Axis 2 : Arterial Stiffness and Hypertension
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:
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
Hypothesis 3
The vascular component of neurodegenerative cognitive disorders
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.
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29. Benetos A, Labat C, Rossignol P, et al. JAMA Intern Med. 2015;175:989-95
30. Mossello E, Pieraccioli M, Nesti N et al. JAMA Intern Med.2015;175:578-85.
31. Streit S, Poortvliet RKE, Gussekloo J. Age Ageing. 2018;47:545-550
32. Williams B, Mancia G, Spiering W, et al. J Hypertens. 2018;36:1953-2041.
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38. Verger A, van der Gucht A, Guedj E, et al. J Hypertens. 2015;33:1378-85
39. Verger A, Hossu G, Kearney-Schwartz A, et al. Cerebrovasc Dis Basel Switz. 2016;42:106-9.
40. Chetouani A, Chawki MB, Hossu G, et al. NeuroImage Clin. 2018;17:804-10.
41. Akbar S, Pinçon A, Lanhers MC, et al. Genomics. 2016, 48:928-35.
42. Pinçon A, Thomas MH, Huguet M, et al. J Alzheimers Dis. 2015;45:195-204.
43. Yen FT, Roitel O, Bonnard L, et al. J Biol Chem. 2008;283:25650-9.
44. Xie T, Stathopoulou MG, Akbar S, et al. Clin Genet. 2018;93:846-52.