Cardiologists appropriately exclude resuscitated out-of-hospital cardiac arrests from emergency coronary angiography.

OBJECTIVE: Emergency coronary angiography after resuscitated out-of-hospital cardiac arrest as a selective or non-selective diagnostic procedure with or without intervention continues to be the subject of debate. This study sought to determine if cardiologists reliably select patients using clinical judgement for emergency coronary angiography without missing acutely ischemic cases requiring revascularization. METHODS: Presenting clinical details and ECGs (within 2 hours) from 52 consecutive out-of-hospital cardiac arrest patients who underwent non-selective coronary angiography were compiled retrospectively. Three out-of-hospital cardiac arrest-experienced interventional cardiologists, blinded to patient outcome, independently determined working diagnosis, and decision for emergency coronary angiography using clinical judgement. Sensitivity of the cardiologists' decision was assessed with respect to the outcome of acute revascularization. Inter-rater differences, consensus in clinical assessment, and influence of working diagnosis were also investigated. RESULTS: Sensitivity of individual cardiologist's decision for emergency coronary angiography with respect to acute revascularization was very high (adjusted overall sensitivity = 95.8%, 95% CI = 89-100, cardiologist range = 93%-100%), and perfect for the consensus of 2 or more cardiologists (100%, 95% CI = 79.4-100). There was no statistical difference in the sensitivity of this decision between cardiologists (P < 0.05), and inter-rater agreement was moderate (78% overall agreement, Κ = 0.56). CONCLUSIONS: Experienced cardiologists recommend emergency coronary angiography in all resuscitated out-of-hospital cardiac arrest requiring acute revascularization and appropriately excluded one-third of patients. Rather than advocating a non-selective, or conversely, a restrictive strategy with respect to coronary angiography after out-of-hospital cardiac arrest, the findings support an individualized approach by a multidisciplinary emergency team that includes experienced cardiologists. The results should be confirmed in a larger prospective study.

TGF-beta1-Induced MAPK activation promotes collagen synthesis, nodule formation, redox stress and cellular senescence in porcine aortic valve interstitial cells.

BACKGROUND AND AIM OF THE STUDY: Aortic valve stenosis is a major cause of valve replacement, particularly in the elderly. TGF-beta1 is upregulated in stenotic valves and induces calcification and collagen synthesis in cultured valve interstitial cells. It has been shown previously that TGF-beta1 increases reactive oxygen species (ROS) in these cells in association with calcifying nodule formation, but the cellular signaling pathways responsible for these TGF-beta1-induced effects are not well defined. METHODS: Cultured porcine aortic valve interstitial cells were used to investigate the effects of inhibitors of TGF-beta1 signaling pathways on 3H-proline incorporation into the extracellular matrix, the peak number of calcifying nodules formed, redox stress as dichlorofluorescein diacetate (DCF-DA) fluorescence, and senescence-associated beta-galactosidase staining. RESULTS: Nodule formation and proline incorporation were inhibited by SB431542, implicating the Smad pathway, by SB203580, implicating the P38 MAPK pathway, and by U0126, implicating the Mekl/2/Erk1/2 pathway in both processes. Fasudil, an inhibitor of the Rho kinase pathway, was selective in inhibiting nodule formation but not proline incorporation. It was verified that Smad2 phosphorylation, Erk1/2 phosphorylation and p38 MAPK phosphorylation were all induced by TGF-beta1, with Smad 2 phosphorylation peaking at 1-2 h and MAPK phosphorylation at 24-48 h. The effect of TGF-beta1 on phosphorylation of Smad 2 was inhibited by SB431542, on the phosphorylation of p38 MAPK was inhibited by SB203580, and on the phosphorylation of Erk1/2 was inhibited by U0126. ROS generation in response to TGF-beta1, measured as 2,7-dichlorofluorescein-diacetate fluorescence, was inhibited significantly by SB203580 and U0126, implicating both the p38 MAPK and Mekl/2/Erk1/2 signaling pathways. Both pathways also mediated TGF-beta1-induced cellular senescence which was localized to cellular aggregates and mature nodules. CONCLUSION: These data imply that the inhibition of either Smad or MAPK signaling pathways may have a therapeutic benefit in ameliorating the adverse pathological changes associated with aortic valve stenosis.

Lack of association between aortic sclerosis and left ventricular hypertrophy in elderly subjects.

BACKGROUND: The presence of aortic sclerosis has been associated with increased LV mass, particularly in hypertensive subjects. However, aortic sclerosis has also been associated with endothelial dysfunction, which may provide stimuli for development of left ventricular hypertrophy independent of afterload. Thus, we have sought to determine whether aortic sclerosis is a determinant of increased left ventricular mass in a non-hypertensive cohort of aging subjects. METHODS: 79 subjects, mean age 68 ± 6 years, without existing cardiovascular disease or previous antihypertensive therapy were studied. LV volumes were calculated from the short axis stack of cardiac MRI and LV mass was indexed to height(2.7). The presence of aortic sclerosis was assessed with echocardiography using backscatter from the aortic valve (AV(BS)) and visual scoring. Plasma asymmetric dimethylarginine levels and vascular responses to salbutamol were used to assess endothelial function. ANCOVA was used to test the relationship between LV mass index and afterload. Univariate and multivariate analyses were performed to find determinants of increased LV mass. RESULTS: 15 (19%) of subjects had aortic sclerosis on the basis of AV(BS); none had aortic valve areas <1.5 cm(2). There was no significant difference in LV mass between subjects with and without aortic sclerosis. While LV mass was directly related to systolic blood pressure, this relationship was independent of the presence/absence of aortic sclerosis. On multivariate analysis, significant correlates of increased LV mass were male gender, systolic blood pressure and increased BMI, but not presence of aortic sclerosis. CONCLUSIONS: In this aging normotensive population free of established cardiovascular disease, aortic sclerosis is not associated with left ventricular hypertrophy.

Inhibition of calcifying nodule formation in cultured porcine aortic valve cells by nitric oxide donors.

Calcific aortic stenosis displays some similarities to atherosclerosis including evidence of endothelial dysfunction. Whether nitric oxide (NO), which is produced by valvular endothelium, has direct protective effects extending to calcification processes in aortic valve cells has not previously been examined. In vitro calcifying nodules in porcine aortic valve interstitial cell cultures, formed in response to transforming growth factor-beta1 (TGF-beta1) 5 ng/ml, were inhibited by NO donors DETA-NONOate 5-100 microM, and sodium nitroprusside (SNP) 3 microM. Raising intracellular cGMP concentrations, via 8-bromo cGMP 1 mM or via brain natiuretic peptide and C-type natiuretic peptide 0.1 microM, inhibited TGF-beta1-induced nodule formation, potentially implicating the cGMP pathway in the NO effect. Stimulation of interstitial cells with substance P or calcium ionophone (A23187) caused NO release and increased intracellular cGMP respectively. However in the presence of TGF-beta1 basal levels of NO production via nitric oxide synthase (NOS) were insufficient to affect nodule formation. Increased dihydroethidium (DHE) fluorescence in response to TGF-beta1, which was inhibited by DETA-NONOate and TEMPOL, suggested a role for intracellular superoxide in TGF-beta1 signalling. Moreover, nodule formation was suppressed by superoxide scavengers TEMPOL, hydralazine and polyethylene glycol-superoxide dismutase (PEG-SOD), but not SOD. In conclusion, NO donors, or agents raising intracellular cGMP levels, may protect aortic valve interstitial cells from early events leading to calcification.

Aortic stenosis is associated with elevated plasma levels of asymmetric dimethylarginine (ADMA).

OBJECTIVES: We tested the hypothesis that the presence of aortic stenosis (AS) is associated with elevation of plasma levels of asymmetric dimethylarginine (ADMA), a physiological inhibitor of nitric oxide synthase, a mediator and marker of endothelial dysfunction and an indicator of incremental cardiovascular risk. BACKGROUND: The presence of aortic sclerosis (ASC), the precursor of AS is independently associated both with endothelial dysfunction, and with incremental coronary event risk. It remains uncertain whether elevations of ADMA levels might mediate endothelial dysfunction in these conditions. METHODS: Forty two consecutive patients referred for echocardiography for evaluation of AS, who had calculated aortic valve areas of <1.4 cm(2) (AS group) were evaluated together with 42 consecutive age-matched referred patients (non-AS group). Plasma ADMA levels were measured by high-performance liquid chromatography (HPLC). Determinants of elevation of plasma ADMA levels were identified via stepwise multiple linear regression analysis. RESULTS: Plasma ADMA levels were not statistically different between the AS and non-AS group (median 0.59 vs 0.54 micromol/L, p=0.13, Mann-Whitney test) on univariate analysis. However, in backward stepwise multiple linear regression, the presence of AS was a significant predictor of elevated ADMA levels (p=0.04, 95% CI=0.001, 0.072). In addition, elevated plasma ADMA levels were also associated with history of atrial fibrillation (p=0.009, 95% CI=0.015, 0.100), and negatively associated with creatinine clearance (p=0.01, 95% CI=-0.002, 0.000), and the use of statin therapy (p=0.01, 95% CI=-0.081, -0.011). CONCLUSIONS: AS is independently associated with elevation of ADMA levels, beyond that implied by "conventional" risk factors for endothelial dysfunction. The clinical status of AS as an incremental marker of cardiovascular risk may reflect ADMA-mediated endothelial dysfunction.

Loss of anti-aggregatory effects of aortic valve tissue in patients with aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: Patients with aortic stenosis (AS) exhibit increased platelet aggregability, and thrombus formation has been documented on calcific and severely stenosed valves. Isolated porcine and canine aortic valves (AV) release nitric oxide (NO) and prostacyclin, which exert local antithrombotic effects; to date, this has not been studied in humans. In the present study the possible interaction of AV tissue with platelet aggregation was examined, using fragments of AV obtained from patients with AS and aortic regurgitation (AR). METHODS: Fragments of AV tissue, excised from patients undergoing AV replacement, were co-incubated with blood samples obtained from normal subjects. The direct effects of valve tissue from patients with AS (n = 14) or with predominant AR (n = 13) on ADP-induced platelet aggregation and intraplatelet cGMP and cAMP content were compared. RESULTS: In whole blood, non-calcified AV fragments from AR patients inhibited platelet aggregation by 57 +/- 6% (p < 0.01); in platelet-rich plasma results were analogous. In order to determine whether this anti-aggregatory effect could be attributed to the valvular release of NO or prostacyclin, intraplatelet cGMP and cAMP formation was assessed, respectively. While there were no significant changes in cGMP content, cAMP increased by 26 +/- 4% (p < 0.02). Both, anti-aggregatory and cAMP-stimulating effects were similar to those produced by 10 nM prostaglandin E1, a prostacyclin mimetic. Fragments from stenotic valves did not inhibit aggregation and did not affect cGMP or cAMP. Furthermore, fragments from heavily calcified regions potentiated aggregation and, in some cases, induced spontaneous aggregation. CONCLUSION: Minimally calcified aortic valves (i.e., AR) and, therefore, presumably also normal valves, exert anti-aggregatory effects, most likely via prostacyclin release. AS is associated with a loss of this effect, thus potentially contributing to thrombotic risk.