Mr. K is a 63-year-old Caucasian man with history of coronary artery disease (CAD) with previous coronary interventions of stent implantations in the left anterior descending and circumflex coronary arteries. His most recent left ventricular ejection fraction (LVEF) is 30%. He has an automatic implantable cardioverter defibrillator (AICD) for primary prevention of sudden cardiac death. He has been receiving optimally uptitrated guideline-directed medical therapy (GDMT) for his heart failure (HF) including carvedilol 25 mg twice daily, lisinopril 20 mg daily, and spironolactone 25 mg daily for more than 12 months. His other medications include aspirin 81 mg daily, atorvastatin 40 mg daily, furosemide 40 mg daily, and potassium chloride 40 mEq daily. He denies angina but reports dyspnea while walking less than 2 blocks, which is stable compared to last year. He denies any resting dyspnea or orthopnea. He has had no hospitalizations for HF exacerbation over the past 12 months. He denies any angina. He has been compliant with his medications and adherent to a low-salt diet. On exam, he appears well-nourished and in no acute distress. His heart rate is 65 bpm and regular. Respirations are 16/minute. Blood pressure is 108/65. His cardiac examination reveals a regular rate and rhythm, and a sustained, laterally displaced apical impulse. There were no extra heart sounds or murmurs. His extremities were warm with no edema. His jugular venous pressure appears to be within normal limits and lungs were clear. His electrocardiogram shows sinus rhythm with a narrow QRS complex. Laboratory tests showed both liver and kidney function to be normal. His echocardiography showed LVEF of 30% and LV end-diastolic diameter of 65 mm.

PHARMACOLOGICAL

HF, a disease with high mortality and increasing prevalence,¹ is characterized by autonomic imbalance, including decreased parasympathetic tone,^2,3 hyperactive sympathetic tone,^4,5 and impaired baroreflex control of sympathetic activity (Figure 29-1).^6,7 Thus far, the drugs shown to improve survival in systolic HF—beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), aldosterone receptor antagonists, and the newest class approved angiotensin receptor-neprilysin inhibitors (ARNIs)—all possess sympatholytic effects and thus help restore autonomic imbalance in patients with systolic HF. For Mr. K, he has already been receiving GDMT and the dosages of his medications are optimally titrated. He is euvolemic on exam ination but still has baseline New York Heart Association (NYHA) class III symptoms.

NONPHARMACOLOGICAL

Although not FDA-approved, several approaches of autonomic modulation at trial level either by implanted devices or interventions have sought to restore the autonomic balance in HF and improve outcomes.^8,9 These measures include spinal cord stimulation, vagus nerve stimulation, baroreceptor activation therapy, and renal sympathetic nerve denervation (Figure 29-2).

Spinal Cord Stimulation

Spinal cord stimulation (SCS) involves the subcutaneous placement of an epidural stimulation lead with distal poles at the level of T₂ to T₄, which is connected to an implanted pulse generator in the paraspinal lumbar region (Figure 29-3). Different stimulation parameters have been used in different trials but it is generally applied at 90% of the motor threshold at a frequency of 50 Hz and a pulse width of 200 ms. SCS is typically applied intermittently with a few hours on and the rest being turned off. Animal studies have demonstrated that SCS works primarily via augmenting vagally mediated effects.¹⁰ SCS was also shown to counteract the heightened sympathetic response during ischemia.¹¹ An elegant canine study¹² by Lopshire et al showed that SCS was significantly better than optimal medical therapy (carvedilol + ramipril) in improvement of LVEF, reduction of ventricular tachyarrhythmias, and decline in serum norepinephrine and brain natriuretic peptide levels in dogs with rapid pacing-induced HF. A number of clinical trials have taken place to assess the efficacy and safety of SCS in systolic HF patients and report conflicting results. Smaller prospective trials^13,14 have yielded relatively positive results—SCS is safe, feasible, and potentially can improve symptoms, functional status, and LV function in patients with severe, symptomatic systolic HF. However, the largest DEFEAT-HF trial¹⁵—a multicenter, prospective, randomized (3:2 fashion) control trial enrolling 66 patients with LVEF ≤35%, NYHA class III HF symptoms while on optimal medical therapy, narrow QRS duration and a dilated LV failed to meet the primary endpoint. SCS did not significantly reduce the LV end-systolic volume index. Therefore, DEFEAT-HF does not provide evidence to support a meaningful change in clinical outcomes for HF patients receiving SCS.¹⁶

Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) utilizes a cuff electrode that is secured around the vagus about 3 cm below the carotid artery bifurcation. A brief stimulation that reduces heart rate by 10% is performed to ensure the correct positioning. The stimulation lead is then tunneled under the skin and over the clavicle to join the intracardiac sensing electrode (placed in the right ventricle, to prevent excessive bradycardia) and the pulse generator in the subcutaneous pocket in the right subclavicular region (Figure 29-4). The stimulation parameter then follows an up-titration protocol to achieve heart rate reduction of 5 to 10 bpm without eliciting adverse reactions.^17,18 Preclinical animal studies have shown that chronic VNS improved LV hemodynamics^19,20 and, more importantly, improved survival in HF.²¹ A myriad of mechanisms have been postulated to explain the beneficial effects of VNS—direct inhibition of cardiac sympathetic activities,²² reduction of the slope of action potential duration restitution curve (and thereby increasing the threshold of ventricular fibrillation),²⁴ increase in the expression of connexin-43,¹⁹ prevention of mitochondrial dysfunction during ischemia-reperfusion,²⁵ and also attenuation of systemic inflammation,^20,23 which, theoretically, may be beneficial in preventing coronary artery disease, the leading cause of HF.²⁶ Two recently published clinical trials have conflicting results. NECTAR-HF failed to demonstrate an improvement in LV end-systolic diameter, the primary endpoint, in 6 months’ time.²⁷ In contrast, Anthem-HF showed that VNS was able to significantly improve LVEF and reduce LV end-systolic diameter in 6 months’ time.²⁸ The same beneficial effects held true in 12 months’ extended follow-up.²⁹ Another much larger trial, INOVATE-HF, with enrollment of 707 patients with similar baseline parameters (LVEF ≤40%, NYHA class III symptoms, and a dilated LV) showed somewhat disappointing results: VNS did not reduce death and HF events. However, the same study did demonstrate a favorable result in terms of quality of life, improvement in NYHA class and exercise capacity associated with VNS treatment.^30,31 The results of this trial will be revealed soon (in 2016 according to its website) and may determine whether VNS is really beneficial in HF.