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Context.— There are no consensus guidelines on submission of pelvic lymph node dissection (PLND) specimens for radical prostatectomies. Complete submission is only performed by a minority of laboratories. Our institution has been following this practice for standard and extended-template PLND. Objective.— To investigate the utility of total submission of PLND specimens for prostate cancer and understand its impact on patients and the laboratory. Design.— Retrospective study examining 733 cases of radical prostatectomies with PLND performed at our institution. Reports and slides with positive lymph nodes (LNs) were reviewed. Data on LN yield, cassette usage, and impact of submission of remaining fat after dissection of grossly identifiable LNs were assessed. Results.— Most cases involved submission of extra cassettes for remaining fat (97.5%, n = 697 of 715). Extended PLND yielded a higher mean number of total and positive LNs versus standard PLND (P < .001). However, they required significantly more cassettes for remaining fat (mean, 8; range, 0–44). There was poor correlation between number of cassettes submitted for PLND with total and positive LN yield and between remaining fat with LN yield. Most positive LNs were grossly identified (88.5%, n = 139 of 157) and were typically larger than those not. Only 4 cases (0.6%, n = 4 of 697) would have been understaged without complete submission of PLND. Conclusions.— Total submission of PLND increases detection of metastasis and LN yield yet increases workload significantly with only minimal patient management impact. Hence, we recommend that meticulous gross identification and submission of all LNs be pursued without the need to submit the remaining fat of PLND.

Background Posttraumatic Stress Disorder (PTSD) is prevalent among patients who survived an acute coronary syndrome, and is associated with adverse outcomes, but the mechanisms underlying these associations are unclear. Individuals with PTSD have enhanced sensitivity of the noradrenergic system to stress which may lead to immune activation. We hypothesized that survivors of a myocardial infarction (MI) who have PTSD would show an enhanced inflammatory response to acute psychological stress compared to those without PTSD. Methods Individuals with a verified history of MI within 8 months and a clinical diagnosis of current PTSD underwent a mental stress speech task. Inflammatory biomarkers including interleukin-6 (IL-6), high-sensitivity C reactive protein (HsCRP), matrix metallopeptidase 9 (MMP-9), intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and monocyte chemoattractant protein (MCP)-1 were measured at rest and 90 min after mental stress. Results Among 271 patients in the study (mean age 51 ± 7 years, 50% female, 60% African-American), the prevalence of PTSD was 12%. Mental stress resulted in a significant increase in IL-6, but the increase was more marked in patients with PTSD (126% increase) than those without (63% increase) (p = 0.001). MCP-1 showed a modest increase with stress which was similar in patients with PTSD (9% increase) and without PTSD (6% increase) (p = 0.35). CRP did not increase with stress in either group. Conclusion MI patients with current PTSD exhibit enhanced IL-6 response to psychosocial stress, suggesting a mechanistic link between PTSD and adverse cardiovascular outcomes as well as other diseases associated with inflammation.

Background Programmed death receptor and programmed death ligand (PD-L1) are immunoregulatory proteins. Nonsmall cell lung cancer bypasses the immune system through the induction of protumorigenic immunosuppressive changes. The better understanding of immunology and antitumor immune responses has brought the promising development of novel immunotherapy agents like programmed death receptor checkpoint inhibitors. The aim of this study was to investigate the expression of PD-L1 in lung adenocarcinoma (ADC), comparing 2 different technologies: immunohistochemistry (IHC) by 2 methods versus RNA in situ hybridization (RISH). Methodology In total, 20 cases of ADC of the lung and 4 samples of metastatic colon ADC were selected. Evaluation of PD-L1 expression was performed by IHC and RISH. RISH was performed using RNAscope. Both methods were scored in tumor cells and quantified using combined intensity and proportion scores. Results Eight of 20 (40%) lung ADC and 2 of 4 (50%) colon ADC were positive for PD-L1 with Cell Signaling IHC, and 65% lung ADC were positive by Dako IHC (13/20). All 4 cases of colon ADC were negative. When evaluated by RISH, 12 lung ADC (60%) and 1 colon ADC (25%) were PD-L1 positive. Conclusions RNAscope probes provide sensitive and specific detection of PD-L1 in lung ADC. Both IHC methods (Cell Signaling and Dako) show PD-L1 expression, with the Dako method more sensitive (40% vs. 65%). This study illustrates the utility of RISH and Cell Signaling IHC as complementary diagnostic tests, and Food and Drug Administration approved Dako IHC as a companion diagnostic test.

Rationale: Blacks compared with whites have a greater risk of adverse cardiovascular outcomes. Impaired regenerative capacity, measured as lower levels of circulating progenitor cells (CPCs), is a novel determinant of adverse outcomes; however, little is known about racial differences in CPCs. Objective: To investigate the number of CPCs, PC-mobilizing factors, PC mobilization during acute myocardial infarction and the predictive value of CPC counts in blacks compared with whites. Methods and Results: CPCs were enumerated by flow cytometry as CD45med + blood mononuclear cells expressing CD34+, CD133+, VEGF2R+, and CXCR4+ epitopes in 1747 subjects, mean age 58.4±13, 55% male, and 26% self-reported black. Patients presenting with acute myocardial infarction (n=91) were analyzed separately. Models were adjusted for relevant clinical variables. SDF-1α (stromal cell-derived factor-1α), VEGF (vascular endothelial growth factor), and MMP-9 (matrix metallopeptidase-9) levels were measured (n=561), and 623 patients were followed for median of 2.2 years for survival analysis. Blacks were younger, more often female, with a higher burden of cardiovascular risk, and lower CPC counts. Blacks had fewer CD34+ cells (−17.6%; [95% confidence interval (CI), −23.5% to −11.3%]; P P P P =0.04) compared with whites. The association between lower CPC counts and black race was not affected by risk factors or cardiovascular disease. Results were validated in a separate cohort of 411 patients. Blacks with acute myocardial infarction had significantly fewer CPCs compared with whites ( P =0.02). Blacks had significantly lower plasma MMP-9 levels ( P P =0.03) and whites (hazard ratio, 1.79; [95% CI, 1.09–2.94]; P =0.02) without significant interaction. Conclusions: Black subjects have lower levels of CPCs compared with whites which is partially dependent on lower circulating MMP-9 levels. Impaired regenerative capacity is predictive of adverse outcomes in blacks and may partly account for their increased risk of cardiovascular events.

Rationale: Circulating progenitor cells (CPCs) mobilize in response to ischemic injury, but their predictive value remains unknown in acute coronary syndrome (ACS). Objective: We aimed to investigate the number of CPCs in ACS compared with those with stable coronary artery disease (CAD), relationship between bone marrow PCs and CPCs, and whether CPC counts predict mortality in patients with ACS. Methods and Results: In 2028 patients, 346 had unstable angina, 183 had an acute myocardial infarction (AMI), and the remaining 1499 patients had stable CAD. Patients with ACS were followed for the primary end point of all-cause death. CPCs were enumerated by flow cytometry as mononuclear cells expressing a combination of CD34+, CD133+, vascular endothelial growth factor receptor 2+, or chemokine (C-X-C motif) receptor 4+. CPC counts were higher in subjects with AMI compared those with stable CAD even after adjustment for age, sex, race, body mass index, renal function, hypertension, diabetes mellitus, hyperlipidemia, and smoking; CD34+, CD34+/CD133+, CD34+/CXCR4+, and CD34+/VEGFR2+ CPC counts were 19%, 25%, 28%, and 142% higher in those with AMI, respectively, compared with stable CAD. There were strong correlations between the concentrations of CPCs and the PC counts in bone marrow aspirates in 20 patients with AMI. During a 2 (interquartile range, 1.31–2.86)-year follow-up period of 529 patients with ACS, 12.4% died. In Cox regression models adjusted for age, sex, body mass index, heart failure history, estimated glomerular filtration rate, and AMI, subjects with low CD34+ cell counts had a 2.46-fold (95% confidence interval, 1.18–5.13) increase in all-cause mortality, P =0.01. CD34+/CD133+ and CD34+/CXCR4+, but not CD34+/VEGFR2+ PC counts, had similar associations with mortality. Results were validated in a separate cohort of 238 patients with ACS. Conclusions: CPC levels are significantly higher in patients after an AMI compared with those with stable CAD and reflect bone marrow PC content. Among patients with ACS, a lower number of hematopoietic-enriched CPCs are associated with a higher mortality.

Circulating soluble urokinase plasminogen activator receptor (suPAR) is a marker of immune activation associated with atherosclerosis. Whether suPAR levels are associated with prevalent peripheral arterial disease (PAD) and its adverse outcomes remains unknown and is the aim of the study.SuPAR levels were measured in 5810 patients (mean age 63 years, 63% male, 77% with obstructive coronary artery disease [CAD]) undergoing cardiac catheterization. The presence of PAD (n = 967, 17%) was classified as carotid (36%), lower/upper extremities (30%), aortic (15%) and multisite disease (19%). Multivariable logistic and Cox regression models were used to determine independent predictors of prevalent PAD and outcomes including all-cause death, cardiovascular death and PAD-related events after adjustment for age, gender, race, body mass index, smoking, diabetes, hypertension, hyperlipidemia, renal function, heart failure history, and obstructive CAD.Plasma suPAR levels were 22.5% (p 0.001) higher in patients with PAD compared to those without PAD. Plasma suPAR was higher in patients with more extensive PAD (≥2 compared to single site) p 0.001. After multivariable adjustment, suPAR was associated with prevalent PAD; odds ratio (OR) for highest compared to lowest tertile of 2.0, 95% CI (1.6-2.5) p 0.001. In Cox survival analyses adjusted for clinical characteristics and medication regimen, suPAR (in the highest vs. lowest tertile) remained an independent predictor of all-cause death [HR 3.1, 95% CI (1.9-5.3)], cardiovascular death [HR 3.5, 95% CI (1.8-7.0)] and PAD-related events [HR = 1.8, 95% CI (1.3-2.6) p 0.001 for all].Plasma suPAR level is predictive of prevalent PAD and of incident cardiovascular and PAD-related events. Whether SuPAR measurement can help screen, risk stratify, or monitor therapeutic responses in PAD requires further investigation.

Background Acute stress may trigger atrial fibrillation (AF), but the underlying mechanisms are unclear. We examined if acute mental stress results in abnormal left atrial electrophysiology as detected by more negative deflection of P-wave terminal force in lead V1 (PTFV1), a well-known marker of AF risk. Methods and results We examined this hypothesis in 422 patients (mean age = 56±10 years; 61% men; 44% white) with stable coronary heart disease who underwent mental (speech task) stress testing. PTFV1 was defined as the duration (ms) times the value of the depth (μV) of the downward deflection (terminal portion) of the P-wave in lead V1 measured on digital electrocardiograms (ECG). Electrocardiographic left atrial abnormality was defined PTFV1 ≤ -4000 μV*ms. Mean PTFV1 values during stress and recovery were compared with rest. The percentage of participants who developed left atrial abnormality during stress and recovery was compared with the percentage at rest. Compared with rest, PTFV1 became more negative during mental stress [mean change = -348, 95%CI = (-515, -182); P

Introduction: The association between restless leg syndrome (RLS) and CV outcomes remains controversial in the general population, and the impact of RLS among patients with coronary artery disease (CAD) is unknown. Hypothesis: We examined our hypothesis that RLS symptoms would be associated with incident adverse CV outcomes in patients with CAD. Methods: We inquired about the presence and frequency of RLS symptoms in 3,176 patients enrolled in the Emory Cardiovascular Biobank (mean age 64, 62% male, 23% Black, and 75% with obstructive CAD), who were prospectively followed for death, myocardial infarction (MI), revascularization, and hospitalization for heart failure (HF). Multivariate Cox proportional hazard models were used to examine the association between RLS symptoms and adverse outcomes after adjustment for demographic and clinical risk factors. Results: Of the total, 914 (28.8%) and 482 (15.2%) patients reported mild (rare or sometimes) and moderate/severe (often to almost always) symptoms of RLS, respectively. Female sex (Odds ratio [OR] 2.11, P Conclusions: Among patients undergoing cardiac catheterization, moderate or severe symptoms of RLS are associated with significantly higher risk of adverse CV outcomes, independent of traditional risk factors. This is the first study to demonstrate an independent adverse impact of RLS symptoms in CAD patients.

Background Young women with coronary artery disease ( CAD ), a group with high psychosocial burden, were previously shown to have higher levels of interleukin‐6 ( IL ‐6) compared with men of similar age. We sought to examine IL ‐6 response to acute stress in CAD patients across sex and age, and contrast results to healthy controls and other biomarkers known to increase with mental stress (monocyte chemoattractant protein‐1 and matrix metallopeptidase‐9) and known limited stress‐reactivity (high‐sensitivity C‐reactive protein). Methods and Results Inflammatory biomarkers were measured at rest and 90 minutes after mental stress (speech task) among 819 patients with CAD and 89 healthy controls. Repeated‐measures models were used to investigate age (continuous) and sex differences across time, before and after adjusting for demographics, CAD risk factors, depressive symptoms, medication use, and CAD severity. Among patients with CAD , the mean age was 60 years (range, 25–79) and 31% were women. Younger women with CAD had significantly higher concentrations of IL ‐6 at rest, 90 minutes after mental stress, as well as a higher response to stress, compared with similarly aged men ( P IL ‐6 increased with age, and there were no sex differences in IL ‐6 levels or response to stress among controls. Inflammatory responses to stress for high‐sensitivity C‐reactive protein, monocyte chemoattractant protein‐1, and matrix metallopeptidase‐9 among CAD patients were similar in women and men. Conclusions IL ‐6 response to mental stress are higher in young women with CAD than men of similar age.

Extremes in sleep duration are associated with higher cardiovascular risk in the general population, but their impact in patients with documented coronary artery disease (CAD) remains unknown and potentially of clinical significance. We hypothesized that both short and long sleep duration are associated with higher mortality in CAD. We inquired about sleep durations in 2,846 patients enrolled in the Emory Cardiovascular Biobank (mean age 64 years, 38% female, 23% Black, and 82% with obstructive CAD, defined by positive coronary angiography), who were then followed for all-cause and cardiovascular mortality. Multivariate Cox proportional hazard models were calculated to examine the association of sleep duration and mortality. Sleep durations of6.5 hours (short), ≥6.5 to7.5 hours (normal), and ≥7.5 hours (long) were reported by 39%, 26% and 35% of the cohort, respectively. On follow-up (median 2.8 years), mortality rates were 15%, 11%, and 17%, respectively. After adjusting for demographics and risk factors, both short and long sleep duration were associated with higher all-cause mortality (hazard ratio 1.44, 95% confidence interval [1.10 to 1.89], and 1.41 [1.08 to 1.85], respectively). A similar pattern was demonstrated for cardiovascular mortality only for short (hazard ratio 1.48 [1.05 to 2.09]), but not long sleep duration. In conclusion, in patients with frank CAD, both short and long sleep duration were independently associated with higher all-cause mortality, and short sleep was independently associated with higher cardiovascular mortality. In conclusion, our study is the first to extend the observations of sleep duration and mortality from population-based studies to patients with documented cardiac disease.

Background: Exposure to psychological stress has been associated with the development of sustained arrhythmias. Acute changes in atrial electrophysiology may serve as intermediate phenotypes for stress-induced arrhythmia. The relationship between atrial electrical changes and stress related changes in heart rate and myocardial ischemia is unknown. We sought to study the effect of altered atrial electrophysiology and stress related rise in HR and myocardial ischemia in females and males. Methods: We examined if acute mental stress was associated with abnormal P-wave axis development in 359 patients (mean age=56 ± 9.9 years; 62% men; 43% white) with stable coronary heart disease and normal baseline P-wave axis (between 0° and 75°) who underwent mental stress testing (speech task). We computed the percentage of patients who had abnormal P-wave axis during stress and recovery. Sex-stratified analyses were performed. A multivariable logistic regression model was used to determine if mental stress ischemia independent predictors of abnormal P-wave axis development. Results: A total of 46 (13%) patients developed abnormal P-wave axis during either stress or recovery (stress: n=43, 12%; recovery: n=12, 3%). A rise in heart rate during mental stress was associated with an increased risk of abnormal P-wave axis development (per 5-unit increase: OR=1.37, 95%CI=1.03, 1.30). Mental stress-induced myocardial ischemia was associated with increased risk of abnormal P-wave axis in women (OR=5.2, 95%CI=1.7, 15.6) and not in men (OR=0.1, 95%CI=0.01, 1.01), p-interaction=0.004). Interactions were not detected for other characteristics. Conclusion: Acute mental stress results in the development of abnormal P-wave axis, and this phenomenon is related to increases in heart rate and, among women, mental stress-induced ischemia. Our data suggest that acute psychological stress can promote adverse transient electrical changes in the atria.

Low diastolic blood pressure (DBP) is associated with increased risk of cardiovascular events. In patients with coronary artery disease (CAD), limitations in coronary blood flow and immune activity are implicated mechanisms, but evidence is lacking. We investigated the association between DBP, biomarkers of myocardial injury, inflammation, immune activation and incident events in patients with CAD.We studied 2448 adults (mean age 65 ± 12 years, 68% male, median follow-up 4.5 years) with CAD. DBP was categorized into 10 mm Hg increments. Biomarkers of myocardial injury (high sensitivity cardiac troponin-I [hs-cTnI]) and immune activity/inflammation (soluble urokinase plasminogen activator receptor [suPAR]) were dichotomized at their median values. DBP 70-79 mm Hg was used as the referent group, and individuals were followed prospectively for adverse outcomes.After adjusting for demographic and clinical covariates, individuals with DBP 60 mm Hg had increased odds of elevated levels of hs-cTnI (OR = 1.68; 95% CI = 1.07, 2.65) and suPAR (OR = 1.71; 95% CI = 1.10, 2.65) compared to the referent group. Additionally, DBP 60 mm Hg was associated with increased adjusted risk of cardiovascular death or MI (HR = 2.04; 95% CI = 1.32, 3.16) and all-cause mortality (HR = 2.41; 95% CI = 1.69, 3.45).In patients with CAD, DBP 60 mm Hg is associated with subclinical myocardial injury, immune/inflammatory dysregulation and incident events. Aggressive BP control may be harmful in these patients, and further investigation is warranted to determine appropriate BP targets in patients with CAD.

Background The associations between high‐sensitivity troponin I (hsTnI) levels and coronary artery disease (CAD) severity and progression remain unclear. We investigated whether there is an association between hsTnI and angiographic severity and progression of CAD and whether the predictive value of hsTnI level for incident cardiovascular outcomes is independent of CAD severity. Methods and Results In 3087 patients (aged 63±12 years, 64% men) undergoing cardiac catheterization without evidence of acute myocardial infarction, the severity of CAD was calculated by the number of major coronary arteries with ≥50% stenosis and the Gensini score. CAD progression was assessed in a subset of 717 patients who had undergone ≥2 coronary angiograms >3 months before enrollment. Patients were followed up for incident all‐cause mortality and incident cardiovascular events. Of the total population, 11% had normal angiograms, 23% had nonobstructive CAD , 20% had 1‐vessel CAD, 20% had 2‐vessel CAD, and 26% had 3‐vessel CAD . After adjusting for age, sex, race, body mass index, smoking, hypertension, diabetes mellitus history, and renal function, hsTnI levels were independently associated with the severity of CAD measured by the Gensini score (log 2 ß=0.31; 95% confidence interval, 0.18–0.44; P CAD progression (log 2 ß=0.36; 95% confidence interval, 0.14–0.58; P =0.001). hsTnI level was also a significant predictor of incident death, cardiovascular death, myocardial infarction, revascularization, and cardiac hospitalizations, independent of the aforementioned covariates and CAD severity. Conclusions Higher hsTnI levels are associated with the underlying burden of coronary atherosclerosis, more rapid progression of CAD , and higher risk of all‐cause mortality and incident cardiovascular events. Whether more aggressive treatment aimed at reducing hsTnI levels can modulate disease progression requires further investigation.

It is unknown whether the association of high-sensitivity troponin I (hs-TnI) with adverse cardiovascular outcomes varies by the presence of chronic kidney disease (CKD). We examined the association of hs-TnI with adverse cardiovascular outcomes in those with and without CKD in 4,107 (mean age, 64 years; 63% men; 20% black) patients from the Emory Cardiovascular Biobank who underwent coronary angiography. CKD (n = 1,073) was defined as estimated glomerular filtration rate 30 mg/g at baseline. Cox regression was used to compute hazard ratios (HR) for the association between hs-TnI levels (per doubling of hs-TnI: log2[hs-TnI] + 1) and death, cardiovascular death, and major adverse cardiac events (MACE), separately. Hs-TnI was a stronger predictor of death (CKD: HR 1.23, 95% confidence interval [CI] 1.15 to 1.31; no CKD: HR 1.11, 95% CI 1.05 to 1.17, p-interaction = 0.023), cardiovascular death (CKD: HR 1.24, 95% CI 1.14 to 1.34; no CKD: HR 1.15, 95% CI 1.07 to 1.22, p-interaction = 0.12), and MACE (CKD: HR 1.18, 95% CI 1.11 to 1.25; no CKD: HR 1.11, 95% CI 1.06 to 1.16, p-interaction = 0.095) in CKD compared with non-CKD. The association between hs-TnI and death in patients with CKD was stronger for patients without obstructive coronary artery disease (no obstructive coronary artery disease: HR 1.60, 95% CI 1.27 to 2.01; obstructive coronary artery disease: HR 1.19, 95% CI 1.11 to 1.27, p-interaction = 0.041). In conclusion, hs-TnI is a stronger predictor of adverse cardiovascular events in patients who have CKD than those without, even in the absence of obstructive coronary artery disease. Hs-TnI may identify CKD patients who are high risk for adverse cardiovascular outcomes in whom aggressive risk factor modification strategies are warranted.

Acute psychological stress can provoke mental stress (MS)-induced myocardial ischemia (MSIMI) in coronary artery disease (CAD). Stromal cell-derived factor 1 alpha (SDF1) is released in response to hypoxia, and higher levels of SDF1 are associated with adverse outcomes. We examined whether change in

Atrial fibrillation (AF) is the most commonly encountered arrhythmia in clinical practice and so is depression with a prevalence of 16% in the United States. Whether depressive symptoms are associated with AF remains unclear, with previous studies yielding inconsistent results. Our objective was to

Background Many patients with coronary artery disease (CAD) are routinely referred for surveillance stress testing despite recommendations against it. Objective To determine whether low levels of resting high-sensitivity cardiac troponin I (hs-cTnI) can identify persons without inducible myocardial ischemia. Design Observational study. Setting A university-affiliated hospital network. Patients Persons with stable CAD: 589 in the derivation group and 118 in the validation cohort. Measurements Presence of inducible myocardial ischemia was determined by myocardial perfusion imaging with technetium-99m single-photon emission computed tomography during either treadmill or pharmacologic stress testing. Resting plasma hs-cTnI was measured within 1 week of the stress test, and the negative predictive value (NPV) for inducible ischemia was calculated. The derivation cohort was followed for 3 years for incident cardiovascular death and myocardial infarction. Results In the derivation cohort, 10 of 101 patients with an hs-cTnI level below 2.5 pg/mL had inducible myocardial ischemia (NPV, 90% [95% CI, 83% to 95%]) and 3 of 101 had inducible ischemia involving at least 10% of the myocardium (NPV, 97% [CI, 92% to 99%]). In the validation cohort, 4 of 32 patients with an hs-cTnI level below 2.5 pg/mL had inducible ischemia (NPV, 88% [CI, 71% to 96%]) and 2 of 32 had ischemia of 10% or greater (NPV, 94% [CI, 79% to 99%]). After a median follow-up of 3 years in the derivation cohort, no adverse events occurred in patients with an hs-cTnI level below 2.5 pg/mL, compared with 33 (7%) cardiovascular deaths or incident myocardial infarctions among those with an hs-cTnI level of 2.5 pg/mL or greater. Limitation The data may not be applicable to a population without known CAD or to persons with unstable angina, and the modest sample sizes warrant further validation in a larger cohort. Conclusion Very low hs-cTnI levels may be useful in excluding inducible myocardial ischemia in patients with stable CAD. Primary funding source National Institutes of Health.

Background: Circulating hematopoietic enriched progenitor cells (PCs) predict adverse cardiovascular outcomes in patients with coronary artery disease (CAD). The additive predictive role of endothelial enriched PCs expressing vascular endothelial growth factor receptor (VEGF) remains controversial.

Background: Obesity is a pro-inflammatory state leading to endothelial cell injury and dysfunction. In particular, central (android) obesity is associated with increased cardiovascular disease risk. Bone marrow derived CD34+ progenitor cells (PC) levels are elevated in patients with high body mass