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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., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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-1 Cre VEGFR-3 f/- ) and wild-type (VEGFR-3 f/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., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Jie Bai et al.)

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 β1-subunit adhesion domain antagonist (βadp1). 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 βadp1 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.

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., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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 (H 2 O 2 ) 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.

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., (Copyright © 2020. Published by Elsevier Inc.)

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.

Aims: Safe and effective decongestion is the main goal of therapy in acute heart failure (AHF). In the non-randomized, prospective TARGET-1 and TARGET-2 studies (NCT03897842), we investigated whether adding the Reprieve System® (which continuously monitors urine output and delivers a matched volume of hydration fluid sufficient to maintain the set fluid balance rate) to standard diuretic-based regimen improves decongestion in AHF., Methods and Results: The population consisted of 19 patients hospitalized with AHF (mean age 67 ± 10 years, 18 male, ejection fraction 34 ± 15%, median N-terminal pro-B-type natriuretic peptide 4492 pg/mL). Patients served as their own controls: each patient underwent 24 h of standard diuretic therapy followed by 24 h of diuretics with Reprieve therapy (with normal saline used for matched volume replacement). The primary efficacy endpoint of actual fluid loss not exceeding the target fluid loss at the end of therapy was met in all 19 (100%) patients. The mean diuresis during Reprieve therapy was 6284 ± 2679 mL (vs. 1966 ± 1057 mL 24 h before therapy) and 2053 ± 888 mL (24 h after therapy) (both P < 0.0001). At the end of therapy, patient global assessment improved from 7.7 ± 1.1 to 3.0 ± 1.3 points (P < 0.001), central venous pressure decreased from 15.5 ± 5.3 mmHg to 12.8 ± 4.8 mmHg (P < 0.05) and the median urine sodium loss was 9.7 [3-13] mmol/h. The Reprieve therapy was safe, systolic blood pressure remained stable, mean creatinine dropped from 1.45 ± 0.4 mg/dL to 1.26 ± 0.4 mg/dL (P < 0.001) and biomarkers of renal injury did not change during treatment., Conclusions: The Reprieve System in conjunction with diuretic therapy supports safe and controlled decongestion in AHF., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

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.

Objectives: This study sought to characterize the course of decongestion among patients hospitalized for acute heart failure (AHF) by history of atrial fibrillation (AF) and/or atrial flutter (AFL)., Background: AF/AFL and chronic heart failure (HF) commonly coexist. Little is known regarding the impact of AF/AFL on relief of congestion among patients who develop AHF., Methods: We pooled patients from 3 randomized trials of AHF conducted within the Heart Failure Network, the DOSE (Diuretic Optimization Strategies) trial, the ROSE (Renal Optimization Strategies) trial, and the CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trial. The association between history of AF/AFL and in-hospital changes in various metrics of congestion was assessed using covariate-adjusted linear and ordinal logistic regression models., Results: Of 750 unique patients, 418 (56%) had a history of AF/AFL. Left ventricular ejection fraction was higher (35% vs. 27%, respectively; p < 0.001), and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were nonsignificantly lower at baseline (4,210 pg/ml vs. 5,037 pg/ml, respectively; p = 0.27) in patients with AF/AFL. After adjustment of covariates, history of AF/AFL was associated with less substantial loss of weight (-5.7% vs. -6.5%, respectively; p = 0.02) and decrease in NT-proBNP levels (-18.7% vs. -31.3%, respectively; p = 0.003) by 72 or 96 h. History of AF/AFL was also associated with a blunted increase in global sense of well being at 72 or 96 h (p = 0.04). There was no association between history of AF/AFL and change in orthodema congestion score (p = 0.67) or 60-day composite clinical endpoint (all-cause mortality or any rehospitalization; hazard ratio: 1.21; 95% confidence interval: 0.92 to 1.59; p = 0.17)., Conclusions: More than half of the patients admitted with AHF had a history of AF/AFL. History of AF/AFL was independently associated with a blunted course of in-hospital decongestion. Further research is required to understand the utility of specific therapies targeting AF/AFL during hospitalization for AHF., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Sialic acids are important components of glycoproteins and glycolipids essential for cellular communication, infection, and metastasis. The importance of sialic acid biosynthesis in human physiology is well illustrated by the severe metabolic disorders in this pathway. However, the biological role of sialic acid catabolism in humans remains unclear. Here, we present evidence that sialic acid catabolism is important for heart and skeletal muscle function and development in humans and zebrafish. In two siblings, presenting with sialuria, exercise intolerance/muscle wasting, and cardiac symptoms in the brother, compound heterozygous mutations [chr1:182775324C>T (c.187C>T; p.Arg63Cys) and chr1:182772897A>G (c.133A>G; p.Asn45Asp)] were found in the N-acetylneuraminate pyruvate lyase gene (NPL). In vitro, NPL activity and sialic acid catabolism were affected, with a cell-type-specific reduction of N-acetyl mannosamine (ManNAc). A knockdown of NPL in zebrafish resulted in severe skeletal myopathy and cardiac edema, mimicking the human phenotype. The phenotype was rescued by expression of wild-type human NPL but not by the p.Arg63Cys or p.Asn45Asp mutants. Importantly, the myopathy phenotype in zebrafish embryos was rescued by treatment with the catabolic products of NPL: N-acetyl glucosamine (GlcNAc) and ManNAc; the latter also rescuing the cardiac phenotype. In conclusion, we provide the first report to our knowledge of a human defect in sialic acid catabolism, which implicates an important role of the sialic acid catabolic pathway in mammalian muscle physiology, and suggests opportunities for monosaccharide replacement therapy in human patients.

Oxidative stress plays a critical task in the biochemical and pathological alteration linked with myocardial ischemic-reperfusion injury (IRI). This warrants identifying agents with a potential for preventing such damage in an effective way. A novel plant based product, Pycnogenol, obtained from the French maritime pine (Pinus pinaster ssp. atlantica) bark extract was known for its tremendous antioxidant potential (both in vivo, in vitro). It was able to attenuate the symptoms of immune dysfunction through restoring a cellular antioxidant status in low micronutrient-induced immune deficient mice. Consequently, the present study was deals with the determination of protective effect of Pycnogenol in ischemic-reperfusion injury (IRI) in rats via Non-recirculating Langendorff's technique. The effect of Pycnogenol  on the level of various key biomarkers in the rat heart homogenate was determined, such as, myocardial thiobarbituric acid reactive substances (TBARS, a marker of lipid peroxidation), lactic dehydrogenase (LDH) (a marker of tissue injury) and effect on endogenous antioxidants, e.g., superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx). The activity of these biomarkers appreciably improved in Pycnogenol-treated group than IRI group (P &lt; 0.05). The effect of Pycnogenol was further confirmed via histopathological examination of cardiac tissues, which suggests that, it considerably improved the injury related to tissue damage through suppression of edema and infiltration of neutrophil compared to IRI group. It also showed modulation of the expression of apoptotic factors, e.g. Bcl-2, bax and caspase-9 as confirmed by western blot analysis.

Background: Following myocardial infarction (MI), peri-infarct myocardial edema formation further impairs cardiac function. Extracellular RNA (eRNA) released from injured cells strongly increases vascular permeability. This study aimed to assess the role of eRNA in MI-induced cardiac edema formation, infarct size, cardiac function, and survival after acute MI and to evaluate the therapeutic potential of ribonuclease 1 (RNase-1) treatment as an eRNA-degrading intervention., Methods and Results: C57BL/6J mice were subjected to MI by permanent ligation of the left anterior descending coronary artery. Plasma eRNA levels were significantly increased compared with those in controls starting from 30 minutes after ligation. Systemic application of RNase-1, but not DNase, significantly reduced myocardial edema formation 24 hours after ligation compared with controls. Consequently, eRNA degradation by RNase-1 significantly improved the perfusion of collateral arteries in the border zone of the infarcted myocardium 24 hours after ligation of the left anterior descending coronary artery, as detected by micro-computed tomography imaging. Although there was no significant difference in the area at risk, the area of vital myocardium was markedly larger in mice treated with RNase-1 compared with controls, as detected by Evans blue and 2,3,5-triphenyltetrazolium chloride staining. The increase in viable myocardium was associated with significantly preserved left ventricular function, as assessed by echocardiography. Moreover, RNase-1 significantly improved 8-week survival following MI., Conclusions: eRNA is an unrecognized permeability factor in vivo, associated with myocardial edema formation after acute MI. RNase-1 counteracts eRNA-induced edema formation and preserves perfusion of the infarction border zone, reducing infarct size and protecting cardiac function after MI., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Several T2-mapping sequences have been recently proposed to quantify myocardial edema by providing T2 relaxation time values. However, no T2-mapping sequence has ever been validated against actual myocardial water content for edema detection. In addition, these T2-mapping sequences are either time-consuming or require specialized software for data acquisition and/or post-processing, factors impeding their routine clinical use. Our objective was to obtain in vivo validation of a sequence for fast and accurate myocardial T2-mapping (T2 gradient-spin-echo [GraSE]) that can be easily integrated in routine protocols., Methods: The study population comprised 25 pigs. Closed-chest 40 min ischemia/reperfusion was performed in 20 pigs. Pigs were sacrificed at 120 min (n = 5), 24 h (n = 5), 4 days (n = 5) and 7 days (n = 5) after reperfusion, and heart tissue extracted for quantification of myocardial water content. For the evaluation of T2 relaxation time, cardiovascular magnetic resonance (CMR) scans, including T2 turbo-spin-echo (T2-TSE, reference standard) mapping and T2-GraSE mapping, were performed at baseline and at every follow-up until sacrifice. Five additional pigs were sacrificed after baseline CMR study and served as controls., Results: Acquisition of T2-GraSE mapping was significantly (3-fold) faster than conventional T2-TSE mapping. Myocardial T2 relaxation measurements performed by T2-TSE and T2-GraSE mapping demonstrated an almost perfect correlation (R(2) = 0.99) and agreement with no systematic error between techniques. The two T2-mapping sequences showed similarly good correlations with myocardial water content: R(2) = 0.75 and R(2) = 0.73 for T2-TSE and T2-GraSE mapping, respectively., Conclusions: We present the first in vivo validation of T2-mapping to assess myocardial edema. Given its shorter acquisition time and no requirement for specific software for data acquisition or post-processing, fast T2-GraSE mapping of the myocardium offers an attractive alternative to current CMR sequences for T2 quantification.

Background: Both intrinsic contrast (T₁ and T₂ relaxation and the equilibrium magnetization) and contrast agent (gadolinium)-enhanced MRI are used to visualize and evaluate acute radiofrequency ablation lesions. However, current methods are imprecise in delineating lesion extent shortly after the ablation., Methods and Results: Fifteen lesions were created in the endocardium of 13 pigs. A multicontrast inversion recovery steady state free precession imaging method was used to delineate the acute ablation lesions, exploiting T₁-weighted contrast. T₂ and Mo(*) maps were also created from fast spin echo data in a subset of pigs (n=5) to help characterize the change in intrinsic contrast in the lesions. Gross pathology was used as reference for the lesion size comparison, and the lesion structures were confirmed with histological data. In addition, a colorimetric iron assay was used to measure ferric and ferrous iron content in the lesions and the healthy myocardium in a subset of pigs (n=2). The lesion sizes measured in inversion recovery steady state free precession images were highly correlated with the extent of lesion core identified in gross pathology. Magnetic resonance relaxometry showed that the radiofrequency ablation procedure changes the intrinsic T₁ value in the lesion core and the intrinsic T₂ in the edematous region. Furthermore, the T₁ shortening appeared to be correlated with the presence of ferric iron, which may have been associated with metmyoglobin and methemoglobin in the lesions., Conclusions: The study suggests that T₁ contrast may be able to separate necrotic cores from the surrounding edematous rims in acute radiofrequency ablation lesions., (© 2014 American Heart Association, Inc.)

Background: Clinically, donor hearts cannot be preserved for >6 hours between explantation and recipient implantation. A better approach is needed to preserve donor hearts for a longer time. We tested whether low-flow perfusion (LFP) could satisfactorily preserve isolated rat hearts with histidine-tryptophan-ketoglutarate (HTK) solution or Fuwai modified (FWM) solution., Methods: We divided 32 male Sprague-Dawley rats randomly into 4 groups (n = 8): H1, H2, F1, and F2. The Langendorff heart model immersed isolated hearts in the H1 and F1 groups in HTK or FWM solution for 8 hours at 4 °C. Isolated hearts in the H2 and F2 groups were low-flow perfused with HTK solution and FWM solution for 8 hours at a pressure of 10 cmH(2)O at 4 °C. After 60 minutes reperfusion, we measured recovery of cardiac function, myocardial water content, and leakage of myocardial enzymes., Results: After reperfusion, no cardiac rebeating was observed among F1 group hearts; in addition, they showed significantly higher myocardial water content and lactate dehydrogenase leakage compared with the other 3 groups (P < .05). The recovery rates of cardiac function among H2 hearts were better than the other 3 groups (P < .05); their myocardial water content and enzyme leakage were less than the other 3 groups (P < .05)., Conclusions: Hypothermic LFP was better than static storage to preserve isolated rat hearts. HTK solution afforded better myocardial protection than FWM., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Myocardial stunning, which is closely related to myocardial edema, is a severe complication that may occur following cardiac surgery. In this study, we examined the expression of aquaporin 1 (AQP1) and Connexin 43 (Cx43) following cardiopulmonary bypass (CPB) surgery in goats. We assessed myocardial muscle tissue water content according to changes in dry-wet weight. Our results showed that AQP1 expression and myocardial muscle tissue water content increased significantly 6 h after CPB surgery, reaching peak levels 48 h after surgery; additionally, the protein expression of Cx43 was inversely correlated with AQP1 expression. Overexpression of AQP1 during CPB surgery enhanced the degree of myocardial edema, whereas the addition of water channel protein inhibitor Hg2+ in cold crystalloid cardioplegia and knockdown of AQP1 during surgery weakened the degree of myocardial edema. These findings revealed that the severity of myocardial edema after CPB surgery is correlated with AQP1 protein expression levels, suggesting the important role played by AQP1 protein in the regulation of Cx43 in the pathological progression of myocardial edema.

Myocardial edema can arise in several disease states. MRI contrast agent can accumulate in edematous tissue, which complicates differential diagnosis with contrast-enhanced (CE)-MRI and might lead to overestimation of infarct size. Sodium Chemical Shift Imaging ((23)Na-CSI) may provide an alternative for edema imaging. We have developed a non-infarct, isolated rat heart model with two levels of edema, which was studied with (23)Na-CSI and CE-MRI. In edematous, but viable tissue the extracellular sodium (Na (e) (+)) signal is hypothesized to increase, but not the intracellular sodium (Na (i) (+)) signal. Isolated hearts were perfused at 60 (n = 6) and 140 mmHg (n = 5). Dimethyl methylphosphonate (DMMP) and phenylphosphonate (PPA) were used to follow edema formation by (31)P-MR Spectroscopy. In separate groups, Thulium(III)1,4,7,10 tetraazacyclododecane-N,N',N″,N'''-tetra(methylenephosphonate) (TmDOTP(5-)) and Gadovist were used for (23)Na-CSI (n = 8) and CE-MRI (n = 6), respectively. PPA normalized signal intensity (SI) was higher at 140 versus 60 mmHg, with a ratio of 1.27 ± 0.12 (p < 0.05). The (DMMP-PPA)/dry weight ratio, as a marker of intracellular volume, remained unchanged. The mid-heart cross sectional area (CSA) of the left ventricle (LV) was significantly increased at 140 mmHg. In addition, at 140 mmHg, the LV Na (e) (+) SI increased with a 140 mmHg/60 mmHg ratio of 1.24 ± 0.18 (p < 0.05). Na (i) (+) SI remained essentially unchanged. With CE-MRI, a subendocardially enhanced CSA was identified, increasing from 0.20 ± 0.02 cm(2) at 60 mmHg to 0.31 ± 0.02 cm(2) at 140 mmHg (p < 0.05). Edema shows up in both CE-MRI and Na (e) (+) . High perfusion pressure causes more edema subendocardially than subepicardially. (23)Na-CSI is an attractive alternative for imaging of edema and is a promising tool to discriminate between edema, acute and chronic MI.

Background/aims: Most cardiac procedures involve the use of cardiopulmonary bypass (CPB), which pumps oxygenated blood to the body while the heart and lungs are isolated. CPB can cause profound alterations V in the homeostasis of physiological fluids, which often results in myocardial edema. In our study, we used sheep CPB model of in vivo and in vitro to assess the relationship between cGMP and AQP1 during CPB., Methods: ODQ, a specific inhibitor of soluble guanylate cyclase (sGC), was used to treat the CPB animals or cardiomyocytes. Left ventricular function of each group was determined by pressure-volume system. Water content of myocardial tissue was assessed by dry-wet weight, and cardiomyocytes water permeability was also calculated. The concentration of cGMP was determined by Radioimmunoassay (RIA). mRNA and protein expression of AQP1 were detected by real-time PCR and western blot, respectively., Results: The relative expression level of AQP1 mRNA and protein at each time point (0, 6, 12, 24 or 48 h) after CPB was significantly increased (1.18-fold at 12 h, 1.77-fold at 24 h and 2.18-fold at 48h) compared with each sham group, the protein expression of AQP1 also showed a rising trend after CPB. The degree of myocardial edema (75.1% at 12 h, 79.3% at 24 h and 81.0% at 48h) increased following the CPB surgery. The mRNA expression level of AQP1 was significantly decreased by 39.7% (p<0.01) upon treatment with ODQ compared with the CPB-only group, and inhibition of cGMP pathway also can significantly decrease the degree of myocardial edema (84.7% in control group, while 75.2% in ODQ group) and improve cardiac function in sheep after CPB. Results of in vitro experiments showed the same changing trends as in vivo., Conclusion: cGMP pathway controls water channels and then affects water intake during CPB through an AQP1-mediated pathway., (© 2013 S. Karger AG, Basel.)

Myocardial edema occurs in a large number of myocardial pathologies particularly during ischemia-reperfusion, and may contribute to cell dysfunction and death occurring in these conditions. Cardiomyocyte cell volume is tightly regulated by modifications in cytosolic osmolality. Changes in membrane water permeability through aquaporin and connexin hemichannels also contribute to cell volume changes while caveolae may be important in sensing cell volume changes sensing and associated signaling. Ischemia-reperfusion alters these mechanisms and increases microvascular permeability by endothelial hypercontracture-induced gap formation, endothelial cell death and basal membrane disruption. Detection of myocardial edema by MRI has many useful diagnostic applications in acute myocardial infarction and other conditions. However, discrimination between intra and extracellular myocardial edema is presently difficult at the bench and impossible at the bedside. Developing methods to differentiate intra from extracellular myocardial water should allow a better understanding of the mechanisms and consequences of myocardial edema and, as a consequence lead to new diagnostic and therapeutic applications., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Treatment with glutamine has been shown to reduce myocardial damage associated with ischemia/reperfusion injury. However, the cardioprotective effect of glutamine specifically after burn injury remains unclear. The present study explores the ability of glutamine to protect against myocardial damage in rats that have been severely burned. Seventy-two Wistar rats were randomly divided into three groups: normal controls (C), burned controls (B) and a glutamine-treated group (G). Groups B and G were subjected to full thickness burns comprising 30% of total body surface area. Group G was administered 1.5 g/ (kg•d) glutamine and group B was given the same dose of alanine via intragastric administration for 3 days. Levels of serum creatine kinase (CK), lactate dehydrogenase (LDH), aspartate transaminase (AST) and blood lactic acid were measured, as well as myocardial ATP and glutathione (GSH) contents. Cardiac function indices and histopathological changes were analyzed at 12, 24, 48 and 72 post-burn hours. In both burned groups, levels of serum CK, LDH, AST and blood lactic acid increased significantly, while myocardial ATP and GSH contents decreased. Compared with group B, CK, LDH, and AST levels were lower and blood lactic acid, myocardial ATP and GSH levels were higher in group G. Moreover, cardiac contractile function inhibition and myocardial histopathological damage were significantly reduced in group G compared to B. Taken together, these results show that glutamine supplementation protects myocardial structure and function after burn injury by improving energy metabolism and by promoted the synthesis of ATP and GSH in cardiac myocytes.

Cardiac conduction through gap junctions is an important determinant of arrhythmia susceptibility. Yet, the relationship between degrees of G(j) uncoupling and conduction velocity (θ) remains controversial. Conflicting results in similar experiments are normally attributed to experimental differences. We hypothesized that interstitial volume modulates conduction velocity and its dependence on G(j). Interstitial volume (V(IS)) was quantified histologically from guinea pig right ventricle. Optical mapping was used to quantify conduction velocity and anisotropy (AR(θ)). Albumin (4 g/l) decreased histologically assessed V(IS), increased transverse θ by 71 ± 10%, and lowered AR(θ). Furthermore, albumin did not change isolated cell size. Conversely, mannitol increased V(IS), decreased transverse θ by 24 ± 4%, and increased AR(θ). Mannitol also decreased cell width by 12%. Furthermore, mannitol was associated with spontaneous ventricular tachycardias in three of eight animals relative to zero of 15 during control. The θ-G(j) relationship was assessed using the G(j) uncoupler carbenoxolone (CBX). Whereas 13 μM CBX did not significantly affect θ during control, it slowed transverse θ by 38 ± 9% during mannitol (edema). These data suggest changes in V(IS) modulate θ, AR(θ), and the θ-G(j) relationship and thereby alter arrhythmia susceptibility. Therefore, V(IS) may underlie arrhythmia susceptibility, particularly in diseases associated with gap junction remodeling.

Background: Inflammation plays a pivotal role in all stages of atherosclerosis. Since edema is known to be an integral part of inflammation, a noninvasive technique that can identify edema in the coronary artery wall may provide unique information regarding plaque activity. In this study, we aimed to determine whether edema induced in porcine coronary arteries by balloon injury could be reliably detected by cardiovascular magnetic resonance (CMR) using a water sensitive T2-weighted short tau inversion recovery sequence (T2-STIR). We also aimed to compare these results to those of conventional T2-weighted (T2W) imaging., Methods: Edema was induced in the proximal left anterior descending (LAD) coronary artery wall in seven pigs by balloon injury. At baseline, and 1-10 days (average four) post injury, the proximal LAD was assessed by water sensitive T2-STIR and conventional T2W sequences in cross-sectional planes. CMR images were matched to histopathology, validated against Evans blue as a marker of increased vessel wall permeability, and correlated with the arterial amount of fibrinogen used as an edema surrogate marker., Results: Post injury, the T2-STIR images of the injured LAD vessel wall showed a significant 72%, relative signal intensity (SI) increase compared with baseline (p = 0.028). Using a threshold value of SI 7 SD above the average SI of the myocardium, T2-STIR detected edema in the vessel wall (i.e. enhancement) with a sensitivity of 100 and a specificity of 71. Twelve out of the 14 (86%) T2-STIR images displaying coronary artery wall enhancement also showed Evans blue uptake in the corresponding histology. The relative signal intensity showed a linear correlation with the amount of fibrinogen detected on the corresponding histopathology (ρ = 0.750, p = 0.05). The conventional T2W images did not show significant changes in SI post injury., Conclusion: T2-STIR CMR enabled detection of coronary artery wall edema and could therefore be a non-invasive diagnostic tool for evaluation of inflammatory coronary artery wall activity.

The heart, perhaps more than any other organ, is exquisitely sensitive to increases in microvascular permeability and the accumulation of myocardial interstitial oedema fluid. Whereas some organs can cope with profound increases in the interstitial fluid volume or oedema formation without a compromise in function, heart function is significantly compromised with only a few percent increase in the interstitial fluid volume. This would be of little consequence if myocardial oedema were an uncommon pathology. On the contrary, myocardial oedema forms in response to many disease states as well as clinical interventions such as cardiopulmonary bypass and cardioplegic arrest common to many cardiothoracic surgical procedures. The heart's inability to function effectively in the presence of myocardial oedema is further confounded by the perplexing fact that the resolution of myocardial oedema does not restore normal cardiac function. We will attempt to provide some insight as to how microvascular permeability and myocardial oedema formation compromise cardiac function and discuss the acute changes that might take place in the myocardium to perpetuate compromised cardiac function following oedema resolution. We will also discuss compensatory changes in the interstitial matrix of the heart in response to chronic myocardial oedema and the role they play to optimize myocardial function during chronic oedemagenic disease.

Pyruvate-fortified cardioplegia protects myocardium and hastens postsurgical recovery of patients undergoing cardiopulmonary bypass (CPB). Pyruvate reportedly suppresses degradation of the alpha-subunit of hypoxia-inducible factor-1 (HIF-1), an activator of the gene encoding the cardioprotective cytokine erythropoietin (EPO). This study tested the hypothesis that pyruvate-enriched cardioplegia evoked EPO expression and mobilized EPO signaling mechanisms in myocardium. Hearts of pigs maintained on CPB were arrested for 60 min with 4:1 blood-crystalloid cardioplegia. The crystalloid component contained 188 mM glucose + or - 24 mM pyruvate. After 30-min cardiac reperfusion with cardioplegia-free blood, the pigs were weaned from CPB. Left ventricular myocardium was sampled 4 h after CPB for immunoblot assessment of HIF-1alpha, EPO and its receptor, the signaling kinases Akt and ERK, and endothelial nitric oxide synthase (eNOS), an effector of EPO signaling. Pyruvate-fortified cardioplegia stabilized arterial pressure post-CPB, induced myocardial EPO mRNA expression, and increased HIF-1alpha, EPO, and EPO-R protein contents by 60, 58, and 123%, respectively, vs. control cardioplegia (P < 0.05). Pyruvate cardioplegia also increased ERK phosphorylation by 61 and 118%, respectively, vs. control cardioplegia-treated and non-CPB sham myocardium (P < 0.01), but did not alter Akt phosphorylation. Nitric oxide synthase (NOS) activity and eNOS content fell 32% following control CPB vs. sham, but pyruvate cardioplegia prevented these declines, yielding 49 and 80% greater NOS activity and eNOS content vs. respective control values (P < 0.01). Pyruvate-fortified cardioplegia induced myocardial EPO expression and mobilized the EPO-ERK-eNOS mechanism. By stabilizing HIF-1alpha, pyruvate-fortified cardioplegia may evoke sustained activation of EPO's cardioprotective signaling cascade in myocardium.

Aims: Ischaemia-reperfusion provokes barrier failure of the coronary microvasculature, impeding functional recovery of the heart during reperfusion. The aim of the present study was to investigate whether the stimulation of cGMP signalling by activation of soluble guanylyl cyclase (sGC) can reduce reperfusion-induced endothelial intercellular gap formation and to determine whether this is due to an influence on endothelial cytosolic Ca(2+) homeostasis during reperfusion., Methods and Results: Experiments were performed with cultured coronary endothelial monolayers and isolated saline-perfused rat hearts. HMR1766 (1 micromol/L) or DEAnonoate (0.5 micromol/L) were used to activate sGC. After exposure to simulated ischaemic conditions, reperfusion of endothelial cells led to a pronounced increase in cytosolic calcium levels and intercellular gaps. Stimulation of cGMP signalling during reperfusion increased Ca(2+) sequestration in the endoplasmic reticulum (ER) and attenuated the reperfusion-induced increase in cytosolic [Ca(2+)]. Phosphorylation of phospholamban was also increased, indicating a de-inhibition of the ER Ca(2+) pump (SERCA). Reperfusion-induced intercellular gap formation was reduced. Reduction of myosin light chain phosphorylation indicated inactivation of the endothelial contractile machinery. Effects on cytsolic Ca(2+) and gaps were abrogated by inhibition of cGMP-dependent protein kinase (PKG) with KT5823. In reperfused hearts, stimulation of cGMP signalling led to decreased oedema development., Conclusion: sGC/PKG activation during reperfusion reduces reperfusion-induced endothelial intercellular gap formation by attenuation of cytosolic calcium overload and reduction of contractile activation in endothelial cells. This mechanism protects the heart against reperfusion-induced oedema.

Background and Aim of the Study: Simultaneous antegrade/retrograde cardioplegia (SARC) has been employed frequently during cardiac surgery to preserve the jeopardized myocardium. However, retrograde perfusion of SARC may interfere with myocardial drainage and disrupt myocardial fluid homeostasis, which may affect the myocardial energy metabolism and contractile function. The study was, therefore, designed to assess the effects of SARC on myocardial fluid homeostasis, cellular volumes, and energy metabolism., Methods: Eight isolated pig hearts were subjected to a protocol consisting of a 20-minute control perfusion, 120-minute SARC, and 20-minute reperfusion. The myocardial water content was monitored using near-infrared spectroscopy. Phosphorus-31 magnetic resonance ((31)P MR) spectroscopy was used to monitor the volumes of both intracellular and extracellular compartments and assess myocardial energy metabolism., Results: The near-infrared spectra showed that the 120-min SARC resulted in a 60 +/- 12% increase in the myocardial water content. (31)P MR spectra showed a 36 +/- 4% increase in the intracellular compartment and a 54 +/- 8% increase in the extracellular compartment during SARC relative to their initial volumes measured during control perfusion (100%). However, the myocardial energy metabolites (adenosine triphosphate [ATP] and phosphocreatine [PCr]) remained unchanged during the 120-minute SARC. Moreover, during reperfusion, the hearts showed an almost complete recovery in the left ventricular-developed pressure., Conclusions: A prolonged SARC resulted in water accumulation in both extracellular and intracellular compartments in the normal myocardium. Although its detrimental effect on tissue fluid homeostasis did not jeopardize the myocardial energy metabolism, a prolonged use of SARC should be avoided, particularly in the diseased hearts.

Myocardial interstitial edema forms as a result of several disease states and clinical interventions. Acute myocardial interstitial edema is associated with compromised systolic and diastolic cardiac function and increased stiffness of the left ventricular chamber. Formation of chronic myocardial interstitial edema results in deposition of interstitial collagen, which causes interstitial fibrosis. To assess the effect of myocardial interstitial edema on the mechanical properties of the left ventricle and the myocardial interstitium, we induced acute and chronic interstitial edema in dogs. Acute myocardial edema was generated by coronary sinus pressure elevation, while chronic myocardial edema was generated by chronic pulmonary artery banding. The pressure-volume relationships of the left ventricular myocardial interstitium and left ventricular chamber for control animals were compared with acutely and chronically edematous animals. Collagen content of nonedematous and chronically edematous animals was also compared. Generating acute myocardial interstitial edema resulted in decreased left ventricular chamber compliance compared with nonedematous animals. With chronic edema, the primary form of collagen changed from type I to III. Left ventricular chamber compliance in animals made chronically edematous was significantly higher than nonedematous animals. The change in primary collagen type secondary to chronic left ventricular myocardial interstitial edema provides direct evidence for structural remodeling. The resulting functional adaptation allows the chronically edematous heart to maintain left ventricular chamber compliance when challenged with acute edema, thus preserving cardiac function over a wide range of interstitial fluid pressures.

Cardiac surgery is performed in approximately 770,000 adults and 30,000 children in the United States of America annually. In this review we outline the mechanistic links between post-operative myocardial stunning and the development of myocardial edema. These interrelated processes cause a decline in myocardial performance that account for significant morbidity and mortality after cardiac surgery. Factors leading to myocardial edema include hemodilution, ischemia and reperfusion as well as osmotic gradients arising from pathological change. Several members of the aquaporin family of water transport proteins have been described in the myocardium although their role in the pathogenesis and resolution of cardiac edema is not established. This review examines evidence for the involvement of aquaporins in myocardial water handling during normal and pathological conditions.

Background: The purpose of this study was to examine regional variation in myocardial water content (%MWC) throughout the iatrogenically edematous pig heart., Methods: Edema was induced by hemodilution in domestic swine (n = 26). Hearts were arrested with potassium chloride. The left ventricular free wall (LVFW), interventricular septum (IVS), and right ventricular free wall (RVFW) were biopsied at the apex, base, and equator. Full-thickness biopsy (Full, 0.5-1 g) and subendocardial (Endo, 0.1-0.2 g) biopsies were removed from each region. %MWC was determined for each biopsy., Results: The %MWC for all hearts were as follows: Endo, 81.1 +/- 0.1, and Full, 80.6 +/- 0.1* (*P < 0.02); apex, 81.1 +/- 0.2*, equator, 80.7 +/- 0.2, and base, 80.4 +/- 0.2 (*P < 0.02); RVFW, 81.4 +/- 0.3*, IVS, 80.8 +/- 0.2*, and LVFW, 80.3 +/- 0.1* (*P < 0.02). For 18 hearts with LV samples with average %MWC >or= 80%, the percentages were apex, 81.4 +/- 0.2*, equator, 81.0 +/- 0.2*, and base, 80.6 +/- 0.2* (*P < 0.02) (repeated measures, ANOVA)., Conclusion: In the iatrogenically edematous porcine heart, a significant water gradient exists, with Endo > Full, apex > equator > base, and RVFW > IVS > LVFW. These results indicate that when examining edema, consistent biopsy results depend on a reproducible sampling site. Water content tends to be highest in thin-walled portions of the heart, suggesting that contractile force may be important in the distribution of edema.

The various options for treatment of diuretic-resistant edema in heart failure and report on their experience with on line bicarbonate daily hemofiltration (135 min) in 16 patients with congestive heart failure IV class NYHA is discussed. The outcome was excellent. Only 6 patients died. Survival averaged 25 weeks in 4 patients. A total of 6 patients are still alive on dialysis after 18 to 52 weeks., (Copyright 2001 by W.B. Saunders Company)

Objective: The mechanism by which chronic myocardial edema causes cardiac dysfunction is poorly understood. We hypothesized that myocardial edema triggers cardiac fibrosis development resulting in cardiac dysfunction. Since collagen is the most abundant constituent of the interstitial matrix, we examined the effects of edema development on cardiac collagen metabolism., Methods: We utilized a chronic pulmonary artery banded rat model that produces right ventricular hypertrophy with myocardial edema and left ventricular edema without hypertrophy or hyperplasia. Wet to dry ratios (index of edema), collagen type I and III concentrations, prolyl 4-hydroxylase (P4-H) and collagen type I and III mRNA levels, collagenase activity and transforming growth factor-beta were measured in both ventricles., Results: Right and left ventricular wet to dry ratios were significantly elevated from 1 to 28 days after pulmonary artery banding compared to sham rats. Right and left ventricular collagen types I and III and P4-H mRNA levels increased significantly at 3 days followed by significant increases in right and left ventricular collagen concentration 7 days after pulmonary artery banding. Right ventricular collagenase activity increased at 3 days while left ventricular collagenase activity decreased 7 days after PA banding., Conclusions: We conclude that myocardial edema preceded the observed increase in collagen deposition and that edema may have triggered increased collagen synthesis by fibroblasts. leading to fibrosis development.

Background: As an alternative to cardioplegic arrest, cardiac surgical conditions have been produced using beta-blocker-induced minimal myocardial contraction (MMC) during cardiopulmonary bypass. The technique of MMC involves the use of high-dose intravenous esmolol to suppress myocardial chronotropy and inotropy sufficiently to produce cardiac surgical conditions. The purpose of this study was to compare conventional crystalloid cardioplegic arrest with MMC in terms of ischemia avoidance, myocardial edema formation, and cardiac function., Methods: Twelve dogs were placed on cardiopulmonary bypass. Six dogs were subjected to crystalloid cardioplegic arrest for 2 hours. Surgical conditions were produced in the other 6 dogs for 2 hours using intravenous esmolol without aortic clamping or cardioplegia. Arterial and coronary sinus lactate concentrations were determined as a gauge of myocardial ischemia. Myocardial water content was determined using microgravimetry and preload recruitable stroke work was determined using sonomicrometry and micromanometry., Results: Significant lactate washout was demonstrated after cardioplegic arrest but not after MMC. Myocardial water content was significantly less during and after MMC compared with cardioplegic arrest (p < 0.05). Preload recruitable stroke work was decreased compared with baseline values in both groups (p < 0.05)., Conclusions: In contrast to a previous study that involved 1 hour of MMC, in this study, ventricular function was decreased to the same extent as with cardioplegic arrest after 2 hours of MMC. This was attributed to the accumulation of ASL-8123, the primary metabolite of esmolol, which possesses beta-antagonist properties. Although postbypass ventricular function is similar in both groups, MMC appears to be superior in terms of ischemia avoidance and myocardial edema formation.

This study is designed to evaluate the effect of hyaluronidase on the canine myocardial edema derived from ischemia/reperfusion injury. The mongrel dog's heart received 90 minutes of ischemia under cardiopulmonary bypass consisting of 30 minutes of normothermia alone and 60 minutes of hypothermia with cardioplegic arrest. Reperfusion for 60 minutes was added thereafter. Two kinds of cardioplegic solution, 4 degrees C St. Thomas' Hospital solution with or without 3000 units/L of hyaluronidase, were prepared. The solution was given antegradely every 30 minutes during cardioplegic arrest. Cardiac lymph was collected continuously from the afferent duct of the cardiac lymph node by cannulation. Hyaluronidase in the cardioplegic solution increased cardiac lymph volume significantly and improved postischemic recovery of cardiac function. A high level of adenosine triphosphate was maintained at that time. The myocardial water content at the end of reperfusion revealed a minimum increase with hyaluronidase use. Active drainage of cardiac lymph by hyaluronidase alleviates the myocardial edema formation, thereby preserving cardiac function.

Background: Although myocardial edema is known to impair diastolic filling of the left ventricle, the interrelation of edema, histologic condition, and function has not been quantitated sufficiently for extrapolation to studies of multifactorial influences on diastolic properties., Methods: Accordingly, ACI rat hearts arrested at 4 degrees C underwent coronary artery perfusion with a cardioplegia solution that was either unaltered (288 mOsm/L, P288 group, n = 6), diluted (144 mOsm/L, P144 group, n = 6), or concentrated (380 mOsm/L, P380 group, n = 6). Postmortem left ventricular pressure-volume curves and myocardial water content were measured. Myocardial samples were fixed in varying dilutions of glutaraldehyde. After dehydration and paraffin embedding, edema was graded subjectively (0 to 5), and myocardial interstitial spaces were determined by use of a semiquantitative method., Results: Mean normalized left ventricular filling volume at 20 mm Hg filling pressure in the P144 group, 189 +/- 16 microliters (SEM), was reduced versus both the P288 (278 +/- 26 microliters) and the P380 (332 +/- 18 microliters) groups (p < 0.05, ANOVA). Mean myocardial water content in the P144 group, 80.7% +/- 1%, was increased versus the P380 (76.7% +/- 0.4%, p < 0.05) but not versus the P288 group (78.4% +/- 0.8%). In hearts preserved with 2.5% glutaraldehyde, mean edema grade and interstitial space in the P144 group (4.0 +/- 0.3) were increased versus the P380 (1.8 +/- 0.3, p < 0.05) but not the P288 group (2.7 +/- 0.5). Derived linear regressions relate water content to filling volume and histologic condition., Conclusions: Coronary perfusate osmolarity is thus associated with predictable changes in myocardial water content, left ventricular filling volume, and edema. These correlations allow definition of new hypotheses for the study of cardiac allograft rejection in patients and experimental animals.

Objective: To investigate the hypothesis that reperfusion edema may kill myocytes., Methods: Adult Sprague-Dawley rat hearts were perfused with a calcium free dissociation buffer containing collagenase 0.03% in a Langedorff system. Intact cells were selected and myocytes were cultured in adherent pretreated dishes. After 3 hours, 80% of cells were rod-shaped. Anoxia was simulated by means of metabolic inhibition by adding NaCN 2 mM to the control media, and reoxygenation by substituting this media with one of the following media non containing NaCN: 1) normo-osmotic (312 mOsm); 2) hypoosmotic (80 mOsm); 3) normo-osmotic with low Na+ (312 mOsm). A group of cells was kept with control media without metabolic inhibition and then submitted to simulated reoxygenation with hypoosmotic media (control group). The number of rod, square and round-shaped cells was monitored, and cell viability was assessed after 5 min of reoxygenation by the Trypan blue test., Results: After 60 min of metabolic inhibition there were no differences in the % of cells without hypercontracture among groups reoxygenated with normo-osmotic, hypoosmotic, low Na+ normo-osmotic and control media (84 +/- 16, 74 +/- 10, 76 +/- 14 and 90 +/- 6% respectively (p = NS). After 5 min of reoxygenation, these values decreased (p < 0.001) to 19 +/- 6, 11 +/- 9 and 13 +/- 3% (p = NS), respectively, in groups with normo-osmotic, hypoosmotic, and low Na+ normo-osmotic reoxygenation, but were not modified in the control group (78 +/- 4). The % of viable cells (Trypan negative) preserved after 5 min of reoxygenation was 67 +/- 29% in the group with normo-osmotic reoxygenation, 31 +/- 23% in the group with hypoosmotic reoxygenation, and 85 +/- 12% in the group with low Na+ normo-osmotic reoxygenation (p < 0.001). Exposing cells without metabolic inhibition to hypoosmotic media resulted in no significative reduction of cell viability., Conclusion: Hypoosmotic reoxygenation following prolonged metabolic inhibition may kill viable myocytes. This effect is not due to the low Na+ concentration in the hypoosmotic medium.

Congestive heart failure is one of the most important causes of peripheral edema seen in clinical practice. Edema in congestive heart failure is the result of the activation of a series of humoral and neurohumoral mechanisms that promote sodium and water reabsorption by the kidneys and expansion of the extracellular fluid. These mechanisms, in concert with abnormal Starling forces such as increased venous capillary pressure and decreased plasma oncotic pressure, promote fluid extravasation and edema formation. The management of edema in congestive heart failure is designed to improve cardiac function and to inhibit the hormonal and neurohumoral pathways that promote edema. The combination of diuretics and vasodilators or angiotensin converting enzyme inhibitors and, in some cases, cardiac inotropic agents is highly effective in achieving these goals and providing significant symptomatic improvement in patients with edema secondary to congestive heart failure.

Sodium spectroscopy and imaging sequences designed to emphasize fast T2 decay or the multiple quantum signal have previously demonstrated a high contrast between normal and pathologic tissue which may be due to changes in intracellular versus extracellular sodium distribution. Since alterations in the amount of signal with fast T2 decay have previously been shown to occur with changes in intracellular sodium content, this study investigated the fast T2 relaxation characteristics of extracellular sodium during pathologic interventions on nonsubmerged perfused rat hearts. T2 data on total sodium content were obtained while global ischemia (stopping all perfusate flow) and extracellular edema (due to long perfusion times) were induced in the heart. The data were fit to a biexponential, with Mf(T2f) the magnitude (time constant) of the fast component of decay. Mf increased significantly in both pathologies (to 319 +/- 26%, n = 3, of baseline for ischemia and to 527 +/- 284%, n = 3, of baseline for edema); the increase with edema was demonstrated to be due to extracellular sodium by intermittently perfusing the heart for a short period with shift reagent. When shift reagent was not used until the conclusion of the edema experiment, Mf increased to 169 +/- 35% of baseline, also due mainly to extracellular sodium. T2f did not exhibit any trends with these experiments, with values ranging from 1.7 to 5.5 ms. We believe that these results indicate that compartmental sodium content will most likely not be quantifiable in pathologic states in the heart with relaxation-based techniques. However, correlations between the pathologic state of the tissue and the sodium NMR signal obtained with pulse sequences or images that emphasize a particular aspect of relaxation may prove to be useful.

Oedema following periods of ischaemic arrest and subsequent reperfusion has been shown experimentally and clinically to affect the functional state of the heart. Tissue water content has been measured in myocardial sections by microscopic interferometry and densitometry, and the results correlated with those obtained by wet and dry weight analysis (r = 0.87; p less than 0.001). Microscopic interferometry also revealed the distribution of the water in the tissue. Experimentally induced ischaemic arrest in isolated rat hearts resulted in predominantly intra-fibrillar oedema, whilst subsequent reperfusion resulted in interfibrillar oedema. Microscopic interferometry facilitates accurate measurement of water content in tissue samples as small as 2 mg wet weight and shows (as conventional wet/dry weight analysis cannot) the distribution of the water in the tissue.

In edematous rats with circulatory insufficiency, the content of water and sodium in the muscle and liver rises while that of potassium declines per 1 g wet weight. The increased sodium and decreased potassium content in the tissues cannot be accounted for only by enlargement of the extracellular volume. In contrast to normal rats, the edematous ones show a negative linear correlation between the content of sodium and potassium in the muscle and liver. The total content of sodium and potassium in the tissues increases. It is assumed that part of intracellular potassium in the test tissues of rats with circulatory insufficiency is replaced by sodium. The proportion of sodium bound to structural components of the cell increases.

Using the formulae of Fazio and coworkers, the regional extravascular lung water per blood volume and flow was calculated in normal volunteers, in patients with left heart failure, sarcoidosis, allergic alveolitis and pneumonia. The double-isotope technique was used. 113mIn-chloride was intravascular tracer and 123I-antipyrine extravascular tracer. They were injected intravenously as rapid bolus. The activity in the lungs was detected with gamma camera and the time-activity curves were generated with PDP-Gamma-11 computer system. Mean transit times were calculated using two different mathematical handlings of the dilution curves, with gamma fitting parameters and by the area-per-height method. The latter method gave mean transit times about double those calculated with gamma fitting parameters, because the peripheral injection decreased the peak height. Therefore, the area per height method to calculate mean transit times by peripheral injection was found to be inaccurate. The control group consisted of 16 healthy adults. In two subjects repeated studies were made in one week. Their individual, regional extravascular lung water values varied somewhat, but were on second examination found to be between the range of the values found from the first examination. The regional extravascular lung water values in patient groups were correlated with corresponding clinical, laboratory and roentgenographic findings. The values for extravascular water discussed on the next page are calculated only by means of transit times with gamma fitting parameters, although the extravascular water values determined by the area-per-height method also significantly increased in patients compared to the control group. The cardiac group consisted of 52 patients, of whom 23 had clinically compensated and 29 decompensated left heart failure. Regional extravascular lung water significantly increased in patients with decompensated heart failure when compared to patients with compensated heart failure. The cardiac group was also divided into three subgroups after radiological grading of pulmonary venous hypertension. Between GR I (n = 17) without signs of venous hypertension and GR II (n = 18) with signs of venous congestion no significant differences in regional extravascular lung water were found. However, in GR I and GR II the values for regional extravascular water increased when compared to the control group, which is probably due to increased perfusion of vessels or increased blood volume in these cardiac patients.(ABSTRACT TRUNCATED AT 400 WORDS)

The mechanisms of oedema in cor pulmonale remain unexplained. On the basis of a small number of studies, cor pulmonale is not caused by cardiac muscle failure, at least in early oedematous phases. Progressive and persistent elevation of pulmonary vascular resistance may exceed the pumping capacity of the right ventricle in later stages. Alternative explanations for the sharp fall in renal blood flow as oedema appears should be sought. The renin-angiotensin-aldosterone system seems causally related to oedema. The curious position of hypercapnia remains an enigma. Surprisingly few studies of hypercapnia, renal blood flow and renal hormones are reported. Redistribution of body water from intracellular to the extracellular space may be in part due to the need to buffer extracellular respiratory acidosis caused by hypercapnia. It provides an explanation for one form of hypercapnic oedema. Cyclical loss and gain of tissue mass seems more evident in cor pulmonale than ischaemic or valvular heart failure.

The effects of 1 and 2 hours of hypothermic anoxic arrest and cardioplegia induced by Mg-lidocaine, K-Mg, or K on left ventricular mitochondrial respiratory function, blood flow, and edema were studied in 41 mongrel dogs. Mitochondrial respiration was assessed by the indices of oxidative phosphorylation. Myocardial temperature recorded in ventricular septum was kept at 20 degrees C during ischemic arrest and 10 minutes of reperfusion. Cardioplegic solutions did not influence noncoronary blood flow during cross-clamping of the aorta. Mitochondrial respiratory function remained at control levels after 1 hour of ischemia induced by hypothermic anoxic arrest or by Mg-lidocaine or K-Mg hypothermic cardioplegia. Mitochondrial state 3 respiration after 2 hours of anoxic arrest was significantly higher in Mg-lidocaine cardioplegia than in anoxic arrest (p less than 0.05), but myocardial edema was equivalent in both groups. Mg in the cardioplegic solution suppressed mitochondrial nonphosphorylating oxygen consumption. These data suggest that mitochondrial function after 1 hour of ischemic arrest at 20 degrees C and 10 minutes of reperfusion is not significantly depressed, but at 2 hours of ischemic arrest, mitochondrial respiration is significantly impaired. However, hypothermic Mg-lidocaine cardioplegia appears to be more effective in sustaining myocardial respiration than does simple hypothermic anoxic arrest when the anoxic period is extended to 2 hours.

Isolated rat and guinea pig hearts show, during perfusion with aequeous salt solutions, myocardial edema formation of different degree. The extent of tissue fluid accumulation is dependent on the species, the osmolality, and the oxygen partial pressure of the perfusion medium. With increasing edema formation there is, in both species, an increasing energy requirement for the same hemodynamic state. Addition of 50 mM mannitol to the perfusion medium can diminish edema of the hypoxic perfused rat heart and improves the myocardial function during hypoxia. The beneficial effect of hyperosmolality in the isolated hypoxic rat heart is discussed in terms of an improvement of myocardial energy balance and coronary microcirculation.