Considerations in the Surgical Management of Unicuspid Aortic Stenosis.

Unicuspid aortic valve (UAV) stenosis is a rare condition accounting for 5% of non-rheumatic aortic stenosis. The diagnosis can be difficult to make prior to surgical intervention and transesophageal echocardiography has been demonstrated to be more accurate in making the diagnosis compared to transthoracic echocardiography. The presence of a posteriorly located aortic orifice on the short-axis views, with one or two visible raphe anteriorly; the absence of commissures (acommissural); or the presence of a lone commissure (unicommissural) between the left and noncoronary, or the left and right cusps suggests the diagnosis. Patients with UAV are predominantly males and present with stenosis about a decade earlier than those with the more prevalent bicuspid aortic valves (BAV). They more commonly present with aortic annular dilatation and have fewer comorbidities at presentation compared to patients with BAV. Surgical management of UAV stenosis includes aortic valve replacement through standard open heart surgery or percutaneous transcatheter aortic valve replacement (TAVR), aortic valve repair either by bicuspidization, tricuspidization or trileaflet reconstruction, or the Ross procedure. Patients with UAV stenosis require less concomitant coronary or other cardiac procedures when they need surgical intervention, but are about a decade younger at the time of their death. UAV stenosis is a distinct congenital anomaly with a different natural course than BAV. Surgical management should be individualized based on the patient's age at presentation, aortoannular anatomy, and associated cardiac conditions.

Surgical Correction of Aberrant Right Coronary Anomalies Stranding an Aortic Commissure with and Without Unroofing.

The technique for successful surgical correction of an anomalous origin of the right coronary artery from the opposite aortic cusp with an aberrant course between the aorta and pulmonary artery is illustrated in a symptomatic 62-year-old woman. The intramural course of the right coronary artery traversed the tip of the commissure between the anterior and posterior leaflets, and its repair entailed unroofing of the intramural segment from inside the aortic intima. This technique required resuspension of the overlying commissure to maintain optimal aortic valve leaflet coaptation and prevent aortic insufficiency. Modifications of this technique have been utilized by us whenever the intramural segment traversed behind the commissure. In these cases, partial or subtotal unroofing of the intramural segment was performed to preserve the integrity of the intima behind the overlying commissure. More recently, we have performed the surgical correction by probing the intramural segment within the aortic wall to its most anterior location and then performing a wide anterior unroofing in the aortic intima, and marsupializing the aortic and coronary intima to avoid dissection or intimal flap development. We favor utilizing these techniques of anatomic correction of the anomalous coronary to other techniques involving coronary artery bypass grafting of the anomalous coronary, especially in adult patients, as unroofing provides more lasting results.

Diagnosis and management of primary effusion lymphoma in the immunocompetent and immunocompromised hosts.

Primary effusion lymphoma (PEL) is an uncommon non-Hodgkin lymphoma associated with human herpes virus-8 (HHV-8) that grows mainly in serous body cavities. The most common presentation of PEL is that of a young immunocompromised male with shortness of breath, as the pleural cavity is most commonly affected. Diagnosis is primarily based on fluid cytology in which PEL cells display variable morphology and a null lymphocyte immunophenotype; however, evidence of HHV-8 infection within the neoplastic cell is essential. Patients have commonly been treated with systemic multidrug chemotherapy and antiretroviral therapy if they were HIV positive or were immunocompromised for other reasons. In the immunocompetent patient, there have been no agreed-upon pathways for management of this condition. Progression of disease is common and median survival is approximately 6 months. Novel intrapleural treatments with antiviral agents such as intracavity cidofovir have shown to be effective in controlling local disease, and ongoing clinical trials may provide some promise in the treatment for this condition.

Myo1e overexpression in lung adenocarcinoma is associated with increased risk of mortality.

This study aims to perform a comprehensive genomic analysis to assess the influence of overexpression of MYO1E in non-small cell lung carcinoma (NSCLC) and whether there are differences in survival and mortality risk in NSCLC patients depending on both DNA methylation and RNA expression of MYO1E. The DNA methylation probe cg13887966 was inversely correlated with MYO1E RNA expression in both LUAD and LUSC subpopulations showing that lower MYO1E RNA expression was associated with higher MYO1E DNA methylation. Late stages of lung cancer showed significantly lower MYO1E DNA methylation and significantly higher MYO1E RNA expression for LUAD but not for LUSC. Low DNA methylation as well as high RNA expression of MYO1E are associated with a shorter median survival time and an increased risk of mortality for LUAD, but not for LUSC. This study suggests that changes in MYO1E methylation and expression in LUAD patients may have an essential role in lung cancer's pathogenesis. It shows the utility of MYO1E DNA methylation and RNA expression in predicting survival for LUAD patients. Also, given the low normal expression of MYO1E in blood cells MYO1E DNA methylation has the potential to be used as circulating tumor marker in liquid biopsies.

Non-small cell lung carcinoma spheroid models in agarose microwells for drug response studies.

There is a growing interest in developing personalized treatment strategies for each cancer patient, especially those with non-small cell lung carcinoma (NSCLC) which annually accounts for the majority of cancer related deaths in the US. Yet identifying the optimal NSCLC treatment strategy for each cancer patient is critical due to a multitude of mutations, some of which develop following initial therapy and can result in drug resistance. A key difficulty in developing personalized therapies in NSCLC is the lack of clinically relevant assay systems that are suitable to evaluate drug sensitivity using a minuscule amount of patient-derived material available following biopsies. Herein we leverage 3D printing to demonstrate a platform based on miniature microwells in agarose to culture cancer cell spheroids. The agarose wells were shaped by 3D printing molds with 1000 microwells with a U-shaped bottom. Three NSCLC cell lines (HCC4006, H1975 and A549) were used to demonstrate size uniformity, spheroid viability, biomarker expressions and drug response in 3D agarose microwells. Results show that our approach yielded spheroids of uniform size (coefficient of variation <22%) and high viability (>83% after 1 week-culture). Studies using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKIs) drugs gefitinib and osimertinib showed clinically relevant responses. Based on the physical features, cell phenotypes, and responses to therapy of our spheroid models, we conclude that our platform is suitable for in vitro culture and drug evaluation, especially in cases when tumor sample is limited.

Surgical Transcatheter Aortic Valve Replacement Explantation Technique.

As transcatheter aortic valve replacement (TAVR) indications expand, cardiac surgeons need to be prepared to manage heretofore rare TAVR complications requiring explantation, such as acute type A dissection, in these typically high-risk patients. This report describes the successful use of an explantation technique that is ready to hand, efficient, and effective at avoiding further injury to the aortic root and coronary ostia.

Mutant ANP induces mitochondrial and ion channel remodeling in a human iPSC-derived atrial fibrillation model.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can model heritable arrhythmias to personalize therapies for individual patients. Although atrial fibrillation (AF) is a leading cause of cardiovascular morbidity and mortality, current platforms to generate iPSC-atrial (a) CMs are inadequate for modeling AF. We applied a combinatorial engineering approach, which integrated multiple physiological cues, including metabolic conditioning and electrical stimulation, to generate mature iPSC-aCMs. Using the patient's own atrial tissue as a gold standard benchmark, we assessed the electrophysiological, structural, metabolic, and molecular maturation of iPSC-aCMs. Unbiased transcriptomic analysis and inference from gene regulatory networks identified key gene expression pathways and transcription factors mediating atrial development and maturation. Only mature iPSC-aCMs generated from patients with heritable AF carrying the non-ion channel gene (NPPA) mutation showed enhanced expression and function of a cardiac potassium channel and revealed mitochondrial electron transport chain dysfunction. Collectively, we propose that ion channel remodeling in conjunction with metabolic defects created an electrophysiological substrate for AF. Overall, our electro-metabolic approach generated mature human iPSC-aCMs that unmasked the underlying mechanism of the first non-ion channel gene, NPPA, that causes AF. Our maturation approach will allow for the investigation of the molecular underpinnings of heritable AF and the development of personalized therapies.

Less-Invasive Aortic Valve Replacement: Trends and Outcomes From The Society of Thoracic Surgeons Database.

BACKGROUND: This study compares outcomes of conventional and less-invasive (LI) approaches for aortic valve replacement (AVR) using The Society of Thoracic Surgeons database. METHODS: Between 2011 and 2017, we identified 122,474 patients undergoing isolated primary AVR. Patients were categorized into 3 groups: (1) full sternotomy (FS) (n = 98,549; 78%), (2) partial sternotomy (PS) (n = 17,306; 15%), and (3) right thoracotomy (RT) (n = 6619; 7%). RESULTS: The rate of LI-AVR increased from 17% in 2011 to 23% in 2016 (P < .001). Femoral cannulation was used in 1.5% of FS, 5.4% of PS, and 71% of RT patients (P < .001). Full sternotomy patients were older and had higher rates of preoperative renal failure, atrial fibrillation, and stroke, and had a higher NYHA function class, lower ejection fraction, and higher STS risk score. Total operative, cardiopulmonary bypass, and cross-clamp time were longest in RT-AVR patients and shortest in those who had FS-AVR. Overall, unadjusted operative mortality was 1.9% (1.05% among low-risk patients) and was not different among the 3 groups (1.97% FS, 1.77% PS, and 1.90% RT; P = .4). The rate of postoperative stroke was 1.2% and was not different among the 3 groups (1.2% FS, 1.3% PS, and 1.1% RT; P = .3). After risk adjustment, these differences remained nonsignificant. After risk adjustment, prolonged ventilation and atrial fibrillation were less common in PS-AVR patients. The adjusted risk for blood transfusion was lower in RT-AVR patients, as was the incidence of renal failure. Femoral cannulation was not associated with increased risk for stroke or mortality after LI-AVR. CONCLUSIONS: Less-invasive AVR is associated with an operative mortality and postoperative stroke rate similar to that of FS. Less-invasive AVRs should serve as a benchmark for comparison between transcatheter aortic valve replacement and surgical AVR in low-risk patients.

Current outcomes of simultaneous carotid endarterectomy and coronary artery bypass graft surgery in North America.

OBJECTIVE: Management of patients with concomitant carotid and coronary artery disease has been controversial. Divergent strategies have been employed, including simultaneous carotid endarterectomy and coronary bypass (SCC) versus various staged procedures. Although no strict comparison group is available, this study defines current outcomes of SCC, compared qualitatively to two reference categories. METHODS: Utilizing the STS database from 2003 to 2007, patients who had SCC were compared with patients with cerebrovascular disease who had coronary bypass (CABG) with prior carotid endarterectomy (CEA), and those with carotid Doppler stenosis >75% and no carotid intervention. Logistic regression analysis adjusted for differences in baseline characteristics and operative mortality (OM), and a composite of neurological complications (NC) was assessed. RESULTS: Of 745,769 patients who underwent isolated CABG with/without CEA, 108,212 (14%) had cerebrovascular disease. Of this group, 5,732 (5%) underwent SCC. The SCC group had more males and lower preoperative risk factors. After statistical adjustment for all baseline differences, SCC had clinically and statistically higher OM and NC compared with any of the reference groups, with 20-40% higher event risk. CONCLUSIONS: Although no quantitative control group exists for comparison, SCC as recently performed in North America has a high risk compared with any of the reference groups. Suboptimal results associated with the SCC strategy suggest a need for quality improvement and research on the optimal management of patients with simultaneous carotid and coronary disease.

Detection of Promoter DNA Methylation in Urine and Plasma Aids the Detection of Non-Small Cell Lung Cancer.

PURPOSE: Low-dose CT screening can reduce lung cancer-related mortality. However, CT screening has an FDR of nearly 96%. We sought to assess whether urine samples can be a source for DNA methylation-based detection of non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: This nested case-control study of subjects with suspicious nodules on CT imaging obtained plasma and urine samples preoperatively. Cases (n = 74) had pathologic confirmation of NSCLC. Controls (n = 27) had a noncancer diagnosis. We detected promoter methylation in plasma and urine samples using methylation on beads and quantitative methylation-specific real-time PCR for cancer-specific genes (CDO1, TAC1, HOXA7, HOXA9, SOX17, and ZFP42). RESULTS: DNA methylation at cancer-specific loci was detected in both plasma and urine, and was more frequent in patients with cancer compared with controls for all six genes in plasma and in CDO1, TAC1, HOXA9, and SOX17 in urine. Univariate and multivariate logistic regression analysis showed that methylation detection in each one of six genes in plasma and CDO1, TAC1, HOXA9, and SOX17 in urine were significantly associated with the diagnosis of NSCLC, independent of age, race, and smoking pack-years. When methylation was detected for three or more genes in both plasma and urine, the sensitivity and specificity for lung cancer diagnosis were 73% and 92%, respectively. CONCLUSIONS: DNA methylation-based biomarkers in plasma and urine could be useful as an adjunct to CT screening to guide decision-making regarding further invasive procedures in patients with pulmonary nodules.

Lipid emulsion is superior to vasopressin in a rodent model of resuscitation from toxin-induced cardiac arrest.

OBJECTIVES: Lipid emulsion infusion is an emerging antidotal therapy for toxin-induced cardiac arrest. To compare the efficacy of resuscitation from bupivacaine-induced asystole using lipid emulsion infusion vs. vasopressin, alone and with epinephrine. DESIGN: Prospective, randomized, animal study. SETTING: University research laboratory. SUBJECTS: Adult, male Sprague-Dawley rats. INTERVENTIONS: Instrumented rats were given an intravenous bolus of 20 mg/kg bupivacaine to induce asystole (zero time). Rats (n = 6 for all groups) were ventilated with 100% oxygen, given chest compressions, and randomized to receive 30% lipid emulsion (L, 5 mL/kg bolus then 1.0 mL/kg/min infusion) and vasopressin 0.4 U/kg bolus alone (V) or combined with epinephrine, 30 microg/kg (V + E); boluses (L, V, or V + E) were repeated at 2.5 and 5 minutes for a rate-pressure product (RPP) less than 20% baseline. MEASUREMENTS AND MAIN RESULTS: The arterial blood pressure and electrocardiogram were measured continuously for 10 minutes when blood was drawn for arterial blood gas analysis, lactate content, and central venous oxygen saturation (ScvpO2). Hemodynamic parameters of the L group at 10 minutes (30,615 +/- 4782 mm Hg/min; 151 +/- 19.1 mm Hg; 197 +/- 8.6 min; RPP, systolic blood pressure and heart rate, respectively) exceeded those of the V group (5395 +/- 1310 mm Hg/min; 85.8 +/- 12 mm Hg; 61 +/- 10.8 min) and the V + E group (11,183 +/- 1857 mm Hg/min; 75.5 +/- 12.9 min, RPP and heart rate, respectively; systolic blood pressure was not different). Metrics indicated better tissue perfusion in the L group (7.24 +/- 0.02; 83% +/- 3.5%; 2.2 +/- 0.36 mmol/L; pH, ScvpO2, lactate, respectively) than V (7.13 +/- 0.02; 29.9% +/- 4.4%; 7.5 +/- 0.6 mmol/L) and V + E groups (7.07 +/- 0.03; 26.2% +/- 8.9%; 7.7 +/- 1 mmol/L). Wet-to-dry lung ratios in V (8.3 +/- 0.6) and V + E (8.7 +/- 0.2) were greater than that in the L group (6.2 +/- 05) (mean +/- sem; p < 0.05 for all shown results). CONCLUSIONS: Lipid emulsion in this rat model provides superior hemodynamic and metabolic recovery from bupivacaine-induced cardiac arrest than do vasopressors. Systolic pressure was not a useful metric in the vasopressor groups. Vasopressin was associated with adverse outcomes.

Epinephrine impairs lipid resuscitation from bupivacaine overdose: a threshold effect.

BACKGROUND: Lipid emulsion infusion reverses local anesthetic-induced cardiac toxicity, but the effect of adding epinephrine has not been studied. We compared escalating doses of epinephrine on recovery with lipid infusion in a rat model of bupivacaine overdose. METHODS: Rats anesthetized with isoflurane received an IV bolus of 20 mg/kg bupivacaine, producing asystole (zero time) in all animals. Ventilation (100% oxygen) and chest compressions were started immediately, and at 3 min the rats received one of six IV treatments (n = 5 for all groups): 5 ml/kg saline followed by infusion for 2 min at 1.0 ml x kg x min, and a second 5 ml/kg bolus at 5 min; or the same bolus and infusion treatment using 30% lipid emulsion plus a single injection of epinephrine at one of five doses: 0 (lipid control), 1, 2.5, 10, or 25 mcg/kg. An electrocardiogram and arterial pressure were monitored continuously, and arterial blood gas was measured at 7.5 and 15 min. RESULTS: Epinephrine improved initial return of spontaneous circulation (rate-pressure product > 30% baseline) but only 3 of 5 rats at 10 mcg/kg and 1 of 5 rats at 25 mcg/kg sustained return of spontaneous circulation by 15 min. Lipid alone resulted in slower but more sustained recovery. Epinephrine doses above a threshold near 10 mcg/kg increased lactate, worsened acidosis, and resulted in poor recovery at 15 min, as compared with lipid controls. There was tight correlation of epinephrine dose to serum lactate at 15 min. CONCLUSIONS: Epinephrine over a threshold dose near 10 mcg/kg impairs lipid resuscitation from bupivacaine overdose, possibly by inducing hyperlactatemia.

Surgical repair of anomalous coronary arteries arising from the opposite sinus of Valsalva in infants and children.

BACKGROUND: Unroofing of anomalous coronary artery originating from the opposite sinus of Valsalva has become the procedure of choice for this congenital lesion, with surgery performed in children as young as two years old. An increasing number of this anomaly is diagnosed in infancy with no clear indication whether surgical repair should be done in this age group. This paper reviews our experience with this anomaly, and focuses on its surgical management in infants. METHODS: Between April 2002 and February 2007, eight patients underwent surgical repair of anomalous coronary artery arising from the opposite sinus of Valsalva and coursing between the aorta and pulmonary artery. Patients' age varied from two months to 28 years with a mean of 11.7 +/- 11.1 years. SURGICAL TECHNIQUE: Surgical repair involved unroofing the intramural segment of the anomalous coronary artery using cardiopulmonary bypass. RESULTS: Two patients were younger than one year (Group A), and six patients were older than one year (group B). The mean intensive care unit stay was 2.5 +/- 0.7 days for Group A and 2.8 +/- 1.9 for Group B. The mean hospital stay was 4 +/- 1.4 days for Group A and 4.3 +/- 2.4 days for Group B. There was no mortality and no complications. The mean follow-up period is 14 +/- 15.7 months with a range of one to 39 months. At the time of the last follow-up, all patients were asymptomatic in New York Heart Association class I and follow-up echocardiography on six of eight patients showed wide open coronary ostium. CONCLUSION: Unroofing the anomalous coronary artery arising from the opposite sinus of valsalva can be done in infants with minimal morbidity and mortality. Longer follow-up is needed to assess long-term results.

Resuscitation with lipid versus epinephrine in a rat model of bupivacaine overdose.

BACKGROUND: Lipid emulsion infusion reverses cardiovascular compromise due to local anesthetic overdose in laboratory and clinical settings. The authors compared resuscitation with lipid, epinephrine, and saline control in a rat model of bupivacaine-induced cardiac toxicity to determine whether lipid provides a benefit over epinephrine. METHODS: Bupivacaine, 20 mg/kg, was infused in rats anesthetized with isoflurane, producing asystole in all subjects. Ventilation with 100% oxygen and chest compressions were begun immediately, along with intravenous treatment with 30% lipid emulsion or saline (5-ml/kg bolus plus continuous infusion at 0.5 ml . kg . min) or epinephrine (30 microg/kg). Chest compressions were continued and boluses were repeated at 2.5 and 5 min until the native rate-pressure product was greater than 20% baseline. Electrocardiogram and arterial pressure were monitored continuously and at 10 min, arterial blood gas, central venous oxygen saturation, and blood lactate were measured. Effect size (Cohen d) was determined for comparisons at 10 min. RESULTS: Lipid infusion resulted in higher rate-pressure product (P < 0.001, d = 3.84), pH (P < 0.01, d = 3.78), arterial oxygen tension (P < 0.05, d = 2.8), and central venous oxygen saturation (P < 0.001, d = 4.9) at 10 min than did epinephrine. Epinephrine treatment caused higher lactate (P < 0.01, d = 1.48), persistent ventricular ectopy in all subjects, pulmonary edema in four of five rats, hypoxemia, and a mixed metabolic and respiratory acidosis by 10 min. CONCLUSIONS: Hemodynamic and metabolic metrics during resuscitation with lipid surpassed those with epinephrine, which were no better than those seen in the saline control group. Further studies are required to optimize the clinical management of systemic local anesthetic toxicity.

Endovascular treatment of aortic aneurysms: techniques and clinical update.

Open repair of abdominal and thoracic aortic aneurysms continues to be associated with considerable morbidity and mortality. Endovascular repair of abdominal and thoracic aortic aneurysms has evolved over the past few years and has significantly reduced the morbidity of aortic aneurysm repair compared with the standard open surgical procedures. Several devices have been approved for clinical use for this purpose. This has allowed the treatment of patients who are otherwise at high risk for open repair. This review paper aims to (1) describe the general principles of use for endovascular devices and review the radiographic features and clinical trials for the devices in current use, (2) present the results of the clinical trials that led to the approval and marketing of the current devices, and (3) review new techniques and approaches for the treatment of aortic aneurysms.

Left Atrial and Carotid Body Paraganglioma.

We report a rare case of left atrial paraganglioma with a synchronous carotid body paraganglioma in a 30-year-old man with succinate dehydrogenase B gene mutation. The patient initially presented with a neck mass and palpitations. Laboratory test results showed elevated catecholamine levels. A cardiac paraganglioma was identified by computed tomography, meta-iodobenzylguanidine scintigraphy, and magnetic resonance imaging. Surgical resection of both paragangliomas were performed on two separate occasions. Serum and urine catecholamine levels returned to normal range. On follow-up, there was no recurrence of the cardiac paraganglioma. Radiotherapy was subsequently initiated for recurrence in the carotid body paraganglioma.