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Sympathetic overdrive in hypertension: clinical and therapeutic relevance

An article from the e-journal of the ESC Council for Cardiology Practice

Recently, there has been renewed interest in the role of the sympathetic nervous system in hypertension for several reasons: 1) findings that sympathetic abnormalities can influence the development and progression of target organ damage; 2) the development of new therapeutic approaches for the control of blood pressure; and 3) findings that sympathetic activation has an adverse prognostic effect in terms of morbidity and mortality on a variety of cardiovascular diseases. This underlines the importance of the modulation of sympathetic activation as a goal for non-pharmacological as well as pharmacological interventions aimed at lowering elevated blood pressure values. Data, however, remain scarce and further research is required to define the role of genetic factors, the relationship between sympathetic function and target organ damage, and the effects of combination drug treatments on sympathetic neural function and its relationship with blood pressure control.

Hypertension


Background

The renewed interest of investigators and clinicians the role of the sympathetic nervous system in hypertension and its relevance as a target for non-pharmacological as well as pharmacological interventions comes from a number of sources. First, the recent finding that sympathetic abnormalities favor the development and progression of target organ damage, independently from blood pressure overload [1,2]. Second, the availability of new therapeutic approaches for the treatment and control of high blood pressure in high-risk conditions such as resistant hypertension, i.e., carotid baroreceptor stimulation and renal nerve radiofrequency ablation [2]. Finally, there is the finding that, in a variety of major cardiovascular diseases, such as congestive heart failure, stroke, myocardial infarction and renal failure-related hypertension, sympathetic activation has an independent adverse prognostic relevance in terms of both morbidity and mortality [3-7].

Taken together, these findings underscore the importance of the modulation of sympathetic activation as a goal for non-pharmacological as well as pharmacological interventions aimed at lowering elevated blood pressure values.

Sympathetic activation in hypertension

Essential hypertensive states have been shown to be characterized not only by an impaired parasympathetic tone but also by marked sympathetic overdrive, with a resulting increase in resting heart rate values [1]. The sympathetic activation contributes to this haemodynamic alteration, due to the well-known positive chronotropic effects of the main adrenergic neurotransmitter, norepinephrine [1]. The two neurogenic abnormalities appear to be already present in the pre-hypertensive stage or in borderline hypertension (2). However, while vagal dysfunction remains stable in magnitude in clinical conditions characterized by more severe increases in blood pressure, sympathetic activation undergoes a progressive potentiation as the severity of the hypertensive state increases [8]. This has been shown particularly via direct approaches to investigate human sympathetic function, such as clinical microneurography, which, by directly recording efferent postganglionic sympathetic neural discharge in the peroneal or brachial nerve in man, allows the well-known limitations of plasma norepinephrine assay as an adrenergic marker to be overcome [2].

The above-mentioned sympathetic dysregulation has been shown in the different stages of hypertension (mild, moderate, severe), in hypertensive forms of young, middle-aged and elderly patients, in white-coat hypertension, masked hypertension and pregnancy-induced high blood pressure [1,2]. Recently, other clinical conditions found to be associated with sympathetic overactivity have been documented. They include dipping or non-dipping hypertension, hypertension complicated by sleep apnoea, metabolic syndrome or renal failure, and true resistant hypertension [1,2,9]. Finally, it should be mentioned that: 1) secondary forms of hypertension, such as renovascular hypertension, do not appear to be associated with sympathetic activation, and 2) the mechanisms responsible for the hypertension-related adrenergic overdrive appear to be complex, including alterations in the neurogenic, reflex as well as metabolic modulation of the sympathetic tone [1,2].

Clinical relevance of the hypertension-related sympathetic overactivity

Direct and indirect evidence is now available that a state of sympathetic activation promotes cardiac and vascular alterations, thus contributing to the elevated morbidity and mortality described in untreated hypertension [1,2]. As far as cardiac alterations are concerned, there is evidence that a heightened cardiac sympathetic drive is detected in hypertensive patients with left ventricular hypertrophy or even with left ventricular diastolic dysfunction, underlining the concept that factors other than blood pressure elevation are of key importance for determining the myocardial structural and functional alterations detectable in the clinical course of the hypertensive state [10,11]. In addition, sympathetic activation has been shown to participate in the development and progression of vascular remodelling, endothelial dysfunction as well as in the increase in arterial stiffening reported in the hypertensive state [12,13]. Finally, recent studies show that both the metabolic and renal abnormalities which characterize not only advanced but also earlier stages of hypertension are indeed associated with sympathetic alterations, which appear to potentiate the adrenergic overdrive already seen in uncomplicated hypertension [14,15].

Sympathoinhibition as a goal of antihypertensive drug treatment

As illustrated in Table 1, a reduction in sympathetic cardiovascular drive may trigger a series of favorable cardiovascular and cardiometabolic consequences. Those more relevant from a clinical view point include: 1) a homogeneous blood pressure control during a 24-hour period, 2) a reduction in 24-hour blood pressure variability, 3) a regression of target organ damage, and 4) an improvement of the metabolic abnormalities associated with hypertension. Conversely, of a totally opposite nature are the cardiovascular and cardiometabolic consequences of sympathoexcitatory drugs (Table 1), which favor, again directly or indirectly, 1) a lesser homogeneous blood pressure control, 2) a greater blood pressure variability, and 3) reduced cardiac organ damage regression as well as a worsening of the metabolic abnormalities associated with hypertension.

Table 1. Hemodynamic and metabolic effects of antihypertensive drugs according to their sympathetic action.

 

Sympathoinhibitory drugs

Sympathoexcitatory drugs

Heart rate and myocardial oxygen demand

decrease

increase

Coronary vascular resistance

 

decrease

increase

Blood pressure variability

decrease

increase

Insulin resistance

decrease

increase

LVH and vascular remodelling

decrease

no change

Cardiac and vascular protection

increase

decrease

LVH: left ventricular hypertrophy

Sympathetic effects of non-pharmacological and pharmacological interventions

As far as non-pharmacological interventions are con­cerned, there is overwhelming evidence demonstrating the sympathomodulatory effects of low-calorie dietary interventions and regular physical exercise programs [16,17]. Since both procedures trigger clear-cut blood pres­sure-lowering effects of a magnitude often related to the degree of the sympathoinhibition, the hypothesis has been advanced that the antihypertensive effects of the two inter­ventions are related to their sympathoinhibitory effects [16,17]. Conversely, an enhancement of the already elevated adrenergic drive has been reported during a long-term and marked low sodium diet [16,17]. This is presumably related to the fact that marked dietary sodium restriction elicits hyperinsu­linemia and renin-angiotensin stimulation, i.e., two effects which promote sympathoexcitation and impair baroreflex control of both vagal and sympathetic drive [1,2]. Recently, two invasive procedures, i.e., implantation of a device capable of stimulating the carotid baroreceptor (and thus inhibiting sympathetic activity and enhancing barore­flex control of cardiac vagal drive), and renal sympathetic denervation through a catheter positioned in a renal artery and connected to a radiofrequency generator, have been successfully developed. They are both under clinical investigation to define their blood pressure-lowering effects, which may be associated with a reduction in sympathetic drive [18,19].

 s far as the effects of antihypertensive drug treatment on autonomic cardiovascular function are concerned, there is evidence that, as shown in Table 2, some pharmacologic classes of antihy­pertensive drugs (such as beta-blockers, ace-inhibitors and angiotensin II receptor blockers) may elicit profound sympathoinhibitory effects, while other classes may leave unchanged (long-acting calcium antagonists), or even further increase (diuretics, short-acting calcium antag­onists), the adrenergic cardiovascular drive [16, 20-22]. Information on the effects of different antihypertensive drug combinations on autonomic cardiovascular function is scarce at present and mainly based on indirect, and thus less sensitive, markers of sympathetic drive such as plasma norepinephrine.

Table 2. Effects of different antihypertensive drug classes on peripheral and cardiac sympathetic drive.

Drug class

Effects on peripheral SNS

Effects on cardiac SNS

Central sympatholytics

marked reduction

reduction

α-blockers

marked reduction

no change

Thiazide diuretics

marked increase

no change

Anti-aldosterone agents

reduction

no change

β-blockers

reduction

marked reduction

Short-acting CA

marked increase

marked increase

Long-acting CA

reduction, no change

no change, increase

ACE inhibitors

reduction, no change

no change

Angiotensin II receptor blockers

reduction, no change

no change

ACE: angiotensin-converting enzyme; CA: calcium antagonists; SNS: sympathetic nervous system

Conclusions

A number of issues related to the role of the sympathetic nervous system in hypertension remain to be defined:

  • the role of genetic factors in hypertension-related sympathetic overdrive;
  • the relationship between the various indices of sympathetic function and the novel markers of target organ damage/arterial dysfunction; and
  • the effects of combination drug treatment on sympathetic neural function and its possible relationship with blood pressure control.

References


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Notes to editor


Author:

Prof. Guido Grassi

Clinica Medica, University of Milano-Bicocca

Ospedale San Gerardo dei Tintori

Via Pergolesi 33, 20052 Monza (Milano), Italy

Phone: +39 039 2336005

Fax: +39 039 2336001

E-mail: guido.grassi@unimib.it

 

Conflict of interest: No conflicts of interest to declare.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.