658 Impairment of strain reserve extends to remote myocardium in the sub-acute phase of ST-elevation myocardial infarction

Aims In ST-elevation myocardial infarction (STEMI), subtle tissutal changes in remote myocardium predict long-term left ventricular (LV) remodelling and prognosis, independently of infarct size and microvascular obstruction. Whether there is a subclinical dysfunction of remote myocardium, detectable by longitudinal strain (LS) at echocardiography, and whether it varies in different locations of STEMI and with adenosine (ADO) challenge, is still unknown. Methods and results Fifty-three patients (age 65 ± 12.5 years, 44 male, 20 anterior and 33 non-anterior, P = 0.01) underwent rest/stress echocardiography at 7 ± 2 days after successfully treated STEMI, and at 6-months follow-up. Global LS (GLS), ischaemic and remote LS (iLS and rLS) were analysed in anterior and non-anterior STEMI. Both at rest and at follow-up, GLS was stratified by ejection fraction (EF) into three groups: EF < 40%, 40–49%, and ≥50%. Normal subjects, undergoing ADO stress echo, represented controls. Anterior STEMI showed lower GLS than controls (P < 0.001) and non-anterior STEMI (P < 0.001). ADO increased GLS in controls (P = 0.05), but neither in anterior nor in non-anterior STEMI, GLS changed during ADO stress, although significantly improved at follow-up (P < 0.001 and P = 0.002, respectively). In anterior STEMI, rLS was comparable to iLS at rest, during stress and at follow-up (P = ns), while in non-anterior STEMI rLS was higher than iLS throughout the study (P < 0.001). Patients with EF < 40% and 40–49% had similar values of GLS, iLS, and rLS, which were, both at rest and at follow-up, lower than those of patients with EF ≥ 50% (P < 0.001). Conclusions In the subacute phase, anterior STEMI shows the worst impairment of LS in both ischaemic and remote regions. Strain reserve to ADO is absent in remote myocardium, as well as in ischaemic zone, regardless of MI location. Global, ischaemic and remote LS may improve at follow-up.

Quantitative and qualitative composition of the innate immune response are equally important in wound healing after myocardial infarction

Background Emergency hematopoiesis (EH) serves as the foundation of monocyte-derived and macrophage (Mφ) driven efferocytosis and ventricular remodeling after myocardial infarction (MI). Excessive myelopoiesis, however, can stipulate maladaptive wound healing and its therapeutic reduction may be a novel approach to preserve cardiac function. All-trans retinoic acid (ATRA) is a pleiotropic modulator of EH and innate immunity shielding hematopoietic stem cells from activation and driving survival and differentiation of myeloid cells. Purpose This study aimed to investigate this intriguing interplay of ATRA in wound healing after MI. Methods MI was induced by permanent coronary ligation in C57BL/6 mice and treated with daily injections of either ATRA (30mg/kg) or DMSO (vehicle) up to five days, starting 24h after ligation. Flow cytometry (FACS) was used for cell cycle analysis and immunophenotyping of leukocytes in bone marrow (BM), blood and heart. Immunohistochemistry (IH), masson trichrome (MT) staining and echocardiography evaluated inflammatory-fibrotic and functional development. Cytokine expression was analyzed by qPCR in bulk infarct and isolated, polarized Mφ-populations of BM-derived and cardiac resident origin. Results On day 2 after MI, EH was significantly reduced in ATRA-treated mice as compared to vehicle controls by means of cell cycle activity (n=6–13 per group; p<0,01) and myeloid cells in BM, blood and infarct tissue (n=5–13; p<0,05). Consequently, mRNA-expression of key inflammatory cytokines, IL-1β and TNFα, was diminished in the infarct tissue in this early phase (n=5–12; p<0,05). These changes, however, failed to preserve cardiac function and ventricular remodeling, 21 days after MI (n=10–11; not significant). By qPCR, non-canonical activation of recruited ATRA-primed monocyte-derived Mφ, was found to propagate a pro-inflammatory phenotype with higher expression of MMP2 and MMP9 in sorted cardiac Mφ (n=4–5; p<0,001). Furthermore, prominent IL-1β-expression in M2-polarized BM-derived Mφ indicated an impaired anti-inflammatory phenotype after ATRA treatment (n=4–6; p<0,05). Strikingly, these changes also occurred in remote myocardium where IH revealed a 2-fold increase of CD11b - positive myeloid cells accompanied by increased expression of TNFα and TGFβ (n=9; p<0,001). MT-staining, performed 21 days after MI, demonstrated an almost 3-fold increase in collagen deposition in remote myocardium of ATRA treated mice in contrast to vehicle controls (n=4–6; p<0,0001). Conclusion Despite a beneficial reduction of EH after MI, short-term treatment with ATRA induced profound and persisting changes in the cytokine expression of monocyte-derived Mφ, which significantly altered their function and thus prevented improvements in cardiac function. Our data provide evidence that quantitative and qualitative changes in innate immunity are equally important for cardiac remodeling after MI. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft

The effect of chronic total coronary occlusion percutaneous coronary intervention on absolute perfusion in remote myocardium

Background Successful revascularization of a chronic total coronary occlusion (CTO) impacts coronary physiology of the remote myocardial territory. Purpose This study evaluated the effect of CTO percutaneous coronary intervention (PCI) on changes in absolute perfusion in remote myocardium as assessed by serial [15O]H2O positron emission tomography (PET) perfusion imaging. Methods A total of 164 patients underwent [15O]H2O PET imaging at baseline and 3 months after successful single-vessel revascularization of a CTO to evaluate changes in hyperemic myocardial blood flow (hMBF) and coronary flow reserve (CFR) in the remote myocardial territory supplied by both non-target coronary arteries. Results Remote hMBF and CFR improved (2.29±0.67 to 2.48±0.75 mL min–1 g–1 and 2.48±0.76 to 2.74±0.85, respectively) after CTO revascularization (p<0.01 for both). Absolute perfusion indices in the CTO vessel and the remote myocardium showed a positive linear correlation, both before (r=0.75, p<0.01 and r=0.77, p<0.01 for hMBF and CFR, respectively) and after (hMBF: r=0.87, p<0.01 and CFR: r=0.81, p<0.01) CTO PCI. Absolute increases in remote myocardial perfusion were largest in patients with a higher increase in hMBF (βeta [β] 0.56; 95% CI: 0.47–0.65; p<0.01) and CFR (β 0.51 (0.42–0.60); p<0.01) in the CTO territory, independent of clinical, angiographic and procedural characteristics. Furthermore, baseline (hMBF: β −0.24 (−0.39, −0.08); p<0.01 and CFR: β −0.26 (−0.41, −0.11); p<0.01) and post-PCI perfusion (hMBF: β 0.36; (0.27, 0.46); p<0.01 and CFR: β 0.30 (0.21, 0.40); p<0.01) in the CTO vessel were independently associated with the increase in remote myocardial perfusion after CTO PCI. Conclusions An overall increase in remote myocardial perfusion was observed following CTO PCI. Absolute perfusion indices in the remote myocardium showed a positive linear correlation with perfusion in the CTO vessel, before and after CTO revascularization. Importantly, baseline, post-PCI and the absolute increase in perfusion in the CTO territory were independently associated with increases in remote myocardial perfusion after revascularization. FUNDunding Acknowledgement Type of funding sources: None. Figure 1 Figure 2

Segmental strain analysis for the detection of chronic ischemic scars in non-contrast cardiac MRI cine images

Cardiac magnetic resonance imaging (MRI) with late gadolinium enhancement (LGE) is considered the gold standard for scar detection after myocardial infarction. In times of increasing skepticism about gadolinium depositions in brain tissue and contraindications of gadolinium administration in some patient groups, tissue strain-based techniques for detecting ischemic scars should be further developed as part of clinical protocols. Therefore, the objective of the present work was to investigate whether segmental strain is noticeably affected in chronic infarcts and thus can be potentially used for infarct detection based on routinely acquired non-contrast cine images in patients with known coronary artery disease (CAD). Forty-six patients with known CAD and chronic scars in LGE images (5 female, mean age 52 ± 19 years) and 24 gender- and age-matched controls with normal cardiac MRI (2 female, mean age 47 ± 13 years) were retrospectively enrolled. Global (global peak circumferential [GPCS], global peak longitudinal [GPLS], global peak radial strain [GPRS]) and segmental (segmental peak circumferential [SPCS], segmental peak longitudinal [SPLS], segmental peak radial strain [SPRS]) strain parameters were calculated from standard non-contrast balanced SSFP cine sequences using commercially available software (Segment CMR, Medviso, Sweden). Visual wall motion assessment of short axis cine images as well as segmental circumferential strain calculations (endo-/epicardially contoured short axis cine and resulting polar plot strain map) of every patient and control were presented in random order to two independent blinded readers, which should localize potentially infarcted segments in those datasets blinded to LGE images and patient information. Global strain values were impaired in patients compared to controls (GPCS p = 0.02; GPLS p = 0.04; GPRS p = 0.01). Patients with preserved ejection fraction showed also impeded GPCS compared to healthy individuals (p = 0.04). In patients, mean SPCS was significantly impaired in subendocardially (− 5.4% ± 2) and in transmurally infarcted segments (− 1.2% ± 3) compared to remote myocardium (− 12.9% ± 3, p = 0.02 and 0.03, respectively). ROC analysis revealed an optimal cut-off value for SPCS for discriminating infarcted from remote myocardium of − 7.2% with a sensitivity of 89.4% and specificity of 85.7%. Mean SPRS was impeded in transmurally infarcted segments (15.9% ± 6) compared to SPRS of remote myocardium (31.4% ± 5; p = 0.02). The optimal cut-off value for SPRS for discriminating scar tissue from remote myocardium was 16.6% with a sensitivity of 83.3% and specificity of 76.5%. 80.3% of all in LGE infarcted segments (118/147) were correctly localized in segmental circumferential strain calculations based on non-contrast cine images compared to 53.7% (79/147) of infarcted segments detected by visual wall motion assessment (p > 0.01). Global strain parameters are impaired in patients with chronic infarcts compared to controls. Mean SPCS and SPRS in scar tissue is impeded compared to remote myocardium in infarcts patients. Blinded to LGE images, two readers correctly localized 80% of infarcted segments in segmental circumferential strain calculations based on non-contrast cine images, in contrast to only 54% of infarcted segments detected due to wall motion abnormalities in visual wall motion assessment. Analysis of segmental circumferential strain shows a promising method for detection of chronic scars in routinely acquired, non-contrast cine images for patients who cannot receive or decline gadolinium.

Myocardial gene expression in patients with myocardial infarction

Funding Acknowledgements Type of funding sources: None. Introduction. Myocardial infarction (MI) and following heart failure (HF) have various clinical scenarios. However, despite the clinical heterogeneity, the management of MI lacks effective personalized approaches. The response to ischemic injury in the infarct zone and remote myocardium has a definite spatio-temporal sequence and underlies the mechanism of adverse cardiac remodeling. Understanding its myocardial biology remains unclear due to insufficiency of heart tissue molecular and genetic analysis. Although animal models play an important role in data accumulation, they failure to reflect all the compounds of response to ischemic injury and following HF syndrome. Purpose. The purpose of the study was to investigate myocardial expression profile in the infarct zone in comparison to remote myocardium in patients with MI. Methods. The study included 4 patients with fatal MI type 1. All patients died within 48 hours of MI. The post-mortem examination was performed according to country policy. In each case, we obtained myocardial samples from the infarct zone and remote myocardium. Genome-wide gene-level expression was assessed by microarray analysis. We used transcriptome analysis software to analyze and visualize global expression patterns of genes. The analysis included normalization process. Differentially expressed genes (DEGs) were defined as gene-level fold change <-2 or >2 and adjusted P-value of <0.05. Results. We studied expression of 21448 genes. A total of 1785 DEGs, including 1692 up-regulated genes and 93 down-regulated genes in the infarct zone, were identified (Figure 1). According to the fold change, the first 10 up-regulated genes were TNFSF10 (TRAIL), SUCLA2, NAE1, PDCL3, OSBPL5, FCGR2C, SELE, CEP63, ST3GAL3, C4orf3. Fold changes for TNFSF10 (TRAIL), SUCLA2, and NAE1 were 19.83 (p = 0.049), 10.68 (p = 0.048), and 10.24 (p = 0.008), respectively. These 3 up-regulated genes were enriched in apoptotic signaling pathways, immune response, angiogenesis, inflammation, tricarboxylic acid cycle, and protein binding. Conclusions. We performed myocardial transcriptomic analysis in patients with MI. DEG analysis clearly distinguishes the infarct zone and remote myocardium. Genes overexpressed in the infarct zone included TNFSF10 (TRAIL), SUCLA2, NAE1. TNFSF10 (TRAIL) regulates vasodilation, angiogenesis, and inflammation. TNFSF10 (TRAIL) regulated effects could be both protective and harmful in ischemic heart disease. The enzyme encoded by SUCLA2 is active in tissues that require a large amount of energy, such as those of the heart, brain, and muscle. Overexpression of NAE1 causes apoptosis through deregulation of NEDD8 conjugation. It is known that the protein encoded by NAE1 binds to the beta-amyloid precursor protein, and it is thought to play a role in the pathogenesis of Alzheimer"s disease. Thus, our pilot study emphasized the potential of translational approach and identified targets to consider for precision diagnostics and therapeutics. Abstract Figure. С1: infarct zone; C2: remote myocardium

Semi-quantitative Analysis of Adenosine Perfusion Magnetic Resonance Imaging Outperforms Visual Analysis in Identifying Fractional Flow Reserve-Altered Intermediate-grade Coronary Artery Stenosis: A Pilot Study

PurposeTo evaluate the diagnostic accuracy of semi-quantitative adenosine perfusion magnetic resonance imaging(MRI) to determine fractional flow reserve(FFR)≤0.80 intermediate-grade coronary stenoses as compared to visual analysis.Methods Forty-six patients (mean age 61±9 years;33 males) with 49 intermediate-grade stenoses underwent adenosine perfusion MRI and FFR measurement within 4 months between 2010 and 2013. Retrospective interpretation of all prospectively acquired data was performed. MRI was visually assessed by 2 experienced readers twice with one-year interval, the second time with the knowledge of the diseased artery. All myocardial enhancement maximal upslopes were evaluated distal to the coronary stenosis (=RISK) and in remote myocardium supplied by normal arteries (=REMOTE); stress subendocardial relative myocardial perfusion index (RMPI; RISK/REMOTE upslopes) was assessed in predicting FFR≤0.80 stenoses. Deep learning boosting models including all RISK and REMOTE upslopes were fitted to confirm the added value of accounting for perfusion changes in remote myocardium for FFR prediction. Results The average FFR value was 0.84±0.09 and 15/49 (31%) stenoses were FFR≤0.80. Both readers had moderate accuracy (range: 36/49(73%)-38/49(78%)) in predicting FFR≤0.80 stenoses, even with the knowledge of the stenosis location. At a cutoff value of 0.84, stress subendocardial RMPI had higher accuracy (43/49(88%)) than individual visual readings to predict FFR≤0.80 stenoses. The best FFR prediction using the boosting model occurred when accounting for REMOTE myocardial perfusion parameters, leading to diagnostic accuracy of 44/49(90%) for FFR≤0.80. Conclusion Semi-quantitative adenosine perfusion MRI accounting for stress perfusion in remote myocardium predicts FFR≤0.80 intermediate-grade coronary stenoses with a higher accuracy than individual visual analysis.