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ECG Lead I and Outflow Tract ArrhythmiaIntroductionOutflow tract ventricular arrhythmia (OTVA) can be complicated to target for ablation when originating from either the periaortic or pulmonary valve (PV) region. Both sites may present with a small R wave in lead V1. However, the utility of lead I in distinguishing these arrhythmia locations is unknown.Methods and ResultsThirty‐six consecutive patients (mean age 41 ± 14 years, 13 male) underwent catheter ablation for OTVA. OTVA origin was determined from intracardiac electrogram tracings and electroanatomic maps. Observers blinded to results measured QRS waveform amplitude and duration from standard 12‐lead ECG tracings. Measurements with highest diagnostic performance were modeled into an algorithm. Sites of successful ablation were anterior right ventricular outflow tract (RVOT; n = 6), posterior RVOT (n = 4), PV (n = 18), and right coronary cusp (RCC; n = 8). Highest performing surface ECG discriminators were from lead I to V1 vectors: RCC, lead I R wave ≥ 1.5 mV, and V1 R wave ≥2.0 mV (sensitivity 87%, specificity 93%); PV, V1 R wave > 0 mV, and lead I R/(R+S) ≤ 0.75 (sensitivity 78%, specificity 72%); anterior RVOT, V1 R wave = 0 mV, and lead I R/(R+S) <0.4 (sensitivity 67%, specificity 97%); posterior RVOT, V1 R wave > 0 mV, and lead I R/(R+S) > 0.75 (sensitivity 75%, specificity 84%). Sequential algorithmic application of these criteria resulted in an overall accuracy of 72% in predicting site of OTVA origin.ConclusionsA relatively large R wave in lead I is seen with RCC origin but not PV origin. A sequential algorithm has limited but potentially significant value beyond assessment of lead I in approaching OTVA.

Background Neurohormonal dysregulation contributes to heart failure (HF) progression. We sought to determine the effect of cardiac resynchronisation therapy (CRT) on the nerve growth factor (NGF), a biomarker that promotes the maturation, and survival of sympathetic nerve endings, and amino-terminal propeptide of type III procollagen (PIIINP), a marker of type III collagen synthesis. Methods This prospective study enrolled 20 healthy age-matched controls and 45 consecutive patients (pts) who received CRT-D. NYHA class, distance of 6-min walk and echocardiography and plasma concentrations of NGF, PIIINP, b-type natriuretic peptide (BNP), norepinephrine (NE), epinephrine (EPI) and dopamine (DA) were measured before and 6 month after CRT. Response to CRT was defined as ≥15% reduction in left ventricular end-systolic volume index (LVESVI) at 6-month follow-up. Results The baseline BNP (557±692 vs 47±35, p<0.01) and PIIINP (8.22±3.76 vs 5.36±1.47, p<0.01) were elevated in HF compared to controls, while NGF, NE, EPI and DA levels were not different. Twenty two of 45 pts (49%) responded to CRT. The responder group demonstrated significant decrease only in BNP level (p=0.04) at 6-month follow-up, parallelling with the clinical improvements (table 1). The baseline PIIINP was lower in CRT responders than non-responders (p=0.04), and it correlated with the reduction of LVESVI (p=0.01, r=−0.50) after CRT. The further multivariate analysis showed only the plasma PIIINP level among clinic characters and all the biomarkers can predict the improvement of LVESV index (OR=8.33, P=0.01). Conclusion The low PIIINP level, which is consistent with possible less cardiac fibrosis and a more plastic ventricle at baseline, is associated with CRT responsiveness. Contrary to previous reports, the NGF levels were not reduced during HF and that there was no NGF rebound in CRT responders.

Key PointsPhenotypic and genotypic profiling of MDM2 in DLBCL. MDM2 as a negative regulator of p53 tumor suppressor function.

An intracranial aneurysm (IA) is a pathological condition of cerebral arteries characterized by local enlargements of the arterial wall, typically into a saccular shape. Rupture of the aneurysm sac can result in devastating cerebral hemorrhage. Hemodynamic factors are believed to play an important role in initiation, development and rupture of IAs [1–3]. However, the coupling between hemodynamics and aneurysm pathophysiology is complex and remains poorly understood. Patient specific diagnostics regarding risk of rupture can be substantially advanced by improving our understanding of the in-vivo response of the aneurysm wall to intra-saccular hemodynamic stresses. A mechanism for fundamental studies of the impact of chronically altered WSS on the intact vascular wall is provided by animal models. However, cerebral aneurysms have not been shown to occur naturally in animals. Thus, a number of animal models have been created for studying aneurysm pathogenesis including those in mice, rats, rabbits, canines, swine and primates. To make meaningful use of these models, it is important to evaluate their relevance to human biomechanics and pathophysiology.

BackgroundRecent studies have shown that magnetic resonance imaging (MRI) of patients with pacemakers can be safely performed under careful monitoring, but they excluded patients with recently implanted devices. Patients with recent implants may be at a greater risk for complications during MRI imaging due to lack of lead and wound maturity.MethodsWe implemented a clinical protocol for MRI imaging of patients with implanted cardiac devices, and prospectively collected data. For this study, we retrospectively analyzed two groups of patients: those with recently implanted (≤42 days) and nonrecently implanted (>42 days) leads at the time of MRI scanning. All devices were interrogated before and after scanning, and were reprogrammed during the scan as per protocol.ResultsOf the 219 scans (in 171 patients), eight included patients with recently implanted (range: 7–36 days) and 211 with only nonrecently implanted pacemaker leads. During the scan, there were no complications in the early or late group. In one patient imaged 79 days postimplant, frequent premature ventricular complexes were noted during the scan, requiring no action. No patient reported pain during or immediately after the procedure. No clinically significant changes in function were seen at subsequent follow up (average 104 days post‐MRI). Compared to patients with nonrecently implanted leads, there was no difference in any parameter between the two groups.ConclusionsWith a strong clinical indication and with careful monitoring, MRI imaging is feasible in patients with recently implanted pacemakers, although experience is limited.

BackgroundPatients with preexisting mild cognitive impairment or dementia may be at increased risk for developing cardiac device complications due to an impaired ability to follow postimplant care instructions. We sought to determine whether rates of infection, lead dislodgement, or appropriate or inappropriate implantable cardioverter defibrillator (ICD) shocks are increased in this population.MethodsMedical charts of 561 patients with mild cognitive impairment or dementia who underwent pacemaker (PM) or ICD implantation between January 2002 and October 2009 at Mayo Clinic were identified. A total of 134 patients who were diagnosed with cognitive impairment or dementia before device implantation or within 1 year of implantation were compared with 134 matched controls. Information was collected on patient characteristics, comorbid medical conditions, ejection fraction, complications, device type, device therapy, and mortality. Device information was prospectively entered into a database and retrospectively reviewed.ResultsOf the 134 patients with mild cognitive impairment and dementia, 99 underwent PM implantation and 35 underwent ICD implantation. Compared to controls, there was no difference in patient characteristics, ejection fraction, or comorbidities except for diabetes, which was more prevalent in the cognitively impaired and demented group (18.7% vs 30.6%, P = 0.02). There was no difference in device therapy and complications (14.4% vs 5.8%, P = 0.268). However, there was a decreased survival in patients with cognitive impairment and dementia when compared to the control group (42% vs 67% at 5 years, P = 0.007).ConclusionPatients with cognitive impairment and standard device indications are not at increased risk for device complications and therapy but their survival is much lower than in matched controls. The cause of this lower survival is unknown but may be related to the underlying neurological disease. Presence of cognitive impairment should therefore be considered when contemplating implantation of a cardiac device.

Accumulating pre-clinical data suggests that matrix metalloproteinase (MMP) expression plays a critical role in the pathophysiology of secondary brain injury. We conducted a prospective multimodal monitoring study in order to characterize the temporal MMP response after severe traumatic brain injury (TBI) in eight critically ill humans and its relationship with outcomes. High-cutoff, cerebral microdialysis ( n =8); external ventricular drainage ( n =3); and arterial and jugular venous bulb catheters were used to collect microdialysate, cerebrospinal fluid, and arterial and jugular bulb blood over 6 days. Levels of MMP-8 and -9 were initially high in microdialysate and then gradually declined over time. After these MMPs decreased, a spike in the microdialysate levels of MMP-2 and -3 occurred, followed by a gradual rise in the microdialysate concentration of MMP-7. Use of generalized estimating equations suggested that MMP-8 concentration in microdialysate was associated with mortality ( p =0.019) and neurological outcome at hospital discharge ( p =0.013). Moreover, the mean microdialysate concentration of MMP-8 was 2.4-fold higher among those who died after severe TBI than in those who survived. Mean microdialysate levels of MMP-8 also rose with increasing intracranial pressure (ICP), whereas those of MMP-7 decreased with increasing cerebral perfusion pressure (CPP). Significant changes in the mean microdialysate concentrations of MMP-1, -2, -3, and -9 and MMP-1, -2, -3, -7, and -9 also occurred with increases in microdialysate glucose and the lactate/pyruvate ratio, respectively. These results imply that monitoring of MMPs following severe TBI in humans is feasible, and that their expression may be associated with clinical outcomes, ICP, CPP, and cerebral metabolism.

AbstractRunx2 is the master transcription factor for bone formation. Haploinsufficiency of RUNX2 is the genetic cause of cleidocranial dysplasia (CCD) that is characterized by hypoplastic clavicles and open fontanels. In this study, we found that Pin1, peptidyl prolyl cis–trans isomerase, is a critical regulator of Runx2 in vivo and in vitro. Pin1 mutant mice developed CCD‐like phenotypes with hypoplastic clavicles and open fontanels as found in the Runx2+/− mice. In addition Runx2 protein level was significantly reduced in Pin1 mutant mice. Moreover Pin1 directly interacts with the Runx2 protein in a phosphorylation‐dependent manner and subsequently stabilizes Runx2 protein. In the absence of Pin1, Runx2 is rapidly degraded by the ubiquitin‐dependent protein degradation pathway. However, Pin1 overexpression strongly attenuated uniquitin‐dependent Runx2 degradation. Collectively conformational change of Runx2 by Pin1 is essential for its protein stability and possibly enhances the level of active Runx2 in vivo. J. Cell. Physiol. 228: 2377–2385, 2013. © 2013 Wiley Periodicals, Inc.

Background and objective Sacroplasty has emerged as a treatment option for patients with painful osteoporotic sacral insufficiency fractures. We report short-term outcomes in a consecutive cohort of patients treated with sacroplasty. Methods We retrospectively reviewed 57 patients treated with sacroplasty for painful osteoporotic sacral fractures at our institution between 2004 and 2011. An 11-point numerical rating scale pain score was recorded at rest and at activity pre- and post-procedure. Opioids prescribed to the patient both pre- and post-procedure were recorded. Results Mean duration of pain prior to sacroplasty was 3 weeks (IQR 2–5). Procedural complications were minimal. Median post-procedure follow-up time was 2.5 weeks (IQR 1–5) among 45 patients with available data. Thirty-seven (82%) of the 45 patients experienced a numerical or descriptive decrease from initial pain at follow-up. Median activity pain scores collected from 13 patients decreased from 10 (IQR 8.5–10) pre-procedure to 6 (IQR 4–6.8) post-procedure (p<0.0001), and median rest pain scores collected from 29 patients decreased from 7 (IQR 4–8.5) to 2 (IQR 1–3.5)(p<0.0001). Twenty-two (76%) of 29 patients had at least a 30% decrease in rest pain scores. The median number of opioids prescribed per patient decreased from 1 (IQR 1–2) pre-procedure to 0 (IQR 0–1) post-procedure (p<0.0001). Thirty-four of 57 patients (60%) had decreased opioid usage, 15 (26%) patients had unchanged usage and 8 (14%) had increased usage. Conclusions Our series demonstrates that sacroplasty is a safe and effective treatment in patients with painful osteoporotic insufficiency fractures.