Cardiac sympathetic nerve activity trends after renal denervation in heart failure with preserved ejection fraction

Abstract

This case report describes the application of ultrasound renal denervation (uRDN) using the Paradise System in a patient with heart failure with preserved ejection fraction. Initially, the cardiac sympathetic nerve activity of the patient exhibited a late heart/mediastinum (H/M) ratio of 2.00 and a washout rate of 66.0% by cardiac iodine‐123 metaiodobenzylguanidine (¹²³I‐MIBG) scintigraphy. Subsequently, the patient underwent transfemoral uRDN targeting the left, right upper, and right lower renal arteries. At the 6 month follow‐up, no significant change was observed in ¹²³I‐MIBG findings; however, the estimated stressed blood volume (eSBV) decreased from 1722 to 1029 mL/70 kg. At 18 months, ¹²³I‐MIBG findings improved, with the late H/M ratio reaching 2.76 and the washout rate decreasing to 43.1%. This case report highlights the potential of uRDN in reducing eSBV within 6 months and subsequently improving cardiac sympathetic nerve activity at the 18 month follow‐up.

Introduction

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with various pathophysiological factors. A hallmark of HFpEF is sympathetic nerve innervation, which is associated with an increased risk of cardiac events.¹ Recent clinical research has demonstrated the effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with HFpEF.² In vivo experiments demonstrated that the inhibition of SGLT2 reduces sympathetic innervation in the kidneys.³ Renal sympathoinhibition is potentially associated with the cardioprotective effects of SGLT2 inhibitors.

Endovascular renal denervation is a method for suppressing renal sympathetic nerve activity and is effective in patients with treatment-resistant hypertension.^4,5 Renal denervation is anticipated to have a cardioprotective effect through sympathoinhibition via the kidney–heart axis. However, previous studies assessing the effects of renal denervation on cardiac sympathetic nerve activity using iodine-123 metaiodobenzylguanidine (¹²³I-MIBG) scintigraphy have not provided definitive findings in relatively short follow-up periods, often <1 year.^6,7 To comprehensively evaluate the impact of renal denervation, an extended follow-up period may be necessary, as indicated by recent findings of significant blood pressure reduction 3 years after renal denervation.⁸

This case report describes the effectiveness of ultrasound renal denervation (uRDN) performed using the Paradise System on cardiac sympathetic nerve activity assessed by ¹²³I-MIBG scintigraphy at 6 and 18 months in a patient diagnosed with HFpEF.

Case report

An 84-year-old man with hypertension and type 2 diabetes mellitus presented with New York Heart Association class II dyspnoea on exertion. The patient had a history of coronary artery disease and underwent percutaneous intervention in the left circumflex coronary artery. For hypertension management, angiotensin receptor blockers and beta-blockers were prescribed. The diagnosis of HFpEF was confirmed through echocardiography and natriuretic peptide criteria,⁹ which indicated a left ventricular ejection fraction of 61%, e′ of 5.9 cm/s, left atrium volume index (LAVi) of 35.3 mL/m², and N-terminal pro-brain natriuretic peptide (NT-proBNP) of 270 pg/mL (Table 1). Computed tomography angiography confirmed no significant stenosis in the duplicated right or left renal arteries (Figure 1A). The patient was enrolled in a clinical trial (RDN-19-001) for patients with heart failure to evaluate the efficacy of uRDN (Paradise System; Otsuka Medical Devices Co., Ltd., Japan) in reducing cardiac sympathetic nerve innervation. The participant provided informed consent, and the clinical trial was performed under the Declaration of Helsinki and was approved by the ethics committee. The Paradise System consists of an ultrasonography-based catheter with a balloon that circulates sterile water and acts as a coolant to protect the arterial walls. The washout rate was assessed using cardiac ¹²³I-MIBG scintigraphy before the intervention and at the 6 month follow-up, as stipulated in the clinical trial. In addition, 18 month cardiac ¹²³I-MIBG scintigraphy was performed with informed consent, separately from the stipulations of the clinical trial. The patient's initial early heart/mediastinum (H/M) ratio was 3.13, the late H/M ratio was 2.00, and the washout rate was 66.0% (Figure 2A,B).

Table 1 Trends in characteristics before and after ultrasound renal denervation

	Baseline	6 months of follow-up	12 months of follow-up	18 months of follow-up
Body weight, kg	55.0	55.7	55.4	54.7
Body mass index	22.9	23.3	22.5	22.6
Blood pressure, mmHg	152/71	100/49	116/59	145/65
Heart rate, b.p.m.	75	70	80	76
Blood test
Haemoglobin, g/dL	11.4	11.7	10.3	10.3
Haematocrit, %	36.2	36.6	32.7	32.6
NT-proBNP, pg/mL	270	296	367	274
BNP, pg/mL	37.1	30.1	52.4	28.5
ANP, pg/mL	42.3	49.8	50	56.7
eGFR, mL/min	66	63	63	61
HbA1c, %	7.0	7.0	7.4	6.5
Adrenaline, ng/mL	0.05	0.08	0.13	0.2
Noradrenaline, ng/mL	0.54	1.3	0.8	1.1
Dopamine, ng/mL	0.03	0.05	0.06	0.1
Echocardiography parameters
LVEF (Simpson), %	61	68	67	61
LVSV, mL	74	82	83	71
LVMi, g/m2	79	78	82	76
LAVi, mL/m2	35.3	29.6	33.3	34.9
E wave, m/s	0.44	0.51	0.5	0.47
A wave, m/s	0.83	0.69	0.81	0.7
E/A	0.53	0.74	0.62	0.67
DcT, ms	375	311	275	245
e′, cm/s	5.9	6.0	5.5	4.7
E/e′	7.5	8.5	9.2	10
TR V max, m/s	2.2	2.6	2.8	2.3
TR gradient, mmHg	19	27	31	21

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The protocol for ¹²³I-MIBG scintigraphy involves the following steps:

• injection of ¹²³I-MIBG via peripheral vein;
• a 15 min rest period;
• early planar imaging using a low-energy collimator, an energy peak of 158–160 keV, a matrix of 256 × 256 pixels, a pixel size of 1.9 mm, and an acquisition time of 5 min;
• late imaging conducted 240 min after the injection;
• setting up regions of interest (ROIs) on the heart and mediastinum;
• the H/M ratio calculated by dividing the average counts in the heart ROI by the average counts in the mediastinal ROI using smartMIBG heart software (Fujifilm Toyama Chemical, Japan); and

• the washout rate calculated using the following equation: $\mathit{\text{Washout rate}}=100\times \frac{\left[\left\{\left(\mathit{\text{early image}}H\right)-\left(\mathit{\text{early image}}M\right)\right\}-\frac{\left\{\left(\mathit{\text{late image}}H\right)-\left(\mathit{\text{late image}}M\right)\right\}}{\mathit{\text{decay factor}}}\right]}{\left[\left(\mathit{\text{early image}}H\right)-\left(\mathit{\text{early image}}M\right)\right]},$ where H and M represent the average counts in the heart and mediastinal ROIs, respectively, and the decay factor was calculated from the time between early and late imaging.

Swan-Ganz right heart catheterization was performed prior to the uRDN (Table 2). During the uRDN procedure, the patient underwent femoral artery access using an 8 Fr sheath under local anaesthesia. The left renal artery was accessed using a 7 Fr renal double curve (RDC) guiding catheter, and the arterial diameter was evaluated using an intravascular ultrasound catheter. While the patient was sedated, a uRDN catheter with a 7.0-mm-diameter balloon generated ablations at two points in the main trunk of the left renal artery for 7 s each (Figure 1B–D). Subsequently, the right lower renal artery was accessed using an 8 Fr hockey stick (HS) guiding catheter, and denervation was performed using a 4.2-mm-diameter balloon catheter at two points (Figure 1E–G). Denervation was also performed at two points in the right upper renal artery (Figure 1H–J). The final angiography revealed no significant stenosis of the renal arteries. An Angio-Seal (Terumo Interventional Systems, Somerset, NJ, USA) was used for haemostasis of the arterial puncture site, and the patient could walk after 4 h of compression.

Table 2 Evaluation of the Swan-Ganz right heart catheterization

	Baseline	6 months of follow-up
Blood pressure, mmHg	160/76	132/58
Pulmonary artery pressure (s/d/m), mmHg	25/9/14	17/4/8
Pulmonary artery wedge pressure (m), mmHg	8	5
Right ventricular pressure (s/b/e), mmHg	27/1/6	22/0/2
Right atrial pressure (m), mmHg	5	2
Systemic vascular resistance index, dynes * s/cm5/m2	4264	2759
Pulmonary vascular resistance index, dynes * s/cm5/m2	211	118
Cardiac index, L/min/m2	2.27	2.03
Estimated stressed blood volume, mL/70 kg	1722	1029

At the 1 month follow-up, elevated blood pressure was confirmed, and amlodipine was started at a dose of 2.5 mg/day. Throughout the follow-up period, no other new medications were prescribed, and there were no discontinuations or dose adjustments of existing medications. At the 6 month follow-up, Swan-Ganz right heart catheterization revealed a reduction in pulmonary artery wedge pressure, pulmonary artery pressure, right ventricular pressure, and right atrial pressure (Table 2). While the patient's body weight and haematocrit remained unchanged, the estimated stressed blood volume (eSBV = [cardiac output {mL/kg/min} + 19.61 × central venous pressure {mmHg} + 3.49 × pulmonary artery wedge pressure {mmHg}] × 0.129)¹⁰ decreased from 1722 to 1029 mL/70 kg (Table 2). In contrast, ¹²³I-MIBG scintigraphy showed no significant change in cardiac sympathetic nerve activity, with an early H/M of 3.12, a late H/M of 2.08, and a washout rate of 63.4% (Figure 2C,D).

At 18 months, there was an improvement in cardiac sympathetic nerve activity, with an early H/M of 3.42, a late H/M of 2.76, and a washout rate of 43.1% (Figure 2E,F). In contrast, no significant change was observed in plasma catecholamines between baseline and 18 month follow-up (Table 1). No adverse renal artery or renal function events related to renal denervation have been reported.

Discussion

This case report highlights the potential of uRDN in reducing eSBV at 6 months and subsequently improving cardiac sympathetic nerve activity, as assessed using MIBG scintigraphy at the 18 month follow-up in patients with HFpEF. MIBG scintigraphy visualizes cardiac sympathetic nerve activity, where the early H/M ratio indicates the integrity of sympathetic nerve terminals, the late H/M ratio represents neuronal function, and the washout rate reflects the neuronal integrity of sympathetic tone.¹¹ The RDT-PEF study, a randomized controlled trial evaluating the effects of radiofrequency RDN in patients with HFpEF, was terminated early due to recruitment difficulties and was underpowered.⁷ The available data from 25 HFpEF patients showed an early H/M ratio of 1.61 and a late H/M ratio of 1.49.⁷ In addition, no significant improvements in cardiac sympathetic nerve function as measured by MIBG scintigraphy were observed after RDN at the 12 month follow-up. In contrast, the current patient had a higher early H/M ratio of 3.13 and a late H/M ratio of 2.00. Compared with a larger HFpEF cohort of 133 patients with a late H/M ratio of 1.94 ± 0.47, the late H/M ratio of the current patient was comparable.¹² Participants in the RDT-PEF study exhibited lower late H/M ratios, indicating more severe sympathetic dysfunction, which may explain the observed limited efficacy of RDN. In cases such as the current patient, who does not have severe cardiac sympathetic dysfunction, RDN may be more beneficial.

In the present case, the sustained reduction in eSBV may have contributed to the delayed improvement in cardiac sympathetic nerve activity. Patients with HFpEF exhibit significant increases in SBV during exercise,¹⁰ emphasizing the importance of therapeutics targeting SBV reduction. SGLT2 inhibitors, which have demonstrated efficacy in HFpEF,² have been shown to reduce eSBV from 1697 ± 312 to 1601 ± 337 mL/70 kg after 12 weeks in patients with heart failure with reduced ejection fraction.¹³ In the current case, a more pronounced reduction in eSBV from 1722 to 1029 mL/70 kg was observed 6 months after uRDN, suggesting an even greater potential effect. Elevated blood pressure 1 month after uRDN led to the initiation of a calcium channel blocker, which may have contributed to the reduction in eSBV. Calcium channel blockers have demonstrated efficacy in improving the washout rate in patients with HFpEF.¹⁴ Therefore, a detailed investigation of the effects of uRDN and calcium channel blockers on eSBV and cardiac sympathetic inhibition in patients with HFpEF is warranted.

Improvement in haemoglobin A1c (HbA1c) levels without change in diabetic medication was confirmed 18 months after uRDN, along with cardiac MIBG scintigraphy findings. While preclinical data suggest that RDN improves glucose tolerance,¹⁵ clinical data are inconclusive. Participation in this study may have led to lifestyle modifications that influenced these results. The current case presented early stages of HFpEF with exertional dyspnoea in the absence of an increase in resting left ventricular filling pressure. Further large cohort studies investigating the efficacy of RDN in patients with HFpEF, particularly in the more advanced stages of HFpEF, are warranted.

In conclusion, this case highlights the potential early effect of RDN in reducing eSBV and subsequently delayed improving cardiac sympathetic nerve activity in patients with HFpEF. The precise mechanism by which RDN improves cardiac sympathetic nerve activity remains unclear, and further research is necessary to elucidate these underlying mechanisms.

Acknowledgements

The authors would like to thank all study co-investigators, nurses, and clinical trial co-ordinators for their contributions to this study. This work was supported by Otsuka Medical Devices Co., Ltd.

Conflict of interest

T.K. and Y.S. received a speaker honorarium from Otsuka Medical Devices Co., Ltd. H.M. received a speaker honorarium from Medtronic. Y.S. received a scholarship donation from Otsuka Medical Devices Co., Ltd. M.A. has a medical advisory contract with Otsuka Medical Devices Co., Ltd. The Department of Cardiovascular Medicine at Osaka University Graduate School of Medicine received a case registration fee from Otsuka Medical Devices Co., Ltd. Other authors declare that they have no conflicts of interest.

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