New Study Clarifies Connection Of Brain And Heart Failure

Findings suggest the development of new therapeutic approaches that  will allow the central nervous system to respond quickly after a heart attack

March 18, 2003 (Bethesda, MD) – The organs of our body, such as the heart, stomach, and intestines, are all regulated by a part of the nervous system called the autonomic nervous system (ANS). The ANS is one component of the peripheral nervous system that controls many organs and muscles within the body.

Background

Most of us are unaware when the ANS is at work.  Its functions are involuntary and reflexive, such as changing the size of blood vessels or causing our hearts to beat faster.  Scientists are well aware that autonomic dysfunction contributes to progression of heart failure.   The most effective treatments for heart failure specifically target the peripheral manifestations of neurohumoral (nerve transmission) activation. Yet the understanding of the mechanisms leading to neurohumoral excitation in heart failure is still quite limited.

Over the last several decades, substantial evidence has been amassed to support the concept that peripheral nerve fibers connecting the heart and vascular tree to the central nervous system are altered in heart failure.  Dysfunction has been described in all components of the reflexes mediated by these cardiovascular afferent systems the afferent fibers themselves, the central processing of the afferent signals, the nerves signals away from the heart, and the key organs themselves.  In general, the influence of low- and high-pressure baroreceptors that normally restrain sympathetic drive and vasopressin release is diminished, whereas the excitatory influences of arterial chemoreceptors and cardiac sympathetic afferent fibers are enhanced.

Central nervous system (CNS) neurons affecting cardiovascular regulation respond to humoral (carried by blood) as well neural signals. Blood-borne neuroactive peptides, too large to readily cross the blood-brain barrier, may influence the brain by activating sensory neurons at specific sites in hindbrain and forebrain that lack a blood-brain barrier or by inducing the release of mediators that do penetrate the barrier. These neuroactive substances are released in excess by peripheral tissues under the stress of heart failure and signal the brain to alter volume regulation and autonomic function. Interestingly, the cardiovascular regions of forebrain that sense and respond to circulating peptides also process the signals originating in cardiovascular afferent nerves and are capable of modulating cardiovascular reflexes.

Until now, the potential importance of humoral heart-brain signaling in the pathogenesis of heart has not been fully examined.  A new study summarizes recent studies supporting the concept that the forebrain plays a critical role in the pathogenesis of ischemia-induced heart failure and suggesting that the forebrain contribution must be considered in designing therapeutic strategies. Of particular emphasis in this study is the concept of forebrain signaling by neuroactive products of the renin-angiotensin system and the immune system.

A New Study

The authors of “Heart Failure and the Brain: New Perspectives,” are  Joseph Francis, Zhi-Hua Zhang, Shun-Guang Wei, and Alan Kim Johnson, from the  University of Iowa and Robert B. Felder and Robert M. Weiss, representing the Research Service, Department of Veterans Affairs Medical Center, all in Iowa City, IA.   Their findings appear in the February 2003 edition of the American Journal of Physiology – Regulatory, Integrative and Comparative Physiology. 

Methodology 

A rat model with ischemia-induced heart failure allowed both acute and chronic interventions to address the key questions regarding the contribution of the forebrain to the progression to heart failure after a myocardial infarction (MI), more commonly known as a heart attack.  The key question to be addressed was “How important is forebrain activation to the course of heart failure after MI?”

To further define the mechanisms activating the forebrain and PVN (paraventricular nucleus) neurons in heart failure, the researchers used a multifaceted approach. They combined venous sampling of circulating peptides, metabolic cage measurements of salt and water consumption and excretion, and electrophysiological recording from central neurons and from sympathetic nerves in rats with a large MI produced by ligation of the left anterior descending coronary artery and confirmed by echocardiography.

Results

The researchers found the characteristic features of heart failure that were present in MI rats with sham AV3V lesion, increased sodium appetite, the decreased sodium and water excretion, and augmented sympathetic drive with blunted baroreflex, were dramatically attenuated in animals with an AV3V lesion.

Second, the expected increase in plasma renin activity did not occur in the AV3V-lesioned MI rats. These findings clearly implicate the forebrain as an active participant in the progression of heart failure and further suggest that the renin response to renal underperfusion after MI may be largely dependent on sympathetic efferent regulation emanating from the forebrain. There is some precedent for that suggestion in previous work demonstrating that electrical stimulation of PVN can increase renin release from the kidney and facilitate the renin response to other usual stimuli.

But perhaps most important was a third finding, the survival of the AV3V-lesioned MI rats was compromised to the extent that most had died three weeks after MI, in contrast to MI rats with sham-AV3V lesion and AV3V-lesioned rats with sham MI.

New strategies directed toward treatment of the central influences of RAAS (renin-angiotensin-aldosterone system) in patients with heart failure will require a reconsideration of pharmacological properties of commonly available drugs and perhaps development of drugs that specifically target the CNS. Although currently used ACE inhibitors, AT₁ receptor blockers, and MC receptor antagonists may act upon the CNS, either by crossing blood-brain barrier or by acting upon the circumventricular organs that lack a blood-brain barrier, their design and clinical usage target peripheral endpoints.  This study and review proposes treating the adverse peripheral consequences of RAAS, e.g., vasoconstriction, cardiac and vascular remodeling, while increasing the ability of these agents to penetrate brain regions whose intrinsic RAAS activity may actually be increased predominantly peripheral ACE inhibition in heart failure. The forebrain circumventricular organs, rich in ACE and AT₁ receptors  and lacking the protection of the blood-brain barrier, would appear to be easily accessible targets for therapeutic intervention. 

Conclusions

Recent experimental studies have confirmed a critical role for the forebrain in the cause of heart failure after a large MI, the most common cause of heart failure in Western societies.  Peripheral systems found responding to myocardial injury and reduced cardiac output release humoral factors that enlist the forebrain to help restore volume and pressure within the cardiovascular system.  Unrestrained by the usual negative feedback mechanisms, peripheral and central compensatory systems persist in a futile effort to restore homeostasis.

The clinical approach to the heart failure syndrome is complicated by the fact that these compensatory mechanisms are initially supportive but are ultimately detrimental. The challenge is to develop therapeutic strategies that recognize the wisdom of adaptive mechanisms but prevent the excesses that promote clinical deterioration. One approach is to moderate but not eliminate these mechanisms. The forebrain may be a prime target for such interventions.

Source: February 2003 edition of the American Journal of Physiology – Regulatory, Integrative and Comparative Physiology.  

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The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

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Editor’s Note: To set up an interview with a member of the research team, please contact Donna Krupa at 703.527.7357 (direct dial), 703.967.2751 (cell) or djkrupa1@aol.com.