Jonathan Diesch

Altered Plasma Versus Vascular Biopterins in Human Atherosclerosis Reveal Relationships Between Endothelial Nitric Oxide Synthase Coupling, Endothelial Function, and Inflammation

Background— Tetrahydrobiopterin (BH4) is a key regulator of endothelial nitric oxide synthase (eNOS) activity and coupling. However, the extent to which vascular and/or systemic BH4 levels are altered in human atherosclerosis and the importance of BH4 bioavailability in determining endothelial function and oxidative stress remain unclear. We sought to define the relationships between plasma and vascular biopterin levels in patients with coronary artery disease and to determine how BH4 levels affect endothelial function, eNOS coupling, and vascular superoxide production. Methods and Results— Samples of saphenous veins and internal mammary arteries were collected from 219 patients with coronary artery disease undergoing coronary artery bypass grafting. We determined plasma and vascular levels of biopterins, vasomotor responses to acetylcholine, and vascular superoxide production in the presence and absence of the eNOS inhibitor NG-nitro-l-arginine methyl ester. High vascular BH4 was associated with greater vasorelaxations to acetylcholine (P<0.05), whereas high plasma BH4 was associated with lower vasorelaxations in response to acetylcholine (P<0.05). Furthermore, an inverse association was observed between plasma and vascular biopterins (P<0.05 for both saphenous veins and internal mammary arteries). High vascular (but not plasma) BH4 was associated with reduced total and NG-nitro-l-arginine methyl ester–inhibitable superoxide, suggesting improved eNOS coupling. Finally, plasma but not vascular biopterin levels were correlated with plasma C-reactive protein levels (P<0.001). Conclusions— An inverse association exists between plasma and vascular biopterins in patients with coronary artery disease. Vascular but not plasma BH4 is an important determinant of eNOS coupling, endothelium-dependent vasodilation, and superoxide production in human vessels, whereas plasma biopterins are a marker of systemic inflammation.

Aldehyde dehydrogenase-2 inhibition blocks remote preconditioning in experimental and human models

Mitochondrial aldehyde dehydrogenase-2 (ALDH-2) is involved in preconditioning pathways, but its role in remote ischaemic preconditioning (rIPC) is unknown. We investigated its role in animal and human models of rIPC. (i) In a rabbit model of myocardial infarction, rIPC alone reduced infarct size [69xa0±xa05.8xa0% (nxa0=xa011) to 40xa0±xa06.5xa0% (nxa0=xa012), Pxa0=xa00.019]. However, rIPC protection was lost after pre-treatment with the ALDH-2 inhibitor cyanamide (62xa0±xa07.6xa0% controls, nxa0=xa010, versus 61xa0±xa06.9xa0% rIPC after cyanamide, nxa0=xa010, Pxa0>xa00.05). (ii) In a forearm plethysmography model of endothelial ischaemia–reperfusion injury, 24 individuals of Asian ethnic origin underwent combined rIPC and ischaemia–reperfusion (IR). 11 had wild-type (WT) enzyme and 13 carried the Glu504Lys (ALDH2*2) polymorphism (rendering ALDH-2 functionally inactive). In WT individuals, rIPC protected against impairment of response to acetylcholine (Pxa0=xa00.9), but rIPC failed to protect carriers of Glu504Lys polymorphism (Pxa0=xa00.004). (iii) In a second model of endothelial IR injury, 12 individuals participated in a double-blind placebo-controlled crossover study, receiving the ALDH-2 inhibitor disulfiram 600xa0mg od or placebo for 48xa0h prior to assessment of flow-mediated dilation (FMD) before and after combined rIPC and IR. With placebo, rIPC was effective with no difference in FMD before and after IR (6.18xa0±xa01.03xa0% and 4.76xa0±xa00.93xa0% Pxa0=xa00.1), but disulfiram inhibited rIPC with a reduction in FMD after IR (7.87xa0±xa01.27xa0% and 3.05xa0±xa00.53xa0%, Pxa0=xa00.001). This study demonstrates that ALDH-2 is involved in the rIPC pathway in three distinct rabbit and human models. This has potential implications for future clinical studies of remote conditioning.

Impaired Endothelial Responses in Apparently Healthy Young People Associated With Subclinical Variation in Blood Pressure and Cardiovascular Phenotype

BACKGROUNDnA phenomenon of endothelial impairment, independent of classical cardiovascular risk factors, has been observed in young people. We identified subjects with persistently reduced, or declining, endothelial function during adolescence and early adulthood, without apparent cardiovascular risk, and investigated the clinical relevance of this finding.nnnMETHODSnEndothelial vasomotor responses were assessed by brachial artery flow-mediated dilatation (FMD) at age 15 years in 47 subjects (22 males) who returned for a repeated measurement at age 25. Subjects underwent quantification of left ventricular mass (LVM) and function by cardiovascular magnetic resonance, central arterial stiffness by applanation tonometry, and common carotid artery intima-media thickness using ultrasound on their visit at age 25.nnnRESULTSnIndividuals with low average FMD over 10-year period, although normotensive, had 5 mm Hg higher systolic blood pressure and, significantly greater LVM (73.48 ± 7.73 vs. 56.25 ± 9.54 g/m(2), P = 0.0001), carotid intima-media thickness (cIMT) (0.53 ± 0.06 vs. 0.47 ± 0.04 mm, P = 0.03), and pulse wave velocity (5.97 ± 0.63 vs. 5.29 ± 0.59 m/s, P = 0.02) than those with higher endothelial responses. Subjects with the greatest decline in FMD over 10 years had a significant increase in mean arterial pressure but similar cardiovascular phenotype.nnnCONCLUSIONnPersistently reduced, or declining, endothelial function during adolescence, in the absence of overt cardiovascular disease, is a sensitive early marker associated with subclinical changes in blood pressure (BP) and an adverse cardiovascular phenotype. The findings highlight the potential importance of endothelial responses during adolescence in primary prevention strategies for hypertension.

Myocardial systolic strain assessed by cardiovascular magnetic resonance relates to subclinical atherosclerosis in healthy young adults

Background Cardiovascular magnetic resonance (CMR) allows quantification of early changes in systolic myocardial function. In the elderly, reduced left ventricular systolic function is related to elevated carotid intima media thickness (IMT), a well-established marker of atherosclerosis. We therefore sought to determine if peak myocardial systolic strain was also related to subclinical variation in carotid IMT and cardiovascular risk factors in young adults. Methods We recruited 68 individuals (39 females, 29 males) with a mean age of 28.29±5.45 (mean±SD). Peak midventricular myocardial circumferential systolic strain and left ventricular mass adjusted for body surface area (LVM) were assessed by CMR. Carotid IMT was measured as a marker of subclinical atherosclerosis using ultrasound. Demographic and anthropometric characteristics were measured as well as metabolic parameters and peripheral blood pressure. Results Individuals with reduced peak myocardial circumferential systolic strain had higher carotid IMT (r=0.406, P=0.001). Elevated total cholesterol and waist to hip ratio were both significantly associated with reduced myocardial strain. Increased LVM, peripheral systolic blood pressure, pulse pressure, glucose, triglycerides, age, BMI and WHR, as well as reduced HDL, were all significantly associated with increased carotid IMT (P<0.01). Males also had higher carotid IMT than females (mean±SD = 0.55±0.071mm vs 0.48±0.059mm, P=0.001). However, the association between carotid IMT and peak myocardial circumferential systolic strain was independent of gender and LVM. Conclusions We show for the first time associations between subclinical cardiac function and subclinical atherosclerosis in young adults. This study demonstrates the ability of CMR to detect subtle changes in cardiac function relevant to cardiovascular disease development in young people.

SHORT TERM ELEVATION OF CHOLESTEROL LEVEL IN NEONATAL LIFE AND LONG TERM CHANGES IN AORTIC STIFFNESS: INSIGHTS FROM USE OF INTRAVENOUS LIPIDS

Introduction Offspring born to hypercholesterolaemic mothers have increased fatty streak formation in the fetal aorta, which persists into adolescence. To understand whether exposure to elevated cholesterol in early life, independent of a maternal history of hypercholesterolaemia, also has a long-term impact on the cardiovascular system we studied the vascular phenotype of adults in whom cholesterol levels were artificially elevated for a short period postnatally. Methods We prospectively followed-up 102 subjects born premature now aged 23 to 28u2005years. Individuals exposed to maternal hypercholesterolaemia were excluded. 18 received intravenous (IV) lipids during the first nine weeks of life and were matched 2:1 for pregnancy and early life complications, age, sex, birthweight and gestational age with controls that did not receive IV lipids. Aortic pulse wave velocity (aPWV), regional aortic distensibility, left ventricular mass and ejection fraction were determined by cardiovascular magnetic resonance. Detailed lifestyle information and anthropometric measurements were collected during childhood and adolescence. Metabolic parameters were measured multiple times per week for the first 9u2005weeks of life and again at follow-up visits. Results Individuals that received IV lipids achieved significantly higher maximum cholesterol levels during the first 9u2005weeks of life than those that did not (mean±SD=4.38±1.65 vs 3.12±0.78u2005mmol/l, p=0.006). Dose given and number of days on IV lipids also associated with maximum cholesterol level during this period (r=0.557, p<0.001 and r=0.567, p<0.001, respectively). There was a graded relation between the maximum elevation in circulating cholesterol postnatally and aortic stiffness (aPWV) in young adulthood (r=0.596, p<0.001). The greatest increase in stiffness was seen in the abdominal aorta, where distensibility was significantly reduced in the group that received IV lipids (mean±SD=9.74±4.27 vs 12.91±4.11/mmu2002Hg×103, p=0.012). There were no differences between the groups in other vascular or left ventricular measures. In a stepwise regression model, maximum cholesterol level achieved in the first few weeks of life was an independent predictor of aPWV in young adulthood (β=0.596, p<0.001) and accounted for 30.9% of the variance in hierarchical multiple regression (β=0.584, p<0.001). Conclusions Brief artificial elevation of cholesterol level in immediate postnatal life is associated with long term changes in aortic function independent of later cholesterol levels. The association is graded depending on the degree of elevation of circulating cholesterol. High cholesterol exposure during sensitive periods of early postnatal life may have long term impacts on the cardiovascular system.

110 Myocardial systolic strain and subclinical atherosclerosis in young adult life

Background In the elderly, reduced left ventricular function is related to elevated carotid intima media thickness (IMT), a well-established subclinical marker of atherosclerosis. Cardiovascular magnetic resonance (CMR) allows for precise quantification of changes in myocardial structure and function. We therefore sought to determine if in young adults, without overt cardiovascular risk factors, there was already evidence of early changes in systolic function related to subclinical atherosclerosis. Methods We studied 81 individuals (44 females, 37 males) without cardiovascular risk factors and with a mean age of 28.42±5.36u2005years (mean±SD). Peak mid-ventricular myocardial circumferential systolic strain and left ventricular mass adjusted for body surface area (LVM) were assessed by CMR. Carotid IMT was measured as a marker of subclinical atherosclerosis using ultrasound. Demographic and anthropometric characteristics were measured as well as metabolic parameters and peripheral and central blood pressure. Results Individuals with reduced peak myocardial circumferential systolic strain had higher carotid IMT (r=0.392, p<0.001). Total cholesterol level and waist to hip ratio were both significantly associated with reduced myocardial strain. Increased LVM, central and peripheral systolic blood pressure, peripheral pulse pressure, glucose, triglycerides, age, body mass index and waist to hip ratio, as well as reduced high-density lipoprotein, were all significantly associated with increased carotid IMT (p<0.01). Males also had higher carotid IMT than females (mean±SD = 0.54±0.068u2005mm vs 0.47±0.042u2005mm, p<0.001). The association between carotid IMT and peak myocardial circumferential systolic strain was independent of gender, smoking, LVM as well as peripheral and central blood pressure measures. Conclusions We have shown for the first time that subclinical changes in cardiac function and subclinical atherosclerosis are closely interrelated in young adults, with associations that extend to those in the normal range of cardiovascular risk. This study further establishes the ability of CMR to detect early changes in cardiovascular disease development.

ENDOTHELIAL FUNCTION DURING ADOLESCENCE PREDICTS LEFT VENTRICULAR MASS IN EARLY ADULT LIFE

Background Left ventricular mass is a powerful independent predictor of mortality and morbidity in adults. Endothelial function may influence cause cardiac hypertrophy through modification of myocardial biology or arterial stiffness. We sought to determine whether endothelial dysfunction during adolescence and early adult life is independently associated with increased left ventricular mass. Methods Thirty healthy normotensive subjects (43% males) underwent assessment of endothelial function by flow mediated dilatation (FMD) of the brachial artery at the age of 15u2005years using ultrasound. Subjects were followed up at the age of 23–26u2005years for assessment of left ventricular mass (LVM) by cardiovascular magnetic resonance imaging (Siemens 1.5u2005T Sonata scanner), adjusted for body surface area (LVMI), and repeated FMD measurements using the same methods. Cardiovascular risk factors including body size, blood pressure, lipid profile, glucose tolerance and smoking were assessed at both time points. Results FMD in early adulthood was significantly related to LVMI (r −0.55, p 0.002). FMD at the age 15 was similarly inversely associated with LVMI 10u2005years later (r −0.41, p 0.02) with greater endothelial responses related to reduced left ventricular mass. Those with FMD consistently above the mean at both age 15 and 25 had significantly lower LVMI compared to those with FMD below the mean (58u2005g/m2 vs 68u2005g/m2 p<0.05). In a multivariate regression model of LVMI, including cardiovascular risk factors, FMD was the main independent predictor of ventricular mass. Conclusion Endothelial responses during adolescence predict left ventricular mass 10u2005years later and those with consistently high endothelial responses over this time period have the lowest left ventricular mass. Endothelial function may influence cardiac structure in young people in the absence of classic risk factors such as hypertension and obesity. Abstract 75 Figure 1 Abstract 75 Figure 2