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QUARTERLY FOCUS ISSUE: HEART FAILURE: STATE-OF-THE-ART PAPER

Sympathetic Nervous System Activation in Human Heart Failure

Clinical Implications of an Updated Model

Mount Sinai Hospital and University Health Network Division of Cardiology, and the University of Toronto, Toronto, Ontario, Canada

Manuscript received January 11, 2009; revised manuscript received March 16, 2009, accepted March 23, 2009.

^_* Reprint requests and correspondence: Dr. John S. Floras, Mount Sinai Hospital, 600 University Avenue, Suite 1614, Toronto, Ontario M5G 1X5, Canada (Email: john.floras{at}utoronto.ca).

Disturbances in cardiovascular neural regulation, influencing both disease course and survival, progress as heart failure worsens. Heart failure due to left ventricular systolic dysfunction has long been considered a state of generalized sympathetic activation, itself a reflex response to alterations in cardiac and peripheral hemodynamics that is initially appropriate, but ultimately pathological. Because arterial baroreceptor reflex vagal control of heart rate is impaired early in heart failure, a parallel reduction in its reflex buffering of sympathetic outflow has been assumed. However, it is now recognized that: 1) the time course and magnitude of sympathetic activation are target organ–specific, not generalized, and independent of ventricular systolic function; and 2) human heart failure is characterized by rapidly responsive arterial baroreflex regulation of muscle sympathetic nerve activity (MSNA), attenuated cardiopulmonary reflex modulation of MSNA, a cardiac sympathoexcitatory reflex related to increased cardiopulmonary filling pressure, and by individual variation in nonbaroreflex-mediated sympathoexcitatory mechanisms, including coexisting sleep apnea, myocardial ischemia, obesity, and reflexes from exercising muscle. Thus, sympathetic activation in the setting of impaired systolic function reflects the net balance and interaction between appropriate reflex compensatory responses to impaired systolic function and excitatory stimuli that elicit adrenergic responses in excess of homeostatic requirements. Recent observations have been incorporated into an updated model of cardiovascular neural regulation in chronic heart failure due to ventricular systolic dysfunction, with implications for the clinical evaluation of patients, application of current treatment, and development of new therapies.

Key Words: baroreceptor reflex • exercise • heart failure • human • norepinephrine • sleep apnea • sympathetic nervous system

Abbreviations and Acronyms   BP = blood pressure   CNES = cardiac norepinephrine spillover   CPAP = continuous positive airway pressure   CSA = central sleep apnea   HF = heart failure   HR = heart rate   HRV = heart rate variability   LBNP = lower body negative pressure   MSNA = muscle sympathetic nerve activity   NE = norepinephrine   OSA = obstructive sleep apnea   RNES = renal norepinephrine spillover   TNES = total body norepinephrine spillover

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