942
Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp
KIM MS et al.
FOCUS REVIEWS ON HEART FAILURE
Heart and Brain Interconnection – Clinical Implications of Changes in Brain Function During Heart Failure – Min-Seok Kim, MD; Jae-Joong Kim, MD
Heart failure (HF) is a highly prevalent disorder worldwide and, consequently, a burden on the healthcare systems of many nations. Although the effects of HF are systemic, many therapeutic targets are focused on cardiac dysfunction. The brain is closely related to the heart, but there are few reports on the relationship between these organs. We describe the effects of the brain on HF progression. Specific brain regions control sympathetic drive and neurohumoral factors, which play an important role in disease exacerbation. In addition, we review some of our previous studies on deranged cerebral metabolism and reduced cerebral blood flow during HF. Although the reasons underlying these effects during HF remain uncertain, we propose plausible mechanisms for these phenomena. In addition, the clinical implications of such conditions in terms of predicting prognosis are discussed. Finally, we investigate cognitive impairment in patients with HF. Cognitive impairment through cerebral infarction or hypoperfusion is associated with adverse outcomes, including death. This brief review of brain function during the development of HF should assist with future strategies to better manage patients with this condition. (Circ J 2015; 79: 942 – 947) Key Words: Brain; Cerebral metabolism; Cerebrovascular circulation; Cognitive function; Heart failure
H
eart failure (HF) is one of the most predominant global diseases because of its high mortality and morbidity rates. Ceaseless efforts have been made to reverse its devastating consequences through the recovery of cardiac dysfunction. However, HF is not a single disease entity limited to the heart itself, but is in fact a complex disease involving whole body systems. The heart interplays with other organs such as the lung, kidney, and liver, and deterioration of cardiac function inevitably leads to other organ dysfunction. The brain is likewise connected closely with the heart, and the communication between the 2 organs is thought to be bidirectional. In a HF state, the brain emits apparent signals to the heart. Although cardiac dysfunction happens first in HF, the brain provides feedback to the heart in the form of sympathetic drive or fluid regulation to sustain the HF disease state.1 In addition, the brain accepts efferent signals from the heart. Although cerebral blood vessels have an autoregulatory mechanism to maintain perfusion, persistent low cardiac output decreases cerebral blood flow (CBF)2 and may cause metabolic abnormalities and cognitive impairment, leading to adverse outcomes.3,4 However, unlike the relationship between the heart and other organs, the interconnection between the heart and the brain has not been extensively studied. This review focuses on brain function during HF, highlighting the type of, and mechanisms underlying, cerebral functional changes and their clinical implications in terms of predicting prognosis during HF progression.
Central Nervous System (CNS) as a Source of Neurohumoral Drive in HF Impaired cardiac function activates neurohumoral systems, particularly the sympathetic nervous system and the reninangiotensin-aldosterone system, and contributes to the progression of HF. However, altered neurohumoral signals also activate the CNS, which plays a persistent role in regulating cardiac function. Some apparatuses of the brain function via crosstalk mechanisms with the heart and the production of neural reflex systems. The circumventricular organs of the lamina terminalis in forebrain regions primarily sense thirst or sodium intake and regulate volume status in HF. They lack a blood-brain barrier and therefore catch the signals of bloodborne neuropeptides. The paraventricular nucleus (PVN) of the hypothalamus is a center for fluid-balance regulation and sympathetic excitation.5 The PVN is located near the third ventricle in the forebrain and comprises different neuronal subgroups. The magnocellular neurons in the PVN project to the posterior pituitary and release humoral factors such as adrenocorticotropic hormone and arginine vasopressin, which may affect sodium and fluid retention.6 In addition, the PVN is mainly involved in regulating sympathetic drive. This process starts with the nucleus tractus solitarius, which transfers vagal and baroreceptor information to the PVN through afferent neural projections.7 The parvocellular neurons in the PVN integrate these data and influence sympathetic nerve activity. These neurons project to the rostal ventrolateral medulla and the intermedio-
Received March 30, 2015; accepted March 30, 2015; released online April 20, 2015 Department of Internal Medicine, Asan Medical Center Heart Institute, University of Ulsan College of Medicine, Seoul, Korea Mailing address: Jae-Joong Kim, Professor, MD, Department of Internal Medicine, Asan Medical Center Heart Institute, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-15-0360 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.79, May 2015
HF and Brain Function
943
Figure 1. Kaplan-Meier curves for outcomes in patients with systolic heart failure according to cerebral blood flow (CBF) with cut-off values of 35.4 ml · min–1 · 100 g–1. (Adapted with permission from Kim MS, et al.29)
lateral cell columns of the spinal cord, which innervate the sympathetic neurons to the heart and kidney.8,9 Sympathetic excitations from these neural connections lead to left ventricular remodeling and dysfunction in the heart, vasoconstriction in the vascular tree, and sodium and fluid retention via renin release. Numerous neurotransmitters have been found within the PVN. Under normal conditions, the PVN is influenced by potent inhibitory mediators such as γ-aminobutyric acid and nitric oxide.10,11 In certain conditions, however, excitatory mediators in the PVN, such as glutamate and angiotensin II, play a role in cardiovascular reflexes.12 Angiotensin II from peripheral tissues can affect the PVN neurons via the activation of the neurons in the circumventricular organs of the lamina terminalis.13 Moreover, angiotensin II produced within the bloodbrain barrier can activate angiotensin type 1 receptors on PVN neurons to influence sympathetic drive.14,15 Excitatory and inhibitory neurotransmitters interact within the PVN, and their balance regulates sympathetic tone during HF. However, the detailed mechanisms underlying the interactions among these neurotransmitters within the PVN are yet to be determined. There is a paucity of study of the effect of modulating CNS neurohumoral factors on HF progression. A previous study reported that brain administration of β-blockers in an animal model of myocardial ischemia reduced mortality more effectively than in the periphery.16 Similarly, blockade of NMDA receptors, which are major ionotropic glutamate receptor, within the PVN through local injection of an NMDA antagonist decreased sympathoexcitation in HF rats.17 These data suggest that regulation of CNS neurohormones contributes to the deterioration of HF. However, further human trials on the influence of altering brain function on HF progression are needed.
Reduction in CBF During HF Brain vessels have autoregulatory functions to maintain blood flow over a diverse range of perfusion pressures. CBF is generally believed to be preserved during HF. Despite a marked decrease in cardiac output during HF, compensatory mechanisms exert every effort to redistribute blood flow towards vital organs and rescue cerebral perfusion.18,19 However, some evidence has suggested that certain HF patients have decreased CBF despite these compensatory mechanisms.20,21 Previously, we reported that global CBF estimated by radionuclide angiography was low in patients with advanced-stage systolic HF. We found in that study that global CBF was approximately 20% less in patients with HF than in control patients (40±4 vs. 49±4 ml · min−1 · 100 g−1, P
Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp
KIM MS et al.
FOCUS REVIEWS ON HEART FAILURE
Heart and Brain Interconnection – Clinical Implications of Changes in Brain Function During Heart Failure – Min-Seok Kim, MD; Jae-Joong Kim, MD
Heart failure (HF) is a highly prevalent disorder worldwide and, consequently, a burden on the healthcare systems of many nations. Although the effects of HF are systemic, many therapeutic targets are focused on cardiac dysfunction. The brain is closely related to the heart, but there are few reports on the relationship between these organs. We describe the effects of the brain on HF progression. Specific brain regions control sympathetic drive and neurohumoral factors, which play an important role in disease exacerbation. In addition, we review some of our previous studies on deranged cerebral metabolism and reduced cerebral blood flow during HF. Although the reasons underlying these effects during HF remain uncertain, we propose plausible mechanisms for these phenomena. In addition, the clinical implications of such conditions in terms of predicting prognosis are discussed. Finally, we investigate cognitive impairment in patients with HF. Cognitive impairment through cerebral infarction or hypoperfusion is associated with adverse outcomes, including death. This brief review of brain function during the development of HF should assist with future strategies to better manage patients with this condition. (Circ J 2015; 79: 942 – 947) Key Words: Brain; Cerebral metabolism; Cerebrovascular circulation; Cognitive function; Heart failure
H
eart failure (HF) is one of the most predominant global diseases because of its high mortality and morbidity rates. Ceaseless efforts have been made to reverse its devastating consequences through the recovery of cardiac dysfunction. However, HF is not a single disease entity limited to the heart itself, but is in fact a complex disease involving whole body systems. The heart interplays with other organs such as the lung, kidney, and liver, and deterioration of cardiac function inevitably leads to other organ dysfunction. The brain is likewise connected closely with the heart, and the communication between the 2 organs is thought to be bidirectional. In a HF state, the brain emits apparent signals to the heart. Although cardiac dysfunction happens first in HF, the brain provides feedback to the heart in the form of sympathetic drive or fluid regulation to sustain the HF disease state.1 In addition, the brain accepts efferent signals from the heart. Although cerebral blood vessels have an autoregulatory mechanism to maintain perfusion, persistent low cardiac output decreases cerebral blood flow (CBF)2 and may cause metabolic abnormalities and cognitive impairment, leading to adverse outcomes.3,4 However, unlike the relationship between the heart and other organs, the interconnection between the heart and the brain has not been extensively studied. This review focuses on brain function during HF, highlighting the type of, and mechanisms underlying, cerebral functional changes and their clinical implications in terms of predicting prognosis during HF progression.
Central Nervous System (CNS) as a Source of Neurohumoral Drive in HF Impaired cardiac function activates neurohumoral systems, particularly the sympathetic nervous system and the reninangiotensin-aldosterone system, and contributes to the progression of HF. However, altered neurohumoral signals also activate the CNS, which plays a persistent role in regulating cardiac function. Some apparatuses of the brain function via crosstalk mechanisms with the heart and the production of neural reflex systems. The circumventricular organs of the lamina terminalis in forebrain regions primarily sense thirst or sodium intake and regulate volume status in HF. They lack a blood-brain barrier and therefore catch the signals of bloodborne neuropeptides. The paraventricular nucleus (PVN) of the hypothalamus is a center for fluid-balance regulation and sympathetic excitation.5 The PVN is located near the third ventricle in the forebrain and comprises different neuronal subgroups. The magnocellular neurons in the PVN project to the posterior pituitary and release humoral factors such as adrenocorticotropic hormone and arginine vasopressin, which may affect sodium and fluid retention.6 In addition, the PVN is mainly involved in regulating sympathetic drive. This process starts with the nucleus tractus solitarius, which transfers vagal and baroreceptor information to the PVN through afferent neural projections.7 The parvocellular neurons in the PVN integrate these data and influence sympathetic nerve activity. These neurons project to the rostal ventrolateral medulla and the intermedio-
Received March 30, 2015; accepted March 30, 2015; released online April 20, 2015 Department of Internal Medicine, Asan Medical Center Heart Institute, University of Ulsan College of Medicine, Seoul, Korea Mailing address: Jae-Joong Kim, Professor, MD, Department of Internal Medicine, Asan Medical Center Heart Institute, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-15-0360 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.79, May 2015
HF and Brain Function
943
Figure 1. Kaplan-Meier curves for outcomes in patients with systolic heart failure according to cerebral blood flow (CBF) with cut-off values of 35.4 ml · min–1 · 100 g–1. (Adapted with permission from Kim MS, et al.29)
lateral cell columns of the spinal cord, which innervate the sympathetic neurons to the heart and kidney.8,9 Sympathetic excitations from these neural connections lead to left ventricular remodeling and dysfunction in the heart, vasoconstriction in the vascular tree, and sodium and fluid retention via renin release. Numerous neurotransmitters have been found within the PVN. Under normal conditions, the PVN is influenced by potent inhibitory mediators such as γ-aminobutyric acid and nitric oxide.10,11 In certain conditions, however, excitatory mediators in the PVN, such as glutamate and angiotensin II, play a role in cardiovascular reflexes.12 Angiotensin II from peripheral tissues can affect the PVN neurons via the activation of the neurons in the circumventricular organs of the lamina terminalis.13 Moreover, angiotensin II produced within the bloodbrain barrier can activate angiotensin type 1 receptors on PVN neurons to influence sympathetic drive.14,15 Excitatory and inhibitory neurotransmitters interact within the PVN, and their balance regulates sympathetic tone during HF. However, the detailed mechanisms underlying the interactions among these neurotransmitters within the PVN are yet to be determined. There is a paucity of study of the effect of modulating CNS neurohumoral factors on HF progression. A previous study reported that brain administration of β-blockers in an animal model of myocardial ischemia reduced mortality more effectively than in the periphery.16 Similarly, blockade of NMDA receptors, which are major ionotropic glutamate receptor, within the PVN through local injection of an NMDA antagonist decreased sympathoexcitation in HF rats.17 These data suggest that regulation of CNS neurohormones contributes to the deterioration of HF. However, further human trials on the influence of altering brain function on HF progression are needed.
Reduction in CBF During HF Brain vessels have autoregulatory functions to maintain blood flow over a diverse range of perfusion pressures. CBF is generally believed to be preserved during HF. Despite a marked decrease in cardiac output during HF, compensatory mechanisms exert every effort to redistribute blood flow towards vital organs and rescue cerebral perfusion.18,19 However, some evidence has suggested that certain HF patients have decreased CBF despite these compensatory mechanisms.20,21 Previously, we reported that global CBF estimated by radionuclide angiography was low in patients with advanced-stage systolic HF. We found in that study that global CBF was approximately 20% less in patients with HF than in control patients (40±4 vs. 49±4 ml · min−1 · 100 g−1, P
