Systems immunology-based drug repurposing framework to target inflammation in atherosclerosis.

The development of new immunotherapies to treat the inflammatory mechanisms that sustain atherosclerotic cardiovascular disease (ASCVD) is urgently needed. Herein, we present a path to drug repurposing to identify immunotherapies for ASCVD. The integration of time-of-flight mass cytometry and RNA sequencing identified unique inflammatory signatures in peripheral blood mononuclear cells stimulated with ASCVD plasma. By comparing these inflammatory signatures to large-scale gene expression data from the LINCS L1000 dataset, we identified drugs that could reverse this inflammatory response. Ex vivo screens, using human samples, showed that saracatinib-a phase 2a-ready SRC and ABL inhibitor-reversed the inflammatory responses induced by ASCVD plasma. In Apoe-/- mice, saracatinib reduced atherosclerosis progression by reprogramming reparative macrophages. In a rabbit model of advanced atherosclerosis, saracatinib reduced plaque inflammation measured by [18F] fluorodeoxyglucose positron emission tomography-magnetic resonance imaging. Here we show a systems immunology-driven drug repurposing with a preclinical validation strategy to aid the development of cardiovascular immunotherapies.

Erratum: Publisher Correction: Systems immunology-based drug repurposing framework to target inflammation in atherosclerosis.

[This corrects the article DOI: 10.1038/s44161-023-00278-y.].

Impact of age on reperfusion success and long-term prognosis in ST-segment elevation myocardial infarction - A cardiac magnetic resonance imaging study.

BACKGROUND: Coronary collateral circulation and conditioning from remote ischemic coronary territories may protect culprit myocardium in the elderly, and younger STEMI patients could suffer from larger infarcts. We evaluated the impact of age on myocardial salvage and long-term prognosis in a contemporary STEMI cohort. METHODS: Of 1603 included STEMI patients 807 underwent cardiac magnetic resonance. To assess the impact of age on infarct size and left ventricular ejection fraction (LVEF) as well as the composite endpoint of death and re-hospitalization for heart failure we stratified the patients by an age cut-off of 60 years. RESULTS: Younger STEMI patients had smaller final infarcts (10% vs. 12%, P = 0.012) and higher final LVEF (60% vs. 58%, P = 0.042). After adjusting for multiple potential confounders age did not remain significantly associated with infarct size and LVEF. During 4-year follow-up, the composite endpoint occurred less often in the young (3.2% vs. 17.2%; P < 0.001) with a univariate hazard ratio of 5.77 (95% CI, 3.75-8.89; p < 0.001). Event estimates of 4 subgroups (young vs. elderly and infarct size beyond vs. below median) showed a gradual increase in the occurrence of the composite endpoint depending on both age and acute infarct size (log-rank p < 0.001). CONCLUSION: Having a STEMI after entering the seventh decade of life more than quadrupled the risk of future death or re-hospitalization for heart failure. Risk of death and re-hospitalization depended on both advanced age and infarct size, albeit no substantial difference was found in infarct size, LVEF and salvage potential between younger and elderly patients with STEMI.

Infarct size following loading with Ticagrelor/Prasugrel versus Clopidogrel in ST-segment elevation myocardial infarction.

BACKGROUND: Treatment with newer direct-acting anti-platelet drugs (Ticagrelor and Prasugrel) prior to primary percutaneous coronary intervention (PCI) is associated with improved outcome in patients with ST-segment elevation myocardial infarction (STEMI) when compared with Clopidogrel. We compared infarct size following treatment with Ticagrelor/Prasugrel versus Clopidogrel in the DANish trial in Acute Myocardial Infarction (DANAMI-3) population of STEMI patients treated with primary PCI. METHODS AND RESULTS: Patients were loaded with Clopidogrel, Ticagrelor or Prasugrel in the ambulance before primary PCI. Infarct size and myocardial salvage index were calculated using cardiac magnetic resonance (CMR) during index admission and at three-month follow-up. Six-hundred-and-ninety-three patients were included in this analysis. Clopidogrel was given to 351 patients and Ticagrelor/Prasugrel to 342 patients. The groups were generally comparable in terms of baseline and procedural characteristics. Median infarct size at three-month follow-up was 12.9% vs 10.0%, in patients treated with Clopidogrel and Ticagrelor/ Prasugrel respectively (p < 0.001), and myocardial salvage index was 66% vs 71% (p < 0.001). Results remained significant in a multiple regression model (p < 0.001). CONCLUSIONS: Pre-hospital loading with Ticagrelor or Prasugrel compared to Clopidogrel, was associated with smaller infarct size and larger myocardial salvage index at three-month follow-up in patients with STEMI treated with primary PCI.

Sub-acute cardiac magnetic resonance to predict irreversible reduction in left ventricular ejection fraction after ST-segment elevation myocardial infarction: A DANAMI-3 sub-study.

AIMS: To predict irreversible reduction in left ventricular ejection fraction (LVEF) during admission for ST-segment elevation myocardial infarction (STEMI) using cardiac magnetic resonance (CMR) in addition to classical clinical parameters. Irreversible reduction in LVEF is an important prognostic factor after STEMI which necessitates medical therapy and implantation of prophylactic implantable cardioverter defibrillator (ICD). METHODS AND RESULTS: A post-hoc analysis of DANAMI-3 trial program (Third DANish Study of Optimal Acute Treatment of Patients With ST-elevation Myocardial Infarction) which recruited 649 patients who had CMR performed during index hospitalization and after 3 months. Patients were divided into two groups according to CMR-LVEF at 3 months: Group 1 with LVEF≤35% and Group 2 with LVEF>35%. Group 1 included 15 patients (2.3%) while Group 2 included 634 patients (97.7%). A multivariate analysis showed that: Killip class >1 (OR 7.39; CI:1.47-36.21, P = 0.01), symptom onset-to-wire ≥6 h (OR 7.19; CI 1.07-50.91, P = 0.04), LVEF≤35% using index echocardiography (OR 7.11; CI: 1.27-47.43, P = 0.03), and infarct size ≥40% of LV on index CMR (OR 42.62; CI:7.83-328.29, P < 0.001) independently correlated with a final LVEF≤35%. Clinical models consisted of these parameters could identify 7 out of 15 patients in Group 1 with 100% positive predictive value. CONCLUSION: Together with other clinical measurements, the assessment of infarct size using late Gadolinium enhancement by CMR during hospitalization is a strong predictor of irreversible reduction in CMR_LVEF ≤35. That could potentially, after validation with future research, aids the selection and treatment of high-risk patients after STEMI, including implantation of prophylactic ICD during index hospitalization.

Complete Revascularization Versus Culprit Lesion Only in Patients With ST-Segment Elevation Myocardial Infarction and Multivessel Disease: A DANAMI-3-PRIMULTI Cardiac Magnetic Resonance Substudy.

OBJECTIVES: The aim of this study was to evaluate the effect of fractional flow reserve (FFR)-guided revascularization compared with culprit-only percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) on infarct size, left ventricular (LV), function, LV remodeling, and the presence of nonculprit infarctions. BACKGROUND: Patients with STEMI with multivessel disease might have improved clinical outcomes after complete revascularization compared with PCI of the infarct-related artery only, but the impact on infarct size, LV function, and remodeling as well as the risk for periprocedural infarction are unknown. METHODS: In this substudy of the DANAMI-3 (Third Danish Trial in Acute Myocardial Infarction)-PRIMULTI (Primary PCI in Patients With ST-Elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization) randomized trial, patients with STEMI with multivessel disease were randomized to receive either complete FFR-guided revascularization or PCI of the culprit vessel only. The patients underwent cardiac magnetic resonance imaging during index admission and at 3-month follow-up. RESULTS: A total of 280 patients (136 patients with infarct-related and 144 with complete FFR-guided revascularization) were included. There were no differences in final infarct size (median 12% [interquartile range: 5% to 19%] vs. 11% [interquartile range: 4% to 18%]; p = 0.62), myocardial salvage index (median 0.71 [interquartile range: 0.54 to 0.89] vs. 0.66 [interquartile range: 0.55 to 0.87]; p = 0.49), LV ejection fraction (mean 58 ± 9% vs. 59 ± 9%; p = 0.39), and LV end-systolic volume remodeling (mean 7 ± 22 ml vs. 7 ± 19 ml; p = 0.63). New nonculprit infarction occurring after the nonculprit intervention was numerically more frequent among patients treated with complete revascularization (6 [4.5%] vs. 1 [0.8%]; p = 0.12). CONCLUSIONS: Complete FFR-guided revascularization in patients with STEMI and multivessel disease did not affect final infarct size, LV function, or remodeling compared with culprit-only PCI.

Early risk stratification using Rubidium-82 positron emission tomography in STEMI patients.

BACKGROUND: Assessment of infarct size after myocardial infarction is predictive of subsequent morphological changes and clinical outcome. This study aimed to assess subacute post-intervention Rubidium-82 (82Rb)-PET imaging in predicting left ventricle ejection fraction, regional wall motion, and final infarct size by CMR at 3-months after STEMI. METHODS: STEMI patients undergoing percutaneous coronary intervention were included prospectively. Rest-only 82Rb-PET perfusion imaging was performed at median 36 hours [IQR: 22 to 50] after the treatment. The extent of hypoperfusion and absolute blood flow (mL·min·g) were estimated on a global and a 17-segment model with dedicated software. At 3-months follow-up patients completed the CMR functional and late gadolinium enhancement imaging. RESULTS: 42 patients were included, but only 35 had follow-up CMR and constituted the study population. Absolute blood flow was significantly lower in the infarct-related territory compared to remote myocardium, P < .005. Extent of hypoperfusion correlated with final infarct size, r = 0.58, P < .001, while blood flow correlated with ejection fraction, r = 0.41, P < .05. In linear mixed models, higher subacute absolute blood flow (ß = 4.6, confidence interval [3.5; 5.2], P < .001, R2 = 0.67) was associated with greater wall motion. Segmental extent of subacute hypoperfusion (ß = 0.43 [0.38; 0.49], P < .001, R2 = 0.58) was associated with the degree of late gadolinium enhancement at 3-months. CONCLUSIONS: Subacute rest-only 82Rb-PET is feasible following STEMI and seems predictive of myocardial function and infarct size at 3-months.

Rubidium-82 PET imaging is feasible in a rat myocardial infarction model.

BACKGROUND: Small-animal myocardial infarct models are frequently used in the assessment of new cardioprotective strategies. A validated quantification of perfusion using a non-cyclotron-dependent PET tracer would be of importance in monitoring response to therapy. We tested whether myocardial PET perfusion imaging is feasible with Rubidium-82 (82Rb) in a small-animal scanner using a rat myocardial infarct model. METHODS: 18 Sprague-Dawley rats underwent permanent coronary artery ligation (infarct group), and 11 rats underwent ischemia-reperfusion (reperfusion group) procedure. 82Rb-PET and magnetic resonance imaging (MRI) were conducted before and after the intervention. Perfusion was compared to both left ventricle ejection fraction (LVEF) and infarct size assessed by MRI. RESULTS: Follow-up global 82Rb-uptake correlated significantly with infarct size (infarct group: r = -0.81, P < 0.001 and reperfusion group: r = -0.61, P = 0.04). Only 82Rb-uptake in the infarct group correlated with LVEF. At follow-up, a higher segmental 82Rb-uptake in the infarct group was associated with better wall motion (ß = 0.034, CI [0.028;0.039], P < 0.001, R2 = 0.30), and inversely associated with scar transmurality (ß = -2.4 [-2.6; -2.2], P < 0.001, R2 = 0.59). The associations were similar for the reperfusion group. CONCLUSION: 82Rb-PET is feasible in small animal scanners despite the long positron range and enables fast and time-efficient myocardial perfusion imaging in rat models.

Assessment of the myocardial area at risk: comparing T2-weighted cardiovascular magnetic resonance imaging with contrast-enhanced cine (CE-SSFP) imaging-a DANAMI3 substudy.

AIMS: Myocardial salvage following treatment for ST-segment elevation myocardial infarction is prognostic for morbidity and mortality. Studies with myocardial salvage as endpoint rely on valid assessment of the myocardial area at risk (AAR). T2-weighted cardiovascular magnetic resonance (CMR) imaging is the preferred method to assess the AAR. However, T2-weighted imaging can be of poor image quality and uninterpretable. Contrast-enhanced (CE) cine imaging can also show AAR and our aim was to investigate if CE-cine can replace T2-weighted imaging. Cine imaging is part of a standard CMR-protocol and implementing CE-cine imaging for assessment of the AAR would mean shorter investigation time. METHODS AND RESULTS: As a DANAMI-3 substudy, we performed successful dual imaging of the AAR in 166 participants using both T2-weighted short tau inversion recovery (T2-STIR) and CE-cine imaging. T2-STIR imaging was non-diagnostic in nine and CE-cine in one scan during the period. CE-cine measured 4.7% of left ventricle (LV) [95% confidence interval 3.2-6.2%] smaller AAR compared with T2-STIR images (P < 0.001). Visual analysis of a plot of infarct size vs. AAR showed an overestimation of the AAR when measured with T2-STIR images. There was no difference in AAR with CE-cine in an interobserver analysis of 46 scans [1.2 g (standard deviation 9.5), P = 0.42]. CONCLUSIONS: CE-cine imaging shows good internal consistency in assessment of the AAR. A visual inspection reveals possible overestimation of AAR with T2-STIR images. There is good interobserver agreement in the analysis of CE-cine imaging. CE-cine can replace T2-STIR imaging resulting in a more valid assessment of the myocardial AAR.

Importance of elevated heart rate in the very early phase of ST-segment elevation myocardial infarction: Results from the DANAMI-3 trial.

BACKGROUND: Elevated heart rate is associated with poor clinical outcome in patients with acute myocardial infarction. However, in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention the importance of elevated heart rate in the very early phase remains unknown. We evaluated the impact of elevated heart rate in the very early pre-hospital phase of ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention on cardiovascular magnetic resonance markers of reperfusion success and clinical outcome. METHODS: In this DANAMI-3 substudy, 1560 ST-segment elevation myocardial infarction patients in sinus rhythm without cardiogenic shock were included in the analyses of clinical outcome and 796 patients underwent cardiovascular magnetic resonance to evaluate area at risk, infarct size and left ventricular ejection fraction. Heart rate was assessed on the first electrocardiogram with ST-elevation (time of diagnosis). RESULTS: Despite equal area at risk (33%±11 versus 36%±16, p=0.174) patients with a pre-hospital heart rate ⩾100 beats per minute developed larger infarcts (19% (interquartile range, 9-17) versus 11% (interquartile range, 10-28), p=0.001) and a lower left ventricular ejection fraction (54%±12 versus 58%±9, p=0.047). Pre-hospital heart rate ⩾100 beats per minute was independently associated with an increased risk of all-cause mortality and heart failure (hazard ratio 2.39 (95% confidence interval 1.58-3.62), p<0.001). CONCLUSIONS: Very early heart rate ⩾100 beats per minute in ST-segment elevation myocardial infarction was independently associated with larger infarct size, reduced left ventricular ejection fraction and an increased risk of all-cause mortality and heart failure, and thus serves as an easily obtainable and powerful tool to identify ST-segment elevation myocardial infarction patients at high risk.

Retention and Functional Effect of Adipose-Derived Stromal Cells Administered in Alginate Hydrogel in a Rat Model of Acute Myocardial Infarction.

BACKGROUND: Cell therapy for heart disease has been proven safe and efficacious, despite poor cell retention in the injected area. Improving cell retention is hypothesized to increase the treatment effect. In the present study, human adipose-derived stromal cells (ASCs) were delivered in an in situ forming alginate hydrogel following acute myocardial infarction (AMI) in rats. METHODS: ASCs were transduced with luciferase and tested for ASC phenotype. AMI was inducted in nude rats, with subsequent injection of saline (controls), 1 × 106 ASCs in saline or 1 × 106 ASCs in 1% (w/v) alginate hydrogel. ASCs were tracked by bioluminescence and functional measurements were assessed by magnetic resonance imaging (MRI) and 82rubidium positron emission tomography (PET). RESULTS: ASCs in both saline and alginate hydrogel significantly increased the ejection fraction (7.2% and 7.8% at 14 days and 7.2% and 8.0% at 28 days, resp.). After 28 days, there was a tendency for decreased infarct area and increased perfusion, compared to controls. No significant differences were observed between ASCs in saline or alginate hydrogel, in terms of retention and functional salvage. CONCLUSION: ASCs improved the myocardial function after AMI, but administration in the alginate hydrogel did not further improve retention of the cells or myocardial function.

Subacute cardiac rubidium-82 positron emission tomography (82Rb-PET) to assess myocardial area at risk, final infarct size, and myocardial salvage after STEMI.

BACKGROUND: Determining infarct size and myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI) is important when assessing the efficacy of new reperfusion strategies. We investigated whether rest 82Rb-PET myocardial perfusion imaging can estimate area at risk, final infarct size, and myocardial salvage index when compared to cardiac SPECT and magnetic resonance (CMR). METHODS: Twelve STEMI patients were injected with 99mTc-Sestamibi intravenously immediate prior to reperfusion. SPECT, 82Rb-PET, and CMR imaging were performed post-reperfusion and at a 3-month follow-up. An automated algorithm determined area at risk, final infarct size, and hence myocardial salvage index. RESULTS: SPECT, CMR, and PET were performed 2.2 ± 0.5, 34 ± 8.5, and 32 ± 24.4 h after reperfusion, respectively. Mean (± SD) area at risk were 35.2 ± 16.6%, 34.7 ± 11.3%, and 28.1 ± 16.1% of the left ventricle (LV) in SPECT, CMR, and PET, respectively, P = 0.04 for difference. Mean final infarct size estimates were 12.3 ± 15.4%, 13.7 ± 10.4%, and 11.9 ± 14.6% of the LV in SPECT, CMR, and PET imaging, respectively, P = .72. Myocardial salvage indices were 0.64 ± 0.33 (SPECT), 0.65 ± 0.20 (CMR), and 0.63 ± 0.28 (PET), (P = .78). CONCLUSIONS: 82Rb-PET underestimates area at risk in patients with STEMI when compared to SPECT and CMR. However, our findings suggest that PET imaging seems feasible when assessing the clinical important parameters of final infarct size and myocardial salvage index, although with great variability, in a selected STEMI population with large infarcts. These findings should be confirmed in a larger population.

Left Ventricular Hypertrophy Is Associated With Increased Infarct Size and Decreased Myocardial Salvage in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

BACKGROUND: Approximately one third of patients with ST-segment elevation myocardial infarction (STEMI) have left ventricular hypertrophy (LVH), which is associated with impaired outcome. However, the causal association between LVH and outcome in STEMI is unknown. We evaluated the association between LVH and: myocardial infarct size, area at risk, myocardial salvage, microvascular obstruction, left ventricular (LV) function (all determined by cardiac magnetic resonance [CMR]), and all-cause mortality and readmission for heart failure in STEMI patients treated with primary percutaneous coronary intervention. METHODS AND RESULTS: In this substudy of the DANAMI-3 trial, 764 patients underwent CMR. LVH was defined by CMR and considered present if LV mass exceeded 77 (men) and 67 g/m2 (women). One hundred seventy-eight patients (24%) had LVH. LVH was associated with a larger final infarct size (15% [interquartile range {IQR}, 10-21] vs 9% [IQR, 3-17]; P<0.001) and smaller final myocardial salvage index (0.6 [IQR, 0.5-0.7] vs 0.7 [IQR, 0.5-0.9]; P<0.001). The LVH group had a higher incidence of microvascular obstruction (66% vs 45%; P<0.001) and lower final LV ejection fraction (LVEF; 53% [IQR, 47-60] vs 61% [IQR, 55-65]; P<0.001). In a Cox regression analysis, LVH was associated with a higher risk of all-cause mortality and readmission for heart failure (hazard ratio 2.59 [95% CI, 1.38-4.90], P=0.003). The results remained statistically significant in multivariable models. CONCLUSIONS: LVH is independently associated with larger infarct size, less myocardial salvage, higher incidence of microvascular obstruction, lower LVEF, and a higher risk of all-cause mortality and incidence of heart failure in STEMI patients treated with primary percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01435408.

Transthoracic Doppler echocardiography compared with positron emission tomography for assessment of coronary microvascular dysfunction: The iPOWER study.

BACKGROUND: Coronary microvascular function can be assessed by transthoracic Doppler echocardiography as a coronary flow velocity reserve (TTDE CFVR) and by positron emission tomography as a myocardial blood flow reserve (PET MBFR). PET MBFR is regarded the noninvasive reference standard for measuring coronary microvascular function but has limited availability. We compared TTDE CFVR with PET MBFR in women with angina pectoris and no obstructive coronary artery disease and assessed repeatability of TTDE CFVR. METHODS: From a cohort of women with angina and no obstructive coronary artery stenosis at invasive coronary angiography, TTDE CFVR by dipyridamole induced stress and MBFR by rubidium-82 PET with adenosine was successfully measured in 107 subjects. Repeatability of TTDE CFVR was assessed in 10 symptomatic women and in 10 healthy individuals. RESULTS: MBFR was systematically higher than CFVR. Median MBFR (interquartile range, IQR) was 2.68 (2.29-3.10) and CFVR (IQR) was 2.31 (1.89-2.72). Pearson's correlation coefficient was 0.36 (p<0.01). Limits of agreement (2·standard deviation) assessed by the Bland-Altman (confidence interval, CI) method was 1.49 (1.29;1.69) and unaffected by time-interval between examinations. Results were similar when adjusting for rate pressure product or focusing on perfusion of the left anterior descending artery region. Limits of agreement (CI) for repeated CFVR in 10 healthy individuals and in 10 women with angina was 0.44 (0.21;0.68) and 0.48 (0.22; 0.74), respectively. CONCLUSION: CFVR had a good repeatability, but the agreement between CFVR and MBFR was modest. Divergence could be due to methodology differences; TTDE estimates flow velocities whereas PET estimates myocardial blood flow.

Coronary microvascular function and myocardial fibrosis in women with angina pectoris and no obstructive coronary artery disease: the iPOWER study.

BACKGROUND: Even in absence of obstructive coronary artery disease women with angina pectoris have a poor prognosis possibly due to coronary microvascular disease. Coronary microvascular disease can be assessed by transthoracic Doppler echocardiography measuring coronary flow velocity reserve (CFVR) and by positron emission tomography measuring myocardial blood flow reserve (MBFR). Diffuse myocardial fibrosis can be assessed by cardiovascular magnetic resonance (CMR) T1 mapping. We hypothesized that coronary microvascular disease is associated with diffuse myocardial fibrosis. METHODS: Women with angina, a clinically indicated coronary angiogram with <50 % stenosis and no diabetes were included. CFVR was measured using dipyridamole (0.84 mg/kg) and MBFR using adenosine (0.84 mg/kg). Focal fibrosis was assessed by 1.5 T CMR late gadolinium enhancement (0.1 mmol/kg) and diffuse myocardial fibrosis by T1 mapping using a modified Look-Locker pulse sequence measuring T1 and extracellular volume fraction (ECV). RESULTS: CFVR and CMR were performed in 64 women, mean (SD) age 62.5 (8.3) years. MBFR was performed in a subgroup of 54 (84 %) of these women. Mean native T1 was 1023 (86) and ECV (%) was 33.7 (3.5); none had focal fibrosis. Median (IQR) CFVR was 2.3 (1.9; 2.7), 23 (36 %) had CFVR < 2 indicating coronary microvascular disease, and median MBFR was 2.7 (2.2; 3.0) and 19 (35 %) had a MBFR value below 2.5. No significant correlations were found between CFVR and ECV or native T1 (R 2 = 0.02; p = 0.27 and R 2 = 0.004; p = 0.61, respectively). There were also no correlations between MBFR and ECV or native T1 (R 2 = 0.1; p = 0.13 and R 2 = 0.004, p = 0.64, respectively). CFVR and MBFR were correlated to hypertension and heart rate. CONCLUSION: In women with angina and no obstructive coronary artery disease we found no association between measures of coronary microvascular disease and myocardial fibrosis, suggesting that myocardial ischemia induced by coronary microvascular disease does not elicit myocardial fibrosis in this population. The examined parameters seem to provide independent information about myocardial and coronary disease.

Coronary flow velocity reserve by echocardiography: feasibility, reproducibility and agreement with PET in overweight and obese patients with stable and revascularized coronary artery disease.

BACKGROUND: Coronary flow velocity reserve (CFVR) measured by transthoracic Doppler echocardiography of the LAD is used to assess microvascular function but validation studies in clinical settings are lacking. We aimed to assess feasibility, reproducibility and agreement with myocardial flow reserve (MFR) measured by PET in overweight and obese patients. METHODS: Participants with revascularized coronary artery disease were examined by CFVR. Subgroups were examined by repeated CFVR (reproducibility) or Rubidium-82-PET (agreement). To account for time variation, results were computed for scans performed within a week (1-week) and for all scans regardless of time gap (total) and to account for scar tissue for patients with and without previous myocardial infarction (MI). RESULTS: Eighty-six patients with median BMI 30.9 (IQR 29.4-32.9) kg × m(-2) and CFVR 2.29 (1.90-2.63) were included. CFVR was feasible in 83 (97 %) using a contrast agent in 14 %. For reproducibility overall (n = 21) limits of agreement (LOA) were (-0.75;0.71), within-subjects coefficient of variation (CV) 11 %, and reliability 0.84. For reproducibility within 1-week (n = 13) LOA were (-0.33;0.25), within-subjects CV 5 %, and reliability 0.97. Agreement with MFR of the LAD territory (n = 35) was without significant bias and overall LOA were (-1.40;1.46). Agreement was best for examinations performed within 1-week of participants without MI of the LAD-territory (n = 12); LOA = (-0.68;0.88). CONCLUSIONS: CFVR was highly feasible with a good reproducibility on par with other contemporary measures applied in cardiology. Agreement with MFR was acceptable, though discrepancy related to prior MI has to be considered. CFVR of LAD is a valid tool in overweight and obese patients.

(123)I-MIBG Scintigraphy in the Subacute State of Takotsubo Cardiomyopathy.

OBJECTIVES: The study sought to investigate adrenergic activity in patients with takotsubo cardiomyopathy (TTC). BACKGROUND: TTC is a specific type of reversible heart failure possibly caused by excessive catecholamine stimulation of the myocardium. Scintigraphic iodine-123-meta-iodobenzylguanidine (mIBG) imaging of the heart and measurement of plasma catecholamines can be used to assess adrenergic activity in vivo. The authors hypothesized that sympathetic nerve activity is increased in the subacute state of TTC, and this study used cardiac mIBG imaging and plasma levels of norepinephrine and epinephrine as markers to assess this hypothesis. METHODS: In this study, 32 patients with TTC and 20 controls were examined at admission and again on follow-up with echocardiography, mIBG scintigraphy, and plasma catecholamine measurements. RESULTS: Ejection fraction (EF) was initially 36 ± 9% but increased to >60% (p = 0.0004) in all patients with TTC. In the control subjects EF was initially higher (51 ± 11%; p = 0.0004) than in the patients with TTC. However, EF of the patients with TTC exceeded that of the control subjects on follow-up (56 ± 8%; p = 0.0007). The mIBG imaging showed a lower late (4-h) heart-to-mediastinum ratio (H/Mlate) (2.00 ± 0.38) and a higher washout rate (WR) (45 ± 12%) in the subacute state of TTC, both when compared with follow-up (H/Mlate: 2.42 ± 0.45; p = 0.0004; WR: 33 ± 14%; p = 0.0004) and when compared with the control group in the subacute state (H/Mlate: 2.34 ± 0.60, p = 0.035; WR: 33 ± 19%, p = 0.026). On follow-up, no differences in mIBG parameters were observed between the TTC and control groups (H/Mlate: 2.41 ± 0.51, p = 0.93; WR: 30 ± 13%, p = 0.48) group. In the TTC group, plasma epinephrine levels were elevated in the subacute state (Log2[epinephrine]: 6.13 ± 1.04 pg/ml), both when compared with follow-up (5.25 ± 0.62 pg/ml; p = 0.0004) and when compared with the control group in the subacute state (5.46 ± 0.69 pg/ml; p = 0.044), and these levels remained elevated in the TTC group on follow-up compared with the control group (4.56 ± 0.95 pg/ml; p = 0.014). No significant differences in plasma norepinephrine levels were observed. CONCLUSIONS: The present study supports a possible role of adrenergic hyperactivity in TTC.