ABSTRACT
In Brazil, Chagas cardiomyopathy is the third most common cause of indication for heart transplantation (HTx). Pulmonary arterial hypertension (PAH) is a severe condition frequently present in patients with terminal heart failure that worsens the prognosis of patients undergoing HTx. The etiological mechanism of PAH is multifactorial, with increased ventricular filling pressure being one of the main ones. Recently, however, several studies have sought to demonstrate the role of the local inflammatory process in contributing to the stiffening of the pulmonary arteries and the emergence or worsening of PAH in the heart failure (HF) setting.
Objectives:
To evaluate the inflammatory process in the pulmonary arteries of chagasic HTx (HTx-C) and non-chagasic (HTx-NC) patients, with and without PAH, through the tissue concentration of inflammatory cytokines obtained at the time of HTx.
Methods:
The levels of interleukins (IL)-6, IL-1β, TNF-α, and CD68 and CD66b neutrophils were measured in fragments of the pulmonary arteries of HTx-C and HTx-NC patients with and without PAH.
Results:
No statistically significant difference (p ≥ 0.05) between the inflammatory biomarkers measured in HTx-C and HTx-NC pulmonary arteries, with or without PAH.
Conclusion:
We observed that HTx-C and HTx-NC patients present the same levels of inflammatory markers expressed in the pulmonary artery tissue, whether or not they have PAH. This fact suggests that PAH in HTx-C and HTx-NC patients is a process that is related to HF itself and not to the patients’ inflammatory profile.
Descriptors
Heart Transplant; Pulmonary Arterial Hypertension; Inflammatory Biomarkers
RESUMO
No Brasil, a miocardiopatia chagásica constitui a terceira causa mais comum de indicação para transplante cardíaco (TxC). A hipertensão arterial pulmonar (HAP) é uma condição grave frequentemente presente em pacientes com insuficiência cardíaca (IC) terminal que piora o prognóstico daqueles submetidos a TxC. O mecanismo etiológico da HAP é multifatorial, sendo o aumento da pressão de enchimento ventricular um dos principais. Recentemente, entretanto, vários trabalhos procuraram demonstrar o papel do processo inflamatório local, contribuindo para o enrijecimento das artérias pulmonares e o surgimento ou piora da HAP no cenário da IC.
Objetivos:
Avaliar o processo inflamatório nas artérias pulmonares de transplantados cardíacos chagásicos (TxC-C) e não chagásicos (TxC-NC), com e sem HAP, por meio da concentração tecidual das citocinas inflamatórias obtidas no momento do TxC.
Métodos:
Os níveis das interleucinas (IL)-6, IL-1β, e do fator de necrose tumoral alfa [tumor necrosis factor alpha) (TNF-α)] e de neutrófilos CD68 e CD66b foram aferidos em fragmentos das artérias pulmonares de pacientes TxC-C e TxC-NC com e sem HAP.
Resultados:
Não houve diferença estatisticamente significativa (p ≥ 0,05) entre os níveis dos biomarcadores inflamatórios aferidos nas artérias pulmonares dos TxC-C e TxC-NC com ou sem HAP.
Conclusão:
Observamos que os pacientes TxC-C e TxC-NC com ou sem HAP apresentam níveis semelhantes de marcadores inflamatórios expressos no tecido das artérias pulmonares. Tal fato sugere que a HAP dos pacientes TxC-C e TxC-NC é um processo que se relaciona com a própria IC e pode não ter relação com o perfil inflamatório dos pacientes.
Descritores
Transplante Cardíaco; Hipertensão Arterial Pulmonar; Biomarcadores Inflamatórios
INTRODUCTION
Heart transplantation (HTx) is an excellent therapeutic option for patients with advanced heart failure (HF) refractory to clinical treatment, according to national and international guidelines11 Rohde LEP, Montera MW, Bocchi EA, Clausell NO, de Albuquerque DC, Rassi S, et al. Diretriz brasileira de insuficiência cardíaca crônica e aguda. Arq Bras Cardiol 2018; 111(3): 436-539. https://doi.org/10.5935/abc.20180190
https://doi.org/10.5935/abc.20180190...
. HF is a progressive disease that affects millions of people. Approximately 10% of patients with HF have the advanced form of the disease or stage D, which is associated with high mortality and inferior quality of life11 Rohde LEP, Montera MW, Bocchi EA, Clausell NO, de Albuquerque DC, Rassi S, et al. Diretriz brasileira de insuficiência cardíaca crônica e aguda. Arq Bras Cardiol 2018; 111(3): 436-539. https://doi.org/10.5935/abc.20180190
https://doi.org/10.5935/abc.20180190...
,22 Bacal F, Marcondes-Braga FG, Rohde LEP, Xavier Júnior JL, Brito F de S, Moura LAZ, et al. 3a Diretriz Brasileira de Transplante Cardíaco. Arq Bras Cardiol 2018; 111(2): 230-89. https://doi.org/10.5935/abc.20180153
https://doi.org/10.5935/abc.20180153...
. There is consensus that HTx, with appropriate selection criteria, increases survival quality of life and exercise capacity and provides a faster return to work compared to conventional treatment11 Rohde LEP, Montera MW, Bocchi EA, Clausell NO, de Albuquerque DC, Rassi S, et al. Diretriz brasileira de insuficiência cardíaca crônica e aguda. Arq Bras Cardiol 2018; 111(3): 436-539. https://doi.org/10.5935/abc.20180190
https://doi.org/10.5935/abc.20180190...
,22 Bacal F, Marcondes-Braga FG, Rohde LEP, Xavier Júnior JL, Brito F de S, Moura LAZ, et al. 3a Diretriz Brasileira de Transplante Cardíaco. Arq Bras Cardiol 2018; 111(2): 230-89. https://doi.org/10.5935/abc.20180153
https://doi.org/10.5935/abc.20180153...
.
Brazil has become increasingly prominent in transplants, especially in Latin America33 Pêgo-Fernandes PM, Pestana JOM, Garcia VD. Transplants in Brazil: where are we? Clinics 2019; 74: 1-2. https://doi.org/10.6061/clinics/2019/e832
https://doi.org/10.6061/clinics/2019/e83...
. In the 2019 International Society for Heart & Lung Transplantation (ISHLT) registry of HTx recipient data, the most frequent diagnoses of the cause of HF were non-ischemic cardiomyopathy (50.8% of cases), ischemic cardiomyopathy (32.4% ), restrictive cardiomyopathy (3.5%), hypertrophic cardiomyopathy (3.4%), congenital heart disease (3.1%), retransplantation (2.8%), valvular cardiomyopathy (2.5%) and others (1 .5%)44 Khush KK, Cherikh WS, Chambers DC, Harhay MO, Hayes D, Hsich E, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: thirty-sixth adult heart transplantation report – 2019; focus theme: donor and recipient size match. J Heart Lung Transplant 2019; 38(10): 1056-66. https://doi.org/10.1016/j.healun.2019.08.004
https://doi.org/10.1016/j.healun.2019.08...
.
Currently, the state of Minas Gerais is the second with the highest number of HTx performed in the country55 Associação Brasileira de Transplantes de Órgãos. Dados numéricos da doação de órgão e transplantes realizados por estado e instituição no período: janeiro/setembro-2022. Registro Brasileiro de Transplantes 2022 [acesso em 27 Dez 2023]. Disponível em: https://site.abto.org.br/wp-content/uploads/2022/11/rbt-naoassociado.pdf
https://site.abto.org.br/wp-content/uplo...
, with Chagas disease (CHD) responsible for 50% of cases66 Araújo E, Silva DA. Transplante cardíaco: co-morbidades e complicações apresentadas por pacientes em um hospital universitário de Belo Horizonte. Dissertação [Mestrado em Enfermagem] – Escola de Enfermagem, Universidade Federal de Minas Gerais; 2011. [acesso em 08 Jan 2024]. Disponível em: https://repositorio.ufmg.br/handle/1843/GCPA-8KUGWN
https://repositorio.ufmg.br/handle/1843/...
. CHD is responsible for the chronic and persistent inflammatory process of the myocardium that leads to the destruction of cardiomyocytes, associated with arrhythmias and embolic events, the leading causes of death77 Rassi A, Rassi A, Marin-Neto JA. Chagas heart disease: pathophysiologic mechanisms, prognostic factors and risk stratification. Mem Inst Oswaldo Cruz 2009; 104: 152-8. https://doi.org/10.1590/S0074-02762009000900021
https://doi.org/10.1590/S0074-0276200900...
.
Pulmonary arterial hypertension (PAH) is often associated with HF due to increased left ventricular filling pressures88 Gelape CL, Nunes M do CP, Bráulio R, Nogueira PH, Andrade SA de, Machado PAB, et al. Pressão pulmonar aferida pela ecocardiografia em pacientes chagásicos indicados para transplante cardíaco. Braz J Cardiovasc Surg 2011; 26(1). https://doi.org/10.1590/S0102-76382011000100012
https://doi.org/10.1590/S0102-7638201100...
. This condition worsens the HTx result and may be a contraindication if very high and fixed88 Gelape CL, Nunes M do CP, Bráulio R, Nogueira PH, Andrade SA de, Machado PAB, et al. Pressão pulmonar aferida pela ecocardiografia em pacientes chagásicos indicados para transplante cardíaco. Braz J Cardiovasc Surg 2011; 26(1). https://doi.org/10.1590/S0102-76382011000100012
https://doi.org/10.1590/S0102-7638201100...
.
PAH is defined as a condition with a mean pulmonary artery pressure greater than 20 mmHg99 Simonneau G, Montani D, Celermajer DS, Denton CP, Gatzoulis MA, Krowka M, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019; 53: 1801913. https://doi.org/10.1183/13993003.01913-2018
https://doi.org/10.1183/13993003.01913-2...
. Recently, it was demonstrated that local inflammation at the tissue level may be a critical aspect in the etiology of PAH and that T cells, B cells, mast cells, macrophages, neutrophils and dendritic cells participate in this process1010 Price LC, Wort SJ, Perros F, Dorfmüller P, Huertas A, Montani D, et al. Inflammation in pulmonary arterial hypertension. Chest 2012; 141: 210-21. https://doi.org/10.1378/chest.11-0793
https://doi.org/10.1378/chest.11-0793...
. There appears to be an initial insult to the endothelium that leads to the propagation of an inflammatory process with the production of cytokines, culminating in vascular remodeling1010 Price LC, Wort SJ, Perros F, Dorfmüller P, Huertas A, Montani D, et al. Inflammation in pulmonary arterial hypertension. Chest 2012; 141: 210-21. https://doi.org/10.1378/chest.11-0793
https://doi.org/10.1378/chest.11-0793...
.
Therefore, understanding the etiology and mechanism of PAH in candidate patients for HTx and the contribution of the local inflammatory process to this condition can open up a new and promising field of research. The aim is to improve the clinical status of patients for HTx and, furthermore, increase the number of candidates for the procedure.
The cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor-alpha (TNF-α) are produced by monocytes/macrophages, endothelial cells and many other types of cells and have pro-inflammatory action1111 Jäättelä M. Biologic activities and mechanisms of action of tumor necrosis factor-alpha/cachectin. Lab Invest 1991; 64: 724-42. [acesso em 10 Jan. 2024]. Disponível em: https://pubmed.ncbi.nlm.nih.gov/1646350/
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,1212 Dinarello CA. Interleukin-1 and interleukin-1 antagonism. Blood 1991; 77(8): 1627-52. https://doi.org/10.1182/blood.V77.8.1627.1627
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. These cytokines may be particularly relevant to the pathogenesis of PAH1313 Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot-Keros L, et al. Increased interleukin-l and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 1995; 151(5). https://doi.org/10.1164/ajrccm.151.5.7735624
https://doi.org/10.1164/ajrccm.151.5.773...
. Cluster of differentiation 66b (CD66b) and 68 (CD68), respectively, markers of neutrophils and macrophages, are reported in patients with PAH1414 Savai R, Pullamsetti SS, Kolbe J, Bieniek E, Voswinckel R, Fink L, et al. Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2012; 186: 897-908. https://doi.org/10.1164/rccm.201202-0335OC
https://doi.org/10.1164/rccm.201202-0335...
,1515 Pugliese SC, Poth JM, Fini MA, Olschewski A, El Kasmi KC, Stenmark KR. The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes. Am J Physiol Lung Cell Mol Physiol 2015; 308: L229-52. https://doi.org/10.1152/ajplung.00238.2014
https://doi.org/10.1152/ajplung.00238.20...
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This study contributes to elucidating pathophysiological mechanisms involved in PAH associated with HTx.
OBJECTIVES
To evaluate the contribution of the local inflammatory process to the etiology of PAH in chagasic and non-chagasic patients who are candidates and undergo HTx.
METHODS
Were included 29 patients undergoing HTx at the Hospital das Clínicas of the Federal University of Minas Gerais (HC-UFMG) and the Hospital Santa Casa de Belo Horizonte from January 2021 to February 2023. The study’s sample size was carried out with a sample of convenience. It was impossible to collect pulmonary artery fragments from all patients undergoing HTx in these reference centers during the study period. The main factors that interfered with the experiments not being carried out were not specifically collecting the pulmonary artery, insufficient quantity of pulmonary arterial tissue for the experiments and resection of adipose tissue devoid of the vessel itself.
This study was approved by the UFMG Research Ethics Committee, CAAE: 39274420.0.0000.5149. All patients signed the free and informed consent form (ICF). It is a comparative cross-sectional study of parallel groups.
The clinical data of the study sample were collected through analysis of medical records accessed in the databases of the participating hospitals.
Inclusion criteria
Recipients who agreed to sign the informed consent form, patients of both sexes, aged 18 or over and with terminal cardiomyopathy undergoing HTx were included.
Exclusion criteria
Exclusion criteria covered patients with cancer, dementia, clinically diagnosable inflammatory process, type I diabetes mellitus, history of surgery or trauma in the last 4 weeks, pregnant women, autoimmune disease, known to have the human immunodeficiency virus, hepatitis C, hepatitis B and those who did not agree to sign the ICF.
PAH was measured by pulmonary manometry during right heart catheterization and by echocardiography performed preoperatively. The echocardiogram defined elevated pulmonary artery systolic pressure (PASP) as higher than 35 mmHg1616 McQuillan BM, Picard MH, Leavitt M, Weyman AE. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiographically normal subjects. Circulation 2001; 104: 2797-802. https://doi.org/10.1161/hc4801.100076
https://doi.org/10.1161/hc4801.100076...
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Pulmonary artery fragments were collected from recipients during cardiectomy and placed in vials with the lactated ringer.
The pulmonary artery was isolated, and the surrounding perivascular tissue was removed. Then, these segments were embedded in Tissue-Tek® OCT™ freezing medium (Sakura®, USA), and cross sections (10 μm) of the arteries were obtained using a cryostat. Slides were fixed in 4% paraformaldehyde solution for 15 minutes before immunofluorescence. CD68 and CD66b neutrophil counts were performed using the immunofluorescence technique. Fiji software (version 1.51j8) was used to quantify positive cells for labeling of interest and nucleus. The result was expressed as the number of positive cells per μm22 Bacal F, Marcondes-Braga FG, Rohde LEP, Xavier Júnior JL, Brito F de S, Moura LAZ, et al. 3a Diretriz Brasileira de Transplante Cardíaco. Arq Bras Cardiol 2018; 111(2): 230-89. https://doi.org/10.5935/abc.20180153
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of tissue.
The inflammatory cytokines IL-1β, TNF-α and IL-6 were quantified in pulmonary artery fragments. The immunosorbent assay technique [enzyme-linked immunosorbent assay (ELISA)] was used to quantify the concentration of TNF-α, IL-6 and IL-1β, as indicated in the instructions of the commercial kits (R&D Systems). Results were presented as picograms (pg) of protein per milliliter of tissue (pg/mL).
In this study, the descriptive measures median (Q2), quartiles (Q1 and Q3), mean, and standard deviation (SD) were presented to describe, respectively, the variables of the quantitative type of non-normal and normal distribution and absolute frequencies (n) and relative (%) as statistics to describe the results of categorical variables. Comparison of the distribution between the variable’s measurements (median, Q1 and Q3) was carried out using the Mann-Whitney tests. A value of p < 0.05 was considered significant.
RESULTS
Samples were collected from 29 patients undergoing HTx, 19 of whom were chagasic patients. Table 1 demonstrates the characteristics of the studied population. The patients’ age was 54.9 ± 9.1 years, 13 of whom were female. Their body mass index (BMI) was 23.1 ± 4.7.
Nineteen patients (65.5%) had chagasic cardiomyopathy; four had non-ischemic cardiomyopathy; three had ischemic cardiomyopathy (10.4%); one (3.4%) had congenital heart disease, and two had other etiologies (6.9%).
Clinical characteristics, expression of the inflammatory cytokines IL-1 β, TNF-α and IL-6 and counts of CD68 macrophages and CD66b neutrophils were evaluated in the pulmonary artery tissue of chagasic (HTx-C) and non-chagasic (HTx) heart transplant patients. -NC) (Table 2).
Descriptive and comparative analyses between HTx-C and HTx-NC recipients regarding clinical, echocardiographic, and manometric variables, number of cells per square micrometer and cytokine concentration (pg/mL).
The data in Table 2 demonstrate that there was no significant difference (p ≥ 0.05) between HTx-C and HTx-NC concerning physiological variables (age and BMI), echocardiographic, manometric and those referring to inflammatory markers.
Table 3 shows data on comparative inflammatory parameters between HTx concerning PAH measurement < 20 mmHg or ≥ 20 mmHg.
There was no statistically significant difference between interleukins when comparing the group with PAH and patients without PAH.
Descriptive and comparative analyses between HTx with mean PT ≥ 20 or mean PT < 20 regarding the number of cells per square micrometer and concentration of cytokines and HTx-C regarding the number of cells per square micrometer.
DISCUSSION
Preliminarily, quantitative analysis of the inflammatory cytokines IL-1 β, TNF-α and IL-6 and the count of CD68 macrophages and CD66b neutrophils in HTx pulmonary artery tissue were carried out. It is believed that the dosage of such inflammatory biomarkers in the pulmonary artery tissue better reflects the inflammatory process in the vessel than the analysis carried out in the plasma of surgical patients, which are known to be very elevated1717 Wan S, Marchant A, DeSmet J-M, Antoine M, Zhang H, Vachiery J-L, et al. Human cytokine responses to cardiac transplantation and coronary artery bypass grafting. J Thorac Cardiovasc Surg 1996; 111: 469-77. https://doi.org/10.1016/S0022-5223(96)70458-0
https://doi.org/10.1016/S0022-5223(96)70...
.
PAH is a condition associated with terminal HF that represents an additional challenge in the care of HTx patients22 Bacal F, Marcondes-Braga FG, Rohde LEP, Xavier Júnior JL, Brito F de S, Moura LAZ, et al. 3a Diretriz Brasileira de Transplante Cardíaco. Arq Bras Cardiol 2018; 111(2): 230-89. https://doi.org/10.5935/abc.20180153
https://doi.org/10.5935/abc.20180153...
. Different mechanisms can explain the pathophysiology of PAH in the setting of HF, but little research exists into the real effect of the local inflammatory process on the development of this serious problem.
Pulmonary vascular lesions occurring in patients with PAH and in animal models of pulmonary hypertension are characterized by varying degrees of perivascular inflammatory infiltrates, comprising T and B lymphocytes, macrophages, dendritic cells, and mast cells1818 Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 2014; 115: 165-75. https://doi.org/10.1161/CIRCRESAHA.113.301141
https://doi.org/10.1161/CIRCRESAHA.113.3...
. In addition to increased perivascular immune cells and intravascular infiltration, circulating levels of specific cytokines are abnormally elevated in PAH, including the cytokines IL-1β, IL-6, and TNF-α1818 Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 2014; 115: 165-75. https://doi.org/10.1161/CIRCRESAHA.113.301141
https://doi.org/10.1161/CIRCRESAHA.113.3...
. Increased pulmonary pressure is one of the most important predictors of death after HTx1919 Tei C, Dujardin KS, Hodge DO, Bailey KR, McGoon MD, Tajik AJ, et al. Doppler echocardiographic index for assessment of global right ventricular function. J Am Soc Echocardiogr 1996; 9: 838-47. https://doi.org/10.1016/S0894-7317(96)90476-9
https://doi.org/10.1016/S0894-7317(96)90...
, determining the importance of analyzing pulmonary arterial pressure and its pulmonary reactivity in the pre-transplant period1919 Tei C, Dujardin KS, Hodge DO, Bailey KR, McGoon MD, Tajik AJ, et al. Doppler echocardiographic index for assessment of global right ventricular function. J Am Soc Echocardiogr 1996; 9: 838-47. https://doi.org/10.1016/S0894-7317(96)90476-9
https://doi.org/10.1016/S0894-7317(96)90...
.
It is known that IL-6 is a pro-inflammatory cytokine that has a significant association with mortality in patients with PAH2020 Mogollón MV, Lage Gallé E, Hinojosa Pérez R, Herruzo Avilés A, Sobrino Márquez JM, Romero Rodríguez N, et al. Prognosis after heart transplant in patients with pulmonary hypertension secondary to cardiopathy. Transplant Proc 2008; 40: 3031-3. https://doi.org/10.1016/j.transproceed.2008.09.051
https://doi.org/10.1016/j.transproceed.2...
. Similar findings have been reported in patients with congestive HF2121 Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL. Cytokines and cytokine receptors in advanced heart failure. Circulation 2001; 103: 2055-9. https://doi.org/10.1161/01.CIR.103.16.2055
https://doi.org/10.1161/01.CIR.103.16.20...
, suggesting that IL-6 plays a role in the pathophysiology of HF and PAH2121 Deswal A, Petersen NJ, Feldman AM, Young JB, White BG, Mann DL. Cytokines and cytokine receptors in advanced heart failure. Circulation 2001; 103: 2055-9. https://doi.org/10.1161/01.CIR.103.16.2055
https://doi.org/10.1161/01.CIR.103.16.20...
. IL-1β is well recognized as clinically relevant in patients with hypertension2222 Dalekos GN, Elisaf M, Bairaktari E, Tsolas O, Siamopoulos KC. Increased serum levels of interleukin-1β in the systemic circulation of patients with essential hypertension: additional risk factor for atherogenesis in hypertensive patients? J Lab Clin Med 1997; 129: 300-8. https://doi.org/10.1016/S0022-2143(97)90178-5
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. Due to its essential role in inflammation, how IL-1β influences changes related to vascular pathology in hypertension has gained much interest and is currently being explored2323 Melton E, Qiu H. Interleukin-1β in multifactorial hypertension: inflammation, vascular smooth muscle cell and extracellular matrix remodeling, and non-coding RNA regulation. Int J Mol Sci 2021; 22: 8639. https://doi.org/10.3390/ijms22168639
https://doi.org/10.3390/ijms22168639...
. For example, recent reports suggest that IL-1β not only participates in the pro-inflammatory response in vessels but also influences the phenotype and functions of vascular smooth muscle cells and vascular remodeling in various types of hypertension through inflammation2424 Postlethwaite A, Raghow R, Stricklin G, Poppleton H, Seyer J, Kang A. Modulation of fibroblast functions by interleukin 1: increased steady-state accumulation of type I procollagen messenger RNAs and stimulation of other functions but not chemotaxis by human recombinant interleukin 1 alpha and beta. J Cell Biol 1988; 106: 311-8. https://doi.org/10.1083/jcb.106.2.311
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.
TNF-α is considered one of the main cytokines related to inflammatory and immune processes2525 Vitale RF, Ribeiro F de AQ. O papel do fator de necrose tumoral alfa (TNF-alfa) no processo de erosão óssea presente no colesteatoma adquirido da orelha média. Braz J Otorhinolaryngol 2007; 73: 123-7. https://doi.org/10.1590/S0034-72992007000100020
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, directly influencing the adhesion of circulating inflammatory cells in tissues2626 Gao X, Zhang H, Belmadani S, Wu J, Xu X, Elford H, et al. Role of TNF-α-induced reactive oxygen species in endothelial dysfunction during reperfusion injury. Am J Physiol - Heart and Circulatory Physiology 2008; 295: H2242-9. https://doi.org/10.1152/ajpheart.00587.2008
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. Studies showed that TNF-α was notably higher in PAH2727 Zhu T, Zhang W, Yin Y, Liu Y, Song P, Xu J, et al. MicroRNA-140-5p targeting tumor necrosis factor-α prevents pulmonary arterial hypertension. J Cell Physiol 2019; 234: 9535-50. https://doi.org/10.1002/jcp.27642
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; however, our study did not corroborate this fact.
Recent research has evaluated the role of perivascular macrophages infiltrating pulmonary arterioles in PAH1818 Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 2014; 115: 165-75. https://doi.org/10.1161/CIRCRESAHA.113.301141
https://doi.org/10.1161/CIRCRESAHA.113.3...
. CD68 macrophages are prominent in advanced plexiform obliterans lesions observed in experimental and clinical studies of PAH2828 Tuder RM, Groves B, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol 1994; 144: 275-85. [acesso em 05 Fev 2024]. Disponível em: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1887146/
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,2929 Vergadi E, Chang MS, Lee C, Liang OD, Liu X, Fernandez-Gonzalez A, et al. Early macrophage recruitment and alternative activation are critical for the later development of hypoxia-induced pulmonary hypertension. Circulation 2011; 123: 1986-95. https://doi.org/10.1161/CIRCULATIONAHA.110.978627
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, and depletion or inactivating macrophages prevents PAH in several experimental study models3030 Thenappan T, Goel A, Marsboom G, Fang Y-H, Toth PT, Zhang HJ, et al. A central role for CD68(+) macrophages in hepatopulmonary syndrome. Am J Respir Crit Care Med 2011; 183: 1080-91. https://doi.org/10.1164/rccm.201008-1303OC
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,3131 Tian W, Jiang X, Tamosiuniene R, Sung YK, Qian J, Dhillon G, et al. Blocking macrophage leukotriene B4 prevents endothelial injury and reverses pulmonary hypertension. Sci Transl Med 2013; 5(200): 200ra117. https://doi.org/10.1126/scitranslmed.3006674
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. M1-type macrophages amplify inflammation by secreting pro-inflammatory factors, while M2-type macrophages promote inflammation and tissue repair, playing an essential role in pulmonary vascular remodeling3232 Funes SC, Rios M, Escobar-Vera J, Kalergis AM. Implications of macrophage polarization in autoimmunity. Immunology 2018; 154: 186-95. https://doi.org/10.1111/imm.12910
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Neutrophils are the most abundant type of white blood cells in human circulation3333 Prausmüller S, Spinka G, Stasek S, Arfsten H, Bartko PE, Goliasch G, et al. Neutrophil activation/maturation markers in chronic heart failure with reduced ejection fraction. Diagnostics 2022; 12: 444.. In contrast to monocytes and macrophages, neutrophils are traditionally considered bystanders of cardiovascular disease, but studies in recent years have demonstrated important functional roles of neutrophils in inflammation and cardiovascular repair3434 Swirski FK, Nahrendorf M. Cardioimmunology: the immune system in cardiac homeostasis and disease. Nat Rev Immunol 2018; 18: 733-44. https://doi.org/10.1038/s41577-018-0065-8
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,3535 Silvestre-Roig C, Braster Q, Ortega-Gomez A, Soehnlein O. Neutrophils as regulators of cardiovascular inflammation. Nat Rev Cardiol 2020; 17: 327-40. https://doi.org/10.1038/s41569-019-0326-7
https://doi.org/10.1038/s41569-019-0326-...
. CD66b is a marker of neutrophil activation3636 Torsteinsdottir I, Arvidson N-G, Hallgren R, Hakansson L. Enhanced expression of integrins and CD66b on peripheral blood neutrophils and eosinophils in patients with rheumatoid arthritis, and the effect of glucocorticoids. Scand J Immunol 1999; 50: 433-9. https://doi.org/10.1046/j.1365-3083.1999.00602.x
https://doi.org/10.1046/j.1365-3083.1999...
.
This research demonstrated that the median mean pressure measured in the pulmonary artery trunk by manometry was 25.3 (19.3-35.0) in chagasic patients and 31.0 (20.9-49.3) in those with non-chagasic patients. When comparing the various pressure parameters measured by right heart catheterization and echocardiography, there was no significant difference between their levels and the fact that the patients were HTx-C and HTx-NC (Table 2). Gelape et al.88 Gelape CL, Nunes M do CP, Bráulio R, Nogueira PH, Andrade SA de, Machado PAB, et al. Pressão pulmonar aferida pela ecocardiografia em pacientes chagásicos indicados para transplante cardíaco. Braz J Cardiovasc Surg 2011; 26(1). https://doi.org/10.1590/S0102-76382011000100012
https://doi.org/10.1590/S0102-7638201100...
found lower pulmonary vascular resistance (PVR) levels based on hemodynamic parameters in patients with Chagas cardiomyopathy, a fact not identified in this study.
The HTx studied here had increased levels of the cytokines IL-1 β, TNF-α and IL-6, regardless of whether the etiology was chagasic (Table 2). This suggests that these inflammatory markers participate in the HF pathophysiological process. This data indicates that the etiology of cardiomyopathy does not influence the different levels of inflammatory cytokines.
Furthermore, we did not find significant differences in the tissue levels of IL-1 β, TNF-α, IL-6, CD66b and CD68 when comparing HTx patients with and without PAH (Table 3). It was also observed that HTx-C with and without PAH presented the same number of CD66b and CD68 inflammatory cells in the tissue. These data suggest that the pathophysiological mechanism of PAH is more related to HF than the inflammatory response.
Patients with advanced HF often develop an increase in pulmonary pressure through a retrograde mechanism.3737 Mogollón MV, Lage Gallé E, Hinojosa Pérez R, Herruzo Avilés A, Sobrino Márquez JM, Romero Rodríguez N, et al. Prognosis after heart transplant in patients with pulmonary hypertension secondary to cardiopathy. Transplant Proc 2008; 40: 3031-3. https://doi.org/10.1016/j.transproceed.2008.09.051
https://doi.org/10.1016/j.transproceed.2...
Left ventricular dysfunction causes an increase in end-diastolic pressure transmitted to the pulmonary vascular bed, increasing venous pressure3737 Mogollón MV, Lage Gallé E, Hinojosa Pérez R, Herruzo Avilés A, Sobrino Márquez JM, Romero Rodríguez N, et al. Prognosis after heart transplant in patients with pulmonary hypertension secondary to cardiopathy. Transplant Proc 2008; 40: 3031-3. https://doi.org/10.1016/j.transproceed.2008.09.051
https://doi.org/10.1016/j.transproceed.2...
. Over time, vascular vasoconstriction and, subsequently, pathological restructuring occur with increased cell proliferation and hypertrophy associated with intimal fibrosis88 Gelape CL, Nunes M do CP, Bráulio R, Nogueira PH, Andrade SA de, Machado PAB, et al. Pressão pulmonar aferida pela ecocardiografia em pacientes chagásicos indicados para transplante cardíaco. Braz J Cardiovasc Surg 2011; 26(1). https://doi.org/10.1590/S0102-76382011000100012
https://doi.org/10.1590/S0102-7638201100...
. Up to a third of patients develop PAH88 Gelape CL, Nunes M do CP, Bráulio R, Nogueira PH, Andrade SA de, Machado PAB, et al. Pressão pulmonar aferida pela ecocardiografia em pacientes chagásicos indicados para transplante cardíaco. Braz J Cardiovasc Surg 2011; 26(1). https://doi.org/10.1590/S0102-76382011000100012
https://doi.org/10.1590/S0102-7638201100...
.
It is known that chronic HF activates the immune system and inflammatory responses characterized by elevated levels of circulating pro-inflammatory cytokines3838 Adamo L, Rocha-Resende C, Prabhu SD, Mann DL. Reappraising the role of inflammation in heart failure. Nat Rev Cardiol 2020; 17: 269-85. https://doi.org/10.1038/s41569-019-0315-x
https://doi.org/10.1038/s41569-019-0315-...
,3939 Marra AM, Arcopinto M, Salzano A, Bobbio E, Milano S, Misiano G, et al. Detectable interleukin-9 plasma levels are associated with impaired cardiopulmonary functional capacity and all-cause mortality in patients with chronic heart failure. Int J Cardiol 2016; 209: 114-7. https://doi.org/10.1016/j.ijcard.2016.02.017
https://doi.org/10.1016/j.ijcard.2016.02...
. Inflammation and immune cells participate in both acute myocyte injury and chronic HF4040 Van Linthout S, Tschöpe C. Inflammation – cause or consequence of heart failure or both? Curr Heart Fail Rep 2017;14:251-65. https://doi.org/10.1007/s11897-017-0337-9
https://doi.org/10.1007/s11897-017-0337-...
. Inflammatory factors such as TNF-α, IL-1β and IL-6 are increased in patients with HF4040 Van Linthout S, Tschöpe C. Inflammation – cause or consequence of heart failure or both? Curr Heart Fail Rep 2017;14:251-65. https://doi.org/10.1007/s11897-017-0337-9
https://doi.org/10.1007/s11897-017-0337-...
. Small animal models of myocarditis and pressure overload suggest immune activation during HF4141 Carrillo-Salinas FJ, Ngwenyama N, Anastasiou M, Kaur K, Alcaide P. Heart inflammation. Am J Pathol 2019; 189: 1482-94. https://doi.org/10.1016/j.ajpath.2019.04.009
https://doi.org/10.1016/j.ajpath.2019.04...
. Such arguments may justify the levels of inflammatory markers being similar in HTx recipients despite the diagnosis of PAH.
CONCLUSION
We observed that HTx-C and HTx-NC, with or without PAH, presented similar levels of inflammatory markers expressed in the pulmonary arteries, which suggests that the mechanism of PAH is more associated with HF itself than with the inflammatory response secondary to associated cardiomyopathy. In this study, Chagas cardiomyopathy, even though it is a disease with a very evident and proven local inflammatory substrate, does not present higher levels of PAH and local inflammation compared to other HF etiologies.
ACKNOWLEDGEMENT
Not applicable.
-
FUNDING
Fundação de Apoio à Pesquisa do Estado de Minas GeraisGrant N.° APQ-01480-21Conselho Nacional de Desenvolvimento Científico e TecnológicoGrant N.°s 311643/2022-1; 406097/2021-6
DATA AVAILABILITY STATEMENT
All dataset were generated or analyzed in the current study.
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38Adamo L, Rocha-Resende C, Prabhu SD, Mann DL. Reappraising the role of inflammation in heart failure. Nat Rev Cardiol 2020; 17: 269-85. https://doi.org/10.1038/s41569-019-0315-x
» https://doi.org/10.1038/s41569-019-0315-x -
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» https://doi.org/10.1007/s11897-017-0337-9 -
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Publication Dates
-
Publication in this collection
12 Aug 2024 -
Date of issue
2024
History
-
Received
26 Jan 2024 -
Accepted
11 June 2024