 months. All had normal pretreatment creatinine levels
less than or equal to 133 mmol/L. Good BP control
(diastolic BP 
90 mm Hg) was maintained in 61 patients,
but in 16% of these patients serum creatinine
concentration had increased by at least 35 mmol/L. The two factors
associated with that increase were older age and black race. These
experiences recall the study showing that renal disease in SHR
progressed despite normalization of BP by drug
treatment.24 Other investigators, however, have suggested
that stabilization of renal function in treated hypertensive patients,
particularly blacks, requires maintenance of
diastolic BP at lower levels than now considered to
represent good BP control.25 26 27
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Black/White Differences in Nephrosclerosis |
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TopAbstractIntroductionBlack/White Differences in the...Black/White Differences in...Keloids as a Corollary...Keloid Pathogenesis and...SummaryReferences |
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In the early part of this century Volhard and Fahr described the renal vascular changes we have generally associated with malignant hypertension. These included fibrinoid necrosis of afferent arterioles; a proliferative change in glomeruli, called glomerulitis; and onion skin thickening of small arteries so severe as to cause marked luminal narrowing. It remained for Muirhead and Pitcock28 many years later to show that malignant nephrosclerosis in blacks had some characteristics different from those described by Volhard and Fahr. They examined kidney biopsy specimens from 41 black patients with very severe hypertension (group average BP, 255/171 mm Hg) and varying degrees of renal functional impairment (creatinine clearance, 7 to 73 mL/min). Renal biopsies were obtained only after arterial pressure had been controlled with a combination of diazoxide, furosemide, and an angiotensin-converting enzyme inhibitor. Also examined were 13 binephrectomy specimens.
Microscopic examination failed to show fibrinoid necrosis of the small arteries and arterioles. The glomeruli were also different from those of white patients, as glomerular proliferation was absent. Instead, the glomeruli appeared to be ischemic, as evidenced by wrinkling of the basement membrane, shrinking of the glomerular tuft, and the presence of eosinophilic material in Bowman's space that resembled connective tissue. There was marked hyalinization of arterioles, which were severely stenosed because of onion skin intimal proliferation and intramural deposition of acid mucopolysaccharide. The arteriolar media was also thickened, contributing to severe glomerular narrowing. Interlobular arteries were greatly narrowed by intimal thickening as well, which appeared to come from a circumferential arrangement of spindle cells in a basophilic matrix. By special stains the matrix was found to contain mucopolysaccharides, mostly represented by chondroitin sulfate and hyaluronic acid.
Electron microscopy showed that the cellular portion of the interlobular abnormality was made up of smooth muscle cells that were often hypertrophied and had ploidy of various nuclei. These and other findings led Muirhead and Pitcock28 to the conclusion that medial smooth muscle cells had migrated into the intima where they proliferated, deposited mucopolysaccharides, and formed collagen. This they termed myointimal hyperplasia. In summary, these findings differed from the histopathology of malignant nephrosclerosis in whites by the lack of fibrinoid necrosis, evidence of glomerular ischemia rather than proliferative glomerulitis, and greater myointimal fibroplasia with deposition of mucopolysaccharides.
The question now arises as to whether there is a corollary to these arterial lesions and other abnormalities found in blacks; keloids seem a likely possibility for comparison, although their prevalence is far less than that of hypertension.29
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Keloids as a Corollary of Nephrosclerosis |
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TopAbstractIntroductionBlack/White Differences in the...Black/White Differences in...Keloids as a Corollary...Keloid Pathogenesis and...SummaryReferences |
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Keloids are benign tumors of the skin or cornea. Usually, they result from trauma but occasionally occur spontaneously. They develop in people with much skin pigment, so they are found in blacks and Asians.30 Keloids occur because of an abnormal healing process, and the scar tissue thus formed extends beyond the boundary of the original trauma. They contain excessive quantities of collagen, fibronectin, and chondroitin sulfate.30
Much has been learned about keloid formation through tissue culture studies comparing growth characteristics of keloid fibroblasts with those of normal skin, normal scars, and fetal or newborn dermis. Keloid fibroblast cultures have been shown to produce more fibronectin than cultures of normal skin fibroblasts.31 Russell et al7 reported that keloid and normal fibroblasts in tissue culture grew equally well in 10% fetal bovine serum and that reducing the concentration to 5% stopped the growth of normal fibroblasts but did not significantly alter that of keloid fibroblasts. The response to TGF-ß was also different. TGF-ß is a cytokine that can either increase or decrease the growth-promoting effects of a number of other cytokines.32 When comparing the influence of TGF-ß on keloid and normal fibroblasts, Russell and colleagues7 found that TGF-ß reduced growth stimulation by epidermal growth factor in normal fibroblast cultures while enhancing growth of keloid fibroblasts. Responses to hydrocortisone were also different in that the growth rate of normal cells was increased, whereas that of keloid fibroblasts was either unaffected or suppressed.
TGF-ß is an attractive candidate for the major role in keloid formation. (As will be detailed below it appears also to be of prime importance in vascular smooth muscle hyperplasia/hypertrophy, at least in the SHR model.10 ) A recent review by Border and Noble33 describes the critical role of TGF-ß in normal and abnormal tissue repair. The cytokine is released at the site of injury where it acts as the "drill master" for repair processes. These processes include formation of extracellular matrix by fibroblasts (collagen, fibronectin, proteoglycans), decreased production of proteases that can degrade matrix components, increased production of protease inhibitors, and modulation of the formation of integrins (cell surface receptors) that promote cellular adhesion to matrix. Normally, when tissue repair has been completed, TGF-ß becomes inactive. In situations such as keloid formation, this cytokine does not become suppressed, and the normal process of tissue repair becomes an abnormal self-perpetuating condition.34
Platelets also play an important role in early responses to injury
and are the major source of PDGF, a potent mitogenic and
chemotactic agent. Haisa et al35 found that keloid
fibroblasts in culture were more responsive to PDGF than normal
fibroblasts, although the two tissue types were not differently
affected by either epidermal growth factor or fibroblast growth factor.
The enhanced response to PDGF was explained by levels of PDGF-
receptors that were increased four to five times more than found in
normal fibroblast cultures.
Considering the dependence of wound healing on cytokine
production and the likely possibility for abnormal
cytokine function in keloid formation, it is of interest to
cite the report of altered cytokine production by
peripheral blood mononuclear cells of patients with
keloids. McCauley et al36 showed that these cells when
stimulated in vitro produced specific cytokines that differed
in amounts from those produced by normal peripheral blood
mononuclear cell preparations: -interferon, 
-interferon,
and tumor necrosis factor–ß were remarkably depressed;
interleukin-6, tumor necrosis factor–, and - and
ß-interferons were increased; and amounts of interleukin-1 and
interleukin-2 produced were the same as found in normal
peripheral blood mononuclear cell preparations.
From the foregoing it seems clear that keloid pathogenesis is related to abnormalities in cytokine production and/or fibroblast responsiveness to cytokines. The next question concerns the relevance of such evidence to vascular disease and particularly the severity of hypertension in blacks.
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Keloid Pathogenesis and Black/White Differences in Hypertension Severity |
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TopAbstractIntroductionBlack/White Differences in the...Black/White Differences in...Keloids as a Corollary...Keloid Pathogenesis and...SummaryReferences |
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Over the past several years a growing body of evidence has indicated that cytokines function as growth factors in the pathogenesis of atherosclerosis.7 8 37 These data lead to a conclusion that without cytokine activation, atherosclerosis would not be the major public health problem that it is today. For this discussion, however, the focus is on small systemic arteries and arterioles, which are sites of the increased resistance that characterizes diastolic hypertension, and on the renal vasculature, which is particularly vulnerable to disease in blacks. Since blacks have severe hypertension more often than do whites and since they, almost alone, are subject to keloid formation, the question raised is whether anything can be learned from available information about keloid formation that has relevance for severe hypertension. Already, evidence indicates that this is not an unreasonable suggestion.
Pauletto et al38 have summarized studies of growth factor influences on cultured smooth muscle cells in some forms of experimental hypertension. They note that Ang II is a potent promoter of VSMC growth by stimulating production of cytokines and increases in PDGF receptors. The circumstances under which Ang II stimulates hyperplasia versus hypertrophy are not yet clear. This confusion may have been settled more recently with the report by Koibuchi and colleagues10 that the cellular effects of Ang II depended on whether PDGF-ß production was stimulated. They used two VSMC cultures, one in which Ang II produced hypertrophy and the other hyperplasia. In both cultures Ang II induced basic fibroblast growth factor fourfold to fivefold, and in both PDGF-ß was increased. However, in the culture exhibiting hyperplasia PDGF-ß was in the active form, whereas in the culture with hypertrophy it was in the latent or inactive form.10 Agrotis et al11 studied the effects of PDGF-ß on cell growth in VSMC cultures from SHR and WKY stimulated with epidermal growth factor, basic fibroblast growth factor, or PDGF isoforms. They found that PDGF-ß stimulated cell growth by these cytokines only in cultures of SHR cells but inhibited growth effects in WKY cultures. These various studies show that there are clear differences in vascular cell responses in experimental hypertensive versus normotensive strains.
Strong support for the present hypothesis comes from a cell culture study by Guicheney et al39 of skin fibroblasts from SHR and WKY that was designed to answer the question of whether the accelerated growth rate of VSMCs from SHR is of genetic origin and could be found in other tissues as well. They found that SHR fibroblasts did indeed exhibit faster growth rates than those of WKY in response to fetal bovine serum, insulin, and epidermal growth factor. This was considered to reflect a "genomic alteration."
The renal vasculature of blacks as opposed to that of whites is particularly sensitive to the damaging effects of hypertension and other elements. This could represent a racial difference in the response of kidney cells to growth factors similar to that exhibited by keloid fibroblasts. Growth factors (cytokines) are involved in renal disease, as shown by the studies summarized by Border and Noble33 and El Nahas.40 Experimental acute glomerulonephritis glomeruli, compared with normal glomeruli, showed elevated levels of PDGF-ß mRNA, producing more proteoglycans and fibronectin.33 Glomerulosclerosis represents a deranged healing process characterized by excessive formation of fibrous tissue replacing normal glomerular tissue.40 TGF-ß appears to play a role by stimulating mesangial and epithelial cells to produce collagen and fibronectin.
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Summary |
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TopAbstractIntroductionBlack/White Differences in the...Black/White Differences in...Keloids as a Corollary...Keloid Pathogenesis and...SummaryReferences |
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The evidence presented here appears to support the hypothesis that the increased severity of hypertension and its accompanying vascular disease reflects a racially specific response of VSMCs to growth factors. In this construct, VSMCs seem similar to skin fibroblasts, whose abnormal growth factor production and responsiveness are expressed as keloids.
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Selected Abbreviations and Acronyms |
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Footnotes |
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This article was presented as a Merck Clinical Conference at the Alton Ochsner Medical Foundation in May 1995. The journal acknowledges the support of this teaching program by Merck, Sharp & Dohme Research Laboratories.
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References |
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TopAbstractIntroductionBlack/White Differences in the...Black/White Differences in...Keloids as a Corollary...Keloid Pathogenesis and...SummaryReferences |
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