Clinical outcomes of patients with low-flow, low-gradient, severe aortic stenosis and either preserved or reduced ejection fraction undergoing transcatheter aortic valve implantation

AIMS Our aim was to evaluate the invasive haemodynamic indices of high-risk symptomatic patients presenting with 'paradoxical' low-flow, low-gradient, severe aortic stenosis (AS) (PLF-LG) and low-flow, low-gradient severe AS (LEF-LG) and to compare clinical outcomes following transcatheter aortic valve implantation (TAVI) among these challenging AS subgroups. METHODS AND RESULTS Of 534 symptomatic patients undergoing TAVI, 385 had a full pre-procedural right and left heart catheterization. A total of 208 patients had high-gradient severe AS [HGAS; mean gradient (MG) ≥40 mmHg], 85 had PLF-LG [MG ≤ 40 mmHg, indexed aortic valve area [iAVA] ≤0.6 cm(2) m(-2), stroke volume index ≤35 mL/m(2), ejection fraction (EF) ≥50%], and 61 had LEF-LG (MG ≤ 40 mmHg, iAVA ≤0.6 cm(2) m(-2), EF ≤40%). Compared with HGAS, PLF-LG and LEF-LG had higher systemic vascular resistances (HGAS: 1912 ± 654 vs. PLF-LG 2006 ± 586 vs. LEF-LG 2216 ± 765 dyne s m(-5), P = 0.007) but lower valvulo-arterial impedances (HGAS: 7.8 ± 2.7 vs. PLF-LG 6.9 ± 1.9 vs. LEF-LG 7.7 ± 2.5 mmHg mL(-1) m(-2), P = 0.027). At 30 days, no differences in cardiac death (6.5 vs. 4.9 vs. 6.6%, P = 0.90) or death (8.4 vs. 6.1 vs. 6.6%, P = 0.88) were observed among HGAS, PLF-LG, and LEF-LG groups, respectively. At 1 year, New York Heart Association functional improvement occurred in most surviving patients (HGAS: 69.2% vs. PLF-LG 71.7% vs. LEF-LG 89.3%, P = 0.09) and no significant differences in overall mortality were observed (17.6 vs. 20.5 vs. 24.5%, P = 0.67). Compared with HGAS, LEF-LG had a higher 1 year cardiac mortality (adjusted hazard ratio 2.45, 95% confidence interval 1.04-5.75, P = 0.04). CONCLUSION TAVI in PLF-LG or LEF-LG patients is associated with overall mortality rates comparable with HGAS patients and all groups profit symptomatically to a similar extent.

Severe aortic stenosis and coronary artery disease

Coronary artery disease (CAD) and aortic stenosis (AS) share pathophysiological mechanisms and risk factors. Moreover, the prevalence of CAD increases among elderly patients with severe AS since disease progression is strongly associated with age for both CAD and AS. These factors contribute to the frequent coexistence of CAD and AS. Patients with concomitant AS and CAD are characterised by higher baseline risk profiles with a larger number of comorbidities as compared to patients with isolated AS. Therefore, adequate therapeutic strategies are crucial for the treatment of these patients. The number of patients undergoing concomitant coronary artery bypass grafting (CABG) and surgical aortic valve replacement (SAVR) doubled during the last decade. Moreover, the development and rapid integration of transcatheter aortic valve implantation (TAVI) into clinical practice in western European countries has further extended invasive treatment of AS to elderly high-risk patients not considered suitable candidates for SAVR, frequently presenting with CAD. The aim of this review article is to provide an overview on CAD prevalence, impact on clinical outcomes, and treatment strategies in patients with severe AS requiring SAVR or TAVI.

Does normalized signal intensity of cervical discs on T2 weighted MRI images change in whiplash patients?

PURPOSE We tested the hypothesis that whiplash trauma leads to changes of the signal intensity of cervical discs in T2-weighted images. METHODS AND MATERIALS 50 whiplash patients (18-65 years) were examined within 48h after motor vehicle accident, and again after 3 and 6 months and compared to 50 age- and sex-matched controls. Signal intensity in ROI's of the discs at the levels C2/3 to C7/T1 and the adjacent vertebral bodies were measured on sagittal T2 weighted MR images and normalized using the average of ROI's in fat tissue. The contrast between discs and both adjacent vertebrae was calculated and disc degeneration was graded by the Pfirrmann-grading system. RESULTS Whiplash trauma did not have a significant effect on the normalized signals from discs and vertebrae, on the contrast between discs and adjacent vertebrae, or on the Pfirrmann grading. However, the contrast between discs and adjacent vertebrae and the Pfirrmann grading showed a strong correlation. In healthy volunteers, the contrast between discs and adjacent vertebrae and Pfirrmann grading increased with age and was dependent on the disc level. CONCLUSION We could not find any trauma related changes of cervical disc signal intensities. Normalized signals of discs and Pfirrmann grading changed with age and varied between disc levels with the used MR sequence.

Normative MR Cervical Spinal Canal Dimensions

Purpose To provide normal values of the cervical spinal canal and spinal cord dimensions in several planes with respect to spinal level, age, sex, and body height. Materials and Methods This study was approved by the institutional review board; all individuals provided signed informed consent. In a prospective multicenter study, two blinded raters independently examined cervical spine magnetic resonance (MR) images of 140 healthy volunteers who were white. The midsagittal diameters and areas of spinal canal and spinal cord, respectively, were measured at the midvertebral levels of C1, C3, and C6. A multivariate general linear model described the influence of sex, body height, age, and spinal level on the measured values. Results There were differences for sex, spinal level, interaction between sex and level, and body height, while age had significant yet limited influence. Normative ranges for the sagittal diameters and areas of spinal canal and spinal cord were defined at C1, C3, and C6 levels for men and women. In addition to a calculation of normative ranges for a specific sex, spinal level, age, and body height data, data for three different height subgroups at 45 years of age were extracted. These results show a range of the spinal canal dimensions at C1 (from 10.7 to 19.7 mm), C3 (from 9.4 to 17.2 mm), and C6 (from 9.2 to 16.8 mm) levels. Conclusion : The dimensions of the cervical spinal canal and cord in healthy individuals are associated with spinal level, sex, age, and height. © RSNA, 2013 Online supplemental material is available for this article.

Risk of very early recurrent cerebrovascular events in symptomatic carotid artery stenosis

OBJECT The risk of recurrence of cerebrovascular events within the first 72 hours of admission in patients hospitalized with symptomatic carotid artery (CA) stenoses and the risks and benefits of emergency CA intervention within the first hours after the onset of symptoms are not well known. Therefore, the authors aimed to assess (1) the ipsilateral recurrence rate within 72 hours of admission, in the period from 72 hours to 7 days, and after 7 days in patients presenting with nondisabling stroke, transient ischemic attack (TIA), or amaurosis fugax (AF), and with an ipsilateral symptomatic CA stenosis of 50% or more, and (2) the risk of stroke in CA interventions within 48 hours of admission versus the risk in interventions performed after 48 hours. METHODS Ninety-four patients were included in this study. These patients were admitted to hospital within 48 hours of a nondisabling stroke, TIA, or AF resulting from a symptomatic CA stenosis of 50% or more. The patients underwent carotid endarterectomy (85 patients) or CA stenting (9 patients). At baseline, the cardiovascular risk factors of the patients, the degree of symptomatic CA stenosis, and the type of secondary preventive treatment were assessed. The in-hospital recurrence rate of stroke, TIA, or AF ipsilateral to the symptomatic CA stenosis was determined for the first 72 hours after admission, from 72 hours to 7 days, and after 7 days. Procedure-related cerebrovascular events were also recorded. RESULTS The median time from symptom onset to CA intervention was 5 days (interquartile range 3.00-9.25 days). Twenty-one patients (22.3%) underwent CA intervention within 48 hours after being admitted. Overall, 15 recurrent cerebrovascular events were observed in 12 patients (12.8%) in the period between admission and CA intervention: 3 strokes (2 strokes in progress and 1 stroke) (3.2%), 5 TIAs (5.3%), and 1 AF (1.1%) occurred within the first 72 hours (total 9.6%) of admission; 1 TIA (1.1%) occurred between 72 hours and 7 days, and 5 TIAs (5.3%) occurred after more than 7 days. The corresponding actuarial cerebrovascular recurrence rates were 11.4% (within 72 hours of admission), 2.4% (between 72 hours and 7 days), and 7.9% (after 7 days). Among baseline characteristics, no predictive factors for cerebrovascular recurrence were identified. Procedure-related cerebrovascular events occurred at a rate of 4.3% (3 strokes and 1 TIA), and procedures performed within the first 48 hours and procedures performed after 48 hours had a similar frequency of these events (4.5% vs. 4.1%, respectively; p = 0.896). CONCLUSIONS The in-hospital recurrence of cerebrovascular events was quite low, but all recurrent strokes occurred within 72 hours. The risk of stroke associated with a CA intervention performed within the first 48 hours was not increased compared with that for later interventions. This raises the question of the optimal timing of CA intervention in symptomatic CA stenosis. To answer this question, more data are needed, preferably from large randomized trials.

Emergency transcatheter aortic valve implantation for decompensated aortic stenosis

We report the case of an 84-year-old male presenting with syncope and dynamic ST-T wave changes due to decompensated severe valvular aortic stenosis undergoing successful emergency transcatheter aortic valve implantation.

Quantification of coronary artery stenosis with high-resolution CT in comparison with histopathology in an ex vivo study

PURPOSE To investigate the ex vivo performance of high-resolution computed tomography (CT) for quantitative assessment of percentage diameter stenosis in coronary arteries compared to histopathology. MATERIALS AND METHODS High-resolution CT was performed in 26 human heart specimens after the injection of iodinated contrast media into the coronary arteries. Coronary artery plaques were visually identified on CT images and the grade of stenosis for each plaque was measured with electronic calipers. All coronary plaques were characterized by histopathology according to the Stary classification, and the percentage of stenosis was measured. RESULTS CT depicted 84% (274/326) of all coronary plaques identified by histology. Missed plaques by CT were of Stary type I (n=31), type II (n=16), and type III (n=5). The stenosis degree significantly correlated between CT and histology (r=0.81, p<0.001). CT systematically overestimated the stenosis of calcified plaques (mean difference - 11.0 ± 9.5%, p<0.01) and systematically underestimated the stenosis of non-calcified plaques (mean difference -6.8 ± 10.4%, p<0.05), while there was no significant difference for mixed-type plaques (mean difference -0.4 ± 11.7%, p=0.85). There was a significant underestimation of stenosis degree as measured by CT for Stary II plaques (mean difference -14 ± 9%, p<0.01) and a significant overestimation for Stary VII plaques (mean difference 9 ± 10%, p<0.05), but there was no significant difference in stenosis degree between both modalities for other plaque types. CONCLUSIONS High-resolution CT reliably depicts advanced stage coronary plaques with an overall good correlation of stenosis degree compared to histology, however, the degree of stenosis is systematically overestimated in calcified and underestimated in non-calcified plaques.

Restoring tactile awareness through the rubber hand illusion in cervical spinal cord injury

BACKGROUND Bodily sensations are an important component of corporeal awareness. Spinal cord injury can leave affected body parts insentient and unmoving, leading to specific disturbances in the mental representation of one's own body and the sense of self. OBJECTIVE Here, we explored how illusions induced by multisensory stimulation influence immediate sensory signals and tactile awareness in patients with spinal cord injuries. METHODS The rubber hand illusion paradigm was applied to 2 patients with chronic and complete spinal cord injury of the sixth cervical spine, with severe somatosensory impairments in 2 of 5 fingers. RESULTS Both patients experienced a strong illusion of ownership of the rubber hand during synchronous, but not asynchronous, stroking. They also, spontaneously reported basic tactile sensations in their previously numb fingers. Tactile awareness from seeing the rubber hand was enhanced by progressively increasing the stimulation duration. CONCLUSIONS Multisensory illusions directly and specifically modulate the reemergence of sensory memories and enhance tactile sensation, despite (or as a result of) prior deafferentation. When sensory inputs are lost, and are later illusorily regained, the brain updates a coherent body image even several years after the body has become permanently unable to feel. This particular example of neural plasticity represents a significant opportunity to strengthen the sense of the self and the feelings of embodiment in patients with spinal cord injury.

Absolute quantitative real-time polymerase chain reaction for the measurement of human papillomavirus E7 mRNA in cervical cytobrush specimens.

BACKGROUND: Few reports of the utilization of an accurate, cost-effective means for measuring HPV oncogene transcripts have been published. Several papers have reported the use of relative quantitation or more expensive Taqman methods. Here, we report a method of absolute quantitative real-time PCR utilizing SYBR-green fluorescence for the measurement of HPV E7 expression in cervical cytobrush specimens. RESULTS: The construction of a standard curve based on the serial dilution of an E7-containing plasmid was the key for being able to accurately compare measurements between cervical samples. The assay was highly reproducible with an overall coefficient of variation of 10.4%. CONCLUSION: The use of highly reproducible and accurate SYBR-based real-time polymerase chain reaction (PCR) assays instead of performing Taqman-type assays allows low-cost, high-throughput analysis of viral mRNA expression. The development of such assays will help in refining the current screening programs for HPV-related carcinomas.

Morphoproteomic evidence of constitutively activated and overexpressed mTOR pathway in cervical squamous carcinoma and high grade squamous intraepithelial lesions.

Human papilloma virus (HPV) infection of the uterine cervix is linked to the pathogenesis of cervical cancer. Preclinical in vitro and in vivo studies using HPV-containing human cervical carcinoma cell lines have shown that the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, erlotinib, can induce growth delay of xenografts. Activation of Akt and mTOR are also observed in cervical squamous cell carcinoma and, the expression of phosphorylated mTOR was reported to serve as a marker to predict response to chemotherapy and survival of cervical cancer patients. Therefore, we investigated: a) the expression level of EGFR in cervical squamous cell carcinoma (SCC) and high-grade squamous intraepithelial lesions (HSIL) versus non-neoplastic cervical squamous epithelium; b) the state of activation of the mTOR pathway in these same tissues; and c) any impact of these signal transduction molecules on cell cycle. Formalin-fixed paraffin-embedded tissue microarray blocks containing 20 samples each of normal cervix, HSIL and invasive SCC, derived from a total of 60 cases of cervical biopsies and cervical conizations were examined. Immunohistochemistry was utilized to detect the following antigens: EGFR; mTOR pathway markers, phosphorylated (p)-mTOR (Ser2448) and p-p70S6K (Thr389); and cell cycle associated proteins, Ki-67 and S phase kinase-associated protein (Skp)2. Protein compartmentalization and expression were quantified in regard to proportion (0-100%) and intensity (0-3+). Mitotic index (MI) was also assessed. An expression index (EI) for pmTOR, p-p70S6K and EGFR, respectively was calculated by taking the product of intensity score and proportion of positively staining cells. We found that plasmalemmal EGFR expression was limited to the basal/parabasal cells (2-3+, EI = 67) in normal cervical epithelium (NL), but was diffusely positive in all HSIL (EI = 237) and SCC (EI 226). The pattern of cytoplasmic p-mTOR and nuclear p-p70S6K expression was similar to that of EGFR; all showed a significantly increased EI in HSIL/SCC versus NL (p<0.02). Nuclear translocation of p-mTOR was observed in all SCC lesions (EI = 202) and was significantly increased versus both HSIL (EI = 89) and NL (EI = 54) with p<0.015 and p<0.0001, respectively. Concomitant increases in MI and proportion of nuclear Ki-67 and Skp2 expression were noted in HSIL and SCC. In conclusion, morphoproteomic analysis reveals constitutive activation and overexpression of the mTOR pathway in HSIL and SCC as evidenced by: increased nuclear translocation of pmTOR and p-p70S6K, phosphorylated at putative sites of activation, Ser2448 and Thr389, respectively; correlative overexpression of the upstream signal transducer, EGFR, and increases in cell cycle correlates, Skp2 and mitotic indices. These results suggest that the mTOR pathway plays a key role in cervical carcinogenesis and targeted therapies may be developed for SCC as well as its precursor lesion, HSIL.

Increased intraoperative epidural pressure in lumbar spinal stenosis patients with a positive nerve root sedimentation sign

Purpose The sedimentation sign (SedSign) has been shown to discriminate well between selected patients with and without lumbar spinal stenosis (LSS). The purpose of this study was to compare the pressure values associated with LSS versus non-LSS and discuss whether a positive SedSign may be related to increased epidural pressure at the level of the stenosis. Methods We measured the intraoperative epidural pressure in five patients without LSS and a negative SedSign, and in five patients with LSS and a positive SedSign using a Codman TM catheter in prone position under radioscopy. Results Patients with a negative SedSign had a median epidural pressure of 9 mmHg independent of the measurement location. Breath and pulse-synchronous waves accounted for 1–3 mmHg. In patients with monosegmental LSS and a positive SedSign, the epidural pressure above and below the stenosis was similar (median 8–9 mmHg). At the level of the stenosis the median epidural pressure was 22 mmHg. A breath and pulse-synchronous wave was present cranial to the stenosis, but absent below. These findings were independent of the cross-sectional area of the spinal canal at the level of the stenosis. Conclusions Patients with LSS have an increased epidural pressure at the level of the stenosis and altered pressure wave characteristics below. We argue that the absence of sedimentation of lumbar nerve roots to the dorsal part of the dural sac in supine position may be due to tethering of affected nerve roots at the level of the stenosis.

Association of biomarkers of lipid modification with functional and morphological indices of coronary stenosis severity in stable coronary artery disease

Biomarkers of blood lipid modification and oxidative stress have been associated with increased cardiovascular morbidity. We sought to determine whether these biomarkers were related to functional indices of stenosis severity among patients with stable coronary artery disease. We studied 197 consecutive patients with stable coronary artery disease due to single vessel disease. Fractional flow reserve (FFR) ≤ 0.80 was assessed as index of a functionally significant lesion. Serum levels of secretory phospholipase A2 (sPLA2) activity, secretory phospholipase A2 type IIA (sPLA2-IIA), myeloperoxydase (MPO), lipoprotein-associated phospholipase A2 (Lp-PLA2), and oxidized low-density lipoprotein (OxLDL) were assessed using commercially available assays. Patients with FFR > 0.8 had higher sPLA2 activity, sPLA2 IIA, and OxLDL levels than patients with FFR ≤ 0.8 (21.25 [16.03-27.28] vs 25.85 [20.58-34.63] U/mL, p < 0.001, 2.0 [1.5-3.4] vs 2.6 [2.0-3.4] ng/mL, p < 0.01; and 53.0 [36.0-71.0] vs 64.5 [50-89.25], p < 0.001 respectively). Patients with FFR > 0.80 had similar Lp-PLA2 and MPO levels versus those with FFR ≤ 0.8. sPLA2 activity, sPLA2 IIA significantly increased area under the curve over baseline characteristics to predict FFR ≤ 0.8 (0.67 to 0.77 (95 % confidence interval [CI]: 0.69-0.85) p < 0.01 and 0.67 to 0.77 (95 % CI: 0.69-0.84) p < 0.01, respectively). Serum sPLA2 activity as well as sPLA2-IIA level is related to functional characteristics of coronary stenoses in patients with stable coronary artery disease.

Coronary artery disease severity and aortic stenosis: clinical outcomes according to SYNTAX score in patients undergoing transcatheter aortic valve implantation.

AIM The aim of this study was to evaluate whether coronary artery disease (CAD) severity exerts a gradient of risk in patients with aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS A total of 445 patients with severe AS undergoing TAVI were included into a prospective registry between 2007 and 2012. The preoperative SYNTAX score (SS) was determined from baseline coronary angiograms. In case of revascularization prior to TAVI, residual SS (rSS) was also determined. Clinical outcomes were compared between patients without CAD (n = 158), patients with low SS (0-22, n = 207), and patients with high SS (SS >22, n = 80). The pre-specified primary endpoint was the composite of cardiovascular death, stroke, or myocardial infarction (MI). At 1 year, CAD severity was associated with higher rates of the primary endpoint (no CAD: 12.5%, low SS: 16.1%, high SS: 29.6%; P = 0.016). This was driven by differences in cardiovascular mortality (no CAD: 8.6%, low SS: 13.6%, high SS: 20.4%; P = 0.029), whereas the risk of stroke (no CAD: 5.1%, low SS: 3.3%, high SS: 6.7%; P = 0.79) and MI (no CAD: 1.5%, low SS: 1.1%, high SS: 4.0%; P = 0.54) was similar across the three groups. Patients with high SS received less complete revascularization as indicated by a higher rSS (21.2 ± 12.0 vs. 4.0 ± 4.4, P < 0.001) compared with patients with low SS. High rSS tertile (>14) was associated with higher rates of the primary endpoint at 1 year (no CAD: 12.5%, low rSS: 16.5%, high rSS: 26.3%, P = 0.043). CONCLUSIONS Severity of CAD appears to be associated with impaired clinical outcomes at 1 year after TAVI. Patients with SS >22 receive less complete revascularization and have a higher risk of cardiovascular death, stroke, or MI than patients without CAD or low SS.