New Approaches in the Management of Sudden Cardiac Death in Patients with Heart Failure-Targeting the Sympathetic Nervous System

Abstract

Cardiovascular diseases (CVDs) have been considered the most predominant cause of death and one of the most critical public health issues worldwide. In the past two decades, cardiovascular (CV) mortality has declined in high-income countries owing to preventive measures that resulted in the reduced burden of coronary artery disease (CAD) and heart failure (HF). In spite of these promising results, CVDs are responsible for ~17 million deaths per year globally with ~25% of these attributable to sudden cardiac death (SCD). Pre-clinical data demonstrated that renal denervation (RDN) decreases sympathetic activation as evaluated by decreased renal catecholamine concentrations. RDN is successful in reducing ventricular arrhythmias (VAs) triggering and its outcome was not found inferior to metoprolol in rat myocardial infarction model. Registry clinical data also suggest an advantageous effect of RDN to prevent VAs in HF patients and electrical storm. An in-depth investigation of how RDN, a minimally invasive and safe method, reduces the burden of HF is urgently needed. Myocardial systolic dysfunction is correlated to neuro-hormonal overactivity as a compensatory mechanism to keep cardiac output in the face of declining cardiac function. Sympathetic nervous system (SNS) overactivity is supported by a rise in plasma noradrenaline (NA) and adrenaline levels, raised central sympathetic outflow, and increased organ-specific spillover of NA into plasma. Cardiac NA spillover in untreated HF individuals can reach ~50-fold higher levels compared to those of healthy individuals under maximal exercise conditions. Increased sympathetic outflow to the renal vascular bed can contribute to the anomalies of renal function commonly associated with HF and feed into a vicious cycle of elevated BP, the progression of renal disease and worsening HF. Increased sympathetic activity, amongst other factors, contribute to the progress of cardiac arrhythmias, which can lead to SCD due to sustained ventricular tachycardia. Targeted therapies to avoid these detrimental consequences comprise antiarrhythmic drugs, surgical resection, endocardial catheter ablation and use of the implantable electronic cardiac devices. Analogous NA agents have been reported for single photon-emission-computed-tomography (SPECT) scans usage, specially the ¹²³I-metaiodobenzylguanidine (¹²³I-MIBG). Currently, HF prognosis assessment has been improved by this tool. Nevertheless, this radiotracer is costly, which makes the use of this diagnostic method limited. Comparatively, positron-emission-tomography (PET) overshadows SPECT imaging, because of its increased spatial definition and broader reckonable methodologies. Numerous ANS radiotracers have been created for cardiac PET imaging. However, so far, [¹¹C]-meta-hydroxyephedrine (HED) has been the most significant PET radiotracer used in the clinical scenario. Growing data has shown the usefulness of [¹¹C]-HED in important clinical situations, such as predicting lethal arrhythmias, SCD, and all-cause of mortality in reduced ejection fraction HF patients. In this article, we discussed the role and relevance of novel tools targeting the SNS, such as the [¹¹C]-HED PET cardiac imaging and RDN to manage patients under of SCD risk.

Keywords: heart failure; hypertension; positron emission tomography; renal denervation; sudden cardiac death; sympathetic nervous system; ventricular arrhythmias.

Figure 1

Muscle sympathetic nerve responses during moderate static exercise in congestive heart failure patients (CRT and control) compared with normal control subjects. (A) Moderate static handgrip exercise at baseline. (B) Moderate static handgrip exercise after a 3-month follow-up. * p < 0.001 vs. normal control. ** p = 0.005 vs. normal control. *** p = 0.003 vs. normal control. CHF = congestive heart failure, CRT = cardiac resynchronization therapy. The bars represent the standard deviation [50].

Figure 2

The illustration depicts postganglionic SNS and PNS nerve endings. The left panel displays the synthesis and release of noradrenaline in postganglionic SNS nerve endings and subsequent binding to postsynaptic receptors on cardiomyocytes. The tracers in red depict SNS pre- and post-synaptic radio analogs. The right panel shows the synthesis and release of acetylcholine in the terminal nerve ending and varicosities of postganglionic PNS nerve endings and subsequent binding to postsynaptic receptors on cardiomyocytes. Tracers in blue depict PNS pre- and post-synaptic radio analogs. AC = adenylyl cyclase, ACh = acetylcholine, AChE = acetylcholinesterase, ATP = adenosine triphosphate, CAT = choline-acetyl-transferase, COM = catechol-O-methyltransferase, cAMP = cyclic adenosine monophosphate, MAO = monoamine oxidase, MR2 = muscarinic receptor 2, NA = noradrenaline, NR α4β2 = nicotinic receptor, VMAT = vesicular monoamine transporter, 18F-6F-DA 6-18F-fluorodopamine, PHEN =phenylephrine, EPI = epinephrine (adrenaline), HED = hydroxyephedrine, MQNB = (R,S)-N-[¹¹C]-methyl-quinuclidin-3-yl benzilate [56].

Figure 3

PET imaging of flow, viability and sympathetic innervation. (A) A subject experiencing sudden cardiac arrest (SCA). There is a mismatch in infarct size (reduced ¹⁸F-2-deoxyglucose [¹⁸FDG]), which was smaller than the volume of sympathetic denervation (reduced ¹¹C-meta-hydroxyephedrine [¹¹C-HED]). There was also reduced perfusion (¹³N-ammonia [¹³NH₃]) with preserved ¹⁸FDG indicating hibernating myocardium. In contrast, (B) shows a subject with matched reductions in flow, infarct volume, and sympathetic denervation. ANT = anterior; INF = inferior; LAT = lateral; PET = positron emission tomography; SEP = septum [59].

Figure 4

PET parameters and sudden cardiac arrest. Kaplan–Meier curves show the incidence of sudden cardiac arrest for tertiles of PET-defined myocardial substrates (median follow-up 4.1 years). As continuous variables, the total volume of denervated myocardium, as well as viable denervated myocardium, predicted sudden cardiac arrest. Neither infarct volume nor hibernating myocardium was significant as continuous variables. SCA = sudden cardiac arrest [59].

Figure 5

RDN significantly reduced the incidence of ventricular arrhythmias. Representative ECG of electrical stimulation, including sinus rhythm (a), ventricular arrhythmias (b) and (c). Ventricular arrhythmias were less easily induced in RDN group rather than in MI group and Met group (d). (* p < 0.05 vs. Control group; # p < 0.05 vs. MI group; & p < 0.05 vs. Met group). MET = metoprolol. MI = myocardial infarction. RDN = renal denervation [97].

Figure 6

Effects of renal denervation on ventricular fibrillation in a pig model for ventricular ischemia and reperfusion. (A) Representative view of the left ventricular during ischemia reperfusion experiments. Atrial electrophysiology was recorded by an epicardial catheter. (B) Incidence of VF during ischemia and the reperfusion phase in RDN-treated compared to SHAM-treated pigs. (C) Representative hemodynamics and electrocardiographic (ECG) tracings during 20 min of left anterior descending coronary artery ligation followed by reperfusion in a SHAM-treated and a RDN-treated animal. RDN = renal denervation. VF = ventricular fibrillation [99,106].

Figure 7

Effects of renal sympathetic denervation. Sympathetic efferent activation is generated in the central nervous system. Efferent sympathetic nerves (red lines) target the heart, kidney, and vessels and produce neprilysin activation (new finding), inotropic effects, but also fibrosis, beta adrenergic down-regulation and contractile dysfunction. In the kidney, the vasoconstriction increases renin activation and enhanced sodium water retention, contributing to fibrosis and kidney damage. Peripheral arterial afterload increases by vasoconstriction and, in the long run, BP is increased. Atherosclerosis is initiated, and media hyperplasia takes place. Interruption of afferent as well as efferent kidney nerve fibers by using renal sympathetic denervation (red cross) reduces sympathetic outflow (interrupted red lines) and potentially reverses these pathological findings [111]. Down arrows = efferent sympathetic activation. Up arrows = afferent sympathetic activation.

Figure 8

Cardiac arrhythmogenic effects provoked by the sympathetic and parasympathetic nervous systems [126]. Blue = parasympathetic nervous system. Red = sympathetic nervous system. Black = Connections between the brain and the parasympathetic and sympathetic nervous systems. Up arrows = increase. Down arrows = decrease. Red line and + = provoke these events. Blue line and − = inhibits these events.

Figure 9

Representations of possible connections amongst different nerve structures [85].

Figure 10

Cardiac innervation patterns provoking sudden cardiac death. Left: Overexpression or underexpression of Sema3a, a class 3-secreted semaphorin, which acts as a potent neural chemorepellant, leads to abnormalities in innervation patterning of sympathetic nerves causing ventricular arrhythmias and sudden cardiac death. Right: Overexpression of NGF leads to a disrupted patterning of sympathetic neurons leading to hyperinnervation, ventricular arrhythmias, and sudden death [121]. Upregulation of secreted nerve growth factor (NGF) from cardiomyocytes in diseased heart (NGF and green arrow) may cause lethal arrhythmia (red arrows) and SCD (black arrows).