European Journal of Internal Medicine 126 (2024) 63–68

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Original Article

Relation of plasma neuropeptide-Y with myocardial function and infarct

severity in acute ST-elevation myocardial infarction
Christina Tiller a, Martin Reindl a, Magdalena Holzknecht a, Ivan Lechner a, Felix Troger b,
Fritz Oberhollenzer a, Sebastian von der Emde a, Thomas Kremser a, Agnes Mayr b, Axel Bauer a,
Bernhard Metzler a, Sebastian J Reinstadler a, *
a
University Clinic of Internal Medicine III, Cardiology and Angiology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria
b
University Clinic of Radiology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Acute myocardial infarction is associated with the release of the co-transmitter neuropeptide-Y
ST-segment elevation myocardial infarction (NPY). NPY acts as a potent vasoconstrictor and is associated with microvascular dysfunction after ST-elevation
Plasma neuropeptide-Y myocardial infarction (STEMI). This study comprehensively evaluated the association of plasma NPY with
Myocardial injury
myocardial function and infarct severity, visualized by cardiac magnetic resonance (CMR) imaging, in STEMI
Cardiac magnetic resonance imaging
patients revascularized by primary percutaneous coronary intervention (PCI).
Risk stratification
Methods: In this observational study, we included 260 STEMI patients enrolled in the prospective MARINA-STEMI
(NCT04113356) study. Plasma NPY concentrations were measured by an immunoassay 24h after PCI from pe­
ripheral venous blood samples. Left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), infarct
size (IS) and microvascular obstruction (MVO) were determined using CMR imaging.
Results: Median plasma concentrations of NPY were 70 [interquartile range (IQR):35-115] pg/ml. NPY levels
above median were significantly associated with lower LVEF (48%vs.52%, p=0.004), decreased GLS (-8.8%vs.-
12.6%, p<0.001) and larger IS (17%vs.13%, p=0.041) in the acute phase after infarction as well as after 4
months (LVEF:50%vs.52%, p=0.030, GLS:-10.5vs.-12.9,p<0.001,IS:13%vs.10%,p=0.011). In addition, NPY
levels were significantly related to presence of MVO (58%vs.52%, p=0.041). Moreover, in multivariable linear
regression analysis, NPY remained significantly associated with all investigated CMR parameters (LVEF:p<0.001,
GLS:p<0.001,IS:p=0.003,MVO:p=0.042) independent of other established clinical variables including high-
sensitivity cardiac troponin T, pre-interventional TIMI flow 0 and left anterior descending artery as culprit
lesion location.
Conclusion: High plasma levels of NPY, measured 24h after STEMI, were independently associated with lower
LVEF, decreased GLS, larger IS as well as presence of MVO, indicating plasma NPY as a novel clinical risk marker
post STEMI.

1. Introduction neurotransmitter norepinephrine, where it can act as a potent vaso­

constrictor in a variety of vascular beds [4]. Recently, Gibbs et al. have
Acute myocardial infarction is associated with high levels of cardiac demonstrated that plasma NPY levels are significantly elevated in STEMI
sympathetic stimulation [1], which is strongly related to poor outcome patients revascularized by primary PCI [5]. However, the clinical rele­
[2]. Prolongation of this sympathetic drive leads to the release of the vance of plasma NPY in STEMI patients is not yet fully understood. NPY
co-transmitter neuropeptide-Y (NPY) with a relatively long half-life, has been linked to heart failure [6], microvascular dysfunction [5] and
abundant in the peripheral nervous system [3]. NPY is released from arrhythmogenic events [7], but no significant differences in cardiac
cardiac sympathetic nerve endings in collaboration with the main magnetic resonance (CMR) determined microvascular injury between

Abbreviations: CMR, cardiac magnetic resonance; GLS, global longitudinal strain; IS, infarct size; IQR, interquartile range; LVEF, left ventricular ejection fraction;
MVO, microvascular obstruction; NPY, neuropeptide Y; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.
* Corresponding author.
E-mail address: [email protected] (S.J. Reinstadler).

https://doi.org/10.1016/j.ejim.2024.03.027
Received 5 January 2024; Received in revised form 1 March 2024; Accepted 25 March 2024
Available online 29 March 2024
0953-6205/© 2024 The Author(s). Published by Elsevier B.V. on behalf of European Federation of Internal Medicine. This is an open access article under the CC BY
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C. Tiller et al. European Journal of Internal Medicine 126 (2024) 63–68

patients with low or high peripheral venous NPY levels could be used to obtain late gadolinium enhancement (LGE) images ~15 min
demonstrated so far. Thus, there is limited data of a precise in vivo after injection of a 0.2 mmol/kg bolus of contrast agent (Gadovist®,
approach to comprehensively characterize myocardial and microvas­ Bayer, Leverkusen, Germany). IS was further quantified at each LGE
cular tissue changes after STEMI in relation to NPY. CMR imaging slice by using a commercially available workstation (Dedalus Health­
currently represents the non-invasive gold standard for the assessment Care GmbH, Bonn, Germany) and expressed as percentages of left ven­
of myocardial function and tissue injury as well as reperfusion injury tricular myocardial mass (LVMM). “Hyperenhancement” was defined as
with high precision and reproducibility [8,9]. Moreover, longitudinal +5 standard deviations above the signal intensity of remote LV
alterations in myocardial function, such as strain analysis, can also be myocardium [13]. Microvascular obstruction (MVO) was defined as
accurately determined by CMR imaging. persisting area of “hypo-enhancement” within the infarcted, hyper­
Altogether, the exact clinical role of NPY as a new biomarker in the enhanced territory, manually contoured on LGE images and presented as
setting of STEMI remains uncertain. We hypothesized that high NPY percentages of LVMM. All CMR images were analysed in a blinded
concentrations in the early phase after STEMI would be associated with fashion by experienced observers.
impaired cardiac function as well as more severe myocardial tissue
injury as assessed by CMR imaging. In addition, we hypothesized that 2.3. Statistical analysis
increased NPY levels are also related to impaired LVEF and larger IS in
the chronic stage. The aim was therefore to investigate the association of Statistical analyses were performed using SPSS Statistics 29.0 (IBM,
plasma NPY with cardiac function, infarct size (IS) and reperfusion Armonk, NY, USA), and MedCalc Version 20.115 (Ostend, Belgium).
injury, depicted by comprehensive CMR imaging in the acute phase as Continuous variables were expressed as median with corresponding
well as after 4 months, in a well characterized cohort of STEMI patients interquartile range (IQR) and categorical variables were presented as
revascularized by primary PCI. absolute numbers with corresponding percentages. Mann–Whitney U-
test was applied for evaluation of differences in continuous variables
2. Methods between two patient groups, differences in categorical variables were
assessed by Chi-square. The relation of NPY with LVEF, GLS, IS and MVO
2.1. Study design and clinical measurements was adjusted for potential confounders in linear multivariable regres­
sion analysis. Clinical parameters showing significant associations
This prospective, observational study included 260 STEMI patients (p<0.05) with LVEF, GLS, IS and MVO in univariable analysis were
enrolled in the ‘Magnetic Resonance Imaging in Acute ST-Elevation further included into the multivariable model. To assess the additive
Myocardial Infarction’ (MARINA-STEMI, NCT04113356) study [10]. prognostic value of NPY over post-interventional TIMI flow and LVEF,
The inclusion criteria were defined by: first STEMI according to the net reclassification improvement (NRI) was calculated by using R
ESC/ACC committee criteria [11], revascularization by primary PCI package ‘PredictABEL’. For all statistical tests, a two-tailed p-value of
within 24 h after onset of symptoms, an estimated glomerular filtration <0.05 was considered as statistically significant.
rate > 30 ml/min/1.73 m2 and Killip class < III at time of CMR.
Exclusion criteria were age <18 years, any history of a previous 3. Results
myocardial infarction or coronary intervention and any contraindica­
tion to CMR examination (pacemaker, claustrophobia, orbital foreign 3.1. Study population and baseline characteristics
body, cerebral aneurysm clip, known or suggested contrast agent allergy
to gadolinium). Median age of the overall cohort of 260 STEMI patients was 57 [IQR:
Peripheral venous blood samples for NPY analyses were drawn 24 ± 51-66] years and 17% (45) were female. The median time from symp­
4 h after primary PCI. NPY concentrations were measured by using a tom onset to PCI of the overall population was 185 [IQR: 111-324]
validated immunoassay (Human NPY ELISA, EZHNPY-25K, Germany, minutes and median door to balloon time was 22 [IQR: 7-74] minutes.
MERCK®) according to the manufacturer’s instructions to measure NPY Median NPY concentration was 70 [IQR: 35-115] pg/ml. The baseline
concentrations with a lower limit of detection of 3 pg/ml. characteristics are presented in Table 1.
The primary objective of the study was to investigate the association Patients with NPY values above median had a significantly higher
of plasma NPY with CMR-determined myocardial function as well as heart rate at admission (79 beats per minutes (bpm) vs. 72 bpm,
injury and microvascular dysfunction in the acute phase after STEMI. p=0.001). Regarding admission systolic and diastolic blood pressure, no
Secondary objective was to evaluate the relation of plasma NPY with significant difference could be observed in patients with NPY levels ≤ 70
cardiac function and scar after 4 months. Before study inclusion, written pg/ml or > 70 pg/ml (systolic blood pressure: 140 mmHg vs. 140
informed consent was obtained from all participants. The study was mmHg, p=0.787; diastolic blood pressure: 85 mmHg vs. 85 mmHg,
approved by the local ethics committee of the Medical University of p=0.522). Furthermore, patients with high NPY levels were significantly
Innsbruck and was conducted in accordance with the Declaration of more likely to have left anterior descending artery (LAD) as culprit
Helsinki. lesion (59% vs. 41%, p=0.036). Median TIMI risk score in the present
cohort was 3 and did not differ in both NPY groups (3 points vs. 3 points,
2.2. Cardiac magnetic resonance imaging p=0.119). A TIMI flow 0/1 after PCI occurred in 2% of our population.
Patients with TIMI flow 0/1 after PCI did not have higher NPY levels
All CMR examinations were performed on a 1.5 Tesla scanner compared with patients with TIMI flow >1 after PCI (67 pg/ml vs. 71
(Magnetom AVANTO, Siemens, Erlangen, Germany) at a median of 4 pg/ml, p=0.806).
[interquartile ranges (IQR): 3–5] days and 4 (IQR: 4–5) months after Regarding inflammatory markers, NPY concentrations showed a
infarction. The standardised imaging protocol as well as post-processing significant correlation to C-reactive protein (r=0.264, p<0.001) and
of our research group was published in detail previously [12]. white blood cell count (r=0.217, p=0.003).
Briefly, left ventricular (LV) volumes and function were obtained on
short-axis (10 to 12 slices) cine images using breath-hold, retrospective 3.2. NPY and CMR parameters
electrocardiogram (ECG)-triggered trueFISP bright-blood sequences.
For post-processing, including LV volumetry and LV strain analysis a High NPY concentrations (defined as NPY above median >70 pg/ml)
standard software (Circle Cardiovascular Imaging Inc®, Calgary, Can­ were significantly associated with lower LVEF both, in the acute (48%
ada) was applied. vs. 52%, p=0.004) as well in the chronic stage, referred to 4 months
ECG-triggered, phase-sensitive inversion recovery sequences were (50% vs. 52%, p=0.030). Patients with higher NPY levels showed a

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C. Tiller et al. European Journal of Internal Medicine 126 (2024) 63–68

Table 1 Table 2
Patient characteristics CMR parameters
Abbreviations: bpm = beats per minute; NPY = Neuropeptide-Y; hs-cTnT = Abbreviations: CMR = Cardiac magnetic resonance; NPY = Neuropeptide-Y;
High-sensitivity cardiac Troponin T; PCI = percutaneous coronary intervention; LVEF = Left ventricular ejection fraction; GLS = Global longitudinal strain; IS
RCA = Right coronary artery; LAD = Left anterior descending artery; LCX = Left = Infarct size; LVMM = Left ventricular myocardial mass; MVO = Microvascular
circumflex artery; ACE = Angiotensin-converting enzyme; ARBs = Angiotensin obstruction.
receptor blockers.
Total NPY ≤ 70 NPY > 70 p-value
Total NPY ≤ 70 NPY > 70 p-value population pg/ml pg/ml
population pg/ml pg/ml (n=260) (n=130, (n=130,
(n=260) (n=130, (n=130, 50%) 50%)
50%) 50%)
LVEF baseline, % 50 [42-57] 52 [44-58] 48 [39-55] 0.004
Age, years 57 [51-66] 56 [51-66] 58 [51-66] 0.853 GLS baseline, % -11 [-8 to -14] -13 [-11 to -9 [-7 to -12] <0.001
Female, n (%) 45 (17) 20 (15) 25 (19) 0.412 -15]
Body mass index, kg/m2 26.4 [24.6- 26.2 [24.7- 26.4 [24.3- 0.631 IS baseline, % of 14 [7-24] 13 [6-21] 16 [7-26] 0.041
28.7] 28.7] 28.4] LVMM
Current smoker, n (%) 134 (52) 68 (52) 66 (51) 0.804 MVO, yes/no 143 (55) 68 (52) 75 (58) 0.041
Diabetes mellitus, n (%) 18 (7) 12 (9) 6 (5) 0.143 LVEF after 4 months, 51 [43-57] 52 [45-58] 50 [42-57] 0.030
Hypertension, n (%) 112 (43) 56 (43) 56 (43) 1.00 %
Hyperlipidaemia, n (%) 131 (50) 66 (51) 65 (50) 0.901 GLS after 4 months, -12 [-9 to -14] -13 [-11 to -11 [-8 to <0.001
Admission heart rate, 77 [65-90] 72 [63-85] 79 [68-91] 0.001 % -15] -13]
bpm IS after 4 months, % 11 [5-18] 10 [5-15] 13 [7-20] 0.011
Admission systolic blood 140 [119- 140 [120- 140 [117- 0.787 of LVMM
pressure, mmHg 159] 160] 158]
Admission diastolic 85 [75-98] 85 [75- 85 [76-95] 0.522
blood pressure, mmHg 100] (β = 0.114, p=0.042), Table 3.
NPY 24h, pg/ml 70 [35-114] 35 [27-46] 114 [93- <0.001 In reclassification analysis, the addition of NPY to a prediction model
139]
including post-interventional TIMI flow and LVEF, resulted in a signif­
hs-cTnT 24h, ng/l 2965 [1354- 2961 3079 0.618
5359] [1340- [1479- icant improvement for the prediction of IS (NRI=0.34, 95% CI 0.11-
5359] 5492] 0.58, p=0.005) and MVO (NRI=0.28, 95% CI 0.07-0.49, p=0.008).
Time from symptom 185 [111- 173 [106- 199 [119- 0.180 In addition, we performed a sub analysis of patients with exclusively
onset to PCI, min 324] 295] 357] anterior infarction (n=128) to determine whether there were differences
Door to balloon time, 22 [7-44] 22 [7-43] 21 [7-51] 0.561
min
in patients with NPY levels above or below median, see Table 4 in the
Culprit lesion, n (%) 0.036 supplements.
RCA 89 (34) 54 (41) 35 (27)
LAD 131 (51) 54 (41) 77 (59) 4. Discussion
LCX 40 (15) 22 (17) 18 (14)
Pre-interventional TIMI 164 (63) 83 (64) 81 (62) 0.797
flow 0, n (%) In the present cohort study, we could demonstrate that in patients
Post-interventional TIMI 5 (2) 3 (2) 2 (1.5) 0.652 with revascularized STEMI, increased levels of plasma NPY are associ­
flow 0/1, n (%) ated with worse LV function and larger IS both in the acute phase as well
Post-interventional TIMI 235 (90) 121 (93) 114 (88) 0.141
as in the chronic phase. In addition, this is the first study to show a
flow 3, n (%)
TIMI Risk Score 3 [2-4] 3 [2-4] 3 [2-5] 0.239 significant link between peripheral plasma NPY and microvascular
Concomitant injury, as depicted by CMR imaging. This association remained signifi­
medication, admission cant even after adjustment for other clinically established markers of
Antiplatelet therapy, n 10 (4) 4 (3) 6 (5) 0.519 infarct severity such as hs-cTnT, pre-interventional TIMI flow and
(%)
ACE inhibitors/ARBs, n 56 (22) 31 (24) 25 (19) 0.182
culprit lesion location. These findings suggest a potential role of NPY as
(%) a novel clinical risk marker in STEMI survivors.
ß-blockers, n (%) 18 (7) 6 (5) 12 (9) 0.147 Circulating NPY is involved in various physiological processes in
Statins, n (%) 25 (10) 8 (6) 17 (13) 0.061 both the central and peripheral nervous systems. Under conditions of
high sympathetic-drive, such as STEMI, NPY is released as a potent
vasoconstrictor in the vascular system causing myocardial injury [1,7,
significantly decreased GLS in the acute phase after infarction (-8.8% vs.
14]. This has been well investigated in both experimental and clinical
-12.6%, p<0.001) and in the chronic phase (-10.5 vs. -12.9, p<0.001).
studies by the administration of NPY and the demonstration of this
Increased NPY concentrations were significantly associated with larger
vasoconstrictive effects [15–17]. Thus, it is not surprising that NPY
IS both in the acute phase (17% vs. 13%, p=0.041) as well as in the
concentrations are increased in STEMI patients as well [1]. Furthermore,
chronic phase (13% vs. 10%, p=0.011). In addition, presence of MVO
NPY levels remain high for at least 48h after PCI due to its long plasma
was more frequent (58% vs. 52%, p=0.041) in patients with increased
half-life [14]. Prior studies already examined whether NPY levels from
plasma NPY (Table 2, Fig. 1).
the coronary sinus (CS) are comparable to peripheral venous NPY
The correlation of NPY and the corresponding linear outcome vari­
measurements, which are strongly correlated to each other across
ables are presented in Fig. 2.
different patient groups including patients with normal coronary ar­
In univariable linear regression analysis, NPY was significantly
teries and patients with STEMI [1]. In a study from Gibbs et al., they
related to baseline LVEF (β = − 0.257, p<0.001), GLS (β = 0.515,
evaluated NPY concentrations exclusively in STEMI patients both from
p<0.001), IS (β = 0.225, p<0.001) and MVO (β = 0.179, p=0.004). Four
the CS as well as from peripheral venous blood immediately after PCI
models were created where either baseline LVEF, GLS, IS, or MVO were
[5]. They demonstrated that NPY levels from CS were significantly
taken as the dependent variable and NPY, high-sensitivity cardiac
higher in patients with CMR-determined myocardial and microvascular
troponin T (hs-cTnT), pre-interventional TIMI flow 0 and LAD as culprit
injury whereas peripheral NPY concentrations were significantly related
lesion as independent variables. In all four models, plasma NPY con­
to reduced LVEF both in the acute phase as well as after 6 months but not
centrations remained significantly associated with LVEF (β = − 0.187,
with myocardial injury [5]. However, NPY levels obtained from CS is not
p<0.001), GLS (β = 0.443, p<0.001), IS (β = 0.146, p=0.003) and MVO
practical in daily clinical routine, in contrast, peripheral NPY values are

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C. Tiller et al. European Journal of Internal Medicine 126 (2024) 63–68

Fig. 1. NPY concentrations in relation to myocardial function and myocardial injury.

Abbreviations: NPY = Neuropeptide-Y, LVEF = Left ventricular ejection fraction, GLS = Global longitudinal strain, IS = Infarct size, LVMM = Left ventricular
myocardial mass, MVO = Microvascular obstruction.

Fig. 2. Scatter diagram of NPY in relation to myocardial function and myocardial injury with corresponding correlation coefficients.
Abbreviations: NPY = Neuropeptide-Y, LVEF = Left ventricular ejection fraction, GLS = Global longitudinal strain, IS = Infarct size.

easily and safely to obtain. In our study, we can confirm a significant remodelling processes after myocardial infarction. Besides the signifi­
association of peripheral venous NPY with impaired LVEF in the acute cant association of plasma NPY and myocardial function, NPY levels also
phase and in the chronic phase, evaluated 4 months after infarction. In showed a significant relation to myocardial injury. So far, there has only
addition, we analysed GLS both in the acute as well as in the chronic been one study investigating the association of NPY with
stage. Myocardial strain analysis not only allows the assessment of CMR-determined myocardial injury. They illustrated a significant asso­
global systolic function but also regional alterations, compared to LVEF ciation of CS-measured NPY with CMR-determined IS in the acute
[18]. Moreover, prior studies investigated the prognostic value of GLS setting after STEMI but not with plasma NPY [5]. However, in our study
which was superior and incremental to LVEF and CMR markers of infarct we could extent prior findings by revealing a significant relationship
severity [19]. Thus, GLS is regarded as powerful complementary prog­ between plasma NPY and IS in the acute phase after STEMI. Over and
nosticator in addition to LVEF, IS and MVO [19]. In the present study, above, this relation of NPY with IS remained significant at 4 months
we could demonstrate that patients with high NPY measurements CMR follow up as well, similar to the findings by Gibbs et al [5]. Of note,
showed a significantly decreased GLS early after infarction and after 4 we could also demonstrate, for the first time, that plasma NPY concen­
months. These findings suggest that NPY has a relevant impact on trations are significantly related with incomplete myocardial tissue

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Table 3 Table 4
Multiple linear regression analysis with either LVEF, GLS, IS or MVO as Patient characteristics exclusively for anterior infarction
dependent variable. Abbreviations: bpm = beats per minute; NPY = Neuropeptide-Y; hs-cTnT =
Abbreviations: LVEF = Left ventricular ejection fraction; GLS = Global longi­ High-sensitivity cardiac Troponin T; PCI = percutaneous coronary intervention;
tudinal strain; IS = Infarct size; MVO = Microvascular obstruction; NPY = RCA = Right coronary artery; LAD = Left anterior descending artery; LCX = Left
Neuropeptide-Y; hs-cTnT = High-sensitivity cardiac troponin T; LAD = Left circumflex artery; ACE = Angiotensin-converting enzyme; ARBs = Angiotensin
anterior descending artery. receptor blockers; CMR = Cardiac magnetic resonance; NPY = Neuropeptide-Y;
LVEF ß p-value
LVEF = Left ventricular ejection fraction; GLS = Global longitudinal strain; IS =
Infarct size; LVMM = Left ventricular myocardial mass; MVO = Microvascular
NPY 24h, pg/ml -0.187 <0.001 obstruction.
Hs-cTnT 24h, ng/l -0.422 <0.001
Pre-interventional TIMI flow 0 0.171 0.006 Total NPY ≤ 70 NPY > 70 p-value
LAD as culprit lesion 0.233 <0.001 population pg/ml pg/ml
(n=128) (n=55, (n=73,
GLS 43%) 57%)
NPY 24h, pg/ml 0.443 <0.001
Hs-cTnT 24h, ng/l 0.298 <0.001 Age, years 58 [51-66] 56 [53-66] 58 [51-68] 0.857
Pre-interventional TIMI flow 0 -0.107 0.042 Female, n (%) 26 (20) 10 (18) 16 (22) 0.603
LAD as culprit lesion -0.249 <0.001 Body mass index, kg/m2 25.7 [24.2- 25.5 [23.9- 26.2 [24.5- 0.632
28.4] 28.7] 28.4]
IS Current smoker, n (%) 60 (47) 25 (46) 35 (48) 0.780
NPY 24h, pg/ml 0.146 0.003 Diabetes mellitus, n (%) 9 (7) 4 (7) 5 (7) 0.926
Hs-cTnT 24h, ng/l 0.557 <0.001 Hypertension, n (%) 55 (43) 25 (46) 30 (41) 0.622
Pre-interventional TIMI flow 0 -0.191 <0.001 Hyperlipidaemia, n (%) 66 (52) 29 (53) 37 (51) 0.819
LAD as culprit lesion -0.177 <0.001 Admission heart rate, 80 [68-90] 75 [66-87] 83 [71-92] 0.035
bpm
MVO Admission systolic blood 141 [125- 140 [126- 141 [123- 0.698
NPY 24h, pg/ml 0.114 0.042 pressure, mmHg 160] 160] 160]
Hs-cTnT 24h, ng/l 0.484 <0.001 Admission diastolic blood 90 [78-100] 93 [80- 89 [77- 0.206
Pre-interventional TIMI flow 0 -0.035 0.536 pressure, mmHg 100] 100]
LAD as culprit lesion -0.202 <0.001 NPY 24h, pg/ml 79 [37-123] 35 [29-49] 119 [93- <0.001
152]
hs-cTnT 24h, ng/l 3210 [1286- 3441 3079 0.457
5964] [1335- [1275-
reperfusion as determined by MVO. Although Gibbs et al. already 6551] 5718]
investigated the relationship between NPY and CMR-determined Time from symptom 175 [112- 172 [106- 185 [114- 0.635
microvascular injury [5], it was not significant in the peripheral onset to PCI, min 307] 300] 317]
Door to balloon time, min 24 [7-45] 21 [7-43] 24 [11-54] 0.166
venous NPY group, only in the CS group. Consequently, with our find­
Pre-interventional TIMI 79 (62) 37 (67) 42 (58) 0.262
ings by showing a significant association of plasma NPY levels with flow 0, n (%)
MVO, we can emphasize the role of plasma NPY. This is of clinical Post-interventional TIMI 5 (4) 3 (6) 2 (3) 0.433
relevance since microvascular injury is increasingly recognized as major flow 0/1, n (%)
prognostic marker for worse clinical outcomes in survived STEMI pa­ Post-interventional TIMI 108 (84) 47 (86) 62 (84) 0.770
flow 3, n (%)
tients [20]. Besides, there is an urgent need for cardioprotection trials to TIMI Risk Score 3 [2-5] 3 [3-4] 3 [2-5] 0.527
improve reperfusion injury. NPY, as a marker of increased sympathetic Concomitant medication,
activity and resulting vasoconstriction, could be used as a potential admission
target in such studies. Additionally, we could demonstrate an incre­ Antiplatelet therapy, n 7 (6) 3 (6) 4 (6) 0.995
(%)
mental benefit of NPY when added to other important clinical risk fac­
ACE inhibitors/ARBs, n 26 (20) 12 (22) 14 (19) 0.674
tors (post-interventional TIMI flow, LVEF) for the prediction of IS and (%)
MVO. Thus, these results further highlight the additive role of NPY in ß-blockers, n (%) 9 (7) 2 (4) 7 (10) 0.201
relation to infarct severity prediction for a more discriminative risk Statins, n (%) 10 (8) 2 (4) 8 (11) 0.133
stratification in survived STEMI patients.
CMR parameters
Furthermore, NPY is also related to inflammatory processes in LVEF baseline, % 45 [38-56] 46 [39-56] 42 [37-53] 0.171
experimental data [21,22]. This is in line with our data showing sig­ GLS baseline, % -9 [-7 to -12] -11 [-8 to -8 [-6 to <0.001
nificant correlation of NPY concentrations with C-reactive protein and -14] -10]
white blood cell count. However, further research is needed elucidating IS baseline, % of LVMM 18 [7-28] 18 [8-28] 18 [7-29] 0.994
MVO, yes/no 80 (63) 35 (64) 45 (62) 0.818
the role of NPY in inflammatory processes in the setting of acute STEMI.
LVEF after 4 months, % 50 [39-57] 50 [40-56] 50 [39-57] 0.737
Regarding angiographic microvascular dysfunction, post- GLS after 4 months, % -11 [-9 to -13 [-10 to -10 [-8 to <0.001
interventional TIMI flow <2 is the angiographic definition of MVO, -13] -14] -12]
however, TIMI grade does not correlate well with CMR-determined IS after 4 months, % of 15 [8-22] 11 [7-18] 17 [8-26] 0.062
MVO, the current non-invasive gold standard [23,24]. This could also LVMM

explain why in our cohort, post-interventional TIMI flow is not associ­

ated with high NPY values. Furthermore, TIMI flow 0/1 is only observed [25]. This could be of interest in regards to the possibility of a blockage
in 2% of the patients in the present study. of the ganglion stellatum in order to reduce ventricular arrhythmias.
Another important topic in the setting of acute myocardial infarction
is the high prevalence of arrhythmias, especially in the first 48 hours
4.1. Limitations
after infarction. Kalla et al. demonstrated that high NPY levels are
significantly related to arrhythmic events after STEMI, especially to
The present study has limitations. First, NPY levels were measured at
ventricular arrythmias [7]. As NPY concentrations remain high until at
24h, thus, the optimal time point for NPY measurement could not be
least 48h after PCI, NPY might also be used as a biomarker-based risk
evaluated. In prior studies, peak values were observed prior PCI but
stratification tool for arrhythmias in the early phase after STEMI. In
remain high for at least 48h after intervention [14]. Second, due to the
animal models, NPY is also stored in large vesicles of ganglion stellatum
exclusion criteria, high-risk patients such as patients with hemodynamic

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C. Tiller et al. European Journal of Internal Medicine 126 (2024) 63–68

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represented in our study. Third, further studies are necessary to evaluate
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5. Conclusion infarct size, reperfusion injury, and adverse remodelling after ST-elevation
myocardial infarction. Eur Heart J Acute Cardiovasc Care 2022;11:113–23.
In acute STEMI patients, increased plasma levels of NPY, measured at https://doi.org/10.1093/ehjacc/zuab110. 2021/12/02.
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ventricular dysfunction and more extensive myocardial injury as doi.org/10.1016/j.jcmg.2022.02.010. 2022/06/10.
determined by comprehensive CMR imaging. Our findings, therefore, [11] Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial
infarction (2018). Eur Heart J 2018;40:237–69. https://doi.org/10.1093/
propose NPY as a novel clinical risk marker post-STEMI which warrants
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further research. [12] Tiller C, Reindl M, Holzknecht M, et al. Relationship between admission Q waves
and microvascular injury in patients with ST-elevation myocardial infarction
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Funding Sources 1–7. https://doi.org/10.1016/j.ijcard.2019.10.009. 2019/10/21.
[13] Bondarenko O, Beek AM, Hofman MB, et al. Standardizing the definition of
This study was supported by grants from the “Austrian Society of hyperenhancement in the quantitative assessment of infarct size and myocardial
viability using delayed contrast-enhanced CMR. J Cardiovasc Magn Reson 2005;7:
Cardiology”, the “Gesellschaft zur Förderung der Herz-Kreislauf-For­
481–5. Research Support, Non-U.S. Gov’t 2005/05/11.
schung”, and the “Tiroler Wissenschaftsfonds”. [14] Cuculi F, Herring N, De Caterina AR, et al. Relationship of plasma neuropeptide Y
with angiographic, electrocardiographic and coronary physiology indices of
reperfusion during ST elevation myocardial infarction. Heart 2013;99:1198–203.
Disclosures https://doi.org/10.1136/heartjnl-2012-303443. 20130212.
[15] Clarke JG, Davies GJ, Kerwin R, et al. Coronary artery infusion of neuropeptide Y
The Authors declare that there is no conflict of interest. in patients with angina pectoris. Lancet 1987;1:1057–9. https://doi.org/10.1016/
s0140-6736(87)90483-1.
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Data availability coronary arteries constricts primarily small coronary arteries to produce
myocardial ischemia in dogs. J Clin Invest 1989;83:1217–24. https://doi.org/
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The data underlying this article will be shared on reasonable request [17] Rosano GMC, Tousoulis D, McFadden E, et al. Effects of neuropeptide Y on
to the corresponding author. coronary artery vasomotion in patients with microvascular angina. Int J Cardiol
2017;238:123–7. https://doi.org/10.1016/j.ijcard.2017.03.024. 20170316.
[18] Smiseth OA, Torp H, Opdahl A, et al. Myocardial strain imaging: how useful is it in
Acknowledgement clinical decision making? Eur Heart J 2016;37:1196–207. https://doi.org/
10.1093/eurheartj/ehv529. 20151027.
Not applicable. [19] Reindl M, Tiller C, Holzknecht M, et al. Prognostic Implications of Global
Longitudinal Strain by Feature-Tracking Cardiac Magnetic Resonance in ST-
Elevation Myocardial Infarction. Circ Cardiovasc Imaging 2019;12:e009404.
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