Is surgery in aCute aortiC disseCtion type A still ContraindiCated in the presenCe of preoperative neurologiCal symptoms?

Gebiet: Kardiologie Abstract: OBJECTIVES: Severe neurologiCal defiCit (ND) due to aCute aortiC disseCtion type A (AADA) was Considered a ContraindiCation for surgery beCause of poor prognosis. ReCently, more aggressive indiCation for surgery despite neurologiCal symptoms has shown aCCeptable – postoperative CliniCal results. The aim of this study was to evaluate early and mid-term outComes of patients with AADA presenting with aCute ND. – – METHODS: Data from 53 patients with new-onset ND who reCeived surgiCal repair for AADA between 2005 and 2012 at our institution were retrospeCtively reviewed. ND was defined as foCal motor or sensory defiCit, hemiplegia, paraplegia, Convulsions or Coma. NeurologiCal symptoms were evaluated preoperatively using the Glasgow Coma SCale (GCS) and modified Rankin SCale (mRS), and at disCharge as well as 3–6 months postoperatively using the mRS and National Institutes of Health Stroke SCale. Involvement of Carotid arteries was assessed in the pre- and postoperative Computed tomography. LogistiC regression analysis was performed to deteCt prediCtive faCtors for reCovery of ND. – – RESULTS: Of the 53 patients, 29 (54.7%) showed Complete reCovery from foCal ND at follow-up. NeurologiCal symptoms persisted in 24 (45.3%) patients, of whiCh 8 (33%) died without neurologiCal assessment at follow-up. Between the two groups (patients with reCovery and – those with persisting ND), there was no signifiCant differenCe regarding the duration of hypothermiC CirCulatory arrest (28 ± 14 vs 36 ± 20 min) or severely reduCed ConsCiousness (GCS <8). Multivariate analysis showed signifiCant differenCes for the preoperative mRS between the two groups (P < 0.007). A high preoperative mRS was assoCiated with persistenCe of neurologiCal symptoms (P < 0.02). CardiovasCular risk faCtors, age or involvement of supra-aortiC branChes were not prediCtive for persistenCe of ND. – – CONCLUSION: More than half of our patients reCovered Completely from ND due to AADA after surgery. Severity of CliniCal symptoms had a prediCtive value. Patients suffering from AADA and presenting with ND before surgery should not be exCluded from emergenCy surgery.

Noninvasive 4D pressure difference mapping derived from 4D flow MRI in patients with repaired aortic coarctation: comparison with young healthy volunteers

To assess spatial and temporal pressure characteristics in patients with repaired aortic coarctation compared to young healthy volunteers using time-resolved velocity-encoded three-dimensional phase-contrast magnetic resonance imaging (4D flow MRI) and derived 4D pressure difference maps. After in vitro validation against invasive catheterization as gold standard, 4D flow MRI of the thoracic aorta was performed at 1.5T in 13 consecutive patients after aortic coarctation repair without recoarctation and 13 healthy volunteers. Using in-house developed processing software, 4D pressure difference maps were computed based on the Navier-Stokes equation. Pressure difference amplitudes, maximum slope of pressure amplitudes and spatial pressure range at mid systole were retrospectively measured by three readers, and twice by one reader to assess inter- and intraobserver agreement. In vitro, pressure differences derived from 4D flow MRI showed excellent agreement to invasive catheter measurements. In vivo, pressure difference amplitudes, maximum slope of pressure difference amplitudes and spatial pressure range at mid systole were significantly increased in patients compared to volunteers in the aortic arch, the proximal descending and the distal descending thoracic aorta (p < 0.05). Greatest differences occurred in the proximal descending aorta with values of the three parameters for patients versus volunteers being 19.7 ± 7.5 versus 10.0 ± 2.0 (p < 0.001), 10.9 ± 10.4 versus 1.9 ± 0.4 (p = 0.002), and 8.7 ± 6.3 versus 1.6 ± 0.9 (p < 0.001). Inter- and intraobserver agreements were excellent (p < 0.001). Noninvasive 4D pressure difference mapping derived from 4D flow MRI enables detection of altered intraluminal aortic pressures and showed significant spatial and temporal changes in patients with repaired aortic coarctation.

Systematic analysis of the radiologic findings of aortic dissections on unenhanced postmortem computed tomography

The aim of this study was to evaluate the diagnostic criteria and to identify the radiological signs (derived from known radiological signs) for the detection of aortic dissections using postmortem computed tomography (PMCT). Thirty-three aortic dissection cases were retrospectively evaluated; all underwent PMCT and autopsy. The images were initially evaluated independently by two readers and were subsequently evaluated in consensus. Known radiological signs, such as dislocated calcification and an intimomedial flap, were identified. The prevalence of the double sedimentation level in the true and false lumen of the dissected aorta was assessed and defined as a postmortem characteristic sign of aortic dissection. Dislocated calcification was detected in 85% of the cases with aortic calcification; whereas in 54% of the non-calcified aortas, the intimomedial flap could also be recognized. Double sedimentation was identified in 16/33 of the cases. Overall, in 76% (25/33) of the study cases, the described signs, which are indicative for aortic dissection, could be identified. In this study, three diagnostic criteria of aortic dissection were identified using non-enhanced PMCT images of autopsy-confirmed dissection cases.

Post-Procedural Troponin Elevation and Clinical Outcomes Following Transcatheter Aortic Valve Implantation.

BACKGROUND Biomarkers of myocardial injury increase frequently during transcatheter aortic valve implantation (TAVI). The impact of postprocedural cardiac troponin (cTn) elevation on short-term outcomes remains controversial, and the association with long-term prognosis is unknown. METHODS AND RESULTS We evaluated 577 consecutive patients with severe aortic stenosis treated with TAVI between 2007 and 2012. Myocardial injury, defined according to the Valve Academic Research Consortium (VARC)-2 as post-TAVI cardiac troponin T (cTnT) >15× the upper limit of normal, occurred in 338 patients (58.1%). In multivariate analyses, myocardial injury was associated with higher risk of all-cause mortality at 30 days (adjusted hazard ratio [HR], 8.77; 95% CI, 2.07-37.12; P=0.003) and remained a significant predictor at 2 years (adjusted HR, 1.98; 95% CI, 1.36-2.88; P<0.001). Higher cTnT cutoffs did not add incremental predictive value compared with the VARC-2-defined cutoff. Whereas myocardial injury occurred more frequently in patients with versus without coronary artery disease (CAD), the relative impact of cTnT elevation on 2-year mortality did not differ between patients without CAD (adjusted HR, 2.59; 95% CI, 1.27-5.26; P=0.009) and those with CAD (adjusted HR, 1.71; 95% CI, 1.10-2.65; P=0.018; P for interaction=0.24). Mortality rates at 2 years were lowest in patients without CAD and no myocardial injury (11.6%) and highest in patients with complex CAD (SYNTAX score >22) and myocardial injury (41.1%). CONCLUSIONS VARC-2-defined cTnT elevation emerged as a strong, independent predictor of 30-day mortality and remained a modest, but significant, predictor throughout 2 years post-TAVI. The prognostic value of cTnT elevation was modified by the presence and complexity of underlying CAD with highest mortality risk observed in patients combining SYNTAX score >22 and evidence of myocardial injury.

Acute Cytomegalovirus Hepatitis in an Immunocompetent Host as a Reason for Upper Right Abdominal Pain

Cytomegalovirus infections are widely distributed with a seroprevalence of up to 100%. The majority of the cases take a silent course or deal with unspecific clinical symptoms. Complications in immunocompetent patients are rare but may affect the liver and lead up to an acute organ failure. In this case report, we describe a 35-year-old immunocompetent female with an acute cytomegalovirus infection presenting as acute hepatitis with ongoing upper right abdominal pain after cholecystectomy. Upper right abdominal pain is a common symptom with a wide range of differential diagnoses. If common reasons can be excluded, we want to sensitize for cytomegalovirus infection as a minor differential diagnosis even in immunocompetent patients.

Clipping techniques in cerebral aneurysm surgery

The history of cerebral aneurysm surgery owes a great tribute to the tenacity of pioneering neurosurgeons who designed and developed the clips used to close the aneurysms neck. However, until the beginning of the past century, surgery of complex and challenging aneurysms was impossible due to the lack of surgical microscope and commercially available sophisticated clips. The modern era of the spring clips began in the second half of last century. Until then, only malleable metal clips and other non-metallic materials were available for intracranial aneurysms. Indeed, the earliest clips were hazardous and difficult to handle. Several neurosurgeons put their effort in developing new clip models, based on their personal experience in the treatment of cerebral aneurysms. Finally, the introduction of the surgical microscope, together with the availability of more sophisticated clips, has allowed the treatment of complex and challenging aneurysms. However, today none of the new instruments or tools for surgical therapy of aneurysms could be used safely and effectively without keeping in mind the lessons on innovative surgical techniques provided by great neurovascular surgeons. Thanks to their legacy, we can now treat many types of aneurysms that had always been considered inoperable. In this article, we review the basic principles of surgical clipping and illustrate some more advanced techniques to be used for complex aneurysms.

Prevention of ischemic complications during aneurysm surgery

Ischemic complications during aneurysm surgery are a frequent cause of postoperative infarctions and new neurological deficits. In this article, we discuss imaging and neurophysiological tools that may help the surgeon to detect intraoperative ischemia. The strength of intraoperative digital subtraction angiography (DSA) is the full view of the arterial and venous vessel. DSA is the gold standard in complex and giant aneurysms, but due to certain disadvantages, it cannot be considered standard of care. Microvascular Doppler sonography is probably the fastest diagnostic tool and can quickly aid diagnosis of large vessel occlusions. Intraoperative indocyanine green videoangiography is the best tool to assess flow in perforating and larger arteries, as well as occlusion of the aneurysm sac. Intraoperative neurophysiological monitoring with somatosensory and motor evoked potentials indirectly measures blood flow by recording neuronal function. It covers all causes of intraoperative ischemia, provided that ischemia occurs in the brain areas under surveillance. However, every method has advantages and disadvantages. No single method is superior to the others in every aspect. Therefore, it is very important for the neurosurgeon to know the strengths and weaknesses of each tool in order to have them available, to know how to use them for each individual situation, and to be ready to apply them within the time window for reversible cerebral ischemia.

The unruptured intracranial aneurysm treatment score: a multidisciplinary consensus.

OBJECTIVE We endeavored to develop an unruptured intracranial aneurysm (UIA) treatment score (UIATS) model that includes and quantifies key factors involved in clinical decision-making in the management of UIAs and to assess agreement for this model among specialists in UIA management and research. METHODS An international multidisciplinary (neurosurgery, neuroradiology, neurology, clinical epidemiology) group of 69 specialists was convened to develop and validate the UIATS model using a Delphi consensus. For internal (39 panel members involved in identification of relevant features) and external validation (30 independent external reviewers), 30 selected UIA cases were used to analyze agreement with UIATS management recommendations based on a 5-point Likert scale (5 indicating strong agreement). Interrater agreement (IRA) was assessed with standardized coefficients of dispersion (vr*) (vr* = 0 indicating excellent agreement and vr* = 1 indicating poor agreement). RESULTS The UIATS accounts for 29 key factors in UIA management. Agreement with UIATS (mean Likert scores) was 4.2 (95% confidence interval [CI] 4.1-4.3) per reviewer for both reviewer cohorts; agreement per case was 4.3 (95% CI 4.1-4.4) for panel members and 4.5 (95% CI 4.3-4.6) for external reviewers (p = 0.017). Mean Likert scores were 4.2 (95% CI 4.1-4.3) for interventional reviewers (n = 56) and 4.1 (95% CI 3.9-4.4) for noninterventional reviewers (n = 12) (p = 0.290). Overall IRA (vr*) for both cohorts was 0.026 (95% CI 0.019-0.033). CONCLUSIONS This novel UIA decision guidance study captures an excellent consensus among highly informed individuals on UIA management, irrespective of their underlying specialty. Clinicians can use the UIATS as a comprehensive mechanism for indicating how a large group of specialists might manage an individual patient with a UIA.

Mechanotransduction pathway activation in familial thoracic aortic aneurysms and dissections

Thoracic aortic aneurysms and dissections (TAAD) are autosomal dominantly inherited in 19% of patients. Mapping studies determined that the disease is genetically heterogeneous with multiple loci and genetic mutations accounting for familial TAAD. However, regardless of the specific mutation, resulting pathology is consistently medial degeneration, characterized by increased proteoglycans and loss of elastic fibers. We tested the hypothesis that genetic mutations leading to familial TAAD alter common pathways in aortic smooth muscle cells (SMCs). Identification of mutations at R460 in TGFBR2 reveals a 5% contribution to TAAD, however downstream analysis of Smad2 phosphorylation in the TGF-β pathway is not commonly altered in familial or sporadic disease when compared to controls. Expression profiling using Illumina's Sentrix HumanRef 8 Expression Beadchip array was done on RNA isolated from SMCs explanted from 6 patients with inherited TAAD with no identified mutation and 3 healthy controls obtained from the International Institute for the Advancement of Medicine. Significant increases in expression of proteoglycan genes in patients' SMCs, specifically lumican, podocan, and decorin were confirmed using Q-PCR and tissue immunofluorescence. NCI's Ingenuity Pathway Analysis predicted alterations in the ERK, insulin receptor and SAPK/JNK pathways (p<0.001), which SMCs activate in response to cyclic stretch. Immunoblotting indicated increased phosphorylation of ERK and GSK-3β, a protein from the insulin receptor pathway, in explanted patient SMCs, also confirmed by increased immunoreactivity against phosphorylated ERK and GSK-3β in the sub-intimal SMCs from patient tissue compared to controls. To determine if mechanotransduction pathway activation was responsible for the medial degeneration a specific inhibitor of GSK-3β, SB216763 was incubated with control cells and significantly increased the expression levels of proteoglycans. Mechanical strain was also applied to control SMCs confirming pathways stimulation with stretch. Incubation with pathway inhibitors against insulin receptor and ERK pathways identify, for the first time that stretch induced GSK-3β phosphorylation may increase proteoglycan expression, and ERK phosphorylation may regulate the expression of MMP2, a protein known to degrade elastic fibers. Furthermore, specific mutations in SMC-specific β-myosin heavy chain and α-actin, in addition to upregulation of pathways activated by cyclic stretch suggest that SMC response to hemodynamic factors, play a role in this disease. ^

Gender associated risk factors of aortic aneurysms and dissections

Objectives. Predict who will develop a dissection. To create male and female prediction models using the risk factors: age, ethnicity, hypertension, high cholesterol, smoking, alcohol use, diabetes, heart attack, congestive heart failure, congenital and non-congenital heart disease, Marfan syndrome, and bicuspid aortic valve. ^ Methods. Using 572 patients diagnosed with aortic aneurysms, a model was developed for each of males and females using 80% of the data and then verified using the remaining 20% of the data. ^ Results. The male model predicted the probability of a male in having a dissection (p=0.076) and the female model predicted the probability of a female in having a dissection (p=0.054). The validation models did not support the choice of the developmental models. ^ Conclusions. The best models obtained suggested that those who are at a greater risk of having a dissection are males with non-congenital heart disease and who drink alcohol, and females with non-congenital heart disease and bicuspid aortic valve.^

Persisting abdominal symptoms after travelers' diarrhea: Is there a genetic predisposition?

Functional gastrointestinal disorders (FGIDs) are defined as ailments of the mid or lower gastrointestinal tract which are not attributable to any discernable anatomic or biochemical defects.1 FGIDs include functional bowel disorders, also known as persisting abdominal symptoms (PAS). Irritable bowel syndrome (IBS) is one of the most common illnesses classified under PAS.2,3 This is the first prospective study that looks at the etiology and pathogenesis of post-infectious PAS in the context of environmental exposure and genetic susceptibility in a cohort of US travelers to Mexico. Our objective was to identify infectious, genetic and environmental factors that predispose to post infectious PAS. ^ Methods. This is a secondary data analysis of a prospective study on a cohort of 704 healthy North American tourists to Cuernavaca, Morelos and Guadalajara, Jalisco in Mexico. The subjects at risk for Travelers' diarrhea were assessed for chronic abdominal symptoms on enrollment and six months after the return to the US. ^ Outcomes. PAS was defined as disturbances of mid and lower gastrointestinal system without any known pathological or radiological abnormalities, or infectious, or metabolic causes. It refers to functional bowel disease, category C of functional gastrointestinal diseases as defined by the Rome II criterion. PAS was sub classified into Irritable bowel syndrome (IBS) and functional abdominal disease (FAD). ^ IBS is defined as recurrent abdominal pain or discomfort present at least 25% and associated with improvement with defecation, change in frequency and form of stool. FAD encompasses other abdominal symptoms of chronic nature that do not meet the criteria for IBS. It includes functional diarrhea, functional constipation, functional bloating: and unspecified bowel symptoms. ^ Results. Among the 704 travelers studied, there were 202 cases of PAS. The PAS cases included 175 cases of FAD and 27 cases of IBS. PAS was more frequent among subjects who developed traveler's diarrhea in Mexico compared to travelers who remained healthy during the short term visit to Mexico (52 vs. 38; OR = 1.8; CI, 1.3–2.5, P < 0.001). A statistically significant difference was noted in the mean age of subjects with PAS compared to healthy controls (28 vs. 34 yrs; OR = 0.97, CI, 0.95–0.98; P < 0.001). Travelers who experienced multiple episodes, a later onset of diarrhea in Mexico and passed greater numbers of unformed stools were more likely to be identified in PAS group at six months. Participants who developed TD caused by enterotoxigenic E.coli in Mexico showed a 2.6 times higher risk of developing FAD (P = 0.003). Infection with Providencia ssp. also demonstrated a greater risk to developing PAS. Subjects who sought treatment for diarrhea while in Mexico also displayed a significantly lower frequency of IBS at six months follow up (OR = 0.30; CI, 0.10–0.80; P = 0.02). ^ Forty six SNPs belonging to 14 genes were studied. Seven SNPs were associated with PAS at 6 months. These included four SNPs from the Caspase Recruitment Domain-Containing Protein 15 gene (CARD15), two SNPs from Surfactant Pulmonary-Associated Protein D gene (SFTPD) and one from Decay-Accelerating Factor For Complement gene (CD55). A genetic risk score (GRS) was composed based on the 7 SNPs that showed significant association with PAS. A 20% greater risk for PAS was noted for every unit increase in GRS. The risk increased by 30% for IBS. The mean GRS was high for IBS (2.2) and PAS (1.1) compared to healthy controls (0.51). These data suggests a role for these genetic polymorphisms in defining the susceptibility to PAS. ^ Conclusions. The study allows us to identify individuals at risk for developing post infectious IBS (PI-IBS) and persisting abdominal symptoms after an episode of TD. The observations in this study will be of use in developing measures to prevent and treat post-infectious irritable bowel syndrome among travelers including pre-travel counseling, the use of vaccines, antibiotic prophylaxis or the initiation of early antimicrobial therapy. This study also provides insights into the pathogenesis of post infectious PAS and IBS. (Abstract shortened by UMI.)^

Identification and characterization of mutations in SMC contractile genes involved in thoracic aortic aneurysms and dissections

Aortic aneurysms and dissections are the 15th most common cause of death in the United States. Genetic factors contribute to the pathogenesis of thoracic aortic aneurysms and dissections (TAAD). Currently, six loci and four genes have been identified for familial TAAD. Notably, mutations in smooth muscle cell (SMC) contractile genes, ACTA2 and MYH11, are responsible for 15% of familial TAAD, suggesting that proper SMC contraction is important for normal aorta function. Therefore, we hypothesize that mutations in other genes encoding SMC contractile proteins also cause familial TAAD. ^ To test this hypothesis, we used a candidate gene approach to identify causative mutations in SMC contractile genes for familial TAAD. Sequencing DNA in 80 TAAD patients from unrelated families, we identified putative mutations in eight contractile genes. We chose myosin light chain kinase (MLCK ) S1759P for further study for the following reasons: (1) Serine 1759 is conserved between vertebrates and invertebrates. (2) S1759P is predicted to be functionally deleterious by bioinformatics. (3) Low blood pressure is observed in SMC-selective MLCK-deficient mice. ^ In the presence of Ca2+/Calmodulin (CaM), MLCK containing CaM binding and kinase domains are activated to phosphorylate myosin light chain, thereby initiate SMC contraction. The CaM binding sequence of MLCK forms an α-helix structure required for CaM binding. MLCK Serine 1759 is located within the CaM binding domain. S1759P is predicted to decrease the α-helix composition in the CaM binding domain. Hence, we hypothesize that MLCK mutations cause TAAD through disturbing CaM binding and MLCK activity. ^ We further sequenced MLCK in DNA samples from additional 86 probands with familial TAAD. Two more mutations, MLCK A1754T and R1480Stop, were identified, supporting that MLCK mutations cause familial TAAD. ^ To define whether MLCK mutations disrupted CaM binding and MLCK activity, we performed co-immunoprecipitation and kinase assays. Decreased CaM binding and kinase activity was detected in A1754T and S1759P. Moreover, R1480Stop is predicted to truncate kinase and CaM binding domains. We conclude that MLCK mutations disrupt CaM binding and MLCK activity. ^ Collectively, our study is first to show mutations in genes regulating SMC contraction cause TAAD. This finding further highlights the importance of SMC contraction in maintaining aorta function. ^