Axis 2 : Arterial Stiffness and Hypertension

Patrick Lacolley

  • Research Director, INSERM
  • Co-Director UMS IBSLor

Athanase Benetos

  • Professor of Geriatrics, University of Lorraine








This axis, developed in the FHU-CARTAGE since 2015, involves three specific research fields:
(1) Hypertension management in very old frail adults, (RETREAT FRAIL randomized trial),
(2) Relations between arterial stiffness and coagulation and
(3) Arterial component of neurodegenerative cognitive diseases

Hypothesis 1


Impact of the Reduction in Antihypertensive Treatment on total mortality in frail subjects with low systolic blood pressure, a randomized, controlled study in subjects over 80 years living in nursing homes:
The RETREAT-FRAIL randomized trial sponsored by the RHUANR program (FIGHT-HF) and RETREATFRAIL AOM16549 / PHRC-16-0549. (Geriatric department and CIC-P, CHRU Nancy)
In patients over the age of 80 with marked frailty and functional decline, several studies showed that low blood pressure levels under antihypertensive treatment are associated with increased mortality, morbidity and cognitive decline (28-31). Presently, there are no specific guidelines for the frailest old hypertensive patients (32). Previous studies showed clear benefits of an antihypertensive treatment (33), especially for lowering systolic BP levels down to 130 mmHg (34), but only in highly selected relatively robust older subjects and by excluding individuals with multiple co-morbidities, significant cognitive impairment and loss of autonomy. In this respect, we coordinate a multicenter (15 French Academic Centers and >100 nursing Homes), randomized controlled trial, called RETREAT-FRAIL, which evaluates the interest of the downtitration of antihypertensive treatments in older subjects with SBP levels lower than 130mmHg under a combination of antihypertensive medications.
More precisely, the RETREAT-FRAIL RCT will examine the effect of antihypertensive medications step-down according to a precise algorithm (intervention group) as compared with a control group in which antihypertensive treatment will not be modified by the algorithm, on all-cause morbidity and mortality during 3 years of follow-up. A total of 1100 patients with ≥ 80 years, a SBP <130 mmHg, living in nursing home and treated with 2 or more anti-hypertensive drugs, are planned to be recruited and clinical and biological phenotypes of frailty will be collected (physical and cognitive functionality, telomere length…). The results (end 2022) will be proposed to establish new guidelines for this population (presently inexistent).

Hypothesis 2


Connections between arterial stiffening and thrombosis in an experimental model of delayed arterial aging: the Naked Mole Rat
Our research on the process of normal and accelerated vascular aging has generated a new concept of an interrelation between arterial stiffening and thrombosis, highlighting the major role of VSMCs plasticity (35). The link involves VSMC proliferation by thrombin or Von Willebrand factor (VWF) and increased coagulation factors such as tissue factor synthetized by vascular cells (endothelial cells, ECs and VSMCs) or activated in plasma. NMRs have a maximum lifespan exceeding 30 years, living approximately ten times longer than a similarly sized mouse, and do not develop arterial stiffening with age (36). We aim to investigate intimal hyperplasia, phenotypes and functions of VSMCs, ECs (VWF, TFPI and micro-vesicles), plasmatic and cellular (VSMCs and ECs) thrombin generation in NMRs at 2, 10 and 20 years old. In order to investigate the lack of cell senescence, we will analyze thoracic 10 arterial composition, as well as phenotypic VSMC and EC changes from primary cultures in NMRs in response to oxidative stress and during aging. Our first results support the concept of a delayed phenotype of arterial aging in NMRs with no intimal thickening, and no difference between 10-year and 2-year-old NMRs in elastin/collagen ratio, in smoothelin and myosin-heavy chain, in focal adhesion dynamics and in VSMCs density (figure). Furthermore, up to 10 years of age, there is no increase in plasma thrombin generation, fibrinogen and factor VIII, whereas these coagulation biomarkers are known to increase with age in common rodent species and in humans.
This program, based on a cross-institution collaboration with King’s College and Queen Mary University (London), is expected to help understanding the mechanisms governing vascular stiffening, thrombosis and fibrosis in aging. This project will additionally benefit from the expertises of Cecile Denis (UMR_S 1176, VWF) and Zhenlin Li (UMR 8256, ECs and VSMC cytoskeletal proteins) and technical facilities of UMS2008 IBSLor platform.

Hypothesis 3


The vascular component of neurodegenerative cognitive disorders
More than 15 years ago our consortium started exploring the role of the CV risk factors and phenotypes of accelerated vascular aging in the process of cognitive decline and neurodegenerative diseases (37). This theme is planned to be further extended through 2 programs presented below:
A- Assessment of the vascular component of cerebral aging with MRI and PET imaging (Nancy imaging department and Nancyclotep platform). We showed previously strong relations between the grey matter metabolism of older hypertensive patients, assessed with 18Ffluorodeoxyglucose positron emission tomography (FDG PET), and vascular phenotype parameters (central blood pressure (38), vascular white-matter diseases at MRI (39)), with the white-matter integrity being further linked to metabolism of Alzheimer-like cortical areas and cognitive performances (40). Two projects are currently on-going: (i) Impact of the Central Blood Pressure Level in Cerebral Metabolic Aging: a FDG PET Study (PACTEP study, recruiting, NCT03345290); (ii) Assessment of Positron Emission Tomography to Early Detect Frailty in Onco-geriatry (FOGTEP study, recruiting, NCT03370809).
B- Lipolysis stimulated lipoprotein receptor (LSR) polymorphisms as determinants of dyslipidemias, risk factors for atherosclerosis, metabolic syndrome and neurodegenerative disorders (URAFPA laboratory: EA 3998, USC INRA 0340): As a receptor for apoB and E lipoproteins, LSR participates in the regulation of lipid homeostasis in both peripheral tissues and the central nervous system. Our previous studies using lsr+/- heterozygote mice, have shown that reduced LSR expression can lead to dyslipidemia, obesity, atherosclerosis, as well as age-related cognitive decline and Alzheimer disease (41-43). We reported recently the influence of LSR polymorphisms on lipid levels of healthy adults (44). The main objective is to assess the relations between these LSR polymorphisms and different CV phenotypes (atherosclerosis, arterial stiffness), and blood biomarkers of lipid metabolism in dyslipidemia-related disorders including Alzheimer’s disease. Identification of LSR-dependent pathways in cell and animal models can be tested as potential biomarkers in cohorts. In addition, significant genetic determinants that interact with LSR polymorphisms detected in association studies may be tested in laboratory models.
References

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