Methods, design, and initial results of an angiographic core lab from VOYAGER-PAD.

Background: Anatomy is critical in risk stratification and therapeutic decision making in coronary disease. The relationship between anatomy and outcomes is not well described in PAD. We sought to develop an angiographic core lab within the VOYAGER-PAD trial. The current report describes the methods of creating this core lab, its study population, and baseline anatomic variables. Methods: Patients undergoing lower-extremity revascularization for symptomatic PAD were randomized in VOYAGER-PAD. The median follow up was 2.25 years. Events were adjudicated by a blinded Clinical Endpoint Committee. Angiograms were collected from study participants; those with available angiograms formed this core lab cohort. Angiograms were scored for anatomic and flow characteristics by trained reviewers blinded to treatment. Ten percent of angiograms were evaluated independently by two reviewers; inter-rater agreement was assessed. Clinical characteristics and the treatment effect of rivaroxaban were compared between the core lab cohort and noncore lab participants. Anatomic data by segment were analyzed. Results: Of 6564 participants randomized in VOYAGER-PAD, catheter-based angiograms from 1666 patients were obtained for this core lab. Anatomic and flow characteristics were collected across 16 anatomic segments by 15 reviewers. Concordance between reviewers for anatomic and flow variables across segments was 90.5% (24,417/26,968). Clinical characteristics were similar between patients in the core lab and those not included. The effect of rivaroxaban on the primary efficacy and safety outcomes was also similar. Conclusions: The VOYAGER-PAD angiographic core lab provides an opportunity to correlate PAD anatomy with independently adjudicated outcomes and provide insights into therapy for PAD. (ClinicalTrials.gov Identifier: NCT02504216).

Longitudinal Abnormalities in White Matter Extracellular Free Water Volume Fraction and Neuropsychological Functioning in Patients with Traumatic Brain Injury.

Traumatic brain injury is a global public health problem associated with chronic neurological complications and long-term disability. Biomarkers that map onto the underlying brain pathology driving these complications are urgently needed to identify individuals at risk for poor recovery and to inform design of clinical trials of neuroprotective therapies. Neuroinflammation and neurodegeneration are two endophenotypes potentially associated with increases in brain extracellular water content, but the nature of extracellular free water abnormalities after neurotrauma and its relationship to measures typically thought to reflect traumatic axonal injury are not well characterized. The objective of this study was to describe the relationship between a neuroimaging biomarker of extracellular free water content and the clinical features of a cohort with primarily complicated mild traumatic brain injury. We analyzed a cohort of 59 adult patients requiring hospitalization for non-penetrating traumatic brain injury of all severities as well as 36 healthy controls. Patients underwent brain magnetic resonance imaging (MRI) at 2 weeks (n = 59) and 6 months (n = 29) post-injury, and controls underwent a single MRI. Of the participants with TBI, 50 underwent clinical neuropsychological assessment at 2 weeks and 28 at 6 months. For each subject, we derived a summary score representing deviations in whole brain white matter extracellular free water volume fraction (VF) and free water-corrected fractional anisotropy (fw-FA). The summary specific anomaly score (SAS) for VF was significantly higher in TBI patients at 2 weeks and 6 months post-injury relative to controls. SAS for VF exhibited moderate correlation with neuropsychological functioning, particularly on measures of executive function. These findings indicate abnormalities in whole brain white matter extracellular water fraction in patients with TBI and are an important step toward identifying and validating noninvasive biomarkers that map onto the pathology driving disability after TBI.

Dynamic contrast enhanced MRI for characterization of blood-brain-barrier dysfunction after traumatic brain injury.

BACKGROUND AND PURPOSE: Dysfunction of the blood-brain-barrier (BBB) is a recognized pathological consequence of traumatic brain injury (TBI) which may play an important role in chronic TBI pathophysiology. We hypothesized that BBB disruption can be detected with dynamic contrast-enhanced (DCE) MRI not only in association with focal traumatic lesions but also in normal-appearing brain tissue of TBI patients, reflecting microscopic microvascular injury. We further hypothesized that BBB integrity would improve but not completely normalize months after TBI. MATERIALS AND METHODS: DCE MRI was performed in 40 adult patients a median of 23 days after hospitalized TBI and in 21 healthy controls. DCE data was analyzed using Patlak and linear models, and derived metrics of BBB leakage including the volume transfer constant (Ktrans) and the normalized permeability index (NPI) were compared between groups. BBB metrics were compared with focal lesion distribution as well as with contemporaneous measures of symptomatology and cognitive function in TBI patients. Finally, BBB metrics were examined longitudinally among 18 TBI patients who returned for a second MRI a median of 204 days postinjury. RESULTS: TBI patients exhibited higher mean Ktrans (p = 0.0028) and proportion of suprathreshold NPI voxels (p = 0.001) relative to controls. Tissue-based analysis confirmed greatest TBI-related BBB disruption in association with focal lesions, however elevated Ktrans was also observed in perilesional (p = 0.011) and nonlesional (p = 0.044) regions. BBB disruption showed inverse correlation with quality of life (rho = -0.51, corrected p = 0.016). Among the subset of TBI patients who underwent a second MRI several months after the initial evaluation, metrics of BBB disruption did not differ significantly at the group level, though variable longitudinal changes were observed at the individual subject level. CONCLUSIONS: This pilot investigation suggests that TBI-related BBB disruption is detectable in the early post-injury period in association with focal and diffuse brain injury.

Impact of advanced imaging techniques on preoperative planning in cardiac surgery.

BACKGROUND AND AIM OF THE STUDY: Review how advanced imaging techniques and a multidisciplinary heart team approach are used to evaluate complex cardiac structural pathology. METHODS: Single-center retrospective case series. RESULTS AND CONCLUSIONS: Cardiac computed tomography angiography in addition to transthoracic and transesophageal echocardiography impacts pre-procedural planning and procedural success.

Vorapaxar for Prevention of Major Adverse Cardiovascular and Limb Events in Peripheral Artery Disease.

Peripheral artery disease (PAD) is a severe manifestation of atherosclerosis. Patients with PAD are at heightened risk for atherothrombotic complications, including myocardial infarction and stroke (MACE); however, there is also an equal or greater risk of major adverse limb events (MALE), such as acute limb ischemia (ALI) and major amputation. Therefore, there is a need for effective medical therapies to reduce the risk of both MACE and MALE. Recent trials have demonstrated the role of thrombin inhibition in reducing the risk of MACE and MALE in PAD patients. One such medical therapy, vorapaxar, is a potent inhibitor of protease activated receptor-1 which mediates the cellular effects of thrombin. Vorapaxar, used in addition to aspirin, has demonstrated robust reductions in MACE and MALE in PAD patients. In this article, we provide a contemporary review of the current state of PAD and the role of antithrombotic medications in the treatment of PAD, as well as the current clinical data on vorapaxar and strategies to integrate vorapaxar into contemporary medical management of peripheral artery disease.

Arterial Spin Labeling Reveals Elevated Cerebral Blood Flow with Distinct Clusters of Hypo- and Hyperperfusion after Traumatic Brain Injury.

Imaging detection of brain perfusion alterations after traumatic brain injury (TBI) may provide prognostic insights. In this study, we used arterial spin labeling (ASL) to quantify cross-sectional and longitudinal changes in cerebral blood flow (CBF) after TBI and correlated changes with clinical outcome. We analyzed magnetic resonance imaging scans from adult participants with TBI requiring hospitalization in the acute (2 weeks post-injury, n = 33) and chronic (6 months post-injury, n = 16) phases, with 13 participants scanned longitudinally at both time points. We also analyzed 18 age- and sex-matched healthy controls. Whole-brain CBF maps were derived using a three-dimensional pseudo-continuous arterial spin label technique. Mean CBF across tissue-based regions (whole brain, gray matter, and white matter) was compared cross-sectionally and longitudinally. In addition, individual-level clusters of abnormal perfusion were identified using voxel-based z-score analysis of relative CBF maps, and number and volume of abnormally hypo- and hyperperfused clusters were assessed cross-sectionally and longitudinally. Finally, all CBF measures were correlated with clinical outcome measures. Mean global and gray matter CBF were significantly elevated in acute and chronic TBI participants compared to controls. Participants with better outcome at 6 months post-injury tended to have higher CBF in the acute phase compared to those with poorer outcome. Acute TBI participants had a significantly greater volume of hypo- and hyperperfused brain tissue compared to controls, with these regions partially normalizing by the chronic phase. Our findings demonstrate global elevation of CBF with focal hypo- and hyperperfusion in the early post-injury period and suggest a reparative role for acute elevation in CBF post-TBI.

Medical Therapy for Secondary Prevention of Atherothrombotic Events in Peripheral Artery Disease.

Patients with peripheral artery disease (PAD) are at risk for severe morbidity and mortality, including ischaemic-related events. Furthermore, there is heterogeneity within the PAD population, where the drivers of risk for cardiovascular and limb-specific ischaemic events differ. Patients with PAD with concomitant coronary artery disease are at increased risk for cardiovascular ischaemic events, whereas patients with PAD with a prior history of lower-extremity revascularization are at increased risk for limb-specific ischaemic events. The current therapeutic challenge is identifying these risk factors to tailor therapy optimally for each patient. Additionally, the majority of our current medical therapeutics in patients with PAD have been shown to reduce atherothrombotic events, such as myocardial infarction, stroke and cardiovascular death, with a paucity of medical therapeutics specifically targeting a reduction in limb-specific ischaemic events. Over the past several years, there have been several contemporary clinical trials evaluating antithrombotic agents and their efficacy in reducing limb-specific ischaemic events. Specifically, rivaroxaban, with the addition of aspirin, has emerged as an efficacious therapeutic. In this article, we provide a review of the current clinical burden of PAD, the rationale behind current PAD medical therapeutics and the contemporary trials that have described the benefit of a novel therapeutic in PAD, rivaroxaban.

Assessment of foot perfusion: Overview of modalities, review of evidence, and identification of evidence gaps.

Patients with critical limb ischemia have nonhealing wounds and/or ischemic rest pain and are at high risk for amputation and mortality. Accurate evaluation of foot perfusion should help avoid unnecessary amputation, guide revascularization strategies, and offer efficient surveillance for patency. Our aim is to review current modalities of assessing foot perfusion in the context of the practical clinical management of patients with critical limb ischemia.

Contemporary Use and Outcomes of Arterial Closure Devices After Percutaneous Coronary Intervention: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program.

Background Arterial closure devices reduce the length of bedrest after invasive cardiac procedures via the femoral approach, but there are conflicting data on their association with major bleeding and vascular complications. We thus sought to evaluate the contemporary use of femoral arterial closure devices and their association with major bleeding among patients undergoing percutaneous coronary intervention. Methods and Results We identified patients undergoing percutaneous intervention via the femoral approach within the Veterans Affairs Healthcare System from December 2004 through September 2018. The association between arterial closure device use and major bleeding was evaluated using both propensity matching and instrumental variable analyses, incorporating contrast-induced nephropathy as a falsification end point. We identified 132 373 percutaneous coronary interventions performed by 681 operators, with closure device use increasing 1.2% each year (linear trend P<0.001). In a propensity-matched cohort, closure devices were associated with a 1.1% reduction in periprocedural bleeding (95% CI, -1.5% to -0.6%). Closure devices were also associated with a numerical decrease in contrast-inducted nephropathy that did not reach statistical significance (-0.6%; 95% CI, -1.3% to 0.1%). In an instrumental variable analysis of closure device use, there was no difference in the bleeding rate between those who received a closure device and those who did not (0.2%; 95% CI, -0.9% to 1.2%). Conclusions Arterial closure devices are associated with a reduction in major bleeding within a propensity-matched cohort. This association dissipates in an instrumental variable analysis, highlighting some of the methodologic limitations of comparative effectiveness research in observational analyses.

Perceptions of Public and Nonpublic Reporting of Interventional Cardiology Outcomes and Its Impact on Practice: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program.

Background Physicians have expressed significant mistrust with public reporting of interventional cardiology outcomes. Similar data are not available on alternative reporting structures, including nonpublic quality improvement programs with internally distributed measures of interventional quality. We thus sought to evaluate the perceptions of public and nonpublic reporting of interventional cardiology outcomes and its impact on clinical practice. Methods and Results A standardized survey was distributed to 218 interventional cardiologists in the Veterans Affairs Healthcare System, with responses received from 62 (28%). The majority of respondents (90%) expressed some or a great deal of trust in the analytic methods used to generate reports in a nonpublic quality improvement system within Veterans Affairs, while a minority (35%) expressed similar trust in the analytic methods in a public reporting system that operates outside Veterans Affairs (P<0.001). Similarly, a minority of respondents (44%) felt that in-hospital and 30-day mortality accurately reflected interventional quality in a nonpublic quality improvement system, though a smaller proportion of survey participants (15%) felt that the same outcome reflected procedural quality in public reporting systems (P<0.001). Despite these sentiments, the majority of operators did not feel pressured to avoid (82% and 75%; P=0.383) or perform (72% and 63%; P=0.096) high-risk procedures within or outside Veterans Affairs. Conclusions Interventional cardiologists express greater trust in analytic methods and clinical outcomes reported in a nonpublic quality improvement program than external public reporting environments. The majority of physicians did not feel pressured to avoid or perform high-risk procedures, which may improve access to interventional care among high-risk patients.

The effects of HIV and smoking on aortic and splenic inflammation.

OBJECTIVE: To determine the association of smoking and HIV status with tissue-specific inflammation measured by flurodeoxyglucose positron emission tomography (PET). DESIGN: A cross-sectional study. METHODS: We prospectively enrolled 55 HIV study participants on stable antiretroviral therapy and 19 age-matched HIV-uninfected controls without known cardiovascular disease. We measured aortic target-to-background ratio (TBR) and spleen standardized uptake values (SUV) 3-h post-FDG, and used regression models to examine the independent association of HIV and smoking status with PET variables. RESULTS: Overall, median (interquartile range) age was 50 (42-55) years; 81% were men and 54% were current smokers (median 0.5 packs/day, 25 pack-years]. Median CD4 of HIV study participants was 690 cells/ml and 88% had HIV-1 RNA less than 20 c/ml; 43% were on a protease inhibitor. In fully adjusted models, HIV was associated with 0.16 (95% confidence interval 0.04-0.27; P = 0.009) higher aortic TBR, whereas current smoking was marginally associated with a lower TBR [-0.11 (95% confidence interval -0.23 to 0.01); P = 0.07]. Spleen SUVmean was not associated with HIV or smoking, and there was no evidence for an HIVsmoking interaction for aortic or spleen models (all P > 0.1). Spleen SUVmean was positively associated with biomarkers of inflammation and coronary artery calcium, but adjustment for traditional cardiovascular disease risk factors attenuated these relationships. CONCLUSION: The FDG-PET study of HIV study participants suggests that HIV is associated with increased aortic inflammation independent of traditional risk factors, but smoking is not. Future studies should continue to explore the mechanistic roles of smoking and inflammation at various stages of clinical and subclinical atherosclerotic vascular disease in HIV.

Effectiveness of Early Invasive Therapy for Atrial Tachycardia in Adult Atrial-Baffle Survivors.

Adults who underwent complex atrial baffling as children via Mustard or Senning procedures are at heightened risk for atrial arrhythmias. Antiarrhythmic therapies are typically ineffective in this population. Accordingly, our team of pediatric and adult electrophysiologists investigated the effectiveness of early invasive transbaffle-access techniques to perform early radiofrequency ablation at the source of these clinically significant arrhythmias. For this retrospective study, we selected 11 adult survivors of atrial baffling (mean age, 34 ± 9 yr) who underwent clinically indicated electrophysiologic study after no more than one trial of antiarrhythmic therapy. Using transbaffle-access techniques and 3-dimensional mapping of the venous atria, we found 12 inducible arrhythmias in 10 patients: intra-atrial reentrant tachycardia (n=6), atrioventricular nodal reentrant tachycardia (n=3), focal atrial tachycardia (n=2), and repetitive double firing of the atrioventricular node (n=1). Defining success as short- and midterm freedom from arrhythmia, we analyzed outcomes of radiofrequency ablation at 1 and 6 months. At 1 month, ablation was 100% successful. At 6 months, after 11 ablations in 9 patients, 5 patients had no clinical recurrence, 2 had improved arrhythmia control from minimal medical therapy, and 2 were to undergo repeat study for recurrent tachycardia. In the recurrence-free patients, arrhythmias during electrophysiology study matched the types found clinically before the study. To our knowledge, this is the largest one-year cohort of adult survivors of atrial baffling to have undergone study by a combined pediatric-adult electrophysiology team. We conclude that early invasive transbaffle access for ablating diverse atrial tachyarrhythmias was effective in these patients.

Effect of rosuvastatin on plasma coenzyme Q10 in HIV-infected individuals on antiretroviral therapy.

BACKGROUND: Coenzyme Q10 (CoQ10) deficiency has been associated with statin-induced myopathy, and supplementation with CoQ10 may reduce inflammation markers. The effects of statins on CoQ10 and its anti-inflammatory properties have not been investigated in HIV-positive patients. OBJECTIVE: The objectives of this study were to examine the effect of rosuvastatin on CoQ10 and CoQ10/LDL ratio over 24-week SATURN-HIV trial, explore the associations between CoQ10 levels and markers of vascular disease, inflammation, and immune activation, and assess whether changes in CoQ10 affected the anti-inflammatory effects of statin therapy or were associated with myalgia symptoms. METHODS: This was a secondary analysis of the SATURN-HIV trial, a 96-week randomized clinical trial of 10 mg daily rosuvastatin vs. placebo in HIV-infected patients on antiretroviral therapy. We assessed the statin treatment effect on CoQ10 levels and CoQ10/LDL ratios and whether changes in these markers were related to myalgias. Relationships between CoQ10, subclinical vascular disease, and biomarkers of inflammation and immune activation were explored using Spearman correlations and multivariable regression models. RESULTS: Overall, 147 patients were included. Median age was 46 years; 78% were male and 68% African American. At baseline, CoQ10 levels and CoQ10/LDL ratio were modestly correlated with markers of HIV disease, immune activation, and carotid distensibility. After 24 weeks of statin therapy, CoQ10 levels decreased (p = 0.002 for between group difference) and CoQ10/LDL ratio increased (p = 0.036). In the statin treatment arm, we did not find evidence of a relationship between changes in CoQ10 or CoQ10/LDL ration and changes in markers of inflammation or immune activation. There was a borderline statistically significant association between changes in CoQ10 and myalgia symptoms [OR 4.0 per 0.1 mg/L decrease in CoQ10, p = 0.07]. CONCLUSION: Twenty-four weeks of 10 mg daily rosuvastatin decreases CoQ10 concentration and increases CoQ10/LDL ratio in HIV-infected patients on antiretroviral therapy.