Anthracycline therapy induces an early decline of cardiac contractility in low-risk patients with breast cancer.

AIMS: Cancer therapy-related cardiac dysfunction (CTRCD) is a dreaded complication of anthracycline therapy. CTRCD most frequently appears in patients with cardiovascular risk factors (CVR) or known cardiovascular disease. However, limited data exist on incidence and course of anthracycline-induced CTRCD in patients without preexisting risk factors. We therefore aimed to longitudinally investigate a cohort of young women on anthracycline treatment due to breast cancer without cardiovascular risk factors or known cardiovascular disease (NCT03940625). METHODS AND RESULTS: We enrolled 59 women with primary breast cancer and scheduled anthracycline-based therapy, but without CVR or preexisting cardiovascular disease. We conducted a longitudinal assessment before, immediately and 12 months after cancer therapy with general laboratory, electrocardiograms, echocardiography and cardiovascular magnetic resonance (CMR), including myocardial relaxometry with T1, T2 and extracellular volume mapping. Every single patient experienced a drop in CMR-measured left ventricular ejection fraction (LVEF) of 6 ± 3% immediately after cancer therapy. According to the novel definition 32 patients (54.2%) developed CTRCD after 12 months defined by reduction in LVEF, global longitudinal strain (GLS) and/or biomarkers elevation, two of them were symptomatic. Global myocardial T2 relaxation times as well as myocardial mass increased coincidently with a decline in wall-thickening. While T2 values and myocardial mass normalized after 12 months, LVEF and GLS remained impaired. CONCLUSION: In every single patient anthracyclines induce a decline of myocardial contractility, even among patients without pre-existing risk factors for CTRCD. Our data suggest to thoroughly evaluate whether this may lead to an increased risk of future cardiovascular events.

Consistency of left ventricular ejection fraction measurements in the early time course of STEMI.

BACKGROUND: Early after ST-segment elevation myocardial infarction (STEMI), initial LV reshaping and hypokinesia may affect analysis of LV function. Concomitant microvascular dysfunction may affect LV function as well. OBJECTIVE: To perform a comparative evaluation of left ventricular ejection fraction (LVEF) and stroke volume (SV) by different imaging modalities to assess LV function early after STEMI. METHODS: LVEF and SV were assessed using serial imaging within 24 h and 5 days after STEMI using cineventriculography (CVG), 2-dimensional echocardiography (2DE), 2D/3D cardiovascular magnetic resonance (CMR) (2D/3D) in 82 patients. RESULTS: 2D analyses of LVEF using CVG, 2DE and 2D CMR yielded uniform results within 24 h and 5 days of STEMI. SV assessment between CVG and 2DE was comparable, whereas values for SV were higher using 2D CMR (p < 0.01 all). This was due to higher LVEDV measurements. LVEF by 2D versus 3D CMR was comparable, 3D CMR yielded higher volumetric values. This was not influenced by infarct location or infarct size. CONCLUSIONS: 2D analysis of LVEF yielded robust results across all imaging techniques implying that CVG, 2DE, and 2D CMR can be used interchangeably early after STEMI. SV measurements differed substantially between imaging techniques due to higher intermodality-differences of absolute volumetric measurements.

Sphingosine-1-phosphate improves outcome of no-reflow acute myocardial infarction via sphingosine-1-phosphate receptor 1.

AIMS: Therapeutic options targeting post-ischaemic cardiac remodelling are sparse. The bioactive sphingolipid sphingosine-1-phosphate (S1P) reduces ischaemia/reperfusion injury. However, its impact on post-ischaemic remodelling independently of its infarct size (IS)-reducing effect is yet unknown and was addressed in this study. METHODS AND RESULTS: Acute myocardial infarction (AMI) in mice was induced by permanent ligation of the left anterior descending artery (LAD). C57Bl6 were treated with the S1P lyase inhibitor 4-deoxypyridoxine (DOP) starting 7 days prior to AMI to increase endogenous S1P concentrations. Cardiac function and myocardial healing were assessed by cardiovascular magnetic resonance imaging (cMRI), murine echocardiography, histomorphology, and gene expression analysis. DOP effects were investigated in cardiomyocyte-specific S1P receptor 1 deficient (S1PR1 Cardio Cre+) and Cre- control mice and S1P concentrations measured by LC-MS/MS. IS and cardiac function did not differ between control and DOP-treated groups on day one after LAD-ligation despite fourfold increase in plasma S1P. In contrast, cardiac function was clearly improved and myocardial scar size reduced, respectively, on Day 21 in DOP-treated mice. The latter also exhibited smaller cardiomyocyte size and reduced embryonic gene expression. The benefit of DOP treatment was abolished in S1PR1 Cardio Cre+. CONCLUSIONS: S1P improves cardiac function and myocardial healing post AMI independently of initial infarct size and accomplishes this via the cardiomyocyte S1PR1. Hence, in addition to its beneficial effects on I/R injury, S1PR1 may be a promising target in post-infarction myocardial remodelling as adjunctive therapy to revascularization as well as in patients not eligible for standard interventional procedures.

Vasodilator Myocardial Perfusion Cardiac Magnetic Resonance Imaging Is Superior to Dobutamine Stress Echocardiography in the Detection of Relevant Coronary Artery Stenosis: A Systematic Review and Meta-Analysis on Their Diagnostic Accuracy.

Objectives: Guideline recommendations for patients with either a high or a low risk of obstructive coronary artery disease (CAD) are clear. However, the evidence for initial risk stratification in patients with an intermediate risk of CAD is still unclear, despite the availability of multiple non-invasive assessment strategies. The aim of this study was to synthesize the evidence for this population to provide more informed recommendations. Background: A meta-analysis was performed to systematically assess the diagnostic accuracy of vasodilator myocardial perfusion cardiovascular magnetic resonance imaging (pCMR) and dobutamine stress echocardiography (DSE) for the detection of relevant CAD. In contrast to previous work, this meta-analysis follows rigorous selection criteria in regards to the risk stratification and a narrowly prespecified definition of their invasive reference tests, resulting in unprecedentedly informative results for this reference group. Data Collection and Analysis: From the 5,634 studies identified, 1,306 relevant articles were selected after title screening and further abstract screening left 865 studies for full-text review. Of these, 47 studies fulfilled all inclusion criteria resulting in a total sample size of 4,742 patients. Results: pCMR studies showed a superior sensitivity [0.88 (95% confidence interval (CI): 0.85-0.90) vs. 0.72 (95% CI: 0.61-0.81)], diagnostic odds ratio (DOR) [38 (95% CI: 29-49) vs. 20 (95% CI: 9-46)] and an augmented post-test probability [negative likelihood ratio (LR) of 0.14 (95% CI: 0.12-0.18) vs. 0.31 (95% CI: 0.21, 0.46)] as compared to DSE. Specificity was statistically indifferent [0.84 (95% CI: 0.81-0.87) vs. 0.89 (95% CI: 0.83-0.93)]. Conclusion: The results of this systematic review and meta-analysis suggest that pCMR has a superior diagnostic test accuracy for relevant CAD compared to DSE. In patients with intermediate risk of CAD only pCMR can reliably rule out relevant stenosis. In this risk cohort, pCMR can be offered for initial risk stratification and guidance of further invasive treatment as it also rules in relevant CAD.

Cardiac magnetic resonance T2 mapping and feature tracking in athlete's heart and HCM.

OBJECTIVES: Distinguishing hypertrophic cardiomyopathy (HCM) from left ventricular hypertrophy (LVH) due to systematic training (athlete's heart, AH) from morphologic assessment remains challenging. The purpose of this study was to examine the role of T2 mapping and deformation imaging obtained by cardiovascular magnetic resonance (CMR) to discriminate AH from HCM with (HOCM) or without outflow tract obstruction (HNCM). METHODS: Thirty-three patients with HOCM, 9 with HNCM, 13 strength-trained athletes as well as individual age- and gender-matched controls received CMR. For T2 mapping, GRASE-derived multi-echo images were obtained and analyzed using dedicated software. Besides T2 mapping analyses, left ventricular (LV) dimensional and functional parameters were obtained including LV mass per body surface area (LVMi), interventricular septum thickness (IVS), and global longitudinal strain (GLS). RESULTS: While LVMi was not significantly different, IVS was thickened in HOCM patients compared to athlete's. Absolute values of GLS were significantly increased in patients with HOCM/HNCM compared to AH. Median T2 values were elevated compared to controls except in athlete's heart. ROC analysis revealed T2 values (AUC 0.78) and GLS (AUC 0.91) as good parameters to discriminate AH from overall HNCM/HOCM. CONCLUSION: Discrimination of pathologic from non-pathologic LVH has implications for risk assessment of competitive sports in athletes. Multiparametric CMR with parametric T2 mapping and deformation imaging may add information to distinguish AH from LVH due to HCM. KEY POINTS: • Structural analyses using T2 mapping cardiovascular magnetic resonance imaging (CMR) may help to further distinguish myocardial diseases. • To differentiate pathologic from non-pathologic left ventricular hypertrophy, CMR including T2 mapping was obtained in patients with hypertrophic obstructive/non-obstructive cardiomyopathy (HOCM/HNCM) as well as in strength-trained athletes. • Elevated median T2 values in HOCM/HNCM compared with athlete's may add information to distinguish athlete's heart from pathologic left ventricular hypertrophy.

Anaemia is associated with severe RBC dysfunction and a reduced circulating NO pool: vascular and cardiac eNOS are crucial for the adaptation to anaemia.

Anaemia is frequently present in patients with acute myocardial infarction (AMI) and contributes to an adverse prognosis. We hypothesised that, besides reduced oxygen carrying capacity, anaemia is associated with (1) red blood cell (RBC) dysfunction and a reduced circulating nitric oxide (NO) pool, (2) compensatory enhancement of vascular and cardiac endothelial nitric oxide synthase (eNOS) activity, and (3) contribution of both, RBC dysfunction and reduced circulatory NO pool to left ventricular (LV) dysfunction and fatal outcome in AMI. In mouse models of subacute and chronic anaemia from repeated mild blood loss the circulating NO pool, RBC, cardiac and vascular function were analysed at baseline and in reperfused AMI. In anaemia, RBC function resulted in profound changes in membrane properties, enhanced turnover, haemolysis, dysregulation of intra-erythrocytotic redox state, and RBC-eNOS. RBC from anaemic mice and from anaemic patients with acute coronary syndrome impaired the recovery of contractile function of isolated mouse hearts following ischaemia/reperfusion. In anaemia, the circulating NO pool was reduced. The cardiac and vascular adaptation to anaemia was characterised by increased arterial eNOS expression and activity and an eNOS-dependent increase of end-diastolic left ventricular volume. Endothelial dysfunction induced through genetic or pharmacologic reduction of eNOS-activity abrogated the anaemia-induced cardio-circulatory compensation. Superimposed AMI was associated with decreased survival. In summary, moderate blood loss anaemia is associated with severe RBC dysfunction and reduced circulating NO pool. Vascular and cardiac eNOS are crucial for the cardio-circulatory adaptation to anaemia. RBC dysfunction together with eNOS dysfunction may contribute to adverse outcomes in AMI.

Cardiovascular Magnetic Resonance Relaxometry Predicts Regional Functional Outcome After Experimental Myocardial Infarction.

BACKGROUND: Cardiovascular magnetic resonance with gadolinium-based contrast agents has established as gold standard for tissue characterization after myocardial infarction (MI). Beyond accurate diagnosis, the value of cardiovascular magnetic resonance to predict the outcome after MI has yet to be substantiated. METHODS AND RESULTS: Recent cardiovascular magnetic resonance approaches were systematically compared for quantification of tissue injury and functional impairment after MI using murine models with permanent left anterior descending coronary artery ligation (n=14) or 50 minutes ischemia/reperfusion (n=13). Cardiovascular magnetic resonance included native/postcontrast T1 maps, T2 maps, and late gadolinium enhancement at days 1 and 21 post-MI. For regional correlation of parametric and functional measures, the left ventricle was analyzed over 200 sectors. For T1 mapping, we used retrospective triggering with variable flip angle analysis. Sectoral analysis of native T1 maps already revealed in the acute phase after MI substantial discrepancies in myocardial tissue texture between the 2 MI models (native T1 day 1: permanent ligation, 1280.0±162.6 ms; ischemia/reperfusion, 1115.0±140.5 ms; P<0.001; n=14/13), which were later associated with differential functional outcome (left ventricular ejection fraction day 21: permanent ligation, 24.5±7.0%; ischemia/reperfusion, 33.7±11.6%; P<0.05; n=14/13). At this early time, any other parameter was indicative for the subsequent worsening of left ventricular ejection fraction in permanent ligation mice. Linear regression of acute individual measures with contractile function in corresponding areas at day 21 demonstrated for early native T1 values the best correlation with the later functional impairment (R2 =0.94). CONCLUSIONS: The present T1 mapping approach permits accurate characterization of local tissue injury and holds the potential for sensitive and graduated prognosis of the functional outcome after MI without gadolinium-based contrast agents.

Abnormal T2 mapping cardiovascular magnetic resonance correlates with adverse clinical outcome in patients with suspected acute myocarditis.

BACKGROUND: While most patients recover from suspected acute myocarditis (sAMC) some develop progressive disease with 5-year mortality up to 20%. Recently, parametric Cardiovascular Magnetic Resonance (CMR) approaches, quantifying native T1 and T2 relaxation time, have demonstrated the ability to increase diagnostic accuracy. However, prognostic implications of T2 values in this cohort are unknown. The purpose of the study was to investigate the prognostic relevance of elevated CMR T2 values in patients with sAMC. METHODS AND RESULTS: We carried out a prospective study in 46 patients with sAMC defined by current ESC recommendations. A combined endpoint was defined by the occurrence of at least one major adverse cardiac event (MACE) and hospitalisation for heart failure. Event rate was 24% (n = 11) for 1-year-MACE and hospitalisation. A follow-up after 11 ± 7 months was performed in 98% of the patients. Global T2 values were significantly increased at acute stage of disease compared to controls and decreased over time. During acute disease, elevated global T2 time (odds ratio 6.3, p < 0.02) as well as myocardial fraction with T2 time >80 ms (odds ratio 4.9, p < 0.04) predicted occurrence of the combined endpoint. Patients with clinical recovery revealed significantly decreased T2 relaxation times at follow-up examinations; however, T2 values were still elevated compared to healthy controls. CONCLUSION: Assessment of myocardial T2 relaxation times at initial presentation facilitates CMR-based risk stratification in patients with acute myocarditis. T2 Mapping may emerge as a new tool to monitor inflammatory myocardial injuries during the course of disease.

Myocardial T2 mapping reveals age- and sex-related differences in volunteers.

BACKGROUND: T2 mapping indicates to be a sensitive method for detection of tissue oedema hidden beyond the detection limits of T2-weighted Cardiovascular Magnetic Resonance (CMR). However, due to variability of baseline T2 values in volunteers, reference values need to be defined. Therefore, the aim of the study was to investigate the effects of age and sex on quantitative T2 mapping with a turbo gradient-spin-echo (GRASE) sequence at 1.5 T. For that reason, we studied sensitivity issues as well as technical and biological effects on GRASE-derived myocardial T2 maps. Furthermore, intra- and interobserver variability were calculated using data from a large volunteer group. METHODS: GRASE-derived multiecho images were analysed using dedicated software. After sequence optimization, validation and sensitivity measurements were performed in muscle phantoms ex vivo and in vivo. The optimized parameters were used to analyse CMR images of 74 volunteers of mixed sex and a wide range of age with typical prevalence of hypertension and diabetes. Myocardial T2 values were analysed globally and according to the 17 segment model. Strain-encoded (SENC) imaging was additionally performed to investigate possible effects of myocardial strain on global or segmental T2 values. RESULTS: Ex vivo studies in muscle phantoms showed, that GRASE-derived T2 values were comparable to those acquired by a standard multiecho spinecho sequence but faster by a factor of 6. Besides that, T2 values reflected tissue water content. The in vivo measurements in volunteers revealed intra- and interobserver correlations with R2=0.91 and R2=0.94 as well as a coefficients of variation of 2.4% and 2.2%, respectively. While global T2 time significantly decreased towards the heart basis, female volunteers had significant higher T2 time irrespective of myocardial region. We found no correlation of segmental T2 values with maximal systolic, diastolic strain or heart rate. Interestingly, volunteers´ age was significantly correlated to T2 time while that was not the case for other coincident cardiovascular risk factors. CONCLUSION: GRASE-derived T2 maps are highly reproducible. However, female sex and aging with typical prevalence of hypertension and diabetes were accompanied by increased myocardial T2 values. Thus, sex and age must be considered as influence factors when using GRASE in a diagnostic manner.