[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Aortic stenosis (AS) leads to diffuse fibrosis in the myocardium, which is linked to adverse outcome. Myocardial T1 values change with tissue composition. OBJECTIVE: To test the hypothesis that our recently developed non-contrast cardiac magnetic resonance (CMR) T1 mapping sequence could identify myocardial fibrosis without contrast agent. DESIGN, SETTING AND PATIENTS: A prospective CMR non-contrast T1 mapping study of 109 patients with moderate and severe AS and 33 age- and gender-matched controls. METHODS: CMR at 1.5 T, including non-contrast T1 mapping using a shortened modified Look-Locker inversion recovery sequence, was carried out. Biopsy samples for histological assessment of collagen volume fraction (CVF%) were obtained in 19 patients undergoing aortic valve replacement. RESULTS: There was a significant correlation between T1 values and CVF% (r=0.65, p=0.002). Mean T1 values were significantly longer in all groups with severe AS (972±33 ms in severe asymptomatic, 1014±38 ms in severe symptomatic) than in normal controls (944±16 ms) (p<0.05). The strongest associations with T1 values were for aortic valve area (r=-0.40, p=0.001) and left ventricular mass index (LVMI) (r=0.36, p=0.008), and these were the only independent predictors on multivariate analysis. CONCLUSIONS: Non-contrast T1 values are increased in patients with severe AS and further increase in symptomatic compared with asymptomatic patients. T1 values lengthened with greater LVMI and correlated with the degree of biopsy-quantified fibrosis. This may provide a useful clinical assessment of diffuse myocardial fibrosis in the future.
[Show abstract][Hide abstract] ABSTRACT: Music goes back a very long way in human experience. Music therapy is now used in many disparate areas-from coronary care units to rehabilitation after a stroke. But its widespread adoption has a poor scientific evidence base, founded more on enthusiasm than on proper evaluation in any controlled way. This has led to a lack of clarity about whether any particular type of music is superior, or whether different types of music should be tailored to differing individuals. We therefore conducted a series of controlled studies in which we examined the effects of different styles of music-from raga to jazz-presented in random order to normal young subjects (both musically trained or not). We found that contrary to many beliefs the effect of a style of music was similar in all subjects, whatever their individual music taste. We also found that this effect appeared to operate at a sub-conscious level through the autonomic nervous system. Furthermore, musical or verbal phrases of a 10 s duration (which coincided with the normal circulatory 'Mayer' waves) induced bigger excursions in blood pressure and heart rate (reciprocal of pulse interval) and so triggered more vagal slowing and feelings of calm. These findings need to now be tested in the clinical setting since, if confirmed, this would greatly simplify the practical use of this promising tool.
Netherlands heart journal: monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 12/2012;
[Show abstract][Hide abstract] ABSTRACT: Endothelial nitric oxide synthase (eNOS) is a critical regulator of vascular homeostasis by generation of nitric oxide (NO) that is dependent on the cofactor tetrahydrobiopterin (BH4). When BH4 availability is limiting, eNOS becomes 'uncoupled', resulting in superoxide production in place of NO. Recent evidence suggests that eNOS uncoupling can also be induced by S- glutathionylation, although the functional relationships between BH4 and S- glutathionylation remain unknown. To address a possible role for BH4 in S- glutathionylation-induced eNOS uncoupling, we expressed either WT or mutant eNOS rendered resistant to S- glutathionylation in cells with tet- regulated expression of human GTP cyclohydrolase I, to regulate intracellular BH4 availablity. We reveal that S- glutathionylation of eNOS, either by exposure to 1,3-bis(2-chloroethyl)-1- nitrosourea (BCNU) or glutathione reductase-specific siRNA, results in diminished NO production and elevated eNOS-derived superoxide production, along with a concomitant reduction in BH4 levels and BH4:BH2 ratio. In eNOS uncoupling induced by BH4 deficiency, BCNU exposure further exacerbates superoxide production, BH4 oxidation and eNOS activity. Following mutation of C908S, BCNU-induced eNOS uncoupling and BH4 oxidation are abolished, whereas uncoupling induced by BH4 deficiency was preserved. Furthermore, BH4 deficiency alone is alone sufficient to reduce intracellular GSH/GSSG ratio and cause eNOS S-glutathionylation. These data provide the first evidence that BH4 deficiency- and S-glutathionylation- induced mechanisms of eNOS uncoupling, whilst mechanistically distinct, are functionally related. We propose that uncoupling of eNOS by S- glutathionylation- or by BH4-dependent mechanisms exemplifies eNOS as an integrated redox 'hub' linking upstream redox-sensitive effects of BH4 and glutathione with redox-dependent targets and pathways that lie downstream of eNOS.
[Show abstract][Hide abstract] ABSTRACT: Molecular imaging is emerging as a key experimental tool for the identification of inflammatory cellular and molecular processes involved in the development of cardiovascular disease. This review summarises current molecular imaging approaches for detection of vascular inflammation using a range of nano- and micro- sized contrast agents. We highlight strategies for detection of cell adhesion molecules, which are key regulators of endothelial activation and leukocyte recruitment in atherogenesis and ischemia-reperfusion injury. In particular, we address the properties of targeted microparticles of iron oxide (MPIO) for MRI detection of endothelial cell-specific activation of adhesion molecules in experimental models of atherosclerosis, acute vascular inflammation and ischemia-reperfusion injury, which are otherwise undetectable by conventional imaging modalities. The ability of targeted MPIO to detect endothelial activation could enable early subclinical disease detection and development of novel therapeutic strategies. We discuss opportunities for further development and potential translation of targeted MPIO for clinical imaging of cardiovascular disease.
[Show abstract][Hide abstract] ABSTRACT: Myocardial constitutive NO production depends on the activity of both endothelial and neuronal NO synthases (eNOS and nNOS, respectively). Stimulation of myocardial β3-AR produces a negative inotropic effect that is dependent on eNOS. We evaluated whether nNOS also plays a role in β3-AR signaling and found that the β3-AR-mediated reduction in cell shortening and [Ca2+]i transient amplitude was abolished both in eNOS-/- and nNOS-/- left ventricular (LV) myocytes and in wild type LV myocytes after nNOS inhibition with S-methyl-L-thiocitrulline (SMTC). LV superoxide (O2-) production was increased in nNOS-/- mice and reduced by L-NAME, indicating uncoupling of eNOS activity. eNOS S-glutathionylation and serine (Ser)-1177 phosphorylation were significantly increased in nNOS-/- myocytes whereas myocardial tetrahydrobiopterin (BH4), eNOS threonine (Thr)-495 phosphorylation, and arginase activity did not differ between genotypes. Although inhibitors of xanthine oxidoreductase (XOR) or NOX2 NADPH oxidase caused a similar reduction in myocardial O2-, only XOR inhibition reduced eNOS S-glutathionylation and Ser-1177 phosphorylation, and restored both eNOS coupled activity and the negative inotropic and [Ca2+]i transient response to β3-AR stimulation in nNOS-/- mice. In summary, our data show that increased O2- production by XOR selectively uncouples eNOS activity and abolishes the negative inotropic effect of β3-AR stimulation in nNOS-/- myocytes. These findings provide unequivocal evidence of a functional interaction between the myocardial constitutive NOS isoforms and indicate that aspects of the myocardial phenotype of nNOS-/- mice result from disruption of eNOS signaling.
[Show abstract][Hide abstract] ABSTRACT: The cofactor tetrahydrobiopterin (BH4) is required for nitric oxide (NO) production by all nitric oxide synthase (NOS) enzymes and is a key regulator of cellular redox signalling. When BH4 levels become limiting NOS enzymes become 'uncoupled' and produce superoxide rather than NO. Endothelial cell BH4 is required for the maintenance of vascular function through NO production, and reduced BH4 levels are associated with vascular dysfunction. Evidence increasingly points to important roles for BH4 and NOS enzymes in other vascular cell types. Leukocytes have a fundamental role in atherosclerosis, and new evidence points to a role in the control of hypertension. Leukocytes are a major site of iNOS expression, and the regulation of this isoform is another mechanism by which BH4 availability may modulate disease. This review provides an overview of BH4 control of NOS function in both endothelial cells and leukocytes in the context of vascular disease and current therapeutic evaluations.
[Show abstract][Hide abstract] ABSTRACT: AimsAs obesity-related cardiovascular mortality, although elevated when compared with normal weight, is lower in females than in males at every body mass index (BMI) level, we aimed to investigate gender-specific differences in left ventricular (LV) hypertrophy in obesity, which themselves have been shown to have varying prognostic value.Method and resultsIn total, 741 subjects (female, n = 399) without identifiable cardiovascular risk factors (BMI 15.7-59.2 kg/m(2)) underwent cardiovascular magnetic resonance (1.5 T) to determine LV mass, end-diastolic volume (EDV, mL), and LV mass/volume ratio (LVM/VR). Across both sexes, there was a strong positive correlation between BMI and LV mass (male r = 0.44, female r = 0.57, both P < 0.001), with males showing a greater LV hypertrophic response (male +2.3 vs. female +1.6 g per BMI point increase, P = 0.001). Concentric hypertrophy was present in both sexes and LVM/VR positively correlated to BMI (male r = 0.45, female r = 0.29, both P < 0.001) on linear regression analysis. However, the degree of concentric hypertrophy was greater in males (male +0.13 vs. female +0.06 LVM/VR increase per BMI point increase, P = 0.001). On the other hand, females showed a greater LV cavity dilatory response (female +1.1 vs. male +0.3 mL per BMI point increase, P < 0.001). Indeed, in contrast to females, where BMI and LV-EDV were positively correlated (r = 0.38, P < 0.001), BMI did not correlate with EDV in men (r = 0.03, P = 0.62).Conclusion
In the absence of traditional cardiovascular risk factors, obese men show predominantly concentric hypertrophy, whereas obese women exhibit both eccentric and concentric hypertrophy. As concentric hypertrophy is more strongly related to cardiovascular mortality than eccentric hypertrophy, our observations may explain the observed gender difference in obesity-related mortality.
[Show abstract][Hide abstract] ABSTRACT: 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.
Hypertension 10/2012; 60(5):1338-45.
Information provided on this web page is aggregated encyclopedic and bibliographical information relating to the named institution. Information provided is not approved by the institution itself. The institution’s logo (and/or other graphical identification, such as a coat of arms) is used only to identify the institution in a nominal way. Under certain jurisdictions it may be property of the institution.