Insulin resistance and sympathetic overdrive in cardiovascular disease

Sympathetic activation and Insulin Resistance: the two “bad companions”

As illustrated in Figure 1, there is, in several pathologic states, a close link between sympathetic activation and cardiovascular risk. This has been shown, for example, in patients with congestive heart failure, in which indirect and direct markers of adrenergic drive, such as venous plasma norepinephrine, heart rate variability, heart rate spectral power and the “net” release at the adrenergic neurotransmitter from sympathetic nerve endings (known as “norepinephrine spillover“) have all shown to bear a close and direct relationship with cardiovascular mortality, disease progression and arrhythmic events, including sudden death (3). Similar findings have been reported in the earlier clinical phases of an acute myocardial infarction, in the post-stroke time period as well as in severe renal failure (Figure 1, lower panels) (4-5).

Interestingly, almost all of the above mentioned clinical conditions have been shown to be characterised by a marked insulin resistance state, which, independently of other confounders (including sympathetic overdrive), also carries an adverse prognostic impact on a patient’s survival (1). These data, which have been strenghtened by solid laboratory observations, have led throughout the years to the hypothesis that the two above mentioned neurometabolic alterations are closely related each other by a cause-effect relationship.

The chicken-egg question revisited

At present it is difficult to determine which of the two above mentioned neurometabolic alterations comes first, i.e. whether the insulin resistance state precedes the adrenergic overdrive or if it represents a consequence of sympathetic activation. Studies performed in different experimental animal models as well as in humans have shown that acute systemic administration of insulin, performed without altering plasma glucose levels in the context of the so-called euglycaemic clamp technique, triggers a marked increase in sympathetic cardiovascular driven (1). In addition, it has been shown that the degree of the insulin resistance state is closely related to the magnitude of the sympathetic activation in a variety of cardiometabolic diseases (6).

Furthermore, recent findings by our group have shown that in obese subjects not yet displaying an insulin resistance state, the degree of sympathetic activation is less for magnitude than that detected in obese patients with a reduced insulin sensitivity (7). Finally, in the metabolic syndrome the obese state (and the concomitant insulin resistance condition) has been documented to represent the driving force for the development and progression of the hyperadrenergic state (7).

As mentioned above, however, there are several lines of experimental and clinical evidence suggesting that insulin resistance, rather being the cause of the sympathetic activation, represents its metabolic consequence. Also this hypothesis is supported by several lines of evidence. For example it is been shown that in humans an increase in adrenergic drive, acutely induced by laboratory stressors, triggers an acute insulin resistance state (1). Furthermore, longitudinal surveys carried out in European and North American countries have shown that individuals developing hypertension during a 10 year follow-up period display an early occurrence of sympathetic activation, which comes several years before the appearance of the insulin resistance state (8). It is thus likely that the neurogenic activation represent the driving force of the metabolic abnormalities involving insulin metabolism.

Therapeutic implications

Based on the already described solid pathophysiological background, sympathoinhibiton appears to be a key goal of the therapeutic approach to a number of cardiovascular disease characterised by insulin and sympathetic abnormalities. Non-pharmacological lifestyle interventions, such as energy-restricted diet and physical training, have been shown to exert sympathoinhibitory, effects which are paralleled by a clearcut improvement in insulin resistance (9).
Sympathetic deactivation, however, also definitely showed to be one of the goals of cardiovascular drug treatment. This goal can be achieved via ACE-inhibitors and angiotensin II receptors blockers, since these drugs exert potent sympathomoderating  properties both in hypertension, heart failure, post-myocardial infarction phase as well as renal failure (9). Sympathoinhibitory effects can be also typical of beta-blocking drugs, particularly rthe new generation, such as carvedilol or nebivolol, which combine their ability to exert cardioprotective effects whit the improvement of insulin sensitivity (9). In contrast, short-acting calcium antagonist and more so diuretics may further exacerbate the already elevated sympathetic cardiovascular drive detected in cardiovascular disease and worsen insulin sensitivity (9). Finally, there is evidence that some drugs acting as insulin sensitizes, such as troglitazione and the related thiazolidinedione compounds are capable not only to improve insulin sensitivity but also to exert sympathoinibitory effects (10).

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.