Synergetic Induction of NGF With Diazoxide and Erythropoietin Attenuates Spinal Cord Ischemic Injury.

BACKGROUND: Paraplegia remains a significant complication of thoracoabdominal aortic intervention. We previously reported that diazoxide (DZ), enhances the neuroprotective efficacy of erythropoietin (EPO). We hypothesized that DZ and EPO combined treatment attenuates spinal cord ischemic injury through upregulation of nerve growth factor (NGF). METHODS: DZ (pretreatment) was given to adult male C57/BL6 mice by oral gavage and EPO (before surgery) was intraperitoneally injected 32 h after administration of DZ. Spinal cords were harvested 0, 2, 4, and 6 h after injection of EPO. NGF expression was analyzed by western blot. After determining the optimal time, NGF expression was compared between DZ (pretreatment) + EPO (before surgery), DZ + PBS, PBS + EPO, and PBS + PBS (ischemic control). Four groups were studied to compare the motor function after ischemia: DZ + EPO (n = 11), ischemic control (n = 9), DZ + EPO + tropomyosin receptor kinase A receptor inhibitor (n = 9), and sham (without cross-clamp, n = 4). Spinal cord ischemia was induced by a 4-min thoracic aortic cross-clamp. Functional scoring (Basso Mouse Score) was done at 12-h intervals until 48 h, and spinal cords were harvested for evaluation of NGF expression and histological changes. RESULTS: NGF expression was significantly upregulated 4 h after administration of EPO. At 4 h after injection of EPO, NGF expression in the DZ + EPO group was significantly higher than that in the other groups. DZ + EPO significantly preserved motor function compared with all other groups. At 48 h after reperfusion, the level of NGF expression in the DZ + EPO group, was significantly higher than in all other groups. CONCLUSIONS: DZ + EPO attenuates spinal cord ischemic injury through upregulation of NGF. Better understanding of this mechanism may serve to further prevent ischemic complications for aortic intervention.

Stool protein mass spectrometry identifies biomarkers for the early detection of diffuse-type gastric cancer.

There is a high unmet need for early detection approaches for diffuse gastric cancer (DGC). We examined whether the stool proteome of mouse models of GC or individuals with hereditary diffuse GC (HDGC) have utility as biomarkers for early detection. Proteomic mass spectrometry of stool from a genetically engineered mouse model driven by oncogenic KrasG12D and loss of p53 and Cdh1 in gastric parietal cells (known as TCON mice) identified differentially abundant proteins compared to littermate controls. Immunoblot assays validated a panel of proteins including actinin alpha 4 (ACTN4), N-acylsphingosine amidohydrolase 2 (ASAH2), dipeptidyl peptidase 4 (DPP4), and valosin-containing protein (VCP) as enriched in TCON stool compared to littermate control stool. Immunofluorescence analysis of these proteins in TCON stomach sections revealed increased protein expression as compared to littermate controls. Proteomic mass spectrometry of stool obtained from HDGC patients with CDH1 mutations identified increased expression of ASAH2, DPP4, VCP, lactotransferrin (LTF), and tropomyosin-2 (TPM2) relative to stool from healthy sex and age-matched donors. Chemical inhibition of ASAH2 using C6-urea ceramide was toxic to GC cell lines and patient derived-GC organoids. This toxicity was reversed by adding downstream products of the S1P synthesis pathway, suggesting a dependency on ASAH2 activity in GC. An exploratory analysis of the HDGC stool microbiome identified features which correlated with patient tumors. Here we provide evidence supporting the potential of analyzing stool biomarkers for the early detection of DGC.

Jones Fracture Treatment: A Novel Surgical Technique and Case Series.

BACKGROUND: Jones fractures remain a challenging treatment entity in orthopaedics. Biomechanical stresses, including increased fifth metatarsal (5MT) lateral angle deviation (MLAD), are associated with increased fracture and refracture rates. Current fixation techniques produce good outcomes; however, they do not address metatarsal morphology, which can predispose to refracture. This study describes a novel surgical technique and case series utilizing intramedullary screw fixation and distal metatarsal corrective osteotomy for the management of Jones fractures. METHODS: A retrospective case series was undertaken, including 22 consecutive Jones fracture patients operated on by a single surgeon. Patient demographics, imaging, and operative information were obtained, with return to sport/previous function and radiological outcomes, including fracture union being the outcomes of interest. The surgical technique utilizes a distal osteotomy of the 5MT followed by retrograde guidewire and drilling utilizing the osteotomy. A cannulated screw is passed antegrade along the entire length of the 5MT with manual MLAD correction. Autograft or bone substitute (Augment) was then injected at the fracture site. RESULTS: Median age was 30 years (Q1, Q3: 18, 49 years). Median time from injury to operation was 13 weeks (Q1, Q3: 9, 30 weeks), and clinical follow-up period was 37 months (Q1, Q3: 14, 74 months). Radiological union was achieved at a median of 12 weeks (Q1, Q3: 8, 15 weeks) with clinical union at 11 weeks (Q1, Q3: 8, 14 weeks). All but one patient returned to preinjury functional levels, including 6 professional athletes who returned to preinjury national competition. No refractures were identified. CONCLUSION: The technique described in this study is a viable and safe means of managing Jones fractures. The technique may be particularly useful in patients with excessive MLAD. LEVELS OF EVIDENCE: Level IV: Retrospective case series.

Comparative effectiveness of revascularization strategies for early coronary artery disease: A multicenter analysis.

OBJECTIVES: The goal of this analysis was to examine the comparative effectiveness of coronary artery bypass grafting versus percutaneous coronary intervention among patients aged less than 60 years. METHODS: We performed a multicenter, retrospective analysis of all cardiac revascularization procedures from 2005 to 2015 among 7 medical centers. Inclusion criteria were age less than 60 years and 70% stenosis or greater in 1 or more major coronary artery distribution. Exclusion criteria were left main 50% or greater, ST-elevation myocardial infarction, emergency status, and prior revascularization procedure. After applying inclusion and exclusion criteria, the final study cohort included 1945 patients who underwent cardiac surgery and 2938 patients who underwent percutaneous coronary intervention. The primary end point was all-cause mortality stratified by revascularization strategy. Secondary end points included stroke, repeat revascularization, and 30-day mortality. We used inverse probability weighting to balance differences among the groups. RESULTS: After adjustment, there was no significant difference in 30-day mortality (surgery: 0.8%; percutaneous coronary intervention: 0.7%, P = .86) for patients with multivessel disease. Patients undergoing surgery had a higher risk of stroke (1.3% [n = 25] vs 0.07% [n = 2], P < .001). Overall, surgery was associated with superior 10-year survival compared with percutaneous coronary intervention (hazard ratio, 0.71; 95% confidence interval, 0.57-0.88; P = .002). Repeat procedures occurred in 13.4% (n = 270) of the surgery group and 36.4% (n = 1068) of the percutaneous coronary intervention group, with both groups mostly undergoing percutaneous coronary intervention as their second operation. Accounting for death as a competing risk, at 10 years, surgery resulted in a lower cumulative incidence of repeat revascularization compared with percutaneous coronary intervention (subdistribution hazard ratio, 0.34; 95% confidence interval, 0.28-0.40; P < .001). CONCLUSIONS: Among patients aged less than 60 years with 2-vessel disease that includes the left anterior descending or 3-vessel coronary artery disease, surgery was associated with greater long-term survival and decreased risk of repeat revascularization.

Pretreatment With Diazoxide Attenuates Spinal Cord Ischemia-Reperfusion Injury Through Signaling Transducer and Activator of Transcription 3 Pathway.

BACKGROUND: Delayed paraplegia remains a feared complication of thoracoabdominal aortic intervention. Pharmacologic preconditioning with diazoxide (DZ), an adenosine 5'-triphosphate-sensitive potassium channel opener, results in neuroprotection against ischemic insult. However, the effects of DZ in spinal cord ischemia-reperfusion injury have not been fully elucidated. We hypothesized that DZ attenuates spinal cord ischemia-reperfusion injury through the signaling transducer and activator of transcription (STAT) 3 pathway. METHODS: Adult male C57/BL6 mice received DZ (20 mg/kg) by oral gavage. Spinal cords were harvested at 0, 12, 24, 36, 48, and 60 hours after administration of DZ. The expression of phosphorylated STAT3 was assessed by Western blot analysis. Five groups were studied: DZ (DZ pretreatment, n = 8), ischemic control (phosphate-buffered saline pretreatment, n = 11), DZ + STAT3 inhibitor LY5 (DZ pretreatment + LY5, n = 8), LY5 (phosphate-buffered saline pretreatment + LY5, n = 8), and sham (without cross-clamping, n = 5). Spinal cord ischemia was induced by 4 minutes of thoracic aortic cross-clamp. Functional scoring (Basso Mouse Score) was done at 12-hour intervals until 48 hours, and spinal cords were harvested for the evaluation of B-cell lymphoma 2 expression and histologic changes. RESULTS: The expression of phosphorylated STAT3 was significantly upregulated 36 hours after the administration of DZ. The motor function in the DZ group was significantly preserved compared with all other groups. The expression of B-cell lymphoma 2 in the DZ group was significantly higher than in the ischemic control, DZ + LY5, and LY5 groups 48 hours after reperfusion. CONCLUSIONS: DZ preserves motor function in spinal cord ischemia-reperfusion injury by the STAT3 pathway. DZ may be beneficial clinically for use in spinal protection in aortic intervention.

Long-term outcomes of coronary-artery bypass grafting versus stent implantation.

BACKGROUND: Several studies have compared outcomes for coronary-artery bypass grafting (CABG) and percutaneous coronary intervention (PCI), but most were done before the availability of stenting, which has revolutionized the latter approach. METHODS: We used New York's cardiac registries to identify 37,212 patients with multivessel disease who underwent CABG and 22,102 patients with multivessel disease who underwent PCI from January 1, 1997, to December 31, 2000. We determined the rates of death and subsequent revascularization within three years after the procedure in various groups of patients according to the number of diseased vessels and the presence or absence of involvement of the left anterior descending coronary artery. The rates of adverse outcomes were adjusted by means of proportional-hazards methods to account for differences in patients' severity of illness before revascularization. RESULTS: Risk-adjusted survival rates were significantly higher among patients who underwent CABG than among those who received a stent in all of the anatomical subgroups studied. For example, the adjusted hazard ratio for the long-term risk of death after CABG relative to stent implantation was 0.64 (95 percent confidence interval, 0.56 to 0.74) for patients with three-vessel disease with involvement of the proximal left anterior descending coronary artery and 0.76 (95 percent confidence interval, 0.60 to 0.96) for patients with two-vessel disease with involvement of the nonproximal left anterior descending coronary artery. Also, the three-year rates of revascularization were considerably higher in the stenting group than in the CABG group (7.8 percent vs. 0.3 percent for subsequent CABG and 27.3 percent vs. 4.6 percent for subsequent PCI). CONCLUSIONS: For patients with two or more diseased coronary arteries, CABG is associated with higher adjusted rates of long-term survival than stenting.

Serious renal dysfunction after percutaneous coronary interventions can be predicted.

BACKGROUND: A prediction rule for determining the post-percutaneous coronary intervention (PCI) risk of developing contrast-induced nephropathy (> or = 25% or > or = 0.5 mg/dL increase in creatinine) has been reported. However, little work has been done on predicting pre-PCI patient-specific risk for developing more serious renal dysfunction (SRD; new dialysis, > or = 2.0 mg/dL absolute increase in creatinine, or a > or = 50% increase in creatinine). We hypothesized that preprocedural patient characteristics could be used to predict the risk of post-PCI SRD. METHODS: Data were prospectively collected on a consecutive series of 11141 patients undergoing PCI without dialysis in northern New England from 2003 to 2005. Multivariate logistic regression model was used to identify the combination of patient characteristics most predictive of developing post-PCI SRD. The ability of the model to discriminate was quantified using a bootstrap validated C-Index (area under the receiver operating characteristic [ROC] curve). Its calibration was tested with a Hosmer-Lemeshow statistic. The model was validated on PCI procedures in 2006. RESULTS: Serious renal dysfunction occurred in 0.74% of patients (83/11141) with an associated inhospital mortality of 19.3% versus 0.9% in those without SRD. The model discriminated well between patients who did and did not develop SRD after PCI (ROC 0.87, 95% CI 0.82-0.91). Preprocedural creatinine (37%), congestive heart failure (24%), and diabetes (15%) accounted for 76% of the predictive ability of the model. The other factors contributed 24%: urgent and emergent priority (10%), preprocedural intra-aortic balloon pump use (8%), age > or = 80 years (5%), and female sex (1%). Validation of the model was successful with ROC: 0.84 (95% CI 0.80-0.89). CONCLUSIONS: Although infrequent, the occurrence of SRD after PCI is associated with a very high inhospital mortality. We developed and validated a robust clinical prediction rule to determine which patients are at high risk for SRD. Use of this model may help physicians perform targeted interventions to reduce this risk.

Clinical, procedural, and pharmacologic correlates of acute and subacute stent thrombosis: results of a multicenter case-control study with 145 thrombosis events.

OBJECTIVES: The aim of this study was to determine correlates of acute/subacute coronary stent thrombosis among unselected patients treated in the era of routine dual antiplatelet therapy and specifically to investigate the influence of prophylactic administration of glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors and use of clopidogrel versus ticlopidine on the development of coronary stent thrombosis (ST). BACKGROUND: Because of a relative infrequency of ST events and relatively uniform practice patterns within randomized trials, previous studies have had a limited ability to address whether the use of different antiplatelet regimens at the time of coronary stenting is associated with differences in ST. METHODS: We performed a multicenter, case-control study to evaluate clinical, angiographic, and pharmacologic/procedural correlates of ST. Between 1996 and 2000, all cases of angiographically-confirmed ST (n = 145) among patients receiving dual antiplatelet therapy were identified from 10 participating clinical sites and were matched with a control without ST randomly selected from the same institution. RESULTS: Multivariable conditional logistic regression identified higher pre-procedure platelet count, stenting for acute myocardial infarction, use of a coil or self-expanding stent, and overt angiographic thrombus prior to the procedure, as independent predictors of ST (all P < .05). After adjusting for these factors, the use of clopidogrel (vs ticlopidine) was independently associated with an increased risk of ST (OR 2.1, 95% CI 1.0-4.1, P = .04). The use of prophylactic glycoprotein IIb/IIIa inhibitors was not associated with reduced ST in the overall analysis, but appeared to confer some protection against ST within the first 24 hours post procedure (OR 0.5 [95% CI 0.2-1.1] for ST during first day, OR 1.7 [95% CI 0.7-4.3] for ST on subsequent days). CONCLUSION: Both biologic and pharmacologic factors are independently associated with acute/subacute ST. The association between clopidogrel use (vs ticlopidine) and increased ST in this analysis requires confirmation in adequately powered clinical trials and suggests a potential role for newer and more potent antiplatelet agents.

Synergistic Reduction of Apoptosis With Diazoxide and Erythropoietin in Spinal Cord Ischemic Injury.

BACKGROUND: Paraplegia remains a devastating complication of thoracoabdominal aortic intervention. Metabolic stress induces expression of beta common receptor subunit of erythropoietin (EPO) receptor (ßcR) to exert a neuroprotective effect in spinal cord ischemia reperfusion injury (SCIR). Diazoxide (DZ) has been shown to induce ischemic tolerance. We previously reported that DZ upregulated ßcR expression and enhanced the neuroprotective effects of EPO through the upregulation of ßcR. We hypothesize that ßcR expression induced by DZ before ischemia amplifies the antiapoptotic effects of EPO in a murine model of SCIR. METHODS: Experimental groups included phosphate-buffered saline (PBS) pretreatment + PBS immediately before the operation, PBS+EPO, DZ+PBS, DZ+EPO, and sham. Spinal cord ischemia was induced by a 4-minute thoracic aortic cross-clamp. Functional scoring (Basso Mouse Score) was done at 12-hour intervals for 48 hours. Spinal cords were harvested for histologic analysis, and antiapoptotic factors (caspase 3, 8, and 9, B-cell lymphoma-2, and neuroglobin) were evaluated by Western blot analysis. RESULTS: The motor function of DZ+EPO group was significantly preserved compared with all other groups. The levels of cleaved caspase 8 and 3 in DZ+EPO were significantly lower than in the other groups. Mice treated with DZ+EPO had significantly fewer terminal deoxynucleotide transferase-mediated deoxy uridine triphosphate nick-end labeling-positive cells than other groups. CONCLUSIONS: Optimized upregulation of ßcR by DZ can increase the extrinsic antiapoptotic effects of EPO. Better understanding of this synergetic mechanism may serve to help prevent ischemic complications caused by aortic intervention.

Optimized induction of beta common receptor enhances the neuroprotective function of erythropoietin in spinal cord ischemic injury.

BACKGROUND: Paraplegia remains the most feared complication of complex thoracoabdominal aortic intervention. Although erythropoietin (EPO) has demonstrated neuroprotective effects in spinal cord ischemia, it does not work until expression of the beta common receptor subunit of the EPO receptor (ßcR) is induced by ischemia. We hypothesized that the ßcR can be induced by diazoxide (DZ), amplifying the neuroprotective effects of EPO in spinal cord ischemia-reperfusion injury. METHODS: For the DZ time trial, adult male C57/BL6 mice received DZ (20 mg/kg) by oral gavage. Spinal cords were harvested after 0, 12, 24, 36, and 48 hours of administration. To evaluate optimal dosing, DZ was administered at 0, 5, 10, 20, and 40 mg/kg. The expression of ßcR was assessed by Western blot analysis. Five groups were studied: PBS (pretreatment)+PBS (immediately before), PBS+EPO, DZ+PBS, DZ+EPO, and sham (without cross-clamping). Spinal cord ischemia was induced by 4 minutes of thoracic aortic cross-clamping. Functional scoring (Basso Mouse Score) was done at 12-hour intervals for 48 hours, and spinal cords were harvested for histological analysis. RESULTS: Western blot analysis demonstrated that optimal ßcR up-regulation occurred at 36 hours after DZ administration, and the optimal DZ dosage for ßcR induction was 20 mg/kg. Motor function at 48 hours after treatment was significantly better preserved in the DZ+EPO group compared with all other groups, and was significantly better preserved in the DZ only and EPO only groups compared with control (PBS+PBS). CONCLUSIONS: Pharmacologic up-regulation of ßcR with DZ can increase the efficacy of EPO in preventing spinal cord ischemia and reperfusion injury. Improved understanding of this synergetic mechanism may serve to further prevent ischemic complications for high-risk aortic intervention.

Characterization of Human gamma-glutamyl hydrolase in solution demonstrates that the enzyme is a non-dissociating homodimer.

Human gamma-glutamyl hydrolase (hGH) is a key enzyme in the metabolism of folic acid and in the pharmacology of many antifolate drugs. hGH catalyzes removal of the poly-gamma-glutamate chains of intracellular folic acid and antifolates. hGH crystallized as a homodimer with two putative active sites. However, the quaternary structure and the number of species of the enzyme in solution have not been determined. hGH has now been characterized using analytical ultracentrifugation and dynamic light scattering. HisTag fusion proteins of wild-type hGH, rat GH, and hGH expressed as a glycosylated protein were studied. Analyses of HisTag wild-type hGH were conducted over a range of protein concentrations (1.4-200 microM), ionic strengths (0-1 M NaCl), and pH (4.5-8.5). A single species with a molecular mass consistent with a homodimer was observed. Glycosylated hGH and HisTag rat gamma-glutamyl hydrolase also formed very stable homodimers. The lack of dissociation of the dimer, the large monomer-monomer interface, and the presence of catalytically essential Tyr-36 in the homodimer interface sequences suggest that homodimer formation is required for the hGH monomer to fold into an active conformation. The conservation of hGH monomer-monomer interface sequences in other mammalian and plant gamma-glutamyl hydrolase molecules suggests that they also exist as stable homodimers.

2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways.

Mitral regurgitation (MR) is a complex valve lesion that can pose significant management challenges for the cardiovascular clinician. This Expert Consensus Document emphasizes that recognition of MR should prompt an assessment of its etiology, mechanism, and severity, as well as indications for treatment. A structured approach to evaluation based on clinical findings, precise echocardiographic imaging, and when necessary, adjunctive testing, can help clarify decision making. Treatment goals include timely intervention by an experienced heart team to prevent left ventricular dysfunction, heart failure, reduced quality of life, and premature death.

Comparing long-term survival of patients with multivessel coronary disease after CABG or PCI: analysis of BARI-like patients in northern New England.

BACKGROUND: Randomized trials comparing coronary artery bypass graft surgery (CABG) with percutaneous coronary interventions (PCIs) for patients with multivessel coronary disease (MVD) report similar long-term survival for CABG and PCI. These studies used a highly selected population of patients and providers, and their results may not be generalizable to actual care. Our goal in this study was to compare long-term survival of MVD patients treated with CABG vs PCI in contemporary practice. METHODS AND RESULTS: From our northern New England registries of consecutive coronary revascularizations, we identified 10,198 CABG and 4,295 PCI patients with MVD who may have been eligible for either procedure between 1994 and 2001. Vital status was obtained by linkage to the National Death Index. Proportional-hazards regression was used to calculate hazard ratios (HRs) for survival in CABG vs PCI patients after adjustment for comorbidities and disease characteristics. CABG patients were older; had more comorbidities, more 3-vessel disease, and lower ejection fractions; and were more completely revascularized. Adjusted long-term survival for patients with 3-vessel disease was better after CABG than PCI (HR, 0.60; P<0.01) but not for patients with 2-vessel disease (HR, 0.98; P=0.77). The survival advantage of CABG for 3-vessel disease patients was present in all patient populations, including women, diabetics, and the elderly and in the era of high stent utilization. CONCLUSIONS: In contemporary practice, survival for patients with 3-vessel coronary disease is better after CABG than PCI, an observation that patients and physicians should carefully consider when deciding on a revascularization strategy.

Gamma-glutamyl hydrolase and drug resistance.

Gamma-glutamyl hydrolase (GGH) is a lysosomal enzyme involved in the metabolism of folates and anti-folates. It acts as an endo- and/or exo-peptidase to cleave gamma-polyglutamate chains that are attached to folates and anti-folates after they enter a mammalian cell. Whereas the addition of multiple glutamates is necessary to enable the cell to retain folates and anti-folates, hydrolysis of the polyglutamate tails by GGH has the opposite effect of making (anti)-folates exportable again. Thus, GGH plays an important role in the cellular homeostasis of folate. Furthermore, high levels of GGH have been associated with cellular resistance to anti-folates, in particular methotrexate. Consequently, GGH also has pharmacological importance. In addition to the intracellular GGH, carboxypeptidase II (also called intestinal folate conjugase, prostate specific membrane antigen or N-acetyl-alpha-linked acidic dipeptidase) is another enzyme with gamma-glutamyl hydrolase activity; it resides, however, in the cellular membrane. Although genetically and biochemically distinct, this enzyme too appears to play a major role in folate homeostasis, by cleaving polyglutamates from extracellular folate-polyglutamates, so that they can be imported into the cell. Finally, there have been reports suggesting that gamma-glutamyl hydrolase plays a role as a tumor marker in breast and lung cancer.

Anisotropic engineered heart tissue made from laser-cut decellularized myocardium.

We have developed an engineered heart tissue (EHT) system that uses laser-cut sheets of decellularized myocardium as scaffolds. This material enables formation of thin muscle strips whose biomechanical characteristics are easily measured and manipulated. To create EHTs, sections of porcine myocardium were laser-cut into ribbon-like shapes, decellularized, and mounted in specialized clips for seeding and culture. Scaffolds were first tested by seeding with neonatal rat ventricular myocytes. EHTs beat synchronously by day five and exhibited robust length-dependent activation by day 21. Fiber orientation within the scaffold affected peak twitch stress, demonstrating its ability to guide cells toward physiologic contractile anisotropy. Scaffold anisotropy also made it possible to probe cellular responses to stretch as a function of fiber angle. Stretch that was aligned with the fiber direction increased expression of brain natriuretic peptide, but off-axis stretches (causing fiber shear) did not. The method also produced robust EHTs from cardiomyocytes derived from human embryonic stem cells and induced pluripotent stem cells (hiPSC). hiPSC-EHTs achieved maximum peak stress of 6.5 mN/mm(2) and twitch kinetics approaching reported values from adult human trabeculae. We conclude that laser-cut EHTs are a viable platform for novel mechanotransduction experiments and characterizing the biomechanical function of patient-derived cardiomyoctyes.

Is the impact of hospital and surgeon volumes on the in-hospital mortality rate for coronary artery bypass graft surgery limited to patients at high risk?

BACKGROUND: Restriction of volume-based referral for CABG surgery to high-risk patients has been suggested, and earlier studies have reached different conclusions regarding volume-based referral for low-risk patients. METHODS AND RESULTS: Patients who underwent isolated CABG surgery in New York from 1997 through 1999 (n=57 150) were separated into low-risk and moderate-to-high-risk groups with a predicted probability of in-hospital death of 2% as the cutoff point. The provider volume-mortality relationship was examined for both groups. For annual hospital volume thresholds between 200 and 600 cases, the adjusted ORs of in-hospital mortality for high-volume to low-volume hospitals ranged from 0.45 to 0.77 and were all significant for the low-risk group; for the moderate-to-high-risk group, ORs ranged from 0.62 to 0.91, and most were significant. The number needed to treat at higher-volume hospitals to avoid 1 death was greater for the low-risk group (a range of 114 to 446 versus 37 to 184). As the annual surgeon volume threshold increased from 50 to 150 cases, the ORs for high- to low-volume surgeons increased from 0.43 to 0.74 for the low-risk group; for the moderate-to-high-risk group, ORs ranged from 0.79 to 0.86. Compared with patients treated by surgeons with volumes of <125 in hospitals with volumes of <600, patients treated by higher-volume surgeons in higher-volume hospitals had a significantly lower risk of death; in particular, the OR was 0.52 for the low-risk group. CONCLUSIONS: For both low-risk and moderate-to-high-risk patients, higher provider volume is associated with lower risk of death.

Medical costs and quality of life 10 to 12 years after randomization to angioplasty or bypass surgery for multivessel coronary artery disease.

BACKGROUND: Coronary bypass surgery (CABG) and angioplasty (PTCA) have been compared in several randomized trials, but data about long-term economic and quality-of-life outcomes are limited. METHODS AND RESULTS: Cost and quality-of-life data were collected prospectively from 934 patients who were randomized in the Bypass Angioplasty Revascularization Investigation (BARI) and followed up for 10 to 12 years. CABG had 53% higher costs initially, but the gap closed to <5% during the first 2 years; after 12 years, the mean cumulative cost of CABG patients was 123,000 dollars versus 120,750 dollars for PTCA, yielding a cost-effectiveness ratio of 14,300 dollars/life-year added. CABG patients experienced significantly greater improvement in their physical functioning for the first 3 years but not in later follow-up. Recurrent angina substantially reduced all quality-of-life measures throughout follow-up. Cumulative costs were significantly higher among patients with diabetes, heart failure, and comorbid conditions and among women; costs also were increased by angina, by the number of revascularization procedures, and among patients who died. CONCLUSIONS: Early differences between CABG and PTCA in costs and quality of life were no longer significant at 10 to 12 years of follow-up. CABG was cost-effective as compared with PTCA for multivessel disease.

Do hospitals and surgeons with higher coronary artery bypass graft surgery volumes still have lower risk-adjusted mortality rates?

BACKGROUND: Studies that are the basis of recommended volume thresholds for CABG surgery are outdated and not reflective of recent advances in the field. This study examines both hospital and surgeon volume-mortality relations for CABG surgery through the use of a population-based clinical data set. METHODS AND RESULTS: Data from New York's clinical CABG surgery registry from 1997 to 1999 (total number of procedures, 57 150) were used to examine the individual and combined impact of annual hospital volume and annual surgeon volume on in-hospital mortality rates after adjusting for differences in severity of illness. Significantly lower risk-adjusted mortality rates occurred above all annual hospital volume thresholds between 200 and 800 and above all surgeon volume thresholds between 50 and 200. The number needed to treat (NNT) at higher-volume providers to avoid a death was minimized for a hospital threshold volume of 100 (NNT=50) and a surgeon threshold volume of 50 (NNT=118). The risk-adjusted mortality rate (RAMR) for patients undergoing surgery performed by surgeons with volumes of > or =125 in hospitals with volumes of > or =600 was 1.89%. The RAMR was significantly higher (2.67%) for patients undergoing surgery performed by surgeons with volumes of <125 in hospitals with volumes of <600. CONCLUSIONS: Higher-volume surgeons and hospitals continue to have lower risk-adjusted mortality rates, and patients undergoing surgery performed by higher-volume surgeons in higher-volume hospitals have the lowest mortality rates.