A mismatch between aortic pulse pressure and pulse wave velocity predicts advanced peripheral arterial disease.

OBJECTIVES: To determine whether increases in central aortic pulse pressure (PPc), but decreases in carotid-femoral pulse wave velocity (PWV) predict the presence of advanced peripheral arterial disease (PAD). METHODS: Applanation tonometry and vascular ultrasound were employed to assess carotid-femoral PWV, PPc, and carotid intima media thickness (IMT) in 136 patients of African ancestry with chronic critical lower limb ischaemia (CLI) and in 1,030 randomly selected healthy adults of African ancestry, 194 of whom were age- and sex matched (controls). RESULTS: With adjustments for confounders, compared with age- and sex-matched controls, participants with CLI had an increased carotid IMT (p = .0001) and PPc (p < .0001), but a markedly reduced PWV (m/second) (CLI = 5.7 ± 3.7, controls = 8.6 ± 3.4, p < .0001). PWV was correlated with PPc in controls (r = .52, p < .0001), but not in CLI (r = -.06). A PPc/PWV mismatch index showed increased values in participants with CLI over the full adult age range assessed. With carotid IMT, PPc, or aortic augmentation index in the same regression model, an increase in the PPc/PWV mismatch index was independently associated with CLI (p < .0001) and a PPc/PWV value upper 95% confidence interval in the community sample predicted CLI (odds ratio = 32 [6-169], p < .0001). PPc/PWV predicted CLI with a similar level of performance and accuracy and a greater specificity (98%) than that of IMT (82%). CONCLUSION: In CLI, while PPc increases, carotid-femoral PWV is markedly reduced. A PPc/PWV mismatch may be a new risk marker for advanced PAD.

Burden of depressive symptoms in South African public healthcare patients with established rheumatoid arthritis: a case-control study.

OBJECTIVES: The burden of depressive symptoms and how demographic and disease characteristics relate to depressive symptoms in patients with rheumatoid arthritis (RA) that belong to developing populations, are currently unknown and were therefore assessed in a case-control study in public healthcare patients in South Africa, a lower-middle income country. Public healthcare attendance is a surrogate of belonging to the developing population in South Africa. METHODS: Demographic and RA features were recorded in 441 public and 202 private healthcare patients. The outcome characteristic was the Arthritis Impact Measure Scales (AIMS) depression score. Relationships of patient characteristics and public healthcare attendance with depressive symptoms were determined in multivariable regression models. RESULTS: The mean ± SD AIMS depression score was 3.6±2.1 and 2.3±1.7 in public and private healthcare patients, respectively (p<0.0001 before and after adjustment for covariates). Physical disability was associated with depressive symptoms in both healthcare sectors. Other characteristics that were related to depressive symptoms comprised younger age, male sex and pain in public healthcare patients and fatigue and non-use of disease modifying agents in private healthcare patients. In all patients, public healthcare attendance (standardised ß [95% CI]=0.22 [0.12, 0.32], p<0.0001) and physical disability (standardised ß [95% CI]=0.25 [0.16, 0.34], p<0.0001) were most strongly associated with depressive symptoms. CONCLUSIONS: The burden of depressive symptoms is markedly enhanced in our developing population with RA, independent of age, sex, ethnic origin and disease characteristics. In this setting, the role of social factors should be assessed and, despite restricted resources, depressive symptoms should be routinely addressed.

Global cardiovascular risk profiles of untreated hypertensives in an urban, developing community in Africa.

INTRODUCTION: Blood pressure (BPR) control in people of African descent is poor, largely because of a lack of treatment. Although the requirements for immediate initiation of antihypertensive drug therapy are defined by global cardiovascular risk, the global cardiovascular risk profiles of untreated hypertensives at a community level are uncertain. AIM: To identify the distribution of global cardiovascular risk profiles of untreated hypertensives in an urban, developing community of African descent in South Africa. METHODS: As part of the African Programme on Genes in Hypertension, we assessed nurse-derived clinic BP (the mean of five standardised BP values obtained according to guidelines), current antihypertensive therapy, and total cardiovascular risk in 1 029 participants older than 16 years of age from randomly selected nuclear families from the South West Township of Gauteng (SOWETO). RESULTS: Approximately 46% of participants had systolic/ diastolic BP values ≥ 140/90 mmHg and ∼23% of participants were hypertensives not receiving antihypertensive medication. Approximately 12% of untreated hypertensives had a high added risk and ∼18% a very high added risk (6.7% of the total sample). In untreated hypertensives, in contrast to the absence of severe hypertension and diabetes mellitus in those with lower risk profiles, a high cardiovascular risk profile in this group was characterised by severe hypertension in ∼52% and diabetes mellitus in ∼33%. Based on a high added risk carrying at least a 20% chance and a very high added risk at least a 30% chance of a cardiovascular event in 10 years, this translates into 1 740 events per 100 000 of the population within 10 years, events that could be prevented through antihypertensive drug therapy. CONCLUSION: In an urban, developing community of African ancestry, a significant proportion (6.7%) of people may have untreated hypertension and a global cardiovascular risk profile that suggests a need for antihypertensive drug therapy. Cardiovascular risk in this group is driven largely by the presence of severe hypertension or diabetes mellitus.

Public healthcare attendance associates with enhanced conventional and non-conventional atherosclerotic cardiovascular disease risk burdens in established rheumatoid arthritis.

OBJECTIVES: To assess whether public healthcare attendance associates with altered atherosclerotic cardiovascular disease risk in established rheumatoid arthritis (RA). METHODS: We determined disparities in major conventional (hypertension, dyslipidemia, smoking and diabetes), other conventional (underweight, obesity, metabolic syndrome, chronic kidney disease, alcohol use, tension, depression and body height) and non-conventional (current and cumulative inflammation markers) cardiovascular risk factors between 424 consecutive public and 202 private healthcare patients in mixed regression models. RESULTS: Eighty-one percent of public healthcare patients were black (67%) or caucasian (14%) and 83% of private healthcare cases were caucasian. Seventy percent of the patients had > or = 1 major conventional risk factor. After adjustment for age, gender, ethnic origin and statin use when appropriate, public healthcare attendance associated with the prevalence of hypertension (odds ratio (OR) [95%CI]=1.72 [1.03, 2.85]), having > or = 1 major conventional risk factor (OR [95%CI]=1.83 [1.09, 3.07]) and an increased mean (SD) number of such risk factors (p=0.03), metabolic syndrome frequency (OR [95%CI]=1.90 [1.07, 3.40]), alcohol use (OR [95%CI]=0.07 [0.03, 0.18]), shorter stature (p<0.0001), higher tension (p=0.02) and depression score (p<0.0001) and higher inflammatory markers including the disease activity score in 28 joints (p=0.005), C-reactive protein concentration (p=0.0006), Health Assessment Questionnaire disability index (p<0.0001), and number of deformed joints (p<0.0001). In sensitivity analyses performed in caucasian Africans, public healthcare attendance associated with increased frequencies of each major conventional risk factor (OR=2.06 to 3.69) and higher other conventional and non-conventional mediated cardiovascular risk. CONCLUSIONS: Public healthcare patients with established RA experience markedly enhanced conventional and non-conventional cardiovascular risk burdens.

High-grade inflammation, circulating adiponectin concentrations and cardiovascular risk factors in severe rheumatoid arthritis.

OBJECTIVE: To assess whether obesity and systemic inflammation are potential determinants of circulating adiponectin concentrations and whether low adiponectin levels cluster with metabolic syndrome features that are previously documented cardiovascular risk factors in rheumatoid arthritis (RA). METHODS: We investigated 33 RA patients who were treated with the TNF-alpha antagonist infliximab, immediately prior to an infliximab infusion. Adiponectin levels were also determined immediately after administration of an infliximab dose. RESULTS: Adiponectin concentrations correlated with age (R=0.465, p=0.008) and were higher in women (mean [95% confidence interval]=21,595 [15,366 to 30,349] ng/ml) than in men (9,310 [5,653 to 15,335] ng/ml)(p=0.008). C-reactive protein (CRP) levels correlated with circulating adiponectin concentrations (partial (p) R=-0.370, p=0.04), independent of age and gender. By contrast, the body mass index (BMI) did not correlate with adiponectin levels (pR=-0.039, p=0.8). Adiponectin concentrations correlated with triglycerides/HDL cholesterol ratios (pR=-0.396, p=0.03), total cholesterol/HDL cholesterol ratios (pR=-0.444, p=0.01) and high fasting plasma glucose levels (pR=-0.366, p=0.04), independent of CRP levels and the BMI. Adiponectin levels did not change (p=0.3) upon infliximab administration. CONCLUSION: In this cohort, high-grade inflammation was independently and negatively correlated with circulating adiponectin concentrations whereas low adiponectin levels clustered with metabolic syndrome features that reportedly contribute to atherogenesis in RA. Circulating adiponectin may be involved in cardiovascular disease in RA. The impact of inflammation on circulating adiponectin concentrations is not likely to be TNF-alpha mediated in RA.

Beta1- and alpha2c-adrenoreceptor variants as predictors of clinical aspects of dilated cardiomyopathy in people of African ancestry.

BACKGROUND: Although the beta1-adrenoreceptor (AR) Gly389Arg and alpha2c-AR Del322-325 gene variants are associated with the response to beta-AR-blocker therapy, whether this effect is associated with the risk for heart failure, or the severity or progression of heart failure is uncertain. AIMS: To assess the relationship between Gly389Arg and Del322-325 variants and the presence, severity and progression of idiopathic dilated cardiomyopathy (IDC) in 403 black South African patients. METHODS: Genotypes were identified using a restriction fragment length polymorphism-based technique and automated sequencing. Left ventricular ejection fraction (LVEF) and dimensions were determined at baseline and in 132 patients after six months of standard medical therapy excluding beta-AR-blockers (not indicated as standard care at the time of completing this study). RESULTS: All patients and controls genotyped for the alpha2c-AR variant were homozygous for the Del322-325 (risk) allele. The Gly389Arg polymorphism was not associated with IDC (control n = 429) (Arg389 allele homozygosity: odds ratio = 1.03, confidence limits = 0.78-1.35), nor did it predict LVEF and cavity dimensions either before or after therapy. CONCLUSION: In patients homozygous for the risk allele of the alpha2c-AR variant, the beta1-AR variant neither increased the risk for IDC nor predicted its severity or progression in patients not receiving beta-AR-blockers.

Beta1- and ? 2c-Adrenoreceptor Variants as Predictors of Clinical Aspects of Dilated Cardiomyopathy in People of African Ancestry : Cardiovascular Topics

Background : Although the Beta1-adrenoreceptor (AR) Gly389Arg and ?2c-AR Del322-325 gene variants are associated with the response to Beta-AR-blocker therapy; whether this effect is associated with the risk for heart failure; or the severity or progression of heart failure is uncertain. Aims : To assess the relationship between Gly389Arg and Del322-325 variants and the presence; severity and progression of idiopathic dilated cardiomyopathy (IDC) in 403 black South African patients. Methods : Genotypes were identified using a restriction fragment length olymorphism-based technique and automated sequencing. Left ventricular ejection fraction (LVEF) and dimensions were determined at baseline and in 132 patients after six months of standard medical therapy excluding Beta- AR-blockers (not indicated as standard care at the time of completing this study). Results : All patients and controls genotyped for the ?2c-AR variant were homozygous for the Del322-325 (risk) allele. The Gly389Arg polymorphism was not associated with IDC (control n = 429) (Arg389 allele homozygosity : odds ratio = 1.03; confidence limits = 0.78-1.35); nor did it predict LVEF and cavity dimensions either before or after therapy. Conclusion : in patients homozygous for the risk allele of the ?2c-AR variant; the Beta1-AR variant neither increased the risk for IDC nor predicted its severity or progression in patients not receiving Beta-AR-blockers

Impact of beta2-adrenoreceptor gene variants on cardiac cavity size and systolic function in idiopathic dilated cardiomyopathy.

In heart failure, the Arg16Gly and Gln27Glu polymorphisms of the beta2-adrenoreceptor (beta2-AR) gene are associated with exercise-capacity, clinical outcomes and response to beta-AR blocker therapy. Whether beta2-AR gene variants mediate these effects in-part through an impact on cardiac structural remodeling and pump function independent of the effects of beta-blockers is uncertain. We evaluated whether the Arg16Gly and Gln27Glu variants of the beta2-AR gene predict left ventricular ejection fraction (LVEF) and LV end diastolic diameter (LVEDD) in patients with idiopathic dilated cardiomyopathy (IDC) before and 6 months after receiving standard medical therapy other than beta-AR blockers. In all, 394 patients with IDC and 393 age and gender-matched controls were genotyped for the beta2-AR gene variants using restriction-fragment length polymorphism-based techniques. LVEF and dimensions were determined in 132 patients (of whom 71 were newly diagnosed) both at baseline and after 6 months. Genotype of neither variant was associated with the presence of IDC. Moreover, beta2-AR genotype did not determine LVEF or LV dimensions prior to initiating therapy. After 6 months of therapy, LVEF increased by 7.1+/-1.0 absolute units (P<0.0001) and LVEDD decreased by 0.27+/-0.06 cm (P<0.02). Adjusting for baseline values as well as gender, age, and type of angiotensin-converting enzyme inhibitor therapy received, genotype was associated with neither final LVEF and LVEDD, nor change in LVEF and LVEDD. In conclusion, these data suggest that in heart failure, the functional Arg16Gly and Gln27Glu variants of the beta2-AR gene have no independent effect on adverse structural remodeling and pump function.

Attenuation of cardiac failure, dilatation, damage, and detrimental interstitial remodeling without regression of hypertrophy in hypertensive rats.

Whether left ventricular (LV) hypertrophy is important in the development of LV failure associated with advanced myocardial damage and detrimental chamber and interstitial remodeling in hypertension has not been established. We examined the effect of an antihypertensive agent without the ability to regress LV hypertrophy on the development of LV changes in spontaneously hypertensive rats (SHR). Hydralazine given to SHR from 5.2 to 26 months of age returned systolic blood pressure to Wistar Kyoto (WKY) control values but failed to prevent the increase in LV mass noted in SHR (at 26 months of age: WKY, 0.99+/-0.02 g; untreated SHR, 1.40+/-0.02 g; treated SHR, 1.36+/-0.02 g; P<0.001 in SHR versus WKY). In comparison to both 16-month-old SHR and age-matched WKY, 26-month-old untreated SHR developed signs consistent with heart failure, LV dilatation (an increased LV internal radius), an eccentric LV geometry, advanced myocyte necrosis, an increase in myocardial collagen solubility (an index of decreases in myocardial collagen cross-linking), and marked increases in myocardial total, type III, and non-cross-linked myocardial collagen concentrations. Despite the inability of hydralazine to regress LV hypertrophy, treated SHR did not develop signs of heart failure, myocyte necrosis, decreases in myocardial collagen cross-linking, or increases in myocardial total, type III, and non-cross-linked collagen at 26 months of age. Moreover, treatment attenuated the development of LV dilatation and an eccentric LV geometry. In conclusion, antihypertensive therapy that does not attenuate LV hypertrophy but achieves normal blood pressure in SHR, is able to hinder the development of heart failure associated with advanced myocardial damage and detrimental chamber and interstitial remodeling.

Association study of eight candidate genes with renin status in mild-to-moderate hypertension in patients of African ancestry.

AIM: We evaluated whether any one variant of genes that encode for substances that could modulate renin-angiotensin-aldosterone (RAA) system activity can account for a substantial proportion of the variability of plasma RAA system profiles in black South African hypertensives (HTs). METHODS: Plasma renin activity (PRA) and aldosterone concentrations (ALD) were determined in 59 black subjects with mild-to-moderate HT off therapy on an ad libitum diet. Patients were genotyped for the angiotensin-converting enzyme (ACE) gene insertion/deletion, angiotensinogen (AGT) gene M235T, A-20C and G-6A, aldosterone synthase (CYP11B2) gene C-344T, G protein beta3-subunit (GNB3) gene C825T, G(s) protein gene C131T, atrial natriuretic peptide (ANP) gene exon 3 stop condon and intron 2, alpha-adducin gene Gly460Trp, and epithelial Na(+) channel (eNa(+) (c)) gene T594M polymorphisms. RESULTS: Risk genotype frequencies for the G(s) (7%), ANP intron 2 (0%), and eNa(+)(c)(7%) variants were too low for each to account for a substantial portion of the variability of plasma RAA profiles in the group studied. Moreover, assuming either recessive or dominant inheritance models, neither ACE, AGT, GNB3, CYP11B2, ANP exon 3 nor alpha-adducin polymorphisms were significantly associated with the variance of PRA, ALD or ALD/PRA. CONCLUSIONS: These results do not support a substantial individual role for the gene candidates studied in contributing to plasma RAA system profiles in black South African HTs. However, a potential small role for some loci may exist, and epistasis or genotype-phenotype interactions as well as alternative inheritance models and variants still need to be evaluated.

Antiadrenergic effects of adenosine in pressure overload hypertrophy.

In the present study, we sought to evaluate whether the antiadrenergic action of adenosine in the heart is altered in pressure overload hypertrophy produced in rats by suprarenal aortic banding. Epicardial and coronary effluent adenosine and inosine concentrations and release were significantly elevated in compensated pressure overload hypertrophy but not in hearts with left ventricular failure. In pressure overload hearts, the contractile response to beta-adrenergic stimulation was less inhibited by incremental concentrations of either adenosine or the selective A(1) receptor agonist chloro-N:(6)-cyclopentyl adenosine than in controls. Furthermore, the extent of desensitization to the antiadrenergic actions of adenosine in pressure overload hypertrophy appeared to be proportional to the extent of chamber dilation and dysfunction. A 60-minute infusion of adenosine produced a sustained antiadrenergic effect that lasted up to 45 minutes after the infusion was terminated in both controls and hearts with compensated hypertrophy. This effect was not observed in the decompensated left ventricular failure group. Subsequent infusion with adenosine of the A(2A) receptor antagonist 8-(3-chlorostyryl)-caffeine to counteract the proadrenergic effect of A(2A) receptor stimulation did not alter the decreased sensitivity to the antiadrenergic actions of adenosine in hypertrophied hearts. Finally, isolated myocytes from hypertrophied hearts demonstrated a decreased ability to suppress isoproterenol-elicited increases in [Ca(2+)](i) transients in the presence of adenosine and the A(2A) receptor antagonist compared with myocytes from control hearts. Myocardial adenosine concentrations increase during the compensated phase of pressure overload hypertrophy but then decrease when there is evidence of decompensation. The antiadrenergic actions of adenosine transduced via the myocardial A(1) receptor are diminished in pressure overload hypertrophied hearts. These factors may render these hearts more vulnerable to the detrimental effects of chronically increased sympathetic activity.

Reduction in myocardial collagen cross-linking parallels left ventricular dilatation in rat models of systolic chamber dysfunction.

BACKGROUND: The transition from compensated left ventricular hypertrophy (LVH) to heart failure is associated with alterations in the myocardial interstitium. We hypothesized that LV dilatation is associated with modifications in collagen cross-linking. METHODS AND RESULTS: We studied 2 rat models of LV dilatation: (1) pressure-overload hypertrophy with heart failure (POH-F) induced by suprarenal abdominal aortic banding and (2) LVH induced by 7 months of isoproterenol (ISO, 0.04 mg x kg(-1) x d(-1)) administration. In POH-F rats and in rats receiving ISO, LV dilatation and a reduced systolic chamber performance were noted. Myocardial hydroxyproline concentrations ([HPRO]) were increased in the POH-F rats, whereas in rats receiving ISO, [HPRO] was decreased. In POH-F rats, the ratio of myocardial collagen type I to type III was increased, but in rats receiving ISO, myocardial collagen I/III was unchanged. In contrast to the diverse changes in myocardial collagen concentrations and phenotypes observed in the 2 models of LV dilatation, the ratio of myocardial insoluble to soluble (relationship between cross-linked and non-cross-linked) collagen was decreased in both the POH-F and ISO groups. Moreover, administration of captopril (0.22 mmol x kg(-1) x d(-1)), which inhibited the ISO-induced reduction in myocardial insoluble/soluble collagen but not the reduction in [HPRO], prevented the ISO-induced alterations in LV dimensions and performance. CONCLUSIONS: Because decreases in the ratio of myocardial insoluble to soluble collagen parallel LV dilatation in rats, reductions in myocardial collagen cross-linking may be an important mechanism contributing to LV dilatation in heart disease.

Substance use/abuse and anxiety sensitivity: what are the relationships?

The eight articles in this special issue on anxiety sensitivity (AS) and substance abuse provide provocative new information on the relationships, or lack of relationships, between AS and several types of substance use and abuse. The eight articles provide data that extend our understanding of the role of AS in substance abuse with younger people, people who use substances other than alcohol, people who have disorders comorbid with substance use disorders, and people who experience chronic headaches. In addition, one of the articles attempts to determine how AS develops in relationship to parental substance abuse. Finally, several of the studies show that the three Anxiety Sensitivity Index (ASI) subscales (physical concerns, social concerns, and psychological concerns) are uniquely associated with different aspects of substance use/abuse. Each of the articles is discussed as to its merits and potential domains that may require additional research. Finally, several general suggestions are provided for new directions that research on the relations of AS and substance use/abuse should take.

Drinking away the hurt: the nature and prevalence of PTSD in substance abuse patients attending a community-based treatment program.

The prevalence of posttraumatic stress disorder (PTSD) was evaluated in 91 participants attending a community-based substance abuse program. The participants were classified as having PTSD, possible PTSD, or no PTSD using the modified PTSD symptom scale (MPSS; Falsetti, Resnick, H. S., Resnick, P. A. & Kilpatrick, 1993). These groups were then compared on measures of anxiety, depression, and fear using the Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Anxiety Sensitivity Index (ASI), and the Fear Questionnaire (FQ). The results showed that 52.8% of participants had either PTSD (37.4%) or possible PTSD (15.4%). Findings also showed that those with PTSD experienced more potentially traumatic events (e.g., rape, being beaten-up) compared to the possible PTSD and no PTSD participants. The PTSD group also reported significantly greater scores on the ASI, BAI, and BDI than did the no PTSD group, and greater scores on the ASI and BAI than did the possible PTSD group. Further, when using a discriminant function analysis, self-report measures correctly classified 70% of the PTSD group and 80% of a composite group of possible PTSD and no PTSD participants. Implications of these results are discussed.

Evidence of a disposition toward fearfulness and vulnerability to posttraumatic stress in dysfunctional pain patients.

Few investigations have addressed whether patient subgroups derived using the Multiaxial Assessment of Pain (MAP) [Turk, D. C., & Rudy, T. E. (1987). Towards a comprehensive assessment of chronic pain patients. Behaviour Research and Therapy, 25, 237-249; Turk, D. C., & Rudy, T. E. (1988). Toward an empirically derived taxonomy of chronic pain patients: integration of psychological assessment data. Journal of Consulting and Clinical Psychology, 56, 233-238.] differ with regard to fear and avoidance. It has, however, been reported that dysfunctional patients exhibit more pain-specific fear and avoidance than patients classified as interpersonally distressed or minimizers/adaptive copers [Asmundson, G. J. G., Norton, G. R., & Allerdings, M. D. (1997). Fear and avoidance in dysfunctional chronic back pain patients. Pain, 69, 231-236.]. We attempted to extend these findings by examining two fear constructs that are receiving increased attention in the chronic pain literature-anxiety sensitivity and PTSD. The sample comprised 115 patients with chronic pain. Of these, 14 (12.2%) were classified as dysfunctional, 21 (18.3%) as interpersonally distressed and 47 (40.8%) as minimizers/adaptive copers. Between-group differences were observed on the fear of cognitive and emotional dyscontrol dimension of anxiety sensitivity, total and symptom cluster scores on the PTSD measure, and depression. No differences were observed for the fear of somatic sensations dimension of anxiety sensitivity or agoraphobia, social phobia, and blood/injury fears. Dysfunctional patients generally exhibited elevated scores relative to one or both of the other MAP subgroups on fear of cognitive and emotional dyscontrol, depressed affect, PTSD symptom total score and PTSD symptom cluster scores. As well, a substantial proportion of dysfunctional and interpersonally distressed patients were classified as having PTSD (71.4 and 42.9%, respectively) when compared to minimizers/adaptive copers (21.3%). These results suggest that MAP subgroups differ with regard to their propensity to be(come) fearful and in their likelihood of having PTSD. Theoretical and clinical implications are discussed.

Alpha-adducin polymorphism in hypertensives of South African ancestry.

The alpha-adducin gene contributes significantly to hypertension in MHS rats (rats of the Milan hypertensive strain) and in some white and Japanese populations, causing a low renin, sodium, and diuretic-sensitive hypertension. No data are available from populations of African ancestry who have a high prevalence of low renin, sodium, and diuretic-sensitive hypertension. We studied the relationship between the 460-Trp variant of alpha-adducin gene with hypertension using a case-control study design in black South Africans. Surprisingly we found that the overall frequency of the 460-Trp allele was low (approximately 6%), but in spite of such relatively low frequency, the 460-Trp allele was 2.5-fold more frequent in hypertensives than normotensives (P = .028), with an odds ratio for hypertension associated to the state of carrier of at least one 460-Trp allele of 2.68. The finding of such low frequency of the 460-Trp allele in individuals of African ancestry points to the substantial ethnic variability of the genes that have been found to be associated with hypertension. On the other hand, it suggests an association of the 460-Trp allele with hypertension also in subjects of African origin.