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Objective: Whether reducing low density lipoprotein cholesterol (LDL-C) is associated with cardiovascular benefits in low risk normocholesterolaemic subjects is unknown. The INTENSITY LOW [Investigating the lowest threshold of vascular benefits from LDL-cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers] study aims to assess whether lowering LDL-C by alirocumab monotherapy can improve endothelial-dependent vascular function compared with placebo (primary objective) in low-risk normocholesterolaemic healthy individuals. Changes in endothelial-dependent or endothelial-independent vascular function, arterial stiffness and biomarkers of systemic inflammation by alirocumab, atorvastatin or their combination are secondary objectives. Study design and methods: This is a single-center, randomized, two-period, single-blind, placebo-controlled clinical trial. The study was registered on clinicaltrials.gov (N03273972). It will include 30 healthy low-risk subjects with LDL-C < 4.1 mmol/l. After passing the screening visit (Visit 1), eligible participants will be randomized 1:1 to either subcutaneous alirocumab 150 mg or placebo. These will be administered as single doses in 2 visits 14 days apart (Visits 2 and 3). Atorvastatin 20 mg once nightly will be prescribed for 14 days at Visit 3 in both groups through to Visit 4. At baseline (Visit 2) and during all post-dose visits (Visits 3-4), endothelial function will be assessed using venous occlusion plethysmography. Specifically, changes in forearm blood flow responses to intra-arterial infusions of acetylcholine, sodium nitroprusside and L-N G -monomethyl-arginine acetate will be assessed as surrogates of endothelial-dependent and -independent vasodilatation. Additionally, arterial stiffness and carotid intima-media thickness will be evaluated at the same timepoints. The above-mentioned changes will be correlated with changes in lipid and systemic inflammation biomarkers., (© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Context: Attainment of safe GH and IGF-1 levels is a central goal of acromegaly management., Objective: The aim of this study was to determine the extent to which reductions in GH and IGF-1 concentrations correlate with amelioration of radiological, metabolic, vascular, cardiac, and respiratory sequelae in a single unselected patient cohort., Study Design: This was a prospective, within-subject comparison in 30 patients with newly diagnosed acromegaly (15 women and 15 men: mean age, 54.3 years; range, 23-78 years) before and after 24 weeks of lanreotide Autogel (ATG) therapy., Results: Reductions in GH and IGF-1 concentrations and tumor volume were observed in all but 2 patients (median changes [Δ]: GH, -6.88 μg/L [interquartile range -16.78 to -3.32, P = .000001]; IGF-1, -1.95 × upper limit of normal [-3.06 to -1.12, P = .000002]; and pituitary tumor volume, -256 mm(3) [-558 to -72.5, P = .0002]). However, apnea/hypopnea index scores showed highly variable responses (P = .11), which were independent of ΔGH or ΔIGF-1, but moderately correlated with Δweight (R(2) = 0.42, P = .0001). Although systolic (P = .33) and diastolic (P = .76) blood pressure were unchanged, improvements in arterial stiffness (aortic pulse wave velocity, -0.4 m/s [-1.2 to +0.2, P = .046]) and endothelial function (flow mediated dilatation, +1.73% [-0.32 to +6.19, P = .0013]) were observed. Left ventricular mass index regressed in men (-11.8 g/cm(2) [-26.6 to -1.75], P = .019) but not in women (P = .98). Vascular and cardiac changes were independent of ΔGH or ΔIGF-1 and also showed considerable interindividual variation. Metabolic parameters were largely unchanged., Conclusions: Presurgical ATG therapy lowers GH and IGF-1 concentrations, induces tumor shrinkage, and ameliorates/reverses cardiac, vascular, and sleep complications in many patients with acromegaly. However, responses vary considerably between individuals, and attainment of biochemical control cannot be assumed to equate to universal complication control.

Background: Arterial stiffness is an important determinant of cardiovascular risk. Elastin is the main elastic component of the arterial wall and can be degraded by a number of enzymes including serine proteases and matrix metalloproteinases (MMPs). Serum MMP-9 levels correlate with arterial stiffness and predict cardiovascular risk. Polymorphisms in the MMP-9 gene are also associated with large artery function in subjects with coronary artery disease. Therefore, we investigated the influence of known MMP-9 (-1562C>T, R279Q) polymorphisms on arterial stiffness in a large cohort of healthy individuals (n=865)., Methods and Results: Aortic pulse wave velocity (PWV) and augmentation index were assessed. Supine blood pressure, biochemical markers, MMP-9 levels, and serum elastase activity (SEA) were also determined. Genomic DNA was extracted and genotyping performed. Aortic PWV, serum MMP-9, and SEA were higher in carriers of the rare alleles for the -1562C>T and R279Q polymorphisms. These polymorphisms were also associated with aortic PWV after correction for other confounding factors. Stepwise regression models with known or likely determinants of arterial stiffness revealed that approximately 60% of the variability in aortic PWV was attributable to age, mean arterial pressure, and genetic variants (P<0.001)., Conclusions: We have demonstrated for the first time that aortic stiffness and elastase activity are influenced by MMP-9 gene polymorphisms. This suggests that the genetic variation in this protein may be involved in the process of large artery stiffening.

Isolated systolic hypertension is a common condition in individuals aged older than 60 years. However, isolated systolic hypertension has also been described in young individuals, although the mechanisms are poorly understood. We hypothesized that in young adults, isolated systolic hypertension and essential hypertension have different hemodynamic mechanisms and the aim of this study was to test this hypothesis in a cohort of subjects from The ENIGMA Study. Peripheral and central blood pressure, aortic pulse wave velocity, cardiac output, stroke volume, and peripheral vascular resistance were determined in 1008 subjects, aged 17 to 27 years. Compared with normotensive subjects, those with isolated systolic hypertension had significantly higher peripheral, central, and mean blood pressure, aortic pulse wave velocity, cardiac output, and stroke volume (P<0.001 for all comparisons). However, there were no differences in pulse pressure amplification, heart rate, or peripheral vascular resistance between the two groups. Compared with subjects with essential hypertension, mean pressure, heart rate, and peripheral vascular resistance were all significantly lower in isolated systolic hypertensive subjects, but pulse pressure amplification, aortic pulse wave velocity, cardiac output, and stroke volume were higher (P<0.001 for all comparisons). We have demonstrated that in young adults, isolated systolic hypertension and essential hypertension arise from different hemodynamic mechanisms. Isolated systolic hypertension appears to result from an increased stroke volume and/or aortic stiffness, whereas the major hemodynamic abnormality underlying essential hypertension is an increased peripheral vascular resistance. Long-term follow-up of these individuals is now required to determine whether they are at increased risk compared with age-matched normotensive individuals.

Background: Arterial stiffness is an independent determinant of cardiovascular risk, and arterial stiffening is the predominant abnormality in systolic hypertension. Elastin is the main elastic component of the arterial wall and can be degraded by a number of enzymes, including matrix metalloproteinase-9 (MMP-9) and MMP-2. We hypothesized that elastase activity would be related to arterial stiffness and tested this using isolated systolic hypertension (ISH) as a model of stiffening and separately in a large cohort of healthy individuals., Methods and Results: A total of 116 subjects with ISH and 114 matched controls, as well as 447 individuals free from cardiovascular disease were studied. Aortic and brachial pulse wave velocity (PWV) and augmentation index were determined. Blood pressure, lipids, C-reactive protein, MMP-9, MMP-2, serum elastase activity (SEA), and tissue-specific inhibitor 2 of metalloproteinases were measured. Aortic and brachial PWV, MMP-9, MMP-2, and SEA levels were increased in ISH subjects compared with controls (P=0.001). MMP-9 levels correlated linearly and significantly with aortic (r=0.45; P=0.001) and brachial PWV (r=0.22; P=0.002), even after adjustments for confounding variables. In the younger, healthy subjects, MMP-9 and SEA were also independently associated with aortic PWV., Conclusions: Aortic stiffness is related to MMP-9 levels and SEA, not only in ISH, but also in younger, apparently healthy individuals. This suggests that elastases including MMP-9 may be involved in the process of arterial stiffening and development of ISH. The relationship between arterial stiffness and elastase activity was examined in isolated systolic hypertension (ISH), and separately in a large cohort of healthy individuals. Aortic stiffness is related to MMP-9, not only in ISH, but also in healthy individuals, suggesting elastases may be involved in the process of arterial stiffening and the development of ISH.