Heart failure (HF) constitutes a significant clinical problem and is associated with a sizeable burden for the healthcare system. Numerous novel techniques, including device interventions, are investigated to improve clinical outcome. Interventions regarding autonomic nervous system imbalance, i.e., baroreflex activation therapy; vagus, splanchnic and cardiopulmonary nerves modulation; respiratory disturbances, i.e., phrenic nerve stimulation and synchronized diaphragmatic therapy; decongestion management, i.e., the Reprieve system, transcatheter renal venous decongestion system, Doraya, preCardia, WhiteSwell and Aquapass, are presented.
Method | Pathophysiological Mechanism | Solution | Trial Design and Size | Primary Outcomes | Evidence | Adverse Events | |||||
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Baroreflex activation therapy | Overactivity of SNS (increased heart rate, arterial pressure, RAAS activity and negative cardiac remodeling). | Stimulation of carotid bodies to restore autonomic system balance. | Multicenter, prospective, controlled trial | n | = 408 | Rate of cardiovascular and HF morbidity, MANCE, Change in: NT-proBNP, 6 MHW, MLWHF QOL |
BeAT-HF showed improvements of quality of life, exercise capacity, functional status and decrease of NT-proBNP [2] | MANCE event-free rate: 97%. A system or procedure-related serious adverse event occurred in seven patients. | |||
Single-center, open-label | n | = 11 | Not reported | Dell’Oro et al. demonstrated significant improvement of EF and reduction in hospitalization [3] | No adverse effects were reported. | ||||||
Vagus nerve stimulation | Overactivity of SNS (increased heart rate, arterial pressure, RAAS activity and negative cardiac remodeling). | Increase of PNS activity. | Multicenter, prospective, randomized, controlled trial | n | = 95 | Change in LVESD, Percentage of surviving patients. |
NECTAR-HF presented significant improvement in quality of life, NYHA class and functional status [4] | There were no significant differences in serious adverse events between control and therapy groups. The overall rate of implantation-related infections was 7.4% |
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Multicenter, open-label, uncontrolled trial | n | = 60 | Change in: LVESV EF, Adverse events. |
ANTHEM-HF showed positive, durable improvement of cardiac function [5] | Serious adverse events occurred in 16 patients. There was one death related to system implantation due to an embolic stroke that occurred 3 days after surgery. |
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Splanchnic nerve stimulation | Excessive cardiac filling pressure due to overactivity of SNS resulting in visceral vasoconstriction and rapid volume shift from visceral to central compartment during exercise. | GSN modulation preventing exercise provoked visceral vasoconstriction and subsequent fluid shift from the visceral compartment to the central venous system. | Single-center, prospective, open-label, uncontrolled trials | n | = 11, | n | = 15 | Change in CVPPAMP PCWP |
Splanchnic-HF 1, and Splanchnic-HF 2 showed a reduction in PCPW and improvement of the cardiac index during exercise [6][7] | Splanchnic-HF 1, and Splanchnic-HF 2 showed a reduction in PCPW and improvement of the cardiac index during exercise [6,7] | No adverse events were reported. |
Multicenter, prospective, uncontrolled, pilot study |
Change in: mean PCPW at rest and exercise (20 W). Adverse events. |
REBALANCE-HF confirmed the reduction in exercise PCPW in HFpEF and NYHA class improvement [8] | There were three non-serious device-related adverse events reported in this study: HF decompensation due to periprocedural fluid overload, transient hypertension and back pain following ablation. | ||||||||
Cardiopulmonary nerve stimulation | Impaired LV contractility and relaxation. | Stimulation of the autonomic system area responsible for LV contractility resulting in positive lusitropic and inotropic effects. | Single-center, first-in-human, proof-of-concept study | n | = 15 | Adverse events. | A proof-of-concept study showed improvement of LV contractility and an increase in mean arterial pressure without affecting the heart rate [9] | No device-related serious adverse events were reported. | |||
Phrenic nerve stimulation | Central apnea due to periodic drop in CO | 2 | partial pressure to below the threshold for triggering the action potential in the respiratory center caused by greater sensitivity to carbon dioxide leading to potent stimulus of rhythmic breathing. | Transvenous stimulation of phrenic nerve during apneas. | Multicenter, randomized, open-label study | n | = 151 | Reduction in AHI and freedom from serious adverse events | The remedē System Pivotal Trial showed significant reduction in AHI, arousal index, desaturation and apnea episodes. It also revealed improvement in quality of life, sleep structure and EF [10][11] | The remedē System Pivotal Trial showed significant reduction in AHI, arousal index, desaturation and apnea episodes. It also revealed improvement in quality of life, sleep structure and EF [10,11] | Cumulatively, 21 (14%) serious adverse events were observed in 5-year follow-ups (15; (10%) in the first 12 months). It predominantly included electrode dysfunction, electrode dislocation and infection of the implantation site [10] |
Asymptomatic diaphragmatic stimulation | High left ventricle pre-load and after-load pressures increase remodeling and HF progression. | Stimulation of diaphragm muscle fibers synchronized with cardiac cycle to decrease intrathoracic pressures. | Single-center, randomized, open-label study | n | = 33 | LVEF improvement | EPIPHRENIC II Study showed significant improvement of LVEF, maximal power on effort, reduction in NYHA class, without differences in 6-min walking test or BNP concentration [12][13] | EPIPHRENIC II Study showed significant improvement of LVEF, maximal power on effort, reduction in NYHA class, without differences in 6-min walking test or BNP concentration [12,13] | Three patients were excluded due to dysfunctional diaphragmatic electrode. No adverse events were observed [12] | ||
Multicenter, non-randomized, open-label study | n | = 15 | Freedom from serious adverse events during procedural recovery or acute therapy | VisONE study showed improvement in LVEF and life quality (evaluated in SF-36); extended walking distance during the 6 MWT was observed at a 1-year follow-up. [13] | No adverse events were observed during procedural recovery, acute therapy (primary outcome) and in 12month follow-up (secondary outcome) [13] | ||||||
Reprieve system | Problems with controlling decongestive therapy to avoid too rapid diuretic response and hypovolemia and, on the other hand, providing too much fluid, which worsens volume overload. | Sustaining the accurate fluid balance by measuring the urine output and providing the exact amount of replacement solution to achieve preset fluid balance. | Non-randomized, single-center, prospective, open-label, studies, both | n | = 19 | Device and procedure-related adverse events and decongestive efficacy | Higher urine output and decrease in CVP in comparison to the baseline. Actual fluid loss did not exceed target fluid loss at the end of therapy in every patient [14] | No serious adverse events were observed. One case of hypokalemia occurred. | |||
Transcatheter renal venous decongestion system | Congestion in renal veins. | Transfemoral inserted flow pump, which reduces renal vein pressure to the desired level. | No results have been published so far. | Device and procedure-related adverse events, technical and procedural feasibility | The trial to evaluate TRVD was terminated prematurely, no results have been published so far. | No results have been published so far. | |||||
Doraya Catheter | Congestion in renal veins. | Partial obstruction of the flow in the inferior vena cava below the level of the renal veins reduces renal vein pressure | First in-human, single-arm, open-label study | n | = 9 | Serious adverse events. | The catheter was successfully deployed in all patients. Clinical symptoms, as well as diuresis and natriuresis, improved [15] | No device-related or embolic events were reported. One serious procedure-related adverse event: bleeding hematoma from the injection site, resolved without sequelae. | |||
preCARDIA | Increased right ventricle preload. | Obstruction of the superior vena cava leading to an intermittent decrease in preload. | Multicenter, prospective, single-arm exploratory safety and feasibility, open-label, trial | n | = 30 | Freedom from device or procedure-related serious adverse events | Successful decrease in right atrial pressure and PCWP, increase in net fluid balance and urine output [16] | No device or procedure-related serious adverse events were observed. | |||
WhiteSwell | Increased preload causes lymphatic congestion, which impairs interstitial drainage and exacerbates oedema. | Reduction in the pressure in the area of lymphatic duct outflow into venous vessels. | The animal model study, | n | = 7 sheep, used in 1 human, | n | = 1 | Serious adverse events. | Examined in a ovine model. Trend toward improved oxygenation an diuresis was noticed [17] | No adverse events were reported in in-human application. | |
AquaPass | Insufficient urine volume removal. | Enhancing the sweat rate to remove fluid directly from interstitial space. | Feasibility and short-term performance, single-arm, open-label study, | n | = 16 | Serious adverse events, treatment tolerance, ability to control skin temperature between 33 and 38 Celsius degrees). | The procedure was safe in HF patients, successful weight loss was observed. Increased skin temperature without elevating core temperature above average was achieved in each patients [18] | No adverse event occurred. |