Dual vs Single Cardioversion of Atrial Fibrillation in Patients With Obesity: A Randomized Clinical Trial.

Importance: Atrial fibrillation and obesity are common, and both are increasing in prevalence. Obesity is associated with failure of cardioversion of atrial fibrillation using a standard single set of defibrillator pads, even at high output. Objective: To compare the efficacy and safety of dual direct-current cardioversion (DCCV) using 2 sets of pads, with each pair simultaneously delivering 200 J, with traditional single 200-J DCCV using 1 set of pads in patients with obesity and atrial fibrillation. Design, Setting, and Participants: This was a prospective, investigator-initiated, patient-blinded, randomized clinical trial spanning 3 years from August 2020 to 2023. As a multicenter trial, the setting included 3 sites in Louisiana. Eligibility criteria included body mass index (BMI) of 35 or higher (calculated as weight in kilograms divided by height in meters squared), age 18 years or older, and planned nonemergent electrical cardioversion for atrial fibrillation. Patients who met inclusion criteria were randomized 1:1. Exclusions occurred due to spontaneous cardioversion, instability, thrombus, or BMI below threshold. Interventions: Dual DCCV vs single DCCV. Main Outcomes and Measures: Return to sinus rhythm, regardless of duration, immediately after the first cardioversion attempt of atrial fibrillation, adverse cardiovascular events, and chest discomfort after the procedure. Results: Of 2079 sequential patients undergoing cardioversion, 276 met inclusion criteria and were approached for participation. Of these, 210 participants were randomized 1:1. After exclusions, 200 patients (median [IQR] age, 67.6 [60.1-72.4] years; 127 male [63.5%]) completed the study. The mean (SD) BMI was 41.2 (6.5). Cardioversion was successful more often with dual DCCV compared with single DCCV (97 of 99 patients [98%] vs 87 of 101 patients [86%]; P = .002). Dual cardioversion predicted success (odds ratio, 6.7; 95% CI, 3.3-13.6; P = .01). Patients in the single cardioversion cohort whose first attempt failed underwent dual cardioversion with all subsequent attempts (up to 3 total), all of which were successful: 12 of 14 after second cardioversion and 2 of 14 after third cardioversion. There was no difference in the rating of postprocedure chest discomfort (median in both groups = 0 of 10; P = .40). There were no cardiovascular complications. Conclusions and Relevance: In patients with obesity (BMI ≥35) undergoing electrical cardioversion for atrial fibrillation, dual DCCV results in greater cardioversion success compared with single DCCV, without any increase in complications or patient discomfort. Trial Registration: ClinicalTrials.gov Identifier: NCT04539158.

Risk of ventricular arrhythmias following implantable cardioverter-defibrillator generator change in patients with recovered ejection fraction: Implications for shared decision-making.

INTRODUCTION: Guidelines indicate primary-prevention implantable cardioverter-defibrillators (ICDs) for most patients with left ventricular ejection fraction (LVEF) ≤ 35%. Some patients' LVEFs improve during the life of their first ICD. In patients with recovered LVEF who never received appropriate ICD therapy, the utility of generator replacement upon battery depletion remains unclear. Here, we evaluate ICD therapy based on LVEF at the time of generator change, to educate shared decision-making regarding whether to replace the depleted ICD. METHODS: We followed patients with a primary-prevention ICD who underwent generator change. Patients who received appropriate ICD therapy for ventricular tachycardia or ventricular fibrillation (VT/VF) before generator change were excluded. The primary endpoint was appropriate ICD therapy, adjusted for the competing risk of death. RESULTS: Among 951 generator changes, 423 met inclusion criteria. During 3.4 ± 2.2 years follow-up, 78 (18%) received appropriate therapy for VT/VF. Compared to patients with recovered LVEF > 35% (n = 161 [38%]), those with LVEF ≤ 35% (n = 262 [62%]) were more likely to require ICD therapy (p = .002; Fine-Gray adjusted 5-year event rates: 12.7% vs. 25.0%). Receiver operating characteristic analysis revealed the optimal LVEF cutoff for VT/VF prediction to be 45%, the use of which further improved risk stratification (p < .001), with Fine-Gray adjusted 5-year rates 6.2% versus 25.1%. CONCLUSION: Following ICD generator change, patients with primary-prevention ICDs and recovered LVEF have significantly lower risk of subsequent ventricular arrhythmias compared to those with persistent LVEF depression. Risk stratification at LVEF 45% offers significant additional negative predictive value over a 35% cutoff, without a significant loss in sensitivity. These data may be useful during shared decision-making at the time of ICD generator battery depletion.

Sacubitril/valsartan: An antiarrhythmic drug?

INTRODUCTION: Heart failure (HF) is a major cause of morbidity and mortality, with nearly half of all HF-related deaths resulting from sudden cardiac death (SCD), most often from an arrhythmic event. The pathophysiologic changes that occur in response to the hemodynamic stress of HF may lead to increased arrhythmogenesis. Theoretically, medications that block these arrhythmogenic substrates would decrease the risk of SCD. The combined angiotensin receptor and neprilysin inhibitor (ARNi; tradename Entresto) is the newest commercially available medication for the treatment of heart failure. METHODS AND RESULTS: We reviewed and synthesized the available literature regarding sacubitril/valsartan and its effects on cardiac rhythm. ARNi has been shown to decrease cardiovascular mortality and hospitalization in patients with HF with reduced ejection fraction (HFrEF). Emerging evidence suggests that ARNi also may play a role in reducing arrhythmogenesis and thereby SCD. CONCLUSION: This review summarizes the current data regarding this ARNi and its potential antiarrhythmic effects.

Epidemiology, evaluation, and management of conduction disturbances after transcatheter aortic valve replacement.

Aortic stenosis is the most common valvulopathy requiring replacement by means of the surgical or transcatheter approach. Transcatheter aortic valve replacement (TAVR) has quickly become a viable and often preferred treatment strategy compared to surgical aortic valve replacement. However, transcatheter heart valve system deployment not infrequently injures the specialized electrical system of the heart, leading to new conduction disorders including high-grade atrioventricular block and complete heart block (CHB) necessitating permanent pacemaker implantation (PPI), which may lead to deleterious effects on cardiac function and patient outcomes. Additional conduction disturbances (e.g., new-onset persistent left bundle branch block, PR/QRS prolongation, and transient CHB) currently lack clearly defined management algorithms leading to variable strategies among institutions. This article outlines the current understanding of the pathophysiology, patient and procedural risk factors, means for further risk stratification and monitoring of patients without a clear indication for PPI, our institutional approach, and future directions in the management and evaluation of post-TAVR conduction disturbances.

The role of atrial fibrillation catheter ablation in patients with heart failure.

Atrial Fibrillation (AF) and heart failure (HF) with reduced ejection fraction (HFrEF) frequently coexist, resulting in significant morbidity and mortality. Therapeutic options for patients with AF and HFrEF are limited due to few antiarrhythmic drug (AAD) choices and historically equivocal effects of procedural interventions on mortality. However, recent randomized trials examining catheter ablation (CA) in AF patients with HFrEF have shown a beneficial effect on arrhythmic burden and HF symptoms, as well as an improvement in mortality. This review focuses on the role of CA for AF patients with HFrEF.

Utility of serial measurement of biomarkers of cardiovascular stress and inflammation in systolic dysfunction.

AIMS: Evidence links markers of systemic inflammation and heart failure (HF) with ventricular arrhythmias (VA) and/or death. Biomarker levels, and the risk they indicate, may vary over time. We evaluated the utility of serial laboratory measurements of inflammatory biomarkers and HF, using time-dependent analysis. METHODS AND RESULTS: We prospectively enrolled ambulatory patients with left ventricular ejection fraction (LVEF) ≤35% and a primary-prevention implanted cardioverter-defibrillator (ICD). Levels of established inflammatory biomarkers [C-reactive protein, erythrocyte sedimentation rate (ESR), suppression of tumourigenicity 2 (ST2), tumour necrosis factor alpha (TNF-α)] and brain natriuretic peptide (BNP) were assessed at 3-month intervals for 1 year. We assessed relationships between biomarkers modelled as time-dependent variables, VA, and death. Among 196 patients (66±14 years, LVEF 23±8%), 33 experienced VA, and 18 died. Using only baseline values, BNP predicted VA, and both BNP and ST2 predicted death. Using serial measurements at 3-month intervals, time-varying BNP independently predicted VA, and time-varying ST2 independently predicted death. C-statistic analysis revealed no significant benefit to repeated testing compared with baseline-only measurement. C-reactive protein, ESR, and TNF-α, either at baseline or over time, did not predict either endpoint. CONCLUSION: In stable ambulatory patients with systolic cardiomyopathy and an ICD, BNP predicts ventricular tachyarrhythmia, and ST2 predicts death. Repeated laboratory measurements over a year's time do not improve risk stratification beyond baseline measurement alone. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01892462 (https://clinicaltrials.gov/ct2/show/NCT01892462).

Positron emission tomography absolute stress myocardial blood flow for risk stratification in nonischemic cardiomyopathy.

INTRODUCTION: Sudden cardiac death is a substantial cause of mortality in patients with cardiomyopathy, but evidence supporting implantable cardioverter-defibrillator (ICD) implantation is less robust in nonischemic cardiomyopathy (NICM) than in ischemic cardiomyopathy. Improved risk stratification is needed. We assessed whether absolute quantification of stress myocardial blood flow (sMBF) measured by positron emission tomography (PET) predicts ventricular arrhythmias (VA) and/or death in patients with NICM. METHODS: In this pilot study, we prospectively followed patients with NICM (left ventricular ejection fraction ≤ 35%) and an ICD who underwent cardiac PET stress imaging with sMBF quantification. NICM was defined as the absence of angiographic obstructive coronary stenosis, significant relative perfusion defects on imaging, coronary revascularization, or acute coronary syndrome. Endpoints were appropriate device therapy for VA and all-cause mortality. Subgroup analysis was performed in patients who had no prior history of VA (ie, the primary prevention population). RESULTS: We followed 37 patients (60 ± 14 years, 46% male) for 41 ± 23 months. The median sMBF was 1.56 mL/g/min (interquartile range: 1.00-1.82). Lower sMBF predicted VA, both in the whole population (hazard ratio [HR] for each 0.1 mL/g/min increase: 0.84, P = .015) and in the primary prevention subset (n = 27; HR for each 0.1 mL/g/min increase: 0.81, P = .049). Patients with sMBF below the median had significantly more VA than those above the median, both in the whole population (P = .004) and in the primary prevention subset (P = .046). Estimated 3-year VA rates in the whole population were 67% among low-flow patients vs 13% among high-flow patients, and 39% vs 8%, respectively, among primary-prevention patients. sMBF did not predict all-cause mortality. CONCLUSIONS: In patients with NICM, lower sMBF predicts VA. This relationship may be useful for risk stratification for ventricular arrhythmia and decision making regarding ICD implantation.

Class 1C antiarrhythmic drugs in atrial fibrillation and coronary artery disease.

BACKGROUND: Class 1C antiarrhythmic drugs (AADs) are effective first-line agents for atrial fibrillation (AF) treatment. However, these agents commonly are avoided in patients with known coronary artery disease (CAD), due to known increased risk in the postmyocardial infarction population. Whether 1C AADs are safe in patients with CAD but without clinical ischemia or infarct is unknown. Reduced coronary flow capacity (CFC) on positron emission tomography (PET) reliably identifies myocardial regions supplied by vessels with CAD causing flow limitation. OBJECTIVE: To assess whether treatment with 1C AADs increases mortality in patients without known CAD but with CFC indicating significantly reduced coronary blood flow. METHODS: In this pilot study, we compared patients with AF and left ventricular ejection fraction ≥50% who were treated with 1C AADs to age-matched AF patients without 1C AAD treatment. No patient had clinically evident CAD (ie, reversible perfusion defect, known ≥70% epicardial lesion, percutaneous coronary intervention, coronary artery bypass grafting, or myocardial infarction). All patients had PET-based quantification of stress myocardial blood flow and CFC. Death was assessed by clinical follow-up and social security death index search. RESULTS: A total of 78 patients with 1C AAD exposure were matched to 78 controls. Over a mean follow-up of 2.0 years, the groups had similar survival (P = .54). Among patients with CFC indicating the presence of occult CAD (ie, reduced CFC involving ≥50% of myocardium), 1C-treated patients had survival similar to (P = .44) those not treated with 1C agents. CONCLUSIONS: In a limited population of AF patients with preserved left ventricle function and PET-CFC indicating occult CAD, treatment with 1C AADs appears not to increase mortality. A larger study would be required to confidently assess the safety of these drugs in this context.

Optimal method of measuring the T-peak to T-end interval for risk stratification in primary prevention.

Aims: Several published investigations demonstrated that a longer T-peak to T-end interval (Tpe) implies increased risk for ventricular tachyarrhythmia (VT/VF) and mortality. Tpe has been measured using diverse methods. We aimed to determine the optimal Tpe measurement method for screening purposes. Methods and results: We evaluated 305 patients with LVEF ≤ 35% and an implantable cardioverter-defibrillator implanted for primary prevention. Tpe was measured using seven different methods described in the literature, including six manual methods and the automated algorithm '12SL', and was corrected for heart rate. Endpoints were VT/VF and death. To account for differences in the magnitude of Tpe measurements, results are expressed in standard deviation (SD) increments. We evaluated the clinical utility of each measurement method based on predictive ability, fraction of immeasurable tracings, and intra- and interobserver correlation. >Over 31 ± 23 months, 82 (27%) patients had VT/VF, and over 49 ± 21 months, 91 (30%) died. Several rate-corrected Tpe measurement methods predicted VT/VF (HR per SD 1.20-1.34; all P < 0.05), and nearly all methods (both corrected and uncorrected) predicted death (HR per SD 1.19-1.35; all P < 0.05). Optimal predictive ability, readability, and correlation were found in the automated 12SL method and the manual tangent method in lead V2. Conclusion: For the prediction of VT/VF, the utility of Tpe depends upon the measurement method, but for the prediction of mortality, most published Tpe measurement methods are similarly predictive. Heart rate correction improves predictive ability. The automated 12SL method performs as well as any manual measurement, and among manual methods, lead V2 is most useful.

Natural History and Implantable Cardioverter-Defibrillator Implantation After Revascularization for Stable Coronary Artery Disease With Depressed Ejection Fraction.

BACKGROUND: Following revascularization, most payors require 3 months of medical therapy, followed by left ventricular ejection fraction (LVEF) reassessment, before implantable cardioverter-defibrillator (ICD) implantation possibly contributing to incomplete follow-up and suboptimal utilization of ICD therapy. The natural history of these patients, and their fate regarding ICD implantation, is unknown. HYPOTHESIS: We hypothesized that a waiting period after revascularization for stable CAD results in missed opportunities to provide care with regard to ICD implantation. METHODS: We followed patients with LVEF ≤ 35% and no ICD who underwent revascularization (coronary artery bypass grafting [CABG] or percutaneous coronary intervention [PCI]) for stable CAD. Follow-up used chart review and scripted telephone interviews. RESULTS: Among 3164 revascularized patients (2198 [69%] PCI, 966 [31%] CABG), only 62 (2%; 33 [53%] male, age 67 ± 12 y, LVEF 28% ± 6%) had stable CAD, depressed LVEF, and no ICD. Over 35 ± 19 months, 35 (56%) of these 62 patients were no longer candidates for ICD based on improved LVEF, 14 (23%) received an ICD, 5 (8%) declined ICD despite physician recommendation, 3 (5%) were not offered ICD despite continued eligibility, 2 (3%) died, 1 (2%) was not a candidate due to substance abuse, and 1 (2%) had ICD implantation temporarily deferred. Only 1 (2%) was lost to follow-up. CONCLUSIONS: Following revascularization for stable CAD with depressed LVEF, ≥50% of patients' ventricular function improved enough to make ICD implantation unnecessary. A waiting period after revascularization prior to ICD implantation appears appropriate and does not significantly negatively impact follow-up or the rate of appropriate ICD implantation.

T-peak to T-end interval for prediction of ventricular tachyarrhythmia and mortality in a primary prevention population with systolic cardiomyopathy.

BACKGROUND: The electrocardiographic T-wave peak to T-wave end interval (Tpe) correlates with dispersion of ventricular repolarization (DVR). Increased DVR increases propensity toward electrical reentry that can cause ventricular tachyarrhythmia. The baseline rate-corrected Tpe (Tpec) has been shown to predict ventricular tachyarrhythmia and death in multiple patient populations but not among cardiomyopathic patients undergoing insertion of an implantable cardioverter-defibrillator (ICD) for primary prevention. OBJECTIVE: The purpose of this study was to assess the risk stratification ability of the Tpec in patients with systolic cardiomyopathy without prior ventricular tachyarrhythmia (ie, the primary prevention population). METHODS: We performed prospective follow-up of 305 patients (73% men; left ventricular ejection fraction [LVEF] 23 ± 7%) with LVEF ≤35% and an ICD implanted for primary prevention. Baseline ECGs were analyzed with automated algorithms. Endpoints were ventricular tachycardia (VT)/ventricular fibrillation (VF), death, and a combined endpoint of VT/VF or death, assessed by device follow-up and Social Security Death Index query. RESULTS: The average Tpec was 107 ± 22 ms. During device clinic follow-up of 31 ± 23 months, 82 patients (27%) had appropriate ICD therapy for VT/VF, and during mortality follow-up of 49 ± 21 months, 91 patients (30%) died. On univariable analysis, Tpec predicted VT/VF, death, and the combined endpoint of VT/VF or death (P < .05 for each endpoint). Multivariable analysis included univariable predictors among demographics, clinical data, laboratory data, medications used, and electrocardiography parameters. After correction, Tpec remained predictive of VT/VF (hazard ratio [HR] per 10-ms increase 1.16, P = .009), all-cause mortality (HR per 10 ms 1.13, P = .05), and the combined endpoint (HR per 10 ms 1.17, P = .001). CONCLUSION: Tpec independently predicts both VT/VF and overall mortality in patients with systolic dysfunction and ICDs implanted for primary prevention.

Endocardial unipolar voltage mapping to identify epicardial substrate in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

BACKGROUND: The risk and success of epicardial substrate ablation for ventricular tachycardia (VT) support the value of techniques identifying the epicardial substrate with endocardial mapping. OBJECTIVE: The purpose of this study was to test the hypothesis that endocardial unipolar voltage mapping in patients with right ventricular (RV) VT and preserved endocardial bipolar voltage abnormalities might identify the extent of epicardial bipolar voltage abnormality. METHODS: Using a cutoff of < 5.5 mV for normal endocardial unipolar voltage derived from 8 control patients without structural heart disease, 10 patients with known ARVC/D (group 1, retrospective) and 13 patients with RV VT (group 2, prospective) with modest or no endocardial bipolar voltage abnormalities underwent detailed endocardial and epicardial mapping. RESULTS: The area of epicardial unipolar voltage abnormality in all 10 group 1 patients with ARVC/D (62 ± 21 cm²) and in 9 of the 13 group 2 patients (8 with criteria for ARVC/D) (53 ± 21 cm²) was on average three times more extensive than the endocardial bipolar abnormality and correlated (r = 0.63, P <.05 and r = 0.81, P <.008, respectively) with the larger area epicardial bipolar abnormality with respect to size (group 1: 82 ± 22 cm²; group 2: 68 ± 41 cm²) and location. In the remaining 4 group 2 patients and 3 additional reference patients without structural heart disease, endocardial bipolar, endocardial unipolar, and, as predicted, epicardial bipolar voltage all were normal. CONCLUSION: Endocardial unipolar mapping with cutoff of 5.5 mV identifies more extensive areas of epicardial bipolar signal abnormalities in patients with ARVC/D and limited endocardial VT substrate.

Outcome of percutaneous coronary intervention in unstable angina pectoris versus stable angina pectoris in two different time periods.

Percutaneous coronary intervention (PCI) for unstable angina pectoris (UAP) has traditionally been associated with a higher risk of ischemic complications than that for stable angina pectoris (SAP). However, PCI procedures have evolved, so this study was designed to determine whether PCI for UAP is still associated with less favorable outcomes. In-hospital and 1-year outcomes in Dynamic Registry patients who presented for PCI with UAP (n = 2,994) or SAP (n = 1,457) between 1997 and 2002 were compared. One-year results were also compared with consecutive patients who underwent angioplasty (n = 2,431) from the 1985 to 1986 Percutaneous Transluminal Coronary Angioplasty Registry. Although Dynamic Registry patients with UAP were older and more likely to smoke (p < 0.05), have diabetes mellitus (p = 0.03), or a previous myocardial infarction (p < 0.001), procedural success was higher than in patients with SAP. By 1 year, there was greater risk of death (4.4% vs 2.6%, p < 0.01), death/myocardial infarction (9.9% vs 6.6%, p < 0.001), and death, myocardial infarction, and coronary artery bypass grafting (15.1% vs 11.6%, p < 0.01) in patients with UAP. In patients with UAP, there was no significant difference in adjusted 1-year death and death/myocardial infarction rates when comparing the waves of the Dynamic Registry with those of the Percutaneous Transluminal Coronary Angioplasty Registry, although death/myocardial infarction rates among Dynamic Registry patients were lower. However, in patients with SAP, the adjusted rate for death/myocardial infarction was lower in wave 3, and for death, myocardial infarction, and revascularization, there was a significant decrease in event rates with each successive recruitment period (p < 0.05 for all comparisons). In conclusion, in contradistinction to patients with SAP, death and death/myocardial infarction rates in patients who have undergone PCI for UAP have not significantly decreased over the past 16 years and patients with UAP remain at a greater risk of ischemic events at 1 year compared with patients with SAP.

Proper management of pericardial tamponade as a late complication of implantable cardiac device placement.

Cardiac tamponade as a late complication of device placement is exceedingly rare, with only several case reports previously published. We sought to characterize our institution's experience with cardiac tamponade occurring >30 days after permanent pacemaker or implantable cardioverter-defibrillator placement. From January 2000 to June 2003, 2,535 patients received an implantable cardiac device at our institution. Four patients (0.17%) presented with cardiac tamponade>30 days after the procedure. A fifth patient who had undergone implantation at another institution but was referred to our group with tamponade was also included in the analysis. The baseline characteristics varied widely with respect to age, gender, device type, and anticoagulation status. Lead parameters were altered in 2 of 5 patients. Two patients were treated with pericardiocentesis, 1 patient had pericardiocentesis followed by lead extraction, and 2 patients required cardiac surgical intervention. Pericardial fluid culture and cytologic findings were negative in all patients. All patients had normal recovery and were well at a mean follow-up of 31 months. In conclusion, cardiac tamponade is a rare, but serious late complication of permanent pacemaker and implantable cardioverter-defibrillator placement. The patient characteristics and mode of presentation vary widely. Once tamponade is recognized and treated, these patients appear well at long-term follow-up, with no other device-related problems. A role for lead manipulation does not appear to exist in the standard treatment of these patients.

An integrated approach to measuring tumor oxygen status using human melanoma xenografts as a model.

Tumor oxygen status is a reliable prognostic marker that impacts malignant progression and outcome of tumor therapy. However, tumor oxygenation is heterogeneous and cannot be sufficiently described by a single parameter. It is influenced by several factors including microvessel density (MVD), blood flow (BF), blood volume (BV), blood oxygen saturation, tissue pO(2), oxygen consumption rate, and hypoxic fraction. The goal of this investigation was to integrate these measurements to obtain a comprehensive profile of tumor oxygenation. Platelet/endothelial cell adhesion molecule immunohistochemistry, the recessed oxygen microelectrode, color and power Doppler ultrasound (DUS), and diffuse light spectroscopy (DLS) were used to measure tumor oxygen status using vascular endothelial growth factor (VEGF)-transfected hypervascular human melanoma xenografts and their nontransfected counterparts as a model. NIH1286 human melanoma cells were transfected with a retroviral vector +/- a 720-bp fragment of human VEGF(121). High VEGF-producing clones were selected by ELISA. Oxygen consumption rate was measured in NIH1286/VEGF+ [VEGF-transfected cells (VEGF+ cells)] and NIH1286/Vec cells [cells transfected with vector alone (Vec cells)] using a standard Clark oxygen electrode. Athymic nude 6-8-week-old mice received s.c. injection in the right flank with 5 x 10(6) VEGF+ or Vec cells. When tumors were 10-14 mm in maximum dimension, serum was analyzed for VEGF by ELISA. Cryopreserved tumor tissue sections were immunostained for platelet/endothelial cell adhesion molecule, and MVD measurements were made. Tumor-bearing mice were anesthetized, and pO(2) measurements were made using Eppendorf pO(2) histograph or the recessed oxygen microelectrode. Tumor BF and BV were measured by quantitative analysis of DUS images. DLS was used to measure tumor BF and blood oxygen saturation variation. VEGF+ cell supernatants had 15,500 pg/ml VEGF, and Vec cells had 10 pg/ml. VEGF+ and Vec cells had equivalent oxygen consumption rates. VEGF+ tumors had a faster growth rate than Vec tumors. Serum from VEGF+ tumor-bearing mice showed 4,211 pg/ml VEGF, whereas VEGF was undetectable in the serum of control mice. MVD values were 74 +/- 11 in VEGF+ tumors and 39 +/- 4 in control tumors at x200 magnification/0.95-mm(2) area. The median pO(2) values were 3.5-fold higher in VEGF+ tumors than in Vec tumors by the recessed oxygen microelectrode and 18-fold higher by Eppendorf pO(2) histograph. DUS showed a 3.3-fold higher mean BF and a 5.5-fold higher BV in VEGF+ tumors than in Vec tumors. DLS showed a 3.2-fold higher mean BF and 1.7-fold higher oxygen saturation in the hypervascular tumors as compared with the control tumor type, consistent with increased BF and BV data by DUS. An integrated approach that yields a comprehensive and consistent profile of oxygen status in tumors could potentially provide critical information for prognosis and treatment.