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 [69 ± 5.8 % (n = 11) to 40 ± 6.5 % (n = 12), P = 0.019]. However, rIPC protection was lost after pre-treatment with the ALDH-2 inhibitor cyanamide (62 ± 7.6 % controls, n = 10, versus 61 ± 6.9 % rIPC after cyanamide, n = 10, P > 0.05). (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 (P = 0.9), but rIPC failed to protect carriers of Glu504Lys polymorphism (P = 0.004). (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 600 mg od or placebo for 48 h 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 (6.18 ± 1.03 % and 4.76 ± 0.93 % P = 0.1), but disulfiram inhibited rIPC with a reduction in FMD after IR (7.87 ± 1.27 % and 3.05 ± 0.53 %, P = 0.001). 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.

Cardiovascular and metabolic risk profile in young people at familial risk of depression.

BACKGROUND: Depression is associated with increased risk of several general medical conditions, including diabetes and cardiovascular disease. The nature of the association is complex and may involve bidirectional causation or a common pathophysiology. AIMS: To determine whether young people without depression but at increased familial risk have altered metabolic and blood pressure markers relative to matched controls. METHOD: We studied young people (n = 85), who had a parent with depression but no personal history of depressive illness (FH+) and healthy controls (n = 69). Cardiovascular risk profile was assessed by a fasting blood sample to measure insulin, glucose, lipids and high-sensitivity C-reactive protein (CRP) and blood pressure was measured centrally and peripherally. Arterial stiffness and waking cortisol concentration were also measured. RESULTS: Compared with controls, the FH+ group demonstrated increased peripheral and central systolic blood pressure, increased arterial stiffness and diminished insulin sensitivity but they did not differ from controls in measures of lipids, CRP or waking cortisol. CONCLUSIONS: Our data suggest that young people at increased familial risk of depression show evidence of altered cardiovascular risk profile in young adulthood even in the absence of depressive symptoms. It is possible therefore that vulnerability to conditions such as hypertension and diabetes may precede the onset of major depression and may share common risk factors.

Short-term exposure to exogenous lipids in premature infants and long-term changes in aortic and cardiac function.

OBJECTIVE: Intravenous lipid use is associated with an acute hyperlipidemia, but long-term consequences have not been studied. We investigated whether elevated lipids in humans during the critical period of preterm neonatal life have a long-term impact on aortic and myocardial function relevant to adult disease. METHODS AND RESULTS: We followed up 102 subjects born prematurely and now aged 23 to 28 years. Eighteen received intravenous lipids as neonates and were matched to controls with equivalent perinatal characteristics. Global and regional aortic stiffness and left ventricular function were assessed by cardiovascular magnetic resonance. Those who received intravenous lipids had greater aortic stiffness in early adulthood (P=0.0002), with greater stiffness in the abdominal aorta (P=0.012). The relationship was graded according to the elevation in neonatal cholesterol induced by intravenous lipids (P<0.0001) but not other metabolic parameters altered by the infusion. Peak systolic circumferential strain was also reduced in the lipid group (P=0.006), which, again, was proportional to neonatal cholesterol level (P<0.01). CONCLUSIONS: Aortic and myocardial function in young adulthood is associated with intralipid exposure during neonatal life for preterm infants, in a graded manner related to the rise in cholesterol. Circulating cholesterol during critical developmental periods may have long-term impacts on the human cardiovascular system.

Preoperative sCD40L levels predict risk of atrial fibrillation after off-pump coronary artery bypass graft surgery.

BACKGROUND: The risk of atrial fibrillation (AF) after coronary bypass surgery has been related to redox state, inflammation, and ischemia. Platelet activation is common to all of these pathways. We investigated the relation between AF and preoperative soluble CD40 ligand (sCD40L), a proinflammatory marker released by activated platelets. Furthermore, we studied the role of inflammation, endothelial function, and redox state in this relation. METHODS AND RESULTS: sCD40L levels were measured in 144 patients in sinus rhythm the day before off-pump coronary artery surgery. Systemic inflammation was assessed from levels of C-reactive protein and soluble intercellular adhesion molecule-1, and endothelial function was assessed from the brachial artery flow-mediated dilatation response. Graft samples were collected during surgery to assess vascular redox state. AF occurred in 33% of patients after surgery, with 3% still in AF after 6 weeks. Preoperative sCD40L levels were significantly higher in those who developed in-hospital AF (odds ratio for a 1-SD increase in log[sCD40L]=1.97; 95% CI, 1.21 to 3.22; P=0.007; after adjustment for age, sex, Euroscore, and total duration of operation). sCD40L and vascular superoxide levels were higher in patients still in AF at 6 weeks, and endothelial function was lower, although the small number of events precluded statistical analysis in this group. Systemic endothelial function, redox state, and preoperative markers of systemic inflammation were not associated with in-hospital postoperative AF. CONCLUSIONS: Preoperative platelet activation, as assessed by sCD40L levels, is a novel predictor of postoperative AF, independent of systemic endothelial function, vascular redox state, and systemic inflammation.

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 N(G)-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 N(G)-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.

Impaired endothelial responses in apparently healthy young people associated with subclinical variation in blood pressure and cardiovascular phenotype.

BACKGROUND: A 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. METHODS: Endothelial 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. RESULTS: Individuals 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. CONCLUSION: Persistently 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.

Unique blood pressure characteristics in mother and offspring after early onset preeclampsia.

Risk of hypertension in mother and offspring after preeclampsia is greater if preeclampsia develops early in pregnancy. We investigated whether those who develop early onset disease have unique adverse blood pressure characteristics. One hundred forty women were studied 6 to 13 years either after a pregnancy complicated by preeclampsia (45 women with early onset preeclampsia before 34 weeks gestation and 45 women with late-onset preeclampsia) or after a normotensive pregnancy (50 women). Forty-seven offspring from these pregnancies also participated. Data on maternal antenatal and postnatal blood pressures were extracted from maternity records and related to peripheral, central, and ambulatory blood pressure measurements in later life. Compared with late-onset preeclampsia, early onset preeclampsia was associated with higher diastolic blood pressure 6 weeks postnatally (86.25 ± 13.46 versus 75.00 ± 5.00 mm Hg, P<0.05), a greater increase in blood pressure relative to booking blood pressure over the subsequent 6 to 13 years, and higher nocturnal systolic and diastolic blood pressures in later life (111.07 ± 13.18 versus 101.13 ± 11.50 mm Hg, P=0.04, and 67.00 ± 7.25 versus 58.60 ± 5.79 mm Hg, P=0.002). Furthermore, at age 6 to 13 years their offspring had higher systolic blood pressure compared with those born to late-onset preeclampsia (96.27 ± 7.30 versus 88.39 ± 7.57 mm Hg, P=0.005). Mothers who developed early onset preeclampsia, and the offspring of that pregnancy display specific adverse blood pressure characteristics later in life. These are not evident in mothers and offspring after late-onset preeclampsia or normotensive pregnancy.

Elevated blood pressure in offspring born premature to hypertensive pregnancy: is endothelial dysfunction the underlying vascular mechanism?

Offspring born to mothers with hypertensive pregnancy have higher childhood blood pressure. We hypothesized this relates to prenatally programmed differences in the underlying vascular pathophysiology of the offspring and that these would be most apparent in those born preterm because of severe hypertension. We carried out a 20-year follow-up study of 71 subjects born preterm, 19 to a hypertensive pregnancy and 52 to a normotensive pregnancy. Findings were compared with 38 subjects born at term to uncomplicated pregnancies. Peripheral and central blood pressures were measured, and then central arterial stiffness was assessed by carotid-femoral pulse wave velocity using applanation tonometry. Ultrasound was used to assess flow-mediated endothelial-dependent and independent brachial artery responses and common carotid artery intima-media thickness. Offspring born preterm to either hypertensive or normotensive pregnancy had higher peripheral and central blood pressure compared with full-term born offspring (central mean arterial pressure after preterm hypertensive pregnancy: 84.92+/-7.0 mm Hg; preterm normotensive pregnancy: 84.13+/-8.9 mm Hg; full-term pregnancy: 76.24+/-7.96 mm Hg; P=0.0009). However, underlying vascular phenotype differed. Preterm offspring of normotensive pregnancy had greater arterial stiffness than offspring of hypertensive pregnancy (5.92+/-0.84 versus 5.42+/-0.73 m/s; P=0.039), whereas offspring of hypertensive pregnancy had greater carotid intima-media thickness (0.52+/-0.04 versus 0.48+/-0.06 mm; P=0.013) and 30% lower flow-mediated dilatation (4.25+/-4.02% versus 6.79+/-4.38%; P=0.05). Prematurity is associated with elevated blood pressure in later life. However, predominant underlying vascular phenotype depends on maternal pathology. Targeting endothelial function may be particularly important for primary prevention after hypertension in pregnancy.

Relation of preoperative radial artery flow-mediated dilatation to nitric oxide bioavailability in radial artery grafts used in off-pump coronary artery bypass grafting.

The radial artery is prone to vasospasm after coronary bypass surgery, and endothelial dysfunction is likely to be a key factor. We investigated whether endothelial dysfunction in radial artery conduits is present, and can be identified, preoperatively using a simple noninvasive ultrasound test of radial artery endothelial response, flow-mediated dilatation (FMD). The study population consisted of 126 patients scheduled for coronary artery bypass grafting. The afternoon before operation, patients had noninvasive ultrasound assessment of endothelial function in the left radial artery by FMD, which measures change in arterial size after an increase in flow-an endothelial-dependent response. Surplus graft segments were obtained at operation and nitric oxide bioavailability within the vessels determined from ex vivo responses to acetylcholine. Preoperative FMD in the radial artery was associated with vasorelaxations to acetylcholine in radial artery grafts (p<0.001 for both dose-response curves and maximum relaxations), although there was weak borderline association between FMD and vasorelaxations of saphenous vein grafts (p=0.07 for dose-response curves and p<0.05 for maximum relaxations). In multivariate analysis including cardiac risk factors, FMD was a predictor of vasorelaxations of radial artery grafts (beta=0.020, SE=0.009, p=0.030), independent of classic risk factors for atherosclerosis. In conclusion, there is significant interindividual variation in the endothelial function of vessels used for coronary artery bypass surgery, particularly the radial artery. These differences are present and can be identified preoperatively by FMD.

GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function.

OBJECTIVES: This study sought to determine the effects of endogenous tetrahydrobiopterin (BH4) bioavailability on endothelial nitric oxide synthase (eNOS) coupling, nitric oxide (NO) bioavailability, and vascular superoxide production in patients with coronary artery disease (CAD). BACKGROUND: GTP-cyclohydrolase I, encoded by the GCH1 gene, is the rate-limiting enzyme in the biosynthesis of BH4, an eNOS cofactor important for maintaining enzymatic coupling. We examined the associations between haplotypes of the GCH1 gene, GCH1 expression and biopterin levels, and the effects on endothelial function and vascular superoxide production. METHODS: Blood samples and segments of internal mammary arteries and saphenous veins were obtained from patients with CAD undergoing coronary artery bypass grafting (n = 347). The GCH1 haplotypes were defined by 3 polymorphisms: rs8007267G

Cardiac output by Portapres.

Portapres derives continuous estimates of cardiac output from the peripheral pulse and has the potential to be an extremely valuable physiological and clinical tool. We assessed Portapres estimates of cardiac output in healthy subjects at rest, during maximal treadmill exercise ( n = 8) and during decreases caused by orthostatic stress ( n = 8). Comparison with a rebreathing method indicated that Portapres tended to overestimate cardiac output. The random errors of the estimates (precision), expressed as +/- 2 S.D. of the differences between paired estimates during steady states, ranged between 1.2 and 2.6 litres/min. We conclude that these errors indicate that the method is probably only useful for assessing changes in individual subjects where large changes are anticipated, as during exercise. When smaller changes occur, as during orthostasis, the errors preclude the use of individual subject data and only permit group average data to be examined.