SCIENCE@home

Splanchnic nerve block with botulinum toxin for therapy of chronic heart failure – mechanism of action (SPONGE‐HF)

M. Fudim,K. Parikh,Arun Ganesh,J. Molinger,N. Ray,Aubrie Coburn,B. Coyne,Ashley G. Swavely,J. Andrews,J. M. Gray,V. Rao,G. Felker,S. Borges-Neto,A. Hernandez,M. Patel

Published 2023 in European Journal of Heart Failure

ABSTRACT

Chronic heart failure (HF) is characterized by limited exercise capacity driven in part by an excessive elevation of cardiac filling pressures.1 The short-term blockade of splanchnic nerves with anaesthetics and long-term blockade with surgical resection or catheter-based ablation has proven to be safe and effective in reducing exercise-induced pressure elevation in patients with HF.2–5 These interventions also improved the functional capacity of patients with HF.2–5 We aimed to investigate the proposed mechanisms of action, including changes in vascular capacity with reduced blood volume shifts from the abdomen to the thorax, and vascular decongestion through an improved cardiorenal function.6 We tested these mechanisms of action using a novel, minimally invasive long-term splanchnic nerve block (SNB) with botulinum toxin. The present study was a prospective, open-label, single-arm interventional study in patients with chronic HF. Eligible patients had a baseline pulmonary capillary wedge pressure (PCWP) ≥25 mmHg with exercise. Patients underwent cardiopulmonary exercise testing (CPET) with invasive haemodynamic assessment, followed by percutaneous unilateral SNB with botulinum toxin (100 units, not more than 1.5 units/kg). Subsequently, patients underwent serial testing at 2, 4 and 8 weeks with repeat supine CPET. Invasive haemodynamics with exercise were repeated at the 4-week exam only. At each exam we repeated non-invasive metrics of whole body and lung water content. Measures requiring radiotracers such as blood volume analysis and radioplethysmography were repeated at the 4-week exam only. The internal jugular vein (8 Fr sheath) and radial artery (5 Fr sheath) were used for access. At baseline, values were averaged across two pressure recordings. Following resting haemodynamics, patients underwent supine cycle ergometry testing with simultaneous expired gas analysis. Patients were tested at a fixed workload of 20 W at a pedaling speed of 55–65 rpm. After reaching steady state, patients were exercised to peak with a stepwise increase of 20 W/min. Pressure tracings were analysed in a blinded fashion. Intra-cardiac pressures were taken as the average end-expiratory values across multiple respiratory cycles over a 10 s period. Breath-by-breath oxygen consumption was measured continuously (Vmax e29; Vyaire Medical, Höchberg, Germany). The pre and post-assessments were performed by the same staff members. The total intravascular blood volume was assessed via blood volume analysis (BVA) with radiolabelled albumin (131I). BVA uses a standardized computerbased technique to administer low-dose (micro-Curie) 131I -labelled albumin intravenously and calculate the blood volume via tracer dilution technique (BVA-100; Daxor Corporation, New York, NY, USA).7 Lung water content was assessed via remote dielectric sensing (ReDS), and the total body water was measured via bioelectrical impedance analysis (Inbody S10, Seoul, Korea, S10) before and after SNB. Blood volume shifts between the thorax and abdomen were measured via radionucleotide plethysmography with 99Tc-labelled red blood cells. Images were obtained at rest and during exercise using General Electric Discovery-630 with system software to mark regions of interest. The ratio between thoracic and abdominal blood volume was calculated in an automated fashion. The protocol was approved by the local Institutional Review Board, and all patients provided written informed consent (NCT04575428). Among five patients enrolled, four met the haemodynamic inclusion criterion and underwent SNB (Table 1). The mean age was 73± 6 years and three were women. Left ventricular ejection fraction was ≥55% in three patients and 35% in one patient. At the 1-month follow-up, there were no changes in diuretics or guideline-directed medical therapy, at 2 months one patient changed 60 mg of furosemide to 40 mg of torsemide every day. No SNB-related complications were encountered. There were no orthostatic blood pressure changes or gastrointestinal symptoms related to the procedure. The mean creatinine increased from baseline to 2 months (1 to 1.1 mg/dl) and the mean N-terminal pro-B-type natriuretic peptide decreased from 724 to 586 pg/ml at 2 months. Following SNB, mean right atrial pressure at rest decreased from 9.3 (± 4.9) (preSNB) to 5.8 (± 2.4) mmHg (post-SNB) and with peak exertion from 24.3 (± 6.8) (preSNB) to 19 (± 3.2) mmHg. SNB reduced mean PCWP at rest from 17.5 (± 9.5) (preSNB) to 14 (± 1.6) mmHg (post-SNB) and exercise-induced PCWP decreased from 44 (± 6.2) (pre-SNB) to 34 (± 8.2) mmHg (post-SNB). The cardiac index changed with peak exercise from 4 (±1.1) (pre-SNB) to 4.5 (±1) L/min/m2 (post-SNB) (Figure 1A). The change in the slope of mean pulmonary arterial pressure over mean cardiac output from rest to 20 W changed from 11.8 (pre-SNB) to 8 mmHg/L/min (post-SNB) and the slope for the mean delta wedge over mean cardiac output from rest to 20 W exercise changed from 15.4 (preSNB) to 7.5 mmHg/L/min (post-SNB). Two months after SNB, patients achieved peak exertion ∼1:50 min later, with increased workload (40 [± 28] W vs. 75 [± 38] W) and a greater 6-min walk distance of 340 (± 50) m vs. 426 (± 92) m. Peak oxygen consumption remained unchanged. At 1 month, the mean total body water decreased by 1100 (± 400) ml and intravascular blood volume by 590 (± 532) ml. Over the same period, the lung water content decreased from 28 (± 2) to 25 (± 5) (unitless values). Using radionucleotide plethysmography SNB decreased resting, and exercise thoracic blood volume measured by a decreased thorax-to-abdomen ratio (n = 2, Figure 1B). We report the first study of long-term SNB with botulinum toxin in chronic HF. In this single arm, pilot study, the reduction in resting and exercise-induced intra-cardiac pressures was accompanied by an improved exercise capacity, decreased whole body water, and intravascular blood volume. Further, SNB led to an increased abdominal blood pooling with reduced intrathoracic blood shifts with exercise. We utilized unique study methods to measure blood volume directly and visualize the change in blood volume with rest and exercise, before and after SNB. A reduction in whole body water and intravascular blood volume could potentially be explained by the fact that splanchnic nerve fibres contribute to the innervation of the kidneys and the interruption of the renal fibres could positively affect salt and water excretion. A decrease in blood volume and whole body water could have been at least in part a driver of the observed decrease in cardiopulmonary filling pressures. We suspect that a combination of a small number of patients and a relatively short follow-up duration of 1 month was insufficient to show improvement of the peak oxygen consumption even in light of the improved haemodynamics. Additionally, the supine position for the CPET could have prevented us to observe gains in functional

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-7 of 7 references · Page 1 of 1

CITED BY

Showing 1-6 of 6 citing papers · Page 1 of 1