Robin Ray

Endothelial Nox4 NADPH Oxidase Enhances Vasodilatation and Reduces Blood Pressure In Vivo

Objective—Increased reactive oxygen species (ROS) production is involved in the pathophysiology of endothelial dysfunction. NADPH oxidase-4 (Nox4) is a ROS-generating enzyme expressed in the endothelium, levels of which increase in pathological settings. Recent studies indicate that it generates predominantly hydrogen peroxide (H2O2), but its role in vivo remains unclear. Methods and Results—We generated transgenic mice with endothelium-targeted Nox4 overexpression (Tg) to study the in vivo role of Nox4. Tg demonstrated significantly greater acetylcholine- or histamine-induced vasodilatation than wild-type littermates. This resulted from increased H2O2 production and H2O2-induced hyperpolarization but not altered nitric oxide bioactivity. Tg had lower systemic blood pressure than wild-type littermates, which was normalized by antioxidants. Conclusion—Endothelial Nox4 exerts potentially beneficial effects on vasodilator function and blood pressure that are attributable to H2O2 production. These effects contrast markedly with those reported for Nox1 and Nox2, which involve superoxide-mediated inactivation of nitric oxide. Our results suggest that therapeutic strategies to modulate ROS production in vascular disease may need to separately target individual Nox isoforms.

Tei index to assess perioperative left ventricular systolic function in patients undergoing mitral valve repair

BACKGROUND Using echocardiography, perioperative assessment of systolic function by fractional area change (FAC) is questionable in patients suffering from mitral regurgitation (MR). Tei index, an index expressing global cardiac function, has been reported to be unchanged after mitral valve surgery. We tested the hypothesis where the Tei index could be useful in assessing the perioperative cardiac function in patients undergoing mitral valve repair (MVR). METHODS Twenty-five patients were enrolled. Transoesophageal echocardiography was performed perioperatively before and after the correction of MR. We compared the impact of the MVR on the left ventricular FAC and the Tei index. FAC was calculated from the transgastric short-axis view and Tei index was determined from the four chambers and deep transgastric views. RESULTS Two patients were excluded because of poor acoustic windows. FAC significantly decreased after MVR from 53 (9)% to 42 (10)% (P<0.001), while Tei index was unaffected [0.46 (0.16) vs 0.47 (0.17), NS]. A significant relationship was found between the preoperative Tei index and the postoperative FAC (R=-0.64, P<0.001). Moreover, a significant and clinically relevant relationship was determined between the predicted (using preoperative Tei index) and the measured postoperative FAC (R=0.64, P<0.001). CONCLUSIONS FAC but not the Tei index is influenced by MVR. The preoperative determination of the Tei index allows predicting postoperative FAC and offers the opportunity to identify patients in whom a severe unsuspected systolic dysfunction could render difficult the weaning from cardiopulmonary bypass.

Mitral valve disease.

In industrially developed countries, moderate or severe mitral valve disease is relatively common and is usually caused by prolapse or is secondary to left ventricular disease. Mitral stenosis (MS), however, is uncommon and usually a sequela of rheumatic fever. This article discusses the natural history of mitral regurgitation and MS and their medical and surgical management.

147 Deriving Coronary Artery Calcium Scores from CT Coronary Angiography: A Potential for Change to the UK Nice Guidelines on Stable Chest Pain

Keywords CT coronary angiography, Coronary calcium score, NICE guidelines Introduction Current UK NICE guidelines recommend an initial CACS scan as a first line investigation in the assessment of patients with stable chest pain with a low pre-test probability of underlying coronary artery disease (CAD), with subsequent evaluation of the coronary tree with CTCA if the CACS lies between 1 and 400. We hypothesised that the CACS can be accurately derived from CT Coronary Angiography (CTCA) allowing a potential change to UK NICE guidelines for the assessment of stable chest pain. Methods 503 consecutive patients undergoing conventional CACS and CTCA were included. A 0.1cm2 region of interest (ROI) was used to determine the mean contrast density on CTCA images either in the left main stem (LM), or – where the LM was heavily calcified - the proximal RCA.Axial contiguous 3mm CTCA images were then scored for calcium using conventional CACS software with a modified threshold calculated as: mean LM contrast density (HU) + 2 standard deviations. The results were compared to the traditionally acquired CACS (130HU threshold) and modelled using linear regression to derive a conversion factor subsequently applied to all CTCA-derived CACS. Bootstrapping (1000 samples) was used to calculate a shrinkage factor to adjust for model over-optimism.Accuracy of this method was determined using weighted Kappa for NICE recommended CACS groupings (0, 1–400, >400) and Bland-Altman analysis for absolute score. Results A final conversion factor of 1.94 (95% CI: 1.88–1.99) was used with excellent agreement between methods both for absolute score (mean difference between scores 7.19 [95% limits of agreement -214.51, 228.89] Figure 1) and when categorising patients into risk groups (k = 0.83). There was excellent discrimination between high (>400) and low risk (<400) scores with a sensitivity and specificity of 83 and 99%, and a PPV and NPV of 91 and 98%, respectively. Both inter and intra-observer agreement were excellent with no significant difference between observers in median CTCA-derived CACS and risk group placement (0 [0–25.9] vs. 0 [0–33.0]; p = 0.49, k = 0.90) and (0 [0–24] vs. 0 [0–27]; p = 0.68), k = 0.94), respectively. There was a significant reduction in radiation exposure with exclusive use of CTCA both overall (4.2 [3.1–6.2] vs. 3.2 [2.3–5.3] mSv; p < 0.0001), and with high pitch single heart-beat acquisition protocol (2.0 [1.7–3.2] vs. 1.2 [1.1–2.3] mSv; p < 0.0001). This represented a reduction of 20.6 ± 12.5% and 33.7 ± 8.2%, respectively. Abstract 147 Figure 1 Method comparison: Bland-Altman plot Conclusion Our proposed method allows a comprehensive assessment of coronary artery pathology through the use of an individualised, semi-automated approach. If incorporated into stable chest pain guidelines this protocol could lead to significant reductions in radiation exposure and the need for further functional testing or invasive angiography could be determined from CTCA alone. The study would support a potential change to guidelines (Figure 2). Abstract 147 Figure 2 Proposed NICE guidance

An unusual case of ventricular ectopy in a military pilot.

BACKGROUND Congenital left ventricular diverticula are an uncommon cardiac malformation. Although they may be asymptomatic, their presence is important to note as they are associated with systemic embolization of mural thrombus, valvular regurgitation, heart failure, focal ventricular arrhythmias, and sudden death. CASE REPORT We describe a case of an asymptomatic pilot with a significant burden of ventricular ectopy. The diagnosis of a large left ventricular diverticulum was made by cardiac CT and confirmed by cardiac magnetic resonance imaging. No specific treatment was warranted; however, regular on-going follow up was required. DISCUSSION It is important to seek out a structural cause for frequent ventricular ectopy even in the absence of symptoms. Transthoracic echocardiography is not always able to delineate the entire left ventricular cavity and other imaging modalities such as ECG-gated cardiac CT or gated MRI may need to be used in conjunction to permit assessment for the presence of structural heart disease in the whole heart. Aircrew with a high burden of ectopy require regular follow-up for complications such as more malignant dysrhythmias or LV impairment. In some cases, pharmacological or even surgical treatment is warranted, which may have a significant bearing for the future licensing of aircrew.

024 Endothelial Nox4 NADPH oxidase enhances vasodilatation via hydrogen peroxide-induced hyperpolarisation and reduces blood pressure

NADPH oxidases (Noxs) are reactive oxygen species-generating enzymes implicated in cardiovascular disease. Nox4 is the most abundantly expressed isoform in endothelial cells but its function remains unknown. We investigated the role of endothelial Nox4 on vascular function and blood pressure (BP) in vivo. We generated transgenic mice with endothelium-specific overexpression of Nox4 (Nox4TG) and studied the effects on endothelial function (aortic …