Investigating the lowest threshold of vascular benefits from LDL cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers - a mechanistic physiological study (INTENSITY-LOW): protocol and study rationale.

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-NG-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

The impact of cardiovascular risk factors on aortic stiffness and wave reflections depends on age: The Anglo-Cardiff Collaborative Trial (ACCT III)

Ageing exerts differential effects on arterial stiffness and wave reflections. However, the impact of cardiovascular risk factors on arterial stiffness and wave reflections and, particularly, how such effects are influenced by ageing has not been assessed within a single large population, covering a sufficiently wide age range. Therefore, we determined the extent to which age alters the impact of traditional cardiovascular risk factors on arterial stiffness and wave reflections. Aortic stiffness and wave reflections were assessed in 4421 individuals (age range 18 to 92 years). When treated as continuous variables, clinic systolic, diastolic, and pulse pressures and glucose levels were independently associated with stiffness, and, with the exception of diastolic pressure, these associations were more marked in older individuals. In contrast, clinic systolic and diastolic pressures and smoking were independently associated with wave reflections, with stronger associations observed in younger individuals. The impact of traditional cardiovascular risk factors on arterial stiffness and wave reflections is strongly dependent on age and is largely driven by blood pressure. Additional studies are required to assess the impact of these arterial measures on cardiovascular outcome within a single population

Adiposity and systolic blood pressure

OBJECTIVES: The positive association between adiposity and hypertension is well recognized. However, not all overweight individuals have elevated blood pressure (BP). Moreover, different factors may be associated with high BP in normal-weight versus overweight individuals. The aim of the current study was to examine the influence of adiposity on the relationship between SBP and underlying haemodynamic mechanisms in young adults. METHOD: Data from 2502 patients were available from the Enigma study. Detailed demographic, biochemical, and haemodynamic data were obtained in all individuals. Data were analysed between lower and upper tertiles of BMI and SBP, separately for each sex. RESULTS: In normal-weight individuals, cardiac output (CO) was elevated in those with higher SBP, independently of body size. Moreover, higher CO was associated with an increased stroke volume in men (P < 0.001), but an increased heart rate in women (P = 0.002). In contrast, in overweight individuals, peripheral vascular resistance (PVR) was elevated in men with higher SBP (P = 0.02) and those with lower SBP had the lowest PVR of all groups. In linear regression analyses, there was a stronger association between SBP and CO in normal-weight individuals, but a stronger association between SBP and PVR in overweight individuals. CONCLUSION: Different haemodynamic mechanisms are associated with elevated SBP in young adults, depending on body size and sex. These data suggest the need for differential approaches to the identification and management of young adults with elevated BP.This work was funded by the British Heart Foundation and the NIHR Cambridge Biomedical Research CentreThis is the final version of the article. It was first available from Lippincott Williams & Wilkins via http://dx.doi.org/10.1097/HJH.000000000000079

Aortic calcification is associated with aortic stiffness and isolated systolic hypertension in healthy individuals

Arterial stiffening is an independent predictor of mortality and underlies the development of isolated systolic hypertension (ISH). A number of factors regulate stiffness, but arterial calcification is also likely to be important. We tested the hypotheses that aortic calcification is associated with aortic stiffness in healthy individuals and that patients with ISH exhibit exaggerated aortic calcification compared with controls. A total of 193 healthy, medication-free subjects (mean age+/-SD: 66+/-8 years) were recruited from the community, together with 15 patients with resistant ISH. Aortic pulse wave velocity (PWV) was measured noninvasively, and aortic calcium content was quantified from high-resolution, thoraco-lumbar computed tomography images using a volume scoring method. In healthy volunteers, calcification was positively and significantly associated with aortic PWV (r=0.6; P<0.0001) but was not related to augmentation index or brachial PWV. Calcification was significantly higher in treatment-resistant and healthy subjects with ISH compared with controls (mean [interquartile range]: 1.92 [1.14 to 3.66], 0.84 [0.35 to 1.75], and 0.19 [0.1 to 0.78] cm3, respectively; P<0.0001 for both). In a multiple regression model, aortic calcium was independently associated with aortic PWV along with age, mean arterial pressure, heart rate, and estimated glomerular filtration rate (R(2)=0.51; P<0.0001). Only age, calcium phosphate product, and aortic PWV were independently associated with calcification. These data suggest that calcification may be important in the process of aortic stiffening and the development of ISH. Calcification may underlie treatment resistance in ISH, and anticalcification strategies may present a novel therapy

The cardiovascular phenotype of elevated blood pressure differs markedly between young males and females: The Enigma Study

Blood pressure in young adults predicts blood pressure in later life. We aimed to identify metabolic, haemodynamic and autonomic characteristics associated with raised blood pressure in young adults and whether these differ between males and females. 3145 healthy subjects, aged 18-40 years, were grouped according to sex and blood pressure category following the recent reclassification of blood pressure as part of American Heart Association/American College of Cardiology 2017 guidelines. All individuals undertook a lifestyle and medical history questionnaire, and detailed metabolic, haemodynamic and autonomic assessments. Stage 1 hypertension and normal blood pressure were the most common blood pressure phenotypes in males (29%) and females (68%), respectively. In both sexes, cardiac output was positively associated with increasing blood pressure category (P<0.001 for both). Similar positive trends were observed for heart rate and stroke volume in males (P<0.001 for both) and heart rate in females (P<0.001). Unlike in males, peripheral vascular resistance, aortic pulse wave velocity and augmentation index were significantly increased in hypertensive females (P<0.001 for all) compared with the other blood pressure categories. Most heart rate variability indices decreased across the blood pressure categories, particularly in males. In young adults, metabolic and haemodynamic abnormalities associated with hypertension are already present at the elevated blood pressure stage and the overall phenotype differed markedly between sexes. While a “cardiac” phenotype was associated with elevated blood pressure and hypertension in males, a “vascular” phenotype, characterized by elevated peripheral vascular resistance, aortic pulse wave velocity and augmentation index, was dominant in females

The role of vascular adaptation in determining systolic BP in young adults

Background: Two individuals can have a similar pulse pressure (PP)but very different levels of systolic blood pressure(SBP),although the underlying mechanisms have not been described. We hypothesised that,for a given level of PP, differences in SBP relate to peripheral vascular resistance (PVR) and we tested this hypothesis in a large cohort of healthy young adults. Methods and Results: Demographic, biochemical and haemodynamic data from 3103 subjects were available for the current analyses.In both males and females, for a given level of PP, higher SBP was associated with significantly higher body weight, body mass index, heart rate and PVR (P<0.05 versus those with lower BP for all comparisons). Moreover, stratifying individuals by tertiles of PP and PVR revealed a stepwise increase in SBP from the lowest to highest tertiles for each variable, with the highest SBP occurring in those in the highest tertile of both PPnand PVRn(P<0.001 for overall trend for both sexes). PVR was also increased with increasing tertile of minimum forearm vascular resistance, in both males (P=0.002)and females (P=0.03). Conclusion: Increased PVR, mediated in part through altered resistance vessel structure,strongly associates with the elevation of SBP for a given level of PP in young adults. An impaired ability to adapt PVR appropriately to a given level of PP may be an important mechanism underlying elevated SBP in young adults

Mechanisms underlying elevated SBP differ with adiposity in young adults

OBJECTIVES: The positive association between adiposity and hypertension is well recognized. However, not all overweight individuals have elevated blood pressure (BP). Moreover, different factors may be associated with high BP in normal-weight versus overweight individuals. The aim of the current study was to examine the influence of adiposity on the relationship between SBP and underlying haemodynamic mechanisms in young adults. METHOD: Data from 2502 patients were available from the Enigma study. Detailed demographic, biochemical, and haemodynamic data were obtained in all individuals. Data were analysed between lower and upper tertiles of BMI and SBP, separately for each sex. RESULTS: In normal-weight individuals, cardiac output (CO) was elevated in those with higher SBP, independently of body size. Moreover, higher CO was associated with an increased stroke volume in men (P < 0.001), but an increased heart rate in women (P = 0.002). In contrast, in overweight individuals, peripheral vascular resistance (PVR) was elevated in men with higher SBP (P = 0.02) and those with lower SBP had the lowest PVR of all groups. In linear regression analyses, there was a stronger association between SBP and CO in normal-weight individuals, but a stronger association between SBP and PVR in overweight individuals. CONCLUSION: Different haemodynamic mechanisms are associated with elevated SBP in young adults, depending on body size and sex. These data suggest the need for differential approaches to the identification and management of young adults with elevated BP

Aortic calcification is associated with aortic stiffness and isolated systolic hypertension in healthy individuals

Arterial stiffening is an independent predictor of mortality and underlies the development of isolated systolic hypertension (ISH). A number of factors regulate stiffness, but arterial calcification is also likely to be important. We tested the hypotheses that aortic calcification is associated with aortic stiffness in healthy individuals and that patients with ISH exhibit exaggerated aortic calcification compared with controls. A total of 193 healthy, medication-free subjects (mean age+/-SD: 66+/-8 years) were recruited from the community, together with 15 patients with resistant ISH. Aortic pulse wave velocity (PWV) was measured noninvasively, and aortic calcium content was quantified from high-resolution, thoraco-lumbar computed tomography images using a volume scoring method. In healthy volunteers, calcification was positively and significantly associated with aortic PWV (r=0.6; P<0.0001) but was not related to augmentation index or brachial PWV. Calcification was significantly higher in treatment-resistant and healthy subjects with ISH compared with controls (mean [interquartile range]: 1.92 [1.14 to 3.66], 0.84 [0.35 to 1.75], and 0.19 [0.1 to 0.78] cm3, respectively; P<0.0001 for both). In a multiple regression model, aortic calcium was independently associated with aortic PWV along with age, mean arterial pressure, heart rate, and estimated glomerular filtration rate (R(2)=0.51; P<0.0001). Only age, calcium phosphate product, and aortic PWV were independently associated with calcification. These data suggest that calcification may be important in the process of aortic stiffening and the development of ISH. Calcification may underlie treatment resistance in ISH, and anticalcification strategies may present a novel therapy