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Purpose To assess the prognostic value of regional quantitative myocardial flow measures as assessed by 13N-ammonia positron emission tomography (PET) myocardial perfusion imaging (MPI) in patients with suspected coronary artery disease (CAD). Methods We retrospectively included 150 consecutive patients with suspected CAD who underwent clinically indicated 13 N-ammonia PET-MPI and who did not undergo revascularization within 90 days of PET-MPI. The presence or absence of a decreased global myocardial flow reserve (i.e., MFR Results Over a median follow-up of 50 months (IQR 38–103), 30 events occurred in 29 patients. Kaplan–Meier analysis showed significantly reduced event-free and overall survival in MFR groups 2 and 3 compared to MFR group 1 (log-rank: p = 0.015 and p = 0.013). In a multivariable Cox regression analysis, decreased regional MFR was an independent predictor for MACE (adjusted HR 3.44, 95% CI 1.17–10.11, p = 0.024) and all-cause death (adjusted HR 4.72, 95% CI 1.07–20.7, p = 0.04). Conclusions A decreased regional MFR as assessed by 13 N-ammonia PET-MPI confers prognostic value by identifying patients at increased risk for future adverse cardiac outcomes and all-cause death.

Background No methodology is available to distinguish truly reduced myocardial flow reserve (MFR) in positron emission tomography myocardial perfusion imaging (PET MPI) from seemingly impaired MFR due to inadequate adenosine response. The adenosine-induced splenic switch-off (SSO) sign has been proposed as a potential marker for adequate adenosine response in cardiac magnetic resonance (CMR). We assessed the feasibility of detecting SSO in nitrogen-13 ammonia PET MPI using SSO in CMR as the standard of reference. Methods and Results Fifty patients underwent simultaneous CMR and PET MPI on a hybrid PET/MR device with co-injection of a gadolinium-based contrast agent and nitrogen-13 ammonia during rest and adenosine-induced stress. In CMR, SSO was assessed visually (positive vs negative SSO) and quantitatively by calculating the ratio of the peak signal intensity of the spleen during stress over rest (SIR). In PET MPI, the splenic signal activity ratio (SAR) was calculated as the maximal standard uptake value of the spleen during stress over rest. The median SIR was significantly lower in patients with positive versus negative SSO in CMR (0.57 [IQR 0.49 to 0.62] vs 0.89 [IQR 0.76 to 0.98]; P P Conclusion Similarly to CMR, SSO can be detected in nitrogen-13 ammonia PET MPI. This might help distinguish adenosine non-responders from patients with truly impaired MFR due to microvascular dysfunction or multivessel coronary artery disease.

Objectives Coronary artery volume indexed to left myocardial mass (CAVi), derived from coronary computed tomography angiography (CCTA), has been proposed as an indicator of diffuse atherosclerosis. We investigated the association of CAVi with quantitative flow parameters and its ability to predict ischemia as derived from 13N-ammonia positron emission tomography myocardial perfusion imaging (PET-MPI). Methods Sixty patients who underwent hybrid CCTA/PET-MPI due to suspected CAD were retrospectively included. CAVi was defined as total coronary artery lumen volume over myocardial mass, both derived from CCTA. From PET-MPI, quantitative stress and rest myocardial blood flow (MBF) and myocardial flow reserve (MFR) were obtained and correlated with CAVi, and semi-quantitative perfusion images were analyzed for the presence of ischemia. Harrell’s c-statistic and net reclassification improvement (NRI) analysis were performed to evaluate the incremental value of CAVi over the CCTA model (i.e., stenosis > 50% and > 70%). Results CAVi correlated moderately with stress MBF and MFR (R = 0.50, p < 0.001, and R = 0.39, p = 0.002). Mean stress MBF and MFR were lower in patients with low (i.e., ≤ 20.2 mm3/g, n = 24) versus high (i.e., > 20.2 mm3/g, n = 36) CAVi (p < 0.001 for both comparisons). CAVi was independently associated with abnormal stress MBF (OR 0.90, 95% CI 0.82–0.998, p = 0.045). CAVi increased the predictive ability of the CCTA model for abnormal stress MBF and ischemia (c-statistic 0.763 versus 0.596, pdiff < 0.05 and 0.770 versus 0.645, pdiff < 0.05, NRI 0.84, p = 0.001 and 0.96, p < 0.001, respectively). Conclusions CAVi exhibits incremental value to predict both abnormal stress MBF and ischemia over CCTA alone. Key Points • Coronary artery volume indexed to left myocardial mass (CAVi), derived from coronary computed tomography angiography (CCTA), is correlated with myocardial blood flow indices derived from13N-ammonia positron emission tomography myocardial perfusion imaging. • CAVi is independently associated with abnormal stress myocardial blood flow. • CAVi provides incremental diagnostic value over CCTA for both abnormal stress MBF and ischemia.

Purpose Amygdalar metabolic activity was shown to independently predict cardiovascular outcomes. However, little is known about age- and sex-dependent variability in neuronal stress responses among individuals free of cardiac disease. This study sought to assess age- and sex-specific differences of resting amygdalar metabolic activity in the absence of clinical cardiovascular disease. Methods Amygdalar metabolic activity was assessed in 563 patients who underwent multimodality imaging by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography and echocardiography for the evaluation of cardiac function. Results After exclusion of 294 patients with structural or functional cardiovascular pathologies, 269 patients (128 women) remained in the final population. 18F-FDG amygdalar activity significantly decreased with age in men (r = − 0.278, P = 0.001), but not in women (r = 0.002, P = 0.983). Similarly, dichotomous analysis confirmed a lower amygdalar activity in men ≥ 50 years as compared to those P = 0.007), which was not observed in women (0.81 ± 0.1 vs. 0.82 ± 0.1, P = 0.549). Accordingly, a fully adjusted linear regression analysis identified age as an independent predictor of amygdalar activity only in men (B-coefficient − 0.278, P = 0.001). Conclusion Amygdalar activity decreases with age in men, but not in women. The use of amygdalar activity for cardiovascular risk stratification merits consideration of inherent age- and sex-dependent variability.

Background Quantitative flow ratio (QFR) is a novel, adenosine-free method for functional lesion interrogation based on 3-dimensional quantitative coronary angiography and computational algorithms. We sought to investigate the diagnostic performance of QFR versus myocardial perfusion imaging positron emission tomography (MPI-PET), which yields the highest accuracy for detection of myocardial ischemia. Methods Diagnostic performance of QFR versus MPI-PET was assessed in consecutive patients undergoing both clinically indicated coronary angiography and 13N-ammonia MPI-PET within a six-month period. Results Out of 176 patients (439 coronary arteries), 19.3% were women. Percent area stenosis was 45 [32–58] %. Myocardial ischemia on 13N-ammonia MPI-PET was detected in 106 (24.1%) vessel territories and hemodynamic significance defined as contrast-flow vessel QFR ≤ 0.80 was observed in 83 (18.9%) vessels. Diagnostic accuracy, sensitivity, and specificity of contrast-flow vessel QFR for the prediction of myocardial ischemia on 13N-ammonia MPI-PET were 92.5 (95% CI 89.6–94.7) %, 73.6 (95% CI 64.1–81.7) %, and 98.5 (95% CI 96.5–99.5) %, respectively. The AUCs for contrast-flow vessel QFR, percent diameter stenosis, and percent area stenosis were 0.85 (95% CI 0.81–0.88, p Conclusions QFR, a novel diagnostic tool for functional coronary lesion assessment, provides good diagnostic agreement with MPI-PET and superior diagnostic accuracy for the detection of myocardial ischemia as compared to anatomic indices. Future studies will have to determine the non-inferiority of QFR to fractional flow reserve with respect to clinical outcomes.

BACKGROUND Coronary computed tomography angiography (CCTA)-based transluminal attenuation gradient (TAG) was suggested to determine the functional significance of a stenosis. However, evidence that TAG acquired by wide-volume scanners can assess the hemodynamic significance of stenosis assessed by single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is lacking. Moreover, coronary cross-sectional area may influence TAG. Hence, we aimed at assessing the diagnostic value of TAG to predict ischemia in SPECT-MPI and the correlation between TAG and the transluminal cross-sectional area gradient (TCG). METHODS Patients undergoing CCTA and SPECT-MPI for suspected coronary artery disease were included. TAG and TCG were calculated measuring the mean vessel attenuation and the cross-sectional area along major coronary vessels at 5-mm intervals. RESULTS A total of 255 coronary arteries of 87 patients were included. TAG and TCG did not discriminate between coronary arteries with or without ischemia as assessed by SPECT-MPI (p = .44 and p = .25, respectively). The area under the curve to predict ischemia was not increased by adding TAG (0.88, 95% CI 0.83-0.92) or TCG (0.87, 95% CI 0.81-0.90) to CCTA alone (0.85, 95% CI 0.80-0.89). There was a significant correlation between TAG and TCG (r = 0.43; p

Previous work indicates that SARS-CoV-2 virus entry proteins angiotensin-converting enzyme 2 (ACE-2) and the cell surface transmembrane protease serine 2 (TMPRSS-2) are regulated by sex hormones. However, clinical studies addressing this association have yielded conflicting results. We sought to analyze the impact of sex hormones, age, and cardiovascular disease on ACE-2 and TMPRSS-2 expression in different mouse models. ACE-2 and TMPRSS-2 expression was analyzed by immunostaining in a variety of tissues obtained from FVB/N mice undergoing either gonadectomy or sham-surgery and being subjected to ischemia–reperfusion injury or transverse aortic constriction surgery. In lung tissues sex did not have a significant impact on the expression of ACE-2 and TMPRSS-2. On the contrary, following myocardial injury, female sex was associated to a lower expression of ACE-2 at the level of the kidney tubules. In addition, after myocardial injury, a significant correlation between younger age and higher expression of both ACE-2 and TMPRSS-2 was observed for lung alveoli and bronchioli, kidney tubules, and liver sinusoids. Our experimental data indicate that gonadal hormones and biological sex do not alter ACE-2 and TMPRSS-2 expression in the respiratory tract in mice, independent of disease state. Thus, sex differences in ACE-2 and TMPRSS-2 protein expression observed in mice may not explain the higher disease burden of COVID-19 among men.

Objective The purpose of this study was to quantify the reduction in radiation dose achievable by using the optimal z-axis coverage in coronary computed tomography (CT) angiography (CCTA) on a latest-generation 256-slice scanner. Methods A total of 408 scans were reviewed that were performed on a wide-range detector scanner allowing up to 16-cm z-axis coverage (adjustable in 2-cm increments). For each CCTA study, we assessed the radiation dose (ie, dose-length product and volume CT dose index) and measured the minimum z-axis coverage necessary to cover the complete cardiac anatomy. We calculated the potential radiation dose savings achievable through reduction of the z-axis coverage to the minimum necessary. Results The majority of the CCTA scans were performed with a z-axis coverage of 16 cm (n = 285, 69.9%), followed by 14 cm (n = 121, 29.7%) and 12 cm (n = 2, 0.5%). In the group that was scanned with a collimation of 16 cm, radiation dose could have been reduced by 12.5% in 55 patients, 25% in 195 patients, and 37.5% in 33 patients when using optimal z-axis coverage for CCTA. In the group that was scanned with a collimation of 14 cm, radiation dose could have been reduced by 14.3% in 90 patients, and 28.6% in 30 patients, whereas in the group that was scanned with a collimation of 12 cm, dose could have been reduced by 16.7% in 2 patients. Conclusions Using correct z-axis coverage in CCTA on a latest-generation 256-slice scanner yields average dose reductions of 22.0% but may be as high as 37.5%.

Today, >50% of medical students are women. This proportion, however, dramatically decreases throughout the higher levels of academia, a phenomenon described as the “leaky pipeline.” This gender disparity is particularly pronounced in academic radiology, mirrored by a significant lack of women in editorial board positions, key authorship positions, and conference keynote lectures. The scientific invisibility is not only a key hurdle facing women in radiology, the lack of female role models and mentors in this context might also negatively affect career choices of young female radiologists thereby further widen the existing gender gap. In this article, the origins of the “leaky pipeline,” the reasons for women’s choice or rejection of careers in academic medicine, as well as solutions as to how the continued loss of a large part of the talent pool can be prevented, are discussed. Active monitoring and intervention are needed to identify problems, plan targeted actions, and evaluate their efficacy. Among those are measures that address a lack of support in the workplace, specific mentoring needs of women, flexible working hours and opportunities to align work and family, financial constraints, and support for returners after career breaks. Cooperative steps of politics and universities need to be taken that ensure a sustainable way forward to enable many talented women in radiology to achieve their full potential.

Objectives The aim of this study was to assess the prognostic impact of post-procedural troponin T increase and mortality in patients undergoing percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) to define the threshold at which procedure-related myocardial injury drives mortality. Background Coronary CTO recanalization represents the most technically challenging PCI. The complexity harbors a significant increased risk for complications with CTO PCI with compared with non-CTO PCI. However, there are evidenced biomarker cutoff levels that help identify those patients at risk for unfavorable clinical outcomes. Methods A total of 3,712 consecutive patients undergoing PCI for at least 1 CTO lesion were enrolled, and comprehensive troponin T measurements were performed 6, 8, and 24 h after the procedure. All-cause mortality was defined as the primary study endpoint. Results Using spline curve analysis, a more than 18-fold increase of troponin above the upper reference limit was significantly associated with mortality. In a Cox regression analysis, the crude hazard ratio was 2.32 (95% confidence interval: 1.83 to 2.93; p Conclusions This large-scale outcome study demonstrates for the first time the prognostic value of post-procedural troponin T elevation after PCI in patients with CTOs. A threshold was defined for procedure-related myocardial injury in patients with CTOs to differentiate them from those without CTOs that may help guide post-procedural clinical care in this high-risk patient population.

Given the current increase in the incidence of coronary artery disease in younger women as well as the high lifetime risk of developing an x-ray-induced malignancy in this population, we aimed at assessing chest radiation in 206 women ≤55 years old undergoing coronary calcium scoring (CACS) by using a Monte Carlo simulation tool. Our data indicate that the simulated radiation dose of the female breast during CACS depends substantially on the starting position of the x-ray tube, with an almost 2 times excess of breast radiation exposure being measured during anterior-posterior tube positioning. Thus, an additional technical feature taking into account the position of the x-ray tube when acquisition is triggered might be an important tool to reduce radiation exposure of the female breast during CACS.

The human pathophysiology of stunned, hibernating and scarred myocardium in ischemic cardiomyopathy is a subject of controversy. While the “smart heart” theory postulates that reduced myocardial blood flow (MBF) at rest is responsible for myocytes switching to a state of hibernation, other theories suggest that a reduced myocardial flow reserve (MFR) may be the cause. We included 110 patients with ischemic cardiomyopathy. Based on quantitative myocardial perfusion assessment and viability imaging with 13N-NH3 and 18F-FDG positron emission tomography, respectively, as well as wall motion assessment from echocardiography, myocardial tissue was characterized as remote (i.e., normal myocardium), stunned (i.e., dysfunctional but viable myocardium with normal rest perfusion), hibernating (i.e., dysfunctional but viable myocardium with impaired rest perfusion), or scarred myocardium (i.e., non-viable myocardium). Compared to remote myocardium, dysfunctional but viable myocardium (including stunned and hibernating) had reduced rest MBF (0.89 mL/min/g vs. 0.79 and 0.76 mL/min/g, respectively; p

Sexual dimorphism in the manifestation of coronary artery disease (CAD) has unleashed a call to reconsider cardiovascular risk assessment. Alterations of bone mineral density (BMD) have been associated with congestive heart failure and appear to be modified by sex. However, the sex-specific association between BMD, myocardial perfusion, and cardiovascular outcomes is currently unknown. A total number of 491 patients (65.9 ± 10.7 years, 32.4% women) underwent 13N-ammonia positron emission tomography/computed tomography for evaluation of CAD, and were tracked for major adverse cardiac events (MACEs). Event-free survival (median follow-up time of 4.3 ± 2.0 years) was significantly reduced in patients with low (≤ 100 Hounsfield units) compared to those with higher BMD (log-rank P = .037). Accordingly, reduced BMD was chosen as significant predictor of MACE in a fully adjusted proportional hazards regression model (P = .015). Further, a first-order interaction term consisting of sex and BMD was statistically significant (P = .007). BMD was significantly lower in patients with abnormal myocardial perfusion or impaired left ventricular ejection fraction (P

Although women with cardiovascular disease experience relatively worse outcomes as compared to men, substantial knowledge gaps remain regarding the unique female determinants of cardiovascular risk. Heart rate (HR) responses to vasodilator stress mirror autonomic activity and may carry important long-term prognostic information in women. Hemodynamic changes during adenosine stress were recorded in a total of 508 consecutive patients (104 women) undergoing clinically indicated 13N-ammonia Positron-Emission-Tomography (PET) at our institution. Following propensity matching, 202 patients (101 women, mean age 61.3 ± 12.6 years) were analyzed. During a median follow-up of 5.6 years, 97 patients had at least one cardiac event, including 17 cardiac deaths. Heart rate reserve (% HRR) during adenosine infusion was significantly higher in women as compared to men (23.8 ± 19.5 vs 17.3 ± 15.3, p = 0.009). A strong association between 10-year cardiovascular endpoints and a blunted HRR was observed in women, while this association was less pronounced in men. Accordingly, in women, but not in men, reduced HRR was selected as a strong predictor for adverse cardiovascular events in a Cox regression model fully adjusted for imaging findings and traditional risk factors (HR 2.41, 95% CI 1.23–4.75, p = 0.011). Receiver operating characteristics (ROC) curves revealed that a blunted HRR

Background Inflammation plays a fundamental role in mediating all stages of atherosclerosis. Given the higher prevalence of inflammatory rheumatologic conditions in women and the female propensity towards worse cardiovascular outcomes, refined strategies are needed to better identify the high-risk female cardiovascular phenotype. Objectives This article aims to assess sex-specific links between inflammatory processes and the development and progression of ischemic heart disease. Patients and Methods The relationship between vertebral bone marrow metabolism—a marker of inflammation—and myocardial injury was retrospectively assessed in 294 patients (28.6% women, mean age: 66.9 ± 10.0 years) who underwent 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and 99mTc-tetrofosmin single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI). Results A significant increase in 18F-FDG bone marrow uptake was observed in women with impaired myocardial perfusion (SPECT-MPI) as compared to women with normal myocardial perfusion (standardized uptake value [SUV]: 2.2 ± 1.2 vs. 1.7 ± 0.5, p = 0.013), while no such difference was observed in men (SUV: 1.6 ± 0.8 vs. 1.6 ± 0.4, p = 0.372). Furthermore, a significant inverse correlation between left ventricular ejection fraction (LVEF) and bone marrow metabolism was seen in women (r = –0.229, p = 0.037), but not in men (r = –0.075, p = 0.289). Accordingly, in women, but not in men, bone marrow activity was identified as an independent predictor of both, reduced LVEF (β-coefficient, –4.537; p = 0.040) and impaired myocardial perfusion (β-coefficient, 0.138; p = 0.014). Conclusion A strong link between bone marrow metabolism and impaired myocardial function and perfusion was observed in women, but not in men. Our data suggest that novel biomarkers of inflammation might help to identify women at risk for ischemic cardiomyopathy and to tailor disease management to the female cardiovascular phenotype.

Positron emission tomography (PET) integrating assessment of perfusion with 13N-ammonia (NH3) and viability with 18F-fluorodeoxyglucose (FDG) has high accuracy to identify viable, hibernating myocardium. We tested whether quantification of myocardial blood flow (MBF) and washout (k2) can predict myocardial viability using FDG as standard of reference. In 180 consecutive patients with ischemic cardiomyopathy, myocardium was categorized on a segment-level into normal, ischemic, hibernating, and scar. From dynamic images, stress MBF, rest MBF, and k2 were derived and myocardial flow reserve (MFR) and volume of distribution (VD) were calculated. Across myocardial tissues, all parameters differed significantly. The area under the curve (AUC) was 0.564 (95% CI 0.527-0.601), 0.635 (0.599-0.671), 0.553 (0.516-0.591), 0.520 (0.482-0.559), and 0.560 (0.522-0.597) for stress MBF, rest MBF, MFR, k2, and VD. The generalized linear mixed model correctly classified 81% of scar as viable, hibernating myocardium. If the threshold of rest MBF to predict viability was set to 0.45 mL·min−1·g−1, sensitivity and specificity were 96% and 12%, respectively. Quantitative NH3 PET parameters have low to moderate diagnostic performance to predict viability in ischemic cardiomyopathy. However, if rest MBF falls below 0.45 mL·min−1·g−1, viability testing by FDG-PET may be safely deferred.

Aims Perivascular fat attenuation index (FAI) has emerged as a novel coronary computed tomography angiography (CCTA)–based biomarker predicting cardiovascular outcomes by capturing early coronary inflammation. It is currently unknown whether FAI adds prognostic value beyond that provided by single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) and CCTA findings including coronary artery calcium scoring (CACS). Methods and results A total of 492 patients (mean age 62.5 ± 10.8 years) underwent clinically indicated multimodality CCTA and electrocardiography (ECG)-gated 99mTc-tetrofosmin SPECT-MPI between May 2005 and December 2008 at our institution, and follow-up data on major adverse cardiovascular events (MACE) was obtained for 314 patients. FAI was obtained from CCTA images and was measured around the right coronary artery (FAI[RCA]), the left anterior descending artery (FAI[LAD]), and the left main coronary artery (FAI[LMCA]). During a median follow-up of 2.7 years, FAI[RCA] > − 70.1 was associated with an increased rate of MACE (log rank p = 0.049), while no such association was seen for FAI[LAD] or FAI[LMCA] (p = NS). A multivariate Cox regression model accounting for cardiovascular risk factors, CCTA and SPECT-MPI findings identified FAI[RCA] as an independent predictor of MACE (HR 2.733, 95% CI: 1.220–6.123, p = 0.015). However, FAI[RCA] was no longer a significant predictor of MACE after adding CACS (p = 0.279). A first-order interaction term consisting of sex and FAI[RCA] was significant in both models (HR 2.119, 95% CI: 1.218–3.686, p = 0.008; and HR 2.071, 95% CI: 1.111–3.861, p = 0.022). Conclusion FAI does not add incremental prognostic value beyond multimodality MPI/CCTA findings including CACS. The diagnostic value of FAI[RCA] is significantly biased by sex.

Purpose Misalignment between positron emission tomography (PET) datasets and attenuation correction (AC) maps is a potential source of artifacts in myocardial perfusion imaging (MPI). We assessed the impact of adenosine on the alignment of AC maps derived from magnetic resonance (MR) and PET datasets during MPI on a hybrid PET/MR scanner. Methods Twenty-eight volunteers underwent adenosine stress and rest 13N-ammonia MPI on a PET/MR. We acquired Dixon sequences for the creation of MRAC maps. After reconstruction of the original non-shifted PET images, we examined MRAC and PET datasets for cardiac spatial misalignment and, if necessary, reconstructed a second set of shifted PET images after manually adjusting co-registration. Summed rest, stress, and difference scores (SRS, SSS, and SDS) were compared between shifted and non-shifted PET images. Additionally, we measured the amount of cranial movement of the heart (i.e., myocardial creep) after termination of adenosine infusion. Results Realignment was necessary for 25 (89.3%) stress and 12 (42.9%) rest PET datasets. Median SRS, SSS, and SDS of the non-shifted images were 6 (IQR = 4–7), 12 (IQR = 7–18), and 8 (IQR = 2–11), respectively, and of the shifted images 2 (IQR = 1–6), 4 (IQR = 7–18), and 1 (IQR = 0–2), respectively. All three scores were significantly higher in non-shifted versus shifted images (all p r = 0.541, p = 0.005). Conclusion Misalignment of MRAC and PET datasets commonly occurs during adenosine stress MPI on a hybrid PET/MR device, potentially leading to an increase in false-positive findings. Our results suggest that myocardial creep may substantially account for this and prompt for a careful review and correction of PET/MRAC data.

Background: Left ventricular (LV) dilatation is a key compensatory feature in patients with chronic aortic regurgitation (AR). However, sex-differences in LV remodeling and outcomes in chronic AR have been poorly investigated so far. Methods: We performed cardiovascular magnetic resonance imaging (CMR) including phase-contrast velocity-encoded imaging for the measurement of regurgitant fraction (RegF) at the sinotubular junction, in consecutive patients with at least mild AR on echocardiography. We assessed LV size (end-diastolic volume indexed to body surface area, LVEDV/BSA) and investigated sex differences between LV remodeling and increasing degrees of AR severity. Cox-regression models were used to test differences in outcomes between men and women using a composite of heart failure hospitalization, unscheduled AR intervention, and cardiovascular death. Results: 270 consecutive patients (59.6% male, 59.8 &plusmn, 20.8 y/o, 59.6% with at least moderate AR on echocardiography) were included. On CMR, mean RegF was 18.1 &plusmn, 17.9% and a total of 65 (24.1%) had a RegF &ge, 30%. LVEDV/BSA was markedly closer related with AR severity (RegF) in men compared to women. Each 1-SD increase in LVEDV/BSA (mL/m2) was associated with a 9.7% increase in RegF in men and 5.9% in women, respectively (p-value for sex-interaction &lt, 0.001). Based on previously published reference values, women&mdash, in contrast to men&mdash, frequently had a normal LV size despite severe AR (e.g., for LVEDV/BSA on CMR: 35.3% versus 8.7%, p &lt, 0.001). In a Cox-regression model adjusted for age, LVEDV/BSA and RegF, women were at significantly higher risk for the composite endpoint when compared to men (adj. HR 1.81 (95%CI 1.09&ndash, 3.03), p = 0.022). Conclusion: In patients with chronic AR, LV remodeling is a hallmark feature in men but not in women. Severity of AR may be underdiagnosed in female patients in the absence of LV dilatation. Future studies need to address the dismal prognosis in female patients with chronic AR.

Evidence to date has failed to reveal unique female determinants of cardiovascular disease. However, a strong association was recently observed between increased metabolic activity in the amygdala, a neural centre involved in the processing of emotions, and impaired myocardial function in women, but not in men. Given the stronger immune responses in females, we sought to retrospectively investigate the interaction between inflammation, perceived stress, and myocardial injury. Overall, 294 patients (mean age 66.9 ± 10.0 years, 28.6% women) underwent both, 99mTc-tetrofosmin single-photon emission computed tomography myocardial perfusion imaging and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography for the assessment of cardiac function, bone marrow metabolism (surrogate marker of inflammation), and resting amygdalar activity. A positive association was found between amygdalar metabolism and 18F-FDG bone marrow uptake in women (r = 0.238, p = 0.029), but not in men (r = 0.060, p = 0.385). Linear regression models selected both, abnormal left ventricular ejection fraction (LVEF) and abnormal myocardial perfusion, as significant indicators of an increased amygdalar activity in women (B-coefficient LVEF, − 0.096; p = 0.021; abnormal myocardial perfusion, 3.227; p = 0.043), but not in men (bone marrow p = 0.076; abnormal myocardial perfusion p = 0.420). Accordingly, an interaction term consisting of sex and LVEF/abnormal myocardial perfusion was significant (p = 0.043 and p = 0.015, respectively). Upregulated amygdalar metabolism is associated with an enhanced inflammatory state in female patients with impaired cardiac function. Given that enhanced activity of the limbic system is associated with worse cardiovascular outcomes, our study suggests that a focus on inflammatory markers and indicators of distress might help to tailor cardiovascular risk assessment and therapy towards the female cardiovascular phenotype.

Background Emerging evidence from China suggests that coronavirus disease 2019 (COVID-19) is deadlier for infected men than women with a 2.8% fatality rate being reported in Chinese men versus 1.7% in women. Further, sex-disaggregated data for COVID-19 in several European countries show a similar number of cases between the sexes, but more severe outcomes in aged men. Case fatality is highest in men with pre-existing cardiovascular conditions. The mechanisms accounting for the reduced case fatality rate in women are currently unclear but may offer potential to develop novel risk stratification tools and therapeutic options for women and men. Content The present review summarizes latest clinical and epidemiological evidence for gender and sex differences in COVID-19 from Europe and China. We discuss potential sex-specific mechanisms modulating the course of disease, such as hormone-regulated expression of genes encoding for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) entry receptors angiotensin converting enzyme (ACE) 2 receptor and TMPRSS2 as well as sex hormone-driven innate and adaptive immune responses and immunoaging. Finally, we elucidate the impact of gender-specific lifestyle, health behavior, psychological stress, and socioeconomic conditions on COVID-19 and discuss sex specific aspects of antiviral therapies. Conclusion The sex and gender disparities observed in COVID-19 vulnerability emphasize the need to better understand the impact of sex and gender on incidence and case fatality of the disease and to tailor treatment according to sex and gender. The ongoing and planned prophylactic and therapeutic treatment studies must include prospective sex- and gender-sensitive analyses.

A reduction in left ventricular apical tracer uptake (apical thinning) is frequently observed in myocardial perfusion imaging (MPI), yet its cause remains a matter of debate, particularly in perfusion emission tomography (PET). This analysis sought to determine whether apical thinning in PET-MPI is attributable to true anatomical thinning of the left ventricular apical myocardium. We retrospectively analyzed 57 patients without any history or signs of apical myocardial infarction who underwent rest PET-MPI with 13N-ammonia and contrast-enhanced cardiac computed tomography (CT). Semi-quantitative normalized percent apical 13N-ammonia uptake at rest, myocardial blood flow (MBF), and k2 wash-out rate constants were compared to apical myocardial wall thickness measurements derived from CT and base-to-apex gradients were calculated. Apical thinning was found in 93% of patients and in 74% when analysis of normalized apical tracer uptake was confined to end-systole. No significant correlation was found between apical myocardial thickness and apical tracer uptake (r = − 0.080, P = .553), MBF (r = − 0.211, P = .115), or k2 wash-out rate (r = − 0.023, P = .872), nor between apical myocardial thickness and any gradients. A statistically significant but small difference in apical myocardial thickness was observed in patients with moderately to severely reduced apical tracer uptake vs patients with normal to mildly reduced uptake (4.3 ± 0.7 mm vs 4.7 ± 0.7 mm; P = .043). Apical thinning is a highly prevalent finding during 13N-ammonia PET-MPI that is not solely attributable to true anatomical apical wall thickness or the partial volume effect. Other factors that yet need to be identified seem to have a more prominent impact.

Objectives The aim of this study was to investigate the prognostic and clinical value of quantitative positron emission tomographic (PET) metrics in patients with ischemic heart failure. Background Although myocardial flow reserve (MFR) is a strong predictor of cardiac risk in patients without heart failure, it is unknown whether quantitative PET metrics improve risk stratification in patients with ischemic heart failure. Methods The study included 254 patients referred for stress and rest myocardial perfusion imaging and viability testing using PET. Major adverse cardiac event(s) (MACE) consisted of death, resuscitated sudden cardiac death, heart transplantation, acute coronary syndrome, hospitalization for heart failure, and late revascularization. Results MACE occurred in 170 patients (67%) during a median follow-up of 3.3 years. In a multivariate Cox proportional hazards model including multiple quantitative PET metrics, only MFR predicted MACE significantly (p = 0.013). Beyond age, symptom severity, diabetes mellitus, previous myocardial infarction or revascularization, 3-vessel disease, renal insufficiency, ejection fraction, as well as presence and burden of ischemia, scar, and hibernating myocardium, MFR was strongly associated with MACE (adjusted hazard ratio per increase in MFR by 1: 0.63; 95% confidence interval: 0.45 to 0.91). Incorporation of MFR into a risk assessment model incrementally improved the prediction of MACE (likelihood ratio chi-square test [16] = 48.61 vs. chi-square test [15] = 39.20; p = 0.002). Conclusions In this retrospective analysis of a single-center cohort, quantitative PET metrics of myocardial blood flow all improved risk stratification in patients with ischemic heart failure. However, in a hypothesis-generating analysis, MFR appears modestly superior to the other metrics as a prognostic index.

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 ± 2.51 μg/mL vs. 7.89 ± 2.99 μg/mL, p = 0.003), while cholesterol esterification rate (CER) was downregulated (253.6 ± 83.9 μM/2 h vs. 315.3 ± 115.0 μM/2 h, p

Objectives This study sought to investigate the prevalence and impact of acute kidney injury (AKI) in elderly patients undergoing percutaneous coronary intervention (PCI). Background AKI may complicate PCI and has been associated with worse outcomes. Data on AKI following PCI in elderly patients are scarce. Methods A total of 458 elderly (≥80 years) patients undergoing PCI at Charite-University Medicine Berlin between January 2009 and December 2014 were stratified according to the presence/absence of AKI. The primary endpoint was all-cause mortality. The secondary endpoint was rate of major adverse cardiovascular events (MACE), a composite of all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, and rehospitalization for heart failure. Median follow-up was 280 (interquartile range 22-1190) days. Results Of the 458 patients, 125 (27.3%) developed AKI following PCI. Age >90 years, congestive heart failure, and C-reactive protein at presentation emerged as independent predictors of AKI. All-cause mortality was 20.0% and 8.4% in patients with and without AKI (P = 0.001), and corresponding rates of MACE were 39.2% and 26.4% (P = 0.01), respectively. The occurrence of AKI was associated with an increased risk of all-cause mortality (adjusted HR 2.41, 95%CI 1.12-5.17, P = 0.02) and MACE (adjusted HR 1.75, 95%CI 1.15-2.67, P = 0.01). Conclusions AKI occurs in a third of elderly (≥80 years) patients undergoing PCI and is associated with increased mortality. These findings underline the unmet clinical need to identify novel strategies for the prevention of AKI in this high-risk patient subset.

Background The association between diagnosed acute ST-elevation myocardial infarction (STEMI) and hockey games in the Canadian population is unknown. Methods We retrospectively analyzed the association between hockey games of the National Hockey League Montreal Canadiens and daily hospital admissions for acute STEMI at the Montreal Heart Institute, Canada. Results Between June 2010 and December 2014, a total of 2199 patients (25.9% women; mean age, 62.6 ± 12.4 years) were admitted for acute STEMI. An increase in STEMI admissions was observed the day after a hockey game of the Montreal Canadiens in the overall population (from 1.3 ± 1.2 to 1.5 ± 1.3), however, this difference was not significant ( P = 0.1). The number of STEMI admissions increased significantly from 0.9 ± 1.0 to 1.2 ± 1.0 per day in men ( P = 0.04), but not in women ( P = 0.7). The association between ice hockey matches and STEMI admission rates was strongest after a victory of the Montreal Canadiens. Accordingly, an increased risk for the occurrence of STEMI was observed in the overall population (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.0-1.3; P = 0.037) when the Montreal Canadiens won a match. This association was present in men (HR, 1.2; 95% CI, 1.03-1.4; P = 0.02) but not in women ( P = 0.87), with a most pronounced effect seen in younger men (younger than 55 years; HR, 1.4; 95% CI, 1.1-1.8; P = 0.009). Conclusions Although a weak association between hockey games and hospital admissions for STEMI was found in our overall population, the event of a hockey game significantly increased the risk for STEMI in younger men. Preventive measures targeting behavioural changes could positively affect this risk.

Evidence to date on the unique female determinants of cardiovascular risk is inadequate. Positron Emission Tomography (PET) is considered to have the highest accuracy for the assessment of myocardial perfusion in patients with suspected coronary artery disease (CAD), but its long-term prognostic accuracy in women has not been established. A total of 619 consecutive patients (138 women, mean age 60.0 ± 11.8 years) underwent clinically indicated 13N-ammonia PET at our institution and were followed up (median 5.7 years) for major adverse cardiovascular events (MACE) including cardiac death, nonfatal myocardial infarction, hospitalization for any cardiac reason and late revascularization. During follow-up, 271 patients had at least one cardiac event, including 64 cardiac deaths and 33 nonfatal myocardial infarctions. In both women and men, abnormal myocardial perfusion was associated with reduced event-free survival (log rank p

AIMS Periprocedural myocardial injury (PMI) is frequently observed after percutaneous coronary interventions (PCI) for chronic total occlusion (CTO). We aimed to investigate the prognostic impact of PMI with the antegrade as compared to the retrograde crossing technique. METHODS AND RESULTS A total of 1,909 patients undergoing CTO PCI were stratified according to the presence/absence of PMI (elevation of cardiac troponin T [cTnT] >5x99th percentile of normal), and divided according to tertiles of the difference between peak and baseline cTnT within 24 hours (∆cTnT). The primary endpoint was all-cause mortality at a median follow-up of 3.1 (interquartile range 3.0-4.4) years. PMI occurred in 19.4% and 25.4% after antegrade (n=1,447) and retrograde (n=462) procedures (p

Objectives: Recommendations regarding sports restriction are lacking for middle-aged athletes with anomalous coronary arteries originating from the opposite sinus of Valsalva (ACAOS). Methods: Sixty-three patients with ACAOS were subdivided into ACAOS with (n = 38) or without (n = 25) an interarterial course (IAC). Sports behavior, either competitive (COMP) or recreational (REC), was evaluated at the time of diagnosis and after a median follow-up of 4.2 years. Results: Mean age was 56 ± 11 years and 48 (76.2%) patients were engaged in sports. Three individuals (4.8%) were surgically corrected after diagnosis. Thirty-eight (60.3%) patients were aware of their diagnosis at follow-up and 12 (19.0%) were counseled by their physician about sports restrictions. Sports behavior at the time of diagnosis and at follow-up did not differ significantly, neither in patients engaged in COMP (17.5 vs. 12.7%, p = 0.619) nor those engaged in REC (58.7 vs. 61.9%, p = 0.856). Sport-related symptoms were not significantly different between ACAOS patients with and without IAC. No athlete had died at follow-up. Conclusions: The majority of middle-aged individuals with ACAOS were involved in sports activities at the time of diagnosis and at follow-up. Awareness and counseling about ACAOS diagnosis had no significant effect on sports behavior. IAC did not have an impact on sport-related symptoms, and outcomes were favorable in all athletes, regardless of surgical correction.

Chronic kidney disease (CKD) adversely affects outcomes in patients with coronary artery disease. Data on the impact of renal impairment on prognosis of patients undergoing percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) are scarce. A total of 2002 patients undergoing CTO PCI were stratified according to baseline renal function (group 1: estimated glomerular filtration rate [eGFR] ≥ 90 ml/min/1.73 m2, group 2: 60 to 89 ml/min/1.73 m2, group 3: 30 to 59 ml/min/1.73 m2, and group 4

OBJECTIVES A single-centre, observational study was performed in order to investigate the relationship between anemia and outcomes after percutaneous coronary intervention (PCI) for chronic total occlusion (CTO). BACKGROUND Anemia has been identified as adverse predictor in patients with coronary artery disease undergoing coronary revascularization. Data on the impact of anemia on outcomes in patients undergoing PCI for CTO lesions are lacking. METHODS A total of 1,964 patients undergoing CTO PCI were stratified according to the presence/absence of anemia (hemoglobin of

Successful recanalization of chronic total occlusions (CTO) has been associated with improved survival. Data on outcomes in patients with left ventricular (LV) systolic dysfunction undergoing percutaneous coronary intervention for CTO, however, are scarce. Between January 2005 and December 2013, a total of 2,002 consecutive patients undergoing elective CTO percutaneous coronary intervention at a tertiary care center were divided into patients with (LV ejection fraction ≤ 40%) and without (LV ejection fraction 40%) LV systolic dysfunction as defined by transthoracic echocardiography. The primary end point was all-cause mortality. Median follow-up was 2.6 (1.1 to 3.1) years. A total of 348 (17.4%) patients had LV dysfunction. All-cause mortality was higher in patients with LV dysfunction (30.2%) than in those with normal LV function (8.2%, p 0.001), and associations remained significant after adjustment for baseline differences (adjusted hazard ratio [HR] 3.39, 95% confidence interval [CI] 2.57 to 4.47, p 0.001). Successful CTO recanalization was independently associated with reduced all-cause mortality, with similar relative risk reductions in both the preserved (6.6% vs 16.9%, adjusted HR 0.48, 95% CI 0.34 to 0.70, p 0.001) and the reduced LV function groups (26.2% vs 45.2%, adjusted HR 0.63, 95% CI 0.41 to 0.98, p = 0.04, interaction p = 0.28). In conclusion, irrespective of LV function, successful CTO recanalization is associated with a clear survival benefit.

AIM The prognostic value of coronary artery dominance pattern in patients with chronic total occlusions (CTO) is unknown. The aim of this study was to assess the influence of coronary vessel dominance on short and long-term outcomes in patients undergoing percutaneous coronary intervention (PCI) for CTO. METHODS AND RESULTS Our study population consisted of 2002 consecutive patients (17% females, mean age 65.2 ± 10.7 years) who underwent PCI of at least one coronary CTO lesion at our center between 01/2005 and 12/2013. Based on the origin of the posterior descending coronary artery, coronary circulation was categorised into left, right, and balanced coronary dominance. Right coronary dominance (RD) was present in 88% (n = 1759), left coronary dominance (LD) in 7% (n = 136), and balanced coronary dominance (BD) in 5% (n = 107) of the study population. After a median follow-up duration of 2.6 years [interquartile range 1.1-3.1 years] all-cause mortality was significantly higher in patients with LD as compared with RD and BD (log rank = 0.001). Accordingly, the presence of a LD system was identified as a significant predictor for all-cause mortality (adjusted HR 1.7, 95% CI: 1.2-2.6, P = .007) and major adverse cardiac events (MACE) (adjusted HR 1.4, 95% CI: 1.1-1.8, P = 0.02). CONCLUSION Our data suggest that LD is an independent predictor of increased all-cause death and MACE in patients with CTO. Therefore, assessment of coronary vessel dominance by angiography may contribute to risk stratification in these patients.

Successful CTO recanalization has been associated with clinical benefit. Outcomes of patients with atrial fibrillation undergoing CTO PCI have not been investigated, yet. This study sought to evaluate the association between atrial fibrillation and outcomes after percutaneous coronary intervention (PCI) for chronic total occlusions (CTO). Consecutive patients undergoing CTO PCI between January 2005 and December 2013 were divided into patients with and without atrial fibrillation, and propensity-matched models used to adjust for baseline differences between groups. The primary outcome was all-cause mortality at a median follow-up of 3.2 (interquartile range 3.1–4.5) years. Of 2002 patients undergoing CTO PCI, atrial fibrillation was present in 169 (8.4%) patients. Patients with atrial fibrillation were older, and more frequently had hypertension, left ventricular systolic dysfunction, and chronic kidney disease. Before matching, all-cause mortality was 39.6 and 14.5% in the atrial fibrillation and the sinus rhythm groups (HR 2.92, 95% CI 2.23–3.82, p

Aims Anomalous origin of a coronary artery from the opposite sinus (ACAOS) has been associated with adverse cardiac events in the young. It remains unknown whether this holds true for middle-aged patients with uncorrected ACAOS as well. We assessed the outcome in middle-aged patients with newly diagnosed ACAOS by coronary computed tomography angiography (CCTA) compared with a matched cohort. Methods and results We retrospectively identified 68 consecutive patients with ACAOS documented by CCTA. ACAOS with a course of the anomalous vessel between the aorta and pulmonary artery were classified as interarterial course (IAC). Each patient with ACAOS was matched to two controls without ACAOS. Major adverse cardiac events (i.e. myocardial infarction, revascularization and cardiac death) were recorded for all patients and controls. Two (3%) patients were lost to follow-up. Thus, 66 patients with ACAOS were included in the final analysis and matched with 132 controls. Mean age of patients was 56 ± 11 years, 73% were male and the mean follow-up was 49 months. Forty (65%) patients were classified as having ACAOS with IAC. The annual event rate of ACAOS vs. controls was 4.9 and 4.8%, the hazard ratio (HR) 0.94 (0.39–2.28, P = 0.89). The annual event rate of ACAOS with IAC compared with their matched controls was 5.2 and 4.3%, and the HR 1.01 (95% CI 0.39–2.58, P = 0.99). Conclusions In middle-aged individuals with newly diagnosed ACAOS mid-term outcome is not statistically different to a matched control cohort without coronary artery anomalies, regardless of whether ACAOS with or without IAC variants are present.

Purpose Clinical positron emission tomography (PET) imaging of the presynaptic norepinephrine transporter (NET) function provides valuable diagnostic information on sympathetic outflow and neuronal status. As data on the NET-targeting PET tracers [11C]meta-hydroxyephedrine ([11C]mHED) and [18F]LMI1195 ([18F]flubrobenguane) in murine experimental models are scarce or lacking, we performed a detailed characterization of their myocardial uptake pattern and investigated [11C]mHED uptake by kinetic modelling. Methods [11C]mHED and [18F]LMI1195 accumulation in the heart was studied by PET/CT in FVB/N mice. To test for specific uptake by NET, desipramine, a selective NET inhibitor, was administered by intraperitoneal injection. [11C]mHED kinetic modelling with input function from an arteriovenous shunt was performed in three mice. Results Both tracers accumulated in the mouse myocardium; however, only [11C]mHED uptake was significantly reduced by excess amount of desipramine. Myocardial [11C]mHED uptake was half-saturated at 88.3 nmol/kg of combined mHED and metaraminol residual. After [11C]mHED injection, a radiometabolite was detected in plasma and urine, but not in the myocardium. [11C]mHED kinetics followed serial two-tissue compartment models with desipramine-sensitive K1. Conclusion PET with [11C]mHED but not [18F]LMI1195 provides information on NET function in the mouse heart. [11C]mHED PET is dose-independent in the mouse myocardium at, EJNMMI Resarch, 10 (1), ISSN:2191-219X

Coronary computed tomography angiography (CCTA) provides critical prognostic information on plaque burden and stenosis severity of coronary arteries. We aimed to investigate the long-term prognostic value of coronary artery volume per myocardial mass as a potential new imaging parameter. Consecutive patients with suspected coronary artery disease (CAD) were included. Coronary artery volume index (CAVi) was defined as volume over myocardial mass. Additionally, obstructive CAD (≥ 70% stenosis) and segment severity score (SSS: sum of all segments scored according to lesion severity with 0 = no lesion, 1 = narrowing

Advances in image reconstruction are necessary to decrease radiation exposure from coronary CT angiography (CCTA) further, but iterative reconstruction has been shown to degrade image quality at high levels. Deep-learning image reconstruction (DLIR) offers unique opportunities to overcome these limitations. The present study compared the impact of DLIR and adaptive statistical iterative reconstruction-Veo (ASiR-V) on quantitative and qualitative image parameters and the diagnostic accuracy of CCTA using invasive coronary angiography (ICA) as the standard of reference.This retrospective study includes 43 patients who underwent clinically indicated CCTA and ICA. Datasets were reconstructed with ASiR-V 70% (using standard [SD] and high-definition [HD] kernels) and with DLIR at different levels (i.e., medium [M] and high [H]). Image noise, image quality, and coronary luminal narrowing were evaluated by three blinded readers. Diagnostic accuracy was compared against ICA.Noise did not significantly differ between ASiR-V SD and DLIR-M (37 vs. 37 HU, p = 1.000), but was significantly lower in DLIR-H (30 HU, p 0.001) and higher in ASiR-V HD (53 HU, p 0.001). Image quality was higher for DLIR-M and DLIR-H (3.4-3.8 and 4.2-4.6) compared to ASiR-V SD and HD (2.1-2.7 and 1.8-2.2; p 0.001), with DLIR-H yielding the highest image quality. Consistently across readers, no significant differences in sensitivity (88% vs. 92%; p = 0.453), specificity (73% vs. 73%; p = 0.583) and diagnostic accuracy (80% vs. 82%; p = 0.366) were found between ASiR-V HD and DLIR-H.DLIR significantly reduces noise in CCTA compared to ASiR-V, while yielding superior image quality at equal diagnostic accuracy.

Although health disparities in women presenting with acute coronary syndrome (ACS) have received growing attention in recent years, clinical outcomes from ACS are still worse for women than for men. Women continue to experience higher patient and system delays and receive less aggressive invasive treatment and pharmacotherapies. Gender- and sex-specific variables that contribute to ACS vulnerability remain largely unknown. Notwithstanding the sex differences in baseline coronary anatomy and function, women and men are treated the same based on guidelines that were established from experimental and clinical trial data over-representing the male population. Importantly, younger women have a particularly unfavourable prognosis and a plethora of unanswered questions remains in this younger population. The present review summarizes contemporary evidence for gender and sex differences in vascular biology, clinical presentation, and outcomes of ACS. We further discuss potential mechanisms and non-traditional risk conditions modulating the course of disease in women and men, such as unrecognized psychosocial factors, sex-specific vascular and neural stress responses, and the potential impact of epigenetic modifications.

Disease occurrence, clinical manifestations, and outcomes differ between men and women. Yet, women and men are most of the time treated similarly, which is often based on experimental data over-representing one sex. Accounting for persisting sex bias in biomedical research is the misconception that the analysis of sex-specific effects would double sample size and costs. We designed an analysis to test the potential benefits of a factorial study design in the context of a study including male and female animals. We chose a 2 × 2 factorial design approach to study the effect of treatment, sex, and an interaction term of treatment and sex in a hypothetical situation. We calculated the sample sizes required to detect an effect of a given magnitude with sufficient power and under different experimental setups. We demonstrated that the inclusion of both sexes in experimental setups, without testing for sex effects, requires no or few additional animals in our scenarios. These experimental designs still allow for the exploration of sex effects at low cost. In a confirmatory instead of an exploratory design, we observed an increase in total sample sizes by 33%, at most. Since the complexities associated with this mathematical model require statistical expertise, we generated and provide a sample size calculator for planning factorial design experiments. For the inclusion of sex, a factorial design is advisable, and a sex-specific analysis can be performed without excessive additional effort. Our easy-to-use calculation tool provides help in designing studies with both sexes and addresses the current sex bias in preclinical studies. KEY MESSAGES: • Both sexes should be included into animal studies. • Exploratory study of sex effects can be conducted with no or small increase in animal number. • Confirmatory analysis of sex effects requires maximum 33% more animals per study. • Our calculation tool supports the design of studies with both sexes.

AIMS Cardiovascular outcomes of women with coronary artery disease (CAD) are perceived as relatively worse when compared to men. Amygdalar metabolic activity has recently been shown to independently predict cardiovascular events in patients without known cardiovascular disease. Given that traditional algorithms for risk prediction perform worse in women than in men, we sought to assess sex-specific associations between amygdalar metabolic activity and cardiac dysfunction with suspected or known CAD. METHODS AND RESULTS This retrospective study included 302 patients (mean age 66.8 ± 10.2 years, 29.1% women) selected for evaluation of CAD, malignant, or inflammatory disease. All patients had undergone both, myocardial perfusion imaging by single photon emission computed tomography (MPI-SPECT) and whole-body fluoro-18-deoxyglucose (18F-FDG) positron emission tomography (PET), within 6 months. 18F-FDG resting amygdalar uptake was significantly increased in women with abnormal MPI scans (standardized uptake value 33.4 ± 6.5 vs. 30.4 ± 4.7, P = 0.043), while no such difference was observed in men (P = 0.808). In women, but not in men, a negative association between 18F-FDG resting amygdalar activity and left ventricular ejection fraction (LVEF) was observed (Pearson r = -0.308, P = 0.004). Accordingly, either LVEF [B-coefficient (standard error, SE) = -0.232 (0.109), P = 0.045] or abnormal MPI [B-coefficient (SE) = 8.264 (2.449), P = 0.003] were selected as significant predictors of high amygdalar 18F-FDG uptake in a fully adjusted linear regression model in women, and a first order interaction term consisting of sex and LVEF or sex and abnormal MPI was significant (P = 0.035 and P = 0.001, respectively). CONCLUSION Resting amygdalar metabolic activity is associated with abnormal cardiac function and perfusion in women, suggesting a link between emotional stress and cardiovascular disease in women.

Aims There are significant sex-specific differences in left ventricular ejection fraction (LVEF), with a higher LVEF being observed in women. We sought to assess the clinical relevance of an increased LVEF in women and men. Methods and results A total of 4632 patients from the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry (44.8% women; mean age 58.7 ± 13.2 years in men and 59.5 ± 13.3 years in women, P = 0.05), in whom LVEF was measured by cardiac computed tomography, were categorized according to LVEF (low 65%). The prevalence of high LVEF was similar in both sexes (33.5% in women and 32.5% in men, P = 0.46). After 6 years of follow-up, no difference in mortality was observed in patients with high LVEF in the overall cohort (P = 0.41). When data were stratified by sex, women with high LVEF died more often from any cause as compared to women with normal LVEF (8.6% vs. 7.1%, log rank P = 0.032), while an opposite trend was observed in men (5.8% vs. 6.8% in normal LVEF, log rank P = 0.89). Accordingly, a first order interaction term of male sex and high LVEF was significant (hazard ratios 0.63, 95% confidence intervals 0.41–0.98, P = 0.043) in a Cox regression model of all-cause mortality adjusted for age, cardiovascular risk factors, and severity of coronary artery disease (CAD). Conclusion Increased LVEF is highly prevalent in patients referred for evaluation of CAD and is associated with an increased risk of death in women, but not in men. Differentiating between normal and hyperdynamic left ventricles might improve risk stratification in women with CAD. Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT01443637.

To assess the functional relevance of a coronary artery stenosis, corrected coronary opacification (CCO) decrease derived from coronary computed tomography angiography (CCTA) has been proposed. The present study aims at validating CCO decrease with quantitative 13N-ammonia positron emission tomography (PET) myocardial perfusion imaging (MPI). This retrospective study consists of 39 patients who underwent hybrid CCTA/PET-MPI. From CCTA, attenuation in the coronary lumen was measured before and after a stenosis and corrected to the aorta to calculate CCO and its decrease. Relative flow reserve (RFR) was calculated by dividing the stress myocardial blood flow (MBF) of a vessel territory subtended by a stenotic coronary by the stress MBF of the reference territories without stenoses. RFR was abnormal in 11 vessel territories (27%). CCO decrease yielded a sensitivity, specificity, negative predictive value, positive predictive value, and accuracy for prediction of an abnormal RFR of 73%, 70%, 88%, 47%, and 70%, respectively. CCTA-derived CCO decrease has moderate diagnostic accuracy to predict an abnormal RFR in PET-MPI. However, its high negative predictive value to rule out functional relevance of a given lesion may confer clinical implications in the diagnostic work-up of patients with a coronary stenosis.

Aim Amongst patients with coronary artery disease (CAD), women experience relatively worse outcomes as compared to men. Evidence to date has failed to explore unique female imaging targets as major determinants of cardiovascular risk. We sought to assess the prognostic value of epicardial (EFV) and intrathoracic fat volume (IFV) quantification in women and men with suspected and known CAD. Methods and results Intrathoracic fat volume and EFV were calculated from non-contrast CT and analyzed in a propensity-matched cohort of 190 patients (95 women, mean age 62.5 ± 11.3 years) undergoing myocardial perfusion imaging (MPI) and coronary computed tomography angiography (CCTA) for evaluation of CAD. IFV and EFV were significantly lower in women as compared to men (198.2 ± 78.4 vs 293.2 ± 114.7 cm3 and 105.6 ± 48.9 vs 135.8 ± 60.9 cm3, p Conclusion Quantification of IFV provides incremental prognostic value for MACE in women, beyond that provided by traditional risk factors and imaging findings.

Background: Recent studies indicate that enhanced neuronal stress responses are associated with adverse cardiovascular outcomes. A chronic inflammatory state seems to mediate this detrimental neuro-cardiac communication. Statins are among the most widely prescribed medications in primary and secondary cardiovascular disease (CVD) prevention and not only lower lipid levels but also exhibit strong anti-inflammatory and neuroprotective effects. We therefore sought to investigate the influence of statins on neuronal stress responses in a patient cohort at risk for CVD. Methods: 563 patients (61.5 ± 14.0 years) who underwent echocardiography and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) were retrospectively identified. Metabolic activity of the amygdala, a part of the brain’s salience network, was quantified by 18F-FDG uptake, while normal cardiac morphology and function were assured by echocardiography. Vertebral bone marrow metabolism, a marker of inflammatory activity, was measured by 18F-FDG PET. Results: Increased neuronal stress responses were associated with an increased inflammatory activity in the bone marrow (r = 0.152, p = 0.015) as well as with a subclinical reduction in left ventricular ejection fraction (LVEF, r = −0.138, p = 0.025). In a fully-adjusted linear regression model, statin treatment was identified as an independent, negative predictor of amygdalar metabolic activity (B-coefficient −0.171, p = 0.043). Conclusions: Our hypothesis-generating investigation suggests a potential link between the anti-inflammatory actions of statins and reduced neuronal stress responses which could lead to improved cardiovascular outcomes. The latter warrants further studies in a larger and prospective population.

Background As technologies of percutaneous coronary intervention (PCI) for coronary chronic total occlusions (CTO) have improved, great uncertainty exists regarding patient selection and long-term benefit of CTO-PCI. Given that white blood cell (WBC) count has been associated with cardiovascular risk, we hypothesized that the latter might provide incremental prognostic value in patients undergoing CTO-PCI. Methods and Results Our study population consisted of 1,262 consecutive patients (76.3% males, mean age of 67.7 ± 10.3 years) who underwent elective PCI at our centre between January 2002 and December 2008. Four hundred seventy-five patients had at least one CTO, while 787 patients with non-occlusive coronary lesions served as controls. Baseline WBC count was higher in CTO patients as compared with controls (8,072 ± 3,459/μL vs. 7,469 ± 2,668/μL, p = 0.001) and independently predicted the occurrence of a CTO lesion (odds ratio: 1.8; 95% confidence interval [CI]: 1.3–2.4; p Conclusion Assessment of the inflammatory status of CTO patients may be an important element in selecting CTO patients at low risk who may be referred to CTO-PCI.

Background The obesity paradox has been described in different patient populations. Data on the relation between obesity and outcomes in patients undergoing percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) are lacking. Therefore, long-term mortality in patients undergoing CTO PCI was assessed according to different body mass index (BMI) categories. Methods A total of 1993 patients undergoing CTO PCI at a tertiary care center between January 2005 and December 2013 were divided into five different BMI categories: underweight, 2 ; normal BMI, 18.5–24.9kg/m 2 ; overweight, 25.0–29.9kg/m 2 ; obese, 30.0–34.9kg/m 2 ; and very obese, ≥35.0kg/m 2 . The primary endpoint was all-cause mortality. Results Median follow-up was 2.6 (interquartile range 1.1–3.1) years. Of the 1993 patients, 461 (23.1%) were of normal weight, 985 (49.4%) overweight, 396 (19.9%) obese, and 144 (7.2%) very obese. Compared with normal weight BMI patients (16.3%), overweight patients had a lower all-cause mortality (10.2%, Log Rank p=0.001), while obese (11.1%, Log Rank p=0.08) and severely obese (13.2%, Log Rank p=0.39) patients had similar mortality rates. Being overweight was significantly associated with a lower all-cause mortality (HR 0.69, 95% CI 0.53–0.89, p=0.005), and associations remained significant after multivariable adjustments for confounding factors (HR 0.73, 95% CI 0.56–0.95, p=0.02). While being overweight was linked with a reduced all-cause mortality in men (HR 0.65, 95% CI 0.48–0.88, p=0.005), it was not in women (HR 1.25, 95% CI 0.60–2.52, p=0.58). Conclusions Overweight is associated with an improved survival in patients undergoing PCI for CTO, particularly in men.

BACKGROUND: Left ventricular (LV) volumetric and functional parameters measured with cardiac computed tomography (cardiac CT) augment risk prediction and discrimination for future mortality. Gender- and age-specific standard values for LV dimensions and systolic function obtained by 64-slice cardiac CT are lacking. METHODS AND RESULTS: 1155 patients from the Coronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter registry (54.5% males, mean age 53.1 ± 12.4 years, range: 18-92 years) without known coronary artery disease (CAD), structural heart disease, diabetes, or hypertension who underwent cardiac CT for various indications were categorized according to age and sex. A cardiac CT data acquisition protocol was used that allowed volumetric measuring of LV function. Image interpretation was performed at each site. Patients with significant CAD (>50% stenosis) on cardiac CT were excluded from the analysis. Overall, mean left ventricular ejection fraction (LVEF) was higher in women when compared with men (66.6 ± 7.7% vs. 64.6 ± 8.1%, P < 0.001). This gender-difference in overall LVEF was caused by a significantly higher LVEF in women ≥70 years when compared with men ≥70 years (69.95 ± 8.89% vs. 65.50 ± 9.42%, P = 0.004). Accordingly, a significant increase in LVEF was observed with age (P = 0.005 for males and P < 0.001 for females), which was more pronounced in females (5.21%) than in males (2.6%). LV end-diastolic volume decreased in females from 122.48 ± 27.87 (70 years; P < 0.001) and in males from 155.22 ± 35.07 (70 years; P < 0.001). CONCLUSION: Our findings indicate that the LV undergoes a lifelong remodelling and highlight the need for age and gender adjusted reference values. info:eu-repo/semantics/publishedVersion

Objective: Positron emission tomography/computed tomography with 18F-fluorodeoxy-glucose (18F-FDG-PET/CT) has become the standard staging modality in various tumor entities. Cancer patients frequently receive cardio-toxic therapies. However, routine cardiovascular assessment in oncologic patients is not performed in current clinical practice. Accordingly, this study sought to assess whether myocardial 18F-FDG uptake patterns of patients undergoing oncologic PET/CT can be used for cardiovascular risk stratification. Methods: Myocardial 18F-FDG uptake pattern was assessed in 302 patients undergoing both oncologic whole-body 18F-FDG-PET/CT and myocardial perfusion imaging by single-photon emission computed tomography (SPECT-MPI) within a six-month period. Primary outcomes were myocardial 18F-FDG uptake pattern, impaired myocardial perfusion, ongoing ischemia, myocardial scar, and left ventricular ejection fraction. Results: Among all patients, 109 (36.1%) displayed no myocardial 18F-FDG uptake, 77 (25.5%) showed diffuse myocardial 18F-FDG uptake, 24 (7.9%) showed focal 18F-FDG uptake, and 92 (30.5%) had a focal on diffuse myocardial 18F-FDG uptake pattern. In contrast to the other uptake patterns, focal myocardial 18F-FDG uptake was predominantly observed in patients with myocardial abnormalities (i.e., abnormal perfusion, impaired LVEF, myocardial ischemia, or scar). Accordingly, a multivariate logistic regression identified focal myocardial 18F-FDG uptake as a strong predictor of abnormal myocardial function/perfusion (odds ratio (OR) 5.32, 95% confidence interval (CI) 1.73&ndash, 16.34, p = 0.003). Similarly, focal myocardial 18F-FDG uptake was an independent predictor of ongoing ischemia and myocardial scar (OR 4.17, 95% CI 1.53&ndash, 11.4, p = 0.005 and OR 3.78, 95% CI 1.47&ndash, 9.69, p = 0.006, respectively). Conclusions: Focal myocardial 18F-FDG uptake seen on oncologic PET/CT indicates a significantly increased risk for multiple myocardial abnormalities. Obtaining and taking this information into account will help to stratify patients according to risk and will reduce unnecessary cardiovascular complications in cancer patients.