Cardiac Pulmonary Edema Research Articles

The Immersion-Induced Pulmonary Edema in Swimming and Diving

Staying in or underwater can lead to acute pulmonary complaints, which clinically present as an acute immersion-induced pulmonary edema (IPE), particular in strenuous swimming (SIPE) or diving (DIPE). The IPE presents as a cardiac pulmonary edema and is induced by several pathophysiological processes during immersion, including fluid-shift, severe breathing, strenuous exercise, ambient cold, and aggravating cardiac pathologies. This clinical review summarizes current evidence about the incidence of IPE in general, SIPE, and DIPE, the main aspects of its complex underlying pathophysiology, clinical symptoms, outcome and prognosis. It furthers provides recommendations for emergency treatment and indication of hospital admission.

Continuous home terlipressin infusion increases handgrip strength and reduces ascites-A prospective randomized crossover study.

Observational studies suggest a beneficial effect of continuous terlipressin infusion (CTI) on ascites and sarcopenia in decompensated cirrhosis with portal hypertension. This single-center, prospective, cross-over study randomized 30 patients with cirrhosis, ascites, and sarcopenia to commence on 12 weeks of home CTI or 12 weeks of observation prior to cross-over. The co-primary outcomes were change in handgrip strength and paracentesis volume. Secondary outcomes included quality of life, sarcopenia measures, renal function, safety, and hospitalization. The median age of participants was 62 years (IQR: 57-64), the median Model for End-Stage Liver Disease-Sodium was 16 (12.3-20.8), and 22 (73%) were male. Handgrip strength increased by a mean adjusted difference (MAD) of 3.09 kg (95% CI: 1.11-5.08 kg) between CTI and observation ( p =0.006); an 11.8% increase from baseline. The total volume of ascites drained decreased by a MAD of 11.39L (2.99-19.85, p =0.01), with 1.75 fewer episodes of paracentesis (0.925-2.59, p <0.001) on CTI. Serum creatinine decreased, urinary sodium excretion increased, and quality of life was significantly higher on CTI (all p <0.001), with an increase in Chronic Liver Disease Questionnaire score of 0.41 points (0.23-0.59). There were 7 minor line-related complications but no cardiac events or pulmonary edema. This novel study demonstrates a significant increase in handgrip strength, reduction in paracentesis volume, and improved quality of life in patients with decompensated cirrhosis treated with continuous terlipressin infusion. These findings provide a strong rationale for the use of ambulatory CTI in appropriately selected patients with cirrhosis.

Isolation and Characterization of a Viable Toxoplasma gondii from Captive Caracal (Caracal caracal).

Toxoplasma gondii is a widespread protozoan parasite that infects most warm-blooded animals, and felids can serve as intermediate and definitive hosts. Pathological diagnosis and serological and etiological investigations were conducted on a captive caracal (Caracal caracal) carcass collected from China in 2022. Pathological diagnosis revealed that cardiac insufficiency, pulmonary edema, hepatic failure, and renal insufficiency were the causes of the caracal's death. A modified agglutination test (cut-off: 1:25) revealed that IgG antibodies against T. gondii were present in the myocardium juice (1:1600), ascitic fluid (1:3200), and hydropericardium (1:800). A viable T. gondii (TgCaracalCHn2) strain was isolated from the tissue samples (heart, brain, spleen, and skeletal muscle) of this caracal using a mouse bioassay. The genotype of TgCaracalCHn2 was ToxoDB#5 (Type II variant), as determined via RFLP-PCR. The strain was avirulent in Swiss mice and matched the prediction of ROP18 and ROP5 gene alleles of TgCaracalCHn2 (2/2). Mild tissue cysts (203 ± 265) were observed in mice brains after inoculation with TgCaracalCHn2 tachyzoites. ToxoDB#5 is the dominant genotype in North American wildlife, and this is the first documented isolation of T. gondii ToxoDB#5 from China. This indicates that caracal plays an important role in the transmission of this T. gondii genotype.

Abstract P1138: Transcriptomic Insights Into How Previously Increased Cardiac Protein O-GlcNAcylation Enhances Susceptibility To Cardiac Dysfunction In A Response To Pressure-Overload

Increased levels of cardiac protein posttranslational β-linked N-acetylglucosamine (O-GlcNAc) modification are implicated in adverse remodeling seen in hypertrophy and diabetes. Our previous work found elevated O-GlcNAc levels in hearts from diabetic mice, and a chronic increase in O-GlcNAc caused adverse cardiac remodeling. In diabetes, increased cardiac disease risk persists even after patients return to tight glycemic control. Thus, we hypothesize that a transient increase in O-GlcNAc is sufficient to exacerbate adverse cardiac remodeling under subsequent pressure-overload, and we propose that this is due to epigenetic modifications causing persistent changes in gene expression. We used an inducible, cardiomyocyte specific, dominant negative O-GlcNAcase (dnOGA) mouse. After a 2-wk induction (which leads to a 1.8-fold increase in O-GlcNAc levels) and subsequent 2-wk washout, Control (Con) and dnOGA mice undergo transverse-aortic constriction (TAC) or Sham surgery. After 8-wks, cardiac function is measured via echocardiography, gravimetric measures at harvest, and RNA-seq analysis is done on cardiac tissue. In both Con+TAC and dnOGA+TAC vs. Sham groups, systolic function is decreased ( -12%, p &lt; 0.001, -11%, p &lt; 0.01 ), and ventricular weight is increased ( +43%, +69%, both p &lt; 0.0001 ), consistent with cardiac hypertrophy. Interestingly, we see further exacerbation of cardiac hypertrophy ( +29%, p &lt; 0.0001 ) and pulmonary edema ( +36%, p &lt; 0.01 ) between dnOGA+TAC vs. Con+TAC groups. Also, RNA-seq results show distinct transcriptomic profiles between the experimental groups via hierarchical clustering ( |FC| &gt; 1.50, FDR &lt; 0.1 ). A candidate gene approach shows enhanced and exacerbated changes in genes associated with cardiac disease states like heart failure and fibrosis (e.g., Atp2a2, Col1a1, &amp; Nox4 ), consistent with cardiac remodeling. Our results support the hypothesis that transient increase in cardiac O-GlcNAc levels increases susceptibility to subsequent cardiac pathology. Moreover, the exacerbation of pathology is consistent with epigenetic mediated effects of transient O-GlcNAc induction; and pertaining to diabetes, provide a possible mechanism into the continued increased of cardiac disease risk.

Rationales and methodology of the noninvasive ventilation in CPAP mode in pre‑hospital care for exacerbations of chronic obstructive pulmonary disease and cardiac pulmonary edema

Review of literature on the rationale and features of the application of noninvasive mechanical ventilation in CPAP mode in providing emergency medical care to patients with exacerbation of COPD and acute cardiogenic pulmonary edema.

Accuracy of Critical Care Ultrasonography Plus Arterial Blood Gas Analysis Based Algorithm in Diagnosing Aetiology of Acute Respiratory Failure.

Lung ultrasound when used in isolation, usually misses out metabolic causes of dyspnoea and differentiating acute exacerbation of COPD from pneumonia and pulmonary embolism is difficult, hence we thought of combining critical care ultrasonography (CCUS) with arterial blood gas analysis (ABG). The objective of this study was to estimate accuracy of Critical Care Ultrasonography (CCUS) plus Arterial blood gas (ABG) based algorithm in diagnosing aetiology of dyspnoea. Accuracy of traditional Chest X-ray (CxR) based algorithm was also validated in the following setting. It was a facility based comparative study, where 174 dyspneic patients were subjected to CCUS plus ABG and CxR based algorithms on admission to ICU. The patients were classified into one of five pathophysiological diagnosis 1) Alveolar( Lung-pneumonia)disorder ; 2) Alveolar (Cardiac-pulmonary edema) disorder; 3) Ventilation with Alveolar defect (COPD) disorder ;4) Perfusion disorder; and 5) Metabolic disorder. We calculated diagnostic test properties of CCUS plus ABG and CXR based algorithm in relation to composite diagnosis and correlated these algorithms for each of the defined pathophysiological diagnosis. The sensitivity of CCUS and ABG based algorithm was 0.85 (95% CI-75.03-92.03) for alveolar (lung) ; 0.94 (95% CI-85.15-98.13) for alveolar (cardiac); 0.83 (95% CI-60.78-94.16) for ventilation with alveolar defect; 0.66 (95% CI-30-90.32) for perfusion defect; 0.63 (95% CI-45.25-77.07) for metabolic disorders.Cohn's kappa correlation coefficient of CCUS plus ABG based algorithm in relation to composite diagnosis was 0.7 for alveolar (lung), 0.85 for alveolar (cardiac), 0.78 for ventilation with alveolar defect, 0.79 for perfusion defect and 0.69 for metabolic disorders. CCUS plus ABG algorithm is highly sensitive and it's agreement with composite diagnosis is far superior. It is a first of it's kind study, where authors have attempted combining two point of care tests and creating an algorithmic approach for timely diagnosis and intervention.

Systemic and Cardiac Amyloidosis in Captive Celebes Crested Macaques (Macacanigra)

Systemic amyloidosis has been described in many animals and the most common form is reactive systemic AA amyloidosis. However, cardiac amyloidosis leading to heart failure is rare in animals. We now describe systemic and cardiac amyloidosis in two captive endangered Celebes crested macaques (Macaca nigra) at the Singapore Zoo. Both animals were geriatric and had chronic morbidities. Physical examination, radiography and ultrasonography revealed cardiac arrhythmia, pleural effusion, pulmonary oedema and ascites, consistent with cardiac failure. Amyloidosis was suspected and confirmed as type AA by immunohistochemistry.

Preoperative cardiac troponin I as a predictor of postoperative cardiac events in patients with end stage renal disease undergoing non-cardiac surgery

We investigated if elevated cardiac troponin I (cTnI) serum levels before non-cardiac surgery were predictors of postoperative cardiac events in patients with end stage renal disease (ESRD) undergoing dialysis. In total, 703 consecutive patients with ESRD undergoing dialysis who underwent non-cardiac surgery were enrolled. Preoperative cTnI serum levels were measured at least once in all patients. The primary endpoint was defined as a composite of cardiac death, myocardial infarction (MI), and pulmonary edema during hospitalization or within 30 days after surgery in patients with a hospitalization longer than 30 days after surgery. Postoperative cardiac events occurred in 48 (6.8%) out of 703 patients (cardiac death 1, MI 18, and pulmonary edema 33). Diabetes mellitus (DM), previous ischemic heart disease, and congestive heart failure were more common in patients with postoperative cardiac events. Peak cTnI serum levels were higher in patients with postoperative cardiac event (180 ± 420 ng/L vs. 80 ± 190 ng/L, p = 0.008), and also elevated peak cTnI levels > 45 ng/L were more common in patients with postoperative cardiac events (66.8% vs. 30.5%, p < 0.001). Multivariate logistic regression analysis showed that DM (odds ratio [OR] 2.509, 95% confidence interval [CI] 1.178–5.345, p = 0.017) and serum peak cTnI levels ≥ 45 ng/L (OR 3.167, 95% CI 1.557–6.444, p = 0.001) were independent predictors for the primary outcome of cardiac death/MI/pulmonary edema. Moreover, cTnI levels ≥ 45 ng/L had an incremental prognostic value to the revised cardiac risk index (RCRI) (Chi-square = 23, p < 0.001), and to the combined RCRI and left ventricular ejection fraction (Chi-square = 12, p = 0.001). Elevated preoperative cTnI levels are predictors of postoperative cardiac events including cardiac death, MI, and pulmonary edema in patients with ESRD undergoing non-cardiac surgery.

Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) represents a small portion of cerebrovascular disease but a disproportionally large percentage of the morbidity and mortality. The overall prognosis depends on the volume of the initial bleeding, rebleeding, and the degree of delayed cerebral ischemia. The presence of cardiac manifestations and neurogenic pulmonary edema at the initial presentation indicates a higher degree of severity and systemic complications. This review covers the pathophysiology, stabilization and assessment, diagnosis and treatment, and disposition and outcomes of SAH. Figures show common saccular aneurysm locations, a noncontrast head computed tomographic scan of an SAH, an angiogram and surgical clipping of a broad-based anterior communicating aneurysm, and a three-dimensional reconstruction angiogram of a complex anterior communicating aneurysm with additional imaging of endoscopic stent-assisted coiling of the same aneurysm. Tables list the natural history of unruptured aneurysms and the annual risk of rupture, common clinical features and syndromes related to aneurysm location, the World Federation of Neurologic Surgeons grading system, the Hunt and Hess grading systems, and the Fisher scale. This review contains 4 highly rendered figures, 5 tables, and 144 references. Key words: aneurysm rupture, cerebral aneurysm, cerebral vasospasm, Fisher scale, Glasgow Coma Scale assessment, Hunt and Hess grading criteria, subarachnoid hemorrhage, World Federation of Neurologic Surgeons grading scale Key Advances CT angiography is an emerging technology that has the diagnostic advantage of being non-invasive. The diagnostic accuracy of CTA varies widely and when compared to the standard digital subtraction angiography (DSA) the sensitivity and specificity range from 77% to 100% and 87%-100% respectively. The 2012 AHA guidelines and the 2011 Neurocritical care society (NCS) consensus guidelines recommend that from the time of symptom onset to securing of the aneurysm, the blood pressure be controlled with a titratable agent with a goal systolic blood pressure of less than 160mmHg or a MAP of less than 110mmHg. Cardiac abnormalities are common following acute SAH. Subendocardial ischemia may result from autonomic stimulation from the brain and circulating catecholamine surge, resulting in an abnormal ECG in 50% to 100% of patients with SAH in the acute phase depending on severity. The International Subarachnoid Aneurysm Trial ISAT was a landmark study that looked at aSAH repair comparing surgical clipping with endoscopic coiling and demonstrated a mortality benefit with coiling in the right patient population.

Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) represents a small portion of cerebrovascular disease but a disproportionally large percentage of the morbidity and mortality. The overall prognosis depends on the volume of the initial bleeding, rebleeding, and the degree of delayed cerebral ischemia. The presence of cardiac manifestations and neurogenic pulmonary edema at the initial presentation indicates a higher degree of severity and systemic complications. This review covers the pathophysiology, stabilization and assessment, diagnosis and treatment, and disposition and outcomes of SAH. Figures show common saccular aneurysm locations, a noncontrast head computed tomographic scan of an SAH, an angiogram and surgical clipping of a broad-based anterior communicating aneurysm, and a three-dimensional reconstruction angiogram of a complex anterior communicating aneurysm with additional imaging of endoscopic stent-assisted coiling of the same aneurysm. Tables list the natural history of unruptured aneurysms and the annual risk of rupture, common clinical features and syndromes related to aneurysm location, the World Federation of Neurologic Surgeons grading system, the Hunt and Hess grading systems, and the Fisher scale. This review contains 4 highly rendered figures, 5 tables, and 144 references. Key words: aneurysm rupture, cerebral aneurysm, cerebral vasospasm, Fisher scale, Glasgow Coma Scale assessment, Hunt and Hess grading criteria, subarachnoid hemorrhage, World Federation of Neurologic Surgeons grading scale

A HeartMate 3 Implantation without Anticoagulation

<h3>Introduction</h3> Left ventricular assist device (LVAD) implantation is an established treatment for advanced heart failure. LVADs are implanted using intra-operative anticoagulation with or without cardiopulmonary bypass. However, the anticoagulation strategy remains uncertain in patients with heparin-induced thrombocytopenia (HIT) and undergoing left ventricular assist device (LVAD) implantation. We report the first anticoagulant free implantation of a HeartMate 3. We prospectively followed a patient with heart failure and HIT. <h3>Case Report</h3> A 65-year-old man with ischemic cardiomyopathy was admitted with cardiac decompensation, pulmonary edema and cardiogenic shock in a regional clinic where VA-ECMO-therapy was initiated. After transfer to our hospital, he had 2 episodes of oxygenator thrombosis and later he was diagnosed with HIT. He was anticoagulated with argatroban for his VA-ECMO. The preoperative course was further complicated due to recurrent bronchial bleeding. A decision was made to proceed with mechanical circulatory support using a HeartMate 3 ventricular assist device (Abbott, Chicago, IL). To avoid the risk of bronchial bleeding, we performed an anticoagulant-free HeartMate 3 implantation through a full sternotomy on perioperative VA-ECMO support. Argatroban infusion was stopped 2 days before surgery and started again 4 days postoperatively and later switched to phenoprocoumon. There were no episodes of bronchial bleeding. More importantly, there was no signs of thrombosis, organ damage or neurological dysfunction and pump parameters remained stable during follow-up. <h3>Summary</h3> Anticoagulant-free HeartMate 3 implantation appears to be a safe alternative to performing implantation using alternative anticoagulation in patients with HIT.

Tele-EMS physicians improve life-threatening conditions during prehospital emergency missions

Almost seven years ago, a telemedicine system was established as an additional component of the city of Aachen’s emergency medical service (EMS). It allows paramedics to engage in an immediate consultation with an EMS physician at any time. The system is not meant to replace the EMS physician on the scene during life-threatening emergencies. The aim of this study was to analyze teleconsultations during life-threatening missions and evaluate whether they improve patient care. Telemedical EMS (tele-EMS) physician consultations that occurred over the course of four years were evaluated. Missions were classified as involving potentially life-threatening conditions based on at least one of the following criteria: documented patient severity score, life-threatening vital signs, the judgement of the onsite EMS physician involved in the mission, or definite life-threatening diagnoses. The proportion of vital signs indicating that the patient was in a life-threatening condition was analyzed as the primary outcome at the start and end of the tele-EMS consultation. The secondary outcome parameters were the administered drug doses, tracer diagnoses made by the onsite EMS physicians during the missions, and quality of the documentation of the missions. From January 2015 to December 2018, a total of 10,362 tele-EMS consultations occurred; in 4,293 (41.4%) of the missions, the patient was initially in a potentially life-threatening condition. Out of those, a total of 3,441 (80.2%) missions were performed without an EMS physician at the scene. Records of 2,007 patients revealed 2,234 life-threatening vital signs of which 1,465 (65.6%) were remedied during the teleconsultation. Significant improvement was detected for oxygen saturation, hypotonia, tachy- and bradycardia, vigilance states, and hypoglycemia. Teleconsultation during missions involving patients with life-threatening conditions can significantly improve those patients' vital signs. Many potentially life-threatening cases could be handled by a tele-EMS physician as they did not require any invasive interventions that needed to be performed by an onsite EMS physician. Diagnoses of myocardial infarction, cardiac pulmonary edema, or malignant dysrhythmias necessitate the presence of onsite EMS physicians. Even during missions involving patients with life-threatening conditions, teleconsultation was feasible and often accessed by the paramedics.

Outcomes of COVID-19-positive acute coronary syndrome patients: A multisource electronic healthcare records study from England.

BackgroundPatients with underlying cardiovascular disease and coronavirus disease 2019 (COVID‐19) infection are at increased risk of morbidity and mortality.ObjectivesThis study was designed to characterize the presenting profile and outcomes of patients hospitalized with acute coronary syndrome (ACS) and COVID‐19 infection.MethodsThis observational cohort study was conducted using multisource data from all acute NHS hospitals in England. All consecutive patients hospitalized with diagnosis of ACS with or without COVID‐19 infection between 1 March and 31 May 2020 were included. The primary outcome was in‐hospital and 30‐day mortality.ResultsA total of 12 958 patients were hospitalized with ACS during the study period, of which 517 (4.0%) were COVID‐19‐positive and were more likely to present with non‐ST‐elevation acute myocardial infarction. The COVID‐19 ACS group were generally older, Black Asian and Minority ethnicity, more comorbid and had unfavourable presenting clinical characteristics such as elevated cardiac troponin, pulmonary oedema, cardiogenic shock and poor left ventricular systolic function compared with the non‐COVID‐19 ACS group. They were less likely to receive an invasive coronary angiography (67.7% vs 81.0%), percutaneous coronary intervention (PCI) (30.2% vs 53.9%) and dual antiplatelet medication (76.3% vs 88.0%). After adjusting for all the baseline differences, patients with COVID‐19 ACS had higher in‐hospital (adjusted odds ratio (aOR): 3.27; 95% confidence interval (CI): 2.41–4.42) and 30‐day mortality (aOR: 6.53; 95% CI: 5.1–8.36) compared to patients with the non‐COVID‐19 ACS.ConclusionCOVID‐19 infection was present in 4% of patients hospitalized with an ACS in England and is associated with lower rates of guideline‐recommended treatment and significant mortality hazard.

Changes in Cellular Metabolic Pathways in Response to Fluoroacetate/Fluorocitrate Toxicity

Fluoroacetate, a severely toxic metabolic poison, has historically been used to control rodent and predator populations. Due to safety concerns, its use is highly restricted in the United States; however, other countries have fewer regulations. Although the mechanism of action is known, no countermeasures have been identified, and accidental or intentional ingestion by humans is often fatal. Case studies documenting exposures describe a variety of nonspecific signs and symptoms, including cardiac dysfunction, pulmonary edema, and neurological symptoms.In cellulo, fluoroacetate is metabolically converted to fluorocitrate, a tightly binding competitive inhibitor of mitochondrial aconitase. Blocking this early step in the citric acid cycle leads to mitochondrial and cellular dysfunction. Characterizing the cellular effects of fluorocitrate allows researchers to strategically select possible therapeutics for screening. Data presented herein recommend activation of alternative energy pathways to support cellular metabolism when glucose oxidation has been blocked. Glutamine and fatty acid metabolism avoid the bottleneck in the citric acid cycle caused by fluorocitrate.Metabolically active immortalized cardiac myocytes model dose‐dependent and time‐dependent responses to fluorocitrate exposure. Past work has established fluorocitrate toxicity as a better model in in vitro systems because of the slow rate of conversion from fluoroacetate to fluorocitrate in cells. Metabolic pathway dependence, flexibility, and capacity were assessed for glucose, glutamine, and fatty acid oxidation over 24 hours in cells exposed to 200 μM fluorocitrate. At the 2‐hour time point, cellular metabolism had begun to shift from glucose oxidation to glutamine oxidation. At the 6‐hour time point, the increase in dependence on glutamine metabolism became significant (p &lt; 0.05) vs. control, while dependence on glucose oxidation continued to decrease. Total glutamine metabolic capacity also increased in response to fluorocitrate exposure, possibly suggesting changes in gene expression to further support this pathway. Complementary data tracking fatty acid metabolism showed an early increase in metabolic flexibility after 1 hour of exposure. These results foreshadowed the increase in dependency observed at the 6‐hour time point. Cells exposed to fluorocitrate for 24 hours were no longer sufficiently metabolically active to be evaluated.These data show cells exposed to a mito‐toxin can shift their metabolic profile to avoid compromised pathways and utilize alternative energy sources. In response to fluorocitrate exposure, inhibited glucose metabolism is countered by increasing metabolic dependence on glutamine and fatty acid oxidation. These data recommend a targeted treatment strategy which supports alternative energy pathways by providing cells with substrates that enter glutamine or fatty acid metabolism.Support or Funding InformationThis research was supported by an interagency agreement between the NIH and USAMRICD and by the ORISE Program administered through an interagency agreement between the US DoE and USAMRDC. The views expressed are solely those of the authors.

Abstract 103: Rewarming Speed Affects Cardiopulmonary and Neurological Functions After Deep Hypothermic Cardiac Arrest

Introduction: The optimal rewarming rate from accidental or induced deep hypothermia is still unknown. Fast extracorporeal rewarming by extracorporeal circulation has been associated with cardiac dysfunction, pulmonary edema and poor neurologic outcome. Hypothesis: This study investigates whether the speed of rewarming after deep hypothermic cardiac arrest has neurological and cardiopulmonary effects. Methods: Thirty male Sprague-Dawley adult rats (450-550g) were rapidly cooled (ice packs) until 15°C core body temperature. Deep hypothermic cardiac arrest was maintained for 60 min. Thereafter rats were randomised to receive slow (90 minutes) or fast (30 minutes) rewarming by cardiopulmonary bypass to a target temperature of 35°C. After 90 minutes of reperfusion all animals underwent hemodynamic assessment by biventricular pressure-volume analysis, brain MRI and heart, lungs and brain were collected. Results: Slow rewarming preserved cardiac systolic and diastolic functions, ventricular arterial coupling and endothelium dependent relaxation. Lung edema was attenuated after slow rewarming. Cardimyocytes pro-survival kinases ERK and Akt activation were significantly higher in the slow rewarming group. MRI demonstrated enhancement of cerebral blood flow and reduction of cerebral edema after slow rewarming. Neurologic inflammatory response measured by IL-6, ICAM-1, CCL5 and TNF-α expression was significantly decreased in the slow rewarming group. Oxidative stress assessed by malondialdehyde was significantly reduced after slow rewarming. Conclusion: Slow rewarming by extracorporeal circulation after deep hypothermic cardiac arrest might improve systolic and diastolic function, preserve ventricular-arterial coupling, attenuate cerebral perfusion impairment and reduce neuronal damage.

P5995A novel biased S1P1 agonist improves renal and cardiac functions in ZSF1 rats, a model of metabolic syndrome-associated Heart Failure with preserved Ejection Fraction

Abstract Background/Introduction Heart Failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with currently no approved treatment. Diastolic dysfunction, dyspnea, intolerance to effort, high cardiac filling pressure, and lung congestion coexist with normal ejection fraction in this clinical syndrome. Ageing, obesity, type 2 diabetes, hypertension and renal dysfunction are the main comorbidities found in this heterogeneous group of patients. Microvascular endothelial dysfunction, driven by these risk factors, may be a common link with other aspects of the HFpEF pathogenesis that include oxidative stress, inflammation, cardiomyocyte stiffness/hypertrophy, and myofibroblast accumulation. Sphingosine-1-phosphate type-1 receptor (S1P1), a G protein–coupled receptor highly expressed in endothelial cells, regulates vascular integrity, vascular development and immune cell trafficking. Compound A is a novel G protein-biased S1P1 agonist that lacks functional antagonism and has endothelial-protective properties. Purpose S1P1 activation could promote phosphorylation of endothelial nitric oxide synthase, restoration of endothelial structure and function, and thus diminish cardiac and vascular stiffness, hypertrophy and fibrosis. The aim of this study was to investigate if compound A could improve renal and cardiac functions in a rat model of HFpEF with metabolic syndrome. Methods 65-week-old obese ZSF1 rats were fed a chow diet containing compound A (8 mg/kg/day) or no compound for 4 weeks. Lean ZSF1 and Wistar rats were included in the study as control groups. Urinary protein/creatinine ratio was measured as an index of glomerular injury. Cardiac hypertrophy and function were assessed by two-dimensional and Doppler echocardiography. Total cardiac and atrial weights and pulmonary edema were assessed. Results The obese ZSF1 rat was confirmed as a relevant model of HFpEF with advanced renal dysfunction. These rats showed severe glomerular filtration impairment, left ventricular and atrial hypertrophy and pulmonary edema. Cardiac systolic function, cardiac output and chamber volumes were preserved, diastolic function was impaired, and left ventricular posterior walls and septal thicknesses were increased compared to control groups. Four weeks of compound A treatment reduced urinary protein/creatinine ratio, blunted cardiac and atrial hypertrophy, and partially restored diastolic function. Circulating lymphocytes were not reduced by compound A, confirming that these pharmacological effects were not associated with S1P1 desensitization. Conclusion Compound A, a novel S1P1 agonist with endothelial properties, improves cardiac and renal functions in a rat model of metabolic syndrome-associated HFpEF. Sustained S1P1 activation with compound A may be a promising strategy for HFpEF treatment.

Myocardial ischemia during ventilator weaning: a prospective multicenter cohort study

BackgroundWeaning-induced cardiac pulmonary edema (WiPO) is one of the main mechanisms of weaning failure during mechanical ventilation. We hypothesized that weaning-induced cardiac ischemia (WiCI) may contribute to weaning failure from cardiac origin.MethodsA prospective cohort study of patients mechanically ventilated for at least 24 h who failed a first spontaneous breathing trial (SBT) was conducted in four intensive care units. Patients were explored during a second SBT using multiple tools (echocardiography, continuous 12-lead ST monitoring, biomarkers) to scrutinize the mechanisms of weaning failure. WiPO definition was based on three criteria (echocardiographic signs of increased left atrial pressure, increase in B-type natriuretic peptides, or increase in protein concentration during SBT) according to a conservative definition (at least two criteria) and a liberal definition (at least one criterion). WiCI was diagnosed according to the third universal definition of myocardial infarction proposed by the European Society of Cardiology (ESC) and the American Heart Association (AHA) statement for exercise testing.ResultsAmong patients who failed a first SBT, WiPO occurred in 124/208 (59.6%) and 44/208 (21.2%) patients, according to the liberal and conservative definition, respectively. Among patients with ST monitoring, WiCI was diagnosed in 36/177 (20.3%) and 12/177 (6.8%) of them, according to the ESC and AHA definitions, respectively. WiCI was not associated with WiPO and was not associated with weaning outcomes. Only two patients of the cohort were treated for an acute coronary syndrome after the second SBT, and seven other patients required coronary angiography during the weaning period.ConclusionsThis observational study showed the common occurrence of pulmonary edema in mechanically ventilated patients who failed a first SBT, but the association with cardiac ischemia and weaning outcomes was weak.

Pharmacokinetics of thiotepa in high-dose regimens for autologous hematopoietic stem cell transplant in Japanese patients with pediatric tumors or adult lymphoma

PurposeThiotepa is used in high-dose chemotherapy (HDT) before autologous hematopoietic stem cell transplantation (HSCT) to treat solid tumors and hematological malignancies. This Phase 1 study was conducted to establish the pharmacokinetics (PK) of thiotepa in a Japanese population.MethodsHDT/HSCT was performed in pediatric patients (≥ 2 years) with solid tumors or brain tumors (thiotepa 200 mg/m2/day IV-infused over 24 h on HSCT Days − 12, − 11, − 5, and − 4 and melphalan 70 mg/m2/day IV-infused over 1 h on Days − 11, − 5, and − 4) and adult patients (≥ 16 years) with malignant lymphoma (thiotepa 200 mg/m2/day 2-h IV-infusion on HSCT Days − 4 and − 3 plus busulfan 0.8 mg/kg 2-h IV-infusion every 6 h from HSCT Days − 8 to − 5). Pharmacokinetics of thiotepa were assessed following initial dose. Safety and efficacy were also evaluated.ResultsNine pediatric and 10 adult patients were enrolled. Mean volume of distribution (Vz) of thiotepa normalized with body surface area (BSA) was lower for pediatric patients (16.4 L/m2) compared with adult patients (26.4 L/m2) as expected due to the higher specific surface area of children. Clearance and biological half-life were similar between pediatric and adult patients. Two serious adverse events (cardiac arrest and pulmonary edema) were observed. Survival rate (Day 100 post-HSCT) was 77.8% (95% CI 36.5–93.9%) for pediatric patients and 100% for adult patients.ConclusionThiotepa elimination was comparable in pediatric and adult patients with cancer. Lower Vz in pediatric compared with adult patients was expected. HDT with thiotepa prior to autologous HSCT was well tolerated.Study registrationJapic CTI-163433.

Contemporary Management of Aneurysmal Subarachnoid Hemorrhage: A Literature Review

AbstractSubarachnoid hemorrhage (SAH) results in significant morbidity and mortality, which leads to additional economic and psychological burden. Atraumatic SAH is normally secondary to a ruptured aneurysm. Diagnosis of aneurysmal subarachnoid hemorrhage (aSAH) is usually made by computed tomography (CT) of the head: noncontrast CT identifies the hemorrhage, and CT angiography identifies the aneurysm.The management of aSAH is focused on securing the aneurysm and prevention of secondary brain injury. Definitive treatment of the aneurysm is done by endovascular coiling or surgical clipping, which should be performed as soon as possible with avoidance of hypertension and strict blood pressure management prior to aneurysm securement. Routine use of nimodipine is recommended by international guidelines as a neuroprotectant. Common neurological complications of aSAH are hydrocephalus, seizures, vasospasm, and delayed cerebral ischemia (DCI). Detection of DCI, especially in patients with poor-grade aSAH, can be challenging. In addition to clinical examination, multiple radiological modalities can be used, with digital subtraction angiography being the gold standard but CT perfusion gaining an increasingly important role. Extracranial complications including cardiac dysfunction, pulmonary edema, and electrolyte abnormalities are common, causing significant morbidity and mortality.In this review, a PubMed literature search was conducted using the terms “subarachnoid hemorrhage” and “management,” with results limited to past 5 years. Journal articles were hand-selected by the authors based on relevance, and the references were reviewed to identify additional relevant publications. Historically important publications were also included.

MCP-1 promotes detrimental cardiac physiology, pulmonary edema, and death in the cpk model of polycystic kidney disease.

Polycystic kidney disease (PKD) is characterized by slowly expanding renal cysts that damage the kidney, typically resulting in renal failure by the fifth decade. The most common cause of death in these patients, however, is cardiovascular disease. Expanding cysts in PKD induce chronic kidney injury that is accompanied by immune cell infiltration, including macrophages, which we and others have shown can promote disease progression in PKD mouse models. Here, we show that monocyte chemoattractant protein-1 [MCP-1/chemokine (C-C motif) ligand 2 (CCL2)] is responsible for the majority of monocyte chemoattractant activity produced by renal PKD cells from both mice and humans. To test whether the absence of MCP-1 lowers renal macrophage concentration and slows disease progression, we generated genetic knockout (KO) of MCP-1 in a mouse model of PKD [congenital polycystic kidney (cpk) mice]. Cpk mice are born with rapidly expanding renal cysts, accompanied by a decline in kidney function and death by postnatal day 21. Here, we report that KO of MCP-1 in these mice increased survival, with some mice living past 3 mo. Surprisingly, however, there was no significant difference in renal macrophage concentration, nor was there improvement in cystic disease or kidney function. Examination of mice revealed cardiac hypertrophy in cpk mice, and measurement of cardiac electrical activity via ECG revealed repolarization abnormalities. MCP-1 KO did not affect the number of cardiac macrophages, nor did it alleviate the cardiac aberrancies. However, MCP-1 KO did prevent the development of pulmonary edema, which occurred in cpk mice, and promoted decreased resting heart rate and increased heart rate variability in both cpk and noncystic mice. These data suggest that in this mouse model of PKD, MCP-1 altered cardiac/pulmonary function and promoted death outside of its role as a macrophage chemoattractant.