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.

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.

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.

Cardiac Involvement in Patients Recovered From COVID-2019 Identified Using Magnetic Resonance Imaging.

Objectives: This study evaluated cardiac involvement in patients recovered from coronavirus disease-2019 (COVID-19) using cardiac magnetic resonance (CMR). Background: Myocardial injury caused by COVID-19 was previously reported in hospitalized patients. It is unknown if there is sustained cardiac involvement after patients' recovery from COVID-19. Methods: Twenty-six patients recovered from COVID-19 who reported cardiac symptoms and underwent CMR examinations were retrospectively included. CMR protocols consisted of conventional sequences (cine, T2-weighted imaging, and late gadolinium enhancement [LGE]) and quantitative mapping sequences (T1, T2, and extracellular volume [ECV] mapping). Edema ratio and LGE were assessed in post-COVID-19 patients. Cardiac function, native T1/T2, and ECV were quantitatively evaluated and compared with controls. Results: Fifteen patients (58%) had abnormal CMR findings on conventional CMR sequences: myocardial edema was found in 14 (54%) patients and LGE was found in 8 (31%) patients. Decreased right ventricle functional parameters including ejection fraction, cardiac index, and stroke volume/body surface area were found in patients with positive conventional CMR findings. Using quantitative mapping, global native T1, T2, and ECV were all found to be significantly elevated in patients with positive conventional CMR findings, compared with patients without positive findings and controls (median [interquartile range]: native T1 1,271 ms [1,243 to 1,298 ms] vs. 1,237 ms [1,216 to 1,262 ms] vs. 1,224 ms [1,217 to 1,245 ms]; mean ± SD: T2 42.7 ± 3.1 ms vs. 38.1 ms ± 2.4 vs. 39.1 ms ± 3.1; median [interquartile range]: 28.2% [24.8% to 36.2%] vs. 24.8% [23.1% to 25.4%] vs. 23.7% [22.2% to 25.2%]; p = 0.002; p < 0.001, and p = 0.002, respectively). Conclusions: Cardiac involvement was found in a proportion of patients recovered from COVID-19. CMR manifestation included myocardial edema, fibrosis, and impaired right ventricle function. Attention should be paid to the possible myocardial involvement in patients recovered from COVID-19 with cardiac symptoms.

Diffusion-weighted imaging in hypertrophic cardiomyopathy: association with high T2-weighted signal intensity in addition to late gadolinium enhancement.

Diffusion-weighted imaging (DWI) has been confirmed to be associated with late gadolinium enhancement (LGE) in hypertrophic cardiomyopathy (HCM). In this context, we aimed to study whether DWI could reflect the active tissue injury and edema information of HCM which were usually indicated by T2 weighted images. Forty HCM patients were examined using a 3.0 T magnetic resonance scanner. Cine, T2-weighted short tau inversion recovery (T2-STIR), DWI and LGE sequences were acquired. T1 mapping was also included to quantify the focal and diffuse fibrosis. Cardiac troponin I (cTnI) was tested to assess the recently myocardial injury. Student's t-test, Mann-Whitney U test, One-way analysis, Kruskal-Wallis analysis, the Spearman correlation analysis, and multivariable regression were used in this study. The apparent diffusion coefficient (ADC) was significantly elevated in the cTnI positive group (P = 0.01) and correlated with LGE (ρ = 0.312, P = 0.049) and HighT2 extent (ρ = 0.443, P = 0.004) in the global level. In the segmental analysis, the ADC significantly differentiated the segments with and without HighT2/LGE presence (P = 0.00). The average ADC values were higher in segments with HighT2 and LGE coexistence than in those with only LGE presence (P < 0.05). Multivariable regression indicated that segmental HighT2 and LGE were both contributing factors to the ADC values. In this study of HCM, we confirmed that ADC as a molecular diffusion parameter reflects the replacement fibrosis of myocardium. Moreover, it also reveals edema extent and its association with serum cTnI.

Letter to the editor: is it time for imaging to level with pathology?

CMR provides pathology-like insights of myocardial abnormality, such as hyperemia, edema, necrosis and fibrosis, which is in-vivo, non-invasive and real-time. Hence, it is most likely to become one alternative tool for mimicking pathology, so-called pathologicalized imaging due to its extraordinary tissue characteristics. This article aims to call for a wider clinical application of CMR with more attention on its tissue characterization value.

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

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

Development of cell oedema in piglet hearts during ischaemia monitored by dielectric spectroscopy.

OBJECTIVE: The aim of this research was to investigate if dielectric spectroscopy between 100 Hz and 1 MHz provides reliable information about water distribution in ischaemic heart tissue and to investigate the influence of temperature on oedema formation. METHODS: We examined hearts of landrace piglets (n = 13) during ischaemia at 35 °C, 25 °C, and 15 °C. The dielectric permittivity ε'(f) and conductivity σ'(f) were calculated from impedance spectra measured between 100Hz and 1MHz. Gap junction uncoupling (GJU) was identified in the sigmoidal time course of ε'(13 kHz). The extracellular space index (ECSI) was estimated by the ratio σ'(100 Hz)/σ'(1 MHz). Intercalated water was analysed in electron microscopy images of the myocardial samples and was used to calculate the extracellular space index ECSIhisto. The ECSI and ECSIhisto were compared during ischaemia. GJU and oedema formation were simulated with an electrical heart model. RESULTS: At the onset of ischaemia, the ECSI was significantly higher than the ECSIhisto (p < .01). GJU during ischaemia was temperature-dependent. After GJU, the values of the ECSI and ECSIhisto matched very well. The simulations confirmed the influence of GJU on the ECSI. SIGNIFICANCE: The estimation of cell oedema with the ECSI is reliable only after GJU. The development of oedema estimated by the ECSI was delayed at cooler temperatures.

Native Coronary Collateral Microcirculation Reserve in Rat Hearts.

Background We occasionally noticed that native collateral blood flow showed a recessive trend in the early stages of acute myocardial infarction in rats, which greatly interferes with the accurate assessment of native collateral circulation levels. Here, we sought to recognize the coronary collateral circulation system in depth, especially the microcirculation part, on this basis. Methods and Results In this study, we detected native collateral flow with positron emission tomography perfusion imaging in rats and found that the native flow is relatively abundant when it is initially recruited. However, this flow is extremely unstable in the early stage of acute myocardial infarction and quickly fails. We used tracers to mark the collateral in an ischemic area and a massive preformed collateral network was labeled. The ultrastructures of these collateral microvessels are flawed, which contributes to extensive leakage and consequent interstitial edema in the ischemic region. Conclusions An unrecognized short-lived native coronary collateral microcirculation reserve is widely distributed in rat hearts. Recession of collateral blood flow transported by coronary collateral microcirculation reserve contributes to instability of native collateral blood flow in the early stage of acute myocardial infarction. The immature structure determines that these microvessels are short-lived and provide conditions for the development of early interstitial edema in acute myocardial infarction.

Native T1 Mapping in the Diagnosis of Cardiac Allograft Rejection: A Prospective Histologically Validated Study.

OBJECTIVES: This study aimed to determine the role of T1 mapping in identifying cardiac allograft rejection. BACKGROUND: Endomyocardial biopsy (EMBx), the current gold standard to diagnose cardiac allograft rejection, is associated with potentially serious complications. Cardiac magnetic resonance (CMR)-based T1 mapping detects interstitial edema and fibrosis, which are important markers of acute and chronic rejection. Therefore, T1 mapping can potentially diagnose cardiac allograft rejection noninvasively. METHODS: Patients underwent CMR within 24 h of EMBx. T1 maps were acquired at 1.5-T. EMBx-determined rejection was graded according to International Society of Heart and Lung Transplant (ISHLT) criteria. RESULTS: Of 112 biopsies with simultaneous CMR, 60 were classified as group 0 (ISHLT grade 0), 35 as group 1 (ISHLT grade 1R), and 17 as group 2 (2R, 3R, clinically diagnosed rejection, antibody-mediated rejection). Native T1 values in patients with grade 0 biopsies and left ventricular ejection fraction >60% (983 ± 42 ms; 95% confidence interval: 972 to 994 ms) were comparable to values in nontransplant healthy control subjects (974 ± 45 ms; 95% confidence interval: 962 to 987 ms). T1 values were significantly higher in group 2 (1,066 ± 78 ms) versus group 0 (984 ± 42 ms; p = 0.0001) and versus group 1 (1,001 ± 54 ms; p = 0.001). After excluding patients with an estimated glomerular filtration rate <50 ml/min/m2, there was a moderate correlation of log-transformed native T1 with high-sensitivity troponin T (r = 0.54, p < 0.0001) and pro-B-type natriuretic peptide (r = 0.67, p < 0.0001). Using a T1 cutoff value of 1,029 ms, the sensitivity, specificity, and negative predictive value were 93%, 79%, and 99%, respectively. CONCLUSIONS: Myocardial tissue characterization with T1 mapping displays excellent negative predictive capacity for the noninvasive detection of cardiac allograft rejection and holds promise to reduce substantially the EMBx requirement in cardiac transplant rejection surveillance.

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

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

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

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

CMR-derived extracellular volume fraction (ECV) in asymptomatic heart transplant recipients: correlations with clinical features and myocardial edema.

Myocardial interstitial expansion seems to be fundamental to the process of adverse left ventricular remodeling. Recent evidence has shown that the extracellular volume fraction (ECV) derived from cardiovascular magnetic resonance (CMR) can be used as a noninvasive method to quantify myocardial interstitial volume in a range of heart diseases. Our aim was to determine whether ECV is increased in asymptomatic orthotopic heart transplant (HTx) patients and its associations with clinical features and T2 values, the elevation of which usually suggests myocardial edema. A group of asymptomatic cardiac transplant recipients and some healthy volunteers were invited to undergo a comprehensive CMR scan, including cine imaging, late gadolinium enhancement, T1 mapping and T2 mapping, from March to June in 2017. All quantitative measurements were averaged from the basal and mid short-axis slices. Fifty-eight recipients (mean age, 42.7 ± 11.5 years; 13 females), at a median of 1.8 years (0.3-6.3 years) after HTx, and 20 healthy volunteers (mean age, 39.5 ± 11.3 years; 5 females) underwent the CMR scan. We found that both the ECV and T2 values were higher in the post-HTx group (ECV: 26.7 ± 3.3 vs. 24.6 ± 2.5%, p = 0.008; T2: 47.7 ± 2.8 vs. 44.5 ± 1.6 ms, p < 0.001) than in the control group. ECV was moderately associated with organ ischemia time at the time of transplantation but not with the hemodynamics parameter or the time since transplantation at CMR. Additionally, a relatively strong correlation was observed between ECV and T2 (r = 0.7, p < 0.001). So, our conclusion is that CMR-derived ECV is increased and associated with peri-transplant ischemia time in asymptomatic HTx patients. And the strong correlation of ECV with elevated T2 indicates that myocardial edema may be an important part of the extracellular volume expansion after heart transplantation.

Acetaminophen Mitigates Myocardial Injury Induced by Lower Extremity Ischemia-Reperfusion in Rat Model.

OBJECTIVE: The injury-reducing effect of acetaminophen, an effective analgesic and antipyretic on ischemia-reperfusion continues to attract great attention. This study analyzed the protective effect of acetaminophen on myocardial injury induced by ischemia-reperfusion in an experimental animal model from lower extremity ischemia-reperfusion. METHODS: Twenty-four Sprague-Dawley female rats were randomized into three groups (n=8) as (i) control group (only laparotomy), (ii) aortic ischemia-reperfusion group (60 min of ischemia and 120 min of reperfusion) and (iii) ischemia-reperfusion + acetaminophen group (15 mg/kg/h intravenous acetaminophen infusion starting 15 minutes before the end of the ischemic period and lasting till the end of the reperfusion period). Sternotomy was performed in all groups at the end of the reperfusion period and the heart was removed for histopathological examination. The removed hearts were histopathologically investigated for myocytolysis, polymorphonuclear leukocyte (PMNL) infiltration, myofibrillar edema and focal hemorrhage. RESULTS: The results of histopathological examination showed that acetaminophen was detected to particularly diminish focal hemorrhage and myofibrillar edema in the ischemia-reperfusion + acetaminophen group (P<0.001, P=0.011), while there were no effects on myocytolysis and PMNL infiltration between the groups (P=1.000, P=0.124). CONCLUSION: Acetaminophen is considered to have cardioprotective effect in rats, by reducing myocardial injury induced by abdominal aortic ischemia-reperfusion.

Acetaminophen mitigates myocardial injury induced by lower extremity ischemia-reperfusion in rat model

Abstract Objective: The injury-reducing effect of acetaminophen, an effective analgesic and antipyretic on ischemia-reperfusion continues to attract great attention. This study analyzed the protective effect of acetaminophen on myocardial injury induced by ischemia-reperfusion in an experimental animal model from lower extremity ischemia-reperfusion. Methods: Twenty-four Sprague-Dawley female rats were randomized into three groups (n=8) as (i) control group (only laparotomy), (ii) aortic ischemia-reperfusion group (60 min of ischemia and 120 min of reperfusion) and (iii) ischemia-reperfusion + acetaminophen group (15 mg/kg/h intravenous acetaminophen infusion starting 15 minutes before the end of the ischemic period and lasting till the end of the reperfusion period). Sternotomy was performed in all groups at the end of the reperfusion period and the heart was removed for histopathological examination. The removed hearts were histopathologically investigated for myocytolysis, polymorphonuclear leukocyte (PMNL) infiltration, myofibrillar edema and focal hemorrhage. Results: The results of histopathological examination showed that acetaminophen was detected to particularly diminish focal hemorrhage and myofibrillar edema in the ischemia-reperfusion + acetaminophen group (P<0.001, P=0.011), while there were no effects on myocytolysis and PMNL infiltration between the groups (P=1.000, P=0.124). Conclusion: Acetaminophen is considered to have cardioprotective effect in rats, by reducing myocardial injury induced by abdominal aortic ischemia-reperfusion.

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

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

Dose-Dependent Cardioprotection of Moderate (32°C) Versus Mild (35°C) Therapeutic Hypothermia in Porcine Acute Myocardial Infarction.

OBJECTIVES: The study investigated whether a dose response exists between myocardial salvage and the depth of therapeutic hypothermia. BACKGROUND: Cardiac protection from mild hypothermia during acute myocardial infarction (AMI) has yielded equivocal clinical trial results. Rapid, deeper hypothermia may improve myocardial salvage. METHODS: Swine (n = 24) undergoing AMI were assigned to 3 reperfusion groups: normothermia (38°C) and mild (35°C) and moderate (32°C) hypothermia. One-hour anterior myocardial ischemia was followed by rapid endovascular cooling to target reperfusion temperature. Cooling began 30 min before reperfusion. Target temperature was reached before reperfusion and was maintained for 60 min. Infarct size (IS) was assessed on day 6 using cardiac magnetic resonance, triphenyl tetrazolium chloride, and histopathology. RESULTS: Triphenyl tetrazolium chloride area at risk (AAR) was equivalent in all groups (p = 0.2), but 32°C exhibited 77% and 91% reductions in IS size per AAR compared with 35°C and 38°C, respectively (AAR: 38°C, 45 ± 12%; 35°C, 17 ± 10%; 32°C, 4 ± 4%; p < 0.001) and comparable reductions per LV mass (LV mass: 38°C, 14 ± 5%; 35°C, 5 ± 3%; 32°C 1 ± 1%; p < 0.001). Importantly, 32°C showed a lower IS AAR (p = 0.013) and increased immunohistochemical granulation tissue versus 35°C, indicating higher tissue salvage. Delayed-enhancement cardiac magnetic resonance IS LV also showed marked reduction at 32°C (38°C: 10 ± 4%, p < 0.001; 35°C: 8 ± 3%; 32°C: 3 ± 2%, p < 0.001). Cardiac output on day 6 was only preserved at 32°C (reduction in cardiac output: 38°C, -29 ± 19%, p = 0.041; 35°C: -17 ± 33%; 32°C: -1 ± 28%, p = 0.041). Using linear regression, the predicted IS reduction was 6.7% (AAR) and 2.1% (LV) per every 1°C reperfusion temperature decrease. CONCLUSIONS: Moderate (32°C) therapeutic hypothermia demonstrated superior and near-complete cardioprotection compared with 35°C and control, warranting further investigation into clinical applications.

Characterization of Gadolinium Contrast Enhancement of Radiofrequency Ablation Lesions in Predicting Edema and Chronic Lesion Size.

BACKGROUND: Magnetic resonance imaging (MRI) has been used to acutely visualize radiofrequency ablation lesions, but its accuracy in predicting chronic lesion size is unknown. The main goal of this study was to characterize different areas of enhancement in late gadolinium enhancement MRI done immediately after ablation to predict acute edema and chronic lesion size. METHODS AND RESULTS: In a canine model (n=10), ventricular radiofrequency lesions were created using ThermoCool SmartTouch (Biosense Webster) catheter. All animals underwent MRI (late gadolinium enhancement and T2-weighted edema imaging) immediately after ablation and after 1, 2, 4, and 8 weeks. Edema, microvascular obstruction, and enhanced volumes were identified in MRI and normalized to chronic histological volume. Immediately after contrast administration, the microvascular obstruction region was 3.2±1.1 times larger than the chronic lesion volume in acute MRI. Even 60 minutes after contrast administration, edema was 8.7±3.31 times and the enhanced area 6.14±2.74 times the chronic lesion volume. Exponential fit to the microvascular obstruction volume was found to be the best predictor of chronic lesion volume at 26.14 minutes (95% prediction interval, 24.35-28.11 minutes) after contrast injection. The edema volume in late gadolinium enhancement correlated well with edema volume in T2-weighted MRI with an R2 of 0.99. CONCLUSION: Microvascular obstruction region on acute late gadolinium enhancement images acquired 26.1 minutes after contrast administration can accurately predict the chronic lesion volume. We also show that T1-weighted MRI images acquired immediately after contrast injection accurately shows edema resulting from radiofrequency ablation.