Characterizing cardiac contractile motion for noninvasive radioablation of ventricular tachycardia.

Background: Respiratory motion management strategies are used to minimize the effects of breathing on the precision of stereotactic ablative radiotherapy for ventricular tachycardia, but the extent of cardiac contractile motion of the human heart has not been systematically explored. Objective: We aim to assess the magnitude of cardiac contractile motion between different directions and locations in the heart. Methods: Patients with intracardiac leads or valves who underwent 4-dimensional cardiac computed tomography (CT) prior to a catheter ablation procedure for atrial or ventricular arrhythmias at 2 medical centers were studied retrospectively. The displacement of transvenous right atrial appendage, right ventricular (RV) implantable cardioverter-defibrillator, coronary sinus lead tips, and prosthetic cardiac devices across the cardiac cycle were measured in orthogonal 3-dimensional views on a maximal-intensity projection CT reconstruction. Results: A total of 31 preablation cardiac 4-dimensional cardiac CT scans were analyzed. The LV lead tip had significantly greater motion compared with the RV lead in the anterior-posterior direction (6.0 ± 2.2 mm vs 3.8 ± 1.7 mm; P = .01) and superior-inferior direction (4.4 ± 2.9 mm vs 3.5 ± 2.0 mm; P = .049). The prosthetic aortic valves had the least movement of all fiducials, specifically compared with the RV lead tip in the left-right direction (3.2 ± 1.2 mm vs 6.1 ± 3.8 mm, P = .04) and the LV lead tip in the anterior-posterior direction (3.8 ± 1.7 mm vs 6.0 ± 2.2 mm, P = .03). Conclusion: The degree of cardiac contractile motion varies significantly (1 mm to 15.2 mm) across different locations in the heart. The effect of contractile motion on the precision of radiotherapy should be assessed on a patient-specific basis.

Acute myocarditis after receiving first dose of BNT162b2 mRNA vaccine.

A 40-year-old man with history of prior coronavirus disease 2019 (COVID-19) infection developed pleuritic chest pain 3 days after receiving the first dose of the BNT162b2 mRNA vaccine. Echocardiography results were significant for mild dysfunction and left ventricular hypertrophy. Cardiac magnetic resonance imaging showed myocardial edema as well as delayed enhancement in the inferior wall of the basal left ventricular myocardium, suggestive of acute myocarditis. This case describes the work-up, diagnosis, risk-stratification, and management of acute myocarditis post BNT162b2 mRNA vaccine. .

Catheter-directed thrombolysis versus suction thrombectomy in the management of acute pulmonary embolism.

BACKGROUND: Catheter-directed thrombolysis (CDT) is increasingly performed for acute pulmonary embolism (PE) because it is presumed to provide similar therapeutic benefits to systemic thrombolysis, while decreasing the dose of thrombolytic required and the associated risks. Contemporary suction thrombectomy (ST) devices have entered the market as minimal or no-lytic alternatives, but there is no evidence on their comparative effectiveness. This study aims to compare clinical outcomes of these two interventional alternatives. METHODS: Consecutive patients who underwent a ST catheter intervention for massive or submassive PE between 2011 and 2017 were identified. For each of these patients, a nearest-neighbor matching was implemented to identify at least three CDT patients who matched as closely as possible on the following six variables: PE type, age, gender, acute deep venous thrombosis, pulmonary disease, and year of procedure. The end point was clinical success defined as meeting all the following criteria: survival to hospital discharge without major bleeding (Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries moderate or severe), perioperative stroke or other major adverse procedure-related event, and decompensation for submassive or persistent shock for massive PE. RESULTS: Of 277 patients who received an intervention for acute PE, 54 CDT (63.5 ± 14.2 years of age; 18 massive PE) were matched with 18 ST (64.1 ± 14.1 years of age; 6 massive PE) patients. In the CDT group, 38 (70.4%) received ultrasound-assisted thrombolysis. The ST group had significantly more patients who had a major contraindication for lytics (1 [1.9%] for CDT vs 9 [50%] for ST; P < .001). There was no difference in major bleeding (8 [14.8%] for CDT vs 3 [16.7%] for ST; P > .999; Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries severe 1 [1.8%] for CDT vs 1 [5.6%] for ST; P > .999), stroke (3.7% for CDT vs 0 for ST; P = .408), or death (3.7% for CDT vs 16.7% for ST; P = .096). One patient in the ST group suffered tricuspid valve rupture and two patients in CDT group required surgical thrombectomy. Clinical success was not statistically different between groups (75.9% for CDT vs 61.1% for ST; P = .224). The association was similar when assessing the right/left ventricular ratio improvement (0.30 ± 0.19 for CDT vs 0.17 ± 0.16 for ST; P = .097), or the subgroup of patients with submassive PE (86.1% for CDT vs 66.7% for ST; P = .135). CONCLUSIONS: CDT seems to have similar outcomes with ST in the management of acute PE, although larger, more homogenous data are needed. In our experience, ST should be viewed as a complementary alternative for patients with contraindication for thrombolytics or severely compromised hemodynamic profile and can yield good outcomes in an otherwise highly morbid population.

An Accumulated Deficits Model Predicts Perioperative and Long-term Adverse Events after Carotid Endarterectomy.

BACKGROUND: There is increasing recognition that decreased reserve in multiple organ systems, known as accumulated deficits (AD), may better stratify perioperative risk than traditional risk indices. We hypothesized that an AD model would predict both perioperative adverse events and long-term survival after carotid endarterectomy (CEA), particularly important in asymptomatic patients. METHODS: Consecutive patients undergoing CEA between 1st January 2000 and 31st December 2010 were retrospectively identified. Seven of the deficit items from the Canadian Study of Health and Aging-frailty index (coronary disease, renal insufficiency, pulmonary disease, peripheral vascular disease, heart failure, hypertension, and diabetes) were tabulated for each patient. Predictors of perioperative and long-term outcomes were evaluated using regression analysis. RESULTS: About 1,782 CEAs in 1,496 patients (mean age: 71.3 ± 9.3 years, 56.3% male, 35.4% symptomatic) were included. The risk of major adverse events (stroke, death, or myocardial infarction) at 30 days for patients with ≤3 deficits was 2.53% vs. 8.81% for patients with ≥4 deficits (P < 0.001). For patients with ≥5 deficits, the risk was 15.18%. Each additional deficit increased the odds of a 30-day major adverse event and hospital stay >2 days by 1.64 (P < 0.001) and 1.15 (P < 0.001), respectively. In multivariate analysis, the presence of ≥4 deficits was more predictive of perioperative major adverse events (odds ratio [OR] = 3.62, P < 0.001) than symptomatology within 6 months (OR = 1.57, P = 0.08) or octogenarian status (OR = 2.00, P = 0.02). Kaplan-Meier analysis showed significantly decreased survival over time with accumulating deficits (P < 0.001). Patients with ≥4 deficits have a hazards ratio for death of 2.6 compared to patients with ≤3 deficits (P < 0.001). Overall survival is estimated at 79.5% (95% confidence interval [CI]: 0.77-0.82) at 5 years in patients with ≤3 deficits versus 52.4% (95% CI: 0.46-0.58) in patients with ≥4 deficits, respectively. In subgroup analysis of asymptomatic patients, 5-year survival for octogenarian male patients with ≥4 deficits was only 26.8%. For asymptomatic males aged 70-79 years with ≥4 deficits, 5-year survival was 59.9%. CONCLUSIONS: An AD model is more predictive of perioperative adverse events after CEA than age or symptomatic status. This model remains predictive of long-term survival. In asymptomatic male octogenarians with 4 or more AD, 5-year survival is severely limited.

Early distal remodeling after elephant trunk repair of thoraco-abdominal aortic aneurysms.

Hemodynamic alterations occur when the elephant trunk (ET) technique is adopted to treat extensive aortic aneurysms. In planning the 2nd stage operation to complete ET repair, surgeons must weigh an adequate recovery time after initial surgery against the risk of postoperative ET-related complications. The purpose of this study was to understand the mechanistic link between the flow alteration caused by the ET graft and the development of premature aortic rupture before the 2nd stage operation. Specifically, fluid-structure interaction (FSI) analysis was performed using the CT imaging data of aorta at different stages of ET repair, and then computational variables were compared to those observed in patients who underwent a prophylactic 2nd stage operation to complete aortic repair. Results show that intramural stress exerted near the distal ET anastomosis (IMS=37.5kPa) at the time of urgent intervention was comparable to that of the extensive aortic aneurysm (IMS=47.4kPa) at initial in-hospital admission, but was considerably higher than that occurring after the 1st stage procedure (IMS=3.5kPa). Pressure index suggested higher peri-graft pressurization than aortic lumen pressure during diastole, imparting an apparent risk of aortic dilatation. These critical hemodynamic and structural parameters are related to the impending rupture of descending aorta observed clinically and can thus guide prophylactic intervention and optimal timing for the 2nd stage operation of a ET technique.

Low incidence of adverse events following varenicline initiation among opioid dependent smokers with comorbid psychiatric illness.

BACKGROUND: Most drug treatment patients smoke cigarettes, yet few data exist on the prevalence and outcomes of varenicline treatment among smokers with comorbid substance use and psychiatric disorders. METHODS: We reviewed all patient charts of opioid-dependent smokers prescribed varenicline between May 2006 and December 2009 in two urban methadone clinics that also provide on-site medical and psychiatric care. We assessed prevalence, adverse events, and effectiveness of varenicline treatment in this cohort. RESULTS: We identified 575 smokers among 690 patients (83.3%), and assessed 82 courses of varenicline treatment prescribed to 70 smokers. Both cardiovascular risk factors and psychiatric illness were highly prevalent among those prescribed varenicline: hypertension, 51%; hyperlipidemia, 23%; diabetes, 20%; depression, 53%; anxiety, 30%; psychotic disorders, 10%; bipolar disorder, 8.6%. Of 82 varenicline courses, nine (11%) were discontinued due to adverse events and two due to depressive symptoms. One patient initiated new psychiatric medications within six months of initiating varenicline, but did not discontinue varenicline. There were no reports of suicidal ideation, agitation prompting clinical intervention, or psychiatric hospitalization. There were no incident cardiac or vascular events within six months of varenicline prescription. Some (8.6%) varenicline-treated smokers quit smoking, and cessation was significantly associated with varenicline treatment duration. CONCLUSIONS: Despite substantial comorbidity, opioid-dependent smokers receiving integrated substance abuse, medical and psychiatric care had few documented adverse events with varenicline treatment. Methadone patients will likely experience little harm and a great deal of benefit from treatment with varenicline for smoking cessation.

Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability.

UNLABELLED: Overexpression of HER-2/Neu occurs in about 25-30% of breast cancer patients and is indicative of poor prognosis. While Her2/Neu overexpression is primarily a result of erbB2 amplification, it has recently been recognized that erbB2 levels are also regulated on the protein level. However, factors that regulate Her2/Neu protein stability are less well understood. The prolyl isomerase Pin1 catalyzes the isomerization of specific pSer/Thr-Pro motifs that have been phosphorylated in response to mitogenic signaling. We have previously reported that Pin1-catalyzed post-phosphorylational modification of signal transduction modulates the oncogenic pathways downstream from c-neu. The goal of this study was to examine the expression of prolyl isomerase Pin1 in human Her2+ breast cancer, and to study if Pin1 affects the expression of Her2/Neu itself. METHODS: Immunohistochemistry for Her2 and Pin1 were performed on two hundred twenty-three human breast cancers, with 59% of the specimen from primary cancers and 41% from metastatic sites. Pin1 inhibition was achieved using siRNA in Her2+ breast cancer cell lines, and its effects were studied using cell viability assays, immunoblotting and immunofluorescence. RESULTS: Sixty-four samples (28.7%) stained positive for Her2 (IHC 3+), and 54% (122/223) of all breast cancers stained positive for Pin1. Of the Her2-positive cancers 40 (62.5%) were also Pin1-positive, based on strong nuclear or nuclear and cytoplasmic staining. Inhibition of Pin1 via RNAi resulted in significant suppression of Her2-positive tumor cell growth in BT474, SKBR3 and AU565 cells. Pin1 inhibition greatly increased the sensitivity of Her2-positive breast cancer cells to the mTOR inhibitor Rapamycin, while it did not increase their sensitivity to Trastuzumab, suggesting that Pin1 might act on Her2 signaling. We found that Pin1 interacted with the protein complex that contains ubiquitinated erbB2 and that Pin1 inhibition accelerated erbB2 degradation, which could be prevented by treatments with the proteasome inhibitor ALLnL. CONCLUSION: Pin1 is a novel regulator of erbB2 that modulates the ubiquitin-mediated degradation of erbB2. The overexpression of Pin1 in a majority of Her2-overexpressing breast cancer may contribute to maintain erbB2 levels. Pin1 inhibition alone and in conjunction with mTOR inhibition suppresses the growth of Her2+ breast cancer cells.

Increased expression of stem cell markers in malignant melanoma.

The potential role of stem cells in neoplasia is a subject of recent interest. Three markers of melanocytic stem cells have been described recently. CD166 is expressed on the surface of mesenchymal stem cells and has been found on human melanoma cell lines. CD133 is expressed on the surface of dermal-derived stem cells that are capable of differentiating into neural cells. Nestin is an intermediate filament expressed in the cytoplasm of neuroepithelial stem cells. In this study, we evaluate the expression of these markers and possible differences among banal nevi, primary melanoma, and metastastic melanoma. Tissue microarrays containing normal tissue and 226 melanocytic lesions (71 banal nevi, 71 in situ and invasive melanomas, and 84 metastatic melanomas) were studied by immunohistochemistry using monoclonal antibodies CD166, CD133, and nestin. A significantly greater percentage of melanomas (combined primary and metastatic) contained cells that expressed CD166 (P=0.005), CD133 (P=0.003), and nestin (P=0.03) than banal nevi. Only nestin showed a statistical difference when comparing primary and metastatic melanoma (P=0.05). A stepwise increase in the proportion of lesions expressing all three markers was observed from banal nevi (2/19) to primary melanomas (8/17) to metastatic melanoma (19/28), P=0.0005. All cases of metastatic melanoma expressed at least one stem cell marker. The increased expression of CD166, CD133, and nestin in melanoma suggests that progression to malignant melanoma likely involves genetic pathways instrumental to stem cell biology and normal tissue development. Further studies and characterization of these pathways may also reveal new prognostic markers for a disease whose prognosis in advanced stages is dismal.