Flap Coverage of Infected Ventricular Assist Devices Influences Patient Outcomes.

BACKGROUND: The use of left ventricular assist devices (LVADs) for patients with end-stage cardiac failure awaiting heart transplantation has become increasingly common. However, ventricular assist device-related infections remain a major problem complicating their long-term use. Poor data exist to determine how to manage these infections after operative debridement. METHODS: Patients who underwent insertion of a ventricular assist device and had a subsequent readmission for LVAD infection at the University of Rochester Medical Center from 2012 to 2022 were identified through accessing the medical records archives of the hospital. Patients were followed retrospectively for an average of 3.2 years. Patient demographics, preoperative diagnosis/disease state, type of ventricular assist device inserted, postoperative day of ventricular assist device infection onset, infectious organism identified at initial washout, infectious organism identified at time of definitive device coverage, timing of coverage procedure after the initial washout for infection, type of flap used for coverage, 90-day complications after definitive coverage, and lifetime return to operating room for infection were reviewed. Comparison analysis with a χ 2 test was used to analyze outcomes. RESULTS: Of 568 patients admitted with an LVAD-related infection 117 underwent operative debridement. Of these, 34 underwent primary closure, 31 underwent closure with secondary intention (negative pressure wound therapy with split thickness skin grafting), and 52 were closed with a flap (pectoralis, omental, latissimus, or vertical rectus abdominus musculocutaneous flap). There was a statistically significant higher incidence of return to the operating room (RTOR) for infection over a lifetime with primary closure compared with secondary intention and flap reconstruction ( P = 0.01, 0.02), but no difference in 90-day complications ( P = 0.76, P = 0.58). Eighty-three patients had a positive culture upon definitive coverage with 24 having a postsurgical complication, 15 of which required lifetime RTOR for infection. Thirty four were closed with negative cultures with 9 having a complication and 4 requiring RTOR for infection. This was not statistically significant for complications or RTOR ( P = 0.79, 0.40). Culture data were further substratified into bacterial cultures (n = 73) versus fungal cultures (n = 10), and there was no statistically significant difference between these compared with complications or RTOR ( P = 0.40, 0.39). CONCLUSIONS: Coverage of infected LVADs with locoregional flaps or allowing to granulate using wound vac therapy has a decreased lifetime RTOR for future infections for these patients without increase in 90-day complications. Timing of RTOR should not be impacted by positive cultures provided there is healthy granulation tissue in the wound.

Variability in Atherosclerotic Disease Progression within the Infrainguinal Arterial Circulation is Dependent on Both Patient and Anatomical Factors.

BACKGROUND: Studies suggest 25% of patients with symptomatic peripheral arterial disease develop symptom progression over time, yet there is minimal data related to actual atherosclerotic progression. METHODS: Patients who underwent consecutive duplex imaging of the lower limb arteries, at least 6 months apart with no intervening arterial intervention, were identified. Atherosclerotic burden was determined for both femoropopliteal (FP) and crural (CR) arterial segments utilizing the Bollinger score (BoS). Overall change in BoS over time was determined, and patients were divided into group 1: disease progression and group 2: no change/disease regression. Patient demographics, comorbidities, and long-term outcomes were collated. RESULTS: A total of 215 FP segments (155 men; median age 74 years) were assessed with 82 limbs showing atherosclerotic disease progression. FP atherosclerotic progression was associated with increased age, a diagnosis of ischemic heart disease and hypertension, and a lack of prescription of both an antiplatelet therapy and an angiotensin-converting enzyme inhibitor (all P < 0.05). FP atherosclerotic progression was also associated with an increased longer term mortality rate. A total of 272 CR arterial segments (190 men; median age 74 years) were assessed with 86 limbs showing atherosclerotic disease progression. CR atherosclerotic disease progression was associated with a diagnosis of diabetes mellitus at baseline (P = 0.019). CONCLUSIONS: A number of variable factors predict atherosclerotic progression. Differences exist between factors and the arterial segments affected (FP/CR). This suggests that underlying atherosclerotic processes may vary depending on arterial segment, warranting further investigation.

Circulating tumor cells shed large extracellular vesicles in capillary-sized bifurcations.

Circulating tumor cells (CTCs) and their clusters are the drivers of metastasis, but their interactions with capillary beds are poorly understood. Using microfluidic models mimicking human capillary bifurcations, we observed cell size- and bifurcation-dependent shedding of nuclei-free fragments by patient CTCs, CTC-derived explant cells and numerous cancer cell lines. Shedding reduced cell sizes up to 61%, facilitating their transit through bifurcations. We demonstrated that shed fragments were a novel class of large extracellular vesicles (LEVs), whose proteome was associated with immune-related and signaling pathways. LEVs were internalized by endothelial and immune cells, disrupted endothelial barrier integrity and polarized monocytes into M2 tumor-promoting macrophages. Cumulatively, these findings suggest that CTCs shed LEVs in capillary beds that drive key processes involved in the formation of pre-metastatic niches.

Functional Characterisation of the ATOH1 Molecular Subtype Indicates a Pro-Metastatic Role in Small Cell Lung Cancer.

Molecular subtypes of Small Cell Lung Cancer (SCLC) have been described based on differential expression of transcription factors (TFs) ASCL1, NEUROD1, POU2F3 and immune-related genes. We previously reported an additional subtype based on expression of the neurogenic TF ATOH1 within our SCLC Circulating tumour cell-Derived eXplant (CDX) model biobank. Here we show that ATOH1 protein was detected in 7/81 preclinical models and 16/102 clinical samples of SCLC. In CDX models, ATOH1 directly regulated neurogenesis and differentiation programs consistent with roles in normal tissues. In ex vivo cultures of ATOH1-positive CDX, ATOH1 was required for cell survival. In vivo, ATOH1 depletion slowed tumour growth and suppressed liver metastasis. Our data validate ATOH1 as a bona fide oncogenic driver of SCLC with tumour cell survival and pro-metastatic functions. Further investigation to explore ATOH1 driven vulnerabilities for targeted treatment with predictive biomarkers is warranted.

Lineage Plasticity in SCLC Generates Non-Neuroendocrine Cells Primed for Vasculogenic Mimicry.

INTRODUCTION: Vasculogenic mimicry (VM), the process of tumor cell transdifferentiation to endow endothelial-like characteristics supporting de novo vessel formation, is associated with poor prognosis in several tumor types, including SCLC. In genetically engineered mouse models (GEMMs) of SCLC, NOTCH, and MYC co-operate to drive a neuroendocrine (NE) to non-NE phenotypic switch, and co-operation between NE and non-NE cells is required for metastasis. Here, we define the phenotype of VM-competent cells and molecular mechanisms underpinning SCLC VM using circulating tumor cell-derived explant (CDX) models and GEMMs. METHODS: We analyzed perfusion within VM vessels and their association with NE and non-NE phenotypes using multiplex immunohistochemistry in CDX, GEMMs, and patient biopsies. We evaluated their three-dimensional structure and defined collagen-integrin interactions. RESULTS: We found that VM vessels are present in 23/25 CDX models, 2 GEMMs, and in 20 patient biopsies of SCLC. Perfused VM vessels support tumor growth and only NOTCH-active non-NE cells are VM-competent in vivo and ex vivo, expressing pseudohypoxia, blood vessel development, and extracellular matrix organization signatures. On Matrigel, VM-primed non-NE cells remodel extracellular matrix into hollow tubules in an integrin ß1-dependent process. CONCLUSIONS: We identified VM as an exemplar of functional heterogeneity and plasticity in SCLC and these findings take considerable steps toward understanding the molecular events that enable VM. These results support therapeutic co-targeting of both NE and non-NE cells to curtail SCLC progression and to improve the outcomes of patients with SCLC in the future.

Real-World Data on Pembrolizumab for Pretreated Non-Small-Cell Lung Cancer: Clinical Outcome and Relevance of the Lung Immune Prognostic Index.

BACKGROUND: Pembrolizumab is licensed for the treatment of pre-treated and PD-L1 positive non-small cell lung cancer (NSCLC), but response is heterogeneous. In this context, the Lung Immune Prognostic Index (LIPI) has been proposed as tool to prognosticate outcome. OBJECTIVE: To investigate the real-world efficacy and safety of pembrolizumab in pre-treated NSCLC patients and the clinical utility of LIPI for patients' selection. PATIENTS AND METHODS: Patients with pre-treated NSCLC and PD-L1 ≥ 1% treated with pembrolizumab were included in this retrospective series. The LIPI was used to classify patients in 3 prognostics subgroups according to the pre-treatment dNLR (derived neutrophil to lymphocyte ratio) and LDH in blood. The prognostic impact of the LIPI on progression free survival (PFS) and overall survival (OS) was evaluated with Cox regression. The combined effect of LIPI and other relevant prognostic factors was explored with multivariate regression. RESULTS: In total, 113 consecutive patients were included. Median (mPFS) and mOS was 4.3 (2.6-6.7) and 13.5 (10.3-17.7) months, respectively. Good-, intermediate-, and poor-LIPI was found in 54 (47.8%), 45 (39.8%), and 8 (7.1%) patients, respectively. Median PFS was 5.1 (2.8-9.1), 3.0 (2.5-6.8), and 1.4 (0.5-18.7) months, and mOS was 17.2 (12.0-26.4), 11.8 (8.4-17.1), and 3.7 (0.5-not calculable) months for good-, intermediate-, and poor-LIPI group, respectively. Patients with intermediate-LIPI and poor-LIPI had worse PFS versus good-LIPI, and statistically significant worse OS (p = 0.030 and p = 0.013, respectively). In the multivariate analysis, intermediate- versus good-LIPI (p = 0.190) was not independently associated to PFS or OS. Patients with both good-LIPI and high (≥ 50%) PD-L1 had better OS than all other subgroups defined by LIPI and PD-L1. Immune-related adverse events (irAEs) occurred in 47 (41.6%) patients (12.4% grade ≥ 3). In a time-varying analysis, irAEs were statistically associated with longer OS (HR 0.51, 0.31-0.84; p = 0.008). CONCLUSION: In our series, the outcome of pembrolizumab in pre-treated NSCLC is consistent with the registration trial. Lung Immune Prognostic Index is a readily available tool able to prognosticate outcome, also in PD-L1-high patients. The positive association between irAEs and OS might aid decision making.

Restoration of T-cell Effector Function, Depletion of Tregs, and Direct Killing of Tumor Cells: The Multiple Mechanisms of Action of a-TIGIT Antagonist Antibodies.

TIGIT is an immune checkpoint inhibitor expressed by effector CD4+ and CD8+ T cells, NK cells, and regulatory T cells (Tregs). Inhibition of TIGIT-ligand binding using antagonistic anti-TIGIT mAbs has shown in vitro potential to restore T-cell function and therapeutic efficacy in murine tumor models when combined with an anti-PD(L)-1 antibody. In the current work, we demonstrate broader TIGIT expression than previously reported in healthy donors and patients with cancer with expression on γδ T cells, particularly in CMV-seropositive donors, and on tumor cells from hematologic malignancies. Quantification of TIGIT density revealed tumor-infiltrating Tregs as the population expressing the highest receptor density. Consequently, the therapeutic potential of anti-TIGIT mAbs might be wider than the previously described anti-PD(L)-1-like restoration of αß T-cell function. CD155 also mediated inhibition of γδ T cells, an immune population not previously described to be sensitive to TIGIT inhibition, which could be fully prevented via use of an antagonistic anti-TIGIT mAb (EOS-448). In PBMCs from patients with cancer, as well as in tumor-infiltrating lymphocytes from mice, the higher TIGIT expression in Tregs correlated with strong antibody-dependent killing and preferential depletion of this highly immunosuppressive population. Accordingly, the ADCC/ADCP-enabling format of the anti-TIGIT mAb had superior antitumor activity, which was dependent upon Fcγ receptor engagement. In addition, the anti-TIGIT mAb was able to induce direct killing of TIGIT-expressing tumor cells both in human patient material and in animal models, providing strong rationale for therapeutic intervention in hematologic malignancies. These findings reveal multiple therapeutic opportunities for anti-TIGIT mAbs in cancer therapeutics.

EPAC-lung: European pooled analysis of the prognostic value of circulating tumour cells in small cell lung cancer.

BACKGROUND: Circulating tumour cell (CTC) number is an independent prognostic factor in patients with small cell lung cancer (SCLC) but there is no consensus on the CTC threshold for prognostic significance. We undertook a pooled analysis of individual patient data to clinically validate CTC enumeration and threshold for prognostication. METHODS: Four European cancer centres, experienced in CellSearch CTC enumeration for SCLC provided pseudo anonymised data for patients who had undergone pre-treatment CTC count. Data was collated, and Cox regression models, stratified by centre, explored the relationship between CTC count and survival. The added value of incorporating CTCs into clinico-pathological models was investigated using likelihood ratio tests. RESULTS: A total of 367 patient records were evaluated. A one-unit increase in log-transformed CTC counts corresponded to an estimated hazard ratio (HR) of 1.24 (95% CI: 1.19-1.29, P<0.0001) for progression free survival (PFS) and 1.23 (95% CI: 1.18-1.28, P<0.0001) for overall survival (OS). CTC count of ≥15 or ≥50 was significantly associated with an increased risk of progression (CTC ≥15: HR 3.20, 95% CI: 2.50-4.09, P<0.001; CTC ≥50: HR 2.56, 95% CI: 2.01-3.25, P<0.001) and an increased risk of death (CTC ≥15: HR 2.90, 95% CI: 2.28-3.70, P<0.001; CTC ≥50: HR 2.47, 95% CI: 1.95-3.13, P<0.001). There was no significant inter-centre heterogeneity observed. Addition of CTC count to clinico-pathological models as a continuous log-transformed variable, offers further prognostic value (both likelihood ratio P<0.001 for OS and PFS). CONCLUSIONS: Higher pre-treatment CTC counts are a negative independent prognostic factor in SCLC when considered as a continuous variable or dichotomised counts of ≥15 or ≥50. Incorporating CTC counts, as a continuous variable, improves clinic-pathological prognostic models.

Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia.

Knowledge of the genomic landscape of chronic lymphocytic leukemia (CLL) grows increasingly detailed, providing challenges in contextualizing the accumulated information. To define the underlying networks, we here perform a multi-platform molecular characterization. We identify major subgroups characterized by genomic instability (GI) or activation of epithelial-mesenchymal-transition (EMT)-like programs, which subdivide into non-inflammatory and inflammatory subtypes. GI CLL exhibit disruption of genome integrity, DNA-damage response and are associated with mutagenesis mediated through activation-induced cytidine deaminase or defective mismatch repair. TP53 wild-type and mutated/deleted cases constitute a transcriptionally uniform entity in GI CLL and show similarly poor progression-free survival at relapse. EMT-like CLL exhibit high genomic stability, reduced benefit from the addition of rituximab and EMT-like differentiation is inhibited by induction of DNA damage. This work extends the perspective on CLL biology and risk categories in TP53 wild-type CLL. Furthermore, molecular targets identified within each subgroup provide opportunities for new treatment approaches.

The Rare YAP1 Subtype of SCLC Revisited in a Biobank of 39 Circulating Tumor Cell Patient Derived Explant Models: A Brief Report.

INTRODUCTION: Recent consensus defines four SCLC subtypes on the basis of transcription factor expression: ASCL1, NEUROD1, POU2F3, and YAP1. The rare YAP1 subtype is associated with "neuroendocrine (NE)-low" cells among SCLC cell lines and patient samples. We evaluated YAP1 in 39 patients with phenotypically diverse circulating tumor cell-derived explant (CDX) models and revisited YAP1 in terms of prevalence, cell phenotype, and intertumor and intratumor heterogeneity. METHODS: YAP1 transcript and protein expression were assessed by RNA sequencing and immunohistochemistry or multiplexed immunofluorescence of NE and non-NE CDX subpopulations. Physically separated NE and non-NE CDX ex vivo culture lysates were Western blotted for YAP1, NE marker SYP, and AXL. RESULTS: RNA sequencing normalized for the four subtype transcription factors identified YAP1 expression in 14 of 39 CDX. A total of 10 CDX expressed YAP1 protein, and eight had strong YAP1 expression confined to rare non-NE cell clusters. This was confirmed in ex vivo CDX cultures in which adherent non-NE cells lacking SYP expression expressed YAP1. However, in two CDX, weaker cellular YAP1 expression was observed, widely dispersed in SYP-positive NE cells. CONCLUSIONS: YAP1 was predominantly expressed in non-NE cell clusters in SCLC CDX, but two of 39 CDX expressed YAP1 in NE cells. CDX22P, with relatively high YAP1 expression, is an ASCL1 NE subtype with a low NE score and an outlier within this subtype in our CDX biobank. These descriptive data reveal subtly different YAP1 expression profiles, paving the way for functional studies to compare YAP1 signaling in non-NE and low NE cell contexts for potentially personalized therapeutic approaches.

Brief report on the clinical characteristics of patients whose samples generate small cell lung cancer circulating tumour cell derived explants.

INTRODUCTION: Small cell lung cancer (SCLC) has a dismal prognosis. Circulating tumour cells (CTCs) can be used to generate CTC derived explants (CDX) for the study of SCLC biology and the development of novel therapeutics. We investigated whether there are demographic or clinical predictors of the success of CDX generation, and whether CDX models are representative of the SCLC patient population. METHODS: This was a single centre, retrospective analysis of SCLC patients who had participated in the CHEMORES Study. Paired blood samples were donated for CTC enumeration and CDX generation attempt at pre-treatment baseline, disease progression and intervening timepoints. Clinical and demographic data was collected from electronic records, and analysed for differences between patients whose samples did and did not generate a CDX. RESULTS: 231 paired blood samples were taken from 147 patients. 45 CDX were generated from 34 patients. CTC number was significantly higher in blood samples which successfully generated a CDX than those which didn't, at both baseline (p=<0.0001) and progression (p = 0.0001). The group with successful blood samples had a poorer performance status (p = 0.0067), and a higher proportion of patients with chemorefractory disease (p = 0.0077). Both progression free survival (PFS) (p = 0.0132) and overall survival (p=< 0.0001) were significantly shorter for patients with successful samples. CONCLUSIONS: Patients whose samples generate CDX models may have a higher disease burden and more aggressive disease. Thus, insights gained by study of SCLC CDX may have a significant impact, particularly in the SCLC subpopulation with the greatest clinical need.

Profiling of Circulating Free DNA Using Targeted and Genome-wide Sequencing in Patients with SCLC.

INTRODUCTION: SCLC accounts for approximately 250,000 deaths worldwide each year. Acquisition of adequate tumor biopsy samples is challenging, and liquid biopsies present an alternative option for patient stratification and response monitoring. METHODS: We applied whole genome next-generation sequencing to circulating free DNA (cfDNA) from 39 patients with limited-stage (LS) SCLC and 30 patients with extensive-stage SCLC to establish genome-wide copy number aberrations and also performed targeted mutation analysis of 110 SCLC associated genes. Quantitative metrics were calculated for copy number aberrations, including percent genome amplified (PGA [the percentage of genomic regions amplified]), Z-score (a measure of standard deviation), and Moran's I (a measure of spatial autocorrelation). In addition CellSearch, an epitope-dependent enrichment platform, was used to enumerate circulating tumor cells (CTCs) from a parallel blood sample. RESULTS: Genome-wide and targeted cfDNA sequencing data identified tumor-related changes in 94% of patients with LS SCLC and 100% of patients with extensive-stage SCLC. Parallel analysis of CTCs based on at least 1 CTC/7.5 mL of blood increased tumor detection frequencies to 95% for LS SCLC. Both CTC counts and cfDNA readouts correlated with disease stage and overall survival. CONCLUSIONS: We demonstrate that a simple cfDNA genome-wide copy number approach provides an effective means of monitoring patients through treatment and show that targeted cfDNA sequencing identifies potential therapeutic targets in more than 50% of patients. We are now incorporating this approach into additional studies and trials of targeted therapies.

A biobank of small cell lung cancer CDX models elucidates inter- and intratumoral phenotypic heterogeneity.

Although small cell lung cancer (SCLC) is treated as a homogeneous disease, biopsies and preclinical models reveal heterogeneity in transcriptomes and morphology. SCLC subtypes were recently defined by neuroendocrine transcription factor (NETF) expression. Circulating-tumor-cell-derived explant models (CDX) recapitulate donor patients' tumor morphology, diagnostic NE marker expression and chemotherapy responses. We describe a biobank of 38 CDX models, including six CDX pairs generated pretreatment and at disease progression revealing complex intra- and intertumoral heterogeneity. Transcriptomic analysis confirmed three of four previously described subtypes based on ASCL1, NEUROD1 and POU2F3 expression and identified a previously unreported subtype based on another NETF, ATOH1. We document evolution during disease progression exemplified by altered MYC and NOTCH gene expression, increased 'variant' cell morphology, and metastasis without strong evidence of epithelial to mesenchymal transition. This CDX biobank provides a research resource to facilitate SCLC personalized medicine.

Molecular analysis of single circulating tumour cells following long-term storage of clinical samples.

The CellSearch® semiautomated CTC enrichment and staining system has been established as the 'gold standard' for CTC enumeration with CellSearch® CTC counts recognized by the FDA as prognostic for a number of cancers. We and others have gone on to show that molecular analysis of CellSearch® CTCs isolated shortly after CellSearch® enrichment provides another valuable layer of information that has potential clinical utility including predicting response to treatment. Although CellSearch® CTCs can be readily isolated after enrichment, the process of analysing a single CellSearch® patient sample, which may contain many CTCs, is both time-consuming and costly. Here, we describe a simple process that will allow storage of all CellSearch® -enriched cells in glycerol at -20 °C for up to 2 years without any measurable loss in the ability to retrieve single cells or in the genome integrity of the isolated cells. To establish the suitability of long-term glycerol storage for single-cell molecular analysis, we isolated individual CellSearch® -enriched cells by DEPArray™ either shortly after CellSearch® enrichment or following storage of matched enriched cells in glycerol at -20 °C. All isolated cells were subjected to whole-genome amplification (WGA), and the efficacy of single-cell WGA was evaluated by multiplex PCR to generate a Genome Integrity Index (GII). The GII results from 409 single cells obtained from both 'spike-in' controls and clinical samples showed no statistical difference between values obtained pre- and postglycerol storage and that there is no further loss in integrity when DEPArray™-isolated cells are then stored at -80 °C for up to 2 years. In summary, we have established simple yet effective 'stop-off' points along the CTC workflow enabling CTC banking and facilitating selection of suitable samples for intensive analysis once patient outcomes are known.

Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer.

In most patients with small-cell lung cancer (SCLC)-a metastatic, aggressive disease-the condition is initially chemosensitive but then relapses with acquired chemoresistance. In a minority of patients, however, relapse occurs within 3 months of initial treatment; in these cases, disease is defined as chemorefractory. The molecular mechanisms that differentiate chemosensitive from chemorefractory disease are currently unknown. To identify genetic features that distinguish chemosensitive from chemorefractory disease, we examined copy-number aberrations (CNAs) in circulating tumor cells (CTCs) from pretreatment SCLC blood samples. After analysis of 88 CTCs isolated from 13 patients (training set), we generated a CNA-based classifier that we validated in 18 additional patients (testing set, 112 CTC samples) and in six SCLC patient-derived CTC explant tumors. The classifier correctly assigned 83.3% of the cases as chemorefractory or chemosensitive. Furthermore, a significant difference was observed in progression-free survival (PFS) (Kaplan-Meier P value = 0.0166) between patients designated as chemorefractory or chemosensitive by using the baseline CNA classifier. Notably, CTC CNA profiles obtained at relapse from five patients with initially chemosensitive disease did not switch to a chemorefractory CNA profile, which suggests that the genetic basis for initial chemoresistance differs from that underlying acquired chemoresistance.

Effect of beta-blocker therapy on mortality rates and future myocardial infarction rates in patients with coronary artery disease but no history of myocardial infarction or congestive heart failure.

Beta-blocker therapy has been shown to benefit patients who have coronary artery disease and present with acute myocardial infarction (AMI) and/or congestive heart failure (HF). However, whether beta-blocker therapy provides a similar benefit in patients who have coronary artery disease but not AMI or HF is unknown. A population of 4,304 patients who did not have HF but did have angiographically confirmed coronary artery disease (>/=1 stenosis of >/=70%) without AMI at hospital presentation was evaluated. Baseline demographics, cardiac risk factors, clinical presentation, therapeutic procedures, and discharge medications were recorded. Patients were followed for a mean of 3.0 +/- 1.9 years (range 1 month to 6.9 years) for outcomes of all-cause death or AMI. Patients' average age was 65 +/- 11 years and 77% were men. Overall, 10% died and 5% had a nonfatal AMI. Discharge beta-blocker prescription was associated with an increased event-free AMI survival rate for all-cause death (no beta blocker 88.3%, beta blocker 94.5%, p <0.001) and death/AMI (no beta blocker 83.4%, beta blocker 89.2%, p <0.001) but not non-fatal AMI (no beta blocker 93.6%, beta blocker 94.1%, p = 0.60). After adjustment for 16 covariates, including statin prescription, angiotensin-converting enzyme inhibitor prescription, and type of baseline therapy, the effect of beta blockers on the combination end point of death/AMI was eliminated. However, the effect of beta blockers on death remained (hazard ratio 0.66, 95% confidence interval 0.47 to 0.93, p = 0.02). Thus, beta blockers are clearly indicated for most patients who have HF or AMI, and our results suggest that patients who have coronary artery disease without these conditions have approximately the same protective benefit against death. No effect was observed on longitudinal incidence of AMI or the combination of death/nonfatal MI.

Prediction of short- and long-term outcomes by electrocardiography in survivors of out-of-hospital cardiac arrest.

BACKGROUND: Programs focusing on early defibrillation have improved both short- and long-term survival of patients with VF out-of-hospital cardiac arrest (OHCA). Subsequent long-term management of survivors would be facilitated by a straight-forward, non-invasive method of identifying those at highest risk for recurrence. Therefore, we assessed the predictive value of the standard ECG to determine both short- and long-term outcomes in survivors of VF OHCA to assist in risk stratification of those patients at highest risk of sudden death. METHODS: All patients with an OHCA between November 1990 and December 2000 who received early defibrillation for VF in Olmsted County Minnesota (MN) were included. Cox proportional hazards modeling was used to examine ECG variables and subsequent ICD deployment and death. RESULTS: Two hundred patients presented in VF OHCA; of these 138 (69%) survived to hospital admission (seven died in the emergency department prior to admission) and 79 (40%) were discharged. The QRS duration (141 +/- 41ms in nonsurvivors, 123 +/- 35 in survivors, P = 0.004) was predictive of short-term mortality in patients who did not survive to hospital discharge. The ventricular rate, PR interval, presence of right or left bundle branch block, QTc, ST elevation myocardial infarction, and atrial fibrillation/flutter were nonpredictive. The average length of follow up for hospital dismissal survivors was 4.8 +/- 3.0 years. In univariate analysis, each 30 ms interval increase in the QRS width and PR interval was associated with increased mortality and ICD deployment hazard ratio of 1.6 (CI 1.1-2.5, P = 0.02) and 1.12 (CI 1.0-1.2, P = 0.05), respectively. In multivariate analysis accounting for admission ejection fraction, a PR > 200 ms [HR 4.5 (CI 1.7-11.8, P = 0.022)], QRS width increase greater than 30 ms [HR 1.9 (CI 1.3-2.8, P < 0.001)], and a QRS > 120 ms [HR 2.4 (CI 1.1-5.4, P = 0.032)] were predictive of long-term mortality and ICD shocks. CONCLUSION: Careful evaluation of the admitting and discharge ECG provides prognostic information for in-hospital and long-term outcomes, respectively in this cohort of out-of-hospital cardiac arrest survivors. The QRS duration on the dismissal ECG following VF OHCA provides prognostic information which might be useful to identify those at highest risk long-term, and who would benefit from more aggressive antiarrhythmic therapy and cardiac stabilization.