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Large Artery Damage: Measurement and Clinical Importance
Published in Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei, Manual of Hypertension of the European Society of Hypertension, 2019
Stéphane Laurent, Michel E. Safar
Pharmacological treatments which are able to reduce arterial stiffness include (7,20) (a) antihypertensive treatment, such as diuretics in the elderly, beta-blockers, ACE inhibitors (29,40), AT1 blockers (23), and calcium channel antagonists (39); (b) treatments of congestive heart failure, such as ACE inhibitors, nitrates and aldosterone antagonists; (c) hypolipidemic agents such as statins; (d) antidiabetic agents such as thiazolidinediones; and (e) advanced glycation end-product (AGE)-breakers, such as alagebrium (ALT-711). Whether the reduction in arterial stiffness after antihypertensive treatment is only due to BP lowering or if additional BP-independent effects are involved is still debated. To our knowledge, some studies unequivocally showed that antihypertensive treatment was able to reduce arterial stiffness and/or wave reflections independent of the reduction in brachial BP, for instance either acutely after a calcium channel blocker (39) or after long-term ACE inhibition (29,40) or angiotensin-receptor blockade (23).
Heart failure with preserved ejection fraction in older adults
Published in Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich, Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
Bharathi Upadhya, Dalane W. Kitzman
Sitaxsentan is an orally active, selective endothelin-A receptor antagonist that provided a modest increase in treadmill exercise time, but did not improve any of the secondary endpoints, such as LV mass or diastolic function, in a small trial with stable HFpEF patients (183). Advanced glycation end products (AGEs) are formed when glucose interacts nonenzymatically with proteins. AGEs can cause increased stiffness of the extracellular matrix directly by cross-linking collagen or elastin and indirectly by stimulating the production of collagen and depleting NO, thereby increasing oxidative stress (184). In a small open-label study with stable HFpEF, alagebrium chloride (AGE breaker), was associated with slightly reduced LV mass and improved diastolic filling and QOL; however, there were no changes in the peak VO2 (185). Interleukin-1 (alpha and beta) are potent proinflammatory cytokines implicated in adverse VV remodeling (186). Interleukin-1 blockade with anakinra for 14 days in a double-blind, randomized, placebo-controlled, crossover trial (Diastolic HF Anakinra Response Trial [D-HART-Pilot]) significantly reduced the systemic inflammatory response and improved aerobic exercise capacity in patients with HFpEF and elevated plasma C-reactive proteins levels. Currently, the D-HART2, phase 2 clinical trial testing anakinra for improving cardiorespiratory fitness, diastolic dysfunction, and elevated inflammation in patients with HFpEF, is underway (NCT01542502).
Impact of Dietary Polyphenols on Arterial Stiffness
Published in Catherina Caballero-George, Natural Products and Cardiovascular Health, 2018
Tess De Bruyne, Lynn Roth, Harry Robberecht, Luc Pieters, Guido De Meyer, Nina Hermans
Almost all classes of anti-hypertensive medications could decrease arterial stiffness. Renin-angiotensin-aldosterone system (RAAS) antagonists (angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, aldosterone antagonists) have shown the most promising results (Lyle and Raaz, 2017; Smulyan et al., 2016; Wu et al., 2015). Besides blood-pressure-lowering drugs, potential beneficial effects can be obtained with statins, oral anti-diabetics, AGE and collagen cross-link breakers (e.g. alagebrium) and anti-inflammatory agents. The susceptible population, amount of evidence and degree of success all vary (Laurent et al., 2006; Lyle and Raaz, 2017; Smulyan et al., 2016; Wu et al., 2015).
Soluble RAGEs and cardiovascular risk factors in adult offspring of patients with premature coronary heart disease
Published in Blood Pressure, 2020
Petra Karnosová, Markéta Mateřánková, Jitka Seidlerová, Otto Mayer, Jan Filipovský, Václav Karnos
Another point is whether we have therapeutic possibilities how to beneficially affect AGE/RAGE axis. Miyata et al. demonstrated that the renin-angiotensin system (RAS) blockers -angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) inhibit the formation of AGEs in Maillard reactions in vitro [38]. Low sRAGE level was associated with significantly higher aPWV only in subjects not treated with RAS blockers in the general population study [15]. Favourable effects of RAS inhibitors are supposed to be in their complex antioxidant, antitrombotic and profibrinolytic activities [39]. Other specific drugs affecting the AGE/RAGE axis such as the crosslinks breakers (alagebrium) or AGE formation inhibitors (aminoguanidin) did not reach clinical utilization [40].
Targeting inflammation in diabetic nephropathy: a tale of hope
Published in Expert Opinion on Investigational Drugs, 2018
Juan Antonio Moreno, Carmen Gomez-Guerrero, Sebastian Mas, Ana Belen Sanz, Oscar Lorenzo, Marta Ruiz-Ortega, Lucas Opazo, Sergio Mezzano, Jesus Egido
Another family of potential interest are those compounds capable to break AGE cross-links, such as Aminoguanidine [121] or Alagebrium [122] both are described to improve diabetic complications as vascular fibrosis for the first [123] and tubulointerstitial damage in the second compound [124] in both cases in STZ rat models and its derivatives ALT-462, ALT-486, and ALT-946 [125]. As many deleterious effects of AGE are mediated via its specific signaling pathway through RAGE, soluble forms of this receptor known (sRAGE) have been proposed to ameliorate diabetic vascular complications [126]. Another RAGE antagonist TPP-488 have shown mild effect on DN phase II trial (NCT00287183) and currently is on fact track development as Alzheimer´s drug.
Diabetic nephropathy: an insight into molecular mechanisms and emerging therapies
Published in Expert Opinion on Therapeutic Targets, 2019
Annabelle M. Warren, Søren T. Knudsen, Mark E. Cooper
AGE and RAGE have been explored as potential targets in DKD. AGEs are found in common foods (e.g., meat, cheese) however reduction of dietary AGE has not shown clear evidence of benefit [96]. The B-group vitamins pyridoxamine (B6) and thiamine (B1) appeared to show evidence for reducing AGEs in preclinical studies, but have failed to show any major impact on DKD in clinical trials [97,98]. Alagebrium, which breaks glucose crosslinks to dismantle AGEs, showed promising renal effects but when trialed in combination with an ACEi it did not confer additional renoprotection [99].