Endometrial Tumor Classification by Histomorphology and Biomarkers in the Nurses’ Health Study

Objective: Endometrial cancers have historically been classified by histomorphologic appearance, which is subject to interobserver disagreement. As molecular and biomarker testing has become increasingly available, the prognostic significance and accuracy of histomorphologic diagnoses have been questioned. To address these issues for a large, prospective cohort study, we provide the results of a centralized pathology review and biomarker analysis of all incidental endometrial carcinomas occurring between 1976 and 2012 in the Nurses' Health Study. Methods: Routine histology of all (n = 360) cases was reviewed for histomorphologic diagnosis. Cases were subsequently planted in a tissue microarray to explore expression of a variety of biomarkers (e.g., ER, PR, p53, PTEN, PAX2, AMACR, HNF1β, Napsin A, p16, PAX8, and GATA3). Results: Histologic subtypes included endometrioid (87.2%), serous (5.6%), carcinosarcoma (3.9%), clear cell (1.7%), and mixed type (1.7%). Biomarker results within histologic subtypes were consistent with existing literature: abnormal p53 was frequent in serous cases (74%), and HNF1β (67%), Napsin A (67%), and AMACR (83%) expression was frequent in clear cell carcinomas. Our dataset also allowed for examination of biomarker expression across non-preselected histologies. The results demonstrated that (1) HNF1β was not specific for clear cell carcinoma, (2) TP53 mutations occurred across many histologies, and (3) GATA3 was expressed across multiple histotypes, with 75% of positive cases demonstrating high-grade features. Conclusions: Our findings establish the subtypes of endometrial cancer occurring in the Nurses' Health Study, corroborate the sensitivity of certain well-established biomarkers, and call into question previously identified associations between certain biomarkers (e.g., HNF1B) and particular histotypes

Safety of guidewire-based measurement of fractional flow reserve and the index of microvascular resistance using intravenous adenosine in patients with acute or recent myocardial infarction

Aims: Coronary guidewire-based diagnostic assessments with hyperemia may cause iatrogenic complications. We assessed the safety of guidewire-based measurement of coronary physiology, using intravenous adenosine, in patients with an acute coronary syndrome. Methods: We prospectively enrolled invasively managed STEMI and NSTEMI patients in two simultaneously conducted studies in 6 centers (NCT01764334; NCT02072850). All of the participants underwent a diagnostic coronary guidewire study using intravenous adenosine (140 μg/kg/min) infusion for 1–2 min. The patients were prospectively assessed for the occurrence of serious adverse events (SAEs) and symptoms and invasively measured hemodynamics were also recorded. Results: 648 patients (n = 298 STEMI patients in 1 hospital; mean time to reperfusion 253 min; n = 350 NSTEMI in 6 hospitals; median time to angiography from index chest pain episode 3 (2, 5) days) were included between March 2011 and May 2013. Two NSTEMI patients (0.03% overall) experienced a coronary dissection related to the guidewire. No guidewire dissections occurred in the STEMI patients. Chest symptoms were reported in the majority (86%) of patient's symptoms during the adenosine infusion. No serious adverse events occurred during infusion of adenosine and all of the symptoms resolved after the infusion ceased. Conclusions: In this multicenter analysis, guidewire-based measurement of FFR and IMR using intravenous adenosine was safe in patients following STEMI or NSTEMI. Self-limiting symptoms were common but not associated with serious adverse events. Finally, coronary dissection in STEMI and NSTEMI patients was noted to be a rare phenomenon

Sex-based associations with microvascular injury and outcomes after ST-segment elevation myocardial infarction

Objectives: We aimed to assess for sex differences in invasive parameters of acute microvascular reperfusion injury and infarct characteristics on cardiac MRI after ST-segment elevation myocardial infarction (STEMI). Methods: Patients with STEMI undergoing emergency percutaneous coronary intervention (PCI) were prospectively enrolled. Index of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured in the culprit artery post-PCI. Contrast-enhanced MRI was used to assess infarct characteristics, microvascular obstruction and myocardial haemorrhage, 2 days and 6 months post-STEMI. Prespecified outcomes were as follows: (i) all-cause death/first heart failure hospitalisation and (ii) cardiac death/non-fatal myocardial infarction/urgent coronary revascularisation (major adverse cardiovascular event, MACE) during 5- year median follow-up. Results: In 324 patients with STEMI (87 women, mean age: 61 ± 12.19 years; 237 men, mean age: 59 ± 11.17 years), women had anterior STEMI less often, fewer prescriptions of beta-blockers at discharge and higher baseline N-terminal pro-B-type natriuretic peptide levels (all p < 0.05). Following emergency PCI, fewer women than men had Thrombolysis in Myocardial Infarction (TIMI) myocardial perfusion grades ≤ 1 (20% vs 32%, p = 0.027) and women had lower corrected TIMI frame counts (12.94 vs 17.65, p = 0.003). However, IMR, CFR, microvascular obstruction, myocardial haemorrhage, infarct size, myocardial salvage index, left ventricular remodelling and ejection fraction did not differ significantly between sexes. Female sex was not associated with MACE or all-cause death/first heart failure hospitalisation. Conclusion: There were no sex differences in microvascular pathology in patients with acute STEMI. Women had less anterior infarcts than men, and beta-blocker therapy at discharge was prescribed less often in women

Persistence of Infarct Zone T2 Hyperintensity at 6 Months after Acute ST-Segment-Elevation Myocardial Infarction:Incidence, Pathophysiology, and Prognostic Implications

Background—The incidence and clinical significance of persistent T2 hyperintensity after acute ST-segment–elevation myocardial infarction (STEMI) is uncertain. Methods and Results—Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI: NCT02072850). Two hundred eighty-three STEMI patients (mean age, 59±12 years; 75% male) had cardiac magnetic resonance with T2 mapping performed at 2 days and 6 months post-STEMI. Persisting T2 hyperintensity was defined as infarct T2 >2 SDs from remote T2 at 6 months. Infarct zone T2 was higher than remote zone T2 at 2 days (66.3±6.1 versus 49.7±2.1 ms; P<0.001) and 6 months (56.8±4.5 versus 49.7±2.3 ms; P<0.001). Remote zone T2 did not change over time (mean change, 0.0±2.7 ms; P=0.837), whereas infarct zone T2 decreased (−9.5±6.4 ms; P<0.001). At 6 months, T2 hyperintensity persisted in 189 (67%) patients, who were more likely to have Thrombus in Myocardial Infarction flow 0 or 1 in the culprit artery (P=0.020), incomplete ST-segment resolution (P=0.037), and higher troponin (P=0.024). Persistent T2 hyperintensity was associated with NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration (0.57 on a log scale [0.42–0.72]; P=0.004) and the likelihood of adverse left ventricular remodeling (>20% change in left ventricular end-diastolic volume; 21.91 [2.75–174.29]; P=0.004). Persistent T2 hyperintensity was associated with all-cause death and heart failure, but the result was not significant (P=0.051). ΔT2 was associated with all-cause death and heart failure (P=0.004) and major adverse cardiac events (P=0.013). Conclusions—Persistent T2 hyperintensity occurs in two thirds of STEMI patients. Persistent T2 hyperintensity was associated with the initial STEMI severity, adverse remodeling, and long-term health outcome. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT02072850

Comparative Prognostic Utility of Indexes of Microvascular Function Alone or in Combination in Patients with an Acute ST-Segment-Elevation Myocardial Infarction

Background—Primary percutaneous coronary intervention (PCI) is frequently successful at restoring coronary artery blood flow in patients with acute ST-segment elevation myocardial infarction, however, failed myocardial reperfusion commonly passes undetected in up to half of these patients. The index of microvascular resistance (IMR) is a novel invasive measure of coronary microvascular function. We aimed to investigate the pathological and prognostic significance of an index of microvascular resistance (IMR>40), alone or in combination with a coronary flow reserve (CFR≤2.0), in the culprit artery after emergency PCI for acute STEMI. Methods—Patients with acute STEMI were prospectively enrolled during emergency PCI, and categorized according to IMR (≤40 or >40) and CFR (≤2.0 or >2.0). Cardiac MRI was acquired 2 days and 6 months post-MI. All-cause death or first heart failure hospitalization was a pre-specified outcome (median follow-up duration 845 days). Results—IMR and CFR were measured in the culprit artery at the end of PCI in 283 STEMI patients (mean age 60 (12) years, 73% male). The median [interquartile range] IMR and CFR were 25 [15-48] and 1.6 [1.1-2.1], respectively. An IMR>40 was a multivariable associate of myocardial hemorrhage (odds ratio (OR) (95% confidence interval (CI)) 2.10 (1.03, 4.27); p=0.042. An IMR>40 was closely associated with microvascular obstruction. Symptom to reperfusion time, TIMI blush grade, and no (≤30%) ST segment resolution, were not associated with these pathologies. An IMR>40 was a multivariable associate of the changes in LV ejection fraction (coefficient (95% CI) (-2.12 (-4.02, -0.23); p=0.028) and LV end-diastolic volume (7.85 (0.41, 15.29); p=0.039) at 6 months, independent of infarct size. An IMR>40 (odds ratio 4.36 (95% CI 2.10, 9.06); p<0.001) was a multivariable associate of all-cause death or heart failure. Compared with an IMR>40, the combination of IMR>40 with CFR≤2.0 did not have incremental prognostic value. Conclusions—An IMR>40 is a multivariable associate of LV and clinical outcomes post-STEMI, independent of the size of infarction. Compared with standard clinical measures of the efficacy of myocardial reperfusion, including the ischemic time, ST-segment elevation, the angiographic blush grade and CFR, IMR has superior clinical value for risk stratification and may be considered as a reference test for failed myocardial reperfusion

Circumferential strain predicts major adverse cardiovascular events following an acute ST-segment-elevation myocardial infarction

Purpose: To investigate the prognostic value of circumferential left ventricular (LV) strain measured by using cardiac MRI for prediction of major adverse cardiac events (MACE) following an acute ST-segment–elevation myocardial infarction (STEMI). Materials and Methods: Participants with acute STEMI were prospectively enrolled from May 11, 2011, to November 22, 2012. Cardiac MRI was performed at 1.5 T during the index hospitalization. Displacement encoding with stimulated echoes (DENSE) and feature tracking of cine cardiac MRI was used to assess circumferential LV strain. MACE that occurred after discharge were independently assessed by cardiologists blinded to the baseline observations. Results: A total of 259 participants (mean age, 58 years ± 11 [standard deviation]; 198 men [mean age, 58 years ± 11] and 61 women [mean age, 58 years ± 12]) underwent cardiac MRI 2.2 days ± 1.9 after STEMI. Average infarct size was 18% ± 13 of LV mass and circumferential strain was −13% ± 3 (DENSE method) and −24% ± 7 (feature- tracking method). Fifty-one percent (131 of 259 participants) had presence of microvascular obstruction. During a median follow-up period of 4 years, 8% (21 of 259) experienced MACE. Area under the curve (AUC) for DENSE was different from that of feature tracking (AUC, 0.76 vs 0.62; P = .03). AUC for DENSE was similar to that of initial infarct size (P = .06) and extent of microvascular obstruction (P = .08). DENSE-derived strain provided incremental prognostic benefit over infarct size for prediction of MACE (hazard ratio, 1.3; P < .01). Conclusion: Circumferential strain has independent prognostic importance in study participants with acute ST-segment–elevation myocardial infarction

Coronary thermodilution waveforms after acute reperfused stsegment-elevation myocardial infarction:Relation to microvascular obstruction and prognosis

Background: Invasive measures of microvascular resistance in the culprit coronary artery have potential for risk stratification in acute ST‐segment–elevation myocardial infarction. We aimed to investigate the pathological and prognostic significance of coronary thermodilution waveforms using a diagnostic guidewire. Methods and Results: Coronary thermodilution was measured at the end of percutaneous coronary intervention, (PCI) and contrast‐enhanced cardiac magnetic resonance imaging (MRI) was intended on day 2 and 6 months later to assess left ventricular (LV) function and pathology. All‐cause death or first heart failure hospitalization was a pre‐specified outcome (median follow‐up duration 1469 days). Thermodilution recordings underwent core laboratory assessment. A total of 278 patients with acute ST‐segment elevation myocardial infarction EMI (72% male, 59±11 years) had coronary thermodilution measurements classified as narrow unimodal (n=143 [51%]), wide unimodal (n=100 [36%]), or bimodal (n=35 [13%]). Microvascular obstruction and myocardial hemorrhage were associated with the thermodilution waveform pattern (P=0.007 and 0.011, respectively), and both pathologies were more prevalent in patients with a bimodal morphology. On multivariate analysis with baseline characteristics, thermodilution waveform status was a multivariable associate of microvascular obstruction (odds ratio [95% confidence interval]=5.29 [1.73, 16.22];, P=0.004) and myocardial hemorrhage (3.45 [1.16, 10.26]; P=0.026), but the relationship was not significant when index of microvascular resistance (IMR) >40 or change in index of microvascular resistance (5 per unit) was included. However, a bimodal thermodilution waveform was independently associated with all‐cause death and hospitalization for heart failure (odds ratio [95% confidence interval]=2.70 [1.10, 6.63]; P=0.031), independent of index of microvascular resistance>40, ST‐segment resolution, and TIMI (Thrombolysis in Myocardial Infarction) Myocardial Perfusion Grade. Conclusions: The thermodilution waveform in the culprit coronary artery is a biomarker of prognosis and may be useful for risk stratification immediately after reperfusion therapy

Persistent Iron Within the Infarct Core After ST-Segment Elevation Myocardial Infarction:Implications for Left Ventricular Remodeling and Health Outcomes

Objectives: This study sought to determine the incidence and prognostic significance of persistent iron in patients post–ST-segment elevation myocardial infarction (STEMI). Background: The clinical significance of persistent iron within the infarct core after STEMI complicated by acute myocardial hemorrhage is poorly understood. Methods: Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI [Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction]). Cardiac magnetic resonance imaging including T2* (observed time constant for the decay of transverse magnetization seen with gradient-echo sequences) mapping was performed at 2 days and 6 months post-STEMI. Myocardial hemorrhage or iron was defined as a hypointense infarct core with T2* signal <20 ms. Results: A total of 203 patients (age 57 ± 11 years, n = 158 [78%] male) had evaluable T2* maps at 2 days and 6 months post-STEMI; 74 (36%) patients had myocardial hemorrhage at baseline, and 44 (59%) of these patients had persistent iron at 6 months. Clinical associates of persistent iron included heart rate (p = 0.009), the absence of a history of hypertension (p = 0.017), and infarct size (p = 0.028). The presence of persistent iron was associated with worsening left ventricular (LV) end-diastolic volume (regression coefficient: 21.10; 95% confidence interval [CI]: 10.92 to 31.27; p < 0.001) and worsening LV ejection fraction (regression coefficient: −6.47; 95% CI: −9.22 to −3.72; p < 0.001). Persistent iron was associated with the subsequent occurrence of all-cause death or heart failure (hazard ratio: 3.91; 95% CI: 1.37 to 11.14; p = 0.011) and major adverse cardiac events (hazard ratio: 3.24; 95% CI: 1.09 to 9.64; p = 0.035) (median follow-up duration 1,457 days [range 233 to 1,734 days]). Conclusions: Persistent iron at 6 months post-STEMI is associated with worse LV and longer-term health outcomes. (Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction [BHF MR-MI]; NCT02072850

Remote Zone Extracellular Volume and Left Ventricular Remodeling in Survivors of ST-Elevation Myocardial Infarction

The natural history and pathophysiological significance of tissue remodeling in the myocardial remote zone after acute ST-elevation myocardial infarction (STEMI) is incompletely understood. Extracellular volume (ECV) in myocardial regions of interest can now be measured with cardiac magnetic resonance imaging. Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI [British Heart Foundation Magnetic Resonance Imaging in Acute ST-Segment Elevation Myocardial Infarction study]). Cardiac magnetic resonance was performed at 1.5 Tesla at 2 days and 6 months post STEMI. T1 modified Look-Locker inversion recovery mapping was performed before and 15 minutes after contrast (0.15 mmol/kg gadoterate meglumine) in 140 patients at 2 days post STEMI (mean age: 59 years, 76% male) and in 131 patients at 6 months post STEMI. Remote zone ECV was lower than infarct zone ECV (25.6±2.8% versus 51.4±8.9%; P<0.001). In multivariable regression, left ventricular ejection fraction was inversely associated with remote zone ECV (P<0.001), and diabetes mellitus was positively associated with remote zone ECV (P=0.010). No ST-segment resolution (P=0.034) and extent of ischemic area at risk (P<0.001) were multivariable associates of the change in remote zone ECV at 6 months (ΔECV). ΔECV was a multivariable associate of the change in left ventricular end-diastolic volume at 6 months (regression coefficient [95% confidence interval]: 1.43 (0.10–2.76); P=0.036). ΔECV is implicated in the pathophysiology of left ventricular remodeling post STEMI, but because the effect size is small, ΔECV has limited use as a clinical biomarker of remodeling

Temporal evolution of myocardial hemorrhage and edema in patients after acute st-segment elevation myocardial infarction:Pathophysiological insights and clinical implications

Background The time course and relationships of myocardial hemorrhage and edema in patients after acute ST‐segment elevation myocardial infarction (STEMI) are uncertain. Methods and Results Patients with ST‐segment elevation myocardial infarction treated by primary percutaneous coronary intervention underwent cardiac magnetic resonance imaging on 4 occasions: at 4 to 12 hours, 3 days, 10 days, and 7 months after reperfusion. Myocardial edema (native T2) and hemorrhage (T2*) were measured in regions of interest in remote and injured myocardium. Myocardial hemorrhage was taken to represent a hypointense infarct core with a T2* value <20 ms. Thirty patients with ST‐segment elevation myocardial infarction (mean age 54 years; 25 [83%] male) gave informed consent. Myocardial hemorrhage occurred in 7 (23%), 13 (43%), 11 (33%), and 4 (13%) patients at 4 to 12 hours, 3 days, 10 days, and 7 months, respectively, consistent with a unimodal pattern. The corresponding median amounts of myocardial hemorrhage (percentage of left ventricular mass) during the first 10 days after myocardial infarction were 2.7% (interquartile range [IQR] 0.0–5.6%), 7.0% (IQR 4.9–7.5%), and 4.1% (IQR 2.6–5.5%; P<0.001). Similar unimodal temporal patterns were observed for myocardial edema (percentage of left ventricular mass) in all patients (P=0.001) and for infarct zone edema (T2, in ms: 62.1 [SD 2.9], 64.4 [SD 4.9], 65.9 [SD 5.3]; P<0.001) in patients without myocardial hemorrhage. Alternatively, in patients with myocardial hemorrhage, infarct zone edema was reduced at day 3 (T2, in ms: 51.8 [SD 4.6]; P<0.001), depicting a bimodal pattern. Left ventricular end‐diastolic volume increased from baseline to 7 months in patients with myocardial hemorrhage (P=0.001) but not in patients without hemorrhage (P=0.377). Conclusions The temporal evolutions of myocardial hemorrhage and edema are unimodal, whereas infarct zone edema (T2 value) has a bimodal pattern. Myocardial hemorrhage is prognostically important and represents a target for therapeutic interventions that are designed to preserve vascular integrity following coronary reperfusion