The ebb and flow of cardiac lymphatics: a tidal wave of new discoveries.

The heart is imbued with a vast lymphatic network that is responsible for fluid homeostasis and immune cell trafficking. Disturbances in the forces that regulate microvascular fluid movement can result in myocardial edema, which has profibrotic and proinflammatory consequences and contributes to cardiovascular dysfunction. This review explores the complex relationship between cardiac lymphatics, myocardial edema, and cardiac disease. It covers the revised paradigm of microvascular forces and fluid movement around the capillary as well as the arsenal of preclinical tools and animal models used to model myocardial edema and cardiac disease. Clinical studies of myocardial edema and their prognostic significance are examined in parallel to the recent elegant animal studies discerning the pathophysiological role and therapeutic potential of cardiac lymphatics in different cardiovascular disease models. This review highlights the outstanding questions of interest to both basic scientists and clinicians regarding the roles of cardiac lymphatics in health and disease.

Mechanisms of the septic heart: From inflammatory response to myocardial edema.

Sepsis-induced myocardial dysfunction (SIMD), also known as sepsis-induced cardiomyopathy (SICM), is linked to significantly increased mortality. Despite its clinical importance, effective therapies for SIMD remain elusive, largely due to an incomplete understanding of its pathogenesis. Over the past five decades, research involving both animal models and human studies has highlighted several pathogenic mechanisms of SICM, yet many aspects remain unexplored. Initially thought to be primarily driven by inflammatory cytokines, current research indicates that these alone are insufficient for the development of cardiac dysfunction. Recent studies have brought attention to additional mechanisms, including excessive nitric oxide production, mitochondrial dysfunction, and disturbances in calcium homeostasis, as contributing factors in SICM. Emerging clinical evidence has highlighted the significant role of myocardial edema in the pathogenesis of SICM, particularly its association with cardiac remodeling in septic shock patients. This review synthesizes our current understanding of SIMD/SICM, focusing on myocardial edema's contribution to cardiac dysfunction and the critical role of the bradykinin receptor B1 (B1R) in altering myocardial microvascular permeability, a potential key player in myocardial edema development during sepsis. Additionally, this review briefly summarizes existing therapeutic strategies and their challenges and explores future research directions. It emphasizes the need for a deeper understanding of SICM to develop more effective treatments.

Hypernatremia and intercalated disc edema synergistically exacerbate long-QT syndrome type 3 phenotype.

Cardiac voltage-gated sodium channel gain-of-function prolongs repolarization in the long-QT syndrome type 3 (LQT3). Previous studies suggest that narrowing the perinexus within the intercalated disc, leading to rapid sodium depletion, attenuates LQT3-associated action potential duration (APD) prolongation. However, it remains unknown whether extracellular sodium concentration modulates APD prolongation during sodium channel gain-of-function. We hypothesized that elevated extracellular sodium concentration and widened perinexus synergistically prolong APD in LQT3. LQT3 was induced with sea anemone toxin (ATXII) in Langendorff-perfused guinea pig hearts (n = 34). Sodium concentration was increased from 145 to 160 mM. Perinexal expansion was induced with mannitol or the sodium channel ß1-subunit adhesion domain antagonist (ßadp1). Epicardial ventricular action potentials were optically mapped. Individual and combined effects of varying clefts and sodium concentrations were simulated in a computational model. With ATXII, both mannitol and ßadp1 significantly widened the perinexus and prolonged APD, respectively. The elevated sodium concentration alone significantly prolonged APD as well. Importantly, the combination of elevated sodium concentration and perinexal widening synergistically prolonged APD. Computational modeling results were consistent with animal experiments. Concurrently elevating extracellular sodium and increasing intercalated disc edema prolongs repolarization more than the individual interventions alone in LQT3. This synergistic effect suggests an important clinical implication that hypernatremia in the presence of cardiac edema can markedly increase LQT3-associated APD prolongation. Therefore, to our knowledge, this is the first study to provide evidence of a tractable and effective strategy to mitigate LQT3 phenotype by means of managing sodium levels and preventing cardiac edema in patients.NEW & NOTEWORTHY This is the first study to demonstrate that the long-QT syndrome type 3 (LQT3) phenotype can be exacerbated or concealed by regulating extracellular sodium concentrations and/or the intercalated disc separation. The animal experiments and computational modeling in the current study reveal a critically important clinical implication: sodium dysregulation in the presence of edema within the intercalated disc can markedly increase the risk of arrhythmia in LQT3. These findings strongly suggest that maintaining extracellular sodium within normal physiological limits may be an effective and inexpensive therapeutic option for patients with congenital or acquired sodium channel gain-of-function diseases.

Adrenomedullin Induces Cardiac Lymphangiogenesis After Myocardial Infarction and Regulates Cardiac Edema Via Connexin 43.

RATIONALE: Cardiac lymphangiogenesis contributes to the reparative process post-myocardial infarction, but the factors and mechanisms regulating it are not well understood. OBJECTIVE: To determine if epicardial-secreted factor AM (adrenomedullin; Adm=gene) improves cardiac lymphangiogenesis post-myocardial infarction via lateralization of Cx43 (connexin 43) in cardiac lymphatic vasculature. METHODS AND RESULTS: Firstly, we identified sex-dependent differences in cardiac lymphatic numbers in uninjured mice using light-sheet microscopy. Using a mouse model of Adm hi/hi ( Adm overexpression) and permanent left anterior descending ligation to induce myocardial infarction, we investigated cardiac lymphatic structure, growth, and function in injured murine hearts. Overexpression of Adm increased lymphangiogenesis and cardiac function post-myocardial infarction while suppressing cardiac edema and correlated with changes in Cx43 localization. Lymphatic function in response to AM treatment was attenuated in mice with a lymphatic-specific Cx43 deletion. In vitro experiments in cultured human lymphatic endothelial cells identified a novel mechanism to improve gap junction coupling by pharmaceutically targeting Cx43 with verapamil. Finally, we show that connexin protein expression in cardiac lymphatics is conserved between mouse and human. CONCLUSIONS: AM is an endogenous, epicardial-derived factor that drives reparative cardiac lymphangiogenesis and function via Cx43, and this represents a new therapeutic pathway for improving myocardial edema after injury.

COVID-19 in patients with heart failure: the new and the old epidemic.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread in nearly 200 countries in less than 4 months since its first identification; accordingly, the coronavirus disease 2019 (COVID 2019) has affirmed itself as a clinical challenge. The prevalence of pre-existing cardiovascular diseases in patients with COVID19 is high and this dreadful combination dictates poor prognosis along with the higher risk of intensive care mortality. In the setting of chronic heart failure, SARS-CoV-2 can be responsible for myocardial injury and acute decompensation through various mechanisms. Given the clinical and epidemiological complexity of COVID-19, patiens with heart failure may require particular care since the viral infection has been identified, considering an adequate re-evaluation of medical therapy and a careful monitoring during ventilation.

Sodium dehydroacetate induces cardiovascular toxicity associated with Ca2+ imbalance in zebrafish.

The environmental effects of additives have attracted increasing attention. Sodium dehydroacetate (DHA-S), as an approved preservative, is widely added in processed foods, cosmetics and personal care products. However, DHA-S has been recently reported to induce hemorrhage and coagulation aberration in rats. Yet little is known about the ecotoxicological effect and underlying mechanisms of DHA-S. Here, we utilized the advantage of zebrafish model to evaluate such effects. DHA-S induced cerebral hemorrhage, mandibular dysplasia and pericardial edema in zebrafish after 24 h exposure (48-72 hpf) at 50 mg/L. We also observed the defective heart looping and apoptosis in DHA-S-treated zebrafish through o-dianisidine and acridine orange staining. Meanwhile, DHA-S induced the deficiency of Ca2+ and vitamin D3 in zebrafish. We further demonstrated that DHA-S stimulated Ca2+ influx resulting in Ca2+-dependent mitochondrial damage in cardiomyocytes. Additionally, DHA-S inhibited glucose uptake and repressed the biosynthesis of amino acids. Finally, we identified that sodium bicarbonate could rescue zebrafish from DHA-S induced cardiovascular toxicity. Altogether, our results suggest that DHA-S is a potential risk for cardiovascular system.

A murine model of increased coronary sinus pressure induces myocardial edema with cardiac lymphatic dilation and fibrosis.

Myocardial edema is a consequence of many cardiovascular stressors, including myocardial infarction, cardiac bypass surgery, and hypertension. The aim of this study was to establish a murine model of myocardial edema and elucidate the response of cardiac lymphatics and the myocardium. Myocardial edema without infarction was induced in mice by cauterizing the coronary sinus, increasing pressure in the coronary venous system, and inducing myocardial edema. In male mice, there was rapid development of edema 3 h following coronary sinus cauterization (CSC), with associated dilation of cardiac lymphatics. By 24 h, males displayed significant cardiovascular contractile dysfunction. In contrast, female mice exhibited a temporal delay in the formation of myocardial edema, with onset of cardiovascular dysfunction by 24 h. Furthermore, myocardial edema induced a ring of fibrosis around the epicardial surface of the left ventricle in both sexes that included fibroblasts, immune cells, and increased lymphatics. Interestingly, the pattern of fibrosis and the cells that make up the fibrotic epicardial ring differ between sexes. We conclude that a novel surgical model of myocardial edema without infarct was established in mice. Cardiac lymphatics compensated by exhibiting both an acute dilatory and chronic growth response. Transient myocardial edema was sufficient to induce a robust epicardial fibrotic and inflammatory response, with distinct sex differences, which underscores the sex-dependent differences that exist in cardiac vascular physiology.NEW & NOTEWORTHY Myocardial edema is a consequence of many cardiovascular stressors, including myocardial infarction, cardiac bypass surgery, and high blood pressure. Cardiac lymphatics regulate interstitial fluid balance and, in a myocardial infarction model, have been shown to be therapeutically targetable by increasing heart function. Cardiac lymphatics have only rarely been studied in a noninfarct setting in the heart, and so we characterized the first murine model of increased coronary sinus pressure to induce myocardial edema, demonstrating distinct sex differences in the response to myocardial edema. The temporal pattern of myocardial edema induction and resolution is different between males and females, underscoring sex-dependent differences in the response to myocardial edema. This model provides an important platform for future research in cardiovascular and lymphatic fields with the potential to develop therapeutic interventions for many common cardiovascular diseases.

Lung Ultrasound for the Diagnosis and Management of Acute Respiratory Failure.

For critically ill patients with acute respiratory failure (ARF), lung ultrasound (LUS) has emerged as an indispensable tool to facilitate diagnosis and rapid therapeutic management. In ARF, there is now evidence to support the use of LUS to diagnose pneumothorax, acute respiratory distress syndrome, cardiogenic pulmonary edema, pneumonia, and acute pulmonary embolism. In addition, the utility of LUS has expanded in recent years to aid in the ongoing management of critically ill patients with ARF, providing guidance in volume status and fluid administration, titration of positive end-expiratory pressure, and ventilator liberation. The aims of this review are to examine the basic foundational concepts regarding the performance and interpretation of LUS, and to appraise the current literature supporting the use of this technique in the diagnosis and continued management of patients with ARF.

Recent Advances in T1 and T2 Mapping in the Assessment of Fulminant Myocarditis by Cardiac Magnetic Resonance.

PURPOSE OF REVIEW: This review was undertaken to summarise recent data relating to T1 and T2 relaxation times in the assessment of myocarditis using cardiac MRI, and the effect new studies have had on the established diagnostic criteria, leading to recently proposed revised criteria for the cardiac MRI assessment of myocarditis. RECENT FINDINGS: In 2018, updates to the 2009 Lake Louise Criteria (LLC) were proposed, based on studies showing improved accuracy of T1 mapping techniques over T1 signal intensity ratio-based imaging, although for the detection of myocardial oedema either T2-weighted images or increased T2 relaxation times can be used. Non-ischaemic distribution of scar on late gadolinium-enhanced (LGE) T1-weighted imaging remains in the newly revised criteria, which, although can have low sensitivity due to fibrosis presenting diffusely or due to CMR being performed early in the disease process before scar formation, remains in the LLC due to its high specificity. Early gadolinium enhancement has been removed from the LLC, as T1 quantification has higher diagnostic accuracy for the detection of myocardial injury. In the CMR assessment of myocarditis, T1 and T2 quantifications are now recommended over T1- and T2-weighted imaging. Late gadolinium enhancement in a non-ischaemic pattern remains in the updated criteria, whereas early gadolinium enhancement has been superseded by T1 quantification.

Enhancement of cardiac lymphangiogenesis by transplantation of CD34+VEGFR-3+ endothelial progenitor cells and sustained release of VEGF-C.

Impairment of cardiac lymphatic vessels leads to cardiac lymphedema. Recent studies have suggested that stimulation of lymphangiogenesis may reduce cardiac lymphedema. However, effects of lymphatic endothelial progenitor cells (LEPCs) on cardiac lymphangiogenesis are poorly understood. Therefore, this study investigated effectiveness of LEPC transplantation and VEGF-C release with self-assembling peptide (SAP) on cardiac lymphangiogenesis after myocardial infarction (MI). CD34+VEGFR-3+ EPCs isolated from rat bone marrow differentiated into lymphatic endothelial cells after VEGF-C induction. VEGF-C also stimulated the cells to incorporate into the lymphatic capillary-like structures. The functionalized SAP could adhere with the cells and released VEGF-C sustainedly. In the condition of hypoxia and serum deprivation or abdominal pouch assay, the SAP hydrogel protected the cells from apoptosis and necrosis. At 4 weeks after intramyocardial transplantation of the cells and VEGF-C loaded with SAP hydrogel in rat MI models, cardiac lymphangiogenesis was increased, cardiac edema and reverse remodeling were reduced, and cardiac function was improved significantly. Delivery with SAP hydrogel favored survival of the engrafted cells. VEGF-C released from the hydrogel promoted differentiation and incorporation of the cells as well as growth of pre-existed lymphatic vessels. Cardiac lymphangiogenesis was beneficial for elimination of the inflammatory cells in the infarcted myocardium. Moreover, angiogenesis and myocardial regeneration were enhanced after reduction of lymphedema. These results demonstrate that the combined delivery of LEPCs and VEGF-C with the functionalized SAP promotes cardiac lymphangiogenesis and repair of the infarcted myocardium effectively. This study represents a novel therapy for relieving myocardial edema in cardiovascular diseases.

Characterization of edema after cryo and radiofrequency ablations based on serial magnetic resonance imaging.

INTRODUCTION: Radiofrequency (RF) and cryoablation are routinely used to treat arrhythmias, but the extent and time course of edema associated with the two different modalities is unknown. Our goal was to follow the lesion maturation and edema formation after RF and cryoablation using serial magnetic resonance imaging (MRI). METHODS AND RESULTS: Ventricular ablation was performed in a canine model (n = 11) using a cryo or an irrigated RF catheter. T2-weighted (T2w) edema imaging and late gadolinium enhancement (LGE)-MRI were done immediately (0 day: acute), 1 to 2 weeks (subacute), and 8 to 12 weeks (chronic) after ablation. After the final MRI, excised hearts underwent pathological evaluation. As a result, 45 ventricular lesions (cryo group: 20; RF group: 25) were evaluated. Acute LGE volume was not significantly different but acute edema volume in cryo group was significantly smaller (1225.0 ± 263.5 vs 1855.2 ± 520.5 mm3 ; P = 0.01). One week after ablation, edema still existed in both group but was similar in size. Two weeks after ablation there was no edema in either of the groups. In the chronic phase, the lesion volume for cryo and RF in LGE-MRI (296.7 ± 156.4 vs 281.6 ± 140.8 mm3 ; P = 0.73); and pathology (243.3 ± 125.9 vs 214.5 ± 148.6 mm3 ; P = 0.49), as well as depth, was comparable. CONCLUSIONS: When comparing cryo and RF lesions of similar chronic size, acute edema is larger for RF lesions. Edema resolves in both cryo and RF lesions in 1 to 2 weeks.

T2STIR preparation for single-shot cardiovascular magnetic resonance myocardial edema imaging.

BACKGROUND: Myocardial edema in acute myocardial infarction (AMI) is commonly imaged using dark-blood short tau inversion recovery turbo spin echo (STIR-TSE) cardiovascular magnetic resonance (CMR). The technique is sensitive to cardiac motion and coil sensitivity variation, leading to myocardial signal nonuniformity and impeding reliable depiction of edematous tissues. T2-prepared balanced steady state free precession (T2p-bSSFP) imaging has been proposed, but its contrast is low, and averaging is commonly needed. T2 mapping is useful but requires a long scan time and breathholding. We propose here a single-shot magnetization prepared sequence that increases the contrast between edema and normal myocardium and apply it to myocardial edema imaging. METHODS: A magnetization preparation module (T2STIR) is designed to exploit the simultaneous elevation of T1 and T2 in edema to improve the depiction of edematous myocardium. The module tips magnetization down to the -z axis after T2 preparation. Transverse magnetization is sampled at the fat null point using bSSFP readout and allows for single-shot myocardial edema imaging. The sequence (T2STIR-bSSFP) was studied for its contrast behavior using simulation and phantoms. It was then evaluated on 7 healthy subjects and 7 AMI patients by comparing it to T2p-bSSFP and T2 mapping using the contrast-to-noise ratio (CNR) and the contrast ratio as performance indices. RESULTS: In simulation and phantom studies, T2STIR-bSSFP had improved contrast between edema and normal myocardium compared with the other two edema imaging techniques. In patients, the CNR of T2STIR-bSSFP was higher than T2p-bSSFP (5.9 ± 2.6 vs. 2.8 ± 2.0, P < 0.05) but had no significant difference compared with that of the T2 map (T2 map: 6.6 ± 3.3 vs. 5.9 ± 2.6, P = 0.62). The contrast ratio of T2STIR-bSSFP (2.4 ± 0.8) was higher than that of the T2 map (1.3 ± 0.1, P < 0.01) and T2p-bSSFP (1.4 ± 0.5, P < 0.05). CONCLUSION: T2STIR-bSSFP has improved contrast between edematous and normal myocardium compared with commonly used bSSFP-based edema imaging techniques. T2STIR-bSSFP also differentiates between fat that was robustly suppressed and fluids around the heart. The technique is useful for single-shot edema imaging in AMI patients.

Higher contact force during radiofrequency ablation leads to a much larger increase in edema as compared to chronic lesion size.

INTRODUCTION: Reversible edema is a part of any radiofrequency ablation but its relationship with contact force is unknown. The goal of this study was to characterize through histology and MRI, acute and chronic ablation lesions and reversible edema with contact force. METHODS AND RESULTS: In a canine model (n = 14), chronic ventricular lesions were created with a 3.5-mm tip ThermoCool SmartTouch (Biosense Webster) catheter at 25 W or 40 W for 30 seconds. Repeat ablation was performed after 3 months to create a second set of lesions (acute). Each ablation procedure was followed by in vivo T2-weighted MRI for edema and late-gadolinium enhancement (LGE) MRI for lesion characterization. For chronic lesions, the mean scar volumes at 25 W and 40 W were 77.8 ± 34.5 mm3 (n = 24) and 139.1 ± 69.7 mm3 (n = 12), respectively. The volume of chronic lesions increased (25 W: P < 0.001, 40 W: P < 0.001) with greater contact force. For acute lesions, the mean volumes of the lesion were 286.0 ± 129.8 mm3 (n = 19) and 422.1 ± 113.1 mm3 (n = 16) for 25 W and 40 W, respectively (P < 0.001 compared to chronic scar). On T2-weighted MRI, the acute edema volume was on average 5.6-8.7 times higher than the acute lesion volume and increased with contact force (25 W: P = 0.001, 40 W: P = 0.011). CONCLUSION: With increasing contact force, there is a marginal increase in lesion size but accompanied with a significantly larger edema. The reversible edema that is much larger than the chronic lesion volume may explain some of the chronic procedure failures.

Dynamic changes in injured myocardium, very early after acute myocardial infarction, quantified using T1 mapping cardiovascular magnetic resonance.

BACKGROUND: It has recently been suggested that myocardial oedema follows a bimodal pattern early post ST-segment elevation myocardial infarction (STEMI). Yet, water content, quantified using tissue desiccation, did not return to normal values unlike oedema quantified by cardiovascular magnetic resonance (CMR) imaging. We studied the temporal changes in the extent and intensity of injured myocardium using T1-mapping technique within the first week after STEMI. METHODS: A first group (n = 31) underwent 3 acute 3 T CMR scans (time-point (TP) < 3 h, 24 h and 6 days), including cine, native shortened modified look-locker inversion recovery T1 mapping, T2* mapping and late gadolinium enhancement (LGE). A second group (n = 17) had a single scan at 24 h with an additional T2-weighted sequence to assess the difference in the extent of area-at-risk (AAR) compared to T1-mapping. RESULTS: The mean T1 relaxation time value within the AAR of the first group was reduced after 24 h (P < 0.001 for TP1 vs.TP2) and subsequently increased at 6 days (P = 0.041 for TP2 vs.TP3). However, the extent of AAR quantified using T1-mapping did not follow the same course, and no change was detected between TP1&TP2 (P = 1.0) but was between TP2 &TP3 (P = 0.019). In the second group, the extent of AAR was significantly larger on T1-mapping compared to T2-weighted (42 ± 15% vs. 39 ± 15%, P = 0.025). No change in LGE was detected while microvascular obstruction and intra-myocardial haemorrhage peaked at different time points within the first week of reperfusion. CONCLUSION: The intensity of oedema post-STEMI followed a bimodal pattern; while the extent of AAR did not track the same course. This discrepancy has implications for use of CMR in this context and may explain the previously reported disagreement between oedema quantified by imaging and tissue desiccation.

Cardiovascular magnetic resonance guided ablation and intra-procedural visualization of evolving radiofrequency lesions in the left ventricle.

BACKGROUND: Radiofrequency (RF) ablation has become a mainstay of treatment for ventricular tachycardia, yet adequate lesion formation remains challenging. This study aims to comprehensively describe the composition and evolution of acute left ventricular (LV) lesions using native-contrast cardiovascular magnetic resonance (CMR) during CMR-guided ablation procedures. METHODS: RF ablation was performed using an actively-tracked CMR-enabled catheter guided into the LV of 12 healthy swine to create 14 RF ablation lesions. T2 maps were acquired immediately post-ablation to visualize myocardial edema at the ablation sites and T1-weighted inversion recovery prepared balanced steady-state free precession (IR-SSFP) imaging was used to visualize the lesions. These sequences were repeated concurrently to assess the physiological response following ablation for up to approximately 3 h. Multi-contrast late enhancement (MCLE) imaging was performed to confirm the final pattern of ablation, which was then validated using gross pathology and histology. RESULTS: Edema at the ablation site was detected in T2 maps acquired as early as 3 min post-ablation. Acute T2-derived edematous regions consistently encompassed the T1-derived lesions, and expanded significantly throughout the 3-h period post-ablation to 1.7 ± 0.2 times their baseline volumes (mean ± SE, estimated using a linear mixed model determined from n = 13 lesions). T1-derived lesions remained approximately stable in volume throughout the same time frame, decreasing to 0.9 ± 0.1 times the baseline volume (mean ± SE, estimated using a linear mixed model, n = 9 lesions). CONCLUSIONS: Combining native T1- and T2-based imaging showed that distinctive regions of ablation injury are reflected by these contrast mechanisms, and these regions evolve separately throughout the time period of an intervention. An integrated description of the T1-derived lesion and T2-derived edema provides a detailed picture of acute lesion composition that would be most clinically useful during an ablation case.

Relationship between CMR-derived parameters of ischemia/reperfusion injury and the timing of CMR after reperfused ST-segment elevation myocardial infarction.

BACKGROUND: To investigate the influence of cardiovascular magnetic resonance (CMR) timing after reperfusion on CMR-derived parameters of ischemia/reperfusion (I/R) injury in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: The study included 163 reperfused STEMI patients undergoing CMR during the index hospitalization. Patients were divided according to the time between revascularization and CMR (Trevasc-CMR: Tertile-1 ≤ 43; 43 < Tertile-2 ≤ 93; Tertile-3 > 93 h). T2-mapping derived area-at-risk (AAR) and intramyocardial-hemorrhage (IMH), and late gadolinium enhancement (LGE)-derived infarct size (IS) and microvascular obstruction (MVO) were quantified. T1-mapping was performed before and > 15 min after Gd-based contrast-agent administration yielding extracellular volume (ECV) of infarct. RESULTS: Main factors influencing I/R injury were homogenously balanced across Trevasc-CMR tertiles. T2 values of infarct and remote regions increased with increasing Trevasc-CMR tertiles (infarct: 60.0 ± 4.9 vs 63.5 ± 5.6 vs 64.8 ± 7.5 ms; P < 0.001; remote: 44.3 ± 2.8 vs 46.1 ± 2.8 vs ± 46.1 ± 3.0; P = 0.001). However, T2 value of infarct largely and significantly exceeded that of remote myocardium in each tertile yielding comparable T2-mapping-derived AAR extent throughout Trevasc-CMR tertiles (17 ± 9% vs 19 ± 9% vs 18 ± 8% of LV, respectively, P = 0.385). Similarly, T2-mapping-based IMH detection and quantification were independent of Trevasc-CMR. LGE-derived IS and MVO were not influenced by Trevasc-CMR (IS: 12 ± 9% vs 12 ± 9% vs 14 ± 9% of LV, respectively, P = 0.646). In 68 patients without MVO, T1-mapping based ECV of infarct region was comparable across Trevasc-CMR tertiles (P = 0.470). CONCLUSION: In STEMI patients, T2 values of infarct and remote myocardium increase with increasing CMR time after revascularization. However, these changes do not give rise to substantial variation of T2-mapping-derived AAR size nor of other CMR-based parameters of I/R. TRIAL REGISTRATION: ISRCTN03522116 . Registered 30.4.2018 (retrospectively registered).

Developmental toxicity and inhibition of the fungicide hymexazol to melanin biosynthesis in zebrafish embryos.

Hymexazol is an efficacious and widely used fungicide. However, its environmental toxicological assessment has not been well documented. It had no report of its toxicity to fish embryo. Fish embryo acute toxicity tests are highly predictive of aquatic embryotoxicity outcome. In this study, zebrafish (Danio rerio) embryos were exposed to hymexazol at varying concentrations for the study of the developmental toxicity, melanin biosynthesis, biochemical and transcriptional endpoints. The embryotoxicity tests indicated that the 96h LC50 value of hymexazol was 649mg/L with a 95% confidence interval range of 632-667mg/L. Hymexazol at concentrations of 417-738mg/L decreased the heart rate and increased the voluntary swing. Hymexazol inhibited normal development at concentrations above 554mg/L. the 96h EC50 was 411mg/L. Hymexazol in a concentration range of 417-738mg/L induced cardiac edema and yolk sac edema. Exposure of hymexazol at such concentrations to zebrafish embryos for 48h decreased the pigment area density compared with the no hymexazol control. Tyrosinase activity was inhibited by hymexazol relative to the untreated control. The P53 mRNA expression level in embryos upon exposure to 480mg/L or greater of hymexazol was significantly higher than that of the control. The results indicated that hymexazol has quite low acute toxicity and low embryotoxicity to zebrafish.

Feature-tracking myocardial strain analysis in acute myocarditis: diagnostic value and association with myocardial oedema.

OBJECTIVES: To investigate the diagnostic value of cardiac magnetic resonance (CMR) feature-tracking (FT) myocardial strain analysis in patients with suspected acute myocarditis and its association with myocardial oedema. METHODS: Forty-eight patients with suspected acute myocarditis and 35 control subjects underwent CMR. FT CMR analysis of systolic longitudinal (LS), circumferential (CS) and radial strain (RS) was performed. Additionally, the protocol allowed for the assessment of T1 and T2 relaxation times. RESULTS: When compared with healthy controls, myocarditis patients demonstrated reduced LS, CS and RS values (LS: -19.5 ± 4.4% vs. -23.6 ± 3.1%, CS: -23.0 ± 5.8% vs. -27.4 ± 3.4%, RS: 28.9 ± 8.5% vs. 32.4 ± 7.4%; P < 0.05, respectively). LS (T1: r = 0.462, P < 0.001; T2: r = 0.436, P < 0.001) and CS (T1: r = 0.429, P < 0.001; T2: r = 0.467, P < 0.001) showed the strongest correlations with T1 and T2 relaxations times. Area under the curve of LS (0.79) was higher compared with those of CS (0.75; P = 0.478) and RS (0.62; P = 0.008). CONCLUSIONS: FT CMR myocardial strain analysis might serve as a new tool for assessment of myocardial dysfunction in the diagnostic work-up of patients suspected of having acute myocarditis. Especially, LS and CS show a sufficient diagnostic performance and were most closely correlated with CMR parameters of myocardial oedema. KEY POINTS: • Myocardial strain measures are considerably reduced in patients with suspected myocarditis. • Myocardial strain measures can sufficiently discriminate between diseased and healthy patients. • Myocardial strain measures show basic associations with the extent of myocardial oedema/inflammation.