Anthony Lemaire

β-Arrestin–mediated β1-adrenergic receptor transactivation of the EGFR confers cardioprotection

Deleterious effects on the heart from chronic stimulation of β-adrenergic receptors (βARs), members of the 7 transmembrane receptor family, have classically been shown to result from Gs-dependent adenylyl cyclase activation. Here, we identify a new signaling mechanism using both in vitro and in vivo systems whereby β-arrestins mediate β1AR signaling to the EGFR. This β-arrestin–dependent transactivation of the EGFR, which is independent of G protein activation, requires the G protein–coupled receptor kinases 5 and 6. In mice undergoing chronic sympathetic stimulation, this novel signaling pathway is shown to promote activation of cardioprotective pathways that counteract the effects of catecholamine toxicity. These findings suggest that drugs that act as classical antagonists for G protein signaling, but also stimulate signaling via β-arrestin–mediated cytoprotective pathways, would represent a novel class of agents that could be developed for multiple members of the 7 transmembrane receptor family.

A comparative analysis of positron emission tomography and mediastinoscopy in staging non–small cell lung cancer

OBJECTIVES Positron emission tomography has been demonstrated to improve the detection of distant metastases in patients with lung cancer. This study compares the efficacy of PET to mediastinoscopy in mediastinal staging of patients with non-small cell lung cancer. METHODS Between May 1995 and May 2000, positron emission tomography was performed on 1988 patients with known or suspected non-small cell lung cancer at Duke University Medical Center. Cervical mediastinoscopy was subsequently performed in patients without demonstrable evidence of distant metastases. The efficacy of mediastinal staging was analyzed by comparing the prospective results of positron emission tomography with the histopathologic results of mediastinoscopy by nodal station. RESULTS In this study 202 patients with non-small cell lung cancer (116 of whom were male) underwent mediastinoscopy after positron emission tomography. Of the 65 patients with positive results of positron emission tomography, only 29 patients had positive results of mediastinoscopy in the corresponding nodal station. Of the 137 patients with negative results of positron emission tomography, 16 patients were demonstrated to have N2 or N3 disease. The sensitivity, specificity, positive and negative predictive values, and accuracy for positron emission tomography were 64.4%, 77.1%, 44.6%, 88.3%, and 74.3%, respectively. Histologic findings in patients with non-small cell lung cancer and false-positive results of mediastinal positron emission tomography included granulomatous inflammation, sinus histiocytosis, and silicosis. CONCLUSIONS Positron emission tomography neither confirms nor excludes involvement of the mediastinum in patients with non-small cell lung cancer. Cervical mediastinoscopy with lymph node biopsy remains the criterion standard for mediastinal staging.

β1-Adrenergic receptors stimulate cardiac contractility and CaMKII activation in vivo and enhance cardiac dysfunction following myocardial infarction

The beta-adrenergic receptor (betaAR) signaling system is one of the most powerful regulators of cardiac function and a key regulator of Ca(2+) homeostasis. We investigated the role of betaAR stimulation in augmenting cardiac function and its role in the activation of Ca(2+)/calmodulin-dependent kinase II (CaMKII) using various betaAR knockouts (KO) including beta(1)ARKO, beta(2)ARKO, and beta(1)/beta(2)AR double-KO (DKO) mice. We employed a murine model of left anterior descending coronary artery ligation to examine the differential contributions of specific betaAR subtypes in the activation of CaMKII in vivo in failing myocardium. Cardiac inotropy, chronotropy, and CaMKII activity following short-term isoproterenol stimulation were significantly attenuated in beta(1)ARKO and DKO compared with either the beta(2)ARKO or wild-type (WT) mice, indicating that beta(1)ARs are required for catecholamine-induced increases in contractility and CaMKII activity. Eight weeks after myocardial infarction (MI), beta(1)ARKO and DKO mice showed a significant attenuation in fractional shortening compared with either the beta(2)ARKO or WT mice. CaMKII activity after MI was significantly increased only in the beta(2)ARKO and WT hearts and not in the beta(1)ARKO and DKO hearts. The border zone of the infarct in the beta(2)ARKO and WT hearts demonstrated significantly increased apoptosis by TUNEL staining compared with the beta(1)ARKO and DKO hearts. Taken together, these data show that cardiac function and CaMKII activity are mediated almost exclusively by the beta(1)AR. Moreover, it appears that beta(1)AR signaling is detrimental to cardiac function following MI, possibly through activation of CaMKII.

The impact of race and insurance type on the outcome of endovascular abdominal aortic aneurysm (AAA) repair

BACKGROUND Although mortality and complication rates for abdominal aortic aneurysm (AAA) have declined over the last 20 years, operative complication rates and perioperative mortality are still high, specifically for repair of ruptures. The goal of this study was to determine the influence of insurance type and ethnicity while controlling for the influences of potential confounders on procedure selection and outcome following endovascular AAA repair (EVAR). METHODS Using the Nationwide Inpatient Sample (NIS) database, we identified patients who underwent EVAR repair of ruptured and elective infrarenal AAA, between 1990 and 2003. Insurance type and ethnicity were analyzed against the primary outcome variables of mortality and major complications. The potential confounders of age, gender, operative location, diabetes, and Deyo index of comorbidities, were controlled. RESULTS Bivariate analyses demonstrated significant differences between insurance types and ethnicity and mortality and complications. Patients who were self pay had adverse outcomes in comparison to Private insurance. Whites encountered less perioperative mortality and postoperative complications than Blacks and Hispanics. CONCLUSIONS After controlling for previously identified associative factors for AAA outcome, ethnicity and insurance type does influence EVAR surgical outcome. Subsequent studies that break down emergent repair vs elective surgery and that longitudinally stratify delay in surgery, or time to admission may be useful.

The Impella Device for Acute Mechanical Circulatory Support in Patients in Cardiogenic Shock

BACKGROUND Acute cardiogenic shock is associated with high mortality rates. Mechanical circulatory devices have been increasingly used in this setting for hemodynamic support. The Impella device (Abiomed Inc, Danvers, MA) is a microaxial left ventricular assist device that can be inserted using a less invasive technique. This study was conducted to determine the outcome of patients who have undergone placement of the Impella device for acute cardiogenic shock in our institution. METHODS A retrospective record review of 47 patients who underwent placement of the Impella device was performed from January 1, 2006, to December 31, 2011. Records were evaluated for demographics, operative details, and postoperative outcomes. Operative mortality was defined as death within 30 days of the operation. RESULTS The patients (33 male) were an average age of 60.23 ± 13 years. The indication for placement of the Impella device included cardiogenic shock in 15 patients (32%) and postcardiotomy cardiogenic shock in 32 (68%). Of the 47 patients, 38 (80%) received the Impella 5.0 and the rest the 2.5 device. Ventricular function recovered in 34 of 47 patients (72%), and the device was removed, with 4 patients (8%) transitioned to long-term ventricular assist devices. The 30-day mortality was 25% (12 of 47 patients). Complications occurred in 14 patients (30%), consisting of device malfunction, high purge pressures, tube fracture, and groin hematoma. CONCLUSIONS This is one of the largest series of patients undergoing placement of the Impella device for acute cardiogenic shock. Our outcomes showed improved results compared with historical data. Myocardial recovery was accomplished in most patients. Finally, the 30-day mortality and complication rate was acceptable in these critical patients. These benefits were all achieved with the Impella device in a less invasive method.

Infectious Complications in Extended Criteria Heart Transplantation

BACKGROUND We have previously shown that extended criteria heart transplant recipient mortality is higher than standard list mortality, but this is not associated with an increased incidence of either primary graft dysfunction or acute rejection. We hypothesized that other adverse outcomes, principally determined by recipient characteristics, occur at a higher rate in extended criteria recipients. METHODS A retrospective review of adult heart transplant recipients was conducted at Duke University Medical Center between January 2000 and July 2007. Infectious complications considered risk factors for recipient mortality were identified. In addition, the incidence of these complications was compared between standard and alternate list recipients. RESULTS Infectious complications, including pneumonia, bacteremia and sepsis, were significant predictors of overall mortality (pneumonia hazard ratio 4.2 [95% CI 2.5 to 7.0], bacteremia hazard ratio 3.0 [95% CI 1.9 to 4.9], sepsis hazard ratio 6.0 [95% CI 3.6 to 10.2]). In addition, pneumonia occurred at a significantly higher rate in extended criteria (EC) than in standard list (SL) patients (27% vs 13%, p = 0.005), and bacteremia and sepsis demonstrated a trend toward higher occurrence in EC patients (36% vs 25%, p = 0.076, and 15% vs 8%, p = 0.114, respectively). In contrast, severe acute cellular rejection (ISHLT Grade >/=3A) was not a predictor of mortality, and had a similar incidence in both groups. Finally, although overall survival among patients in the SL group was not influenced by the occurrence of a major infectious complication, survival in the extended criteria group was significantly impacted by major infectious complications (p < 0.001). CONCLUSIONS Infectious complications may account for decreased survival in extended criteria heart transplant recipients.

MINIMALLY INVASIVE MITRAL VALVE SURGERY: THE NEW GOLD STANDARD?

Full sternotomy was the traditional approach to mitral valve surgery, but minimally invasive techniques, like right anterior mini-thoracotomy, have the proposed benefits of shorter length of stay (LOS) and fewer complications. Opponents of mini-thoracotomy, however, describe poor exposure and longer

Pericardial Angiosarcoma: An Elusive Diagnosis

The diagnosis of pericardial angiosarcoma is rare. We present a 33 year-old man with recurrent hemorrhagic pericardial effusions ultimately diagnosed with pericardial angiosarcoma by surgical biopsy. This case report highlights the challenges in diagnosing primary pericardial malignancy.

The Impella Device as a Temporary Bridge for Acute Mechanical CirculatorySupport

The mortality rate from cardiogenic shock after acute myocardialinfarction (MI) is high without reperfusion (70%-80%) [1]. Early revascularization is the basis of treatment of acute MI complicated by cardiogenic shock. Mechanical circulatory devices provide additional support for patients with refractory cardiogenic shock after revascularization alone has failed. These devices have been shown in the literature to improve outcomes in contrast to pharmacologic agents and/or intra-aortic balloon pump (IABP) demonstrated in the literature [2]. Short-term ventricular assists devices (VADs) can be initiated quickly and do not necessarily require a sternotomy. The Impella devices are minimally invasively placed, catheter mounted microaxial flow pumps. They are designed to directly unload the left ventricle, reduce myocardial workload and oxygen consumption while increasing cardiac output, coronary and end-organ perfusion. The purpose of our study is to review a patient who presented with acute cardiogenic shock and was treated with an Impella 5.0 device for temporarymechanical support.

Refractory Hypertension Leads to both Type A and B Aortic Dissections in a Single Patient

more prevalent in the population of patients with Type B dissections at 76.7% vs. those with Type A dissections at 69.3% there was no significant difference between the high proportion in these two groups (p=0.08) [8]. This contribution to aortic dissection is also remarkable in that the most affected demographic for either aortic dissection type is typically male (65.3%) and Caucasian (82.8%) with a mean age of 63.1 ± 14 years, with the rest of the patient population comprised of only1.7% African American and 13.5% Asian patients [8]. In each circumstance, the most common presenting symptom was found to be abrupt onset of sharp pain of the utmost severity either in the anterior chest in Type A dissections (p<0.001) or back in Type B dissections (p<0.001), which this patient also experienced. Patients were also found to present with systolic hypertension on physical exam most commonly (49%) with significantly more during a Type B vs [8]. Type A aortic dissection (70.1% vs. 35.7% respectively, p<0.001), with Type A dissections presenting significantly more with new-onset murmur of aortic insufficiency (44%, p<0.001), pulse deficit (18.7%, p=0.006), and congestive heart failure (8.8%, p=0.02) [8]. The most common imaging modality used to detect aortic dissection was computed tomography (61.1%) [8], which was used in the diagnosis of this patient (Figure 1). Only 3.9% of patients with a Type A aortic dissection had experienced a previous unspecified type dissection versus 10.6% of patients with a Type B aortic dissection (p<0.005), making this