Cardiac resynchronization therapy (CRT) benefits a subset of patients with congestive heart failure, improving symptoms, quality of life, and survival and providing an effective alternative treatment for this disease.
Correction of biventricular electrical and mechanical dyssynchrony is considered the underlying beneficial mechanism of CRT. Although heart failure is associated with an abnormally activated sympathetic nervous system, manifested by increased concentration of circulating catecholamines, attenuated cardiovascular reflexes, impaired cardiac vagal reflexes, and downregulation of adrenergic nerve terminals, the effect of CRT on cardiac neurohormonal function has not been well characterized.
Cardiac adrenergic control is governed by norepinephrine, a sympathetic transmitter, which is synthesized within neurons and released to the synaptic cleft. Most norepinephrine undergoes reuptake into presynaptic nerve terminals by the uptake-1 mechanism. Nerve growth factor belongs to a family of proteins termed neurotrophins that play a critical role in the development of sympathetic innervation.
Several radiolabeled compounds have been synthesized for noninvasive imaging of cardiac neuronal function. The catecholamine analogue 123iodine metaiodobenzylguanidine (123I-MIBG) is the most commonly used tracer for mapping myocardial presynaptic sympathetic innervation and activity. Carbon-11 hydroxyephedrine (11CHED), an alternative norepinephrine analogue, is used as a positron emission tomography (PET) tracer for assessing presynaptic uptake-1 transport function.
Mayo Clinic researchers, led by Yong-Mei Cha, M.D., have examined the effect of CRT on neuronal integrity, the cardiac presynaptic sympathetic function determined by these nuclear cardiac imaging modalities. Furthermore, they are evaluating whether neurohormonal profiles and sympathetic function can predict the likelihood of response to CRT.
Early results indicate that CRT reverses cardiac autonomic remodeling by upregulating presynaptic receptor function, with increased 123I-MIBG uptake and 11CHED retention index at the sympathetic terminal level in parallel with improvements in heart rate variability, indicating a favorable rebalance of cardiac sympathetic function. The study results suggest that CRT improves cardiac presynaptic sympathetic activity similar to pharmacologic therapy with β-blockage or renin-angiotensin-aldosterone axis inhibition.
Furthermore, cardiac sympathetic reserve assessed by 123I-MIBG scintigraphy appears to be a potential predictor of clinical response to CRT. The baseline sympathetic uptake function in patients who responded to CRT was similar to that in controls, representing a preserved sympathetic function. Conversely, those with severely impaired baseline sympathetic function were less likely to benefit from CRT.
Mayo researchers speculate that in responders the cardiac sympathetic ending might be hibernating as an adaptation to elevated sympathetic control (functional deactivation), whereas nonresponders may have structural deficits in the cardiac sympathetic neurons due to scarred myocardium or anatomic cardiac denervation. This hypothesis appears to be supported by these early findings and is being examined in larger-scale studies.