Screening tools for the detection of clinically silent cardiac sarcoidosis.

BACKGROUND: clinically silent cardiac sarcoidosis (CS) may be associated with adverse outcomes, hence the rationale for screening patients with extracardiac sarcoidosis. The optimal screening strategy has not been clearly defined. METHODS: patients with extra-cardiac sarcoidosis were prospectively included and underwent screening consisting of symptom history, electrocardiography (ECG), transthoracic echocardiogram, Holter, and signal-averaged ECG (SAECG). Cardiac magnetic resonance (CMR) was performed in all patients. Clinically silent CS was defined as CMR demonstrating late gadolinium enhancement (LGE) in a pattern compatible with CS according to a majority of independent and blinded CMR experts. Significant cardiac involvement was defined as the presence of LGE ≥6% and/or a positive fluorodeoxyglucose-positron emission tomography. RESULTS: among the 129 patients included, clinically silent CS was diagnosed in 29/129 (22.5%), and 19/129 patients (14.7%) were classified as CS with significant cardiac involvement. There was a strong association between hypertension and CS (p < 0.05). Individual screening tools provided low diagnostic yield; however, combination of tests performed better, for example, a normal Holter and a normal SAECG had negative predictive values of 91.7%. We found consistently better diagnostic accuracy for the detection of CS with significant cardiac involvement. CONCLUSION: clinically silent CS and CS with significant cardiac involvement were found in 22.5% and 14.7% of patients with extra-cardiac sarcoidosis. The association with hypertension raises the possibility that some cases of hypertensive cardiomyopathy may be mistaken for CS. Screening with readily available tools, for example Holter and SAECG, may help identifying patients without CS where additional CMR is not needed.

Non-invasive diagnosis of vasospastic angina.

Vasospastic angina (VSA), or variant angina, is an under-recognized cause of chest pain and myocardial infarction, especially in Western countries. VSA leads to a declined quality of life and is associated with increased morbidity and mortality. Currently, the diagnosis of VSA relies on invasive testing that requires the direct intracoronary administration of ergonovine or acetylcholine. However, invasive vasoreactivity testing is underutilized. Several non-invasive imaging alternatives have been proposed to screen for VSA. This review aims to discuss the strengths and limitations of available non-invasive imaging tests for vasospastic angina.

Use of conventional cardiac troponin assay for diagnosis of non-ST-elevation myocardial infarction: 'The Ottawa Troponin Pathway'.

BACKGROUND: Serial conventional cardiac troponin (cTn) measurements 6-9 hours apart are recommended for non-ST-elevation MI (NSTEMI) diagnosis. We sought to develop a pathway with 3-hour changes for major adverse cardiac event (MACE) identification and assess the added value of the HEART [History, Electrocardiogram (ECG), Age, Risk factors, Troponin] score to the pathway. METHODS: We prospectively enrolled adults with NSTEMI symptoms at two-large emergency departments (EDs) over 32-months. Patients with STEMI, unstable angina and one cTn were excluded. We collected baseline characteristics, Siemens Vista conventional cTnI at 0, 3 or 6-hours after ED presentation; HEART score predictors; disposition and ED length of stay (LOS). Adjudicated primary outcome was 15-day MACE (acute MI, revascularization, or death due to cardiac ischemia/unknown cause). We analyzed multiples of 99th percentile cut-off cTnI values (45, 100 and 250ng/L). RESULTS: 1,683 patients (mean age 64.7 years; 55.3% female; median LOS 7-hours; 88 patients with 15-day MACE) were included. 1,346 (80.0%) patients with both cTnI≤45 ng/L; and 155 (9.2%) of the 213 patients with one value≥100ng/L but both<250ng/L or ≤20% change did not suffer MACE. Among 124 patients (7.4%) with one of the two values>45ng/L but<100ng/L based on 3 or 6-hour cTnI, one patient with absolute change<10ng/L and 6 of the 19 patients with≥20ng/L were diagnosed with NSTEMI (patients with Δ10-19ng/L between first and second cTnI had third one at 6-hours). Based on the results, we developed the Ottawa Troponin Pathway (OTP) with a 98.9% sensitivity (95% CI 93.8-100%) and 94.6% specificity (95% CI 93.3-95.6%). Addition of the HEART score improved the sensitivity to 100% (95% CI 95.9-100%) and decreased the specificity to 26.5% (95% CI 24.3-28.7%). CONCLUSION: The OTP with conventional cTnI 3-hours apart, should lead to better NSTEMI identification particularly those with values >99th percentile, standardize management and reduce the ED LOS.

Elevated level of lecithin:cholesterol acyltransferase (LCAT) is associated with reduced coronary atheroma burden.

BACKGROUND AND AIMS: Lecithin:cholesterol acyltransferase (LCAT), a key enzyme in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT), has been associated with atheroprotection. However, its relation to plaque characteristics has not been confirmed to date. We aimed to determine the relationship between plasma LCAT mass concentration and plaque burden in a multi-center imaging study. METHODS: Two hundred sixty-seven patients with angiographically proven coronary artery disease (CAD) underwent intravascular ultrasonography (IVUS) imaging. Ninety-six patients without CAD served as controls for biochemistry assessments. RESULTS: Plasma LCAT mass concentration was higher in CAD patients as compared to controls (8.94 ±â€¯2.51 µg/mL vs. 7.89 ±â€¯2.99 µg/mL, p = 0.003), while cholesterol esterification rate (CER) was downregulated (253.6 ±â€¯83.9 µM/2 h vs. 315.3 ±â€¯115.0 µM/2 h, p<0.0001). Both parameters correlated inversely with total atheroma volume (r = -0.14, p = 0.027 and r = -0.14, p = 0.024, respectively), while only LCAT mass was found to be a significant predictor of atheroma volume (ß-coefficient -0.18, p = 0.0047) when tested in a stepwise linear regression model against known CAD risk factors as predictor variables. Accordingly, patients with LCAT mass in the highest quartile had significantly less atheroma burden than those in the lower quartiles (39.7 ±â€¯10.7% vs. 45.4 ±â€¯10.4%, p = 0.0014 for highest vs. lowest quartile of LCAT mass). CONCLUSIONS: Plasma LCAT mass concentration is upregulated in CAD patients and inversely related to plaque volume, suggesting atheroprotective effects. LCAT mass concentration outperformed LCAT activity in risk prediction models for atheroma burden, suggesting that LCAT mass is a key variable in atheroprotection. Further studies assessing LCAT as a therapeutic target in cardiovascular disease are warranted.

Role of inflammation in the pathogenesis of atherosclerosis and therapeutic interventions.

Rudolph Virchow (1821-1902) recognized inflammation in histological preparations of coronary arteries and proposed that inflammation plays a causal role in atherosclerosis. Despite this seminal observation, the main focus of research and drug development programs has been cholesterol alone, and inflammation received less attention over time. However, during the past several decades extensive observations supported the importance of inflammation in the development and destabilization of atherosclerosis. Studies in patients affected by rheumatological diseases suggested an interaction between chronic inflammation and atherosclerotic cardiovascular disease. Randomized clinical studies with lipid lowering agents suggested that part of the beneficial effect may have been related to reduction in inflammation. More recently, a few studies were designed to directly address the role of anti-inflammatory treatments in reducing risk of atherosclerotic heart disease beyond traditional risk factors. In this article, we review the pathophysiologic contribution of inflammation to atherosclerosis, biomarkers of inflammation and the evidence collected in observational studies regarding the role of chronic inflammation in the development of atherosclerotic heart disease. Finally, we discuss the most recent randomized clinical trials of anti-inflammatory agents directed at stemming atherosclerotic cardiovascular disease.

Design of the effect of adaptive servo-ventilation on survival and cardiovascular hospital admissions in patients with heart failure and sleep apnoea: the ADVENT-HF trial.

INTRODUCTION: Both types of sleep-disordered breathing (SDB), obstructive and central sleep apnoea (OSA and CSA, respectively), are common in patients with heart failure and reduced ejection fraction (HFrEF). In such patients, SDB is associated with increased cardiovascular morbidity and mortality but it remains uncertain whether treating SDB by adaptive servo-ventilation (ASV) in such patients reduces morbidity and mortality. AIM: ADVENT-HF is designed to assess the effects of treating SDB with ASV on morbidity and mortality in patients with HFrEF. METHODS: ADVENT-HF is a multicentre, multinational, randomized, parallel-group, open-label trial with blinded assessment of endpoints of standard medical therapy for HFrEF alone vs. with the addition of ASV in patients with HFrEF and SDB. Patients with a history of HFrEF undergo echocardiography and polysomnography. Those with a left ventricular ejection fraction ≤45% and SDB (apnoea-hypopnoea index ≥15) are eligible. SDB is stratified into OSA with ≥50% of events obstructive or CSA with >50% of events central. Those with OSA must not have excessive daytime sleepiness (Epworth score of ≤10). Patients are then randomized to receive or not receive ASV. The primary outcome is the composite of all-cause mortality, cardiovascular hospital admissions, new-onset atrial fibrillation requiring anti-coagulation but not hospitalization, and delivery of an appropriate discharge from an implantable cardioverter-defibrillator not resulting in hospitalization during a maximum follow-up time of 5 years. CONCLUSION: The ADVENT-HF trial will help to determine whether treating SDB by ASV in patients with HFrEF improves morbidity and mortality.

Prognostic significance of blood pressure response during vasodilator stress Rb-82 positron emission tomography myocardial perfusion imaging.

BACKGROUND: A drop in blood pressure (BP) or blunted BP response is an established high-risk marker during exercise myocardial perfusion imaging (MPI); however, data are sparse regarding the prognostic value of BP response in patients undergoing vasodilator stress rubidium-82 (Rb-82) Positron Emission Tomography (PET) MPI. METHODS AND RESULTS: From the PET Prognosis Multicenter Registry, a cohort of 3413 patients underwent vasodilator stress Rb-82 PET MPI with dipyridamole or adenosine. We used multivariable Cox proportional hazard regression to analyze the association with mortality of four BP variables: stress minus rest systolic BP (∆SBP), stress minus rest diastolic BP (∆DBP), resting systolic BP (rSBP), and resting diastolic BP (rDBP). Covariates that had univariate P values <.10 were entered into the multivariable model. After median 1.7 years follow-up, 270 patients died. In univariate analyses, ∆SBP (P = .082), rSBP (P = .008), and rDBP (P < .001) were of potential prognostic value (P < .10), but ∆DBP was not (P = .96). After adjustment for other clinical and MPI variables, ∆SBP no longer independently predicted mortality (P = .082); only lower rSBP (P = .026) and lower rDBP (P = .045) remained independently prognostic. CONCLUSIONS: In patients undergoing vasodilator stress MPI, only lower resting BP is an independent predictor of mortality along with other clinical and MPI variables; BP response does not appear to add to risk stratification in these patients.

Reduced Myocardial Flow in Heart Failure Patients With Preserved Ejection Fraction.

BACKGROUND: There remains limited insight into the pathophysiology and therapeutic advances directed at improving prognosis for patients with heart failure with preserved ejection fraction (HFpEF). Recent studies have suggested a role for coronary microvascular dysfunction in HFpEF. Rb-82 cardiac positron emission tomography imaging is a noninvasive, quantitative approach to measuring myocardial flow reserve (MFR), a surrogate marker for coronary vascular health. The aim of this study was to determine whether abnormalities exist in MFR in patients with HFpEF without epicardial coronary artery disease. METHODS AND RESULTS: A total of 376 patients with ejection fraction ≥50%, no known history of obstructive coronary artery disease, and a confirmed diagnosis of heart failure (n=78) were compared with patients with no evidence of heart failure (n=298), further stratified into those with (n=186) and without (n=112) hypertension. Global and regional left ventricular MFR was calculated as stress/rest myocardial blood flow using Rb-82 positron emission tomography. Patients with HFpEF were more likely to be older, female, and have comorbid hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, anemia, and renal dysfunction. HFpEF was associated with a significant reduction in global MFR (2.16±0.69 in HFpEF versus 2.54±0.80 in hypertensive controls; P<0.02 and 2.89±0.70 in normotensive controls; P<0.001). A diagnosis of HFpEF was associated with 2.62 times greater unadjusted odds of having low global MFR (defined as <2.0) and remained a significant predictor of reduced global MFR after adjusting for comorbidities. CONCLUSIONS: HFpEF, in the absence of known history for obstructive epicardial coronary artery disease, is associated with reduced MFR independent of other risk factors.

The CREATE Method for Expressing Continuous Outcome Data in Absolute Terms for Use in Patient Treatment Decision Aids: A Validation Study.

BACKGROUND: Patient decision aids (PtDAs) supplement advice from health care professionals by communicating the absolute risk or benefit of treatment options (i.e., X/100). As such, PtDAs have been amenable to binary outcomes only. We aimed to develop and test the validity of the Conversion to Risk Estimates through Application of Normal Theory (CREATE) method for estimating absolute risk based on continuous outcome data. METHODS: CREATE is designed to derive an estimate of the proportion of those who experience a clinically relevant degree of change (CRDoC). We used a 2-stage validation process using real and simulated change score data, respectively. First, using raw data from published intervention trials, we calculated the proportion of patients with a CRDoC and compared that with our CREATE-derived estimate using chi-square tests of association. Second, 200,000 simulated distributions of change scores were generated with widely varying distribution characteristics. Actual and CREATE-derived estimates were compared for each simulated distribution, and relative differences were summarized graphically. RESULTS: The absolute difference between the estimated and actual CRDoC did not exceed 5% for any of the samples based on real data. Applying the CREATE method to 200,000 simulated scenarios demonstrated that the CREATE method should be avoided for outcomes where the underlying distribution can be reasonably assumed to have high levels of skew or kurtosis. CONCLUSION: Our results suggest that standard statistical theory can be used to estimate continuous outcomes in absolute terms with reasonable accuracy for use in PtDAs; caution is advised if outcome summary statistics are assumed to have been derived from highly skewed distributions.

Granulocyte colony-stimulating factor therapy for stem cell mobilization following anterior wall myocardial infarction: the CAPITAL STEM MI randomized trial.

BACKGROUND: Small studies have yielded divergent results for administration of granulocyte colony-stimulating factor (G-CSF) after acute myocardial infarction. Adequately powered studies involving patients with at least moderate left ventricular dysfunction are lacking. METHODS: Patients with left ventricular ejection fraction less than 45% after anterior-wall myocardial infarction were treated with G-CSF (10 µg/kg daily for 4 days) or placebo. After initial randomization of 86 patients, 41 in the placebo group and 39 in the G-CSF group completed 6-month follow-up and underwent measurement of left ventricular ejection fraction by radionuclide angiography. RESULTS: Baseline and 6-week mean ejection fraction was similar for the G-CSF and placebo groups: 34.8% (95% confidence interval [CI] 32.6%-37.0%) v. 36.4% (95% CI 33.5%-39.2%) at baseline and 39.8% (95% CI 36.2%-43.4%) v. 43.1% (95% CI 39.2%-47.0%) at 6 weeks. However, G-CSF therapy was associated with a lower ejection fraction at 6 months relative to placebo (40.8% [95% CI 37.4%-44.2%] v. 46.0% [95% CI 42.7%-44.3%]). Both groups had improved left ventricular function, but change in left ventricular ejection fraction was lower in patients treated with G-CSF than in those who received placebo (5.7 [95% CI 3.4-8.1] percentage points v. 9.2 [95% CI 6.3-12.1] percentage points). One or more of a composite of several major adverse cardiac events occurred in 8 patients (19%) within each group, with similar rates of target-vessel revascularization. INTERPRETATION: In patients with moderate left ventricular dysfunction following anterior-wall infarction, G-CSF therapy was associated with a lower 6-month left ventricular ejection fraction but no increased risk of major adverse cardiac events. Future studies of G-CSF in patients with left ventricular dysfunction should be monitored closely for safety. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT00394498.

Influence of sex on risk stratification with stress myocardial perfusion Rb-82 positron emission tomography: Results from the PET (Positron Emission Tomography) Prognosis Multicenter Registry.

OBJECTIVES: The aim of the current analysis was to compare sex differences in the prognostic accuracy of stress myocardial perfusion rubidum-82 (Rb-82) positron emission tomography (PET). BACKGROUND: The diagnostic evaluation of women presenting with suspected cardiac symptoms is challenging with reported reduced accuracy, attenuation artifact, and more recent concerns regarding radiation safety. Stress myocardial perfusion Rb-82 PET is a diagnostic alternative with improved image quality and radiation dosimetry. Currently, the prognostic accuracy of stress Rb-82 PET in women has not been established. METHODS: A total of 6,037 women and men were enrolled in the PET Prognosis Multicenter Registry. Patients were followed for the occurrence of coronary artery disease (CAD) mortality, with a median follow-up of 2.2 years. Cox proportional hazards modeling was used to estimate CAD mortality. The net re-classification improvement index (NRI) was calculated. RESULTS: The 5-year CAD mortality was 3.7% for women and 6.0% for men (p < 0.0001). Unadjusted CAD mortality ranged from 0.9% to 12.9% for women (p < 0.0001) and from 1.5% to 17.4% for men (p < 0.0001) for 0% to ≥15% abnormal myocardium at stress. In multivariable models, the percentage of abnormal stress myocardium was independently predictive of CAD mortality in women and men. An interaction term of sex by the percentage of abnormal stress myocardium was nonsignificant (p = 0.39). The categorical NRI when Rb-82 PET data was added to a clinical risk model was 0.12 for women and 0.17 for men. Only 2 cardiac deaths were reported in women <55 years of age; accordingly the percentage of abnormal myocardium at stress was of borderline significance (p = 0.063), but it was highly significant for women ≥55 years of age (p < 0.0001), with an increased NRI of 0.21 (95% confidence interval: 0.09 to 0.34), including 17% of CAD deaths and 3.9% of CAD survivors that were correctly re-classified in this older female subset. CONCLUSIONS: Stress Rb-82 PET provides significant and clinically meaningful effective risk stratification of women and men, supporting this modality as an alternative to comparative imaging modalities. Rb-82 PET findings were particularly helpful at identifying high-risk, older women.

Identifying high-risk asymptomatic carotid stenosis.

INTRODUCTION: With more intensive medical therapy, the risk of stroke in patients with asymptomatic carotid stenosis (ACS) is now below the risk of carotid endarterectomy or stenting (intervention); ∼ 90% of patients would be better with only medical therapy. It is important, therefore, to have methods to identify the ∼ 10% of patients who stand to benefit from intervention. AREAS COVERED: We review the evidence that the risk of asymptomatic stenosis is now below the risk of intervention, and evidence for several approaches to identifying high-risk ACS: transcranial Doppler embolus detection, echolucency and neovascularity on ultrasound, ulceration on three-dimensional ultrasound, plaque composition on magnetic resonance imaging (MRI), plaque inflammation on positron emission tomography and assessment of cerebral blood flow reserve. EXPERT OPINION: Carotid endarterectomy or stenting should be performed only in patients with ACS if they have microemboli on transcranial Doppler, three or more ulcers detected on three-dimensional ultrasound or other features of unstable plaque such as plaque echolucency on ultrasound, intraplaque hemorrhage detected on MRI, inflamed plaques detected on PET/CT or reduced cerebral blood flow reserve. Most patients with ACS (∼ 90%) would be better off with intensive medical therapy than with intervention.

Greater response to cardiac resynchronization therapy in patients with true complete left bundle branch block: a PREDICT substudy.

AIMS: Cardiac resynchronization therapy (CRT) benefits patients with heart failure and a wide QRS complex. Still, one-third derive no clinical benefit and a majority of patients demonstrate no objective improvement of left ventricular (LV) function. Left bundle branch block (LBBB) is a strong predictor of response to CRT. We evaluated whether absence of electrocardiogram (ECG) markers of residual left bundle (LB) conduction in guideline-defined LBBB predicted a greater response to CRT. METHODS AND RESULTS: An r wave ≥1 mm in lead V1 (r-V1) and/or a q wave ≥1 mm in lead aVL (q-aVL) was used to identify patients with residual LB conduction. Forty patients with a wide QRS were prospectively enrolled and subdivided into three groups: complete LBBB (cLBBB), LBBB without r-V1 or q-aVL (n = 12); LBBB with residual LB conduction (rLBBB), LBBB with r-V1 and/or q-aVL (n = 15); and non-specific intraventricular conduction delay (IVCD), (n = 13). Following CRT: mean change in left ventricular ejection fraction was 11.9 ± 11.9% in cLBBB, 3.8 ± 5.4% in rLBBB (P= 0.045), and 2.5 ± 4.4% in IVCD (P= 0.02 cLBBB vs. IVCD); mean reduction in left ventricular end-systolic volume was 26.4 ± 39.2% in cLBBB, 14.3 ± 22.9% in rLBBB (P= 0.35), and 5.6 ± 17.3% in IVCD (P= 0.11 cLBBB vs. IVCD); mean change in native QRS duration was -8.0 ± 11.0 ms in cLBBB, -0.8 ± 8.24 ms in rLBBB (P= 0.07), and 0.15 ± 8.0 ms in IVCD (P= 0.048 cLBBB vs. IVCD). CONCLUSION: In patients with guideline-defined LBBB, the absence of ECG markers of residual LB conduction was predictive of a greater improvement in LV function with CRT.

Quantification of regional myocardial blood flow in a canine model of stunned and infarcted myocardium: comparison of rubidium-82 positron emission tomography with microspheres.

BACKGROUND: Myocardial viability and quantification of regional myocardial blood flow (MBF) are important for the diagnosis of heart disease. Positron emission tomography is the current gold standard for determining myocardial viability, but most positron-emitting perfusion tracers require an on-site cyclotron. Rubidium-82 ((82)Rb) is a myocardial perfusion tracer that is produced using an on-site generator. This study investigates (82)Rb-measured MBF in canine models of stunned and infarcted myocardium compared with selected measurements obtained concurrently using microspheres. METHODS: Myocardial stunning and infarction were created in canines by occluding the left anterior descending for 15 min and 2 h, respectively. Stunning was produced in all animals; six animals were reperfused after the 2 h occlusion, whereas the other six animals remained occluded permanently. Regional MBF was measured in each group during rest and dobutamine stress at acute and chronic (8 weeks postinsult) time points using dynamic (82)Rb perfusion imaging and radioactively labeled microspheres. RESULTS: Average resting MBF with microspheres and Rb was 0.68+/-0.02 versus 0.73+/-0.01 (P<0.001) in nonischemic tissue, and 0.53+/-0.03 versus 0.42+/-0.02 (P<0.001) in the region-at-risk tissue, respectively. Average MBF during stress with microspheres and Rb was 2.78+/-0.15 versus 3.53+/-0.16 (P<0.05) in the nonischemic tissue, and 1.90+/-0.20 versus 2.31+/-0.26 (P = NS) in the region-at-risk tissue, respectively. CONCLUSION: Despite the small significant differences, the dynamic (82)Rb measurements provide estimates of MBF in stunned and acutely and chronically infarcted tissue at rest and during hyperemia that correspond with clinical interpretation.

Concomitant treatment with oral L-arginine improves the efficacy of surgical angiogenesis in patients with severe diffuse coronary artery disease: the Endothelial Modulation in Angiogenic Therapy randomized controlled trial.

OBJECTIVE: Endothelial dysfunction and decreased nitric oxide bioavailability may explain why therapeutic angiogenesis and cell therapy have mostly failed in humans. Building from previous large animal work, the Phase I Endothelial Modulation in Angiogenic Therapy trial tested the hypothesis that L-arginine, a nitric oxide donor, may be safe and effective in potentiating surgical angiogenesis in humans. METHODS: Patients with surgical triple-vessel coronary disease and a severely diffusely diseased left anterior descending artery were randomized in 2 x 2 factorial fashion to receive ten 200-microg injections of vascular endothelial growth factor-165 plasmid DNA or placebo in the anterior myocardium along the proximal and mid-left anterior descending arteries, plus oral L-arginine supplementation at a dose of 6 g per day or placebo for 3 months. The distal left anterior descending artery and other coronary arteries were grafted. End points included 3-month changes in myocardial perfusion and contractility of the anterior myocardium, using (13)N-ammonia positron emission tomography and echocardiography. Baseline scans were obtained 3 to 7 days postoperatively to delineate treatment effects from the effects of coronary artery bypass grafting. RESULTS: Patient (N = 19) characteristics were equivalent between groups. There was no perioperative or late mortality. Patients who received the combination of vascular endothelial growth factor and L-arginine had improved anterior wall perfusion on positron emission tomography (P = .02), a trend toward smaller perfusion defects (P = .10), and better anterior wall contractility (P = .02, Kruskal-Wallis) at 3 months versus baseline. This was corroborated by a trend toward better disease perception at 3 months versus baseline on the Seattle Angina Questionnaire (score improvement of 47 +/- 35, combination treatment group; P = .1, Kruskal-Wallis). CONCLUSION: To our knowledge, this is the first study to examine concomitant substrate modification in patients undergoing new biosurgical therapies by using vascular endothelial growth factor angiogenesis. The results suggest safety and efficacy. Concomitant endothelial modulation with L-arginine not only has the potential to make angiogenesis effective but also may have implications for cell therapy trials.