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. 2024 Apr 5;11(4):2113–2119. doi: 10.1002/ehf2.14785

The peptide neuromedin U (NMU) is elevated in NYHA II and III heart failure

Vincent Healy 1, Therese Ruane O'Hora 1, Farouk Markos 1,✉
PMCID: PMC11287313  PMID: 38581170

Abstract

Aims

Currently, there is no reliable biomarker to detect pre‐heart failure in humans. An early risk signal is an elevated left atrial pressure (LAP) and preliminary results from animal studies strongly suggest the neuropeptide neuromedin U (NMU) is released in response to this increase in LAP. However, it is unknown whether NMU is elevated in patients with heart failure. Therefore, the aim of this study was to assess if NMU levels are elevated in human cases of heart failure.

Methods and results

Twenty‐four serum samples were obtained from patients in stage II and III heart failure from the Royal Papworth Hospital in Cambridge UK and tested using a selective NMU‐ELISA; the data were compared with serum obtained commercially from self‐declared healthy donors. NMU concentrations in serum from heart failure patients were significantly higher (P = 0.0007; unpaired Student's t‐test) than control, 8.48 ± 0.67 ng/mL (mean ± SEM) versus 5.43 ± 0.46 ng/mL. There was no significant difference between NYHA stage II and III patients (P = 0.85, unpaired Student's t‐test), which were 8.33 ± 0.89 ng/mL (n = 9) and 8.6 ± 0.95 ng/mL (n = 15), respectively. Only mean right atrial pressure was found to have a significant correlation with serum NMU (R = 0.81, P < 0.00001; regression analysis).

Conclusions

NMU is elevated in serum from stage II and III heart failure patients, supporting data from our pre‐heart failure animal model; however, further study is needed to determine whether NMU is a reliable biomarker for pre‐heart failure.

Keywords: Biomarker, Elevated left atrial pressure, Human, Pre‐heart failure

Introduction

A sustained increase of left atrial pressure typically precedes and hence is the earliest sign of impeding heart failure. 1 , 2 So much so that it is likely to be a useful diagnostic indicator of cardiac dysfunction 3 , and real‐time monitoring of pulmonary capillary wedge pressure (PCWP) is a useful tool for the management of patients with heart failure. 2 , 4 However, detection of this increase in pressure during routine, non‐invasive examination is unlikely due to the lack of a consistent outward symptom. 5 Therefore, finding a reliable biomarker for a maintained rise in left atrial pressure would be of benefit. In experimental animals, an acute sustained increase in left atrial pressure is known to induce a rapid onset diuresis, 6 which is dependent on intact vagi and is not mediated by any currently identified natriuretic or diuretic agent. 7 , 8 Recent ongoing experiments conducted on the anaesthetized pig in our laboratory have identified the neuropeptide neuromedin (NMU) as the potential mediator of this diuresis. NMU is a 25 amino acid neuropeptide widely expressed; this is the version present in humans with the highest levels of immunoreactivity being found in the gastrointestinal tract and brain of rats and humans. 9 , 10 This protein exists in several forms and has been sequenced in many other species including rabbit, dog, frog, and pig. 11 A truncated 8‐amino acid portion (NMU‐8) is released into the circulation and induces the biological effect of this neuropeptide. 12 The ELISA used in the present study is sensitive to both the full and shortened version of NMU.

NMU levels in pig serum were significantly elevated following balloon distension of the left atrium, to increase pressure, with the concomitant diuresis; in addition, exogenously infused NMU caused a significant diuresis without a natriuresis (unpublished findings). Also, this response is dependent on intact vagi. These observations suggest that NMU, released from the CNS, could be the blood borne biomarker of an elevated left atrial pressure, and if so, it would be potentially useful as an indicator for pre‐heart failure. However, it is unknown if NMU is altered in any way by heart failure, so the first priority is to accurately measure NMU in a human circulation in health and heart failure.

Therefore, the aim of this study was to assess whether circulating NMU concentration is increased in humans with heart failure, 24 heart failure serum samples from patients from the Royal Papworth Hospital in Cambridge were obtained to assess NMU levels.

Methods

Serum samples

Serum samples (0.25 mL), collected from 24 patients with stage II and III heart failure, were obtained from the Royal Papworth Hospital in Cambridge, UK. Accompanying clinical data for these patients were also provided (Table  1 ). Control serum samples (0.5 mL), collected from 10 self‐reported healthy donors (five male and five female) were obtained from Central BioHub GmbH, Hennigsdorf, Germany. Also, an additional nine control samples (five female and four male) were obtained from a small study conducted by the Physiology Department in University College Cork.

Table 1.

Patient data

Tissue bank no. Patient study no. Assessment date Gender Age Height (cm) Weight (kg) BMI (kg/m2) Body surface area (m2) Aetiology (mmHg) New York Heart Association (NYHA) Heart rate (b.p.m.) Systolic BP (mmHg) Diastolic BP (mmHg) Mean arterial pressure (mmHg)
TB14.1017 Cork01 24/06/2014 F 50 153 66 28.2 1.64 DCM 3 103 101 67 78
TB14.1151 Cork02 15/07/2014 M 26 178 69 21.8 1.86 CHD 2 65 87 59 68
TB14.1194 Cork03 22/07/2014 M 24 186 101 29.2 2.26 DCM 3 72 104 65 78
TB14.1202 Cork04 22/07/2014 M 60 170 59 20.3 1.68 ICM 3 70 85 57 66
TB14.1326 Cork05 12/08/2014 M 51 175 75 24.6 1.91 Pericarditis 2 78 103 71 82
TB14.1453 Cork06 02/09/2014 F 62 163 81 30.4 1.87 AVC 3 72 122 76 91
TB14.1454 Cork07 02/09/2014 F 52 171 75 25.8 1.87 HCM 2 70 107 64 78
TB14.1677 Cork08 07/10/2014 M 51 162 70 26.7 1.75 ICM 2 65 106 67 80
TB14.1687 Cork09 07/10/2014 M 45 191 113 31.1 2.42 DCM 3 79 99 73 82
TB14.1725 Cork10 14/10/2014 F 49 162 62 23.6 1.66 ICM 3 80 96 66 76
TB14.1728 Cork11 14/10/2014 M 52 171 70 23.9 1.82 DCM 3 90 109 87 94
TB14.1837 Cork13 04/11/2014 M 52 169 89 31.2 2.00 DCM 3 90 92 54 67
TB14.1887 Cork14 11/11/2014 M 59 169 82 28.7 1.93 DCM 2 69 100 58 72
TB14.1938 Cork15 18/11/2014 F 58 166 75 27.3 1.83 DCM 3 80 120 76 91
TB14.1982 Cork16 25/11/2014 F 31 165 84 30.9 1.91 DCM 2 68 84 55 65
TB14.2011 Cork17 02/12/2014 M 42 178 109 34.3 2.26 DCM 2 75 98 61 73
TB14.2048 Cork18 09/12/2014 M 53 175 88 28.6 2.03 DCM 3 70 103 80 88
TB14.2096 Cork19 16/12/2014 F 40 162 66 25.3 1.71 DCM 3 60 122 70 87
TB14.2097 Cork20 16/12/2014 F 43 163 42 15.6 1.41 CHD 3 74 129 76 94
TB15.0016 Cork21 06/01/2015 M 54 170 84 29.0 1.95 ICM 3 60 112 59 77
TB15.0018 Cork22 06/01/2015 M 58 192 110 29.8 2.40 DCM 2 82 100 79 86
TB15.0094 Cork23 20/01/2015 M 52 176 86 27.6 2.02 DCM 3 75 103 69 80
TB15.0133 Cork24 27/01/2015 F 29 159 45 18.0 1.43 DCM 2 76 94 61 72
TB15.0183 Cork25 03/02/2015 M 47 175 104 34.0 2.19 DCM 3 85 108 67 81
Left ventricular internal diameter diastolic (LVIDD) (mm) Left ventricular ejection fraction (LVEF) (%) Tricuspid annular plane systolic excursion (TAPSE) (mm) Haemoglobin (g/L) Blood/serum sodium (mEq/L) Blood/serum urea (mmol/L) Blood/serum creatinine (μmol/L) Blood/serum bilirubin (μmol/L) NT‐proBNP (pg/mL) Blood group
54 12.5 13 105 143 7.9 96 4 573 A
75 12.5 NA 155 134 18.5 140 28 8581 O
60 20 14 154 143 16.7 148 42 6153 A
52 32 15 132 136 28.8 155 18 3344 A
52 22.5 10 179 142 5.7 114 21 1257 A
51 40 17 125 142 7.1 96 6 255 A
57 27.5 19 125 142 11.7 107 8 1798 A
51 27.5 15 136 137 6.1 94 9 674 O
80 15 14 147 141 8.2 119 23 1552 B
58 25 21 121 137 36 257 16 6438 O
58 12.5 17 161 141 7.8 115 13 3305 O
81 15 22 146 142 14.5 163 64 14 682 A
73 39 8 136 140 8 83 29 2488 O
62 25 18 120 141 6.3 104 8 163 A
64 12.5 15 117 142 4 80 16 1422 B
73 17.5 23 132 138 6.4 84 10 1811 O
53 40 11 160 139 6.9 107 14 293 A
57 42.5 23 122 139 5.5 91 13 1259 A
35 40 15 137 133 10.3 126 5 783 A
53 37 15 104 144 22.3 1075 5 14 568 B
83 25 20 119 140 10.5 125 16 2695 O
53 22.5 19 120 140 13.5 775 15 2681 B
58 25 16 128 135 2.9 53 17 3043 O
61 22.5 13 136 132 13.4 157 20 2609 A
Peak VO2 (mL/kg/min) Peak respiratory exchange ratio (RER) Six‐minute walk distance (6MWD) Cardiac output (thermodilution) (L/min) Cardiac output (Fick) (L/min) Cardiac index (thermo): CO/surface area (L/min/m2) Cardiac index (Fick): CO/surface area (L/min/m2) Right atrial pressure mean (mmHg) Pulmonary artery pressure mean (mmHg)
13.0 1.10 228 4.42 3.11 2.70 1.90 3 28
20.0 NA 523 2.79 1.68 1.50 0.90 8 41
NA NA 97 3.39 2.80 1.50 1.24 10 45
10.8 1.03 181 2.52 2.45 1.50 1.46 13 20
26.0 1.16 500 3.43 2.00 1.80 1.05 19 24
10.6 1.00 180 NA 3.17 NA 1.70 10 16
14.9 1.12 411 4.41 3.97 2.35 2.12 3 17
14.0 1.12 358 4.37 3.60 2.50 2.06 12 19
14.0 1.21 463 2.66 3.60 1.10 1.49 14 45
12.0 1.23 236 4.32 4.32 2.60 2.60 20 25
13.0 1.10 343 2.80 3.12 1.54 1.72 7 43
10.2 1.05 384 3.39 2.99 1.70 1.50 19 34
15.5 1.14 368 4.10 3.65 2.13 1.89 10 30
10.3 0.92 438 5.32 4.22 2.90 2.30 2 17
12.5 1.20 NA 2.32 2.55 1.21 1.33 11 18
13.0 1.07 373 6.32 5.06 2.80 2.24 9 38
19.0 1.14 NA 3.66 3.25 1.80 1.60 1 12
12.8 1.21 317 4.27 3.35 2.50 1.96 22 30
14.3 1.01 118 3.09 2.28 2.20 1.62 7 14
6.0 0.80 151 2.34 3.32 1.20 1.70 12 22
13.0 1.15 363 5.75 5.65 2.40 2.36 14 34
15.5 1.13 296 4.24 3.84 2.10 1.90 7 15
17.0 1.04 NA 3.44 2.80 2.40 1.95 5 35
9.0 1.10 142 4.15 4.13 1.90 1.89 18 27
Pulmonary capillary wedge pressure (PCWP) mean (mmHg) COPD Diabetes Smoker Angiotensinconverting enzyme (ACE) Angiotensin II receptor blockers (ARB) Beta‐blockers (BB) Mineralocorticoid receptor antagonist (MRA) Loop diuretics (Loop) Cardiac resuscitation therapy (CRT) Implantable cardioverter defibrillator (ICD)
18 N N N N Y Y N Y N N
33 N N N Y N Y Y Y Y Y
26 N N N Y N Y Y Y N N
17 N N N N N Y Y Y Y Y
20 N N N Y N Y Y Y N N
11 N N N N N Y Y Y N Y
11 Y N N Y N Y Y Y Y Y
12 N N N Y N Y Y N N N
22 N N N Y N Y Y Y Y Y
18 N N N Y N Y N Y Y Y
34 N N N Y N Y N Y N N
26 N N N Y N Y Y Y Y Y
14 N N N Y N Y Y Y N N
6 N N N N Y N Y Y Y Y
10 N Y N Y N Y Y Y N N
30 N N N Y N Y Y Y N Y
1 N N N N N Y Y Y N N
24 N N N N N N N Y N N
6 N N N Y N N Y Y Y Y
9 N N N Y N Y N N N N
24 N N N Y N Y Y Y Y N
7 N Y N N Y Y Y N N N
29 N N N Y N Y Y N N N
24 N N N Y N Y N Y N N
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AVC, accident vasculaire cérébral/stroke; CHD, coronary heart disease; DCM, dilated cardiomyopathy; ICM, ischaemic cardiomyopathy.

Measurement of NMU

A human neuromedin U‐25 ELISA kit was obtained from BMA Biomedicals, Rheinstrasse, Switzerland. All serum samples, diluted 1:10 with ELISA buffer, were assayed in triplicate according to manufacturer's instructions. Standard curves, generated from NMU‐25 standards provided with the kit, were used to calculated serum NMU concentrations.

Ethical statement

Tissue used in the research study was obtained from the Papworth Hospital Research Tissue bank using Papworth Hospital Tissue Bank's ethical approval (East of England – Cambridge East Research Ethics Committee). The Cork study was approved by the Clinical Research Ethical Committee (CREC) of University College Cork, reference number: ECM 4 (r) 14/08/18.

Statistical analysis

Power analysis using G*Power (version 3.1.9.6) was used to estimate the necessary sample size; inputting an effect size (d) of 1.58 (calculated from sample means and pooled SD) and for 90% power, the calculator yielded a recommended minimum of 10 individuals for the two groups. Data presented in text are given as mean ± SEM and were analysed using unpaired Student's t‐test; regression analysis was also used to calculate correlation coefficients significance level, where appropriate, using Microsoft Excel. P < 0.05 was considered significant.

Results

Table 1 details the full patient data obtained from the Papworth team, 24 serum samples from NYHA stage II and III patients were obtained. For the purposes of the present study, it is noteworthy that pooled sample mean left (PCWP) and right atrial pressure as well mean pulmonary pressures are much higher than in health, despite medication. As can be seen from Table 1 , all but three patients are on beta‐blockers as well as other medication: angiotensin‐converting enzyme inhibitors, mineralocorticoid receptor antagonists, and loop diuretics.

Importantly, NMU concentration in serum from NYHA stage II and III heart failure patients was found to be significantly higher than control serum (Table  2 ), which is a novel finding. No significant difference (P = 0.85, unpaired Student's t‐test) was found between NMU levels stage II (8.33 ± 0.89 ng/mL; n = 9) and III (8.6 ± 0.95 ng/mL; n = 15).

Table 2.

Serum NMU is significantly elevated in heart failure patients

Papworth serum i.d. [NMU] ng/mL Control serum i.d. [NMU] ng/mL
TB14.1017 5.44 89 578 4.59
TB14.1151 4.98 89 659 4.91
TB14.1194 5.68 89 576 6.35
TB14.1202 8.75 89 582 6.45
TB14.1326 12.19 89 641 4.38
TB14.1453 4.34 89 728 3.51
TB14.1454 6.45 89 735 8.47
TB14.1677 7.27 89 736 5.44
TB14.1687 9.82 89 765 4.03
TB14.1725 14.08 89 766 6.12
TB14.1728 7.68 F1 6.040
TB14.1837 11.08 F2 4.040
TB14.1887 8.01 F3 4.410
TB14.1938 4.59 F4 5.250
TB14.1982 8.35 F5 9.490
TB14.2011 5.00 M1 3.300
TB14.2048 6.32 M2 2.280
TB14.2096 16.71 M3 4.410
TB14.2097 9.50 M4 6.680
TB15.0016 8.48
TB15.0018 11.76
TB15.0094 5.27
TB15.0133 9.15
TB15.0183 12.55
Mean 8.48 5.27
SD 3.27 1.76
SEM 0.67 0.40
n 24 19
P * 0.0002
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*

Unpaired Student's t‐test.

Mean right atrial pressure is strongly correlated with NMU concentration (Figure  1 ), whereas there was no significant correlation between mean PCWP or mean pulmonary artery pressure with serum NMU (Figure  2 ).

Figure 1.

Figure 1

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There is a significant correlation between mean right atrial pressure and NMU serum concentration in heart failure patients. R = 0.81, P < 0.00001 (regression).

Figure 2.

Figure 2

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There is no significant correlation between mean PCWP (top, R = 0.24, P = 0.27) or mean right atrial pressure (bottom, R = 0.11, P = 0.6; ANOVA) and NMU serum concentration in heart failure patients.

Discussion

The primary aim of the present study was to provide evidence from humans to support observations in ongoing animal work that shows a link between increased circulating NMU in response to an elevated left atrial pressure, which is an early signal of impending heart failure. Simply, the research question posed is whether NMU is elevated in humans with heart failure, if not this would indicate that observations made in our animal model are not valid for human‐pre or full onset heart failure. The results of this study show that NMU is elevated in stage II and III heart failure patients when compared to control samples, but that this increase was not evident in every sample. The control values obtained from ‘self‐declared’ healthy patients are within the range reported in the literature in humans. 13 , 14 Ultimately, the goal is to uncover a diagnostic biomarker indicative of pre‐heart failure. Such a test would have obvious benefit as measurement of PCWP (a surrogate for left atrial pressure) is highly invasive, not without risk, and would not be an option for routine screening. A reliable biomarker, detectable by a simple blood test has obvious advantages, and earlier detection of a predisposition to heart failure is highly desirable clinically, where intervention could reduce morbidity and mortality.

As mentioned, this study was conducted in large part to provide supporting evidence from human samples for our ongoing pig work. The pig data (study in progress) indicate that NMU doubles within 10 min of an acute increase in mean left atrial pressure (above 15 mmHg); this increase in NMU is maintained for the duration of the rise in pressure and that a significant diuresis results (unpublished pre‐clinical observations). This finding confirms previous data obtained in the original dog studies over 50 years ago and also adds to it by identifying NMU as the potential mediator of this diuresis. 15 In addition, the resultant pig diuresis was not accompanied by a natriuresis, which suggests a novel action by NMU on the kidney. However, it should be noted that the pig data are preliminary and need to be completed.

One other observation was the very strong correlation between the detected levels of NMU and mean right atrial pressure, whereas there was no such so such correlation with mean PCWP or mean pulmonary artery pressure. However, it is probably advisable not to over‐interpret these pressure‐NMU findings or to attempt to further data‐mine the available patient numbers to infer causality. The limitations of this study have to be kept in mind, the sample size is small, and this cohort of patients are experiencing major cardiac dysfunction, which would inevitably affect the physiological pattern of responses to pressure and output changes. In addition, all are on a number of medications, which would undoubtedly have an effect on the pressures recorded during their examination. Note that in some patients the reported right atrial, pulmonary artery, and PCWP are either normal or even below normal, but the combined sample mean values for these pressures are above the normal physiological range.

In conclusion, the neuropeptide NMU was found to be elevated in serum from stage II and III heart failure patients; this finding provides support for our pre‐heart failure animal model; however, further study specifically on pre‐heart failure patients is needed to assess whether NMU could be a reliable biomarker for the earliest signals of heart failure.

Conflict of interest

None declared.

Acknowledgements

We would like to thank the patients and staff at the Royal Papworth Hospital for their help, especially Ms. Chet Malgapo, Dr. Stephen Pettit, and Ms. Lorraine Gargiulo.

Open access funding provided by IReL.

Healy, V. , O'Hora, T. R. , and Markos, F. (2024) The peptide neuromedin U (NMU) is elevated in NYHA II and III heart failure. ESC Heart Failure, 11: 2113–2119. 10.1002/ehf2.14785.

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