Skip to content

Advertisement

  • Case Report
  • Open Access

Tryptase as a marker of severity of aortic valve stenosis

  • 1,
  • 1,
  • 1,
  • 2,
  • 1 and
  • 1, 3Email author
Clinical and Molecular Allergy201816:17

https://doi.org/10.1186/s12948-018-0095-6

  • Received: 24 January 2018
  • Accepted: 27 July 2018
  • Published:

Abstract

Background

Severe aortic valve stenosis is one of the most common cause of mortality in adult patients affected with metabolic syndrome, a condition associated with an active inflammatory process involving also mast cells and their mediators, in particular tryptase. The aim of this study was to characterize the possible long-term prognostic role of tryptase in severe aortic valve stenosis.

Case presentation

The baseline serum tryptase was measured in 5 consecutive patients admitted to our Hospital to undergo aortic valve replacement for severe acquired stenosis. Within 2 years after, the patients were evaluated for the occurrence of major cardiovascular events (MACE). The tryptase measurements were higher in patients experiencing MACE (10.9, 11.7 and 9.32 ng/ml) than in non-MACE ones (5.69 and 5.58 ng/ml).

Conclusions

In patients affected with severe aortic stenosis, baseline serum tryptase may predict occurence of MACE. Further studies are needed to demonstrate the long-term prognostic role of this biomarker.

Keywords

  • Aortic valve stenosis
  • Biomarker
  • Tryptase

Background

Severe aortic valve stenosis is one of the most common cause of mortality in adult patients affected with metabolic syndrome [1], i.e. a clinical condition characterized from visceral obesity that is traduced into insulin resistance, atherogenic dyslipidemia and proinflammatory state [2]. It is frequently due to an active process involving several pathways, including lipid infiltration, chronic inflammation, fibrosis formation, osteoblasts activation, and valve mineralization. Other causes are congenital valve defects, systemic inflammatory diseases, and endocarditis [3]. Prevalence is between 2 and 9% in subjects over 65 years and it increases significantly in forthcoming decades as a consequence of the ageing population and of more accurate diagnostic methods [4]. Severe aortic stenosis is defined by the presence of maximum aortic velocity ≥ 4 m/s, or aortic valve area ≤ 1.0 cm2, or by the presence of severe leaflet calcification and severely reduced leaflet opening. Surgical aortic valve replacement is indicated in symptomatic patients with severe high-gradient aortic stenosis, and in asymptomatic ones with severe aortic stenosis and left ventricular ejection fraction < 50% [5]. Its natural history results in the obstruction of the left ventricular outflow, followed by pressure overload and compensatory hypertrophy of the left ventricle. Excessive hypertrophy may decrease coronary blood flow reserve, increase collagen synthesis, interstitial fibrosis, and myocyte degeneration resulting in ischemic cardiac disease, sudden death and heart failure syndrome. Moreover, these patients have major risk of bleeding due to angiodysplasia, alterated platelets function and low concentration of von Willebrand factor [3]. High-sensitivity cardiac troponin T (hsTnT) is usefulness for risk stratification of severity and mortality [6]. However, recently some authors described the role of mast cells in calcified aortic stenosis [7] and an autoptic study detected these cells in the excised valves of patient undergoing elective aortic valve replacement in comparison with normal aortic valves from five healthy subjects obtained on autopsy served as negative controls [8]. In light of the above, we studied basal serum tryptase as a new serological prognostic biomarker in aortic valve stenosis. Tryptase is a mast cell serine protease that provides information about mast cell number, distribution, and activation depending on the clinical context [9]. In some cardiovascular diseases, this enzyme has important implications and represents an index of mast cells’ burden [10, 11]. In particular, in subjects affected with acute coronary syndrome we found higher basal tryptase values in so defined ‘cardiovascular complex’ patients than in ‘non-complex’ ones [12]. Moreover, in the same population the basal serum tryptase was significantly correlated to the development of major cardiovascular events’ (MACE) up to 2 years, demonstrating a possible long-term prognostic role of this biomarker [13].

Cases report

Herein, we described a total of 5 consecutive patients admitted to our Hospital from January 2015 to December 2016, to undergo aortic valve replacement for severe acquired stenosis. None was affected with autoimmunity diseases, severe allergies, cancer, renal failure, mastocytosis, refractory anemia, myelodysplastic syndromes, and hypereosinophilic syndrome. After admission, we collected from all the patients medical history, echo-cardiogram, serum tryptase, C-reactive protein, hsTnT, plasma glucose, and lipid parameters. Serum tryptase levels were measured by ImmunoCAP tryptase in vitro fluoro-enzyme-immunoassay test (Phadia, now Thermo Fisher Scientific, Uppsala, Sweden), according to the manufacturer’s instruction. Within 2 years after the aortic valve replacement, the patients were evaluated for the occurrence of MACE including myocardial infarction, cardiac arrhythmias, stroke, systemic embolism, heart failure and sudden death. Table 1 shows patients’ clinical characteristics. At 2-year follow up, 3 patients experienced MACE: 1 died and 2 had acute coronary syndrome. In these patients tryptase levels were 10.9, 11.7 and 9.32 ng/ml respectively, about twofold higher than in non-MACE ones: 5.69 and 5.58 ng/ml.
Table 1

Clinical characteristics of study patients

Sex/age, years

MACE-patients

Non-MACE patients

M/85

F/58

F/53

F/72

F/77

Clinical history

 Hypertension

Yes

Yes

Yes

Yes

Yes

 Hypercolesterolemia

No

Yes

No

Yes

Yes

 Currently smoking

Yes

No

No

No

No

 Diabetes mellitus

No

Yes

No

No

No

 Obesity

No

No

No

No

Yes

 COPD

Yes

No

No

No

No

Left ventricle ejection fraction during index hospitalization

 Ejection fraction (%)

30

58

56

40

60

 Mean transvalvular gradient (mmHg)

70

75

70

65

65

Diagnostic findings

 Tryptase, ng/ml

10.9

11.7

9.32

5.69

5.58

 CRP, mg/dl

3.2

0.8

0.2

0.3

1.1

 hsTnT, ng/l

49.5

8.0

7.9

40

7.2

 Serum triglycerides, mg/dl

117

189

150

176

68

 HDL cholesterol, mg/dl

32

40

38

37

72

 LDL cholesterol, mg/dl

90

97

100

116

89

 Plasma glucose, mg/dl

119

181

104

87

114

Major cardiovascular events

Sudden death

STEACS

STEACS

None

None

STEACS ST elevation acute coronary syndrome, COPD Chronic obstructive pulmonary disease, CRP C-reactive protein, hsTnT high-sensitivity cardiac troponin T, HDL high-density lipoprotein, LDL low-density lipoprotein, MACE major cardiovascular events

Conclusions

Our results could be in agreement with the literature of the last few decades, in which a relationship between high tryptase levels and the development of MACE in acute coronary syndrome patients was found, to demonstrate the tryptase role as a marker of the inflammatory and atherosclerotic process [13, 14]. Indeed, in stenotic aortic valves mast cells secrete tryptase, chymase, cathepsin G and vascular endothelial growth factor inducing extracellular matrix degradation and valvular neovascularization [15].

In conclusion, we hypothesized that high tryptase levels may be a risk factor of development of MACE in severe aortic stenosis. Further studies on largest populations are required to confirm this hypothesis.

Abbreviations

MACE: 

major cardiovascular events

hsTnT: 

high-sensitivity cardiac troponin T

Declarations

Authors’ contributions

In particular, LML and EAP made substantial contributions to conception and design; MC, LF, and FL, made acquisition of data, and analysis and interpretation of data; CM, reviewed it critically for important intellectual content. All authors read and approved the final manuscript.

Acknowledgements

None.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

The data used in the current study are available from the corresponding author on reasonable request.

Consent for publication

Written informed consent was obtained from 5 patients for the study and for the publication of this report.

Ethics approval and consent to participate

The study was approved by the Ethics Commitee of the Niguarda Ca' Hospital: Protocol Registration System Clinical Trials .gov Number 193_05/2012.

Funding

None.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
The Department of Allergology and Immunology, A.S.S.T. Grande Ospedale Metropolitano Niguarda, Milan, Italy
(2)
The Department of Laboratory Medicine, A.S.S.T. Grande Ospedale Metropolitano Niguarda, Milan, Italy
(3)
Unit of Allergy and Immunology, Niguarda Ca’ Granda Hospital, Piazza Ospedale Maggiore, 3, 20162 Milan, Italy

Reference

  1. Pagé A, Dumesnil JG, Clavel MA, Chan KL, Teo KK, Tam JW, Mathieu P, Després JP, Pibarot P, ASTRONOMER Investigators. Metabolic syndrome is associated with more pronounced impairment of left ventricle geometry and function in patients with calcific aortic stenosis: a substudy of the ASTRONOMER (Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin). J Am Coll Cardiol. 2010;55(17):1867–74.View ArticlePubMedGoogle Scholar
  2. Després JP, Lemieux I, Bergeron J, Pibarot P, Mathieu P, Larose E, Rodés-Cabau J, Bertrand OF, Poirier P. Abdominal obesity and the metabolic syndrome: contribution to global cardiometabolic risk. Arterioscler Thromb Vasc Biol. 2008;28(6):1039–49.View ArticlePubMedGoogle Scholar
  3. Olszowska M. Pathogenesis and pathophysiology of aortic valve stenosis in adults. Pol Arch Med Wewn. 2011;121(11):409–13.PubMedGoogle Scholar
  4. Townsend CM, et al. Sabiston textbook of surgery. 18th ed. New York: Saunders; 2008. p. 1841–4.Google Scholar
  5. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, O’Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM 3rd, Thomas JD, American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(22):2438–88.View ArticlePubMedGoogle Scholar
  6. Dahou A, Clavel MA, Capoulade R, O’Connor K, Ribeiro HB, Côté N, Le Ven F, Rodés-Cabau J, Dumesnil JG, Mathieu P, Pibarot P. B-type natriuretic peptide and high-sensitivity cardiac troponin for risk stratification in low-flow, low-gradient aortic stenosis: a substudy of the TOPAS study. JACC Cardiovasc Imaging. 2017. https://doi.org/10.1016/j.jcmg.2017.06.018.View ArticleGoogle Scholar
  7. Steiner I, Krbal L, Rozkoš T, Harrer J, Laco J. Calcific aortic valve stenosis: immunohistochemical analysis of inflammatory infiltrate. Pathol Res Pract. 2012;208(4):231–4.View ArticlePubMedGoogle Scholar
  8. Wypasek E, Natorska J, Grudzień G, Filip G, Sadowski J, Undas A. Mast cells in human stenotic aortic valves are associated with the severity of stenosis. Inflammation. 2013;36:449–56.View ArticlePubMedGoogle Scholar
  9. Valent P. Mast cell activation syndromes: definition and classification. Allergy. 2013;68(4):417–24.View ArticlePubMedGoogle Scholar
  10. Searle J, Danne O, Müller C, Mockel M. Biomarkers in acute coronary syndrome and percutaneous coronary intervention. Minerva Cardioangiol. 2011; 59:203-23.PubMedGoogle Scholar
  11. Kounis NG, Tsigkas G, Almpanis G, Kounis GN, Mazarakis A, Hahalis G. Tryptase levels in coronary syndrome and in hypersensitivity episodes: a common path was towards Kounis syndrome. Atherosclerosis. 2011;219(1):28–9.View ArticlePubMedGoogle Scholar
  12. Morici N, Farioli L, Losappio LM, Colombo G, Nichelatti M, Preziosi D, Micarelli G, Oliva F, Giannattasio C, Klugmann S, Pastorello EA. Mast cells and acute coronary syndromes: relationship between serum tryptase clinical outcomes and severity of coronary artery disease. Open Heart. 2016;3(2).View ArticlePubMedPubMed CentralGoogle Scholar
  13. Pastorello EA, Farioli L, Losappio LM, Morici N, Di Biase M, Nichelatti M, Schroeder JW, Balossi L, Klugmann S. Serum tryptase detected during acute coronary syndrome is significantly related to the development of major adverse cardiovascular events after 2 years. Clin Mol Allergy. 2015;13(1):14.View ArticlePubMedPubMed CentralGoogle Scholar
  14. Helske S, Lindstedt KA, Laine M, Mäyränpää M, Werkkala K, Lommi J, Turto H, Kupari M, Kovanen PT. Induction of local Angiotensin II producing systems in stenotic aortic valves. J Am Coll Cardiol. 2004;44(9):1859–66.View ArticlePubMedGoogle Scholar
  15. Syva¨ranta S, Helske S, Laine M, Lappalainen J, Kupari M, Ma¨yra¨npa¨a¨ MI, Lindstedt KA, Kovanen PT. Vascular endothelial growth factor-secreting mast cells and myofibroblasts: a novel self-perpetuating angiogenic pathway in aortic valve stenosis. Arterioscler Thromb Vasc Biol. 2010;30(6):1220–7.View ArticleGoogle Scholar

Copyright

© The Author(s) 2018

Advertisement