Clinical trial NCT05806411: Calcific Aortic Valve Disease:the Role of Bacteria as Trigger of a Chronic Inflammation
Official title: Calcific Aortic Valve Disease: a Multidisciplinary Approach to Investigate the Role of Bacteria as Trigger of a Chronic Inflammation in the Pathogenesis of Calcification
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Calcific Aortic Valve Diasease
Keywords: Calcific aortic valve disease
Lead sponsor: Fondazione IRCCS Policlinico San Matteo di Pavia
Sponsor class: OTHER
Collaborators: name: University of Pavia
First posted: 2023-04-10
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with calcific aortic sclerosis (stage III and IV) that are going to be treated with traditional surgery according to International Guidelines will be enrolled as cases.

Brief summary: Calcific aoric valve disease (CAVD) is extremely common worldwide, affecting almost 50% of the population over 85 years of age, with a lethality higher than 50% at 2 years for symptomatic patients, unless aortic-valve replacement is performed. CAVD is characterized by slowly progressive fibro-calcific remodelling of the valve leaflets causing aortic stenosis. The spectrum of the disease progression starts with leaflet degeneration and progresses from early lesions to valve stenosis/obstruction, which is initially mild to moderate but eventually becomes severe. Risk factors for CAVD partly overlap those for atherosclerosis but also intake age-related tissue changes and effects of comorbiditiies (e.g. renal failure) in the overall complex mechanisms of valve leaflet degeneration, which is, at present, unpreventable, leaving aortic valve repair the only treatment option for severe aortic stenosis. In the first phase of the disease the valve becomes thickened and mildly calcified, then the disease evolves to severe valve calcification with impaired leaflet motion and vast blood flow obstruction. Calcific AS valves show advanced osteogenic metaplasia with the presence of osteoblast-like cells and chondrocytes associated with dense inflammatory infiltrates. Bacteria have been detected in the absence of diagnosis of acute infective endocarditis, but their role is still unknown. Different bacterial species (C. acnes (59%), E. faecalis (16%), S. aureus (15%), and S. pyogenes (10%)) have been typed and intramural bacterial colonization has been observed in patients with calcified structural valvular heart disease. Indeed, it has been recently demonstrated that bacterial infections can directly affect osteoblast differentiation/activation.

The Authors hypothesized that a subclinical or latent valvular bacterial infiltration facilitates a chronic inflammation and contributes to accelerated structural valve degeneration. An interdisciplinary team has been established to investigate the infective, biochemical and structural features of calcific aortic valve disease.

Detailed description: The primary objective of the study is to dissect the bacteria contribution to valve calcification. The Authors hypothesized that a subclinical or latent valvular bacterial infiltration facilitates a chronic inflammation and contributes to accelerated structural valve degeneration. The Authors expect to find a correlation between bacterial detection (as qualitative -positive/negative, quantitative -quantitative PCR) and bone calcification markers on valves. To dissect the bacteria contribution to valve calcification, the osteogenic differentiation capabilities of primary cells obtained from cusp explanted from control and from non-calcified cusp of CAVD patients will be assessed in vitro in absence and in presence of bacterial infection. There are currently no data in the literature that can be referred to for the calculation of the sample size. Cusp calcifications do not equally affect all cusps, considering calcified cusp as cases and non-calcified cusp of the same valve as matched controls, if the probability of bacterial detection among sampled control non calcified cusps is 10% (Cohen, doi: 10.1016/S0003-4975(03)01454-1), a sample of 32 patients (with 32 calcified cusp and 96cusps) can be enrolled. This sample of 96 cusps achieves 81% power to detect an odds ratio of 5.00 versus the alternative of equal odds using a McNemar test with a 0.05 significance level. This calculation is done considering that the probability of bacterial detection in each cusp is almost independent from other cusps of the same valve (intra-valve correlation coefficient= 0.10). The Authors expect a total study duration of 24 months. The Authors estimate to complete recruitment in 12 months. The estimated primary completion is month 15 (3 months after last subject enrollment) and study completion on month 24 (12 months after last patient inclusion)

Eligibility criteria: Inclusion Criteria:

* Age\>18 years.
* Calcific aortic sclerosis (stage III and IV)

Exclusion Criteria:

- Inability to comply with the requirements of the protocol.

Primary outcomes:
measure: To analyze subclinical or latent valvular bacterial infiltration in patients with calcific aortic disease
timeFrame: 2 years
measure: To evaluate the correlation between bacterial detection (as qualitative-positive/negative-, quantitative -quantitative PCR-) and bone calcification markers on valves
timeFrame: 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San MAtteo
Study officials:
affiliation: Fondazione IRCCS Policlinico San MAtteo
name: Elena Seminari, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Oberbach A, Schlichting N, Friedrich M, Lehmann S, Kullnick Y, Pichlmaier M, Hagl C, Bagaev E; CardiOmics group; Clinical Microbiology group; Clinical Management group. Quantification of Multiple Bacteria in Calcified Structural Valvular Heart Disease. Semin Thorac Cardiovasc Surg. 2020 Summer;32(2):255-263. doi: 10.1053/j.semtcvs.2019.10.003. Epub 2019 Oct 9.
citation: Kwon Y, Park C, Lee J, Park DH, Jeong S, Yun CH, Park OJ, Han SH. Regulation of Bone Cell Differentiation and Activation by Microbe-Associated Molecular Patterns. Int J Mol Sci. 2021 May 28;22(11):5805. doi: 10.3390/ijms22115805.
citation: Cohen DJ, Malave D, Ghidoni JJ, Iakovidis P, Everett MM, You S, Liu Y, Boyan BD. Role of oral bacterial flora in calcific aortic stenosis: an animal model. Ann Thorac Surg. 2004 Feb;77(2):537-43. doi: 10.1016/S0003-4975(03)01454-1.
citation: Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation. 2005 Jun 21;111(24):3316-26. doi: 10.1161/CIRCULATIONAHA.104.486738. No abstract available.