Neuromodulation for Refractory Angina, Heart Failure and Peripheral Vascular Disease
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.302461
Source of Support: None, Conflict of Interest: None
Keywords: Angina pectoris, heart failure, peripheral vascular disease, spinal cord stimulation
Spinal cord stimulation (SCS) has a yielded beneficial outcome in sustained pain relief, and an improved quality of life in the treatment of chronic intractable pain of different origins such as peripheral vascular disease (PVD), refractory angina pectoris (RAP), and recently also as device-based therapy to preserve the sympathovagal imbalance that develops in heart failure (HF)., In this review, we will describe the current complexities and neuromodulatory approaches to these disorders.
Peripheral vascular disease (PVD) is a common disease mostly involving arteries of the extremities. It usually results from progressive narrowing of arteries in the lower extremities, caused by atherosclerosis. PVD prevalence in the United States has ranged as high as 30% in adult populations and is closely associated with elevated risk of cardiovascular disease morbidity and mortality.,
Severe limb pain, claudication, ulcerations, and limb amputation are common complications of PVD, especially among patients with kidney disease and diabetes.,
Increased knowledge of the underlying pathophysiology in the development of ischemic heart disease has promoted the development of a large armamentarium of therapies for this illness. However, to date ischemic heart disease still continues to be a serious concern with regards to the morbidity and mortality in the western world. In the recent times, improved primary prevention methods and surgical treatment strategies has led to an increase in the patients overall survival. However, there has been a steady increase in the number of patients with uncontrolled chronic pain. These patients with an unmet medical need, report severe disabling chest pain occurring with minimal exercise or even at rest. This pain is often refractory to the standard medical therapies advocated. It is defined by the European study group on the treatment of refractory angina as: “ a chronic condition characterized by the presence of angina, caused by coronary insufficiency in the presence of coronary artery disease (CAD), which cannot be adequately controlled by a combination of medical therapy, angioplasty and coronary bypass surgery. The presence of myocardial ischemia should be clinically established to be the cause of symptoms”.
Heart failure (HF) is the final stage of cardiovascular diseases. It leads to autonomic nervous system dysfunction, as a result of sympatho - excitation and deficiency of vagal nerve activity. Both left ventricular diastolic and systolic dysfunctions have excess sympathetic activity, caused by different mechanisms such as arterial baroflex failure, attenuation of cardiopulmonary reflex, sleep apnea and myocardial ischemia. Mitigation of the deleterious effects of the sympathetic activity using beta blockers is fundamental in current HF treatment, but to achieve further improvement in a 5 year survival rate for HF patients, intervention with the autonomic nerve dysfunction via devices such as SCS is needed.,
Peripheral vascular disease
SCS was first introduced in the late 1960’ but it was not until 1976 when Cook and colleagues presented SCS as a therapeutic option for vascular disease of the limbs. Since then multiple studies were done to prove and assess the efficacy of SCS for the treatment of PVD. Most of the studies reviewed use similar selection criteria. To be included, patients must have recurring ischemic rest pain (usually of 2 weeks or more duration) and unreconstructable disease of the lower extremity, meaning an ankle\ brachial index of less than 0.4 or great tow pressure more than 30 mmHg. Inclusion criteria usually limits ischemic ulcers to a diameter of no more than 3 cm2, and the severity of PVD is often assessed with the La Fontain classification: 1 asymptomatic, 2 intermittent claudication, 3 pain at rest and 4 pain at rest along with ulcers. Multiple studies have investigated the improvement of ischemic pain after SCS. One of the largest prospective, controlled studies was of Amann et al., they have evaluated 71 patients and showed a significant reduction of pain in the SCS treated group as well as an improvement in limb survival rate. Other studies such as the Reig & Abejon and the Ubbnik &Vermelun all demonstrated significant improvement in limb survival rate and reduction of ischemic pain., Several investigators have examined the impact of SCS on the microcirculatory blood flow in order to better understand the effect of SCS. The microcirculatory blood flow can be assessed by cappiloroscopy, transcutaneous oxygenation (TCpO2) or by a Doppler test. Kumar and colleagues prospectively studied 39 patients and concluded that SCS provides benefits as measured by TCpO2, blood flow velocities, pulse volume and improved both microcirculation and microcirculation. Outcome among patients with stage 4 La Fontain disease is relevant with respect to claudication and ulcer healing. Tallis,, reported the efficacy of SCS in a series of ten patients who showed improvement in mean claudication distance., Brummer and colleagues in their prospective study reported the absence of new skin ulcers development in all patients treated with SCS.
Refractory angina pectoris is a condition of chronic chest pain accompanied by jaw and arm pain caused by imbalance between myocardial oxygen supply and demand. It is often secondary to atherosclerotic CAD, but may possibly be due to coronary vasospasm. Patients who are not surgical candidates for coronary artery bypass graft (CABG), are medically treated with beta blockers, calcium channel blockers or SCS. One of the first largest trial, ESBY (Electrical Stimulation versus Coronary Bypass Surgery in sever angina pectoris) investigated 104 patients at a high risk for surgery who were assigned randomly to CABG or SCS. Both therapies reduced angina and the use of nitrates. The SCS group had a lower 6 month mortality (1.9% vs 13.7%) and fewer cerebrovascular events. Despite the lower mortality rate they concluded that CABG and SCS appear to be equivalent methods in terms of symptom relief, and that SCS could be an alternative for patients with increased risk of surgical complications.
In a more recent systemic review, a grand meta-analysis completed by Pan et al. 2016, the long term efficacy and safety of SCS in RAP was evaluated. 12 retrospective studies were included with a total of 476 patients, maximum follow up interval was 24 months. The main outcomes included were, exercise time after intervention, changes in angina classes, Visual analogue score, physical limitation, angina stability, angina frequency, treatment satisfactions, disease perception and nitroglycerine use. This review demonstrated that SCS applied in RAP was effective and safe as being reflected mostly in an increased exercise time, a decrease of nitroglycerine consumption and significant improvement in the quality of life.,,, Furthermore, most studies confirmed that SCS device could decrease the frequency of angina and disease perception.
Abnormal neurohormonal activation is often responsible for the progress of heart failure. Treatment often includes drug therapy to modulate this neuro axis instability. The first in-human prospective multicenter study was the SCS HEART (Thoracic Spinal Cord Stimulation for Heart Failure as a Restorative Treatment) study aiming to evaluate the safety and efficacy of a SCS treatment for systolic HF. 22 patients were enrolled with a NYHA (new York Heart Association classification) class 3, LEVF (Left Ventricular Ejection Fraction) 20%-35%. 17 patients were implanted with a dual SCS leads at T1-T3 vertebral level. Results showed that a high thoracic SCS is safe and feasible, and could potentially improve symptoms, functional status and LV functions.
The second and more recent large prospective study was the DEFEAT-HF (Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Heart Failure), a multicenter, randomized, single blinded controlled study. The aim of the study was to assess if SCS could improve parameters such as heart size, HF biomarkers, functional capacity and symptoms within the HF patient group. 81 patients with a NYHA class 3, LEVF less than 35, QRS more than 120 ms and a left ventricular end diastolic dimension less than 55 mm were tested. Of the 81, 66 patients were implanted with a SCS device for a six months period. Results showed no significant change in LVEF over 6 months.
The results of these two main studies are discordant and could be explained because of differences in the surgical technique and SCS stimulation parameters.
SCS is used as an additional treatment for IHD for the reduction of frequency and intensity of angina it also increases the exercise capacity, and does not mask the warning signs of a myocardial infarction.
The implantation technique of SCS is fairly simple and has some similarities with the technique used in pain management: the electrode is implanted in the epidural space under local anesthesia with the tip at T1 thoracic vertebra level. The electrode is placed at the desired location and advanced under fluoroscopy for location verification.
Stimulation parameters differ between different publications, but are usually employed as 200-210 ms pulse width at 50-85 Hz suprathreshold. The selection of cathode and anode is fluctuated by patient feedback until upper thoracic coverage is confirmed (covering the painful area with paranesthesia during stimulation). The electrode is then sutured to the fascia at its exit from the spinal column, and the proximal portion of the lead is tunneled subcutaneously to the buttock and connected to a subcutaneously implanted pulse generator.
In PVD the same implantation technique is used as in IHD except that the tip of the electrode is positioned at T10-11 thoracic vertebra.
Although there have been advances in the interpretation of SCS mediated antinociception, the evidence clarifying the role of electrical pulses when applied to the epidural space is missing and our knowledge of the mechanisms of actions dramatically falls behind clinical data. The “gate control” theory by Melzack and Wall published in 1965 was the first to offer explanation to SCS effect., They have argued that non painful input closes the nerve “gate” to painful input, which prevent pain sensation from travelling to the CNS through the spino- thalamic tract. According this theory, continuous stimulation of the A-beta large nonnicipetive fibers in the dorsal columns would lead to transmitter release via their spinal collaterals, which will than lead to the inhibition on unmyelinated, longer term chronic pain C- fibers and myelin quick intense pain A- delta fibers. This inhibition in the dorsal horn neurons will close the gate and reduce central transmission of pain.
A few mechanisms have been proposed by which SCS acts in the treatment of PVD AP and HF. This refers to dorsal root stimulation, dorsal horn stimulation, spinal-supraspinal loop and central influence such as dorsolateral funiculi (DLF).
Stimulation of the dorsal root ganglia leads to the activation of cell-signaling molecules such as extracellular signal-regulated kinase (ERK) and protein kinase B (AKT), this initiate a cascade of cell signaling activation that ends with release of vasodilators such as calcitonin gene-related peptide (CGRP) that in turn stimulate the release of niric oxide (NO) which causes smooth muscle cell relaxation end by that decrease vascular resistance and increase blood flow.
In addition, SCS suppresses sympathetic vasoconstriction through inhibition of sympathetic nicotinic transmission at the ganglionic and postganglionic junction.,, Pain relief is achieved by release of endogenous opioid-like peptides such as met-enkephalin. The exact nature of neurohumoral effects mediated by dorsal root small-diameter afferents or the sympathetic fibers remains unclear.
Prostaglandin-mediated vasodilatation caused by antidromic stimulation of dorsal root afferents has been suggested. It has also been suggested that pain relief in itself might relieve vasoconstriction. Speculation has also centered on the release of vasoactive substances with local and possibly systemic effects, including vasoactive intestinal peptide, substance P, and calcitonin gene-related peptide.
It may be possible that several mechanisms are active simultaneously, with inhibition of autonomically mediated vasoconstriction and activation of vasoactive substances participating in the efficacy of SCS.,
Stimulation of the dorsal horn neurons through a dorsal column-brain stemspinal loop could explain the effect of the SCS though it is not clear whether the inhibitory action of SCS on hyper-excitable wide-dynamic range neurons exciting in the dorsal horn is mediated via reducing their excitatory input, increasing their inhibitory input, modulating the electrophysiological properties of these neurons, or a combination of these effects.
Saade and Linderoth reported that activation of the dorsal columns is relayed to supraspinal centers, probably through the descending fibers in the dorsolateral funiculi (DLF), which is involved in pain modulation and play a significant role in the attenuation of pain-related signs by SCS. One impulse path is an antidromic impulse generated in the DCs activate inhibitory interneurons with an enhanced release of gamma aminobutyric acid, which can reduce the activation at the hyperexcitable second-order neurons. As a result, improved microvascular blood flow. Another major impulse path is orthodromic to the brain, activating circuitry in the brain stem ultimately giving rise to descending impulses through the DLF, amplifying the inhibitory processes at the spinal level. [Figure 1] encapsulates the accepted theory for the mechanism of action.
SCS is being used for indications other than pain control. As we learn more about the neural pathways controlling other non-nervous disorders, the indications may expand further.
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