Robert K. Lewis

Cardioprotective and Antiapoptotic Effects of Heme Oxygenase-1 in the Failing Heart

Background— Heme oxygenase-1 (HO-1) is an inducible stress-response protein that imparts antioxidant and antiapoptotic effects. However, its pathophysiological role in cardiac remodeling and chronic heart failure (HF) is unknown. We hypothesized that induction of HO-1 in HF alleviates pathological remodeling. Methods and Results— Adult male nontransgenic and myocyte-restricted HO-1 transgenic mice underwent either sham operation or coronary ligation to induce HF. Four weeks after ligation, nontransgenic HF mice exhibited postinfarction left ventricular (LV) remodeling and dysfunction, hypertrophy, fibrosis, oxidative stress, apoptosis, and reduced capillary density, associated with a 2-fold increase in HO-1 expression in noninfarcted myocardium. Compared with nontransgenic mice, HO-1 transgenic HF mice exhibited significantly (P<0.05) improved postinfarction survival (94% versus 57%) and less LV dilatation (end-diastolic volume, 46±8 versus 85±32 &mgr;L), mechanical dysfunction (ejection fraction, 65±9% versus 49±16%), hypertrophy (LV/tibia length 4.4±0.4 versus 5.2±0.6 mg/mm), interstitial fibrosis (11.2±3.1% versus 18.5±3.5%), and oxidative stress (3-fold reduction in tissue malondialdehyde). Moreover, myocyte-specific HO-1 overexpression in HF promoted tissue neovascularization and ameliorated myocardial p53 expression (2-fold reduction) and apoptosis. In isolated mitochondria, mitochondrial permeability transition was inhibited by HO-1 in a carbon monoxide (CO)–dependent manner and was recapitulated by the CO donor tricarbonylchloro(glycinato)ruthenium(II) (CORM-3). HO-1–derived CO also prevented H2O2-induced cardiomyocyte apoptosis and cell death. Finally, in vivo treatment with CORM-3 alleviated postinfarction LV remodeling, p53 expression, and apoptosis. Conclusions— HO-1 induction in the failing heart is an important cardioprotective adaptation that opposes pathological LV remodeling, and this effect is mediated, at least in part, by CO-dependent inhibition of mitochondrial permeability transition and apoptosis. Augmentation of HO-1 or its product, CO, may represent a novel therapeutic strategy for ameliorating HF.

Outcomes of transplantation using organs from a donor infected with Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae

Transmission of pathogens from donor to recipient is a potential complication of organ transplantation. Herein, we describe the clinical course and outcomes of 4 transplant recipients who received tissues from a donor with multi‐organ infection with Klebsiella pneumoniae carbapenemase (KPC)‐producing K. pneumoniae. Recipient 1 underwent simultaneous liver and kidney transplantation for alpha‐1 antitrypsin deficiency and alcohol‐related cirrhosis, and acute tubular necrosis, respectively. Soon after transplantation, he developed an infected hematoma and peritonitis due to KPC‐producing K. pneumoniae despite receiving tigecycline prophylaxis. He was treated with a prolonged course of tigecycline, amikacin, and meropenem, in conjunction with surgical evacuation and percutaneous drainage of the infected fluid collections. Recipient 2 underwent living‐donor liver transplantation for cholangiocarcinoma and primary sclerosing cholangitis using vein graft from the donor infected with KPC‐producing K. pneumoniae. Culture of the preservation fluid containing the vein graft was positive for KPC‐producing K. pneumoniae. The patient received preemptive amikacin and tigecycline, and he did not develop any infection (as evidenced by negative surveillance blood cultures). The isolates from the donor and Recipients 1 and 2 were indistinguishable by pulsed‐field gel electrophoresis. Recipients 3 and 4 underwent kidney and heart transplantation, respectively; both patients received perioperative tigecycline prophylaxis and did not develop infections due to KPC‐producing K. pneumoniae. All transplant recipients had good short‐term outcomes. These cases highlight the importance of inter‐institutional communication and collaboration to ensure the successful management of recipients of organs from donors infected with multidrug‐resistant organisms.

A pilot study to determine the feasibility of continuous cefazolin infusion.

BACKGROUND Animal studies have shown that continuous infusion of beta-lactam antibiotics is more effective than intermittent dosing. We studied several dosing regimens of cefazolin in humans to determine safety and whether or not adequate serum and tissue antibiotic concentrations could be achieved in patients undergoing cardiac bypass. METHODS A prospective, randomized pilot study was conducted at a university-affiliated teaching hospital over a 2-year period in patients undergoing first-time coronary artery bypass grafting. One hundred and thirty-seven patients were randomized to one of three groups. Group 1 (n = 64) received 1 g of cefazolin intravenously before operation and 1 g intravenously at the end of cardiopulmonary bypass. Group 2 (n = 35) received 2 g of cefazolin intravenously before operation, followed by a continuous intravenous infusion of cefazolin at 20 mg/min throughout surgery. Group 3 (n = 38) received 3 g of cefazolin intravenously before operation, followed by a continuous intravenous infusion of cefazolin at 15 mg/min throughout surgery. Venous blood and subcutaneous fat samples were obtained from the sternal wound in a subset of 34 patients at incision, 0.25 h, 0.5 h, and 1 h; at the end of cardiopulmonary bypass; and at wound closure. Venous blood was sampled in the recovery room and on postoperative day 1. Cefazolin concentrations in the samples were determined by reverse-phase high-performance liquid chromatography using a C18 column. RESULTS Serum cefazolin concentrations were higher for group 3 when compared with group 1 at all six intraoperative intervals (p < 0.02) and for group 2 when compared with group 1 at four of six intraoperative intervals (p < 0.04). When compared with group 1, tissue cefazolin concentrations were higher for group 3 at all intraoperative intervals (p < 0.02). No related toxicity or adverse events were observed. CONCLUSION Cefazolin administered as a large preoperative bolus with continuous intraoperative infusion resulted in higher serum and tissue concentrations when compared with conventional intermittent dosing. Pharmacodynamically, continuous infusion of beta-lactam antibiotics may be superior to intermittent dosing when used for perioperative prophylaxis against wound infection, especially for cases in which the antibiotic is not redosed intraoperatively.

Cable externalization and electrical failure of the Riata family of implantable cardioverter-defibrillator leads: A systematic review and meta-analysis.

BACKGROUND The Riata class of defibrillator leads were placed under US Food and Drug Association (FDA) advisory as of November 2011 because of high rates of cable externalization (CE) and electrical failure (EF). The overall rates of these complications remain unknown. OBJECTIVE The purpose of this study was to systematically search the literature for rates of Riata lead failure and to perform a meta-analysis to estimate failure rates. METHODS We conducted a meta-analysis of observational studies examining the rates of EF, CE, and the interaction of the two. We identified 23 English language manuscripts addressing 1 or more of these questions. RESULTS Across 23 studies, the overall CE rate was 23.1% (95% confidence interval [CI] 19.0%-27.6%). The overall EF rate was 6.3% (95% CI 4.7%-8.2%). The presence of CE was associated with a more than 6-fold increase in the rate of EF compared to no CE (17.3% [95% CI 11.2%-25.9%] vs 2.7% [95% CI 1.4%-5.2%], respectively). The rate of CE was 3-fold higher for 8Fr leads compared to 7Fr leads, but rates of EF were similar (4.6%; 95% CI 3.2-6.6] and 3.9%; 95% CI 2.4-6.1], respectively). Rates of both CE and EF were higher in dual coil vs single coil leads, but confidence intervals overlapped. CONCLUSION In clinical practice, rates of CE in Riata leads are substantial. While CE is associated with a significant increase in the risk of EF, the incidence of EF without externalization is not trivial.

Preprocedural ECG‐Gated Computed Tomography for Prevention of Complications during Lead Extraction

Preprocedural multidetector computed tomography (MDCT) may identify patients at risk for mechanical complications during lead extraction.

Evaluation of SLC11A1 as an inflammatory bowel disease candidate gene

BackgroundSignificant evidence suggests that a promoter polymorphism withinthe gene SLC11A1 is involved in susceptibility to both autoimmune and infectious disorders. The aim of this study was to evaluate whether SLC11A1 has a role in the susceptibility to inflammatory bowel disease (IBD) by characterizing a promoter polymorphism within the gene and two short tandem repeat (STR) markers in genetic proximity to SLC11A1.MethodsThe studied population consisted of 484 Caucasians with IBD, 144 population controls, and 348 non-IBD-affected first-degree relatives of IBD patients. IBD subjects were re-categorized at the sub-disease phenotypic level to characterize possible SLC11A1 genotype-phenotype correlations. Polymorphic markers were amplified from germline DNA and typed using gel electrophoresis. Genotype-phenotype correlations were defined using case-control, haplotype, and family-based association studies.ResultsThis study did not provide compelling evidence for SLC11A1 disease association; most significantly, there was no apparent evidence of SLC11A1 promoter allele association in the studied Crohns disease population.ConclusionOur results therefore refute previous studies that have shown SLC11A1 promoter polymorphisms are involved in susceptibility to this form of IBD.

Outcomes Associated With Extraction Versus Capping and Abandoning Pacing and Defibrillator Leads

Background: Lead management is an increasingly important aspect of care in patients with cardiac implantable electronic devices; however, relatively little is known about long-term outcomes after capping and abandoning leads. Methods: Using the 5% Medicare sample, we identified patients with de novo cardiac implantable electronic device implantations between January 1, 2000, and December 31, 2013, and with a subsequent lead addition or extraction ≥12 months after the de novo implantation. Patients who underwent extraction for infection were excluded. Using multivariable Cox proportional hazards models, we compared cumulative incidence of all-cause mortality, device-related infection, device revision, and lead extraction at 1 and 5 years for the extraction versus the cap and abandon group. Results: Among 6859 patients, 1113 (16.2%) underwent extraction, whereas 5746 (83.8%) underwent capping and abandonment. Extraction patients tended to be younger (median, 78 versus 79 years; P<0.0001), were less likely to be male (65% versus 68%; P=0.05), and had shorter lead dwell time (median, 3.0 versus 4.0 years; P<0.0001) and fewer comorbidities. Over a median follow-up of 2.4 years (25th, 75th percentiles, 1.0, 4.3 years), the overall 1-year and 5-year cumulative incidence of mortality was 13.5% (95% confidence interval [CI], 12.7–14.4) and 54.3% (95% CI, 52.8–55.8), respectively. Extraction was associated with a lower risk of device infection at 5 years relative to capping (adjusted hazard ratio, 0.78; 95% CI, 0.62–0.97; P=0.027). There was no association between extraction and mortality, lead revision, or lead extraction at 5 years. Conclusions: Elective lead extraction for noninfectious indications had similar long-term survival to that for capping and abandoning leads in a Medicare population. However, extraction was associated with lower risk of device infections at 5 years.

Optimal Management of Riata Leads with No Known Electrical Abnormalities or Externalization: A Decision Analysis

Riata and Riata ST implantable cardioverter‐defibrillator (ICD) leads (St. Jude Medical, Sylmar, CA, USA) can develop conductor cable externalization and/or electrical failure. Optimal management of these leads remains unknown.

Impact of Valvular Calcification on the Diagnostic Accuracy of Transesophageal Echocardiography for the Detection of Congenital Aortic Valve Malformation

Background: Degeneration of congenital bicuspid or unicuspid aortic valves can progress more rapidly than that of tricuspid valves, and an early diagnosis significantly impacts decision making and outcome. We hypothesized that the extent of valvular calcification would negatively influence the diagnostic accuracy of multiplane transesophageal echocardiography (TEE) for the diagnosis of congenital aortic valve disease. Methods: TEE was performed in 57 patients undergoing aortic valve replacement surgery for aortic stenosis (n = 46), pure regurgitation (n = 9), or significant regurgitation with less than severe aortic stenosis (n = 2). The degree of aortic valve calcification and the number of valve cusps were determined at surgery. Results: Surgical inspection confirmed 14 bicuspid and 43 tricuspid aortic valves. Sensitivity and specificity of TEE for the diagnosis of congenital aortic valve malformation was 93% (13/14) and 91% (39/43) (P = 0.0001), respectively. In patients with no or mild aortic valve calcification (n = 13), sensitivity and specificity of TEE for the diagnosis of congenitally malformed aortic valve was 100% (5/5) and 100% (8/8) (P = 0.001), respectively. In patients with moderate or marked aortic valve calcification (n = 44), sensitivity and specificity of TEE for the diagnosis of congenitally malformed aortic valve was 89% (8/9) and 89% (31/35) (P<0.0001), respectively. In this subgroup of 44 patients, there were four false‐positive and one false‐negative diagnoses due to valvular calcification. Conclusions: Although TEE is highly sensitive and specific for the detection of congenital aortic valve malformations, presence of moderate or marked calcification of the aortic valve may result in false positive and false negative diagnoses.

Suppository administration of chemotherapeutic drugs with concomitant radiation for rectal cancer

PURPOSE: Preoperative radiation with combined chemotherapy is effective in shrinking advanced rectal cancer locally and facilitating subsequent surgery. Suppository delivery of 5-fluorouracil is associated with less toxicity and higher rectal tissue concentrations than intravenous administration. This prompted us to evaluate suppository and intravenous administration of 5-fluorouracil and mitomycin C with concomitant radiation to determine associated toxicity. METHODS: Rectal, liver, lymph node, and lung tissue and systemic and portal blood were collected serially from male Sprague Dawley rats to determine drug concentrations following suppository or intravenous delivery of 5-fluorouracil or mitomycin C. Thirty-six animals were randomly assigned to treatment groups and received 5-fluorouracil suppositories, mitomycin C suppositories, or an equivalent intravenous dose of 5-fluorouracil or mitomycin C 30 minutes before radiation therapy. Before and 3, 6, 10, and 15 days following this treatment, blood was collected, colonoscopy was performed, and rectal tissue was harvested for histologic examination. RESULTS: Mitomycin C suppository was significantly less toxic compared with intravenous delivery, and higher rectal tissue concentrations were observed from 10 to 30 minutes (P< 0.05). Compared with intravenous 5-fluorouracil administration and radiation, 5-fluorouracil suppository and radiation resulted in additive myelosuppression at day 6 (P<0.05) with rapid recovery. CONCLUSIONS: 5-Fluorouracil and mitomycin C suppository delivery combined with radiation causes less systemic toxicity and is more effective than intravenous administration.