Neural control of cardiovascular function in black adults: implications for racial differences in autonomic regulation

Abstract

Black adults are at increased risk for developing hypertension and cardiovascular and chronic kidney disease and have greater associated morbidity/mortality than white adults who are otherwise demographically similar. Despite the key role of the autonomic nervous system in the regulation of cardiovascular function, the mechanistic contributions of sympathetic nerves to racial differences in cardiovascular dysfunction and disease remain poorly understood. In this review, we present an update and synthesis of current understanding regarding the roles of autonomic neural mechanisms in normal and pathophysiological cardiovascular control in black and white adults. At rest, many hemodynamic and autonomic variables, including blood pressure, cardiac output, and sympathetic nerve activity, are similar in healthy black and white adults. However, resting sympathetic vascular transduction and carotid baroreflex responses are altered in ways that tend to promote increased vasoconstriction and higher blood pressure, even in healthy, normotensive black adults. Acute sympathoexcitatory maneuvers, including exercise and cold pressor test, often result in augmented sympathetic and hemodynamic responses in healthy black adults. Clinically, although mechanistic evidence is scarce in this area, existing data support the idea that excessive sympathetic activation and/or transduction into peripheral vasoconstriction contribute importantly to the pathophysiology of hypertension and chronic kidney disease in black compared with white adults. Important areas for future work include more detailed study of sympathetic and hemodynamic reactivity to exercise and other stressors in male and female black adults and, particularly, sympathetic control of renal function, an important area of clinical concern in black patients.

INTRODUCTION

The autonomic nervous system is the major integrator of blood pressure (BP) regulation in humans. Cardiac parasympathetic and sympathetic nerves control heart rate (HR) and cardiac contractility, whereas vascular sympathetic nerves control vasoconstriction and vasodilation in the periphery and, thus, are major contributors to total peripheral resistance. Renal sympathetic nerves, which control renal vascular, glomerular, tubular, and hormonal function, are an important link between sympathetic neural control of the circulation and renal control of blood volume and fluid homeostasis.

From a public health perspective, it is known that there are racial differences in BP regulation and that differences in autonomic regulation may play a role. In particular, black adults are at higher risk for development of hypertension than are non-Hispanic white adults (6). Indeed, the prevalence of hypertension is substantially higher for both males and females of African descent than for white adults of similar age (57). The increased rates of hypertension put black adults at increased risk for early morbidity and mortality from stroke, myocardial infarction, and end-stage renal disease (ESRD). Although data such as these are available epidemiologically, the mechanisms underpinning the population differences are less clear. Given the greater level of chronic stress often experienced by black adults due to systemic racism and social and environmental factors, the associated negative impact of increased stress on cardiovascular health could underlie the physiological differences in BP regulation between black and white adults (14). From a clinical perspective, increasing evidence indicates that hypertension must be addressed in a multifactorial manner, not only from medical and pharmacological perspectives, but with approaches that incorporate social and cultural components as well (74). The focus of this brief review is limited to the physiological aspects of potential differences between black and white adults in BP control by the autonomic nervous system.

OVERVIEW OF AUTONOMIC CONTROL OF CARDIOVASCULAR FUNCTION IN HUMANS

The autonomic nervous system is the primary neural regulator of cardiovascular function in humans. In terms of cardiovascular control, the autonomic system has two functional subsystems: the sympathetic and parasympathetic nervous systems. These systems are often presented to students in terms of the “fight-or-flight” response, which is an important (and emphatic) way to present the function of the sympathetic arm of the autonomic nervous system. However, the fight-or-flight response presents the autonomic nervous system in terms of an “all-or-none” response surge in the cardiovascular system. In actuality, regulation of blood flow and BP by the autonomic nervous system is usually much more subtle, but no less critical to health and well-being, than fighting or fleeing for one’s life.

Sympathetic and parasympathetic innervation of the heart, blood vessels, kidneys, and adrenal medulla provide beat-to-beat regulation of blood flow and BP, as well as long-term regulation that extends over hours, days, and months (26, 52, 77). Sympathetic postganglionic nerves release norepinephrine (NE), which interacts with α-adrenergic receptors at the level of the heart and blood vessels, and cotransmitters (e.g., ATP and neuropeptide Y), which are often released with higher levels or different patterns of sympathetic stimulation (46, 54). The major effects of sympathetic activation are increases in HR (via stimulation of sinoatrial and atrioventricular nodes at the heart), cardiac contractility (via the myocardium), and increases in peripheral vascular resistance via adrenergic receptor-mediated vasoconstriction (16). Since sympathetic activation augments all three factors that contribute to arterial BP regulation [i.e., mean arterial BP (MAP) = HR × stroke volume × total peripheral resistance], activation of the sympathetic nervous system (SNS) results (when all else is equal) in an increase in arterial pressure.

Parasympathetic activation in humans occurs primarily via the cardiac vagus nerve and mainly affects HR. The vagus nerve releases acetylcholine, which interacts with muscarinic cholinergic receptors at the sinoatrial and atrioventricular nodes to slow the rate of cardiac contraction. Because of the tonic activity of the vagus nerve at rest in healthy humans, a decrease in parasympathetic/vagal activity is a rapid way to increase HR. Both sympathetic and parasympathetic influences on HR occur via the diastolic depolarization (pacemaker potential) phase of the autorhythmic components of sinoatrial and atrioventricular node cells. NE binding to β-adrenergic receptors causes an increase in the slope of the diastolic depolarization, thus increasing HR (30). Acetylcholine has the opposite effect, causing hyperpolarization and a decrease in the slope and decreasing HR.

The autonomic nervous system is responsible for the rapid changes in blood flow and BP in response to daily activities such as changes in posture, temperature, and activity. Autonomically mediated increases in HR and contractility, as well as peripheral sympathetic vasoconstriction, are essential for “successful” orthostasis in healthy people (i.e., standing up without feeling dizzy, lightheaded, or fatigued) (20). During exercise, autonomic control of blood flow and BP allows appropriate increases in perfusion of active skeletal muscle while maintaining blood flow and perfusion pressure at appropriate levels for the rest of the body (31). Changes in body temperature elicit important responses in sympathetic control of skin blood flow and sweating, which are required to keep body temperature within a safe range during environmental stressors of heat and cold and during exercise (15).

Because of the importance of responses such as these for successful activities of daily living, it was historically thought that the autonomic nervous system only controlled BP in the very short term, over seconds to minutes. However, over recent years, increasing evidence indicates important roles for autonomic control mechanisms in long-term control of arterial pressure in humans (26, 52, 77). Thus, tonic levels of sympathetic and parasympathetic nerve activity, as well as responsiveness to various stressors, are important contributors to long-term BP control and cardiovascular health over the lifespan.

MEASUREMENT OF AUTONOMIC NERVOUS SYSTEM ACTIVITY IN HUMANS

Direct measurement of autonomic neural activity in humans is challenging (38, 44). Traditionally, a relatively simple way to measure global sympathetic activation was to measure circulating NE (and epinephrine) levels in the plasma. While plasma NE can provide a good index of sympathetic activation in many situations (28, 39, 41), these values can be misleading under some circumstances due to differences in NE release, reuptake, clearance, and/or metabolism that can occur in different situations or populations. A more direct approach is to directly measure activity in peripheral sympathetic nerves via microneurography, where a microelectrode is inserted percutaneously near the nerve of interest (usually the fibular, tibial, median, or radial nerve) (44, 64, 96). The major strength of microneurography is the ability to directly record the electrical activity of sympathetic nerves in real time. Limitations are that microneurography is very labor-intensive and requires a high level of skill and training, and the subject must keep the limb with the recording electrode relaxed, limiting the types of stimuli (such as whole body exercise) that can be applied during recordings.

The NE-spillover technique (26) involves infusion of radiolabeled NE to quantify noradrenergic innervation to specific vascular beds. Given that sympathetic innervation can be heterogeneous, a major advantage of the NE-spillover technique is the ability to quantify organ- or tissue-specific sympathetic activation in areas that are inaccessible by microneurography. However, its use is limited because of its invasive nature and the requirement for extensive laboratory and medical resources.

Spectral (or frequency) analysis describes a range of approaches that can be used to analyze the variability of HR or BP in the frequency domain (8, 71). With use of certain assumptions regarding neural transmission frequency and neurotransmitter-receptor dynamics, the variability of HR is analyzed in terms of its frequency characteristics (7). While these approaches are popular due to their ease of use (since many automated systems can detect HR variability indexes with only a 3-lead electrocardiogram), one must be cautious not to overinterpret data (63).

Doppler ultrasound has been utilized as a more feasible and noninvasive approach to assess sympathetic neural outflow directed to the kidneys in humans (70). As sympathetically mediated renal vasoconstriction occurs in the afferent arterioles within the renal cortex inside the kidneys, changes in renal vascular resistance occur downstream of the renal arteries, resulting in changes in blood flow velocity and, therefore, blood flow in the renal arteries themselves. Therefore, Doppler ultrasound can be used to measure the beat-to-beat velocity of blood flowing through a renal artery, and an index of renal vascular resistance is calculated based on the renal blood flow velocity. As renal arterial diameter does not change with decreased or increased renal blood flow as assessed by renal angiography, renal blood flow velocity can be taken to represent renal blood flow (65). While this approach is technically challenging, it has been used to provide an index of sympathetically mediated renal vasoconstriction at rest and during experimental interventions including exercise (23), cold pressor test (CPT) (86), mental stress (56), and orthostatic stress (18).

NEURAL CONTROL OF CARDIOVASCULAR FUNCTION IN HEALTHY BLACK ADULTS

Historically, most of the literature on the neural control of cardiovascular function in humans has been based on studies of groups that were wholly or predominantly volunteers who identified as white, with the inclusion of smaller percentages of individuals from other racial identity groups, such as blacks, Asians, and Native Americans (when included at all). This has resulted in a paucity of research on racial differences in the neural control of cardiovascular function in humans. Importantly, this relative lack of research focus has occurred despite clear health disparities among different racial identity groups, such as the higher incidence of hypertension and renal disease in black adults (14, 93). Therefore, while some research has been conducted in this area in recent years, more studies focused on assessing racial differences in the neural control of cardiovascular function in humans are necessary from both clinical and basic science perspectives to provide foundational knowledge that can be used to more comprehensively address existing significant health disparities related to racial identity.

Autonomic and Cardiovascular Values at Rest

The majority of studies have shown that healthy young black and white adults have similar resting systolic BP (SBP), diastolic BP (DBP), and mean BP (4, 12, 33, 34, 48, 49, 87, 88, 91, 94, 95). Some studies have reported slightly higher resting BPs (25, 92), greater central SBP (measured in the aorta, rather than the brachial artery) (45), and a higher likelihood of reduced SBP “dipping” during nighttime sleep in black than white adults (90). Similar resting values between black and white adults have also been identified for HR (4, 12, 33, 34, 48, 49, 87, 88, 91, 94, 95), cardiac output (48, 95), muscle sympathetic nerve activity (MSNA) burst frequency and incidence (12, 33, 87, 94), forearm and systemic NE spillover (91), forearm vascular resistance/conductance and blood flow (4, 34, 87, 91), and leg vascular resistance/conductance and blood flow (94). Current findings comparing spontaneous sympathetic and cardiovagal baroreflex sensitivity in black and white adults show either similar values (33, 34) or lower spontaneous cardiovagal baroreflex sensitivity in healthy young female black adults (59), with HR variability in terms of low-frequency/high-frequency power shown to be either similar in black and white adults (34) or lower in black adults (17). However, potential differences between healthy young black and white adults have been identified in two areas of neural control of cardiovascular function: sympathetic vascular transduction and carotid baroreflex function.

Sympathetic vascular transduction (defined as the increase in vascular resistance in response to a given increase in sympathetic nerve activity) appears to be greater in black than white adults (24, 91, 94). Furthermore, infusion of phenylephrine, an α₁-adrenergic agonist, has been shown to cause a larger percent decrease in forearm blood flow (91) and a greater increase in SBP (24) in black than white individuals. Vranish et al. reported that, on a beat-to-beat basis, black adults exhibited larger percent decreases in leg and total vascular conductance and a greater increase in MAP following MSNA bursts at rest than white adults (94) (Fig. 1). Total peripheral resistance has also been shown to be higher at rest in black than white adults (95). Black adults have smaller increases in forearm blood flow in response to intra-arterial infusion of the β-adrenergic agonist isoproterenol (91). This reduced vasodilatory capacity in black compared with white adults may lead to less dampening of the transduction of sympathetic nerve activity into increased vascular resistance in this population, thereby amplifying the apparent enhanced vasoconstrictor responsiveness observed in black adults. Therefore, these findings support the idea that a heightened sensitivity of vascular α₁-adrenergic receptors in healthy young black adults contributes to exaggerated sympathetic vascular transduction.

Fig. 1.

Effect of spontaneous muscle sympathetic nerve activity (MSNA) bursts on mean arterial pressure (MAP). A: absolute increases in MAP over the 10 cardiac cycles immediately following spontaneous MSNA bursts. B: peak increase in MAP following spontaneous MSNA bursts. Black (AA) participants are denoted by filled symbols and bars and white (CA) participants by open symbols and bars. *P < 0.05 vs. white participants (CA). [From Vranish et al. (94) with permission.]

Regarding carotid baroreflex function, whereby acute baroreflex-mediated HR and MAP responses to simulated hypotension and hypertension at the carotid baroreceptors are assessed, Holwerda et al. identified smaller MAP and HR decreases in response to acute carotid hypertension at rest in black than white adults (49, 50). These authors also reported a smaller MAP increase in response to acute carotid hypotension at rest in black than white adults in one, but not both, of their recent studies (49, 50), with the reason for these discrepant findings remaining unclear. The implication of these findings is that healthy young black adults have a reduced ability to withdraw sympathetic neural outflow to the heart and vasculature and/or restore cardiac parasympathetic activity to “correct” an acute hypertensive stimulus.

Collectively, observations in healthy young black adults indicate that they likely exhibit greater sympathetic responsiveness via exaggerated sympathetic vascular transduction. From a long-term health perspective, this could be one mechanism by which the risk for development of hypertension tends to be higher for black than white adults (14, 93). An important note regarding these existing observations is that most studies involved only male volunteers. Of 19 studies, 11 included only men (4, 24, 32, 34, 45, 49, 50, 88, 91, 94, 95), 2 included only women (48, 59), and only 6 included both men and women (12, 17, 25, 87, 90, 92). Given the clinical significance of understanding neural control of cardiovascular function in both men and women, and considering the greater incidence and prevalence of cardiovascular and renal diseases in black adults, it is imperative that future studies in this area involve both male and female volunteers to provide data that can uncover the potential physiological mechanisms underlying the increased cardiovascular risk in this population.

Exercise

Whether the BP response to exercise in healthy black adults is augmented compared with healthy white adults is unclear. In some studies, the SBP increase during exercise was greater in black than white adults (25, 92, 95), while in other studies, this response was similar between groups (24, 25, 50). A greater DBP increase during exercise was identified in black than white adults in most (24, 67, 95), but not all (50), studies. In some studies (24, 95), the MAP increase during exercise was greater in black than white adults; in other studies, the response was similar in black and white adults (4, 50). Overall, it appears that healthy young black adults may exhibit a greater DBP increase in response to exercise, while the SBP and MAP increases are more variable. The disparities among findings could be due to the different modes of exercise (e.g., treadmill exercise, stepping, cycling, or isometric or rhythmic handgrip) and the associated muscle mass involved, the duration and/or intensity of the exercise, and the distribution of male and female volunteers. Of these seven studies that assessed the BP response to exercise in black adults (4, 24, 25, 50, 67, 92, 95), all included men, but only three also included women.

Given that the BP response to exercise is determined by the interaction between cardiac output and total peripheral resistance, important information can be discerned from examining those physiological mechanisms during exercise that could explain this apparent greater DBP increase during exercise in black adults. The increase in cardiac output during exercise has been shown to be similar in black and white adults (95), as has the HR increase during exercise (4, 24, 50, 67, 95). However, total peripheral resistance during exercise has been found to be greater in black adults (95), as has forearm vascular resistance following exercise (5). A smaller increase in forearm vascular conductance during exercise was reported in black adults, resulting in a smaller forearm blood flow increase during exercise (4) (Fig. 2). Interestingly, brachial artery vasodilation during exercise and flow-mediated dilation were not different between black and white adults (4), suggesting that black adults did not have a reduced vasodilatory capacity. Thus, a higher level of vascular resistance likely contributes to the greater DBP increase during exercise in healthy black adults. This heightened vascular resistance during exercise in black adults is in line with the exaggerated sympathetic vascular transduction that appears to exist in this population.

Fig. 2.

Forearm vascular conductance (A), forearm blood flow (B), and mean arterial pressure (C) in healthy young male white (CA) and black (AA) participants at rest [baseline (BL)] and at the end of rhythmic handgrip trials with incremental absolute workloads from 4 to 24 kg. *P < 0.05 vs. black participants (AA). [From Barbosa et al. (4).]

Similar to findings at rest, carotid baroreflex control of cardiovascular function also appears different between healthy young black and white adults during exercise. Smaller MAP and HR decreases in response to acute carotid hypertension during exercise have been described in black than white adults (50). These smaller negative chronotropic and depressor responses during exercise in black adults imply that the ability of the carotid baroreflex to respond appropriately to an acute hypertensive stimulus during exercise is impaired in this group.

Collectively, current findings in healthy young black adults during exercise suggest a tendency toward a higher level of vascular resistance, leading to a greater DBP increase, and a lower ability to buffer BP in response to acute hypertensive stimuli. These observations align with findings of exaggerated sympathetic vascular transduction and a reduced capacity to withdraw sympathetic neural outflow to the heart and vasculature and/or restore cardiac parasympathetic activity in response to a hypertensive stimulus in this population at rest.

Cold Pressor Test

In response to a CPT, a non-baroreflex-mediated sympathetic stressor involving immersion of a hand or foot in ice water, black adults exhibit a greater increase in SBP (67, 88, 92) than white adults, with a similar increase in DBP (67, 88, 92). When MAP has been reported, the increase in MAP in response to a CPT is either larger in black than white adults (12) or similar in black and white adults (91). Given the association between a heightened SBP response to CPT and greater future incidence of hypertension (69), this exaggerated SBP reactivity to CPT in healthy young black adults is in line with the concept that black adults develop hypertension at a greater rate and from an earlier age than white adults (93).

Regarding potential mechanisms for these CPT responses, the HR increase to CPT is similar in black and white adults (67, 88, 91). However, greater increases in MSNA burst frequency and total MSNA during CPT have been reported in black than white adults (12). A larger increase in forearm vascular resistance in black than white adults, along with similar levels of forearm and systemic NE spillover in response to CPT in black and white adults, has also been documented (91). These findings imply that enhanced sympathetic neural outflow to the vasculature and/or heightened sympathetic vascular transduction, rather than cardiac-related mechanisms, likely contribute to the greater increase in SBP in response to a CPT in black adults.

Findings from a longitudinal study involving female black adults showed that SBP and MAP increases in response to CPT were attenuated following aerobic exercise training (10). However, findings from a cross-sectional study of male black adults found that increases in SBP, DBP, MAP, HR, cardiac index, forearm blood flow, and total peripheral resistance in response to CPT were similar in volunteers who regularly performed aerobic exercise and volunteers who were not physically active (9). Whether the difference between these findings represents a sex difference in the influence of exercise training on hemodynamic responsiveness to CPT between male and female black adults requires further study.

Overall, findings from studies utilizing CPT are consistent with the concept of exaggerated sympathetic reactivity in healthy young black compared with white adults. Importantly, it appears possible that this exaggerated sympathetic responsiveness can be reduced following aerobic exercise training. As an acute laboratory-based protocol, CPT has been shown to invoke reproducible MSNA responses, although the racial identity of the participants was not stated by the authors (27). Therefore, studies involving more comprehensive measurements of sympathetic and cardiovascular variables would be helpful in providing more detailed information about these neurovascular responses to a CPT before and after exercise training, particularly given the potential therapeutic benefits of exercise training.

Mental Stress

Mental stress in the form of acute laboratory-based protocols designed to induce psychological stress with minimal physical movement, such as performance of mental arithmetic or the Stroop color-naming task, has been shown to cause a smaller (67) or similar (67, 88) SBP increase, a similar DBP increase (67, 88), or a tendency for smaller SBP, DBP, and MAP increases (33) in healthy black than white adults. The HR increase to mental stress was similar in black and white adults (33, 67, 88). From these somewhat inconsistent findings, it is unclear if there are disparate BP responses to mental stress in black and white adults. Furthermore, without specific measurements of stroke volume, cardiac output, and total peripheral resistance during mental stress in black adults, it is unknown whether there are differences in the cardiac and/or peripheral vasoconstrictor responses to mental stress in black and white adults and whether differences in either or both of these physiological mechanisms contribute to any disparate BP responses to mental stress between these groups.

A decrease in MSNA burst frequency during the first minute of mental stress in black adults, in contrast to an increase in MSNA burst frequency in white adults, has been reported (33). In this study, similar MSNA burst incidence and total MSNA changes in each minute of mental stress between black and white adults were also observed (33). Close inspection of these data reveals that during the first minute of mental stress in which these divergent MSNA burst frequency responses occurred in black and white adults, both groups exhibit almost identical increases in SBP, DBP, and MAP (33). These intriguing findings could align with the concept of exaggerated sympathetic vascular transduction in black adults, in that a larger BP increase per MSNA burst occurred during mental stress in this population.

Future studies focusing on these sympathetic and cardiovascular changes would provide further insight into the mechanisms contributing to these neurovascular responses to mental stress in black adults. In light of the greater levels of psychological stress often experienced in this population and the associated negative impacts of increased stress on cardiovascular health in black adults (11, 98), future findings in this area would be of high clinical importance. Of additional consideration, information regarding participants’ education level and socioeconomic status in existing studies in this area has been included but only briefly discussed (88), partially included but not statistically analyzed (67), or not included (33). For future studies, it would be informative to include information and/or a more thorough assessment regarding participants’ education level and socioeconomic status to consider the level of matching for these factors in participants across racial identity groups. Also, an area related to mental stress that is beginning to receive greater attention in research is sleep quality and duration and the associated links with cardiovascular disease. The effects of sleep quality and duration on sympathetic reactivity in black adults is an important topic that warrants investigation, particularly given the higher incidence of poorer sleep quality and duration in this population (14) and their greater risk of developing hypertension and cardiovascular and renal diseases (14, 93).

Orthostatic Stress

Orthostatic stress, defined as the gravitational stress experienced by cardiovascular and other systems when an individual moves from a supine to an upright position, can be simulated using lower-body negative pressure (LBNP). During LBNP, similar decreases in SBP and no changes in DBP and MAP have been observed in black and white adults (48, 87, 91). Similar HR increases in response to simulated orthostatic stress have been illustrated in some (87, 91), but not all (48), studies of black and white adults. In a group of female black adults, Hinds and Stachenfeld reported a greater HR increase during simulated orthostatic stress that likely contributed to a greater level of orthostatic stress in the female black adults than the female white adults in this study (48). Higher plasma NE levels in the female black adults suggested that increased sympathetic reactivity to LBNP may have also contributed to their improved LBNP tolerance (48).

In response to acute simulations of orthostatic stress, black adults have been shown to exhibit neurovascular responses that are mostly similar to those of white adults. These similar neurovascular responses include increased MSNA burst frequency (87), unchanged forearm and systemic NE spillover (91), increased forearm vascular resistance (87, 91), decreased forearm blood flow (87, 91), and spontaneous cardiovagal baroreflex sensitivity (48). In one study, however, the increase in total MSNA during simulated orthostatic stress was smaller in black than white adults (87). In this study, as the smaller total MSNA increase in black adults occurred with a similar increase in forearm vascular resistance in both black and white adults, this finding implies greater sympathetic vascular transduction in black than white adults (87) and further supports this concept. Black adults have also been documented to experience a greater increase in plasma renin activity in response to simulated orthostatic stress than white adults (48). Although it is unclear if this larger response was linked with the lower baseline plasma renin activity level in black adults (48), this finding suggests that sympathetic neural outflow directed to the kidneys may be higher in black than white adults. Given the importance of this physiological mechanism to BP regulation and the greater incidence of hypertension in the black population, further information regarding this area of neurovascular control would be clinically beneficial.

SYMPATHETIC FUNCTION IN DISEASE STATES IN BLACK ADULTS

Emerging evidence suggests racial differences in sympathetic reactivity, transduction, and regulation in healthy individuals. While much is still unknown in this area, healthy male black adults have been shown to have chronic overactivation and increased neurovascular transduction of the SNS that may predispose this population to a greater risk of developing hypertension and cardiovascular disease. Even less is known about autonomic function in disease states in black adults. Multiple chronic diseases associated with increased cardiovascular disease risk, including hypertension, chronic kidney disease (CKD), heart failure, vascular disease, obesity, obstructive sleep apnea, and posttraumatic stress disorder, are characterized by SNS overactivity that has clinical prognostic significance (1, 13, 39, 40, 60, 75, 82). While burdens of these chronic diseases are higher in black adults and autonomic physiology within these patient groups is likely impacted and affects clinical outcomes, there is a paucity of data regarding racial differences in autonomic function in chronic disease states. To our knowledge, there have been no studies of racial differences in neural control of the cardiovascular system in coronary or peripheral vascular disease or chronic heart failure, while only a few studies of hypertension and CKD have either directly compared or included a significant proportion of black patients. In this section, we will review autonomic function in hypertension (both essential and obesity-related) and CKD in black adults and highlight potential areas of future research.

Hypertension

Approximately 29% of US adults have hypertension, a major risk factor for stroke, coronary disease, renal disease, and heart failure (36). The prevalence of hypertension is substantially higher among non-Hispanic black adults (~41%) than non-Hispanic white adults, while hypertension control rates remain substantially lower in black adults (36). Moreover, black adults have poorer hypertension-related disease outcomes, including a twofold greater risk of stroke, as well as earlier onset of hypertension-related complications such as kidney disease (57). Hypertension accounts for 50% of the racial disparities in life expectancy between black and white adults (74). The socioeconomic and biological mechanisms that underlie racial disparities in hypertension prevalence, severity, and outcomes are complex and not fully elucidated; potential mechanisms include differences in salt sensitivity, medication adherence, and adrenergic reactivity (29, 57, 74).

Most (39, 99), although not all (72), studies have shown that resting MSNA is elevated in patients with essential hypertension. Although black adults appear to exhibit increased sympathetically mediated vasoconstriction that likely increases their propensity for developing hypertension, whether resting MSNA in black patients with established essential hypertension is further augmented is less clear. One study showed no differences in resting MSNA or MSNA and BP reactivity during sympathoexcitation between 13 black patients with hypertension and 13 matched white patients with hypertension (13), suggesting that sympathetic nerve activity directed to the muscle is not greater in hypertensive black than white adults with a similar degree of established hypertension. Another study showed no differences in baroreceptor reflex sensitivity between hypertensive black and hypertensive white patients (89).

While sympathetic nerve activity may not be augmented in black compared with white adults with comorbid hypertension, there is greater evidence that vasoconstriction in response to sympathetic activation (94), i.e., sympathetic neurovascular transduction, is elevated in black adults with hypertension (similar to that seen in normotensive black and white groups). This heightened neurovascular transduction in black adults appears to persist after the development of comorbid hypertension. Early work showed heightened BP responses to infused NE in hypertensive black adults who consumed a high-salt diet, whereas pressor sensitivity was blunted in hypertensive white adults who consumed a high-salt diet (21). Similarly, an acute hypertonic saline load led to a greater BP responsiveness to a given increase in serum sodium concentrations in black than white adults (97). Stein et al. showed that black adults have heightened vascular α₁-adrenergic receptor sensitivity (91), which could be one potential mechanism contributing to enhanced sympathetic neurovascular transduction in black adults with hypertension. Whether heightened adrenergic sensitivity is accompanied by derangements in end-organ function or augmented sympathetically mediated vasoconstriction in organs such as the kidney remains unclear.

In contrast to essential hypertension, in which resting MSNA is generally not elevated in black compared with white adults with established hypertension, SNS overactivity appears to play a greater mechanistic role in the link between obesity and obesity-related hypertension in black adults. People who are overweight or obese tend to have chronic elevations in MSNA, augmented sympathetic reactivity, and impaired baroreflex sensitivity, the mechanisms of which include hyperleptinemia, hyperinsulinemia, and activation of the renin-angiotensin system (3, 42, 58, 83). A previous study showed significantly higher resting MSNA in otherwise healthy female black adults with increasing adiposity than in lean female black adults, whereas resting MSNA was significantly higher in male black than male white adults, independent of obesity (1). In a subsequent study, weight reduction through diet had no effect on MSNA in male black adults, whereas MSNA was significantly reduced by weight loss in female black adults (2). Longitudinal studies are needed to determine whether SNS overactivity in black adults with hypertension is linked to poorer long-term cardiovascular and mortality outcomes and whether interventions such as weight loss can be optimized to improve autonomic balance and clinical outcomes in these patients.

Chronic Kidney Disease

Approximately 30 million people (~14% of US adults) have CKD and are at up to 5- to 15-fold greater risk of cardiovascular complications and mortality than the general population (37, 66). Even minimal reductions in renal function are associated with significantly higher cardiovascular risk (37, 47, 66), and decreased renal function itself is an independent risk factor for death. One major mechanism underlying increased cardiovascular risk in CKD is a chronic elevation of SNS activity (53). Studies have shown that MSNA is chronically elevated in patients with both ESRD and CKD, beginning at early stages of CKD (40, 55, 78, 79). Mechanisms by which reduced renal function is linked to SNS overactivation include renal afferent nerve activation, impaired baroreflex sensitivity, accumulation of uremic toxins such as asymmetric dimethylarginine, activation of the renin-angiotensin system, and oxidative stress (51, 76).

Black adults are at significantly greater risk of developing kidney disease than are white adults. While black adults comprise 15% of the US population, they make up 30% of patients with CKD (43). Black adults have a significantly greater risk of progressing to ESRD than white adults and reach ESRD at an earlier age (68). In addition, data from the National Health and Nutrition Examination suggest that while the prevalence of CKD has stabilized in non-Hispanic white adults, the prevalence of CKD continues to increase over time in black adults (73). Genetic factors, particularly mutations in apolipoprotein L1 found exclusively in individuals of African descent, confer a substantially increased risk of a spectrum of kidney diseases, including hypertension-associated kidney disease, and are also associated with a more rapid decline in kidney function over time in black adults (35, 85).

To our knowledge, none of the earlier studies of CKD patients directly compared autonomic function within CKD and ESRD cohorts between racial identity groups. Indeed, most studies did not report the distribution of racial identities in the study population (19, 55, 61, 100). More recently, in a study comprising primarily male black adults, resting MSNA was not higher in those with CKD stages III and IV than in matched hypertensive controls without kidney disease (84). However, the same study showed exaggerated BP reactivity in CKD patients during handgrip exercise. After BP responses were equalized and differences in arterial baroreflex modulation were eliminated, patients with CKD had exaggerated increases in MSNA due to heightened muscle mechanoreceptor-mediated activation. Thus, heightened BP reactivity during exercise in a primarily black cohort of CKD patients was, in part, due to augmented SNS activation. In a study that enrolled >85% black patients with CKD (22), augmented BP responses during a maximal treadmill test correlated with endothelial dysfunction, quantified as low brachial artery flow-mediated dilation. Subsequent studies have shown that MSNA and BP can be acutely lowered with mindfulness meditation in male black patients with CKD (81) (Fig. 3) and that chronic treatment with tetrahydrobiopterin, a cofactor for nitric oxide synthase, lowers resting MSNA and improves measures of vascular stiffness in a study population comprising predominantly male black patients (30 black and 2 white patients) (80). Tetrahydrobiopterin treatment was also shown to ameliorate the exaggerated exercise pressor response in black patients with CKD (62). Future studies are needed to determine the role of autonomic imbalance in progression of renal disease in black adults and potential new therapeutic interventions that could ameliorate SNS overactivation and, thereby, improve clinical outcomes in this high-risk patient population.

Fig. 3.

Change in mean arterial pressure (MAP, A) and muscle sympathetic nerve activity (MSNA, B) during mindfulness meditation (MM) vs. control intervention in male black patients with chronic kidney disease. [Adapted from Park et al. (81).]

Perspectives and Significance

It is clear from the public health literature that male black adults have higher rates of cardiovascular and renal disease, particularly hypertension and CKD, than male and female white adults. Some physiological evidence suggests that this may be due in part to exaggerated vascular responsiveness to sympathetic neural activity, resulting in greater vasoconstriction and higher peripheral vascular resistance (Fig. 4). Interestingly, in this context, resting sympathetic neural activity is not consistently different between black and white racial identity groups, but acute sympathetic neural responses to some stimuli are augmented in black adults. Important gaps in existing knowledge include a need for more work to clarify sex differences in this area, particularly between male and female black adults. More studies are also needed to further elucidate the neurovascular responses to exercise, a time of significant sympathetic neural activation, in both male and female black adults. Additionally, it will be helpful in future work to quantify more detailed (e.g., beat-to-beat) information about relationships between sympathetic activation and blood flow/BP at rest and during exercise and other sympathetic stressors in male and female black adults. Studying the effects of interventions such as exercise training, weight reduction, mindfulness meditation, and pharmacological treatments (e.g., tetrahydrobiopterin) on the neural control of BP in black adults will provide clinically relevant insight with important implications for informing the development of potentially beneficial therapeutic approaches. Collectively, these findings in black adults will contribute to a more comprehensive understanding of mechanisms and potential sites for clinical intervention in this at-risk population.

Fig. 4.

Schematic representation of sympathetic regulation of cardiovascular function in black compared with white adults. Green left-right arrow denotes no difference between black and white adults. Red arrow denotes either higher (up arrow) or lower (down arrow) level in black compared with white adults. Question mark denotes either unclear or unknown comparison between black and white adults.

GRANTS

This work was supported by Department of Veterans Affairs Clinical Sciences Research and Development Program Merit Review Award I01CX001065 and National Institutes of Health Grants R01 HL-135183 and R61 AT-010457.

DISCLAIMERS

The views, opinions, and/or findings contained in this article are those of the authors and should not be construed as an official US Department of the Army position, or decision, unless so designated by other official documentation. Approved for public release; distribution unlimited. Citations of commercial organizations and trade names in this report do not constitute an official Department of the Army endorsement or approval of the products or services of these organizations.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

R.C.D., N.C., and J.P. conceived and designed research; R.C.D., N.C., and J.P. prepared figures; R.C.D., N.C., and J.P. drafted manuscript; R.C.D., N.C., and J.P. edited and revised manuscript; R.C.D., N.C., and J.P. approved final version of manuscript.