Altered Proximal Aortic Stiffness and Endothelin Plasma Levels in Diabetic Patients With End-Stage Renal Disease

Karakitsos, Dimitrios; Patrianakos, Alexandros; Parthenakis, F.; Malliaraki, Niki; Nikitovic, Dragana; Kyriazis, John; Karabinis, Andréas; Groothoff, Jaap W.; Groot, Eric de; Fourtounas, Costas; Daphnis, Eugene; Vardas, Panos

doi:10.1097/mat.0b013e318050d607

Cited by 7 publications

(5 citation statements)

References 39 publications

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“…Plasma ET‐1 is likely increased in dialysis patients for the same reasons as in CKD patients (inflammation, reduced clearance, hypertension and vascular injury) as well as due to erythropoiesis‐stimulating agents and flow through the arteriovenous fistula . In particular, there is a strong correlation between plasma ET‐1 and C‐reactive protein, atherosclerosis and proximal aorta stiffness in dialysis patients . Pre‐clinical studies indicate that ET‐1 may be important in vascular calcification in the setting of CKD , while ETA receptor blockade caused regression of vascular calcification in a model of isolated systolic hypertension .…”

Section: Endothelin Antagonists In End‐stage Kidney Diseasementioning

confidence: 99%

Endothelin antagonists for diabetic and non‐diabetic chronic kidney disease

Kohan

Pollock

2013

Brit J Clinical Pharma

105

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Numerous pre-clinical studies have implicated endothelin-1 in the pathogenesis of diabetic and non-diabetic chronic kidney disease (CKD). Renal endothelin-1 production is almost universally increased in kidney disease. The pathologic effects of endothelin-1, including vasoconstriction, proteinuria, inflammation, cellular injury and fibrosis, are likely mediated by the endothelin A (ETA) receptor. ETA antagonism alone, and/or combined ETA/B blockade, reduces CKD progression. Based on the strong pre-clinical data, several clinical trials using ETA antagonists were conducted. Small trials involving acute intravenous endothelin receptor blockade suggest that ETA, but not ETB, blockade exerts protective renal and vascular effects in CKD patients. A large phase 3 trial (ASCEND) examined the effects of avosentan, an endothelin receptor antagonist, on renal disease progression in diabetic nephropathy. Proteinuria was reduced after 3-6 months of treatment. However the study was terminated due to increased morbidity and mortality associated with avosentan-induced fluid retention. Several phase 2 trials using avosentan at lower doses than in ASCEND, atrasentan or sitaxsentan (the latter two being highly ETA-selective) showed reductions in proteinuria on top of renin-angiotensin system blockade. Infrequent and clinically insignificant fluid retention was observed at the most effective doses. Additional trials using ETA blockers are ongoing or being planned in patients with diabetic nephropathy or focal segmental glomerulosclerosis. Moving forward, such studies must be conducted with careful patient selection and attention to dosing in order to minimize adverse side effects. Nonetheless, there is cause for optimism that this class of agents will ultimately prove to be effective for the treatment of CKD.

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Section: Endothelin Antagonists In End‐stage Kidney Diseasementioning

confidence: 99%

Endothelin antagonists for diabetic and non‐diabetic chronic kidney disease

Kohan

Pollock

2013

Brit J Clinical Pharma

105

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“…Plasma ET-1 levels correlate with left ventricular hypertrophy (LVH) and arterial intima-media thickening in patients with end-stage renal disease (ESRD) [63]. There is also strong concordance between proximal aortic stiffness and ET-1 in diabetics with ESRD [64].…”

Section: Endothelin System and Blood Vesselsmentioning

confidence: 96%

Endothelin receptor antagonists as antihypertensives: the next frontier

Epstein

Anderson

2009

Expert Review of Cardiovascular Therapy

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The endothelin system is a pivotal player along the continuum of cardiovascular disease. There is convincing evidence that the system not only exerts a potent pressor effect but also promotes end-organ damage independent from blood pressure changes. The role of endothelin receptor antagonists (ERAs) in the treatment of hypertension is rapidly evolving. Recent studies demonstrate a formidable antihypertensive effect. Utility of ERAs is likely to be greatest in patients with resistant hypertension. Beyond blood pressure lowering, ERAs exert several properties that may confer additional protection, including effects on endothelial function, atherosclerosis, arterial stiffening, renal function and proteinuria. The full potential of this class will only be realized when the results of ongoing and future studies in hypertension, heart failure and other forms of cardiovascular disease are completed.

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“…In patients with end stage renal disease (ESRD), Demuth et al demonstrated that plasma ET-1 levels are elevated and associated with LVH and arterial intima-media thickening [152]. In diabetics with ESRD, proximal aortic stiffness and ET-1 levels are increased and the relationship between each is closely correlated [153]. Infusion of ET-1 into anesthetized sheep significantly increases PWV in the iliac artery and this effect can be reversed with administration of an ET A receptor antagonist [154].…”

Section: Endothelin Systemmentioning

confidence: 98%

Actions of Selected Cardiovascular Hormones on Arterial Stiffness and Wave Reflections

Nichols

Epstein²

2009

CPD

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The large conduit arteries of the thorax and abdomen are elastic while those in the arms and legs are muscular. Alterations in wall properties of elastic arteries occur over time and are usually permanent in nature; acute changes can, however, occur is response to a change in transmural pressure. Chronic alterations in properties of muscular arteries are minimal but changes (e.g vasoconstriction, vasodilation or tone) do occur in response to smooth muscle cell (SMC) stimulation. In general an increase in arterial stiffness (and wave reflection) increases systolic blood pressure (BP) and is detrimental while a decrease is beneficial. The augmentation in systolic BP increases left ventricular (LV) mass, wasted energy, tension-time index (TTI) and myocardial oxygen demand while the fall in diastolic BP decreases coronary artery perfusion causing a mismatch in ventricular/vascular coupling and an imbalance in the myocardial oxygen supply/demand ratio. Cardiovascular hormones such as renin, angiotensin, aldosterone, parathormone, sympathomimetic amines and endothelin induce vasoconstriction and increase arterial stiffness while insulin, thyroxine, testosterone, atrial natriuretic peptide (ANP), estrogen and nitric oxide (NO) have the opposite effect. The undesirable effects can be reversed with selected blocking agents. Vasodilator drugs have little direct active effect on large elastic arteries and unaugmented BP but can markedly reduce wave reflection amplitude and duration and augmentation index by decreasing stiffness of the muscular arteries and reducing transmission velocity of the reflected wave from the periphery to the heart. This decrease in amplitude and increase in travel time (or delay) of the reflected wave causes a generalized decrease in systolic BP, arterial wall stress, wasted LV energy and TTI.

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Altered Proximal Aortic Stiffness and Endothelin Plasma Levels in Diabetic Patients With End-Stage Renal Disease

Cited by 7 publications

References 39 publications

Endothelin antagonists for diabetic and non‐diabetic chronic kidney disease

Endothelin antagonists for diabetic and non‐diabetic chronic kidney disease

Endothelin receptor antagonists as antihypertensives: the next frontier

Actions of Selected Cardiovascular Hormones on Arterial Stiffness and Wave Reflections

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