Inhibition of ATGL in adipose tissue ameliorates isoproterenol-induced cardiac remodeling by reducing adipose tissue inflammation.

Following cardiac injury, increased adrenergic drive plays an important role in compensating for reduced cardiac function. However, chronic excess adrenergic stimulation can be detrimental to cardiac pathophysiology and can also affect other organs including adipose tissue, leading to increased lipolysis. Interestingly, inhibition of adipose triglyceride lipase (ATGL), a rate-limiting enzyme in lipolysis, in adipocytes ameliorates cardiac dysfunction in a heart failure model. Thus, we investigated whether inhibition of adipocyte ATGL can mitigate the adverse cardiac effects of chronic adrenergic stimulation and explored the underlying mechanisms. To do this, isoproterenol (ISO) was continuously administered to C57Bl/6N mice for 2 wk with or without an ATGL inhibitor (Atglistatin). We found that Atglistatin alleviated ISO-induced cardiac remodeling and reduced ISO-induced upregulation of galectin-3, a marker of activated macrophages and a potent inducer of fibrosis, in white adipose tissue (WAT), heart, and the circulation. To test whether the beneficial effects of Atglistatin occur via inhibition of adipocyte ATGL, adipocyte-specific ATGL knockout (atATGL-KO) mice were utilized for similar experiments. Subsequently, the same cardioprotective effects of atATGL-KO following ISO administration were observed. Furthermore, Atglistatin and atATGL-KO abolished ISO-induced galectin-3 secretion from excised WAT. We further demonstrated that activation of cardiac fibroblasts by the conditioned media of ISO-stimulated WAT is galectin-3-dependent. In conclusion, the inhibition of adipocyte ATGL ameliorated ISO-induced cardiac remodeling possibly by reducing galectin-3 secretion from adipose tissue. Thus, inhibition of adipocyte ATGL might be a potential target to prevent some of the adverse effects of chronic excess adrenergic drive.NEW & NOTEWORTHY The reduction of lipolysis by adipocyte ATGL inhibition ameliorates cardiac remodeling induced by chronic ß-adrenergic stimulation likely via reducing galectin-3 secretion from adipose tissue. Our findings highlight that suppressing lipolysis in adipocytes may be a potential therapeutic target for patients with heart failure whose sympathetic nervous system is activated. Furthermore, galectin-3 might be involved in the mechanisms by which excessive lipolysis in adipose tissues influences remote cardiac pathologies and thus warrants further investigation.

The beneficial effects of reducing NLRP3 inflammasome activation in the cardiotoxicity and the anti-cancer effects of doxorubicin.

Doxorubicin (DOX) is a powerful broad-spectrum anti-neoplastic anthracycline antibiotic. However, DOX may cause a dose-dependent cardiotoxicity that can eventually progress to congestive heart failure and death. Numerous molecular mechanisms have been implicated in the cardiotoxic effect of DOX including topoisomerase IIß and generation of free radicals. However, targeting these pathways appears to be insufficient to mitigate the cardiotoxic effects of DOX and/or ultimately reduces the anti-tumor activity of DOX. Thus, there remains a crucial need to identify novel pharmacological targets that can alleviate the cardiotoxic effects of DOX without reducing its anti-tumor activity. Recent studies have suggested that the Nucleotide-Binding Domain-Like Receptor Protein 3 (NLRP3) inflammasome is implicated in tumor progression and the chemoresistance of cancer cells to DOX. Of interest, reducing NLRP3 inflammasome activity alleviates DOX-induced cardiotoxicity. Therefore, we postulate that strategies that target the NLRP3 inflammasome can help mitigate the cardiotoxic effects of DOX while maintaining and/or even enhancing its anti-cancer activity. Herein, we review the current knowledge about the potential implication of the NLRP3 inflammasome in the anti-cancer and cardiotoxic effects of DOX.

Empagliflozin suppresses inflammation and protects against acute septic renal injury.

BACKGROUND: Sepsis-induced systemic inflammation response syndrome is the leading cause of morbidity and mortality among patients in intensive care units in North America. While sepsis is associated with multiple organ damage, acute renal injury represents a hallmark of sepsis. Since systemic and renal inflammation is known to play a vital role in morbidity and mortality associated with sepsis, identifying a potent anti-inflammatory agent may help minimize morbidity and mortality associated with acute septic kidney injury. Since recent work has suggested that empagliflozin, a renal sodium-glucose cotransporter 2 (SGLT2) inhibitor, may assist in the treatment of inflammatory diseases, our objective was to examine the effect of empagliflozin on acute sepsis-induced renal injury. METHOD: Mice were treated with three daily doses of empagliflozin or vehicle, with lipopolysaccharide (LPS) administered on the third day, at the same time as the third dose of empagliflozin or vehicle. In another cohort, mice were injected with a single dose of LPS 3 h before a dose of empagliflozin. RESULTS: Our results show that empagliflozin improves survival in a mouse model of LPS-induced septic shock. We further demonstrate that the beneficial effects of empagliflozin are likely mediated via reducing LPS-induced acute renal injury. Moreover, our data indicate that empagliflozin significantly reduces systemic and renal inflammation to contribute to the improvements observed in an LPS-model of acute septic renal injury. CONCLUSION: Overall, the findings of this study suggest that empagliflozin could be repurposed to reduce morbidity and mortality in patients with acute septic renal injury. TRIAL REGISTRATION: Not applicable.

Breast cancer diagnosis is associated with relative left ventricular hypertrophy and elevated endothelin-1 signaling.

BACKGROUND: The survival rates of women with breast cancer have improved significantly over the last four decades due to advances in breast cancer early diagnosis and therapy. However, breast cancer survivors have an increased risk of cardiovascular complications following chemotherapy. While this increased risk of later occurring structural cardiac remodeling and/or dysfunction has largely been attributed to the cardiotoxic effects of breast cancer therapies, the effect of the breast tumor itself on the heart prior to cancer treatment has been largely overlooked. Thus, the objectives of this study were to assess the cardiac phenotype in breast cancer patients prior to cancer chemotherapy and to determine the effects of human breast cancer cells on cardiomyocytes. METHODS: We investigated left ventricular (LV) function and structure using cardiac magnetic resonance imaging in women with breast cancer prior to systemic therapy and a control cohort of women with comparable baseline factors. In addition, we explored how breast cancer cells communicate with the cardiomyocytes using cultured human cardiac and breast cancer cells. RESULTS: Our results indicate that even prior to full cancer treatment, breast cancer patients already exhibit relative LV hypertrophy (LVH). We further demonstrate that breast cancer cells likely contribute to cardiomyocyte hypertrophy through the secretion of soluble factors and that at least one of these factors is endothelin-1. CONCLUSION: Overall, the findings of this study suggest that breast cancer cells play a greater role in inducing structural cardiac remodeling than previously appreciated and that tumor-derived endothelin-1 may play a pivotal role in this process.

The anti-inflammatory and analgesic effects of formulated full-spectrum cannabis extract in the treatment of neuropathic pain associated with multiple sclerosis.

PURPOSE: Cannabis has been used for thousands of years in many cultures for the treatment of several ailments including pain. The benefits of cannabis are mediated largely by cannabinoids, the most prominent of which are tetrahydrocannabinol (THC) and cannabidiol (CBD). As such, THC and/or CBD have been investigated in clinical studies for the treatment of many conditions including neuropathic pain and acute or chronic inflammation. While a plethora of studies have examined the biochemical effects of purified THC and/or CBD, only a few have focused on the effects of full-spectrum cannabis plant extract. Accordingly, studies using purified THC or CBD may not accurately reflect the potential health benefits of full-spectrum cannabis extracts. Indeed, the cannabis plant produces a wide range of cannabinoids, terpenes, flavonoids, and other bioactive molecules which are likely to contribute to the different biological effects. The presence of all these bioactive molecules in cannabis extracts has garnered much attention of late especially with regard to their potential role in the treatment of neuropathic pain associated with multiple sclerosis. METHODS: Literature review was performed to further understand the effect of clinically used full-spectrum cannabis extract in patients with multiple sclerosis. RESULTS: Herein, the current knowledge about the potential beneficial effects of existing products of full-spectrum cannabis extract in clinical studies involving patients with multiple sclerosis is extensively reviewed. In addition, the possible adverse effects associated with cannabis use is discussed along with how the method of extraction and the delivery mechanisms of different cannabis extracts contribute to the pharmacokinetic and biological effects of full-spectrum cannabis extracts.Herein, the current knowledge about the potential beneficial effects of existing products of full-spectrum cannabis extract in clinical studies involving patients with multiple sclerosis is extensively reviewed. In addition, the possible adverse effects associated with cannabis use is discussed along with how the method of extraction and the delivery mechanisms of different cannabis extracts contribute to the pharmacokinetic and biological effects of full-spectrum cannabis extracts.

Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice.

Germline mutations in BRAF are a major cause of cardio-facio-cutaneous (CFC) syndrome, which is characterized by heart defects, characteristic craniofacial dysmorphology and dermatologic abnormalities. Patients with CFC syndrome also commonly show gastrointestinal dysfunction, including feeding and swallowing difficulties and gastroesophageal reflux. We have previously found that knock-in mice expressing a Braf Q241R mutation exhibit CFC syndrome-related phenotypes, such as growth retardation, craniofacial dysmorphisms, congenital heart defects and learning deficits. However, it remains unclear whether BrafQ241R/+ mice exhibit gastrointestinal dysfunction. Here, we report that BrafQ241R/+ mice have neonatal feeding difficulties and esophageal dilation. The esophagus tissues from BrafQ241R/+ mice displayed incomplete replacement of smooth muscle with skeletal muscle and decreased contraction. Furthermore, the BrafQ241R/+ mice showed hyperkeratosis and a thickened muscle layer in the forestomach. Treatment with MEK inhibitors ameliorated the growth retardation, esophageal dilation, hyperkeratosis and thickened muscle layer in the forestomach in BrafQ241R/+ mice. The esophageal dilation with aberrant skeletal-smooth muscle boundary in BrafQ241R/+ mice were recovered after treatment with the histone H3K27 demethylase inhibitor GSK-J4. Our results provide clues to elucidate the pathogenesis and possible treatment of gastrointestinal dysfunction and failure to thrive in patients with CFC syndrome.

Resveratrol improves cardiac function and exercise performance in MI-induced heart failure through the inhibition of cardiotoxic HETE metabolites.

Numerous epidemiological studies have demonstrated that approximately 40% of myocardial infarctions (MI) are associated with heart failure (HF). Resveratrol, a naturally occurring polyphenol, has been shown to be beneficial in the treatment of MI-induced HF in rodent models. However, the mechanism responsible for the effects of resveratrol are poorly understood. Interestingly, resveratrol is known to inhibit cytochrome P450 1B1 (CYP1B1) which is involved in the formation of cardiotoxic hydroxyeicosatetraenoic acid (HETE) metabolites. Therefore, we investigated whether resveratrol could improve MI-induced cardiac remodeling and HF in rats through the inhibition of CYP1B1 and its metabolites. To do this, rats were subjected to either sham surgery or a surgery to ligate the left anterior descending artery to induce a MI and subsequent HF. Three weeks post-surgery, rats with established HF were treated with control diet or administered a diet containing low dose of resveratrol. Our results showed that low dose resveratrol treatment significantly improves % ejection fraction in MI rats and reduces MI-induced left ventricular and atrial remodeling. Furthermore, non-cardiac symptoms of HF such as reduced physical activity improved with low dose resveratrol treatment. Mechanistically, low dose resveratrol treatment of rats with established HF restored levels of fatty acid oxidation and significantly improved cardiac energy metabolism as well as significantly inhibited CYP1B1 and cardiotoxic HETE metabolites induced in MI rats. Overall, the present work provides evidence that low dose resveratrol reduces the severity of MI-induced HF, at least in part, through the inhibition of CYP1B1 and cardiotoxic HETE metabolites.

Atglistatin ameliorates functional decline in heart failure via adipocyte-specific inhibition of adipose triglyceride lipase.

Despite advancements in therapies for cardiovascular disease and heart failure (HF), the incidence and prevalence of HF are increasing. Previous work has suggested that inhibiting adipose triglyceride lipase (ATGL) in adipose tissue during HF development may assist in the treatment of HF. The ability to specifically target the adipocyte as a potential treatment for HF is a novel approach that could significantly influence the management of HF in the future. Our objectives were to assess the cardiac structural and functional effects of pharmacological inhibition of ATGL in mice with HF, to assess whether ATGL inhibition works in an adipocyte-autonomous manner, and to determine the role that adiposity and glucose homeostasis play in this HF treatment approach. Using a known ATGL inhibitor, atglistatin, as well as mice with germline deletion of adipocyte-specific ATGL, we tested the effectiveness of ATGL inhibition in mice with pressure overload-induced HF. Here, we show that atglistatin can prevent the functional decline in HF and provide evidence that specifically targeting ATGL in the adipocyte is sufficient to prevent worsening of HF. We further demonstrate that the benefit resulting from atglistatin in HF is not dependent on previously suggested improvements in glucose homeostasis, nor are the benefits derived from increased adiposity. Overall, the results of this study suggest that adipocyte-specific pharmacological inhibition of ATGL may represent a novel therapeutic option for HF. NEW & NOTEWORTHY This work shows for the first time that the adipose triglyceride lipase (ATGL)-specific inhibitor atglistatin can prevent worsening heart failure. Furthermore, using mice with adipocyte-specific ATGL ablation, this study demonstrates that ATGL inhibition works in an adipocyte-autonomous manner to ameliorate a functional decline in heart failure. Overall, this work demonstrates that specifically targeting the adipocyte to inhibit ATGL is a potential treatment for heart failure.

[Preoperative Use of Tolvaptan in a Patient with Constrictive Pericarditis].

Tolvaptan is a new selective vasopression V2-receptor antagonist. We report our experience with a use of tolvaptan for preoperative fluid management in a patient with severe constrictive pericarditis. A 66-year-old man presented with heart failure symptoms derived from constrictive pericarditis. Chest X-ray showed right pleural effusion and chest computed tomography demonstrated severe pericardial calcification. Despite that he received optimal conventional medical treatments, his hemodynamic condition further exacerbated during hospitalization. We administered tolvaptan in an attempt to optimize preoperative fluid management. Tolvaptan was found to be remarkably effective in that regard. The body weight decreased and the heart failure symptoms improved. Pericardiectomy was performed successfully, and he recovered uneventfully.

[Mycotic Aneurysm of Distal Aortic Arch, after Total Arch Replacement with Open-stent Graft;Report of a Case].

The patient was a 72-year-old man, who had undergone total arch replacement with an open-stent graft due to saccular aneurysm of distal arch, 2 years before. He was admitted to a local hospital with the complaint of high fever, and was diagnosed as having pyothorax, after computed tomography (CT) scanning. After transferred to our hospital, he was treated by drainage, and antibiotic therapy. But CT scans showed the enlargement of distal arch aneurysm, and migration of the stent graft. Urgent operation was performed. We approached to the site by a full sternotomy, and left anterolateral thoracotomy. Segment 1+2 of the left lung was resected to avoid bleeding and lung injury. Graft replacement of distal arch and descending aorta was performed on cardiopulmonary bypass, with hypothermia, selective brain perfusion and systemic circulatory arrest. To protect from recurrence of infection, the omental flap was transposed to the graft site. Until now, there is no recurrence of infection.

[Successful postoperative percutaneous cardiopulmonary support( PCPS) for the right-heart failure in a patient with recurrent mitral valve stenosis and a calcified left atrium; report of a case].

A 79-year-old female underwent open mitral commissurotomy and thrombectomy for mitral valve stenosis and thrombus in the left atrium 21 years ago. She was admitted for congestive heart failure because of recurrent mitral valve stenosis. Cardiac echocardiography showed severe mitral valve stenosis and the calcification of the left atrium wall. We performed mitral valve replacement and removal of thrombus calcification in the left atrium. Cardiopulmonary bypass was weaned successfully. In the intensive care unit, her blood pressure (BP) dropped, central venous pressure (CVP) increased, and urine volume decreased. Cardiac echocardiography revealed functional deterioration and dilatation of the right ventricle. As medical therapy was not effective, percutaneous cardiopulmonary support(PCPS)was established through the femoral artery and vein. Then her BP increased, CVP decreased, and the right ventricular function and the dilatation improved. PCPS was removed after 3 days, and the respirator on the 13th postoperative day. She moved out of the intensive care unit on the 24th postoperative day.

[Y-graft replacement with left renal artery reconstruction for acute aortic dissection type B].

A 56-year-old male was admitted to our hospital for acute type B aortic dissection. He received conservative therapy but follow-up computed tomography (CT) revealed a low-enhanced left kidney and severe stenosis of the left common iliac artery due to the expansion of the false lumen. Serum blood urea nitrogen (BUN) and creatinine increased and renovascular hypertension worsened with severe intermittent claudication of the left leg. We performed Y-graft replacement with reconstruction of the left renal artery. Postoperative CT showed a well-enhanced left kidney and no stenosis of the left common iliac artery. Intermittent claudication and renal dysfunction improved and his hypertension became controllable. He was discharged on the 17th postoperative day.

Modified composite-graft technique for aortic root replacement.

This report describes a novel modification of a self-assembled composite graft to replace the aortic root and left ventricular outflow tract (LVOT). This technique enables the implantation of a larger valve than conventional ways and simultaneous reconstruction of LVOT. This technique comprises Inspiris Resilia aortic valve and Gelweave Valsalva graft. By placing the valve in the sinus portion of the graft, the bioprosthesis that is 1 mm smaller than the graft can be accommodated, providing a proper length of the collar for LVOT reconstruction. This technique is useful for patients who require redo-aortic root replacement and have restricted LVOT.

Endothelin Receptor Blocker Reverses Breast Cancer-Induced Cardiac Remodeling.

Background: Although some cancer therapies have overt and/or subclinical cardiotoxic effects that increase subsequent cardiovascular risk in breast cancer patients, we have recently shown that the breast tumor itself can also induce cardiac hypertrophy through the activation of the endothelin system to contribute to cardiovascular risk. However, the extent to which the suppression of the activation of the endothelin system could improve cardiac remodeling in breast cancer patients has yet to be investigated. Objectives: We aimed to retrospectively assess the cardiac morphology/function in patients with breast cancer before receiving cancer chemotherapy and to investigate if the suppression of the activation of the endothelin system improves cardiac remodeling in a mouse model of breast cancer. Methods: Our study involved 28 previously studied women with breast cancer (including 24 after tumor resection) before receiving adjuvant therapy and 17 control healthy women. In addition, we explored how the endothelin system contributed to breast cancer-induced cardiac remodeling using a mouse model of breast cancer. Results: Our results indicate that before chemotherapy, breast cancer patients already exhibit relative cardiac remodeling and subclinical cardiac dysfunction, which was associated with the activation of the endothelin system. Importantly, our mouse data also show that the endothelin receptor blocker atrasentan significantly lessened cardiac remodeling and improved cardiac function in a preclinical model of breast cancer. Conclusions: Although our findings should be further examined in other preclinical/clinical models, our data suggest that endothelin receptor blockers may play a role in cardiac health in individuals with breast cancer. (Understanding and Treating Heart Failure With Preserved Ejection Fraction: Novel Mechanisms, Diagnostics and Potential Therapeutics [Alberta HEART]; NCT02052804 and Multidisciplinary Team Intervention in Cardio-Oncology [TITAN]; NCT01621659).

Heart Transplantation From DCD Donors in Australia: Lessons Learned From the First 74 Cases.

Heart transplantation from donation after circulatory death (DCD) donors has the potential to substantially increase overall heart transplant activity. The aim of this report is to review the first 8 y of our clinical heart transplant program at St Vincent's Hospital Sydney, to describe how our program has evolved and to report the impact that changes to our retrieval protocols have had on posttransplant outcomes. Since 2014, we have performed 74 DCD heart transplants from DCD donors utilizing a direct procurement protocol followed by normothermic machine perfusion. Changes to our retrieval protocol have resulted in a higher retrieval rate from DCD donors and fewer rejections of DCD hearts during normothermic machine perfusion. Compared with our previously reported early experience in the first 23 transplants, we have observed a significant reduction in the incidence of severe primary graft dysfunction from 35% (8/23) to 8% (4/51) in the subsequent 51 transplant recipients ( P < 0.01). The only withdrawal time interval significantly associated with severe primary graft dysfunction was the asystolic warm ischemic time: 15 (12-17) versus 13 (11-14) min ( P < 0.05). One- and 5-y survival of DCD heart transplant recipients was 94% and 88%, comparable to that of a contemporary cohort of donation after brain death recipients: 87 and 81% ( P -value was not significant). In conclusion, heart transplantation from DCD donors has become a major contributor to our overall transplant activity accounting for almost 30% of all transplants performed by our program in the last 2 y, with similar DCD and donation after brain death outcomes.

[New technique of concomitant replacement of the aortic valve and the ascending aorta with enlargement of the aortic annulus for congenital bicuspid aortic valve].

Congenital bicuspid aortic valve (BAV) is one of the most common congenital heart diseases, with a high incidence of associated valvular lesions and aortic abnormalities including aortic stenosis( AS), aortic regurgitation, aortic dilatation, and aortic dissection. Patients with BAV and AS often have a small aortic annulus. We encountered a case of BAV in which a 51-year-old woman with severe AS having a small aortic annulus and a dilated ascending aorta required surgical intervention. We performed the surgery using new technique that involved concomitant replacement of the aortic valve and the ascending aorta with enlargement of the aortic annulus using a single uniquely-shaped graft to avoid prosthesis patient mismatch. We trimmed the proximal end of the straight graft in shape of 2 teardrops hanging on it to fit the cut annulus. It requires only a single suture line to replace the ascending aorta and enlarge the aortic annulus, which entails a decreased risk of bleeding during surgery. We believe that it could be applicable to many cases requiring concomitant surgery.

Regression of oesophageal varices in total anomalous pulmonary venous connection.

The coexisting of oesophageal varices with total anomalous pulmonary venous connection is extremely rare but contains a potential leading to a lethal haemorrhage. The fate of the oesophageal varices after total anomalous pulmonary vein connection repair remains largely unknown. We herein report a case with infracardiac type total anomalous pulmonary venous connection with remarkable oesophageal varices. In the present case, of note, the oesophageal varices were completely regressed after total anomalous pulmonary venous connection repair without any intervention. This case might help a surgical team reduce the hesitation to repair the total anomalous pulmonary venous connection regardless of oesophageal varices, a potentially fatal condition.

Ketone therapy for heart failure: current evidence for clinical use.

During conditions that result in depleted circulating glucose levels, ketone bodies synthesized in the liver are necessary fuel substrates for the brain. In other organs, such as the heart, the reliance on ketones for generating energy in the absence of glucose is less important as the heart can utilize alternative fuel sources, such as fatty acids. However, during pathophysiological conditions, such as heart failure, cardiac defects in metabolic processes that normally allow for sufficient energy production from fatty acids and carbohydrates contribute to a decline in contractile function. As such, it has been proposed that the failing heart relies more on ketone bodies as an energy source than previously appreciated. Furthermore, it has been shown that ketone bodies function as signaling molecules that can suppress systemic and cardiac inflammation. Thus, it is possible that intentionally elevating circulating ketones may be beneficial as an adjunct treatment for heart failure. Although many approaches can be used for 'ketone therapy', each of these has their own advantages and disadvantages in the treatment of heart failure. Thus, we summarize current preclinical and clinical studies involving various types of ketone therapy in cardiac disease and discuss the advantages and disadvantages of each modality as possible treatments for heart failure.

Clinical assessment of efficacy of poly-L-lactide sternal pin on sternal stability and post-operative pain: a prospective randomized trial in cardiovascular surgery.

BACKGROUND: Although the incident rate is low, sternal dislocation and dehiscence due to unstable sternal fixation after cardiovascular surgery could cause potentially lethal complications. Thus, to enforce the stability of closed sternum, the sternal pins have been utilized at surgeon's discretion. However, there is no randomized clinical trial to test whether these pins are effective to stabilize a sternum. Hence, this study aimed to examine the clinical efficacy of bioabsorbable poly-L-lactide (PLLA) sternal pins in reinforcing sternal stability and preventing instability of the sternum after full sternotomy. METHODS: We conducted a single institutional, prospective, randomized, single-blinded clinical study involving 100 patients who underwent an initial cardiovascular surgery via sternotomy. Patients were randomly allocated into two groups: with (group P) and without (group N) PLLA sternal pins, at 1:1 ratio from November 2013 to April 2016. Sternal deviation and stability were assessed with postoperative computed tomography (CT) at two postures to put shear stress on the sternum. Additionally, information on patient demographic indices was obtained prospectively, and patient's pain intensity was assessed with numerical rating scoring system during rehabilitation. Furthermore, propensity score matching was performed for further comparative sub-analysis. RESULTS: Ninety-one patients (43 in group P and 48 in group N) were analyzed using the intention-to-treat method. Group N had a significantly higher proportion of males (P=0.015) and ischemic disease as a primary diagnosis (P=0.040) than group P. Postoperative CT showed that the degree of sternal deviation and stability were comparable between the groups. Similarly, the numerical rating score of pain during rehabilitation showed no difference between the groups. Even after adjusting for patient characteristics using propensity score matching method, no significant differences in sternal gaps, stability, and numerical rating score of pain were observed. Of note, no material-related adverse event such as wound infection was found. CONCLUSIONS: We could not identify the efficacy of the sternal pin in enforcing sternal stability based on CT measurements with mild shear stress on sternum after cardiovascular surgery. Nevertheless, our results with no adverse events might encourage further investigations with a more specific cohort who is susceptible to infection but requires an additional sternal fixation. TRIAL REGISTRATION: This study was registered in University Hospital Medical Information Network Clinical Trial Registry (UMIN000017357).

Exogenous ketone ester administration attenuates systemic inflammation and reduces organ damage in a lipopolysaccharide model of sepsis.

AIMS: Sepsis is a life-threatening condition of organ dysfunction caused by dysregulated inflammation which predisposes patients to developing cardiovascular disease. The ketone ß-hydroxybutyrate is reported to be cardioprotective in cardiovascular disease and this may be due to their signaling properties that contribute to reducing inflammation. While exogenous ketone esters (KE) increase blood ketone levels, it remains unknown whether KEs can reduce the enhanced inflammatory response and multi-organ dysfunction that is observed in sepsis. Thus, this study assesses whether a recently developed and clinically safe KE can effectively improve the inflammatory response and organ dysfunction in sepsis. METHODS AND RESULTS: To assess the anti-inflammatory effects of a KE, we utilized a model of lipopolysaccharide (LPS)-induced sepsis in which an enhanced inflammatory response results in multi-organ dysfunction. Oral administration of KE for three days prior to LPS-injection significantly protected mice against the profound systemic inflammation compared to their vehicle-treated counterparts. In assessing organ dysfunction, KE protected mice from sepsis-induced cardiac dysfunction as well as renal dysfunction and fibrosis. Furthermore, KE administration attenuated the sepsis-induced inflammation in the heart, kidney, and liver. Moreover, these protective effects occurred independent of changes to enzymes involved in ketone metabolism. CONCLUSION: These data show that the use of an exogenous KE attenuates the dysregulated systemic and organ inflammation as well as organ dysfunction in a model of severe inflammation. We postulate that this exogenous KE is an appealing and promising approach to capitalize on the protective anti-inflammatory effects of ketones in sepsis and/or other inflammatory responses.