William T. O'Donnell

Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome.

Fragile X syndrome results from the absence of the RNA binding FMR protein. Here, mRNA was coimmunoprecipitated with the FMRP ribonucleoprotein complex and used to interrogate microarrays. We identified 432 associated mRNAs from mouse brain. Quantitative RT-PCR confirmed some to be >60-fold enriched in the immunoprecipitant. In parallel studies, mRNAs from polyribosomes of fragile X cells were used to probe microarrays. Despite equivalent cytoplasmic abundance, 251 mRNAs had an abnormal polyribosome profile in the absence of FMRP. Although this represents <2% of the total messages, 50% of the coimmunoprecipitated mRNAs with expressed human orthologs were found in this group. Nearly 70% of those transcripts found in both studies contain a G quartet structure, demonstrated as an in vitro FMRP target. We conclude that translational dysregulation of mRNAs normally associated with FMRP may be the proximal cause of fragile X syndrome, and we identify candidate genes relevant to this phenotype.

Comparison of Invasive and Noninvasive Assessment of Aortic Stenosis Severity in the Elderly

Background— Aortic valve area (AVA) in aortic stenosis (AS) can be assessed noninvasively or invasively, typically with similar results. These techniques have not been validated in elderly patients, where common assumptions make them most prone to error. Accurate assessment of AVA is crucial to determine which patients are appropriate candidates for aortic valve replacement. Methods and Results— Fifty elderly patients (mean 86 years, 46% female) referred for cardiac catheterization to evaluate AS also underwent transthoracic echocardiography within 24 hours. To minimize assumptions all patients had 3-dimensional echocardiography (Echo-3D), and at catheterization using directly measured oxygen consumption (Cath-mVo2) and thermodilution cardiac output (Cath-TD). Correlation between Cath-mVo2 and Echo-3D AVA was poor (r=0.41). Cath-TD AVA had a moderate correlation with Echo-3D AVA (r=0.59). Cath-mVo2 (AVA=0.69 cm2) and Cath-TD (AVA=0.66 cm2) underestimated AVA compared with Echo-3D (AVA=0.76 cm2; P=0.08 for comparison with Cath-mVo2; P=0.001 for Cath-TD). Compared with Echo-3D, the sensitivity and specificity for determining critical disease (AVA <0.8 cm2) were 81% and 42% for Cath-mVo2, and 97% and 53% for Cath-TD. The only independent predictor of the difference between noninvasive and invasive AVA was stroke volume index (P<0.01). Resistance, a less flow-dependent measure, showed a stronger correlation between Echo-3D and Cath-mVo2 (r=0.69), and Echo-3D and Cath-TD (r=0.77). Conclusions— Standard techniques of AVA assessment for AS show poor correlation in elderly patients, with frequent misclassification of critical AS. Less flow-dependent measures, such as resistance, should be considered to ensure that only appropriate patients are treated with aortic valve replacement.

Application of appropriate use criteria to cardiac stress testing in the hospital setting: limitations of the criteria and areas for improved practice.

Imaging cardiac stress test use has risen significantly, leading to the development of appropriate use criteria. Prior studies have suggested the rate of inappropriate testing is 13% to 14%, but inappropriate testing in hospitalized patients has not been well studied.

Pulmonary Hypertension is a Manifestation of Congestive Heart Failure and Left Ventricular Diastolic Dysfunction in Octogenarians with Severe Aortic Stenosis

Previous studies have suggested that pulmonary hypertension (PH) in severe aortic stenosis (AS) is a risk factor for operative mortality with aortic valve replacement (AVR). Conversely, others have shown that patients with AS and PH extract a large symptomatic and survival benefit from AVR compared with those patients not treated surgically. We sought to evaluate the prevalence, severity, and mechanism of PH in an elderly patient cohort with severe AS. We prospectively evaluated 41 patients aged ≥80 years with severe AS. All patients underwent cardiac catheterization and transthoracic echocardiography within 24 hours. We found that PH was common in this cohort: 32 patients (78%) had PH; however, the predominant mechanism of PH was left heart congestion. Patients with PH had nearly double the pulmonary artery wedge pressure of patients without PH (23 vs. 13 mmHg; P ≤ 0.001). In patients with PH compared with those without, pulmonary vascular resistance was higher yet still under 3 Wood units (WU; 2.9 vs. 1.5 WU; P = 0.001), and the transpulmonary gradient (11 vs. 7 mmHg; P = 0.01) and diastolic pulmonary gradient (DPG; 3.0 vs. 2.7 mmHg; P = 0.74) were in normal range. Left ventricular diastolic abnormalities were more common in patients with severe AS and PH. Right ventricular (RV) dysfunction was common (13/41 patients, 32%), but the PH and non-PH groups had similar tricuspid annular plane systolic excursion (2.0 vs. 2.3 cm; P = 0.15). Only 2 subjects had both RV dysfunction and an elevated DPG. In conclusion, PH is common in elderly patients with severe AS. This occurs largely due to left heart congestion, with a relative absence of pulmonary vascular disease and RV dysfunction, and as such, PH may serve as a heart failure equivalent in these patients.

Estimation of Oxygen Consumption in Elderly Patients With Aortic Stenosis

Invasive evaluation of aortic stenosis requires measuring cardiac output. With the Fick equation, a measure of oxygen consumption (VO2) is required. Standard equations for estimating VO2 were derived in younger and healthier populations than the ones referred for possible transcatheter aortic valve replacement. The goal of this study was to determine the best method of estimating VO2 in elderly patients with aortic stenosis.