African Ancestry and Uncontrolled Hypertension: Current Knowledge and Future Perspectives

Hypertension is a major, but modifiable, contributory factor in cardiovascular disease. Its prevalence is constantly rising for several reasons which include the progressive aging of the population.1 Randomized controlled trials have convincingly shown that treatment of hypertension reduces the risk of coronary heart disease and stroke.2 Nonetheless, inadequate blood pressure (BP) control is frequently reported among treated hypertensive patients. It contributes significantly to increased risk of sequelae such as myocardial infarction, heart failure, stroke, kidney disease, and mortality.2 The most comprehensive information concerning the prevalence and determinants of uncontrolled hypertension derives from population-based surveys, community studies, health maintenance organizations, and reports of physician office practices. To date, estimations from population-based surveys suggest that control of hypertension among men is 9.8% in developing countries and 10.8% in developed countries. Similarly, among women control of hypertension is 16.2% and 17.3% in developing and developed countries, respectively.3 Studies spanning several decades have identified several determinants and predictors of poor BP control or conditions associated with uncontrolled hypertension.4 In this context, African Americans and others individuals of African descent may have higher BP beginning in childhood, as well as a higher incidence and prevalence of hypertension across the entire lifespan.5 The age-adjusted prevalence of hypertension in African Americans is about 45%, significantly higher than in other ethnicities, including about 32% among non-Hispanic whites and about 30% among Hispanics.5 Interestingly, blacks accumulate more sodium with increasing sodium intake than whites, resulting in suppression of the renin–aldosterone–angiotensin system due to volume-loading (typically beginning in childhood) and in a low-renin state.6,7 Thus, a low-renin state, which compensates for the relative tendency to retain sodium, ensues. Of note, low-renin hypertension is a frequent cause of hypertension, with a prevalence of 20%–30%, and higher in African Americans.6 In this complex scenario, the analysis of the “Surinamese in the Netherlands: Study on Ethnicity and health” (SUNSET) Study published in the current issue of The American Journal of Hypertension8 adds further insights to understand the potential complex phenomenon linking African ancestry with developing uncontrolled hypertension. Briefly, Brewster et al.8 analyzed data from 1,405 participants to assess performance characteristics of creatine kinase (CK, as a single serum biomarker) vs. self-defined ancestry (African vs. non-African) in predicting uncontrolled hypertension in treated subjects. Control rates (as defined by systolic BP <140 mm Hg and diastolic BP <90 mm Hg) were similar by ancestry (40% in African ancestry vs. 41% in non-African ancestry participants). Mean values of CK in patients with treated controlled and treated uncontrolled hypertension were 124 and 160 IU/l, respectively. Furthermore, control rates of patients with low vs. high CK were 67% vs. 22% for African ancestry and 52% vs. 32% in non-African participants.8 Finally, Brewster et al.8 extended the results of a previous analysis by the same study group9 documenting that CK has the potential to identify hypertensive patients at risk for uncontrolled hypertension across different ancestry groups. More specifically, they demonstrated with their prediction models a better performance characteristics for CK than African ancestry (area under the curve of 0.51 for African ancestry vs. 0.64 for CK; P = 0.02).8 Viewed in the context of available data, the work by Brewster et al.8 has distinct value in that it remarks unresolved concerns about uncontrolled hypertension. Several pathophysiological mechanisms potentially promoting uncontrolled hypertension in individuals of African descent have been documented.6 They include renin–aldosterone–angiotensin system activation, endothelial dysfunction, kidney injury and function, insulin resistance, impaired baroreflex, oxidative stress, genetic factors, adrenomedullary/cortical hormones, blood volume, salt retention, and socioeconomic determinants.6 Several serum biomarkers linked to the aforementioned mechanisms have been investigated to distinguish between uncontrolled and controlled hypertensive patients.10 Three cycles of the third National Health and Nutrition Examination Survey (NHANES III), 2005–2006, 2007–2008, and 2009–2010, were combined to evaluate the causal biomarker pathways of uncontrolled hypertension.10 Results demonstrated that albumin to creatinine ratio, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, apolipoprotein B, and transferrin receptor were associated with the risk of uncontrolled hypertension compared with that of controlled hypertension.10 In this context, results of the analysis by Brewster et al.8 suggest that CK might be employed in clinical practice for the diagnosis and assessment of the severity of hypertension. Although, multidisciplinary studies have established molecular, cellular, organ, and somatic functions of CK, the functions of this enzyme and its high-energy product phosphocreatine are not completely understood. It regenerates adenosine triphosphate in striated muscle, myocardium, and blood vessels and its activity may promote hypertension through enhanced vascular contractility and sodium retention in the kidney.11 Interestingly, some studies showed that serum CK is independently associated with measures of obesity12 and it is a predictor of BP levels and failure of antihypertensive therapy.9,11 Despite years of speculations on the potential mechanisms of uncontrolled hypertension, epidemiological data on BP control in patients of African ancestry are still inconclusive. Moreover, analyses of disparities in BP control often do not take into account several factors linked to pharmacological treatment resistance (medication nonadherence, therapeutic inertia, comorbidities, and target organ damages). The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study found an association between African American race and refractory hypertension (Figure 1a).13 Associations of African ancestry with uncontrolled/resistant hypertension. Data from refs. 8, 13, 14, 18. See text for details. *Hypertensive participants except those with refractory hypertension.. Using electronic health records of European-American and African-American patients with hypertension, Shuey et al. demonstrated that the prevalence of resistant hypertension was higher among African-American patients (Figure 1b).14 Moreover, African-American patients were younger, heavier, more often female and had a higher incidence of type 2 diabetes and higher BP values than European-American.14 A recent analysis of multiple NHANES cycles showed that refractory hypertension (as defined by uncontrolled BP when on 5 or more classes of antihypertensive medication) was associated with advancing age, lower household income, black race, chronic kidney disease, albuminuria, diabetes, prior stroke, and coronary heart disease.15 Conversely, other studies,16,17 including the Resistant Hypertension Optimal Treatment (ReHOT) randomized study (Figure 1c)18 and the present analysis by Brewster et al. (Figure 1d),8 do not support the association between African ancestry and poorer BP control. Notably, the ReHOT study18 evaluated the association between genetic ancestry (defined using a panel of 192 polymorphic markers) and resistant hypertension (as defined by uncontrolled BP despite treatment with 3 or more antihypertensive medications, including a diuretic in adequate doses). It evaluated 1,358 patients, of which 167 were defined as resistant hypertensive. The genetic ancestry was similar in resistant and nonresistant hypertensive patients. Only a statistically suggestive association of African ancestry with resistant hypertension in nonwhite patient groups was documented.18 In conclusion, despite the well-documented evidence of the increased cardiovascular risk associated with uncontrolled hypertension and the multiple documentations of benefits of treating this condition, many challenges remain. Several factors related to poor BP control have been identified, including patient-related (age, sex, race, ethnicity, severity of disease, health habits, and comorbidities) and physician-related factors (knowledge base, perceptions about the care delivered, and practice patterns).4 In addition to the underlying pathophysiology, the impact of African ancestry on the risk of developing uncontrolled hypertension needs to be fully elucidated. In our opinion, clinical and genetic data of African ancestry should be interpreted with caution. In clinical practice, it is more important to evaluate a patient’s family history, habits, comorbidity, and development of target organ damages than to assess his or her race. In other words, a clinical evaluation focusing exclusively on one level (race) lose track of interlevel connections (diet, history, biochemical data, comorbidities, and social status). We share the opinion of Brewster et al. that the use of race as a driving factor in hypertension therapeutic individualization should be disregarded. Remarkably, black race or African ancestry may be related in a complex manner to hypertension control for the potential interaction with multiple additional factors, including immigrant status, access to care, susceptibility to hypertension, comorbid conditions, and geographic region.4,19 For example, an analysis of the NHANES III calculated the age-adjusted prevalence rates of uncontrolled hypertension in US-born northern African Americans, US-born southern African Americans, and foreign-born African Americans.19 Hypertension was more common among southern African-American men and women, compared with northern African-American men and women (42.2% vs. 34.1%, P < 0.002 for men; 42.7% vs. 37.2%, P = 0.02 for women).19 Furthermore, uncontrolled hypertension was also more common among hypertensive southern African-American women compared with hypertensive northern African-American women (79.8% vs. 70.4%).19 Finally, epidemiological evidence supporting the worse prognosis associated with uncontrolled hypertension provides a strong basis for developing risk prediction models to identify patients at increased risk of developing this condition. Remarkably, Buhnerkempe et al. modeled a novel easy-to-use clinical score (using patient characteristics at index visit as predictors) that discriminated well between patients with or without the development of apparent treatment-resistant hypertension.20 The development of risk prediction models is often difficult for several reasons, including the impact of complex and frequently interconnected potential determinants. In our case, we are facing several important factors beyond race which may include medication adherence, presence of comorbid illness, patient knowledge, patterns of treatment, and systems of care. Further studies are needed to provide a better understanding of the key basic processes in the development of uncontrolled hypertension. Current data, including the promising role of CK as shown by Brewster et al.,8 do not yet support the use of a single condition or biomarker to predict this phenomenon. None of the authors has financial or other reasons that could lead to a conflict of interest.