Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT04432337 |
| Other study ID # |
19_RIPH2-15 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2021 |
| Est. completion date |
March 1, 2021 |
Study information
| Verified date |
July 2023 |
| Source |
University Hospital Center of Martinique |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Adult cardiac surgery ensures the surgical treatment of valvular and coronary pathologies and
of heart failure with the placement of ventricular assistance. Extracorporeal circulation
(ECC) is one of the major technical advances associated with cardiac surgery to replace
cardiac and pulmonary functions during surgery. ECC can nevertheless lead to postoperative
complications, the origin of which is linked to the patient's initial contact with the
circuit and membranes of the ECC. This contact triggers a series of humoral and cellular
reactions that occur in the first few hours after the ECC and the inflammatory syndrome post
ECC fades on its own and usually disappears between the 4th and 6th postoperative day. If the
inflammatory response post ECC is most often transient, certain conditions will maintain and
intensify this response at the origin of postoperative complications, possibly leading to the
patient's death. Among these situations, the investigators find the notion of emergency
cardiac surgery, a patient's age over 75 years and a preoperative history of decompensated
heart failure, renal failure or type 2 diabetes (T2D).
The inflammasome family of receptors of the nucleotide oligomerization domain (NOD) type,
pyrin domain containing 3, NLRP3, is a multi-protein platform of recent discovery which plays
a major role in the signaling pathways of the innate inflammatory response.
The role of the activation of the NLRP3 inflammasome in cardiovascular pathologies is now
well established and its metabolic priming by hyperglycemia could explain the greater
seriousness of these pathologies in T2D patients due to an exacerbated inflammatory response.
What is the effect of T2D status on the inflammatory response post ECC, mediated by the NLRP3
inflammasome, in patients after cardiac surgery?
Description:
Adult cardiac surgery provides surgical treatment of valvular, coronary, and heart failure
pathologies with the installation of ventricular assistance. Extracorporeal circulation (ECC)
is one of the major technical advances associated with cardiac surgery to replace cardiac and
pulmonary functions during surgery. However, ECC can lead to postoperative complications, the
origin of which is linked to the patient's initial contact with the circuit and membranes of
the ECC. This contact triggers a series of humoral and cellular reactions such as activation
of the plasma contact system and complement, coagulation and fibrinolysis, activation of
endothelial cells and leukocytes, as well as the release into the circulating blood of many
mediators of inflammation such as cytokines TNF-α, interleukin IL -1β, interleukin IL6 and
interleukin IL8. These reactions occur in the first hours after the ECC and the inflammatory
syndrome post ECC fades by itself and usually disappears between the 4th and 6th
postoperative day. Different technical and pharmacological modalities (biocompatibility of
circuits, hemofiltration, leukocyte filter, antioxidants, anti-inflammatories, corticoids)
have helped reduce the inflammatory syndrome post ECC, but their partial effectiveness
highlights the need to better understand the molecular mechanisms of inflammation. post ECC
in order to improve its prevention.
If the inflammatory response post ECC is most often transient, certain conditions will
maintain and intensify this response at the origin of postoperative complications, possibly
leading to the patient's death. Among these situations, The investigators find the notion of
emergency cardiac surgery, a patient's age> 75 years and a preoperative history of
decompensated heart failure, renal failure or type 2 diabetes (T2D).
Defined according to the criteria proposed by the World Health Organization (WHO) and the
American Diabetes Association (ADA), DT2 is a major independent risk factor for morbidity and
mortality from general surgery, and from surgery especially the heart. The risk of
cardiovascular and infectious complications after cardiac surgery in T2D patients increases
by 17% for each unit of glycemia above 6 mmol / L. Strict control of blood sugar during the
perioperative phase, however, significantly reduces the risk of complications in T2D
patients. Physiopathologically, the higher incidence of postoperative complications in T2D
patients is attributed to the exacerbation of the postoperative inflammatory response and its
deleterious effects on vascular function. A recent study confirms that the expression of
messenger RNAs coding for the inflammation genes (IL-1β, IL8) and the transitional activation
factors (MYC / JUN) is increased in T2D patients and that this chronic state of low grade
preoperative would promote deregulation of the inflammatory response after cardiac surgery,
and the occurrence of cardiovascular complications. The level of inflammation in T2D patients
is also usually reflected by an increase in plasma levels of proteins in the acute phase of
inflammation (C-reactive protein CRP, in particular) and other pro-inflammatory cytokines
(TNF-α IL6). These different results suggest that the activation of the NOD-like receptor
family pyrin domain containing 3, (NLRP3) inflammasome may play a central role in low-level
chronic inflammatory status in T2D patients.
The inflammasome NOD-like receptor family pyrin domain containing 3, NLRP3, is a
multi-protein platform whose activation is involved in the signaling pathways of the innate
inflammatory response in many inflammatory and infectious diseases, as well as metabolic
pathologies like gout and type 2 diabetes. The assembly of the NLRP3 inflammasome results in
the activation of inflammatory caspases allowing the cleavage of the pro-cytokines IL-1β and
IL-18 into mature and active cytokines. Several studies show that T2D hyperglycemia is a
pre-activation or priming factor for NLRP3 which potentiates the secondary activation of
NLRP3 and the synthesis of the interleukins of IL-1β and IL18. During T2D, other metabolic
signals such as the accumulation of free fatty acids, the release of cellular debris
(damage-associated molecular patterns, DAMPs), and reactive oxygen species (ROS) are also
responsible for the priming of NLRP3. Among the molecular motifs DAMPs, mitochondrial DNA
(mtDNA) is a powerful activator of the NLRP3 inflammasome due to the ancestral bacterial
origin of mitochondria.
The role of the activation of the NLRP3 inflammasome in cardiovascular pathologies is now
well established and its metabolic priming by hyperglycemia could explain the greater
seriousness of these pathologies in T2D patients due to an exacerbated inflammatory response.
Currently, there is no human data on the role of NLRP3 inflammasome activation in post-ECC
inflammatory syndrome. The investigators envision that the extracorporeal circulation (ECC),
responsible for cellular damage, is accompanied by a release of molecular patterns of DAMPs
type at the origin of the activation of the NLRP3 inflammasome.
