Utility of ECG-gated computed tomography angiography for the improved diagnosis of bicuspid aortic valve disease prior to transcatheter aortic valve replacement

Background: Diagnosis of a bicuspid aortic valve (BAV) morphology has important prognostic implications due to early valve degeneration and an associated aortopathy. Presence of a BAV also has technical implications for transcatheter aortic valve replacement (TAVR) procedural planning and implantation. BAV is often first identified on transthoracic echocardiography (TTE), but diagnosis may be limited by imaging windows, operator skill, and valve calcification. ECG-gated computed tomography angiography (CTA) may improve identification of BAV. Methods: 335 patients who underwent TAVR between 5/1/18 and 12/20/18 were retrospectively evaluated. Routine pre-procedure planning retrospectively ECG-gated CTA studies were performed with reconstruction phases at 10% increments through the R-R cycle. 50% or greater commissural fusion was categorized as a BAV. Valve morphology from the preprocedural TTE reports was also abstracted. Of 335 patients, 17 patients had prosthetic valves. Of the remaining 318 patients, 267 (52.4% male, age 79 ± 27) had TTE grading of aortic valve morphology. Results: BAV was identified by TTE in 23 patients (8.6% of cohort, age 75 ± 20 years) whereas CTA identified 26 patients (9.7% of cohort, age 74 ± 21 years) with a bicuspid valve. Direct correlation between CTA and TTE was modest (R-value = 0.38). With CTA as the reference standard, TTE had a sensitivity, specificity, positive predictive value and negative predictive value of 88.5%, 100%, 100% and 98.8% respectively. The age of patients with tricuspid vs BAV was 80 ± 28 years vs 74 ± 21 years, respectively. Aortic size in tricuspid vs BAV patients was 34.2 ± 15 vs 37.9 ± 30 mm (p=0.001). In BAV patients, 82% of the patients had no aortic dilation greater than 40mm. Conclusions: In patients referred for TAVR, CTA is valuable tool for diagnosis of BAV and associated aortopathies, particularly when valve morphology cannot be characterized by TTE. In our cohort, BAV patients were older and rarely had significant aortopathy, suggesting an increased prevalence of degenerative valve fusion relative to congenital BAV disease. Further study is required to categorize and distinguish BAV sub-types and their effect on TAVR procedure results

“Transcaval First” Alternative Access Strategy For Transcatheter Aortic Valve Replacement Guided By Computed Tomography Angiography

Introduction: Patients with small caliber or otherwise hostile iliofemoral vasculature are at high risk for vascular injury when undergoing transcatheter aortic valve replacement (TAVR). Computed tomography angiography (CTA) guides alternative access feasibility including techniques such as transcaval access. Methods: 339 patients (51.6% male, 87.0% white, age 79 ± 1 years) who underwent TAVR at an urban tertiary care facility between 1/2/18 and 12/20/18 were retrospectively studied. Pre-procedure CTA of major vasculature was performed per institutional protocol. Femoral arteries with minimal luminal diameter (MLD) ≤5.5 mm triggered alterative access planning for transcaval, transcarotid, transaxillary, and transseptal anterograde routes. Decision for alternative access was made by a multidisciplinary heart team consensus utilizing a “transcaval first” strategy. Results: Of 339 patients, alternative access was used in 72 (21.2%) of patients with outcomes similar to transfemoral. Strategies were transcaval in 58 (17.1%), transcarotid in 10 (2.9%), transaxillary in 3 (0.9%), and transseptal anterograde in 1 (0.3%). Bilateral femoral arteries ≤5.5 mm were present in 25 (7.4%) of patients. Conclusions: CTA planning identifies patients who may benefit from transcaval access as a first line alternative access strategy

Dynamic conformational changes of the left ventricular outflow tract compared to the aortic annulus and implications on transcatheter aortic valve selection and sizing

Background ECG-gated computed tomography angiography (CTA) has become the standard for assessing the aortic root prior to transcatheter aortic valve replacement (TAVR). Current techniques rely primarily on systolic annular sizing for the selection and sizing of valve prostheses. We sought to evaluate the dynamic conformational changes of the LVOT compared to the aortic annulus, and determine whether LVOT morphology can have implications on prosthetic valve sizing and selection. Methods Preprocedural ECG-gated CTA data of 339 patients (aged 79 ±8.7 years, 52.6% male) who underwent TAVR were analyzed in this single-center retrospective study. The area of the aortic annulus and LVOT were measured by planimetry at 10% intervals throughout the cardiac cycle. Annular measurements were obtained inferior to the coronary cusps, and 10% of sub-annular calcifications were included in the calculated size. LVOT measurements were recorded 5mm inferior to the aortic annulus in a double oblique plane. Results In systole, the average annular size was 452.19 ± 19.52 mm2 compared to 455.74 ± 23.52 mm2 in the LVOT. In diastole, the average annular size was 420.98 ± 18.71 mm2 compared to 430 ± 25.42 mm2 in the LVOT. On average, the LVOT was 3.5mm2 (0.77%) larger in systole and 10mm2 (2.37%) larger in diastole compared to the annulus. Furthermore, a strong linear correlation was noted between the systolic and diastolic sizes of the annulus and LVOT, with a pooled value correlation coefficient (r) value of 0.72 and 0.73, respectively. Conclusion There is a statistically significant difference between the size of the aortic annulus and the LVOT in both systole and diastole. The difference is more pronounced in diastole. The data also shows a strong linear correlation between both the systolic and diastolic sizes of the annulus and the LVOT. The distal portion of the LVOT is within the TAVR valve landing zone but has frequently been neglected in the selection and sizing of valve prostheses. We have found that LVOT morphology varies throughout the cardiac cycle, especially diastole. Further study is required to identify whether distinct LVOT morphologies can be used to improve TAVR valve sizing and procedural outcomes

Targeted exclusion of proximal obstructive coronary disease on coronary computed tomography angiography for deferral of routine invasive coronary angiography prior to transcatheter aortic valve replacement

Background: Aortic stenosis is associated with coronary artery disease (CAD) and routine invasive coronary angiography (ICA) is performed prior to transcatheter aortic valve replacement (TAVR). Evaluation of CAD on computed tomography angiography (CTA) is limited due to coronary calcification, cardiac motion and absence of sublingual nitroglycerin but may be feasible for the exclusion of only proximal CAD. Methods: 339 patients (52% male, age 79 ± 27) who underwent TAVR between 5/1/18 and 12/20/18 were retrospectively studied. Routine pre-procedure ECG-gated CTA was performed with reconstruction phases in 10% increments. CTA evaluation of proximal CAD performed clinically on request from multidisciplinary heart team. CAD analysis performed on 3D workstations by experienced cardiologists and radiologists. Stenosis grades: 0=normal, 1=1-25%, 2=26-50%, 3=51-70%, 4=71-99%, 5=occluded, 8=absent, 9=uninterpretable. Results: Of 339 patients, 62 (18%) patients had CTA coronary analysis of which 49 (14%) also had ICA before or at time of TAVR. Of these patients, 21 (43%) patients had no stenosis more than 50% on CTA, and of those 21 patients, 19 (91%) also had no stenosis more than 50% on ICA. 28 patients who had both ICA and CTA had ≥50% stenosis in at least one coronary artery on CTA. Of these, 22 (79%) also had ≥50% stenosis on ICA. When excluding those with coronary artery bypass grafts (12 patients), 63% of patients had ≥50% stenosis on both CTA and ICA.13 patients had CTA without follow up ICA. Overall including all patients with no CAD on ICA and those who were deferred ICA based on CTA results, 32 (52%) patients avoided or could have avoided ICA, leading to a total theoretical cost saving of $155,000-310,000. No patients had acute coronary syndrome (ACS) at the time of discharge post TAVR. Conclusions: Exclusion of proximal obstructive CAD on routine pre- TAVR CTA is feasible and can decrease utilization of ICA with no increase in ACS at the time discharge post TAVR implantation. This strategy can decrease invasive procedures and potentially reduce cost. Further study is needed on longitudinal outcomes with this strategy

Utility Of Standardized Pre-CTA Hydration Protocol On Patients Referred For Transcatheter Aortic Valve Replacement

Introduction: ECG-gate computed tomography angiography (CTA) is the standard technique for pre-procedural planning prior to transcatheter aortic valve replacement (TAVR). CTA requires use of potentially nephrotoxic iodinated contrast, limiting use in patients with renal dysfunction. We evaluated the utility of a tiered hydration protocol in patients with renal dysfunction referred for TAVR. Methods: 258 patients (52.7% male, age 79 ± 8 years) who underwent TAVR between 1/1/18 and 12/30/18 were retrospectively evaluated. Pre-procedural CTA was performed per institutional protocols with weight based contrast dosing. Patients requiring hemodialysis prior to CTA were excluded. Patients with GFR \u3c22ml/min did not receive CTA. Patients with GFR 22 - 40 ml/min underwent hydration protocol guidelines: Outpatients received normal saline (NS) at ≤3 mL/kg over one hour pre-procedure/test and 1 to 1.5 mL/kg/hour during and up to six hours post-procedure/test. Inpatients received normal saline for 1 mL/kg/hour for 6 to 12 hours pre-procedure/test, intra-procedure, and up to 12 hours post-procedure. Results: Total baseline creatinine was 1.08 ± 0.41 ng/dL. Hydration protocol patient creatinine levels were 1.67 ± 0.41 ng/dL. Upper quartile of creatinine was 1.91 ng/dL (range 0.79 - 2.65 ng/dL). Average CTA contrast dose was 100 ± 23 mL. 43 (17%) of patients received pre-CTA hydration protocol. Hydration protocol NS total infusion volumes were 490 ± 119 mL (range 40-100ml). Duration between CT and TAVR was 86 ± 155 days. Pre-TAVR creatinine was 1.09 ± 0.39, creatinine at discharge was 1.06 ± 0.73. 3 patients (1%) had ≥1 increase in CKD grade at discharge. No patients required dialysis prior to discharge or within 1 month of TAVR. No complications from hydration protocol were identified. Conclusions: Utilization of a routine pre-TAVR CT hydration protocol in patients at risk for contrast induced nephropathy is feasible and associated with no new renal dysfunction prior to TAVR, and low rates of new renal dysfunction post TAVR. In TAVR patients hydration carries risks and further study is needed to identify whether a more conservative hydration protocol can be utilized

Insulin-IGF signaling affects cell transformation in the BALB/c 3T3 cell model

The increased cancer mortality of diabetes type 2 patients is most likely an evidence of the tight connection between tumor development and energy metabolism. A major focus of today’s research is still the identification of key proteins of both diseases and the development of corresponding inhibitors. In this study we combined the two-stage BALB/c-3T3 cell transformation assay (BALB-CTA) with the IR/IGF-1R inhibitor OSI-906 (linsitinib) and analyzed alterations in protein activity and energy parameters in non-transformed as well as transformed cells. OSI-906 successfully inhibited the phosphorylation of IR/IGF-1R and decreased cell growth in non-transformed cells. In the BALB-CTA, a permanent treatment with OSI-906 reduced cellular transformation dose-dependently, whereas a temporary treatment gave evidence for a preventive effect in the promotion phase. Furthermore, even though several key proteins were affected, it was possible to show that the phosphorylation of GSK3, Erk 1/2 and the S6 protein are not crucial for the cell foci reducing effect of OSI-906. Taken together, the BALB-CTA confirmed results of OSI-906 from animal studies and enhanced the knowledge of its mode of action. Therefore, the BALB-CTA offers the opportunity to analyze alterations in the transformation process more precisely and will be helpful to identify effective cancer treatments

Metabolomics in rheumatic diseases: desperately seeking biomarkers

Metabolomics enables the profiling of large numbers of small molecules in cells, tissues and biological fluids. These molecules, which include amino acids, carbohydrates, lipids, nucleotides and their metabolites, can be detected quantitatively. Metabolomic methods, often focused on the information-rich analytical techniques of NMR spectroscopy and mass spectrometry, have potential for early diagnosis, monitoring therapy and defining disease pathogenesis in many therapeutic areas, including rheumatic diseases. By performing global metabolite profiling, also known as untargeted metabolomics, new discoveries linking cellular pathways to biological mechanisms are being revealed and are shaping our understanding of cell biology, physiology and medicine. These pathways can potentially be targeted to diagnose and treat patients with immune-mediated diseases