Diagnostic performance of unenhanced electrocardiogram-gated cardiac CT for detecting myocardial edema.

To assess the diagnostic performance of unenhanced electrocardiogram (ECG)-gated cardiac computed tomography (CT) for detecting myocardial edema, using MRI T2 mapping as the reference standard. This retrospective study protocol was approved by our institutional review board, which waived the requirement for written informed consent. Between December 2017 to February 2019, consecutive patients who had undergone T2 mapping for myocardial tissue characterization were identified. We excluded patients who did not undergo unenhanced ECG-gated cardiac CT within 3 months from MRI T2 mapping or who had poor CT image quality. All patients underwent unenhanced ECG-gated cardiac CT with an axial scan using a third-generation, 320 × 0.5 mm detector-row CT unit. Two radiologists together drew regions of interest (ROIs) in the interventricular septum on the unenhanced ECG-gated cardiac CT images. Using T2 mapping as the reference standard, the diagnostic performance of unenhanced cardiac CT for detecting myocardial edema was evaluated by using the area under the receiver operating characteristic curve with sensitivity and specificity. Youden index was used to find an optimal sensitivity-specificity cutoff point. A cardiovascular radiologist independently performed the measurements, and interobserver reliability was assessed using intraclass correlation coefficients for CT value measurements. A P value of <.05 was considered statistically significant. We included 257 patients who had undergone MRI T2 mapping. Of the 257 patients, 35 patients underwent unenhanced ECG-gated cardiac CT. One patient was excluded from the study because of poor CT image quality. Finally, 34 patients (23 men; age 64.7 ±â€…14.6 years) comprised our study group. Using T2 mapping, we identified myocardial edema in 19 patients. Mean CT and T2 values for 34 patients were 46.3 ±â€…2.7 Hounsfield unit and 49.0 ±â€…4.9 ms, respectively. Mean CT values moderately correlated with mean T2 values (Rho = -0.41; P < .05). Mean CT values provided a sensitivity of 63.2% and a specificity of 93.3% for detecting myocardial edema, with a cutoff value of ≤45.0 Hounsfield unit (area under the receiver operating characteristic curve = 0.77; P < .01). Inter-observer reproducibility in measuring mean CT values was excellent (intraclass correlation coefficient = 0.93; [95% confidence interval: 0.86, 0.96]). Myocardial edema could be detected by CT value of myocardium in unenhanced ECG-gated cardiac CT.

Embryonic Ethanol but Not Cannabinoid Exposure Affects Zebrafish Cardiac Development via Agrin and Sonic Hedgehog Interaction.

Recent studies demonstrate the adverse effects of cannabinoids on development, including via pathways shared with ethanol exposure. Our laboratory has shown that both the nervous system and cardiac development are dependent on agrin modulation of sonic hedgehog (shh) and fibroblast growth factor (Fgf) signaling pathways. As both ethanol and cannabinoids impact these signaling molecules, we examined their role on zebrafish heart development. Zebrafish embryos were exposed to a range of ethanol and/or cannabinoid receptor 1 and 2 agonist concentrations in the absence or presence of morpholino oligonucleotides that disrupt agrin or shh expression. In situ hybridization was employed to analyze cardiac marker gene expression. Exposure to cannabinoid receptor agonists disrupted midbrain-hindbrain boundary development, but had no effect on heart development, as assessed by the presence of cardiac edema or the altered expression of cardiac marker genes. In contrast, exposure to 1.5% ethanol induced cardiac edema and the altered expression of cardiac marker genes. Combined exposure to agrin or shh morpholino and 0.5% ethanol disrupted the cmlc2 gene expression pattern, with the restoration of the normal expression following shh mRNA overexpression. These studies provide evidence that signaling pathways critical to heart development are sensitive to ethanol exposure, but not cannabinoids, during early zebrafish embryogenesis.

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.

Angiotensin II Induces Cardiac Edema and Hypertrophic Remodeling through Lymphatic-Dependent Mechanisms.

Cardiac lymphatic vessel growth (lymphangiogenesis) and integrity play an essential role in maintaining tissue fluid balance. Inhibition of lymphatic lymphangiogenesis is involved in cardiac edema and cardiac remodeling after ischemic injury or pressure overload. However, whether lymphatic vessel integrity is disrupted during angiotensin II- (Ang II-) induced cardiac remodeling remains to be investigated. In this study, cardiac remodeling models were established by Ang II (1000 ng/kg/min) in VEGFR-3 knockdown (Lyve-1Cre VEGFR-3f/-) and wild-type (VEGFR-3f/f) littermates. Our results indicated that Ang II infusion not only induced cardiac lymphangiogenesis and upregulation of VEGF-C and VEGFR-3 expression in the time-dependent manner but also enhanced proteasome activity, MKP5 and VE-cadherin degradation, p38 MAPK activation, and lymphatic vessel hyperpermeability. Moreover, VEGFR-3 knockdown significantly inhibited cardiac lymphangiogenesis in mice, resulting in exacerbation of tissue edema, hypertrophy, fibrosis superoxide production, inflammation, and heart failure (HF). Conversely, administration of epoxomicin (a selective proteasome inhibitor) markedly mitigated Ang II-induced cardiac edema, remodeling, and dysfunction; upregulated MKP5 and VE-cadherin expression; inactivated p38 MAPK; and reduced lymphatic vessel hyperpermeability in WT mice, indicating that inhibition of proteasome activity is required to maintain lymphatic endothelial cell (LEC) integrity. Our results show that both cardiac lymphangiogenesis and lymphatic barrier hyperpermeability are implicated in Ang II-induced adaptive hypertrophic remodeling and dysfunction. Proteasome-mediated hyperpermeability of LEC junctions plays a predominant role in the development of cardiac remodeling. Selective stimulation of lymphangiogenesis or inhibition of proteasome activity may be a potential therapeutic option for treating hypertension-induced cardiac remodeling.

Clinical outcomes in patients with COPD hospitalized with SARS-CoV-2 versus non- SARS-CoV-2 community-acquired pneumonia.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have poor outcomes in the setting of community-acquired pneumonia (CAP) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The primary objective is to compare outcomes of SARS-CoV-2 CAP and non-SARS-CoV-2 CAP in patients with COPD. The secondary objective is to compare outcomes of SARS-CoV-2 CAP with and without COPD. METHODS: In this analysis of two observational studies, three cohorts were analyzed: (1) patients with COPD and SARS-CoV-2 CAP; (2) patients with COPD and non-SARS-CoV-2 CAP; and (3) patients with SARS-CoV-2 CAP without COPD. Outcomes included length of stay, ICU admission, cardiac events, and in-hospital mortality. RESULTS: Ninety-six patients with COPD and SARS-CoV-2 CAP were compared to 1129 patients with COPD and non-SARS-CoV-2 CAP. 536 patients without COPD and SARS-CoV-2 CAP were analyzed for the secondary objective. Patients with COPD and SARS-CoV-2 CAP had longer hospital stay (15 vs 5 days, p < 0.001), 4.98 higher odds of cardiac events (95% CI: 3.74-6.69), and 7.31 higher odds of death (95% CI: 5.36-10.12) in comparison to patients with COPD and non-SARS-CoV-2 CAP. In patients with SARS-CoV-2 CAP, presence of COPD was associated with 1.74 (95% CI: 1.39-2.19) higher odds of ICU admission and 1.47 (95% CI: 1.05-2.05) higher odds of death. CONCLUSION: In patients with COPD and CAP, presence of SARS-CoV-2 as an etiologic agent is associated with more cardiovascular events, longer hospital stay, and seven-fold increase in mortality. In patients with SARS-CoV-2 CAP, presence of COPD is associated with 1.5-fold increase in mortality.

Xinshuitong Capsule extract attenuates doxorubicin-induced myocardial edema via regulation of cardiac aquaporins in the chronic heart failure rats.

Doxorubicin (Dox), an effective antineoplastic drug, was limited use for cardiotoxicity. Xinshuitong Capsule (XST), a patented herbal formula, showed desirable beneficial effects in the treatment of chronic heart failure (CHF) patients. However, the drug on Dox-induced cardiotoxicity remains unclear. Ninety male Sprague-Dawley rats were randomized into two groups: 15 rats were selected as the normal group and 75 rats were injected intraperitoneally with Dox to establish CHF rat models, the success ones were randomly divided into five groups: low XST (LXST), medium XST (MXST) or high XST (HXST) (4.9, 9.8, or 19.6 g/kg d) administrated intragastrically twice a day for 4 weeks, with the captopril-treated group and the model group as comparison. The model group showed the cardiac functions generally impaired, and CHF mortality rate higher (47%) than those in the XST-treated groups (averaged 24%, P < 0.05). Compared with XST-treated groups, myocardial remodeling, inflammation and desarcomerization, and higher water content more severe in the cardiac tissue in the model group (P < 0.05), which was associated with higher expressions of mRNA or protein levels of AQP1, 4 and 7. Dox-impaired cardiac functions, cardiac remodeling and myocardial edema could be dose-dependently reverted by XST treatment. XST could inhibit AQP1, 4 and 7 at mRNA levels or at protein levels, which was associated with the attenuation of myocardial edema and cardiac remodeling, decreasing the ventricular stiffness and improving the cardiac functions and rats' survival. AQPs is involved in cardiac edema composed one of the mechanisms of Dox-induced cardiotoxicity, XSTvia inhibition of AQPs relieved the Dox-induced side effects.

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.

Developmental phenotypic and transcriptomic effects of exposure to nanomolar levels of metformin in zebrafish.

Metformin is found in the majority of lakes and streams in the United States, leading to widespread environmental exposure. Results of the present study indicate that extended duration metformin exposure at critical developmental periods leads to decreased survival rates in zebrafish (danio rerio), an NIH approved human model. Significant abnormalities are seen with extended duration metformin exposure from 4 h post fertilization up to 5 days post fertilization, although short term metformin exposure for 24 h at 4-5 days post fertilization did not lead to any significant abnormalities. Both extended and short term duration did however have an impact on locomotor activity of zebrafish, and several genes involved in neurological and cardiovascular development were differentially expressed after exposure to metformin. The changes seen in behavior, gene expression and morphological abnormalities caused by metformin exposure should be examined further in future studies in order to assess their potential human health implications as metformin prescriptions continue to increase worldwide.

Case of type 2 diabetes mellitus with edema resulting in subcutaneous insulin resistance syndrome.

Subcutaneous insulin resistance syndrome caused by obesity, induration at the injection site, skin temperature and other factors is common clinically, whereas resistance events caused by edema are relatively rare. This article introduced a case of a woman with type 2 diabetes mellitus with heart failure edema. Her blood glucose control was significantly associated with the level of edema. Excluding other factors, it can be concluded that edema might lead to subcutaneous insulin resistance syndrome, even if the edema at the injection site is not obvious.

Oxidative stress inducers potentiate 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated pre-cardiac edema in larval zebrafish.

We reported the involvement of oxidative stress and prostaglandins including thromboxane and prostacyclin in pre-cardiac edema (early edema) caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). While the involvement of oxidative stress in TCDD-induced toxicity has been frequently reported, the mechanism of its action is still unclear. In the present study, oxidative stress inducers including paraquat, hydrogen peroxide (H2O2) and rotenone augmented early edema (edema) induced by a low concentration of TCDD (0.1 ppb) at 55 hr post fertilization (hpf), while each of them alone did not cause edema. Edema caused by TCDD plus oxidative stress inducers was almost abolished by antioxidants, an antagonist for thromboxane receptor (ICI-192,605) and an agonist for prostacyclin receptor (beraprost), suggesting that the site of action of these inducers was in the regular signaling pathway after activation of aryl hydrocarbon receptor type 2 (AHR2) by TCDD. Oxidative stress inducers also enhanced edema caused by an agonist for the thromboxane receptor (U46619), and the enhancement was also inhibited by antioxidants. Sulforaphane and auranofin, activators of Nrf2 that is a master regulator of anti-oxidative response, did not affect U46619-evoked edema but almost abolished TCDD-induced edema and potentiation by paraquat in both TCDD- and U46619-induced edema. Taken together, the results suggest that oxidative stress augments pre-cardiac edema caused by TCDD via activation of thromboxane receptor-mediated signaling in developing zebrafish. As paraquat and other oxidative stress inducers used also are environmental pollutants, interaction between dioxin-like compounds and exogenous source of oxidative stress should also be considered.

[Current role of cardiac magnetic resonance (CMR) in diagnosis and therapy of myocardial diseases]. / Aktueller Stellenwert der Kardio-MRT in Diagnostik und Therapie.

Cardiac magnetic resonance is the only imaging modality, that allows for characterising myocardial tissue with respect to fibrosis and edema. It has therefore become gold standard in diagnosing myocardial inflammation by combining scar, fibrosis and edema imaging. Recent developements in T1- and T2 mapping have improved diagnostic accuracy and prognostic information.

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.

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.

Clinical Importance of Myocardial T2 Mapping and Texture Analysis.

Late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) is valuable for diagnosis and assessment of the severity of various myocardial diseases owing to its potential to visualize myocardial scars. T1 mapping is complementary to LGE because it can quantify the degree of myocardial fibrosis or edema. As such, T1-weighted imaging techniques, including LGE using an inversion recovery sequence, contribute to cardiac MRI. T2-weighted imaging is widely used to characterize the tissue of many organs. T2-weighted imaging is used in cardiac MRI to identify myocardial edema related to chest pain, acute myocardial diseases, or severe myocardial injuries. However, it is difficult to determine the presence and extent of myocardial edema because of the low contrast between normal and diseased myocardium and image artifacts of T2-weighted images and the lack of an established method to quantify the images. T2 mapping quantifies myocardial T2 values and help identify myocardial edema. The T2 values are significantly related to the clinical symptoms or severity of nonischemic cardiomyopathy. Texture analysis is a postprocessing method to quantify tissue alterations that are reflected in the T2-weighted images. Texture analysis provides a variety of parameters, such as skewness, entropy, and grey-scale non-uniformity, without the need for additional sequences. The abnormal signal intensity on T2-weighted images or T2 values may correspond to not only myocardial edema but also other tissue alterations. In this review, the techniques of cardiac T2 mapping and texture analysis and their clinical relevance are described.

The role of inflammation in stress cardiomyopathy.

Stress cardiomyopathy (SC) is an increasingly recognized form of acute heart failure, which has been linked to a wide variety of emotional and physical triggers. The pathophysiological mechanisms of the disease remain incompletely understood, however, inflammation has been recently shown to play a pivotal role. This review summarizes the most notable findings of myocardial inflammation, demonstrated from biopsies and cardiac magnetic resonance imaging in humans. In the acute stage macrophage infiltration appears to represent the substrate for myocardial edema, together defining the local myocardial inflammation. This appears to evolve into a low grade systemic chronic inflammation which could explain the protracted clinical course of these patients and raises hope for finding a specific SC cardiac biomarker as well as a therapeutic breakthrough. As a parallel to the human findings the review covers some of the emerging mechanistic insights from experimental models, which, albeit not proven in the human condition, highlight the possible importance in pursuing distinct paths of investigation such as the beta-receptor signaling, aberrations of nitric oxide generation and signaling and the contribution of the vascular endothelium/permeability to edema and inflammation during the acute stage.

Advanced cardiac magnetic resonance imaging in takotsubo cardiomyopathy.

Takotsubo cardiomyopathy (TC) is a reversible condition in which there is transient left ventricular (LV) dysfunction characterised most commonly by basal hyperkinesis and mid-apical LV ballooning and hypokinesia. It is said to be triggered by stress and mimics, such as acute coronary syndrome (ACS) clinically. Diagnosis is usually suspected on echocardiography due to the characteristic contraction pattern in a patient with symptoms and signs of ACS but normal coronary arteries on catheter angiography. Cardiac magnetic resonance (CMR), with its latest advancements, is the diagnostic modality of choice for diagnosis, prognosis and follow-up of patients. The advances in CMR (including T1, T2, ECV mapping and threshold-based late gadolinium enhancement (LGE) measurements have revolutionised the role of CMR in tissue characterisation and prognostication in patients with TC. In this review, we highlight the current role of CMR in management of TC and enumerate the CMR findings in TC as well the current advances in the field of CMR, which could help in prognosticating these patients.