Obesity-Mediated Disruption of Natriuretic Peptide–Blood Pressure Rhythms

James L. Januzzi, JR, MD; Reza Mohebi, MD


J Am Coll Cardiol. 2021;77(18):2304-2306. 

Five hundred million adults in the world are estimated to be obese, and if the epidemic of obesity continues unaddressed, 1 billion adults will be obese by 2030.[1] Being obese is well known to have serious health consequences that mediate risk for incident heart disease. Among these is a higher incidence and prevalence of high blood pressure among obese patients, although the underlying mechanism(s) explaining this association are complex. One possible explanation might be disruption of normative processes involved in the circadian variation of blood pressure regulation in obese individuals. Understanding the influences of internal factors on diurnal blood pressure regulation might help clarify causes of the diagnosis of hypertension and might be important for better management of the diagnosis.[2]

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are functionally considered to be the main endocrine products of the heart. Although many recognize these peptides for their role in patients with heart failure, both ANP and BNP play a critically important role in normative physiological regulation of salt and water handling, which in turn has important effects on blood pressure. The endocrine heart acts to control blood pressure by natriuretic peptide secretion. In the kidneys, natriuretic peptides intensify glomerular filtration rate, antagonize the renin-angiotensin-aldosterone system,[3] and hinder sodium reabsorption at the level of the renal collecting duct.[4] Furthermore, natriuretic peptides also have multiple actions on autonomic nervous system activity: they lessen cardiac and pulmonary baroreceptor and chemoreceptor activity, thus reducing sympathetic outflow to the heart. This decrease in sympathetic activity together with the increase in vagal afferent activity result in a reduction in heart rate and cardiac output.[5] Natriuretic peptides also reduce vascular smooth muscle tone and peripheral vascular resistance.[6] Moreover, they inhibit secretion of vasopressin from the posterior pituitary, leading to reduction in water reabsorption.[7] The magnitude of importance of natriuretic peptides for regulation of blood pressure was illustrated in a study of BNP knockout animals, where systemic hypertension and reduced survival developed; this deleterious phenotype was rescued with BNP overexpression.[8]

Notably, animal models and small human studies have shown the existence of a diurnal rhythm in secretion of natriuretic peptides,[9,10] and such rhythms may have important associations with regulation of blood pressure under normal conditions.[11] However, normative physiological processes, such as natriuretic peptide-mediated blood pressure regulation, may have vulnerabilities: as an example, natriuretic peptide gene expression and protein function may be substantially disrupted in certain pathophysiological states such as obesity, where lower concentrations of natriuretic peptides are seen among those with higher body mass index. Because obesity-mediated natriuretic peptide reduction involves not only the biologically active ANP or BNP but also their corresponding inactive N-terminal pro-peptides (midregional proANP, N-terminal proBNP), the majority of obesity's effect on natriuretic peptides is likely at the NPPA and NPPB gene level, and when present, this obesity-mediated natriuretic peptide "handicap" has been proposed as an independent risk factor for development of cardiovascular disease, including hypertension.[12] Epidemiological studies have attributed approximately 40% of the population burden of hypertension to obesity,[12] and low NP levels in such individuals have been invoked as a potential mechanism.[13] Yet, how exactly obesity affects natriuretic peptide regulation of blood pressure remains uncertain, and prior studies of natriuretic chronobiology did not include individuals with obesity.

It is in this context that the interesting analysis by Parcha et al.[14] in this issue of the Journal lends some insights into this complex question. The authors performed a small prospective physiological clinical study with an excellent mix of subjects (50% women, 65% Black individuals), and examined the relationship of natriuretic peptide rhythm with blood pressure rhythm in lean and obese individuals. First, the investigators identified a diurnal rhythm of midregional proANP, BNP, and N-terminal proBNP concentration in the study participants, with peptide values highest in the daytime and lowest at night. This cosine-like rhythm of natriuretic peptide concentration tracked closely with the diurnal rhythm of blood pressure, offset by approximately 2 h. Further, the investigators showed a large phase difference between midregional proANP blood pressure rhythm (−4.9 h) and BNP blood pressure rhythm (−3.3 h) in obese individuals, indicating a natriuretic peptide blood pressure rhythm misalignment in tandem with lower absolute natriuretic peptide concentrations. A relatively preserved cosine-shaped diurnal rhythm of renin and aldosterone was seen in study individuals that was antiphase to the natriuretic peptides, indicating a rhythmic natriuretic peptide/renin angiotensin aldosterone system/blood pressure axis. Thus, with fragmentation of the natriuretic peptide–blood pressure relationship and lower absolute ANP or BNP concentrations, together with a less-opposed renin angiotensin aldosterone system, one might hypothesize that obese patients might be unable to counter-regulate salt and water retention or vasodilate. To this point, the investigators found no diurnal variation in normalized systolic blood pressure over 24 h in obese individuals.

Certain limitations of this study should be acknowledged. Although well-designed and executed, the study was small and performed in a single center. Further, by excluding individuals with a body mass index in the overweight range (25 to 29.9 kg/m2), the results do not clearly apply to this very large population of individuals. The study did not account for important confounders of circadian rhythm such as disruption of sleep quality or duration—something very relevant in obese patients, given the high prevalence of sleep apnea in such individuals. Future studies might, in fact, explore whether exaggerated disruption of natriuretic peptide blood pressure rhythms might explain the well-described link between sleep apnea and hypertension. Of course, the etiology of hypertension in obese individuals is far more complex than can be explained by this one finding, which must be put into context (Figure 1). Last, the findings of the study do not provide therapeutic insights into the links between obesity and hypertension.

Figure 1.

Summary of Mechanisms of Obesity-Induced Hypertension
Na = sodium; RAAS = renin angiotensin aldosterone system.

Given the rapidly worsening global pandemic of obesity, the incidence and prevalence of hypertension will continue to grow. The results of Parcha et al.[14] identify a possibly important target for attenuating how obesity leads to accelerated cardiovascular disease. It is tempting to speculate that means raising circulating ANP or BNP in obese patients, either pharmacologically with neprilysin inhibition or even more specifically by weight loss, might specifically target the disrupted associations between natriuretic peptides and blood pressure. In fact, in obese individuals, bariatric surgery produces a substantial increase in normal natriuretic peptide concentrations and a greater tolerance for sodium loading,[15,16] but how weight loss affects the disrupted natriuretic peptide–blood pressure chronobiology in obese individuals remains uncertain and should be investigated.