Study shows why exercise is beneficial for people with heart failure

Research group describes how cardiac rehabilitation modulates certain receptors in muscle tissue and promotes reductions in sympathetic nerve activity.

By Karina Toledo

Agência FAPESP – For people who suffer from heart failure (cardiac insufficiency), simple everyday activities such as climbing stairs, shopping or taking a bath can cause tachycardia, fatigue and breathlessness.

According to data in the scientific literature, this intolerance of effort is due to hyperactivity of the sympathetic nervous system, the part of the autonomic nervous system responsible for controlling heart rate, blood pressure, and contraction and relaxation of blood vessels.

The molecular mechanisms that underlie sympathetic hyperactivity and the beneficial effects of exercise training in modulating this system were investigated by Lígia M. Antunes-Corrêa while working toward her PhD at the University of São Paulo’s Heart Institute (INCOR-USP), as part of the Thematic Project “Cellular and functional bases of exercise in cardiovascular diseases,” coordinated by Carlos Eduardo Negrão, a professor at INCOR-USP and a member of FAPESP’s Life Sciences Area Panel.

The findings were described in a paper published recently in the American Journal of Physiology – Heart and Circulatory Physiology.

“There are two kinds of receptor in muscle tissue: metaboreceptors and mechanoreceptors,” Antunes-Corrêa explained. “When these receptors are stimulated, sympathetic activity increases. In patients with heart failure, this increase is excessive, apparently owing to mechanoreceptor hyperactivity, so that they more easily become fatigued. We wanted to understand exactly why this happens.”

Mechanoreceptors are cells that respond to mechanical stimuli such as muscle contraction and pressure, whereas metaboreceptors are cells that act as chemical sensors by responding to the increase in metabolites produced during muscle contraction.

In healthy people, these receptors are stimulated during exercise to increase the activity of the cardiorespiratory system and to ensure an adequate supply of blood and oxygen to the cells involved.

“However, previous research has shown that, because the skeletal muscles of people with heart failure undergo metabolic changes due to reduced blood flow and sympathetic hyperactivity, their metaboreceptors are continuously in contact with several overproduced metabolites, even during light exercise or everyday activities, and eventually lose sensitivity. The mechanoreceptors are hyperactivated to compensate for this loss,” Antunes-Corrêa said.

The INCOR research group collected biopsies from the vastus lateralis muscle in the thighs of patients with heart failure and found that the loss of metaboreceptor sensitivity was associated with reduced expression of two other adjacent receptors, TRPV1 and CB1.

Mechanoreceptor hyperactivity was associated with increased muscle inflammation mediated by the enzyme cyclooxygenase-2 (COX2).

“This enzyme participates in the production of prostacyclin, prostaglandin and thromboxane, which are molecules that can modulate mechanoreceptor sensitivity,” Antunes-Corrêa said.

Cardiac rehabilitation

To determine what happens to these receptors when a person with heart failure is submitted to a moderate program of aerobic exercise, a study was performed with 34 patients who were attending INCOR for treatment.

The volunteers, who were receiving optimized drug-based treatment, were divided randomly into two groups. Half continued with the conventional clinical protocol; the rest were submitted to three sessions a week on a stationary bicycle and four months of localized exercises.

In addition to the muscle biopsy, they underwent a number of tests before and after the training period to evaluate heart function, cardiopulmonary performance and sympathetic nervous activity.

In the group of patients who participated in the training program, sympathetic activity during passive exercise mechanoreceptor stimulation (muscle contraction) decreased by approximately 10%.

This decrease was accompanied by a 50% reduction in COX2 expression, as well as an anti-inflammatory effect on muscles.

The muscle biopsies from those in the training group also showed increased expression of TRPV1 and CB1 receptors, which suggests recovery of metaboreceptor sensitivity.

“This improvement in the balance between mechanoreceptors and metaboreceptors contributes to a reduction in sympathetic activity during both rest and day-to-day activities. It’s associated with an improvement in the patient’s prognosis because it reduces cardiac arrhythmia and peripheral vasoconstriction,” Antunes-Corrêa said.

Antunes-Corrêa’s work is the continuation of a long line of research led by Negrão at INCOR. In a 2001 study also published in the American Journal of Physiology – Heart and Circulatory Physiology, the researchers showed for the first time that sympathetic activity is altered in heart failure patients during mechanoreceptor and metaboreceptor stimulation. Another study by the group showed a correlation between greater hyperactivity in heart failure patients and poorer prognosis.

In a paper published in 2003 in the Journal of the American College of Cardiology, the group showed that exercise training significantly reduces sympathetic nerve activity.

“We’ve now advanced our understanding of how exercise modulates the action of these receptors. The key difference in this research is the translational aspect, i.e., the association between molecular findings and the patient’s clinical condition,” Antunes-Corrêa said.

The INCOR group is also collaborating with Holly Middlekauff, a professor and researcher at the University of California, Los Angeles (UCLA) Medical School and the author of several papers demonstrating increased mechanoreceptor sensitivity in heart failure patients and the link with the COX2 pathway.