Renal Denervation for Chronic Heart Failure: Background and Pathophysiological Rationale

In chronic heart failure, the activation of the sympathetic nervous system,1) the renin-angiotensin system,2) as well as pro-inflammatory activation3) are associated with remodeling processes and maladaptive cardiac signal transduction.4) Sympathetic activation plays a crucial role and is closely related to cardiovascular outcomes as judged from circulating norepinephrine concentrations.5), 6) It is also likely to be involved in the progression of the syndrome because norepinephrine concentrations are already increased in asymptomatic left ventricular dysfunction before clinically relevant heart failure symptoms develop.7)

Sympathetic activation is generated by the nucleus tractus solitarius in the midbrain and rostreal ventrolateral medulla.8) Efferent signaling to the heart adapts cardiac output to peripheral stress situations with an increase of chronotropy, inotropy, and dromotropy as well as increasing intraventricular conduction velocity (bathmotropy). After longstanding activation, cardiac phenotypes can change, resulting in hypertrophy and fibrosis making the heart more prone to arrhythmia development, as well as pump function and relaxation disturbances. In heart failure, vasoconstriction and sodium retention are the result of α-adrenoceptor stimulation,9) whereas after longstanding neuroendocrine stimulation, endothelial dysfunction and oxidative stress are harbingers of structural changes of the vasculature8) and end organ damage, in particular impaired renal function.10), 11) In the liver, sympathetic activation increases gluconeogenesis and glycogenolysis. Furthermore, sympathetic activation by α-adrenoceptor-mediated vasoconstriction shifts the blood flow away from insulin sensitive organs and might make patients more prone to develop impaired glucose tolerance and diabetes mellitus type 2.12), 13) In the central nervous system, CO₂ sensitivity is enhanced, contributing to dyspnea and conditions like heart failure,14) particularly with congestion and volume overload.15) Furthermore, sleep apnea is associated with sympathetic activation in hypertensives and patients with chronic heart failure.16), 17) Blood pressure is upregulated by an increase of β1-adrenoceptor-mediated renin activation, sodium retention and an impairment of renal blood flow.8) All these conditions resemble those disturbances that are observed in chronic heart failure and in patients presenting with impaired myocardial function which is associated with a high likelihood of developing comorbidities like diabetes mellitus type 2, renal impairment and arrhythmias like atrial fibrillation or even sudden cardiac death.18) The interaction of centrally generated sympathetic drive with peripheral organs is summarized in Fig. 1.

Fig. 1
Pathophysiological interaction between the brain, the kidney and other peripheral organs like heart, liver and vasculature after sympathetic activity is enhanced. Efferent signals generated in the sympathetic nervous system stimulate the heart and other organs producing maladaptive responses. In the kidney, sympathetic activation reduces renal blood flow, increases sodium retention and activates renin-angiotensin system. Efferents further enhance sympathetic outflow providing a vicious cycle in the stepwise increase of the sympathetic activation in the interaction between the heart and the brain. modified from reference 11. RAAS: renin angiotension aldosteron system.

• Click for larger image
• Download as PowerPoint slide

Among these mechanisms, the interplay between renal sympathetic activity and the central nervous system is crucial.19) While activated efferent nerves from the brain increase sodium retention and reduce renal blood flow, the renal afferent nerves provide feedback to the brain with some of the signals being mediated by adenosine, oxidative stress, ischemia and acidosis.11), 20), 21) Afferent stimulation of the brain further increases sympathetic efferent activation leading to a vicious cycle in the interaction between brain and kidneys further enhancing total body sympathetic activity.8), 11) It has been shown that sympathetic activation occurring in different forms of hypertension22) is further enhanced in heart failure,1) and in its comorbidities such as metabolic syndrome13) and renal failure.23) Thus, a sympathetic cardiorenovascular continuum occurs during the progression from mild to severe organ damage, and contributes to cardiac or renal-associated comorbidities.

Norepinephrine released from the sympathetic nerves in the heart produces excessive beta-adrenergic receptor stimulation.24) As a consequence, beta receptors are downregulated,25) and post-receptor events, such as an increase of inhibitory G-proteins,26) produce an impaired effectiveness of cAMP-dependent positive inotropic agents like beta-adrenergic agonists and phosphodiesterase type 3 inhibitors.25), 26) Beyond the receptor and post receptor defects, there is a depletion of cardiac norepinephrine storing and a defect of uptake in the failing heart (Fig. 2).27), 28) Serum norepinephrine concentrations are associated with mortality in chronic heart failure.5), 6) In addition, not only cardiac but also renal norepinephrine spillover is increased and related to the severity of heart failure.29) Interestingly, renal spillover is also associated with poor outcomes.30) The above mentioned aspects provide the pathophysiologic background for the hypothesis that an intervention at the renal sympathetic nervous system could influence the outcome in chronic heart failure by reducing detrimental sympathetic activation.

Fig. 2
Summary of beta-adrenergic signal transduction in heart failure. Modified from reference.28) AR: adrenoreceptor, NA: noradrenaline, Gs: stimulatory G protein, AC: adenylyl cyclase, Gi: inhibitory G protein, mRNA: messenger ribonucleic acid, Gia: inhibitory guanine binding protein.

• Click for larger image
• Download as PowerPoint slide

The first clinical studies on lumbal splanchnicectomy involving sympathetic renal denervation were done in severe hypertension in the 1950's. Total paralumbar splanchnicectomy led to an increase of survival rates in patients with severe hypertension and cardiovascular disease.31, 32, 33) Severe adverse effects and high mortality were observed and the method was discontinued after the development of efficient and tolerable antihypertensive drugs.

Renal sympathetic denervation was performed in patients with resistant hypertension (patients being on 3 or more drugs where one has to be a diuretic, and not achieving an optimal blood pressure control 34, 35, 36, 37, 38)). The associated blood pressure reduction was not accompanied by chronotropic incompetence,39) but was able to reduce peripheral artery stiffness,40) and to reduce myocardial hypertrophy, which appeared at least partly blood pressure independent.41) These studies in hypertensives provided evidence that reducing sympathetic activity is able to reduce cardiovascular function due to reducing myocardial hypertrophy,41) thus setting the stage to conduct trials in heart failure.

Heart failure is often affected by low blood pressure hampering the possibilities for applying evidence-proven drugs often associated with further blood pressure reductions and improved outcomes. For this reason, a first pilot study (REACH, NCT 01639378) studied renal denervation in heart failure patients with reduced ejection fraction and a blood pressure above 120 mmHg systolic in an open label, uncontrolled fashion.42) Blood pressure before and after the procedure remained stable in these patients during 6 months of follow-up. Interestingly, after renal denervation there was an increase of 6-minute walk test despite no change in blood pressure. The reason might be that renal sympathetic denervation can redistribute the blood flow after reduction of sympathetic activation, and counteract the sympathetically mediated reduction of the venous reservoir and sodium water retention, thereby reducing congestion.43) However, given the uncontrolled fashion of the study, one has also to consider potential placebo effects.