scholarly journals Telomerase Activation to Reverse Immunosenescence in Elderly Patients With Acute Coronary Syndrome: Protocol for a Randomized Pilot Trial (Preprint)

2020 ◽  
Author(s):  
Rebecca Maier ◽  
Bilal Bawamia ◽  
Karim Bennaceur ◽  
Sarah Dunn ◽  
Leanne Marsay ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
European Union ◽  
Clinical Trials ◽  
T Cells ◽  
Acute Coronary Syndrome ◽  
Elderly Patients ◽  
Endothelial Function ◽  
Telomere Length ◽  
Pilot Trial ◽  
Coronary Syndrome

BACKGROUND Inflammation plays a key role in the pathophysiology of coronary heart disease (CHD) and its acute manifestation, acute coronary syndrome (ACS). Aging is associated with a decline of the immune system, a process known as immunosenescence. This is characterized by an increase in highly proinflammatory T cells that are involved in CHD progression, plaque destabilization, and myocardial ischemia–reperfusion injury. Telomere dysfunction has been implicated in immunosenescence of T lymphocytes. Telomerase is the enzyme responsible for maintaining telomeres during cell divisions. It has a protective effect on cells under oxidative stress and helps regulate flow-mediated dilation in microvasculature. OBJECTIVE The TACTIC (Telomerase ACTivator to reverse Immunosenescence in Acute Coronary Syndrome) trial will investigate whether a telomerase activator, TA-65MD, can reduce the proportion of senescent T cells in patients with ACS with confirmed CHD. It will also assess the effect of TA-65MD on decreasing telomere shortening, reducing oxidative stress, and improving endothelial function. METHODS The study was designed as a single-center, randomized, double-blind, parallel-group, placebo-controlled phase II trial. Recruitment started in January 2019. A total of 90 patients, aged 65 years or older, with treated ACS who have had CHD confirmed by angiography will be enrolled. They will be randomized to one of two groups: TA-65MD oral therapy (8 mg twice daily) or placebo taken for 12 months. The primary outcome is the effect on immunosenescence determined by a decrease in the proportion of CD8+ TEMRA (T effector memory cells re-expressing CD45RA [CD45 expressing exon A]) cells at 12 months. Secondary outcomes include leukocyte telomere length, endothelial function, cardiac function as measured by echocardiography and NT-proBNP (N-terminal fragment of the prohormone brain-type natriuretic peptide), systemic inflammation, oxidative stress, and telomerase activity. RESULTS The study received National Health Service (NHS) ethics approval on August 9, 2018; Medicines and Healthcare products Regulatory Agency approval on October 19, 2018; and NHS Health Research Authority approval on October 22, 2018. The trial began recruiting participants in January 2019 and completed recruitment in March 2020; the trial is due to report results in 2021. CONCLUSIONS This pilot trial in older patients with CHD will explore outcomes not previously investigated outside in vitro or preclinical models. The robust design ensures that bias has been minimized. Should the results indicate reduced frequency of immunosenescent CD8+ T cells as well as improvements in telomere length and endothelial function, we will plan a larger, multicenter trial in patients to determine if TA-65MD is beneficial in the treatment of CHD in elderly patients. CLINICALTRIAL ISRCTN Registry ISRCTN16613292; http://www.isrctn.com/ISRCTN16613292 and European Union Drug Regulating Authorities Clinical Trials Database (EudraCT), European Union Clinical Trials Register 2017-002876-26; https://tinyurl.com/y4m2so8g INTERNATIONAL REGISTERED REPORT DERR1-10.2196/19456

scholarly journals Telomerase Activation to Reverse Immunosenescence in Elderly Patients With Acute Coronary Syndrome: Protocol for a Randomized Pilot Trial

10.2196/19456 ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. e19456
Author(s):  
Rebecca Maier ◽  
Bilal Bawamia ◽  
Karim Bennaceur ◽  
Sarah Dunn ◽  
Leanne Marsay ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
European Union ◽  
Clinical Trials ◽  
T Cells ◽  
Acute Coronary Syndrome ◽  
Elderly Patients ◽  
Endothelial Function ◽  
Telomere Length ◽  
Pilot Trial ◽  
Coronary Syndrome

Background Inflammation plays a key role in the pathophysiology of coronary heart disease (CHD) and its acute manifestation, acute coronary syndrome (ACS). Aging is associated with a decline of the immune system, a process known as immunosenescence. This is characterized by an increase in highly proinflammatory T cells that are involved in CHD progression, plaque destabilization, and myocardial ischemia–reperfusion injury. Telomere dysfunction has been implicated in immunosenescence of T lymphocytes. Telomerase is the enzyme responsible for maintaining telomeres during cell divisions. It has a protective effect on cells under oxidative stress and helps regulate flow-mediated dilation in microvasculature. Objective The TACTIC (Telomerase ACTivator to reverse Immunosenescence in Acute Coronary Syndrome) trial will investigate whether a telomerase activator, TA-65MD, can reduce the proportion of senescent T cells in patients with ACS with confirmed CHD. It will also assess the effect of TA-65MD on decreasing telomere shortening, reducing oxidative stress, and improving endothelial function. Methods The study was designed as a single-center, randomized, double-blind, parallel-group, placebo-controlled phase II trial. Recruitment started in January 2019. A total of 90 patients, aged 65 years or older, with treated ACS who have had CHD confirmed by angiography will be enrolled. They will be randomized to one of two groups: TA-65MD oral therapy (8 mg twice daily) or placebo taken for 12 months. The primary outcome is the effect on immunosenescence determined by a decrease in the proportion of CD8+ TEMRA (T effector memory cells re-expressing CD45RA [CD45 expressing exon A]) cells at 12 months. Secondary outcomes include leukocyte telomere length, endothelial function, cardiac function as measured by echocardiography and NT-proBNP (N-terminal fragment of the prohormone brain-type natriuretic peptide), systemic inflammation, oxidative stress, and telomerase activity. Results The study received National Health Service (NHS) ethics approval on August 9, 2018; Medicines and Healthcare products Regulatory Agency approval on October 19, 2018; and NHS Health Research Authority approval on October 22, 2018. The trial began recruiting participants in January 2019 and completed recruitment in March 2020; the trial is due to report results in 2021. Conclusions This pilot trial in older patients with CHD will explore outcomes not previously investigated outside in vitro or preclinical models. The robust design ensures that bias has been minimized. Should the results indicate reduced frequency of immunosenescent CD8+ T cells as well as improvements in telomere length and endothelial function, we will plan a larger, multicenter trial in patients to determine if TA-65MD is beneficial in the treatment of CHD in elderly patients. Trial Registration ISRCTN Registry ISRCTN16613292; http://www.isrctn.com/ISRCTN16613292 and European Union Drug Regulating Authorities Clinical Trials Database (EudraCT), European Union Clinical Trials Register 2017-002876-26; https://tinyurl.com/y4m2so8g International Registered Report Identifier (IRRID) DERR1-10.2196/19456

scholarly journals Acute Coronary Syndrome in Octogenerians: Management Perspectives

2020 ◽  
pp. 1-4
Author(s):  
Ranjan Modi ◽  
Sunil Modi ◽  
Ranjan Modi
Keyword(s):  
Clinical Trials ◽  
Acute Coronary Syndrome ◽  
Elderly Patients ◽  
Medical Therapy ◽  
Randomized Clinical Trials ◽  
Coronary Syndrome ◽  
Younger Age ◽  
Current Guidelines ◽  
Term Data

Current guidelines for acute coronary syndrome are derived from the data in randomized clinical trials and metanalysis conducted in patients. These patients are generally of younger age. The data of acute coronary syndrome in octogenarians is mainly derived from registries. This mid and long-term data regarding medical therapy or interventions in octogenarians is low in number with smaller subsets of patients. Most of the physicians are reluctant to use the same guidelines in these elderly patients due to increased chances of complications. This article reviews the available data and literature in acute coronary syndrome in octogenarians and provides management perspectives for these elderly patients.

scholarly journals Acute coronary syndrome in elderly: aspects of patient management

The Clinician ◽  
2019 ◽  
Vol 13 (1-2) ◽  
pp. 19-26 ◽  
Author(s):  
Yu. D. Ryzhkova ◽  
E. V. Kanareykina ◽  
M. R. Atabegashvili ◽  
E. V. Konstantinova ◽  
M. Yu. Gilyarov
Keyword(s):  
Clinical Trials ◽  
Acute Coronary Syndrome ◽  
Elderly Patients ◽  
Randomized Clinical Trials ◽  
The Elderly ◽  
Developed Countries ◽  
Interventional Treatment ◽  
Coronary Syndrome ◽  
Age Related ◽  
Related Association

Coronary heart disease is the leading cause of death worldwide. Over the past few decades, life expectancy has increased, which has led to an aging population in developed countries, so the average age of patients with acute coronary syndrome (ACS) has steadily increased in recent decades. The inclusion of elderly and senile patients in randomized clinical trials does not reflect the age-related association of these diseases. However, antithrombotic therapy and interventional treatment are the basis of treatment in patients with ACS of any age, including the elderly. For older patients, there may be a mismatch between chronological and biological age. The question of how close the treatment of elderly patients with ACS is to the level of current recommendations and whether it is possible to apply them unconditionally in this group of patients does not have a definite answer. Current recommendations and the underlying randomized clinical trials are focused on any one disease, whereas in the elderly in most cases multimorbid pathology occurs. In general, elderly patients with ACS should be treated using the same methods as younger patients, however, the presence of comorbid diseases in an elderly patient naturally increases the risk of complications, makes the patient’s prognosis heavier, significantly affects treatment tactics, limits the possibility of using conventional approaches when choosing a drug therapy.

scholarly journals Oxidative stress response in regulatory and conventional T cells: a comparison between patients with chronic coronary syndrome and healthy subjects

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Anna K. Lundberg ◽  
Rosanna W. S. Chung ◽  
Louise Zeijlon ◽  
Gustav Fernström ◽  
Lena Jonasson
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Thioredoxin Reductase ◽  
Healthy Controls ◽  
Antioxidant Genes ◽  
Consistent Finding ◽  
Coronary Syndrome ◽  
Thioredoxin Reductase 1

Abstract Background Inflammation and oxidative stress form a vicious circle in atherosclerosis. Oxidative stress can have detrimental effects on T cells. A unique subset of CD4+ T cells, known as regulatory T (Treg) cells, has been associated with atheroprotective effects. Reduced numbers of Treg cells is a consistent finding in patients with chronic coronary syndrome (CCS). However, it is unclear to what extent these cells are sensitive to oxidative stress. In this pilot study, we tested the hypothesis that oxidative stress might be a potential contributor to the Treg cell deficit in CCS patients. Methods Thirty patients with CCS and 24 healthy controls were included. Treg (CD4+CD25+CD127−) and conventional T (CD4+CD25−, Tconv) cells were isolated and treated with increasing doses of H2O2. Intracellular ROS levels and cell death were measured after 2 and 18 h, respectively. The expression of antioxidant genes was measured in freshly isolated Treg and Tconv cells. Also, total antioxidant capacity (TAC) was measured in fresh peripheral blood mononuclear cells, and oxidized (ox) LDL/LDL ratios were determined in plasma. Results At all doses of H2O2, Treg cells accumulated more ROS and exhibited higher rates of death than their Tconv counterparts, p < 0.0001. Treg cells also expressed higher levels of antioxidant genes, including thioredoxin and thioredoxin reductase-1 (p < 0.0001), though without any differences between CCS patients and controls. Tconv cells from CCS patients were, on the other hand, more sensitive to oxidative stress ex vivo and expressed more thioredoxin reductase-1 than Tconv cells from controls, p < 0.05. Also, TAC levels were lower in patients, 0.97 vs 1.53 UAE/100 µg, p = 0.001, while oxLDL/LDL ratios were higher, 29 vs 22, p = 0.006. Conclusion Treg cells isolated from either CCS patients or healthy controls were all highly sensitive to oxidative stress ex vivo. There were signs of oxidant-antioxidant imbalance in CCS patients and we thus assume that oxidative stress may play a role in the reduction of Treg cells in vivo.

scholarly journals Impact of timing of randomization after an acute coronary syndrome and subsequent events in patients with type 2 diabetes mellitus: an analysis of the EXAMINE trial

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Elharram ◽  
A Sharma ◽  
W White ◽  
G Bakris ◽  
P Rossignol ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Clinical Trials ◽  
Type 2 Diabetes Mellitus ◽  
Acute Coronary Syndrome ◽  
Primary Outcome ◽  
Funding Source ◽  
Coronary Syndrome ◽  
The Impact

Abstract Background The timing of enrolment following an acute coronary syndrome (ACS) may influence cardiovascular (CV) outcomes and potentially treatment effect in clinical trials. Using a large contemporary trial in patients with type 2 diabetes mellitus (T2DM) post-ACS, we examined the impact of timing of enrolment on subsequent CV outcomes. Methods EXAMINE was a randomized trial of alogliptin versus placebo in 5380 patients with T2DM and a recent ACS. The primary outcome was a composite of CV death, non-fatal myocardial infarction [MI], or non-fatal stroke. The median follow-up was 18 months. In this post hoc analysis, we examined the occurrence of subsequent CV events by timing of enrollment divided by tertiles of time from ACS to randomization: 8–34, 35–56, and 57–141 days. Results Patients randomized early (compared to the latest times) had less comorbidities at baseline including a history of heart failure (HF; 24.7% vs. 33.0%), prior coronary artery bypass graft (9.6% vs. 15.9%), or atrial fibrillation (5.9% vs. 9.4%). Despite the reduced comorbidity burden, the risk of the primary outcome was highest in patients randomized early compared to the latest time (adjusted hazard ratio [aHR] 1.47; 95% CI 1.21–1.74) (Figure 1). Similarly, patients randomized early had an increased risk of recurrent MI (aHR 1.51; 95% CI 1.17–1.96) and HF hospitalization (1.49; 95% CI 1.05–2.10). Conclusion In a contemporary cohort of T2DM with a recent ACS, early randomization following the ACS increases the risk of CV events including recurrent MI and HF hospitalization. This should be taken into account when designing future clinical trials. Figure 1 Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Takeda Pharmaceutical

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