Computed tomography coronary angiography accuracy in women and men at low to intermediate risk of coronary artery disease

Objectives

To investigate the diagnostic accuracy of CT coronary angiography (CTCA) in women at low to intermediate pre-test probability of coronary artery disease (CAD) compared with men.

Methods

In this retrospective study we included symptomatic patients with low to intermediate risk who underwent both invasive coronary angiography and CTCA. Exclusion criteria were previous revascularisation or myocardial infarction. The pre-test probability of CAD was estimated using the Duke risk score. Thresholds of less than 30?% and 30–90?% were used for determining low and intermediate risk, respectively. The diagnostic accuracy of CTCA in detecting obstructive CAD (≥50?% lumen diameter narrowing) was calculated on patient level. P?<?0.05 was considered significant.

Results

A total of 570 patients (46?% women [262/570]) were included and stratified as low (women 73?% [80/109]) and intermediate risk (women 39?% [182/461]). Sensitivity, specificity, PPV and NPV were not significantly different in and between women and men at low and intermediate risk. For women vs. men at low risk they were 97?% vs. 100?%, 79?% vs. 90?%, 80?% vs. 80?% and 97?% vs. 100?%, respectively. For intermediate risk they were 99?% vs. 99?%, 72?% vs. 83?%, 88?% vs. 93?% and 98?% vs. 99?%, respectively.

Conclusion

CTCA has similar diagnostic accuracy in women and men at low and intermediate risk.

Key Points

? Coronary artery disease (CAD) is increasingly investigated by computed tomography angiography (CTCA). ? CAD detection or exclusion by CTCA is not different between sexes. ? CTCA diagnostic accuracy was similar between low and intermediate risk sex-specific-groups. ? CTCA rarely misses obstructive CAD in low–intermediate risk women and men. ? CAD yield by invasive coronary angiography after positive CTCA is similar between sex-risk-specific groups.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

Value of preprocedure multislice computed tomographic coronary angiography to predict the outcome of percutaneous recanalization of chronic total occlusions

We performed multislice computed tomographic coronary angiography in 45 patients who had chronic total occlusions and were scheduled for percutaneous recanalization. Multivariate analysis identified a blunt stump (by conventional angiography), occlusion length >15 mm, and severe calcification (by multislice computed tomographic coronary angiography) as independent predictors of procedural failure.     

Identification of an oncogenic form of the thrombopoietin receptor MPL using retrovirus-mediated gene transfer

Thrombopoietin and its receptor (MPL) are important regulators of megakaryopoiesis. We have identified an activating mutation of MPL using a combination of a retrovirus-mediated gene transfer and polymerase chain reaction-driven random mutagenesis. This point mutation causes a single amino acid substitution from Ser498 to Asn498 in the transmembrane region and abrogates factor-dependency of all interleukin-3-dependent cell lines tested. Murine interleukin-3- dependent Ba/F3 cells expressing the mutated but not the normal form of MPL were tumorigenic when transduced into syngeneic mice. Analysis of intracellular signaling pathways indicated that the mutant MPL protein constitutively activated two distinct signaling pathways, SHC-Raf-MAPK and JAK2-STAT3/STAT5.     

Multislice spiral computed tomography coronary angiography in patients with stable angina pectoris

OBJECTIVES: This study was designed to prospectively evaluate the diagnostic performance of multislice spiral computed tomography (MSCT) coronary angiography for the detection of significant lesions in all segments of the coronary tree potentially suitable for revascularization. BACKGROUND: Noninvasive MSCT coronary angiography is a promising coronary imaging technique. METHODS: Sixteen-row MSCT coronary angiography was performed in 128 patients (89% men, mean age 58.9 +/- 11.7 years) in sinus rhythm with stable angina pectoris scheduled for conventional coronary angiography. Sixty percent (77 of 128) of patients received pre-scan oral beta-blockers, resulting in a mean heart rate of 57.7 +/- 7.7 beats/min. The diagnostic performance of MSCT for detection of significant lesions (> or =50% diameter reduction) was compared with that of quantitative coronary angiography (QCA). RESULTS: The sensitivity of MSCT for detection of significant lesions was 92% (216 of 234, 95% confidence interval [CI]: 88 to 95). Specificity was 95% (1,092 of 1,150, 95% CI: 93 to 96), positive predictive value 79% (216 of 274, 95% CI: 73 to 88), and negative predictive value 98% (1,092 of 1,110, 95% CI: 97 to 99). Two > or =50% lesions were missed because of motion artifacts and two because of severe coronary calcifications. The rest (78%, 14 of 18) were detected but incorrectly classified as <50% obstructions. All patients with and 86% (18 of 21) of patients without significant lesions on QCA were correctly classified by MSCT. All patients with significant left main disease or total occlusions were correctly identified on MSCT. CONCLUSIONS: Sixteen-row MSCT coronary angiography permits reliable detection of significant obstructive coronary artery disease in patients with stable angina in sinus rhythm.