Ignite Creation Date:
2024-05-06 @ 8:16 PM
Last Modification Date:
2024-10-26 @ 3:23 PM
Study NCT ID:
NCT06313645
Status:
RECRUITING
Last Update Posted:
2024-03-19
First Post:
2024-03-11
Brief Title:
Vascular Senescence and Atherosclerotic Plaque Vulnerability
Sponsor:
Niguarda Hospital
Organization:
Niguarda Hospital
Study Overview
Official Title:
Cellular and Molecular Mechanisms of Vascular Senescence and atherosclerotIC Plaque Vulnerability the TelOmere-mitochondRIa Cross-tAlk Study
Status:
RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
VICTORIA
Brief Summary:
Chronological aging significantly contributes to structural and functional alterations in the vasculature making it a major risk factor for atherosclerotic disease and its acute thrombotic events DNA damage including telomeric non-telomeric and mitochondrial damage is recognized as a key initiator of vascular aging and atherogenesis There is abundant evidence indicating the presence of oxidative DNA lesions telomere erosion and mitochondrial DNA damage in both experimental and human plaques as well as in the peripheral cells of atherosclerotic patients
It is increasingly evident that genomic instability activates signaling pathways that lead to a multitude of pathophysiological cellular and molecular changes These changes promote inflammation apoptosis autophagy and ultimately cellular senescence accompanied by the senescence-associated secretory phenotype SASP However the precise mechanisms linking the DNA damage response DDR to senescence SASP in vascular cells and the pathogenesis of atherosclerosis and vulnerable atheroma are yet to be fully understood Additional research is needed to delineate the underlying mechanisms through which mitochondrial dysfunction influences telomere length and vice versa and how their interaction contributes to the vascular aging process Progress in this area has the potential to uncover therapeutic targets and novel more precise diagnostic and prognostic indicators
The objectives of the VICTORIA study are to examine the levels of aging-related non-coding RNA deregulation specifically lncRNA TERRA and mitomiR and peripheral markers of cell aging including telomere length and mitochondrial DNA content across the various spectra of angina pectoris stable angina unstable angina NSTEMI and STEMI Additionally the study aims to determine whether these markers are correlated with vulnerable plaque characteristics and major adverse cardiovascular events
It is increasingly evident that genomic instability activates signaling pathways that lead to a multitude of pathophysiological cellular and molecular changes These changes promote inflammation apoptosis autophagy and ultimately cellular senescence accompanied by the senescence-associated secretory phenotype SASP However the precise mechanisms linking the DNA damage response DDR to senescence SASP in vascular cells and the pathogenesis of atherosclerosis and vulnerable atheroma are yet to be fully understood Additional research is needed to delineate the underlying mechanisms through which mitochondrial dysfunction influences telomere length and vice versa and how their interaction contributes to the vascular aging process Progress in this area has the potential to uncover therapeutic targets and novel more precise diagnostic and prognostic indicators
The objectives of the VICTORIA study are to examine the levels of aging-related non-coding RNA deregulation specifically lncRNA TERRA and mitomiR and peripheral markers of cell aging including telomere length and mitochondrial DNA content across the various spectra of angina pectoris stable angina unstable angina NSTEMI and STEMI Additionally the study aims to determine whether these markers are correlated with vulnerable plaque characteristics and major adverse cardiovascular events
Detailed Description:
Background - The process of chronological aging significantly contributes to structural and functional changes within the vasculature emerging as a major risk factor for atherosclerotic disease and acute thrombotic events Furthermore age-related vascular deterioration can be influenced by lifestyle choices environmental factors and external stimuli resulting in a gradual decline in vascular integrity and functionality
In order to identify potential targets for therapeutic intervention to delay or reverse the deleterious consequences of vascular aging it is crucial to better understand the cellular and molecular mechanisms of vascular aging as well as to better define how environmental factors can accelerate the process
Over the past decades DNA damage-both telomeric and non-telomeric alongside mitochondrial impairments-has emerged as a pivotal trigger in vascular aging and the development of atherosclerosis A wealth of evidence supports the presence of oxidative DNA lesions telomere attrition and mitochondrial DNA damage in both experimental models and human plaque samples as well as in the peripheral cells of individuals with atherosclerosis
Moreover it is increasingly evident that genomic instability can directly impact vascular cellular function by triggering signaling pathways that lead to a multitude of pathophysiological changes These changes encompass inflammation apoptosis autophagy and ultimately cellular senescence which is marked by the secretion of the senescence-associated secretory phenotype SASP The robust mechanistic association between DNA damage and cellular aging underscores DNA damage as a prime candidate for the primary cause of aging Targeting DNA damage and its mechanistic correlates may provide a logical basis for the development of unified interventions aimed at mitigating age-related dysfunction and disease
Nevertheless the precise mechanisms linking DNA damage to SASP in vascular cells as well as its role in the pathogenesis of atherosclerosis and vulnerable atheroma remain elusive
Recent evidence underscores mutual crosstalk between telomere dysfunction and mitochondrial dysmetabolism in the process of cellular senescence 23-26 emphasizing the need to further elucidate this complex and intricate connection which can open new potential therapeutic strategies for age-related disease
Further studies are warranted to understand the underlying mechanisms by which mitochondrial dysfunction influences telomere length and vice versa and how their interplay contributes to the process of vascular aging
We hypothesize that complex molecular mechanisms that link telomere dysfunction mtDNA damage and non-coding RNA deregulation are involved in the process of vascular aging promoting the development and progression of atherosclerosis Consequently peripheral aging markers of genetic damage and non-coding RNA may be useful to characterize the development of a vulnerable plaque in culprit vessels and to improve the prognosis of patients
Aims - The specific aims of the present proposal are 1 to investigate the association between peripheral markers of cell aging telomere length LTL and mitochondrial DNA mtDNAcn content and non-coding RNA deregulation lncRNA TERRA MitomiR in the different spectra of angina pectoris stable angina unstable NSTEMI and STEMI and 2 to evaluate their association with major adverse cardiovascular events MACE within 12 months of enrolment
Patients with cardiac shock congestive heart failure end-stage renal disease and coronary artery bypass graft will be excluded An accurate evaluation of the plaque morphology will be acquired for patients who will be screened for optical coherence tomography OCT examination or intravascular ultrasound IVUS of the culprit artery
Study design - Prospective single center non-randomized observational study Sample and data collection - A peripheral blood sample approximately 10 mL will be collected in each patient before undergoing diagnostic or therapeutic angiography procedures and used for the extraction of DNA andor RNA A biobank of other biological samples whole blood plasma serum clot PBMCs will be established Approximately 12 months after enrollment a clinical follow-up will be performed for all patients enrolled in the study through a routine medical visit or telephone interview to evaluate adverse cardiovascular events MACE - death myocardial infarction or need for subsequent revascularizations
Biomarkers determination - LTL and mtDNAcn are measured after DNA extraction from blood leucocytes while lnc-RNA TERRA and mitomiR after RNA extraction from blood leucocytes and analyzed using Real-Time PCR techniques
Sample size - To detect a medium effect size f 025 in the difference of the mean LTL value between the groups we estimate that a sample size of at least 232 total patients is required with an alpha level of 005 and a power of 90 or higher Accounting for a 10 dropout rate the total number of patients to be enrolled should be at least 260
Statistical analysis - The normal distribution of the data will be tested using the Kolmogorov-Smirnov test
Continuous variables will be presented as mean standard deviation median first and third quartile Categorical variables will be expressed as numbers and percentages
Comparisons between two groups will be performed using the Students t test for independent samples for continuous variables and the chi-square test or Fishers exact test for categorical ones Comparisons between more than two groups will be tested with the one-way analysis of variance ANOVA followed by Bonferroni post-hoc tests for 2-group comparisons If the assumption of normality of the data distribution is not satisfied the equivalent non-parametric tests will be used The Pearson or Spearman coefficient will be calculated to investigate the correlation between the variables in a univariate way Event-free survival curves will be constructed using the Kaplan-Meier model and tested with the log-rank test between different groups The univariate and multivariate Cox proportional hazards model will be used to identify the predictive value of each variable against the MACE event the data will be expressed with HR and their 95 confidence interval
In order to identify potential targets for therapeutic intervention to delay or reverse the deleterious consequences of vascular aging it is crucial to better understand the cellular and molecular mechanisms of vascular aging as well as to better define how environmental factors can accelerate the process
Over the past decades DNA damage-both telomeric and non-telomeric alongside mitochondrial impairments-has emerged as a pivotal trigger in vascular aging and the development of atherosclerosis A wealth of evidence supports the presence of oxidative DNA lesions telomere attrition and mitochondrial DNA damage in both experimental models and human plaque samples as well as in the peripheral cells of individuals with atherosclerosis
Moreover it is increasingly evident that genomic instability can directly impact vascular cellular function by triggering signaling pathways that lead to a multitude of pathophysiological changes These changes encompass inflammation apoptosis autophagy and ultimately cellular senescence which is marked by the secretion of the senescence-associated secretory phenotype SASP The robust mechanistic association between DNA damage and cellular aging underscores DNA damage as a prime candidate for the primary cause of aging Targeting DNA damage and its mechanistic correlates may provide a logical basis for the development of unified interventions aimed at mitigating age-related dysfunction and disease
Nevertheless the precise mechanisms linking DNA damage to SASP in vascular cells as well as its role in the pathogenesis of atherosclerosis and vulnerable atheroma remain elusive
Recent evidence underscores mutual crosstalk between telomere dysfunction and mitochondrial dysmetabolism in the process of cellular senescence 23-26 emphasizing the need to further elucidate this complex and intricate connection which can open new potential therapeutic strategies for age-related disease
Further studies are warranted to understand the underlying mechanisms by which mitochondrial dysfunction influences telomere length and vice versa and how their interplay contributes to the process of vascular aging
We hypothesize that complex molecular mechanisms that link telomere dysfunction mtDNA damage and non-coding RNA deregulation are involved in the process of vascular aging promoting the development and progression of atherosclerosis Consequently peripheral aging markers of genetic damage and non-coding RNA may be useful to characterize the development of a vulnerable plaque in culprit vessels and to improve the prognosis of patients
Aims - The specific aims of the present proposal are 1 to investigate the association between peripheral markers of cell aging telomere length LTL and mitochondrial DNA mtDNAcn content and non-coding RNA deregulation lncRNA TERRA MitomiR in the different spectra of angina pectoris stable angina unstable NSTEMI and STEMI and 2 to evaluate their association with major adverse cardiovascular events MACE within 12 months of enrolment
Patients with cardiac shock congestive heart failure end-stage renal disease and coronary artery bypass graft will be excluded An accurate evaluation of the plaque morphology will be acquired for patients who will be screened for optical coherence tomography OCT examination or intravascular ultrasound IVUS of the culprit artery
Study design - Prospective single center non-randomized observational study Sample and data collection - A peripheral blood sample approximately 10 mL will be collected in each patient before undergoing diagnostic or therapeutic angiography procedures and used for the extraction of DNA andor RNA A biobank of other biological samples whole blood plasma serum clot PBMCs will be established Approximately 12 months after enrollment a clinical follow-up will be performed for all patients enrolled in the study through a routine medical visit or telephone interview to evaluate adverse cardiovascular events MACE - death myocardial infarction or need for subsequent revascularizations
Biomarkers determination - LTL and mtDNAcn are measured after DNA extraction from blood leucocytes while lnc-RNA TERRA and mitomiR after RNA extraction from blood leucocytes and analyzed using Real-Time PCR techniques
Sample size - To detect a medium effect size f 025 in the difference of the mean LTL value between the groups we estimate that a sample size of at least 232 total patients is required with an alpha level of 005 and a power of 90 or higher Accounting for a 10 dropout rate the total number of patients to be enrolled should be at least 260
Statistical analysis - The normal distribution of the data will be tested using the Kolmogorov-Smirnov test
Continuous variables will be presented as mean standard deviation median first and third quartile Categorical variables will be expressed as numbers and percentages
Comparisons between two groups will be performed using the Students t test for independent samples for continuous variables and the chi-square test or Fishers exact test for categorical ones Comparisons between more than two groups will be tested with the one-way analysis of variance ANOVA followed by Bonferroni post-hoc tests for 2-group comparisons If the assumption of normality of the data distribution is not satisfied the equivalent non-parametric tests will be used The Pearson or Spearman coefficient will be calculated to investigate the correlation between the variables in a univariate way Event-free survival curves will be constructed using the Kaplan-Meier model and tested with the log-rank test between different groups The univariate and multivariate Cox proportional hazards model will be used to identify the predictive value of each variable against the MACE event the data will be expressed with HR and their 95 confidence interval
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None