Endothelial Factors in The Pathogenesis and Treatment of Chronic Kidney Disease Part II: Role in Disease Conditions. A Joint Consensus Statement from the ESH Working Group on Endothelin and Endothelial Factors And The Japanese Society of Hypertension

: After examining in Part I the general mechanisms of endothelial cell injury in the kidney, the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension and the Japanese Society of Hypertension will herein review current knowledge on the role of endothelial dysfunction in multiple disease conditions that affect the kidney, including diabetes mellitus, preeclampsia, solid organ transplantation, hyperhomocysteinemia and antiangiogenic therapy in cancer. The few available randomized controlled clinical trials specifically designed to evaluate strategies for correcting endothelial dysfunction in patients with hypertension and/or chronic kidney disease are also discussed alongside their cardiovascular and renal outcomes

Multiple common comorbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress, and myocardial stiffening

Aims More than 50% of patients with heart failure have preserved ejection fraction characterized by diastolic dysfunction. The prevalance of diastolic dysfunction is higher in females and associates with multiple comorbidities such as hypertension (HT), obesity, hypercholesterolemia (HC), and diabetes mellitus (DM). Although its pathophysiology remains incompletely understood, it has been proposed that these comorbidities induce systemic inflammation, coronary microvascular dysfunction, and oxidative stress, leading to myocardial fibrosis, myocyte stiffening and, ultimately, diastolic dysfunction. Here, we tested this hypothesis in a swine model chronically exposed to three common comorbidities.Methods and results DM (induced by streptozotocin), HC (produced by high fat diet), and HT (resulting from renal artery embolization), were produced in 10 female swine, which were followed for 6 months. Eight female healthy swine on normal pig-chow served as controls. The DM+HC+HT group showed hyperglycemia, HC, hypertriglyceridemia, renal dysfunction and HT, which were associated with systemic inflammation. Myocardial superoxide production was markedly increased, due to increased NOX activity and eNOS uncoupling, and associated with reduced NO production, and impaired coronary small artery endothelium-dependent vasodilation. These abnormalities were accompanied by increased myocardial collagen content, reduced capillary/fiber ratio, and elevated passive cardiomyocyte stiffness, resulting in an increased left ventricular end-diastolic stiffness (measured by pressure-volume catheter) and a trend towards a reduced E/A ratio (measured by cardiac MRI), while ejection fraction was maintained.Conclusions The combination of three common comorbidities leads to systemic inflammation, myocardial oxidative stress, and coronary microvascular dysfunction, which associate with myocardial stiffening and LV diastolic dysfunction with preserved ejection fraction

Therapeutic strategies to slow chronic kidney disease progression

Childhood chronic kidney disease commonly progresses toward end-stage renal failure, largely independent of the underlying disorder, once a critical impairment of renal function has occurred. Hypertension and proteinuria are the most important independent risk factors for renal disease progression. Therefore, current therapeutic strategies to prevent progression aim at controlling blood pressure and reducing urinary protein excretion. Renin-angiotensin-system (RAS) antagonists preserve kidney function not only by lowering blood pressure but also by their antiproteinuric, antifibrotic, and anti-inflammatory properties. Intensified blood pressure control, probably aiming for a target blood pressure below the 75th percentile, may exert additional renoprotective effects. Other factors contributing in a multifactorial manner to renal disease progression include dyslipidemia, anemia, and disorders of mineral metabolism. Measures to preserve renal function should therefore also comprise the maintenance of hemoglobin, serum lipid, and calcium-phosphorus ion product levels in the normal range

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

Plasma semicarbazide-sensitive amine oxidase (SSAO) is an independent prognostic marker for mortality in chronic heart failure

Aims Experimental evidence has suggested that semicarbazide-sensitive amine oxidase is involved in vascular endothelial damage and in the process of atherosclerosis, through the formation of reactive aldehydes, hydrogen peroxide and ammonia from endogenous substrates. Recent evidence indicates that semicarbazide-sensitive amine oxidase may be identical with the vascular adhesion protein-1. In patients with diabetes mellitus and chronic heart failure the plasma activity is raised relative to the severity of the disease. The prognostic value of plasma semicarbazide-sensitive amine oxidase is not known. Methods and Results Plasma semicarbazide-sensitive amine oxidase activity was measured at baseline in patients with moderate to severe chronic heart failure who participated in a large European study (PRIME-II). The 372 patients who took part in a pre-defined substudy in The Netherlands were investigated and a survival follow-up (maximum 5.4 years, mean 3.4 years) was carried out. Within the follow-up period 195 patients died. Plasma semicarbazide-sensitive amine oxidase was higher at baseline in those who died than in the survivors (653 +/- 258 vs 540 +/- 242 mU.l(-1), P550 mU.l(-1) had a 1.50 (95% CI, 1.10-2.04) times increased risk of death. Conclusion The finding that plasma semicarbazide-sensitive amine oxidase is an independent prognostic marker for mortality in chronic heart failure supports the concept that an elevated plasma semicarbazide-sensitive amine oxidase level has deleterious effects, possibly due to vascular endothelial damage. (Eur Heart J 2000; 21: 1859-1863, doi:10,1053/euhj.2000. 2176) (C) 2000 The European Society of Cardiology

Reconstruction of brachial artery pressure from noninvasive finger pressure measurements

Background Pulse wave distortions, mainly caused by reflections, and pressure gradients, caused by flow in the resistive vascular tree, may cause differences between finger and brachial artery pressures. These differences may limit the use of finger pressure measurements. We investigated whether brachial artery pressure waves could be reconstructed from finger pressure measurements by correcting for the pressure gradient in addition to correction for pulse wave distortion with a previously described filter. Methods and Results Finger artery pressure (with Finapres), intra-arterial brachial artery pressure (BAP), Riva-Rocci/Korotkoff (RRK), oscillometric, and return-to-flow (RTF) measurements were simultaneously performed in 57 healthy elderly subjects and patients with vascular disease and/or hypertension. A generalized waveform filter was used to correct for pulse wave distortions. Correction equations for the pressure gradient, based on finger pressure, RRK, RTF, or oscillometric measurements, were obtained in 28 randomly selected subjects and tested in 29. Before reconstruction, Finapres underestimated mean and diastolic BAP (finger pressure minus BAP: systolic, -3.2±16.9 mm Hg; mean, -13.0±10.5 mm Hg; diastolic, -8.4±9.0 mm Hg [mean±SD]). After filtering, reconstructed BAP waves were similar to actual BAP in shape but not in pressure level. Optimal correction for the pressure gradient with an equation based on RTF measurements reduced the pressure differences to meet American Association for the Advancement of Medical Instrumentation criteria (reconstructed finger pressure minus BAP: systolic, 3.7±7.0 mm Hg; mean, 0.7±4.6 mm Hg; and diastolic, 1.0±4.9 mm Hg). Conclusions BAP waves can be reconstructed from noninvasive finger pressure registrations when finger pressure waves are corrected for pulse wave distortion and individual pressure gradients

Effect of lower body negative pressure in patients with mild congestive heart failure

In conclusion, patients with moderate-to-severe CHF as well as those with mild CHF are characterized by reduced cardiopulmonary baroreflex function