Angiotensin receptor blockade and neprilysin (NEP) inhibition together offer potential benefits for the treatment of hypertension and heart failure. LCZ696 is a novel single molecule comprising molecular moieties of valsartan and NEP inhibitor prodrug AHU377 (1:1 ratio). Oral administration of LCZ696 caused dose-dependent increases in atrial natriuretic peptide immunoreactivity (due to NEP inhibition) in Sprague-Dawley rats and provided sustained, dose-dependent blood pressure reductions in hypertensive double-transgenic rats. In healthy participants, a randomized, double-blind, placebo-controlled study (n = 80) of single-dose (200-1200 mg) and multiple-dose (50-900 mg once daily for 14 days) oral administration of LCZ696 showed that peak plasma concentrations were reached rapidly for valsartan (1.6-4.9 hours), AHU377 (0.5-1.1 hours), and its active moiety, LBQ657 (1.8-3.5 hours). LCZ696 treatment was associated with increases in plasma cGMP, renin concentration and activity, and angiotensin II, providing evidence for NEP inhibition and angiotensin receptor blockade. In a randomized, open-label crossover study in healthy participants (n = 56), oral LCZ696 400 mg and valsartan 320 mg were shown to provide similar exposure to valsartan (geometric mean ratio [90% confidence interval]: AUC(0-infinity) 0.90 [0.82-0.99]). LCZ696 was safe and well tolerated. These data support further clinical development of LCZ696, a novel, orally bioavailable, dual-acting angiotensin receptor-NEP inhibitor (ARNi) for hypertension and heart failure.

SummaryBackground and objectives Most deaths in autosomal dominant polycystic kidney disease (ADPKD) are attributable to cardiovascular disease (CVD). We examined novel CVD biomarkers in different stages of AD-PKD.Design, setting, participants, & measurements We recruited 50 hypertensive subjects with ADPKD with estimated GFR (eGFR) of Ͼ60 ml/min per 1.73 m 2 ; 52 hypertensive subjects with ADPKD with eGFR of 25 to 60 ml/min per 1.73 m 2 ; 42 normotensive subjects with ADPKD and eGFR of Ͼ60 ml/min per 1.73 m 2 ; and 50 healthy controls. We assayed serum C-reactive protein and IL-6 as markers of inflammation; plasma 8-epi-prostaglandin F 2␣ (8-epi-PGF2␣ ) and superoxide dismutase (SOD) as markers of oxidative stress; and homeostasis model assessment (HOMA) as a measure of insulin resistance. ResultsThe hypertensive ADPKD eGFR of 25 to 60 group had higher levels of C-reactive protein and IL-6 than controls, normotensive ADPKD with eGFR of Ͼ60, and hypertensive ADPKD with eGFR of Ͼ60. The normotensive ADPKD eGFR Ͼ60, hypertensive ADPKD eGFR Ͼ60, and hypertensive ADPKD eGFR 25 to 60 groups had higher 8-epi-PGF 2␣ and lower SOD than controls, with no difference between the ADPKD groups. There was no difference in HOMA levels between any of the groups. Adjustment for age, race, gender, and body mass index did not alter these relationships. ConclusionsInflammation and oxidative stress are evident early in ADPKD even with preserved kidney function. Inflammation exhibits a graded relationship with levels of kidney function, whereas oxidative stress demonstrates a threshold effect. These pathways may be therapeutic targets for CVD risk mitigation.

Given the high burden of atherosclerotic cardiovascular disease in dialysis patients, we hypothesized that cognitive testing would reveal subtle abnormalities in subcortical brain function, a measure frequently associated with cerebrovascular disease. Detailed neurocognitive testing was performed in 25 hemodialysis patients. All patients had Mini-Mental State Examination (MMSE) scores >24 and had no history of cerebrovascular disease. Where appropriate, scores were normalized for age, gender, and education. One-sample t tests were used to compare differences in cognitive function between dialysis patients and normative data. The mean age was 57 years, and the mean MMSE was 27.5. Fourteen subjects (56%) were females, and 15 white (60%). Results of the North American Adult Reading Test, a measure of verbal intelligence, were comparable with the general population. Similarly, measures of cortical function, namely retention and recognition scores from the Word List Learning subtest of the Wechsler Memory Scale-III, were preserved when compared with normative data where reference = 10. Significant deficits were seen on tests assessing subcortical function: scores (mean+/-standard deviation) for block design, and symbol coding subtests of the Wechsler Adult Intelligence Scale-III were 7.0+/-1.7 and 7.7+/-3.1, respectively (p<0.001 for both comparisons with normative data). Similarly, adjusted scores on the trails A and B tests were 40.5+/-8.3 and 41.8+/-11.3, respectively (p<0.001 for both comparisons with normative data where reference= 50). These results suggest that, despite relatively normal MMSE scores, mild cognitive impairment may be prevalent in hemodialysis patients. The pattern of cognitive dysfunction is primarily subcortical in nature.