Cardiac Sympathetic Afferent Denervation Attenuates Cardiac Remodeling and Improves Cardiovascular Dysfunction in Rats With Heart Failure

Abstract

The enhanced cardiac sympathetic afferent reflex (CSAR) contributes to the exaggerated sympatho-excitation in chronic heart failure (CHF). Increased sympatho-excitation is positively related to mortality in CHF patients. However, the potential beneficial effects of chronic CSAR deletion on cardiac and autonomic function in CHF have not been previously explored. Here we determined the effects of chronic CSAR deletion on cardiac remodeling and autonomic dysfunction in CHF. In order to selectively delete the transient receptor potential vanilloid 1 receptor (TRPV1) -expressing CSAR afferents, epicardial application of resiniferatoxin (RTX, 50 μg/ml), an ultrapotent analogue of capsaicin, was performed during myocardium infarction (MI) surgery in rats. This procedure largely abolished the enhanced CSAR, prevented the exaggerated renal and cardiac sympathetic nerve activity and improved baroreflex sensitivity in CHF rats. Most importantly, we found that epicardial application of RTX largely prevented the elevated LVEDP, lung edema and cardiac hypertrophy, partially reduced left ventricular dimensions in the failing heart and increased cardiac contractile reserve in response to β-adrenergic receptor stimulation with isoproterenol in CHF rats. Molecular evidence showed that RTX attenuated cardiac fibrosis and apoptosis and reduced expression of fibrotic markers and TGF β-receptor I in CHF rats. Pressure - volume loop analysis showed that RTX reduced the end diastolic pressure volume relations in CHF rats indicating improved cardiac compliance. In summary, cardiac sympathetic afferent deletion exhibits protective effects against deleterious cardiac remodeling and autonomic dysfunction in CHF. These data suggest a potential new paradigm and therapeutic potential in the management of CHF.

Arterial baroreceptor reflex control of renal sympathetic nerve activity following chronic myocardial infarction in male, female, and ovariectomized female rats

“…The role the arterial baroreflex plays in driving the increase in renal sympathetic activity in heart failure remains controversial. In male rats the attenuation of the arterial baroreflex control of renal SNA in MI-induced heart failure, typically presented as a reduced gain and range, is associated with elevated renal SNA (10,13,40,55,61,56). However, the current findings in ovary-intact females with large MI demonstrate that it is possible to have significantly elevated renal SNA in association with preserved arterial baroreflex regulation.…”

“…Normalization of renal SNA is the most commonly used form of analysis for direct recordings of renal SNA, although there appears to be no consistent method of normalization between studies (13,40,55,61,50,56). The strong linear correlation observed in the present study in males and OVX females between left ventricular ejection fraction and arterial baroreflex range of control as measured in normalized units does suggest there is merit in presenting normalized renal SNA data.…”

Renal denervation improves cardiac function in rats with chronic heart failure: Effects on expression of β-adrenoceptors

“…Specifically, increased sympathetic activation of the cardiac innervation has been shown in rats with HF (43,45). Consistent with these observations, cardiac NE spillover is also reported to be increased in patients with HF (10).…”

Inflammation, oxidative stress, and glial cell activation characterize stellate ganglia from humans with electrical storm

“…The trigger for increased neuronal activity and oxidative stress may be increased cardiac afferent neurotransmission, which increases efferent sympathetic tone via a spinal reflex mechanism (17). Other etiologies may include circulating neurohormonal signals such as angiotensin II (18,19) or brainstem-mediated increases in efferent sympathetic outflow (20), all of which have been described in CMY and heart failure states.…”