Basel Ramlawi

Factors Associated With Primary Graft Failure After Heart Transplantation

Background. Primary graft failure (PGF) is the most common cause of short-term mortality after cardiac transplantation. The low prevalence of PGF has limited efforts at identifying risk factors for its development. The purpose of this study was to evaluate risk factors associated with PGF after heart transplantation. Methods. Deidentified data were obtained from United Network for Organ Sharing. Analysis included heart transplant recipients more than or equal to 18 years transplanted between January 1, 1999, and December 31, 2007 (n=16,716). PGF was studied from the perspective of “hard outcomes” including death or retransplantation within 90 days of transplant due to graft failure, not related to rejection or infection. Multivariate regression analysis was performed (backward, remove P>0.15) to assess the simultaneous effect of multiple variables on PGF. The odds ratio and 95% confidence interval were reported for each factor. Results. Among the 414 heart transplants complicated by PGF, 354 (85.5%) recipients died and 60 (14.5%) were retransplanted. PGF accounted for 23.4% (n=364) of all deaths (n=1555) in the first 90 days posttransplant. Categories of pretransplant variables associated with PGF included: ischemic time, donor gender, donor age, multiorgan donation, center volume, extracorporeal membrane oxygenation, mechanical circulatory support, etiology of heart failure, and reoperative heart transplant. The area under the receiver operative characteristic curve for the multivariate model was 0.764 (0.733–0.796). Conclusions. Pretransplant recipient and donor characteristics are associated with PGF. Identification of risk factors may aid in understanding the mechanisms underlying PGF and in matching recipients with donors in efforts to diminish the high mortality associated with this complication.

Serologic Markers of Brain Injury and Cognitive Function After Cardiopulmonary Bypass

Objective:To examine the association between biochemical markers of brain injury (MBI) and the inflammatory response in relation to neurocognitive deficiency (NCD) after cardiopulmonary bypass (CPB). Summary Background Data:In cardiac surgery, NCD is a common but underdiagnosed complication with an unclear pathophysiology leading to significant morbidity. Despite extensive investigation, identification of a MBI for clinical use and clarifying the pathophysiology of NCD have not been achieved. Methods:Forty patients undergoing CABG and/or valve procedures using CPB were administered a validated neurocognitive battery preoperatively and postoperatively at day 4 and 3 months. S-100b, neuron specific enolase (NSE), and tau protein were assayed as MBIs preoperatively and postoperatively at 6 hours and day 4. C-reactive protein (CRP), interleukin (IL)-6, C3a, and total peroxide levels were also quantified from serum. Impact of cardiotomy suction and antifibrinolytics on markers of brain injury was assessed. Results:The incidence of early NCD was 40% (16 of 40). NSE and tau protein at the 6-hour time point were both significantly elevated in the presence of NCD (NCD group) compared with those without NCD (NORM group) (8.69 ± 0.82 vs. 5.98 ± 0.61; P = 0.018 and 68.8 vs. 29.2%; P = 0.015; respectively). S-100b increase was not different between the NCD and NORM groups. Cardiotomy suction significantly elevated S-100b levels, whereas NSE and tau were not significantly influenced. Aprotinin did not have an effect on NCD or levels of MBIs. Also, the NCD group had significantly elevated CRP and peroxide levels compared with the NORM group at postoperative day 4 while C3a was significantly elevated at 6 hours. Conclusion:NSE and tau are better associated with NCD and less influenced by cardiotomy suction compared with S-100β. Inflammatory and oxidative stress is associated with NCD post-CPB.

Functional, Cellular, and Molecular Characterization of the Angiogenic Response to Chronic Myocardial Ischemia in Diabetes

Background— Ischemic heart disease is the most common cause of mortality in diabetic patients. Although therapeutic angiogenesis is an attractive option for these patients, they appear to have reduced collateral formation in response to myocardial ischemia. The aims of this study were to establish a large animal model of diabetes and chronic myocardial ischemia, evaluate the effects of diabetes on the angiogenic response, and elucidate the molecular pathways involved. Methods and Results— Diabetes was induced in male Yucatan miniswine using a pancreatic β-cell specific toxin, alloxan (150 mg/kg; n=8). Age-matched swine served as controls (n=8). Eight weeks after induction, chronic ischemia was induced by ameroid constrictor placement around the circumflex coronary artery. Myocardial perfusion and function were assessed at 3 and 7 weeks after ameroid placement using isotope-labeled microspheres. Endothelial cell density and myocardial expression of angiogenic mediators was evaluated. Diabetic animals exhibited significant endothelial dysfunction. Collateral dependent perfusion and LV function were significantly impaired in diabetic animals. Diabetic animals also demonstrated reduced endothelial cell density (173±14 versus 234±23 cells/hpf, P=0.03). Expression of VEGF, Ang-1, and Tie-2 was reduced, whereas antiangiogenic proteins, angiostatin (4.4±0.9-fold increase, P<0.001), and endostatin (2.9±0.4-fold increase, P=0.03) were significantly elevated in the diabetic myocardium. Conclusions— Diabetes results in a profound impairment in the myocardial angiogenic response to chronic ischemia. Pro- and antiangiogenic mediators identified in this study offer novel targets for the modulation of the angiogenic response in diabetes.

Indices of Apoptosis Activation After Blood Cardioplegia and Cardiopulmonary Bypass

Background— Cardioplegic arrest (CA) using cold blood cardioplegia (CBC) has been reported to reduce ischemia-reperfusion (IR)-induced myocardial injury via apoptosis. We studied key apoptotic mediators via the caspase-dependent and intrinsic pathways as well as poly(ADP)-ribosylating protein (PARP) activity in myocardial and peripheral tissues after CA and cardiopulmonary bypass (CBP). Methods and Results— Right atrial (RA) and skeletal muscle(SM) was harvested from cardiac surgical patients with similar baseline characteristics (N =6) before and after CPB and CBC. Total and modified caspase-3, Bcl-2, Bad, apoptosis-inducing factor (AIF), and PARP were quantified by immunoblotting. Terminal caspase-3 activity was assessed and immunohistochemistry was performed for PARP and AIF. TUNEL staining was used for identification of apoptotic cells. Microarray gene expression analysis was performed using Affymetrix U95 GeneChip. In RA tissue, CA with CBC significantly increased phosphorylation of Bcl-2 (Ser70), Bad (Ser112) (2.63±0.4 and 1.77±0.3-fold respectively; P<0.05), and cleavage of the downstream caspase 3 (1.45±0.1-fold; P<0.05). There was no significant change in total protein levels. Also, there was an increase in mature AIF (57 kDa) levels (1.22±0.01-fold; P<0.05) and a trend toward nuclear translocation on histological staining. Caspase 3 activity was increased 1.5±0.14-fold (P<0.05). The number of apoptotic cells in atrial tissue increased after compared with before CPB/CA using TUNEL staining (1.55±0.66 versus 0.325±0.05%, respectively; P=0.03). In contrast, SM samples did not show any of the changes observed in RA tissue after CPB. Conclusion— Despite optimal current surgical myocardial protection, we found that CA with CBC induced both programmed cell death and survival signaling in myocardial tissue.

Role of Stromal-Derived Factor-1α in the Induction of Circulating CD34+CXCR4+ Progenitor Cells After Cardiac Surgery

Background— Cardioplegia and cardiopulmonary bypass (CP/CPB) leads to an increase in circulating progenitor cells. The role of stromal-derived factor-1&agr; (SDF-1&agr;), a key regulator of progenitor cell mobilization, and other cytokines in this process is not clear. Methods and Results— Peripheral blood (n=24), atrial and skeletal tissue (n=6) samples were taken from patients undergoing CP/CPB before (pre-CP/CPB), 4 hours (post-CP/CPB), and 4 days (POD4) after CP/CPB. The number of circulating CD34+CXCR4+ cells increased post-CP/CPB (442±53 versus 286±27; P=0.04 versus pre-CP/CPB), but not at POD4 (382±50; P=0.28 versus pre-CP/CPB). Plasma levels of SDF-1&agr; increased post-CP/CPB as compared with pre-CP/CPB (3325±325 versus 2911±165 pg/mL; P=0.046) but returned to baseline at POD4 (2838±224 pg/mL; P=0.90). Plasma levels of vascular endothelial growth factor were similar post-CP/CPB (P=0.90 versus pre-CP/CPB) but increased at POD4 (220±40 pg/mL versus 134±26 pg/mL; P=0.04 versus pre-CP/CPB). Serum levels of granulocyte-colony stimulating factor (G-CSF) increased early after CP/CPB as compared with pre-CP/CPB (265.0±41.7 versus 11.1±1.1 pg/mL; P<0.001) and returned to baseline at POD4 (P=0.84 versus pre-CP/CPB). The circulating CD34+CXCR4+ cells were positively correlated with plasma levels of SDF-1&agr; early after CP/CPB (r=0.56, P<0.01), but not at other times. Protein expression of SDF-1&agr; was elevated in the atrial myocardium after CP/CPB (9.4-fold; P=0.03). Conclusions— Exposure to CP/CPB leads to an increase in circulating CD34+CXCR4+ progenitor cells, which is associated with increased myocardial SDF-1&agr; expression. The numbers of CD34+CXCR4+ progenitor cells positively correlate with the plasma levels of SDF-1&agr; post-CP/CPB, suggesting an important role of SDF-1&agr; in progenitor cell mobilization.

High-Dose Atorvastatin Improves Hypercholesterolemic Coronary Endothelial Dysfunction Without Improving the Angiogenic Response

Background— Although 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) can restore endothelial function in coronary disease, in vitro and murine studies have shown their effects on myocardial angiogenesis to be biphasic and dose dependent. We investigated the functional and molecular effects of high-dose atorvastatin on the endogenous angiogenic response to chronic myocardial ischemia in hypercholesterolemic swine. Methods and Results— Yucatan pigs were fed either a normal (NORM group; n=7) or high-cholesterol diet, with (CHOL-ATR group; n=7) or without (CHOL group; n=6) atorvastatin (3 mg/kg per day) for 13 weeks. Chronic ischemia was induced by ameroid constrictor placement around the circumflex artery. Seven weeks later, microvessel relaxation responses, myocardial perfusion, and myocardial protein expression were assessed. The CHOL group demonstrated impaired microvessel relaxation to adenosine diphosphate (29±3% versus 61±6%, CHOL versus NORM; P<0.05), which was normalized in the CHOL-ATR group (67±2%; P=NS versus NORM). Collateral-dependent myocardial perfusion, adjusted for baseline, was significantly reduced in the CHOL group (−0.27±0.07 mL/min per gram versus NORM; P<0.001) as well as the CHOL-ATR group (−0.35±0.07 mL/min per gram versus NORM; P<0.001). Atorvastatin treatment was associated with increased phosphorylation of Akt (5.7-fold increase versus NORM; P=0.001), decreased vascular endothelial growth factor expression (−68±8%; P<0.001 versus NORM), and increased expression of the antiangiogenic protein endostatin (210±48%; P=0.004 versus NORM). Conclusions— Atorvastatin improves hypercholesterolemia-induced endothelial dysfunction without appreciable changes in collateral-dependent perfusion. Increased myocardial expression of endostatin, decreased expression of vascular endothelial growth factor, and chronic Akt activation associated with atorvastatin treatment may account for the diminished angiogenic response.

Surgical Treatment of Primary Cardiac Sarcomas: Review of a Single-Institution Experience

BACKGROUND Primary cardiac sarcomas are rare, aggressive, and usually lethal. Surgical management protocols are not defined because of the lack of extensive experience in treating these patients. In this study, we reviewed our outcomes with primary cardiac sarcoma, and we make recommendations regarding management. METHODS Review of the Houston Methodist Hospital cardiac tumor database from 1990 to 2015 (25 years) yielded 131 primary cardiac evaluations of possible cardiac sarcoma. From these we identified 95 patients who underwent surgical excision. A computer search of cardiac sarcomas yielded 131 tumors that were coded as primary cardiac sarcoma or possible primary cardiac sarcoma. Retrospective data collection and clinical outcomes were evaluated for all 95 patients. Medical records and follow-up material were requested for all patients through clinic visits and contacting the physician of the patient, the hospital record department, and the cardiac tumor board after previous approval. The procedures were performed using an institutional review board-approved cardiac tumor protocol, and the patients gave full consent. RESULTS All 95 patients were diagnosed as having primary cardiac sarcoma by histologic appearance. Age ranged from 15 to 84 years at the time of presentation (mean, 44 years). Male patients made up 57% of the sample. The most common site for the cardiac sarcoma was the right atrium (37 patients) followed by the left atrium (31 patients). Postoperative 1-year mortality was 35% (33 patients). The most common tumor histologic type was angiosarcoma (40%) followed by spindle cell sarcoma (11%). CONCLUSIONS Primary cardiac sarcoma is a rare but lethal disease. Surgical intervention is associated with acceptable surgical mortality in this high-risk group of patients.

Vascular Graft Infections, Mycotic Aneurysms, and Endovascular Infections: A Scientific Statement From the American Heart Association

### Background The use of synthetic material for reconstructive vascular surgery was first reported during the early 1950s. Infection involving vascular graft prostheses is an infrequent but devastating complication of reconstructive vascular graft surgery and is associated with a high morbidity and, in some situations, mortality. Improvements in surgical techniques and graft design, including the use of native venous or arterial tissue, have reduced the frequency of infection and severity of complications from vascular graft infection (VGI). However, these advances have also led to more frequent vascular graft procedures occurring in a patient population with multiple underlying comorbidities that would have previously disqualified them as candidates for vascular reconstructive surgery. Underlying comorbidities, such as diabetes mellitus or immune compromise, increase the risk of infection and serious infection-related complications. The major complications of VGI include sepsis, amputation, disruption of infected anastomotic suture line with rupture or pseudoaneurysm formation, embolization of infected thrombi, reinfection of reconstructed vascular grafts, enteric fistulae to the small or large bowel, bacteremic spread of infection to other sites, and death. VGIs can be categorized broadly into those that occur in an extracavitary location, primarily in the groin or lower extremities, or in an intracavitary location, primarily within the abdomen or less commonly within the thorax. ### Frequency The frequency of VGI depends on the anatomic location of the graft. The infection rate is 1.5% to 2% for most extracavitary grafts and as high as 6% with vascular grafts in the groin.1–9 For intracavitary grafts, the infection rate is ≈1% to 5%.1–6 Graft infection is most common after emergency procedures and after reoperation.1–4,10 Aortic graft erosion or fistulous communication into the duodenum or other areas of the bowel reportedly occurs in 1% to 2% of patients after aortic reconstruction.11, …

Contemporary Surgical Management of Cardiac Paragangliomas

BACKGROUND Cardiac paragangliomas are an extremely rare subset of chromaffin cell tumors that develop from neural crest cells. METHODS Between March 2004 and October 2010, 7 male patients from our two institutions who underwent surgical resection of cardiac paraganglioma were retrospectively reviewed. RESULTS In 5 patients, paragangliomas originated from the roof of the left atrium, and in 2 patients, they originated from the aortic root. Hospital mortality was 14%. CONCLUSIONS Complete surgical resection remains the mainstay of therapy and can be curative, but carries a significant risk of intraoperative bleeding and usually requires cardiopulmonary bypass and often complex resection techniques, including cardiac autotransplantation.

Outcomes After Right-Side Heart Sarcoma Resection

BACKGROUND In patients with primary cardiac sarcoma, the tumors location is more important than cell type in determining patient presentation, therapy options, and outcomes. The purpose of the current study was to investigate the outcomes after right-side heart sarcoma resection. METHODS Clinicopathologic data from patients who underwent right-side heart sarcoma resection at our institution and patients identified in a literature search were examined. Morbidity and the 30-day mortality rate and survival were determined. We used univariate and multivariate analyses to identify independent predictors of overall survival. RESULTS We identified 57 patients who underwent right-side heart sarcoma resection. Right-side heart failure was the most common complication (4 patients, 19%), and the 30-day mortality was 14% (3 patients). The overall 5-year survival rate was 17%, and the median overall survival duration was 9 months. Multivariate analyses revealed that surgical margin status was the only independent predictor of survival. Patients with negative surgical margins had a longer median overall survival duration (27 months versus 4 months) and a significantly higher overall 5-year survival rate (36% versus 0%; p = 0.0003) than patients with positive surgical margins. CONCLUSIONS The patients with right-side heart sarcoma resection had worse survival after resection than that reported for our patients who underwent resection for left-side heart sarcoma or pulmonary artery sarcoma. Because positive surgical margin status is an independent predictor of reduced survival, induction chemotherapy should considered to enhance resectability in right-side heart sarcoma patients, thus maximizing the possibility of obtaining negative surgical margins.