Age, polycystic ovary syndrome (PCOS), low body mass index (BMI), high antral follicle count (AFC), increased anti-Muller hormone (AMH) levels, and elevated serum estradiol (E2) concentrations are risk factors for ovarian hyperstimulation syndrome (OHSS). However, data on the relationship between risk factors and OHSS severity in patients with PCOS are rare.in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).This retrospective study examined the risk factors for OHSS and their effect on OHSS severity in patients with PCOS undergoing The records of 2,699 women were reviewed and included in this study. These women were diagnosed with PCOS during their first IVF/ICSI cycle between January 2010 and December 2017. We analyzed the association between each of the interrogated risk factors  and OHSS. The effects of each risk factor on OHSS severity were further explored. Logistic regression was performed as part of the above analysis.Of the 2,699 women with PCOS who underwent assisted reproductive technology (ART), 75.2% had a normal response to controlled ovarian hyperstimulation (COH), while 24.8% developed OHSS. All OHSS patients were younger and had lower BMIs and basal serum follicle-stimulating hormone (FSH) and E2 levels but higher AFCs than those in the normal group. AFC demonstrated a strong correlation with OHSS, with a cutoff value of 24 in patients with PCOS. A total of 19.5% of the patients had mild OHSS, while 80.5% had moderate OHSS. Compared with those in the moderate OHSS group, those in the mild OHSS group were older and had higher basal serum FSH levels and lower serum E2 and T levels. However, BMI and AFC were not different between the mild and moderate OHSS groups. Basal serum E2 showed a strong correlation with OHSS severity, with a cutoff value of 37.94 pg/ml.AFC is a strong marker of OHSS, and basal serum E2 is the best predictor of OHSS severity in women with PCOS undergoing IVF treatment. Ovarian hyperstimulation syndrome (OHSS) is a complication that occurs frequently during controlled ovarian stimulation (COH) , 2. ModePrevious studies have shown that polycystic ovary syndrome (PCOS), a history of OHSS, young age, low body mass index (BMI), and a high antral follicle count (AFC) might lead to OHSS. Other risk factors include a history of allergies, high levels of anti-Muller hormone (AMH), high doses of gonadotropins, and high serum E2 levels , 7. FollThe current literature indicates that AMH values >3.4 ng/ml, AFC >24, and estradiol values >3,500 pg/ml are particularly associated with an increased risk of OHSS in patients undergoing fertility treatment . Howeverin vitro fertilization (IVF)/intracytoplasmic sperm injection-embryo transfer (ICSI-ET) cycles using long agonist protocols and were diagnosed with PCOS based on the 2003 Rotterdam criteria. The diagnosis was based on at least two of the following three criteria: 1) Oligo/anovulation; 2) Clinical and/or biochemical signs of hyperandrogenism; or 3) Polycystic ovaries as well as exclusion of other etiologies  . And the OHSS group was divided into mild OHSS group and moderate OHSS group according to the following criteria.. The diagnosis of OHSS was based on the 2016 published clinical practice guidelines, which highlight moderate abdominal pain, nausea, and vomiting as OHSS symptoms . Mild hyAll the included patients used long-acting protocol and they were given a starting dose of 87.5–225 IU human recombination follicle stimulating hormone (rFSH). Ovulation was induced using gonadotropin (Gn), and the dose was adjusted in a timely manner depending on the number, size, and growth of follicles. The clinician determined the increase or decrease based on hormone levels and follicular development. HCG injection depended on the size of one primary follicle (≥20 mm), with the diameter of the other follicle being ≥18 mm or more than 2/3 of the follicles having a follicle diameter ≥14 mm. The patient’s clinical serum E2 levels and follicle condition determined the trigger drug and HCG exposure time. Eggs were retrieved 36–37 h after HCG administration. Conventional IVF or ICSI was performed based on the semen quality and previous fertilization history. In summary, all patients were treated with a gonadotropin releasing hormone (GnRH) agonist protocol to achieve a receptive endometrium for the implantation of embryos. Intramuscular injection of progesterone was used for endometrial transformation. Luteal gel was used for luteal support after transplantation. HCG was not used.P<0.05 was considered statistically significant.R version 3.4.4 (14) and SAS 9.4  were used to analyze the data. The numerical data are presented as the mean with standard deviation (SD), while categorical variables are shown as % (n/N). A t test was used for continuous variables, while the chi-square test was used for categorical variables. We performed logistic regression to explore the effects of each risk factor on OHSS and OHSS severity. The curve fit was used to clarify the relationships between OHSS and antral follicular count and basal follicle stimulating hormone (FSH). The results are reported as adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Two-tailed 2 is predictive of OHSS severity.Of the 50,518 ART patients who began treatment between 2010 and 2017, 2,699 who had PCOS were included in the present study. There were 2,030 (75.2%) patients who had a normal response to COH, while 669 (24.8%) developed OHSS in response to COH  of the cycles involved mild OHSS, while 527 (80.5%) involved moderate OHSS. The baseline characteristics of the mild and moderate OHSS patients are listed in Compared with the normal group, the OHSS group was associated with fewer starting dosages of Gn, a longer length of stimulation, more retrieved oocytes, a lower MII oocyte rate, and fewer good-quality embryos, as shown in The mild OHSS group had a smaller ovarian volume before and after HCG trigger . The moderate OHSS group had a much higher serum E2 level  and thicker endometrium on HCG+3 , as shown in Logistic regression analysis, incorporating conventional markers such as age, BMI, baseline hormone levels and AFC in the model, showed that only baseline hormone levels  and AFC were significantly predictive of OHSS  had moderate accuracy for predicting OHSS . Therefore, basal serum E2 showed a stronger correlation with OHSS severity and needs further study. A previous study showed that the number of retrieved oocytes is a risk factor for the occurrence of OHSS, and those with very high blood E2 levels and too many oocytes retrieved have an increased incidence of moderate-to-severe OHSS  levels, and estrogen has been implicated as a potential etiologic factor, one of the possible reason is that when the estradiol elevated, capillary permeability and the chemical mediators or precursors that augment fluid extravasation increased and thus moderate OHSS developed . The resere OHSS . In our Our study revealed that AFCs have the most important impact on the occurrence of OHSS, especially in patients with PCOS. However, our study was conducted retrospectively and only involved a single medical center. In addition, serum AMH was measured in only a few patients, and thus these measurements were not included in this study. Finally, all patients undergoing ovarian induction were treated with a gonadotropin releasing hormone (GnRH) agonist protocol, weakening the generalizability of the findings.In summary, AFC is an independent risk factor for OHSS in women with PCOS undergoing their first ovarian stimulation cycle. Besides, basal serum E2 is a predictive factor for OHSS severity. Meanwhile, patients with PCOS undergoing IVF/ICSI who are at risk of OHSS can be identified by careful ultrasonography of the ovaries before treatment. AFC >24 specifically is associated with an increased risk of OHSS, and the cutoff value is the same with NPCO patients, which indicates that patients with PCOS do not need the use of GnRH agonist cycles with low-dose FSH. This strategy will guide cycles of fresh embryo transfer instead of using a freeze-all strategy, improve the rates of live birth and lower the risks of OHSS.The data were obtained from the ART electronic medical record system (CCRM) at the Reproductive Medicine Center of the First Affiliated Hospital of Zhengzhou University . All medical histories, ART treatment processes and the outcomes of every cycle are recorded in the CCRM. The records are validated by the Technical Standard for Human Assisted Reproduction issued by the Chinese Ministry of Health. The surveillance staff consults the patient information and performs quality control periodically.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Zhengzhou University.BS and YM: designed study, analyzed data, and drafted the manuscript. LL: revised the manuscript. LH, FW, and SD: collected data. LH and YZ: reviewed the manuscript. YS: study conceptualization and review. All authors contributed to the article and approved the submitted version.This work was funded by the International  Cooperation and Exchange (ICE) Projects of the National Natural Science Foundation of China (NSFC) (FDN-81820108016), the Chinese Medical Association Clinical Medical Research Special Fund Project (FDN-17020190688), the Medical Science and Technology Research Project Joint Co-construction Project of Henan Province (FDN-2018020116), and the Henan Provincial Higher Education Key Re- search Project Plan (FDN-19A320056).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Lactate and cardiac troponin I levels increased from 1.4 ± 0.2 to 4.9 ± 0.7 mmol/L (p = 0.001) and from 0.05 ± 0.02 to 14.74 ± 2.59 µg/L (p = 0.001), respectively. All haemodynamic changes were stable over a three-hour period with a 71% survival rate. The necrotic volume (n = 5) represented 24.0 ± 1.9% of total ventricular mass. No sham exhibited any variation under general anaesthesia. We described and characterized, for the first time, a stable, reproducible sheep model of cardiogenic shock obtained by percutaneous intracoronary ethanol administration.To develop a reproducible and stable closed chest model of ischemic cardiogenic shock in sheep, with high survival rate and potential insight into human pathology. We established a protocol for multi-step myocardial alcoholisation of the left anterior descending coronary artery by percutaneous ethanol injection. A thorough hemodynamic assessment was obtained by invasive and non-invasive monitoring devices. Repeated blood samples were obtained to determine haemoglobin and alcohol concentration, electrolytes, blood gas parameters and cardiac troponin I. After sacrifice, tissue was excised for quantification of infarction and histology. Cardiogenic shock was characterized by a significant decrease in mean arterial pressure (− 33%), cardiac output (− 29%), dP/d Insights into the pathophysiology of CS remain crucial to the development of new approaches, either pharmacological or mechanical, to reduce local and systemic effects of CS, and to appraise safety and efficacy of novel procedures prior to clinical translation. In this context, large animal models may provide a heuristic methodology to test pathophysiological hypotheses and new therapeutic procedures. These models should mimic human pathology, be reproducible, allow for control of the extent of ischemia, rely on minimally invasive techniques, require short preparation time and easy animal management, lead to impaired cardiac function and be cost-effective. Several models of myocardial infarction exist and are based on coronary artery ligation, coronary artery occlusion , or intra-coronary alcoholisation. However, the current large animal models are suboptimal for several reasons, e.g. high mortality rate2, inconsistency in infarct size3 and the invasive approach itself4. Development of a consistent and stable model of CS, is needed to more fully evaluate the interplay between hemodynamic and heart mechanics on one hand and STMCS on the other. Moreover, the current models do not fully mimic the clinical scenario of CS induced by selective coronary occlusion for several reasons. First, systemic or selective coronary hypoxemia5 is responsible for a generalized diminished cardiac function due to the hibernating myocardial condition: in this setting, cellular mechanisms of adaptation are not the same than in distinct infarcted myocardium. Similar concerns should be taken into account in the case of global toxicity, induced by carbon monoxide6. The use of microspheres could overcome this difficulty7, but the injection in the left main coronary artery has a generalized effect on the left ventricle and is associated with a jeopardized cellular death in the whole myocardial wall thickness. Furthermore, the set-up of several studies requires STMCS activation soon after7 or even before8 CS induction in order to avoid premature death of animals, or an open-chest procedure for coronary ligatures9, which completely modifies the heart-pericardium and heart–lung interactions. In recent studies suggesting that early mechanical percutaneous support prior to revascularization might reduce the size of myocardial necrosis10, a condition of mild systemic hypo-perfusion is obtained rather than an effective hemodynamic CS.Five to 10% of patients presenting with acute myocardial infarction (AMI) develop cardiogenic shock (CS). This population has a high mortality rate (40%–50%)The present study aimed to describe a reproducible closed chest model of acute CS due to myocardial infarction, mimicking the clinical setting and taking into account some specific aspects of human pathology, such as myocardial cell death, in a precise delineated coronary territory involving the whole myocardial wall thickness. This model was intended to be relatively stable in time, reproducible and have a high rate of survival after the induction of CS.A total of thirty-two female Dorset sheep were used in this study. Their mean body weight was 49.0 ± 1.5 kg and they were 35 ± 6 months old. All animals received humane care in compliance with “European Community Standards on the Care and Use of Laboratory Animals” published on September 2010 . The ethical committee N°050 of the French Ministry for Research and Innovation approved the project on 25 of September 2017.−1), acepromazine 0.1 mg kg−1 (5 mg mL−1) and buprenorphine (0.03 mL kg−1). Surface electrocardiographic leads were applied and a single lumen peripheral catheter (18 G) was then placed in a peripheral vein of the front limb. Propofol (2 mg kg-1) was given for induction of anaesthesia while its maintenance was ensured by isoflurane (inspired fraction 0.5 to 1.2%) and continuous infusion of midazolam (0.1 mg kg−1 h−1) after endotracheal intubation. Sufentanyl was administered for analgesia and animal comfort (0.15 µg kg−1 h−1). Anaesthesia depth was adjusted during animal preparation by monitoring vital signs and pupil position, then kept stable during the procedure. Myorelaxation was ensured by a bolus dose of rocuronium (0.6 mg kg−1) followed by a continuous intravenous infusion (0.3 mg kg−1 h−1). Volume controlled mechanical ventilation was used to maintain gas exchange and relied on an Aysis CS2 station  set on controlled volume mode . The ventilation was adjusted to maintain an ETCO2 between 35 and 40 mmHg, and the FiO2, initially set to 0.5, was titrated to keep the PaO2 over 80 mmHg. 8 mL kg−1 of balanced crystalloids solution  was administrated hourly. If intravascular volume expansion was required, hydroxyethyl starch was administered. 20 mg kg−1 of cefuroxime was given at the beginning of the experiment followed by 10 mg kg−1 re-injection every 2 h. Heart rhythm irregularities were prevented by using continuous infusion of amiodarone (1 mg  kg−1 h−1), magnesium sulphate (35 mg kg−1 h−1) and xylocaine (5 mg kg−1 h−1). A unfractioned heparin bolus (100 UI kg−1) was given after neck incision, followed by a continuous intravenous infusion (100 UI kg−1 h−1). A three-lumen catheter  placed in the left jugular vein was used for these purposes. Body temperature was monitored by a thermal probe and stabilized between 36 and 37 °C by an external heating system. Gastric and bladder tubes were inserted to empty respectively the stomach and monitor urine outflow.Animals were fasted overnight with free access to water, and premedicated with intramuscular injection of ketamine  and used to monitor heart rhythm and identify any abnormalities. Surface electrocardiogram was used to synchronize echocardiographic imaging.A 6-F arterial catheter was placed in an artery of the anterior limb for continuous arterial pressure monitoring. TrueWave transducers  were used for this purpose.A Doppler probe  was positioned around the left carotid artery.2) and core body temperature.A CCOmbo pulmonary artery catheter (Edwards Lifescience) connected to a Vigilance monitor (Edwards Lifescience) was inserted in the left jugular vein through a 9-F introducer allowing for continuous monitoring of pulmonary and central venous pressures, cardiac index by thermodilution, venous oxygen saturation (SvOtmax) and negative (dP/dtmin) left ventricular pressure derivatives were calculated from the left ventricular pressure signal. The probe position was checked with radioscopy, transthoracic echocardiography and analysis of the collected signals. Volume calibration of the Millar conductance catheter was obtained by calculation of parallel conductance after distal pulmonary artery injection of a 15%-hypertonic saline solution. A 9-F introduction kit was placed in the right femoral vein and used to introduce a tip-ballooned 8F Fogarty catheter (Edwards Lifescience) up to the inferior vena cava junction with the right atrium, in order to control venous blood flow and allow end-systolic pressure–volume relationship calculation . During dynamic manoeuvres, a respiratory pause was performed to limit the cardio-respiratory interactions induced by mechanical ventilation.A conductance catheter (Millar Inc) with 7-mm-spaced segments was inserted through an 8-F introducer in the right carotid artery. The probe was positioned in the left ventricle to collect ventricular pressures and volumes. The maximal positive  was used for data collection and Labchart 8 (ADInstruments Ltd) for data analysis. Systems and captors were calibrated at the beginning of each experiment. A drift of the signals from the conductance catheter was researched before each point of intervention.Transthoracic echocardiographic examination  was performed concomitant to hemodynamic data collection at each point of intervention. Loops were recorded and a blinded-analysis was conducted. In the parasternal mid-papillary short axis plane, endocardial borders were traced in end-diastolic and end-systolic frames: LV end-diastolic (LVEDA) and end-systolic (LVESA) areas were used to calculate the fractional area change (FAC = [LVEDA − LVESA)/LVEDA] × 100).+, K+, Cl-, Ca2+)  before infarct induction and prior to sacrifice.At each haemodynamic reading, blood samples were simultaneously obtained via the peripheral and pulmonary arterial catheters for blood gas analysis with lactate . Blood samples were also taken to determine concentration of haemoglobin , cardiac troponin I by immuno-assay, ethanol and key electrolytes , an over-the-wire OPT 12 mm balloon catheter  was placed through a guide wire at different sites, progressing from the most distal to the most proximal. At each site, a sufficient volume of 99.9% ethyl alcohol was injected in order to completely block the blood flow distal to balloon inflation. Complete occlusion of the coronary artery was defined as TIMI  flow ≤ 1 after alcohol injection. The injected alcohol volume depended on distal flow exclusion and rhythm disorder manifestations. The number of injected sites depended on the systemic hemodynamic consequences of necrosis extension. In accordance with previous animal models12, CS obtention was defined as a drop of more than 30% in mean arterial pressure and/or cardiac index associated to a rise of lactate concentration above 2.5 mmol L−1 in the hour following the last alcoholisation. Twenty-four animals underwent intracoronary alcoholisation (SHOCK group) and eight sham animals underwent interventricular coronary artery catheterization without any alcoholisation (SHAM group). A complete set of haemodynamic data  was first collected after a 10 min stabilization period following the complete animal technical conditioning (Baseline 1), thirty minutes after CS constitution or one hour later for the SHAM group (Baseline 2) and every hour during a three-hour period  solution to discriminate infarcted and the area-at-risk (AAR). Both sides of each section were photographed and analysed using NIH Image J software to obtain a planimetric quantification of the infarcted area, expressed as a percentage of the left ventricle AAR and total ventricular mass; values for all sections from each heart were averaged.Optical histology-specimens were fixed in 10% formalin, cut and stained with haematoxylin–eosin (H/E) or Masson’s trichrome (M/T), after which they were examined for pathological changes in the infarcted myocardium and alcohol-injured LAD region.Electron Microscopy-specimens were snap frozen directly in optimum cutting temperature (OCT) compound; after being frozen at − 80 °C, samples were cut into sections measuring 20 nm and analysed for tissue oedema, mitochondrial morphology and disruption of the intercellular tight-junctions in order to evaluate the effects of ventricular wall stress.One section per animal was used for histologic and protein analyses. Biopsies of healthy and infarcted myocardium were processed for the following analyses:Results are expressed as mean ± SEM. A student’s t-test was used to compare two mean values. An ANOVA was performed for comparison of multiple means and post-hoc test analysis was performed using a Newman–Keuls test. A p-value < 0.05 was required to reject the null hypothesis.SHOCK), according to our protocol, and seven expired prior to completion of the protocol due to refractory rhythmic complications, thus the procedure had a 71% survival rate. Among the remaining 17 SHOCK animals, 5 required a very low dose (mean dose ≤ 0.01 µg kg−1 min−1) continuous epinephrine infusion as a rescue therapy after reversal of ventricular fibrillation or tachycardia to maintain systolic arterial pressure ≥ 55 mmHg, after the induction of CS. The mean intracoronary alcohol volume necessary to obtain CS was 6.1 ± 0.8 mL. The mean time between beginning of the alcoholisation procedure and shock instauration was 84 ± 8 min. There were no significant differences in electrolytes concentration between the SHOCK and SHAM groups . Ethanol concentrations were undetectable in blood obtained from animals in which CS was induced.Twenty-four animals underwent CS induction (tmax (− 28%). A greater decrease in the dP/dtmin was observed (− 55%). Carotid blood flow (− 22%) and left ventricular fractional shortening (− 28%) also decreased, while left ventricle tele-diastolic pressure increased (+ 38%). Due to the progressive complexity of our hemodynamic monitoring, Millar-derived parameters were not available for all animals . The Millar-derived parameter ESPVR was significantly reduced (− 51%). A significant decrease in SvO2 was also observed. Lactate and cardiac troponin I levels increased from 1.4 ± 0.2 to 4.9 ± 0.7 mmol/L (p = 0.001) and from 0.05 ± 0.02 to 14.74 ± 2.59 µg/L (p = 0.001), respectively. These variations remained stable in SHOCK animals during the follow-up period while SHAM animals (n = 8) did not exhibit any variation at any timepoint  uniformly showed transmural perfusion defects in the apico-antero-septal wall; the necrotic volume and overall ischemic region (AAR) represented respectively 24.0 ± 1.9% and 43.9 ± 3.8% of LV volume, yielding an ‘infarct to AAR ratio’ of 0.55 ± 0.03  and SHOCK (n = 1) animals. In samples from the SHAM animal the mitochondria were very dense and not swollen, and the inner membrane folding (Cristae) was well preserved  completely altered , dP/dtmin (− 55%), carotid blood flow (− 22%), left ventricular fractional shortening (− 28%), left ventricle end-systolic pressure–volume relationship (− 51%) and remained stable over a three-hours period. Microscopic analysis revealed signs of myocardial cellular degeneration, e.g. loss of cross striations, contraction bands, some oedema with haemorrhage and neutrophil infiltrate; electron microscopy analysis revealed swollen mitochondria with the inner membrane folding completely altered in infarcted tissue.We described here, for the first time, a reproductible CS model obtained in sheep by percutaneous intracoronary ethanol injection that demonstrates a significant decrease in mean arterial pressure (− 33%), cardiac output (− 29%), dP/d13. Several characteristics make sheep a valuable species; unlike canine models and similar to humans, they do not sufficiently develop a collateral circulation network beneath the epicardium: as a result, it is easier to induce myocardial infarction in a reproducible manner, including the related issues of myocardial hibernation, myocardial stunning14, and LV aneurysm15. Moreover, unlike bovine models and similar to humans, sheep allow studies on angiogenesis16. Even if swine have a cardiac morphology very similar to that of humans17, they grow up relatively rapidly, which makes it harder to conduct long-term studies; furthermore, it is challenging to set up devices for thoracotomy and cardiopulmonary bypass in this species18.The use of large animal models in cardiac physiology offers some advantages, including clinical relevancy, the possibility to test delivery devices based on catheters and to study the dose–effect relationships19 and postinfarction heart failure20 had a disadvantage in that they required a thoracotomy due to the variability of coronary arterial anatomy. Contrary to them, all closed-chest models have the advantage to profoundly limit the huge trauma of thoracotomy, thus respecting cardiac and whole-body physiology and favouring recovery. Percutaneous methods also show reliability and reproducibility, and are able to induce myocardial infarction with a pathophysiology mimicking that of myocardial ischemia in human clinical setting. However, they have inherent limitations. (1) In percutaneous models employing a microsphere embolization technique, the precise quantity of particles injected is required14, the volume and the anatomical location of myocardial necrosis cannot be selectively produced, thus rendering the extent of myocardial damage poorly predictable21; moreover, in some dog models, left ventricular function is acutely and severely depressed, leading to a high mortality, while survivors experience an almost complete recovery, partially due to the rich collateral circulation of the canine heart22. (2) The exploration of well-defined ischemia and related cardioprotective therapies are barely explored by models established with coronary thrombosis because of the variability of time needed for occlusive thrombus formation, and of the difficult control of duration and severity of ischemia23. (3) Models employing angioplasty balloon inflation and deflation are typically used to explore the myocardial reperfusion phenomenon, but they are burdened with high incidence of left ventricular fibrillation24. (4) When a metallic coil embolization technique is utilized, it is almost impossible to determine in advance the site of the arterial obstruction, which results in considerable variability of the ischemic areas sizes among different animal species25. (5) Gelatine sponge embolization procedure as well is complicated by high rate of ventricular fibrillation, ventricular tachycardia and mortality2. In our view, this totally closed-chest sheep CS model addresses and overcomes many of these limitations and importantly, it has a high survival rate of (71%). Although few authors specifically reported this criterion26, this high survival rate appears to be another strength of this model: we provide, as additional data, a table summarizing the main features of known cardiogenic shock animal models  the fact that all our animals were maintained under general anaesthesia, including myorelaxant agents, which could be responsible for a profound decrease in oxygen consumption; (2) the high level of arterial oxygenation during the entirety of the experiment. However, a profound end-organ hypoperfusion state was confirmed by a significant increase in lactate value. More severe CS has been previously reported12, but most of these authors implanted a mechanical circulatory support device before the induction of CS or immediately after8. In our model, heart rate was slightly but significantly lower after CS induction. Such a slight decrease is unlikely to be responsible for the drop in cardiac output, or the low systolic volume and consequently affected left ventricular ejection fraction. Most previously reported models of CS noted a compensatory tachycardia28, rather than bradycardia. However, our findings may be easily explained by the fact that at the beginning of the experiment, all animals received analgesia based on sufentanyl associated to a mixture of xylocaine, amiodarone and sulphate magnesium to prevent arrhythmic irregularities. These drugs are known to induce bradycardia and could have influenced the hemodynamic profile of our model31. These bradycardizing effects could have been accentuated by ischemic dysfunction of the sinus node. Finally, as we were unable to detect any alcohol plasma concentrations in animals, an inhibition of baroreflex bradycardia through GABA receptors by ethanol injection32 is highly unlikely. It should be noted that an absence of compensatory tachycardia has been widely reported by others developing animal model of CS34. Lastly, five animals received epinephrine. Because the mean dose was ≤ 0.01 µg kg−1 min−1, it is highly unlikely that a such dose could significantly modify the hemodynamic profile of cardiogenic shock in our model.As expected, our closed-chest CS model is characterized by approximately a 30% decrease of systemic arterial pressure and cardiac output as well as inotropic parameters. As previously reported, myocardial infarction appears to affect more severely lusitropic properties35, and to relieve the ventricular pressure gradient in symptomatic patients suffering from obstructive hypertrophic cardiomyopathy36. Inspired by these clinical settings, intracoronary alcohol injection has become a supplemental approach in animal models of ischemic myocardial dysfunction: under video-fluoroscopic guidance, an ethyl alcohol solution (at variable percentage) is injected in specific coronary vessels according to predetermined experimental goals. This method has proven to be simple and reproducible38 and, compared to other techniques, it enables the TIMI flow grade evaluation immediately after the injection and without removing the balloon device13.Intracoronary alcohol injection was firstly used to treat arrhythmias in patients suffering from chronic ischemic heart disease or myocarditis39 and that the severity of myocardial damage tends to be greater with solutions that have a higher ethyl alcohol concentration (50 to 100%)37. The use of pure alcohol for coronary embolization in our experimental model allowed us to obtain homogeneous infarct sizes of 24 ± 4% of ventricular mass. These results differ from measures reported by a recent review paper27 in which infarct size measured by TTC staining is described as ranging from 30 to 60% of the total LV volume. We are not able to fully explain these discrepancies: studies cited by Linsdey27 vary in several ways  whereas studies describing alcohol concentration do not express infarct size as a percentage of total ventricular mass37.Previous findings have shown that solutions with slight ethyl alcohol concentration are not adequate to induce tissue damage40. Accordingly, although a variable number of regions of the LAD territory were injected with alcohol, we were able to obtain a homogeneous percentage of AAR and “infarct size to AAR ratio” (infarct to AAR volume ratio 0.55 ± 0.03).It has previously been demonstrated that infarct size strongly depends on the extension of the occluded coronary bed, rather than the anatomic occlusion site, regardless of the oxygen demand-supply balance37. As regards intraluminal response, a persistent and extensive thrombi constitution is prompted by high concentrations of alcohol, distally to the injection site35 due to sub-endothelium exposure. Progressively, thrombus is organized and calcified and a chronic total occlusion ensues18. As regards myocardial structure, myocardial necrosis occurs from 100% ethanol injection into the canine coronary circulation, either arterial or venous: it is focal or patchy and non-confluent, and involves more than half the thickness of the left ventricular wall35. Direct intra-myocardial alcohol injection induces myocardial necrosis without intraluminal thrombosi41.Differential effects of intracoronary alcohol injection on coronary vessels or myocardial tissue have been previously described42. According to studies on reperfused infarction in sheep, it would seem that the mid-myocardium is more vulnerable to ischemic injury whereas the sub-endocardium is relatively resistant43.If severe ischemia lasts more than 20- to 30-min, cardiomyocytes in the subendocardial area undergo irreversible changes ranging from sarcolemmal disruption to striking perturbations in mitochondrial architecture; typical mitochondrial ultrastructural alterations are represented by amorphous matrix densities and severe swelling. All cardiomyocytes showing these ultrastructural alterations cannot be rescued and they will constitute the infarct environment after death; indicating that the mitochondria were broken and unable to provide any energetic supply for cell survival44.Accordingly, we found thrombi in ischemic tissue and coagulative necrosis at an early stage. Optical microscopy revealed that the full myocardial thickness was involved in the ischemic process, with muscular fibres appearing to be hyper-contracted, while nuclei were still present because animals were sacrificed before their disappearance (18–24 h). Electron microscopic analysis revealed that the mitochondrial network was disorganized, mitochondria swollen, and the inner membrane folding completely altered45. As ischemia progresses (less than 15 min), the myocardium turns into stunning and is not forthwith responsive to reperfusion46. Whenever injury continues, myocytes death leads to infarction47. Several clinical and experimental observations49 suggest that CS complicating myocardial infarction is accompanied by extensive myocardial injury and that at least 40% of left ventricular volume should be ischemic to induce CS. Nevertheless, in the clinical scenario, a severe degree of myocardial insult is not always necessary to cause CS45.The fall in coronary blood flow is immediately followed by myocardial ischemia, which implies myocardial anaerobic metabolism, fast ATP depletion, and metabolic waste amassing; the myocardial mechanism is severely altered and results in harsh systolic and diastolic dysfunction, and the ischemic muscle stretches instead of shortens during systole46. Moreover, previous studies showed that hemodynamic variables become abnormal when the area at risk is larger than 25%50 or the infarct size is between 12 and 13%28 : nevertheless, all findings found in SHOCK animals are pathognomonic of infarcted cardiac tissue and not present in controls.Very few specimens have been used for microscopy investigation: one 25: our model exposes myocardial tissue to a rapid sequence of ischemia–reperfusion phases when the balloon catheter is progressively pulled from the distal to the final proximal site of ethyl alcohol injection. Nevertheless, the intracoronary thrombosis remains irreversible.The use of an ischemia–reperfusion model is usually suggested in order to explore potential strategies prompting a reduction of acute myocardial infarct size11; nevertheless, almost all animal models are confronted with this limitation.We used healthy animals, whereas human patients with acute ischemic heart failure belong a population exhibiting several risk factors, such as diabetes, hypertension, and atherosclerosis8. The main reason of our choice to limit the study period is practical. The preparation of the experimental setting and CS induction took approximately 4–5 h. Consequently, an observation time of only three consecutive hours was compatible with operatory room organization.Lastly, the observation time was limited to three consecutive hours. This study period may appear to be short but it is similar to those proposed by other authorNo model is devoid of flaws.52. In such a specific context, our experimental set-up could lead to a better understanding of mechanical interaction between short-term mechanical circulatory support or LVAD and an acutely failing ventricle, thus allowing a precise tuning of flow and pressure generated by an assist device. The potential usefulness or harmfulness of vasoactive and inotropic drugs  in patients assisted with those devices might also be explored in this model. Moreover, the impact of ventricular support on early remodelling of non-ischemic territory could be more fully investigated, as well as the time-course evolution of the AAR in cases where it is not possible to reperfuse: while LV mechanical unloading prior to coronary revascularization may theoretically reduce infarct size by reducing the AAR10, no experimental investigation has been undertaken in the case of permanent coronary occlusion.As previously outlined, few large animal models of consistent and stable refractory cardiogenic shock are available for research purpose to-date, and the previously established models do not completely mimic the clinical scenario of CS induced by selective coronary occlusion. In our experimental model, we do not use coronary hypoxemia or hypercarbia thus minimizing the hibernating myocardial condition, and we are able to obtain homogeneous trans-mural myocardial damage without jeopardizing cellular death in a precise coronary artery territory. Furthermore, permanent coronary occlusion mimics the clinical situation of patients enduring acute myocardial without timely or successful reperfusion because of contraindications or logistic issuesWe described and exhaustively characterized a unique, reproductible, homogenous and stable sheep model of CS obtained by percutaneous intracoronary ethanol administration. This technique grants trans-mural infarct formation with a clinical profile close to the human one. We think that our model may be appropriate to better understand the mechanical interaction between short-term mechanical circulatory support and/or LVAD and an acutely failing ventricle, the impact of ventricular support on early remodelling of non-ischemic territory, as well as the time-course evolution of AAR in the case of impossible reperfusion.Supplementary information


Reentrant cardiac arrhythmias such as atrial fibrillation (AF) and ventricular fibrillation (VF) are common cardiac arrhythmias that account for substantial morbidity and mortality throughout the world. However, the mechanisms and optimal ablation treatment strategies for such arrhythmias are still unclear. Using 2D optical mapping of a mouse model with AF and VF, we have identified regional heterogeneity of the action potential duration (APD) in the atria and ventricles of the heart as key drivers for the initiation and persistence of reentry. The purpose of this paper is to discuss theoretical patterns of dispersion, demonstrate patterns of dispersion seen in our mouse model and discuss the computational analysis of APD dispersion patterns. These analyses and discussions may lead to better understanding of dispersion patterns in patients with these arrhythmias, as well as help comprehend whether and how reducing dispersion can lead to arrhythmia risk stratification and treatment strategies for arrhythmias. Complex reentrant cardiac arrhythmias such as atrial fibrillation (AF), and ventricular fibrillation (VF) are prevalent clinical cardiac diseases affecting millions of people around the world. AF may result in clot formation in the atria of the heart leading to stroke, and when uncontrolled, may lead to heart failure. AF has also been found to be an independent risk factor for cognitive decline and dementia . The mecIt is thought that the mechanism of AF reentry in the atria of the heart also occurs in the ventricles, deteriorating into VF . VF accoReentry refers to the persisting activation sequence of a wavefront that repeatedly propagates around an anatomic or functional region, referred to as a core . The subIncreased temporal dispersion of excitation recovery in the heart has previously been established to enhance the development of complex reentry, namely fibrillation and nonuniform recovery of excitability. This further emphasizes the role of nonuniformity of excitability and conduction velocity during the relative refractory period in the initiation of turbulent impulse propagation . DispersThe refractory period is the interval from depolarization to the recovery of excitability , 12. ActIn this paper, we will present APD dispersion data from a mouse model of atrial and ventricular fibrillation. This double transgenic (TG) mouse model of tetracycline inducible, cardiac-specific overexpression of F1759A SCN5A, initially created to study long QT3, spontaneously develops sustained atrial and ventricular fibrillation, secondary to late persistent sodium current . DispersWe propose in this paper several patterns of APD dispersion that may be theoretically observed .Uniform dispersion: areas of dispersion that are evenly spaced over a spatial region of the tissue. This pattern can be observed in genetically modified expression systems, where selected areas have higher dispersion, such as in monolayers with adenovirus inoculation allowing for channelrhodopsin light activation.Random dispersion: areas of dispersion that have unpredictable distribution. A given area of dispersion is equally likely to occur at any location. There is no cell specific regulation causing dispersion evident in that area, which can occur with either relatively low sodium channel expression or little fibrosis or scar. This can even be present for example, in young mice with a structurally normal heart and little to no fibrosis.Clustered dispersion: areas of dispersion that are clumped into groups, causing a patchy distribution or islands of areas of dispersion, especially near the anatomic borders, for example, post-myocardial infarction with dispersion along border zones.V1.5, was generated as previously described .Group data are presented as mean ± standard error of the mean (SEM). Statistical comparisons between the groups were tested using a one sample We performed 2D epicardial surface voltage optical mapping on the atria and ventricles of Langendorff perfused TG mice , 3. Surp+ current, in which we had previously shown homogenous atrial APD maps  and did not exhibit any dispersion, as seen on Representative images from 3 TG AF mice mapped after hyperkalemic induced sinus conversion and 10 Hz pacing are displayed in APD maps . We obseAPD maps  that theAPD maps . The ave+ current, that had completely homogenous ventricular APD maps  and did not show any dispersion , inward potassium current (IK1) and transient outward potassium current (Ito). Alterations in ICa, Ito and IK1 can be modulated by intracellular decreased ATP and pH or decreased calcium, all of which are metabolic fluctuations observed in ischemia  or magnetic resonance imaging (MRI) with deep learning algorithms. The purpose of this integration would be to study the effects of structural changes such as fibrosis and hypertrophy on arrhythmogenesis. These measurements can be derived through myocardial wall thickness measurements from the reconstructed CT, while MRI scans can give us access to complementary information like fibrosis and myocardial fiber orientation. Merging the spatial information from different imaging modalities may allow for a more in-depth three-dimensional characterization of the arrhythmogenic substrate. Visualizing how anatomical markers correlate with arrhythmia mechanisms and translating this information clinically would result in improved understanding of disease progression. Consequently, interactions and inter-dependence of functional and structural measurements through the fusion of multi-imaging modalities may lead to better arrhythmia risk stratification performance.in vivo model with known spontaneous and sustained atrial and ventricular arrhythmias, and exhibits structural and functional changes similar to what is observed in human patients with these clinical arrhythmias. Future investigation will include additional pacing experiments in this murine model to confirm that tissues with areas of high APD dispersion have a high likelihood of inducible reentrant arrhythmias. Further studies evaluating the arrhythmia risk stratification performance of the APD dispersion computational analysis approach presented herein may provide further insight into how to study, prevent and treat patients.Finally, our study is limited by the usage of a single mouse model but it is an Analysis and discussion of APD dispersion patterns, which may be a leading cause of cardiac arrhythmogenesis, may be helpful to improve computational modeling and justify further studies to characterize and quantify APD dispersion for risk stratification of atrial and ventricular arrhythmias. Further comprehension of dispersion patterns may lead to better understanding of whether and how reduction of APD dispersion may lead to new treatment strategies for patients with arrhythmias.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by The Institutional Animal Care and Use Committee at Columbia University.UA and EW designed the study, performed experiments, and collected and analyzed the data. UA, LM, JK, SL, and EW wrote the manuscript. UA and LM were involved in generating the figures. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past collaboration with the author EW.


Atrial fibrillation (AF) is frequent in shock patients admitted to the intensive care unit (ICU) , 2 and iPharmacological options to control AF-related tachycardia are limited. Calcium channel blockers are not frequently used because of long-term negative inotropic effects. Amiodarone is the most used drug but its optimal dosage to fine tune heart rate remains an issue, as well as its potential lung toxicity, especially in case of acute respiratory disease. Landiolol is a beta-blocker with highly β1 selective activity, used either in AF patients either to control heart rate or to prevent supraventricular arrhythmia occurrence in the context of cardiac surgery. Landiolol has an ultrashort half-life of 4 min and weaker negative inotropic effect compared with other intravenous β-blockers .Here, we described in critically ill patients admitted to the ICU for SARS-CoV-2 infections presenting with AF, our experience of Landiolol use in terms of efficacy and safety.In our 18-bed intensive care unit, we prospectively collected data from adult patients admitted for SARS-CoV-2 infections with persistent AF. When heart rate was over 120 bpm, Landiolol was started at a minimum dose of 0.2 µg/kg/min and progressively increased by steps of 0.2–0.4 µg/kg/min every hour to achieve 20% reduction in heart rate, without bolus. Hemodynamic parameters were recorded every 2 h during the first 24 h of drug infusion.p < 0.01, Wilcoxon signed-rank test), without any negative impact on global hemodynamic or tissue perfusion parameters   had a history of chronic AF, and the other had recent AF resistant to electric cardioversion. Median left ventricular (LV) function was 55% [50–57] (Table In this observational uncontrolled study, Landiolol was safely used to lower heart rate in critically ill patients with AF with normal or moderately altered cardiac function. Given that most patients under mechanical ventilation for SARS-CoV-2 infections received norepinephrine and that some of them had moderate left ventricular systolic function, Landiolol infusion was started at very low doses and maximal infusion rate at 24 h was lower than reported in studies on non-critically ill patients . Using t


The composite cement sample  had higher ultimate force as the bone-cement sample . There were no significant differences between composite samples with 24 hours  and 6 weeks polymerization periods . The composite cement samples with drill hole  were weaker than those without it . This study shows that the bond between the old and new cement was stronger than the bond between cement and bone. This suggests that it is better to leave the cement that is not loosened from the bone and perform cement in cement revision, than compromising bone stock by removal of the old cement with the resulting weaker cement-bone interface. The results support performing cement-in-cement revision arthroplasty The drill holes in the old cement mantle decrease cement binding strength and are not recommended in this type of surgery.This study compares the strength of the native bone-cement bond and the old-new cement bond under cyclic loading, using third generation cementing technique, rasping and contamination of the surface of the old cement with biological tissue. The possible advantages of additional drilling of the cement surface is also taken into account. Femoral heads from 21 patients who underwent a total hip arthroplasty performed for hip arthritis were used to prepare bone-cement samples. The following groups of samples were prepared. A bone—cement sample and a composite sample of a 6 weeks old cement part attached to new cement were tested 24 hours after preparation to avoid bone decay. Additionally, a uniform cement sample was prepared as control (6 weeks polymerization time) and 2 groups of cement-cement samples with and without anchoring drill hole on its surface, where the old cement polymerized for 6 weeks before preparing composite samples and then another 6 weeks after preparation. The uniaxial cyclic tension-compression tests were carried out using the Zwick-Roell Z020 testing machine. The uniform cement sample had the highest ultimate force of all specimens ( The cement-in-cement revision hip arthroplasty is a well-established method of revising cemented femoral stems –6. It isThe advantages of cement-in-cement revisions include shorter operative time, smaller blood loss and lower risk of intraoperative femur fractures , 15, 18.Several biomechanical studies in the past have been performed to analyze the bond between the old and the new cement , 23 in cUntil now, only one biomechanical study investigates a relative strength of the cement-in-cement and bone-cement interface. It concluded that the bone-cement bond after revision with the old cement removal is weaker than the old-new cement interface, thus favoring cement-in-cement revisions . AnotherThe aim of this study is to compare the strength of the native bone-cement bond and the old-new cement bond under cyclic loading, using third generation cementing technique, rasping of the surface, as well as the contamination of the surface of the old cement with subsequent clearing. The possible advantages of additional drilling of the cement surface was also taken into account.Femoral heads were retrieved from 21 consecutive patients  who underwent a standard total hip arthroplasty performed for hip arthritis between 1. March and 21. December 2018 in the Department of Orthopedic Surgery, Medical University of Gdansk, Poland. Mean age was 68 years old . The femoral head retrieval did not affect decision making in their treatment and did not change the course of the surgical procedure. All patients gave their informed written consent to participate in the study. Patients with suspected metastatic neoplasms, femoral neck fractures, rheumatoid arthritis or any other condition that could affect bone quality were excluded from the study. This study was approved by the Independent Bioethics Committee at the Medical University of Gdansk, Poland .The Biomet Plus Bone Cement was used . It was prepared with third generation cementing technique, using the Zimmer Biomet Compact Vacuum Cement Mixing System. For all samples, the cement was attached under pressure and kept pressurized for 10 minutes as the operative technique requires.The femoral heads were cut fresh to form cylinders of 3 cm of side length and 18 mm in diameter. On average, two samples were retrieved from every femoral head. The side that was cut from the subchondral bone from the center of the head was then marked, to make sure that every cement block was attached to the same part of femoral head subchondral bone. The bone samples were then frozen and stored for future examination.The bone samples were then defrosted to room temperature and cleared from marrow with a standard pulsatile jet lavage. Next, the bone samples were embedded in methylmethacrylate to allow proper clamping by grips of the testing machine .3 injection syringes as forms for the cement. This preparation was performed by the same investigator (MC) in every case with the attempt to apply similar pressure to every sample. After preparation the samples were stored in cool in a refrigerator (4°C) to avoid bone decay before testing. The samples were tested in the testing machine 24 hours after preparation , a hole 2 mm in diameter and 2 mm deep was drilled to allow better cement attachment by increasing of the contact area  were tested within 24 hours from preparation to ensure similar polymerization time of the new cement to the bone—cement samples. The remaining composite samples were left for another 6 weeks to allow cement polymerization.A group of samples without the drill hole (d = 10 mm (radius r = 5 mm), therefore the contact surface S1 in composite samples was S1 = πr2 = 3.14 x 52= 78.54 mm2.The diameter of the cement samples was d = 2 mm in diameter (r = 1 mm) and 2 mm in depth (h = 2 mm). The increased contact surface S2 was the outer surface of a cylinder.The drill hole was S3 of the drilled samples was S3= S1+ S2= 78.54 mm2+ 12.57 mm2= 91.11mm2.The total contact surface x = 16% (x = S2/S1·100%). However, the contact surface of this sample became three-dimensional and calculation of the surface just including its increase by the hole may be an oversimplification. The surface of the cancellous bone, as well as the cement surface that is roughened with a rasp, is also three-dimensional, but microscopically. Therefore, the contact surface of the composite sample parts should be considered to be plain, disregarding any surface irregularities in calculations, and the drilling of a hole should be treated as surface preparation similar as roughening of the cement surface with a rasp.The estimated increase of contact surface for the drilled versus undrilled samples was approximately The samples were tested at the Zwick Roell Z020 uniaxial testing machine Figs  and 5.The testing protocol was the fully reversed cyclic loading test—with increasing amplitude that included subsequent compression and tension phases . The prep = 0.01). The ANOVA test was used for comparisons between groups. The T-Student test was used to individually compare between groups with normal distribution. For the individual comparisons that included the composite samples with 24 hours polymerization time the Mann-Whitney U test was used. Significance level was p < 0.05.The statistical evaluation was performed using Statistica 13.3 software. The Kolomgorov-Smirnoff test was used to assess the normal distribution. All samples results were normally distributed except for strength results for composite samples with 24 h polymerization time . There were no significant differences between the composite samples that polymerized for 24 hours before testing and those that polymerized for 6 weeks .The composite cement samples with 24 hour polymerization time were significantly stronger than bone-cement samples, as seen in p < 0.001). All differences in these groups were significant in ANOVA test (p < 0.001). The composite cement samples with drill hole on its surface were weaker than those without it (T-Student test p = 0.046).When comparing samples that polymerized for 6 weeks, the uniform cement sample was obviously the strongest of all specimens when comparing individually those samples and both types of composite samples, as seen in This study was designed to overcome some technical aspects that were criticized in previous studies. The bone samples were prepared as the third generation cementing technique requires: the bones were cleared with pulsatile lavage, the cement was prepared with an original vacuum system, applied under pressure and kept pressurized for 10 minutes. A long period of cement polymerization was ensured , 23, conThere are some limitations to this study. Shear forces more closely resemble forces found in femoral or humeral stem revision. In this study, for technical simplicity in manufacturing and for good reproducibility of the samples, the samples were constructed for tensile-compression strength testing only , 25, 31.In this study, cyclic loading was performed, what much better represents in vivo forces , 27. CycThe uniform cement samples fractured near the grips where the stress occurs concentration because of clamping, but the all the composite samples fractured at the connection interface, therefore these results of the study can be considered not confounded by the influence of the testing machine. The results shows the cement-cement bond, although much weaker than the uniform cement, is stronger than the bone-cement bond, assuming that old cement has mechanical and chemical properties similar to the new one . AlthougOverall, in all composite samples the strength of the connection is variable. The large differences between samples shows that the binding strength of the bone-cement and cement-cement interface may have significant local differences in actual revision arthroplasty .The comparison of the results of this study with previous biomechanical studies is limited because significant differences in preparation of the samples and testing protocol.A study by Dohmae et al. showed that the shear strength of bone-cement interface is reduced to 20.6% when the original cement mantle is removed and new cement is applied to the previously cemented femoral canal in first revision arthroplasty, and to only 6.8% in the second revision. This suggests that the original cement mantle, when not loose from the bone, may probably be still much stronger than any subsequent cementing of bone that is cleared of the original cement mantle. Unfortunately this study did not investigate the bond between old and new cement mantle, as the current study does.A study of bone-cement interface used similar samples and tensile forces to test them . The diaRosenstein et al.  performeIn Rosenstein et al., the “old” cement was tested after only 90 minutes, what is considered insufficient At least 24 hours of polymerization time of the cement is recommended before testing, since although initial polymerization and hardening of the cement occurs within 10 minutes after mixing of the components, but it continues for a much longer period of time [Li et al.  did not In the current study, the strength of composite specimens showed a reduction of 72% (specimens without hole) and 84% (specimens with hole) of that of the uniform cement mantle. The reduction in strength of specimens without a hole was less than reported by Li et al. , most liThis study supports cement-in-cement revision arthroplasty. It should be concluded that it is better to leave the cement that is not loosened from the bone and perform cement in cement revision, than compromising bone stock by removal of the old cement. The bond between the old and new cement will still be stronger than the bond between cement and bone, and therefore it is theoretically less likely for loosening to occur at the cement-cement rather than on the bone-cement interface. The drill holes weaken the cement-cement connection, most likely because they collect fluid that cannot be reliably removed from it during surgery and which limit the binding of the new cement to the old one. Therefore drill holes in the old cement mantle are not recommended in this type of surgery.S1 File(XLSX)Click here for additional data file.


There is a high prevalence of left ventricular diastolic dysfunction (LVDD) in systemic sclerosis (SSc) which is associated with high mortality. Thus, early detection of LVDD could be important in management of SSc. We hypothesised that exercise echocardiography in SSc patients with normal resting haemodynamics may expose early phase LVDD, which could affect its prognosis, defined as cardiovascular death and unplanned hospitalisation for heart failure.Between January 2014 and December 2018, we prospectively enrolled 140 patients with SSc who underwent 6-minute walk (6MW) stress echocardiographic studies with normal range of estimated mean pulmonary arterial pressure (mPAP) (<25 mm Hg) and mean pulmonary artery wedge pressure (mPAWP) (<15 mm Hg) at rest. We used ΔmPAP/Δcardiac output (CO) to assess pulmonary vascular reserve and ΔmPAWP/ΔCO to assess LV cardiac reserve between resting and post-6MW.During a median period of 3.6 years (IQR 2.0–5.1 years), 25 patients (18%) reached the composite outcome. Both ΔmPAP/ΔCO and ΔmPAWP/ΔCO in patients with events were significantly greater than in those without events . Patients with both impaired LV cardiac reserve (ΔmPAWP/ΔCO>1.4 mm Hg/L/min) and impaired pulmonary vascular reserve (ΔmPAP/ΔCO>3.0 mm Hg/L/min) had worse outcomes compared with those without these abnormalities (p<0.001).The 6MW stress echocardiography revealed impaired LV cardiac reserve in SSc patients with normal resting haemodynamics. Furthermore, LV cardiac reserve independently associates with clinical worsening in SSc, providing incremental prognostic utility, in addition to pulmonary vascular parameters. The myocardial involvement of systemic sclerosis (SSc) clinically causes cardiac dysfunction, especially left ventricular diastolic dysfunction (LVDD). Several studies have shown that LVDD in SSc is highly prevalent and is associated with increased risk of clinical worsening. In addition, LVDD may occur before clinical manifestation.ΔmPAP/ΔCO and ΔmPAWP/ΔCO in the event group were significantly increased compared with the non-event group.Impaired LV cardiac reserve and pulmonary vascular reserve were independent predictors of clinical worsening in SSc.Exercise echocardiography may reveal an early stage of LVDD, despite showing normal resting filling pressure.These results indicate that 6-minute stress echocardiographic study may predict a high-risk group of patients with SSc.Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterised by fibrosis of the skin and internal organs, and vasculopathy.Recently, it has been demonstrated that exercise echocardiography may evaluate an early stage of LVDD, despite showing normal resting filling pressure.Individual anonymised data supporting the analyses contained in the manuscript will be made available on reasonable written request from researchers whose proposed use of the data for a specific purpose has been approved.Patients or the public were not involved in the design, or conduct, reporting or dissemination plans of our research.We prospectively enrolled consecutive patients with SSc who underwent 6MW stress echocardiographic studies and had normal range of estimated mean pulmonary arterial pressure (mPAP) (<25 mm Hg) and normal range of estimated mPAWP (<15 mm Hg) at rest. Patients were referred to our echocardiographic examination centre between January 2014 and December 2018. Definitions of SSc were based on the American College of Rheumatology diagnostic criteria.Transthoracic echocardiography was performed by experienced sonographers/doctors using a commercially available ultrasound machine . Measurements and recordings were obtained according to the American Society of Echocardiography recommendations.Peak systolic longitudinal strain measurements were obtained from greyscale images recorded in the apical 4-chamber, 2-chamber and long-axis views. The frame rate was maintained at >40 frame/s. All strains were analysed offline using speckle tracking vender-independent software . Global longitudinal strain (GLS) was obtained by averaging all segmental strain values from the apical 4-chamber, 2-chamber and long-axis views. In RV longitudinal strain analysis from the RV focused apical 4-chamber view, the interventricular septum was included in the region-of-interest for speckle-tracking echocardiography, but only the free wall strain values were included and the septal strain values were discarded to avoid LV interaction. GLS and RV longitudinal strain were obtained at rest.10.1136/openhrt-2020-001559.supp1Supplementary videoIn 14 patients, exercise right heart catheterisation was performed using a Swan-Ganz catheter to assess the actual haemodynamics. Pressure measurements were obtained at rest and during supine bicycle ergometery. The workload was increased at 25 W increments every 3 min. Average peak workload was 50 W in our cohort. The following haemodynamic parameters were recorded at the peak workload: PAWP, mPAP and CO. Thermodilution CO were analysed after averaging the sum of three measurements at rest and during exercise.All patients were followed up at our hospital according to the research protocol (follow-up every 3 months). The composite outcome was time to clinical worsening, which was determined on the basis of time from baseline to the first occurrence of any of the following: cardiovascular death or unplanned hospitalisation for heart failure. Unplanned hospitalisation for heart failure was defined by an independent adjudicator as an overnight admission for heart failure (excluding emergency department only stays) which was not for an elective purpose or procedure. The duration of follow-up was begun at the time of the initial stress echocardiogram and ended in December 2019. The 6MW stress echocardiographic data were blinded to physicians at follow-up clinic after study initiation.Data are presented as mean±SD. Statistical significance of differences between the groups was assessed using the Student’s t-test for data with normal distribution, and the Mann-Whitney U test was used for data that were not normally distributed. For categorical variables, the Fisher’s exact test was used. The association of clinical variables with outcome was identified by Cox proportional hazards models in univariate and multivariate analyses. A HR with a 95% CI was calculated for each variable. The scaled Schoenfeld residuals for each independent variable were plotted against time to assess the assumption of proportional hazards; these correlations were found to be non-significant. Receiver operating characteristic (ROC) curves were generated to determine optimal cut-off values of continuous variables. The best cut-off value was defined as the upper limit of the CI of the Youden index. To assess prognostic value, reference values of ΔmPAP/ΔCO (3.0 mm Hg/L/min based on our previous paper)Baseline characteristics of the study group are presented in 10.1136/openhrt-2020-001559.supp2Supplementary data10.1136/openhrt-2020-001559.supp3Supplementary dataDuring a median period of 3.6 years (IQR 2.0–5.1 years), 25 patients (18%) reached the composite outcome . HRs of the relevant parameters in univariate models are shown in In the multivariate model, ΔmPAP/ΔCO, ΔmPAWP/ΔCO and their interaction were selected to test the clinical utility of these variables . InteresOur study brings several new insights into the understanding of cardiac and pulmonary functions in patients with SSc: (1) The ΔmPAP/ΔCO and ΔmPAWP/ΔCO in the event group was significantly increased compared with that of the non-event group. (2) Impaired LV cardiac reserve and PV reserve were independent predictors of clinical worsening. (3) There was good correlation between echocardiography-based parameters after 6MW testing and catheter-based parameters during ergometer stress. We believe that the reliability of the 6MW stress echocardiography is acceptable in this cohort. Those results indicated that a 6MW stress echocardiographic study may predict a high-risk group in patients with SSc, even within 3 months after diagnosis. The invasive measurements were made during peak exercise load during ergometric testing, a good correlation may be helpful to convince those who are concerned about the reliability of the 6MW echo test, where measurements are performed after the exercise.Recently, there has been focused discussion on the importance of LVDD in SSc. Previous studies demonstrated that LVDD has a high prevalence and may be an independent predictor of mortality in SSc.The balance of PAWP and CO is key to evaluate LVDD. As long as the Frank-Starling mechanism functions effectively, CO increases after dynamic preload stress; however, it does not apply to patients with severely impaired LV relaxation, which results in only slightly increased CO on significantly elevated PAWP.PH is a severe complication of SSc, and currently early detection and management of PAH is recommended.In our analysis, although most of the resting echocardiographic measurements, including GLS and RVLS, did not have predictive values in SSc, the value of 6MW stress echocardiography related to clinical worsening in both LV cardiac reserve (ΔmPAWP/ΔCO) and PV reserve (ΔmPAP/ΔCO). Importantly, CO change was a more prominent factor associated with adverse outcomes in univariate analysis. CO is a key diagnostic parameter and a major prognostic factor in PAH. We should take CO into account when we assess pulmonary artery pressure. In the setting of impaired PV reserve, 6MW stress echocardiography revealed that SSc patients with LVDD had worse prognoses than those without LVDD, consistent with previous studies. Interestingly, in the setting of normal PV reserve, SSc patients with LVDD had worse prognosis than those without LVDD. These results indicate that impaired LV cardiac reserve in SSc, enhanced by 6MW stress echocardiography, can be an independent prognostic factor prior to development of complications, including PH, or treatment, since our cohort was examined at an initial naïve state. Therefore, it is essential to assess LV function as soon as SSc is diagnosed.It is clinically important to monitor high-risk patients and treat those who show an abnormal pulmonary arterial bed. This is a single centre study that included a selected patient population. The data are a little limited by a large number of patients early in the study without useable echocardiographic data.Impairments in both the PV and the LV reserve assessed by 6MW stress echocardiography were associated with significant increase in the risk of the composite event . Thus, 6MW stress echocardiography can be applied to treat naïve patients with SSc.


The impact of heart failure (HF) on perceived and objectively measured levels of physical activity (PA) can inform risk stratification and treatment recommendation. We aimed to compare self-reported and objectively measured PA levels in a large sample of participants with and without HF.A validated PA questionnaire was used to estimate self-reported weekly PA among 1600 participants with HF and 387 580 participants without HF. Accelerometer data were studied in 596 participants with HF and 96 105 participants without HF for a period of 7 days. Using multivariable linear regression models, we compared the PA levels between participants with HF and without HF, focusing on both the average daily PA levels and the intensity of PAs throughout the day.PA levels were significantly lower in participants with HF using both self-report  vs 34.7 (95% CI 34.5 to 34.9), respectively (p<0.001)) and accelerometer measures (mean accelerations of 23.7 milligravity (95% CI 23.1 to 24.4) vs 28.1 milligravity (95% CI 28.0 to 28.1), respectively (p<0.001)). Findings were consistent across different PA intensities. Hour-by-hour comparisons showed that accelerometer-derived PA levels of patients with HF were reduced throughout the day.Perceived and objectively recorded PA levels of patients with chronic HF are significantly lower than those of individuals without HF. This difference is continuous throughout the different hours of the day, with individuals with HF being on average 16% less active than individuals without HF. In patients with HF, increases in everyday activity may be a potential alternative to structured exercise programmes. Reduced levels of physical activity (PA) in heart failure (HF) patients have been associated with more severe levels of breathlessness and an increased risk of long-term mortality, however rlittle is known about PA levels of HF patients throughout the day and in comparison with non-HF individuals.In this study, we compare self-reported and accelerometer-derived PA levels in a large group of individuals with and without HF and show that both perceived and objectively recorded PA levels of patients with chronic HF are significantly lower than those of individuals without HF. In our study, accelerometer-derived measures revealed that PA levels of patients with HF are significantly reduced throughout the day.This research allows clinical staff to gain a better understanding of the impact of HF on patients’ day-to-day life. We show that both patients self-reported (perceived) and accelerometer-derived (objective) PA is significantly lower than in participants without HF when adjusting for age and sex. Furthermore, through the added detail provided by accelerometer recordings, we show that PA levels of patients with HF are significantly attenuated throughout the entire day with the exception of night hours, suggesting that HF affects the ability of patients to conduct even basic everyday PA. The latter may also suggest that increases in the activeness during everyday activities may be a potential alternative to a structured physical exercise regimen. Such interventions may be of particular benefit to patients who express concern about potential adverse effects of physical exercise.In patients with heart failure (HF), increases in levels of physical activity (PA) improve quality of lifeFactors influencing the adherence to recommended PA guidelines in HF include fluctuating health and patients’ external and internal motivations.While exercise intolerance is a well-studied symptom of HF, levels of everyday PA are less well understood.This study set out to compare PA behaviour of people with and without HF using both self-reported (perceived) and accelerometer-derived (objective) measures and to investigate objectively recorded PA levels of patients with HF throughout the day.This research has been conducted using the UK Biobank ResourceInformation about health-related outcomes (before and after the baseline assessment) were obtained through linkage of the UK Biobank with data from the Office for National Statistics for death and emigration information and the Department of Health’s Hospital Episode Statistics for hospital-admission diagnoses (up until March 2015 for English residents that were either NHS-funded or NHS-treated).Baseline assessment included information on self-reported PA measured through an adapted version of the International PA questionnaire (IPAQ)et alSelf-reported PA data were processed using the method described by Bradbury Accelerometer data were collected for a subset of approximately 100 000 participants between May 2013 and 2015.et al.The raw accelerometer data were calibratedWe defined prevalent HF as any primary or secondary discharge diagnosis of HF as indicated by the following codes: ICD10 code 'I500', 'I501' or 'I509' and ICD9 code ‘4280’ or ‘4281’ prior to the assessment of PA. Given that accelerometer data were collected after questionnaire-based PA assessment and were restricted to a subsample of the total cohort, we had two partially overlapping HF populations .Age was defined as age at the time of each PA measurement. All other covariates were based on data collected at baseline. Smoking and alcohol status were divided into never, previous or current. Social deprivation was determined using the Townsend Deprivation Index, which is an area-of-residence-based social deprivation index.We used multivariable linear regression to compare the mean PA between participants with HF and without HF. Analyses were carried out separately for self-reported and accelerometer-derived PA levels. Primary analyses were adjusted for age and sex. Secondary analyses were additionally adjusted for ethnicity, baseline Body Mass Index (BMI), alcohol status, smoking status and socioeconomic status. We performed two sensitivity analyses to test the impact of timing of HF diagnosis and PA assessment on the observed outcomes. In the first sensitivity analysis, we restricted comparisons to participants who had HF at baseline (ignoring any participants with incident HF report between baseline assessment and accelerometer data collection) to ensure that any observed differences between self-reported and objectively assessed PA levels were not due to a change in population classification over time. In a second sensitivity analysis, we investigated the impact of time since diagnosis of HF on any observed differences in PA levels between HF and non-HF participants. Given that both time since incident diagnosis of HF and time since last admission to hospital with HF could impact PA levels, we selected three time intervals as alternative explanatory variables: time since first report of HF, time since last report of HF hospitalisation where HF was the primary discharge diagnosis and time since last report of HF hospitalisation where HF was the primary or secondary discharge diagnosis. All analyses were done in R.Out of a total of 502 602 UK Biobank participants, 389 180 provided valid self-reported PA information at baseline. This included 1600 participants with previously diagnosed HF. Accelerometer-based PA data of sufficient quality  were collected for 96 701 UK Biobank participants between 2013 and 2015, of whom 596 had an HF diagnosis prior to the recording. A subset of these participants (n=244) had HF at baseline; others were diagnosed with HF between the baseline assessment and the recording of accelerometer data. Out of the total of 80 121 with self-reported PA data at baseline and a valid accelerometer recording (overlapping group), 190 had a diagnosis of HF at baseline see .Characteristics of participants in the three subpopulations  by HF status are presented in The mean age/sex-adjusted self-reported PA level per week was 26.5 (95% CI 24.7 to 28.4) MET-hours per week for participants with diagnosed HF vs 34.7 (95% CI 34.5 to 34.9) MET-hours per week for participants without any prior diagnosis of HF (p<0.01) see . The resDuring the assessment, participants with diagnosed HF wore their accelerometers for a median of 6.9 . Participants without HF wore the devices for an average of 6.9 (6.7 and 7.0) days. The mean acceleration values were significantly higher in participants without HF than those with HF (28.1 (95% CI 28.0 to 28.1) milligravity vs 23.7 (95% CI 23.1 to 24.4) milligravity, respectively; p<0.001) . This reThe age/sex-adjusted analysis of the percentage time spent within certain PA intensities showed that patients with HF spent a larger proportion of time sedentary and less time in light, moderate and vigorous PAs . The anaMedian times since first HF-related hospitalisation were 3.6 (95% CI 1.6 to 6.1) years for the self-reported analysis and 4.2 (95% CI 2.0 to 8.2) years for the accelerometer analysis. Median times since last hospitalisation were 2.9 (95% CI 1.2 to 5.5) years and 3.3 (95% CI 1.3 to 6.9) years, respectively. The time since first report of HF or since last HF-related hospitalisation did not have a significant impact on the mean acceleration values measured . The res10.1136/openhrt-2019-001099.supp1Supplementary dataOur analysis of PA levels in the UK Biobank population showed that both perceived and objectively measured PA levels of patients with HF were significantly reduced in comparison with people without HF.The accelerometer-derived PA comparison showed that individuals with HF were on average 16% less physically active than individuals without a prior diagnosis of HF. This is in agreement with, although slightly lower than, previous findings from small-scale studies, which suggested that patients with HF are 44%–65% less physically active (based on step counts/movement-related activity) than individuals without HF.Past studies have shown that self-reported PA levels are low to moderately correlated with objectively recorded PA levelset al,PA levels of patients with HF within this cohort were not significantly affected by time after diagnosis of HF. These results contrast with findings by Miura Limitations of this study include its cross-sectional nature and the fact that both the self-reported and accelerometer data provided by the UK Biobank might be affected by selection bias, resulting in a healthier than normal study population represented in this analysis.In summary, our results show that perceived and objectively recorded PA levels of patients with chronic HF are significantly lower than those of individuals without HF. This difference is continuous throughout the different hours of the day and suggests that increases in everyday activity may be a potential alternative to structured exercise programmes.


Despite three decades of study, it is still challenging to discriminate acute apical variant stress cardiomyopathy (AVSCM) from acute left anterior descending‐myocardial infarction (LAD‐MI) at the time of presentation. A biomarker or practical imaging modality that can differentiate these two entities is highly desirable. Our objective was to characterize left ventricular (LV) mechanical deformation using 2‐dimensional (2D) echocardiographic strain imaging in an attempt to discriminate AVSCM from LAD‐MI at presentation.P ≤ .05). Mean LS of the basal inferior and inferolateral segments was significantly higher in the LAD‐MI vs. AVSCM group . Using ROC curve analysis, segmental strain ratio of average basal inferior and inferolateral segments LS to average mid‐ and basal anterior and anteroseptum segments LS of ≥1.58 was 90% specific for LAD‐MI .We studied 108 women . All underwent echocardiography within 48 hours of presentation. 2D longitudinal strain (LS) from an 18‐segment LV model was performed, with global LS (GLS) taken as the average of all 18 segments. GLS was abnormal, but did not differentiate AVSCM from LAD‐MI. Mean LS of the basal and mid‐anterior, basal, and mid‐anteroseptum segments were significantly lower in LAD‐MI vs AVSCM group (−14 ± 9% vs −20 ± 8%; −11 ± 7% vs −14 ± 6%; −9 ± 8% vs −14 ± 8%; −9 ± 7% vs −13 ± 5%, respectively, all Longitudinal strain patterns are useful in discriminating AVSCM from LAD‐MI patients at presentation and may be valuable in stratifying patients for invasive evaluation. Electronic medical records were reviewed to confirm the presence of SCM by Mayo Clinic diagnostic criteria2.2Each participant underwent a clinically indicated transthoracic echocardiogram within 48 hours of the coronary angiogram. Echocardiography was performed with a commercially available standard ultrasound scanner using Vivid 7 (GE) and Phillips IE‐33 machines. Images were analyzed by two experienced investigators blinded to the clinical data. Left ventricular (LV) ejection fraction (EF) was calculated using by Simpson's method, and LV dimensions were measured by the methods recommended by the American Society of Echocardiography (ASE) guidelines.P = .85); mid‐inferolateral (%) −13 ± 6 in SCM vs −13 ± 7 LAD‐MI group (P = .88)].The time to peak strain was measured from the beginning of the QRS complex on the electrocardiogram (ECG), and the standard deviation of the 18 different time intervals to peak longitudinal strain in each participant was calculated to quantify LV mechanical dispersion reflecting myocardial contraction heterogeneity as previously described.2.32) or Fisher's exact test, as appropriate. For mechanical dispersion , statistical difference was determined by using the F test. Receiver operating characteristic (ROC) curve analysis was performed to identify the best cutoff values for continuous variables predicting LAD‐MI. We further performed prespecified stratified sensitivity analyses in subgroups based on the location of LAD lesion , and absence or presence of nonculprit coronary artery lesions (more than 50% stenosis). Performance of the segmental strain ratio cutoff identified from the general sample was measured using ROC curve analysis in these subgroups. Statistical significance for all tests was defined as P value ≤ 0.05.Continuous data are presented as mean ± standard deviation (SD) unless otherwise specified. Comparisons of continuous variables were performed by using t tests, and comparisons of categorical variables were performed by using the chi‐square (χ3P = .009) and less likely to have diabetes mellitus . ST segment elevation was present in 33% of the AVSCM patients on presentation, and corrected QT interval was significantly prolonged when compared to LAD‐MI group . This is consistent with previous findings that patients with AVSCM have significant QT prolongation and are at risk of Torsades de pointes and ventricular fibrillation.P < .001). On presentation, average heart rate and systolic blood pressure were similar between the two groups. LVEF was equally reduced in both groups (37 ± 12% for AVSCM vs 38 ± 12% for LAD‐MI). In LAD‐MI group, nonculprit coronary artery lesions were present in a third of the participants .Of the total 108 female participants, 60 patients had acute AVSCM and 48 patients had ST segment elevation LAD‐MI. Baseline characteristics of study participants are depicted in Table 3.1Overall analysis was possible in 1656 out of 1944 segments providing a feasibility of 85% for the study. The inter‐ and intra‐observer variability in measurement of global and segmental longitudinal strain in our laboratory has previously been reported at 12.2% and 10.7%, respectively.3.2P = .32). Table P ≤ .05 for all comparisons; Figure P ≤ .05 for both comparisons; Figure GLS was significantly but equally reduced between the AVSCM and LAD‐MI groups .Median segmental strain ratio in the LAD‐MI group was 2.1 (interquartile range of 1.3–3.6) and 1.0 (interquartile range of 0.6–1.5) in the AVSCM group. Using ROC curve analysis, segmental strain ratio of ≥1.58 was 90% specific and 73% sensitive for LAD‐MI . Moreover, the segmental strain ratio will likely be higher for echocardiograms performed prior to revascularization and thus increasing difference between the two groups. Another limitation is the absence of B‐type natriuretic peptide (BNP) measurements for most of our participants. In a retrospective cohort analysis, Randhawa et al found BNP to be significantly elevated in SCM patients when compared to MI patients.6In this cross‐sectional study, we have demonstrated significant differences in segmental LS pattern between acute AVSCM and LAD‐MI. To our knowledge, this is the largest cohort comparison aimed at identifying the differences in myocardial strain between the two groups. We, for the first time, describe a segmental strain ratio which can discriminate between these two entities with high sensitivity and specificity. This novel ratio has the potential to be used in stratifying patients for invasive studies in the acute care settings. Future prospective validation studies are warranted in larger cohorts.None.Figure S1. Receiver‐operating characteristic (ROC) curve for the association of segmental strain ratio and myocardial infarction based on the location of LAD lesion. Segmental strain ratio of ≥1.58 is 90% specific for prediction of LAD‐MI in both subgroups with area under the curve (AUC) of 0.88 for proximal‐LAD and 0.86 for mid‐LAD subgroup.Figure S2. Receiver‐operating characteristic (ROC) curve for the association of segmental strain ratio and left anterior descending coronary artery myocardial infarction (LAD‐MI) in subgroups based on absence of non‐culprit coronary artery lesions. Segmental strain ratio of ≥1.58 is 90% specific for prediction of LAD‐MI in both subgroups with area under the curve (AUC) of 0.89 for those without non‐culprit coronary artery lesions and 0.82 for those with non‐culprit coronary artery lesions.Click here for additional data file.