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Substrate-based catheter ablation approaches to ventricular tachycardia (VT) focus on low-voltage areas and abnormal electrograms. However, specific electrogram characteristics in sinus rhythm are not clearly defined and can be subject to variable interpretation. We analyzed the potential ablation target size using automatic abnormal electrogram detection and studied findings during substrate mapping in the VT isthmus area.Electrogram characteristics in 61 patients undergoing scar-related VT ablation using ultrahigh-density 3D-mapping with a 64-electrode mini-basket catheter were analyzed retrospectively. Forty-four complete substrate maps with a mean number of 10319 ± 889 points were acquired. Fractionated potentials detected by automated annotation and manual review were present in 43 ± 21% of the entire low-voltage area (1.0 mV), highly fractionated potentials in 7 ± 8%, late potentials in 13 ± 15%, fractionated late potentials in 7 ± 9% and isolated late potentials in 2 ± 4%, respectively. Highly fractionated potentials (10 ± 1 fractionations) were found in all isthmus areas of identified VT during substrate mapping, while isolated late potentials were distant from the critical isthmus area in 29%.The ablation target area varies enormously in size, depending on the definition of abnormal electrograms. Clear linking of abnormal electrograms with critical VT isthmus areas during substrate mapping remains difficult due to a lack of specificity rather than sensitivity. However, highly fractionated, low-voltage electrograms were found to be present in all critical VT isthmus sites.

Purpose Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is an increasingly used treatment option for patients in need of mechanical cardiopulmonary support, while available outcome data is limited. The aim of this study was to identify predictors for 30-day in-hospital mortality. Material and methods We analyzed baseline characteristics and outcomes of 8351 VA-ECMO procedures performed in Germany from 2007 to 2015. Using a multivariable model, we identified the ten most important variables to allow for prediction of 30-day in-hospital mortality. Based on these variables, we created a mortality prediction score (ECMO-ACCEPTS score) to enhance decision making in patients considered for or treated with VA-ECMO support. Results Of 8351 patients (71.7% male) 3567 had prior CPR. Mean age was 62 years in the present cohort. The overall 30-day in-hospital mortality was 61%. The ECMO-ACCEPTS score, derived among randomly selected 4175 patients, included ten independent predictors for in-hospital mortality. Internal validation in the remaining 4176 patients confirmed strong differentiation between low and high risk of 30-day in-hospital mortality (r = 0.97 for correlation of predicted with observed mortality, p Conclusions The ECMO-ACCEPTS score might help clinicians to improve risk prediction among VA-ECMO patients for refractory cardiogenic shock.

Background Neuron-specific-enolase (NSE) is frequently used to predict the neurologic outcome in persistently unconscious patients after cardiopulmonary resuscitation (CPR). However, its predictive value is unclear in the setting of veno-arterial extracorporeal membrane oxygenation therapy (ECMO). Aim of this project is to evaluate the predictive value of NSE in ECMO patients. Methods NSE was measured after 24, 48, and 72 h in post-CPR ECMO patients. Neurologic status was evaluated using the best Cerebral Performance Categories Score (CPC) during the hospital stay. Patients who deceased within the first 24 h and patients who were awake during the first 24 h were excluded. ROC curves were calculated to assess the discriminative ability of single NSE measurements. Trajectories of serial NSE values were investigated using latent class mixed models. Results The derivation cohort consisted of 65 patients, 30-day all-cause mortality was 47.7% and a poor neurological outcome with a CPC score of 4–5 was seen 30.7%. NSE measurement after 48 h showed the best discrimination for poor neurological outcome (AUC of 0.87 in the ROC curve; cut-off value of 70 μg/L). Specificity was highest if using serial NSE measurements at all three time points. These results could be validated in an external cohort of 64 patients. Conclusion In post-CPR patients on ECMO, NSE can be used to assess the neurologic outcome. Importantly, specificity was highest if using serial NSE measurements. Further research using prospective datasets is needed to verify these findings.

Objectives: This report relates the authors' ongoing experience with percutaneous left ventricular (LV) unloading by using a transaortic LV assist device in combination with venoarterial ex...

Background Ablation of scar-related ventricular tachycardia (VT), especially in non-inducible VT or hemodynamically unstable patients, can be challenging. Thus, we evaluated feasibility of an ultra high-density 3D-mapping approach to characterize the ventricular substrate and, if possible, to map VT. Methods and results Twenty-two patients (67±2 years, mean LV-EF 36±3%) with both ischemic and non-ischemic cardiomyopathy and documented VT underwent mapping and catheter ablation using a 64-electrode mini-basket catheter. Substrate characterization included ultra high-density voltage maps, identification of areas of slow conduction and late potentials. Whenever VT was inducible activation mapping was performed. In 13/22 patients the presumed clinical VT (in 16/22 any VT) was inducible. A total of 50 maps were generated (22 substrate maps, 28 during VT), mapping time was 33±4 minutes, number of points was 10937±1923. Low voltage areas were related with the site of origin in all mapped VT. Isochronal maps indicated areas of slow conduction in 14/22 patients, all in border zone scar. In 95% of patients late potentials were found. Mapping time during VT was 9±2 minutes, number of points 6740±1140. Covered cycle length was 82±5% (16 re-entry, 10 focal and 2 undetermined). During 4 months follow-up 90% remained free from VT recurrence. Conclusion Ultra high-density mapping in patients with scar-related VT is feasible, safe and enables detailed insight into tachycardia mechanisms. Critical sites can be identified (1) by precise substrate characterization when VT is not inducible or hemodynamically not tolerated and (2) during short lasting episodes of VT in order to guide catheter ablation. This article is protected by copyright. All rights reserved

BACKGROUND Extensive and repeated substrate modification (SM) is frequently performed as an ablation strategy in persistent atrial fibrillation (persAF). The effect of these extended ablation strategies on atrial function has not been investigated sufficiently so far. The purpose was to assess atrial function by cardiac magnetic resonance (CMR) and its association with left atrial (LA) scar burden by electroanatomical voltage-mapping after multiple persAF ablation procedures. METHODS We included 16 persAF patients who had ≥2 SM procedures and a control group (CG) of 21 persAF patients without prior ablation. CMR was performed in sinus rhythm at least 4 weeks after the last cardioversion. Active left and right (RA) atrial emptying fractions (AEF) as well as peak active left atrial appendage (LAA) emptying velocities were obtained by CMR flow measurements. Furthermore, LA scar burden was quantified on electroanatomical voltage maps by the portion of points with local voltage amplitude

Aims Atrial contractile dysfunction is associated with increased mortality in heart failure (HF). We have shown previously that a metabolic syndrome-based model of HFpEF and a model of hypertensive heart disease (HHD) have impaired left atrial (LA) function in vivo (rat). In this study we postulate, that left atrial cardiomyocyte (CM) and cardiac fibroblast (CF) paracrine interaction related to the inositol 1,4,5-trisphosphate signalling cascade is pivotal for the manifestation of atrial mechanical dysfunction in HF and that quantitative atrial remodeling is highly disease-dependent. Methods and results Differential remodeling was observed in HHD and HFpEF as indicated by an increase of atrial size in vivo (HFpEF), unchanged fibrosis (HHD and HFpEF) and a decrease of CM size (HHD). Baseline contractile performance of rat CM in vitro was enhanced in HFpEF. Upon treatment with conditioned medium from their respective stretched CF (CM-SF), CM (at 21 weeks) of WT showed increased Ca2+ transient (CaT) amplitudes related to the paracrine activity of the inotrope endothelin (ET-1) and inositol 1,4,5-trisphosphate induced Ca2+ release. Concentration of ET-1 was increased in CM-SF and atrial tissue from WT as compared to HHD and HFpEF. In HHD, CM-SF had no relevant effect on CaT kinetics. However, in HFpEF, CM-SF increased diastolic Ca2+ and slowed Ca2+ removal, potentially contributing to an in-vivo decompensation. During disease progression (i.e. at 27 weeks), HFpEF displayed dysfunctional excitation-contraction-coupling (ECC) due to lower sarcoplasmic-reticulum Ca2+ content unrelated to CF-CM interaction or ET-1, but associated with enhanced nuclear [Ca2+]. In human patients, tissue ET-1 was not related to the presence of arterial hypertension or obesity. Conclusions Atrial remodeling is a complex entity that is highly disease and stage dependent. The activity of fibrosis related to paracrine interaction (e.g. ET-1) might contribute to in vitro and in vivo atrial dysfunction. However, during later stages of disease, ECC is impaired unrelated to CF.

Heart failure is a consequence of various cardiovascular diseases and associated with poor prognosis. Despite progress in the treatment of heart failure in the past decades, prevalence and hospitalisation rates are still increasing. Heart failure is typically associated with cardiac remodelling. Here, inflammation and fibrosis are thought to play crucial roles. During cardiac inflammation, immune cells invade the cardiac tissue and modulate tissue-damaging responses. Cardiac fibrosis, however, is characterised by an increased amount and a disrupted composition of extracellular matrix proteins. As evidence exists that cardiac inflammation and fibrosis are potentially reversible in experimental and clinical set ups, they are interesting targets for innovative heart failure treatments. In this context, animal models are important as they mimic clinical conditions of heart failure patients. The advantages of mice in this respect are short generation times and genetic modifications. As numerous murine models of heart failure exist, the selection of a proper disease model for a distinct research question is demanding. To facilitate this selection, this review aims to provide an overview about the current understanding of the pathogenesis of cardiac inflammation and fibrosis in six frequently used murine models of heart failure. Hence, it compares the models of myocardial infarction with or without reperfusion, transverse aortic constriction, chronic subjection to angiotensin II or deoxycorticosterone acetate, and coxsackievirus B3-induced viral myocarditis in this context. It furthermore provides information about the clinical relevance and the limitations of each model, and, if applicable, about the recent advancements in their methodological proceedings.

Obesity is a risk factor for heart failure (HF) and identification of symptomatic, and obese HF patients are challenging, because obesity can mimic HF symptoms. We aimed to evaluate novel biomarkers for HF in obese subjects of the general population. Midregional proadrenomedullin (MR-proADM), growth differentiation factor-15 (GDF-15), midregional pro-atrial natriuretic peptide (MR-proANP), and NT-proBNP were measured in 5000 individuals of the population-based Gutenberg Health Study (GHS), including 1204 obese individuals (BMI ≥ 30 kg/m2) and 107 individuals with HF. NT-proBNP and MR-proANP were lower in obese vs. non-obese HF individuals (p = 0.013 and p = 0.01, respectively), whereas GDF-15 was similar and MR-proADM was higher in obese vs. non-obese HF individuals. All biomarkers increased the odds ratio (OR) for prevalent HF. For NT-proBNP and MR-proANP, this increase was lower in obese vs. non-obese individuals, whereas it was comparable for MR-proADM and GDF-15. All biomarkers were associated with increased all-cause mortality (median follow-up 7.3 years, 211 events). Results were validated in 8373 individuals (n = 1734 with BMI ≥ 30 kg/m2) of the FINRISK study with a median follow-up of 13.8 years (1030 events). Using a dichotomized biomarker cutoff for HF, the best predictor for all-cause mortality in obese subjects was GDF-15 (p

Aims Left-ventricular (LV) remodelling impacts on the LV end-diastolic pressure–volume relationship (EDPVR), which is different in heart failure (HF) with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). In a large-scale, population-based cohort (Gutenberg Health Study), we aimed to investigate alterations of the EDPVR in HF patients and their association to risk factors and all-cause mortality in non-HF individuals. Methods and results Based on clinical and echocardiographic data, participants were divided into ‘No HF’ ( n = 14487), HFrEF ( n = 215), and HFpEF ( n = 79). We estimated the position of the EDPVR and its stiffness-coefficient β from echocardiographic data using a single-beat method. The EDPVR was shifted rightward in HFrEF and leftward in HFpEF compared with ‘No HF’, while the stiffness-coefficient β was increased in both HFrEF and HFpEF. In ‘No HF’, a higher stiffness-coefficient β was associated with age, female gender, hypertension, diabetes, and obesity, while age and female gender were associated with a leftward shift of the EDPVR, whereas dyslipidaemia, obesity, smoking, and impaired renal function were associated with a rightward shift of the EDPVR. Both changes of the EDPVR were associated with increased all-cause mortality. Conclusion In a large-scale, population-based cohort, we show distinct alterations of the EDPVR in HFrEF and HFpEF. Already in non-HF individuals, the presence of risk factors for HF is linked alterations of the EDPVR, which are associated with increased mortality.

Increased adrenomedullin (ADM) levels are associated with various cardiac diseases such as myocardial infarction (MI). ADM is cleaved off from the full-length precursor protein proadrenomedullin (ProADM) during its posttranslational processing. To date, no biological effect of ProADM is reported, while ADM infusion leads to antiapoptotic effects and improved cardiac function. Using an MI mouse model, we found an induction of ProADM gene as well as protein expression during the early phase of MI. This was accompanied by apoptosis and increasing inflammation, which substantially influence the post-MI remodeling processes. Simulating ischemia in vitro, we demonstrate that ProADM expression was increased in cardiomyocytes and cardiac fibroblasts. Subsequently, we treated ischemic cardiomyocytes with either ProADM or ADM and found that both proteins increased survival. This effect was diminishable by blocking the ADM(1) receptor. To investigate whether ProADM and ADM play a role in the regulation of cardiac inflammation, we analyzed chemokine expression after treatment of cells with both proteins. While ProADM induced an expression of proinflammatory cytokines, thus promoting inflammation, ADM reduced chemokine expression. On leukocytes, both proteins repressed chemokine expression, revealing antiinflammatory effects. However, ProADM but not ADM dampened concurrent activation of leukocytes. Our data show that the full-length precursor ProADM is biologically active by reducing apoptosis to a similar extent as ADM. We further assume that ProADM induces local inflammation in affected cardiac tissue but attenuates exaggerated inflammation, whereas ADM has low impact. Our data suggest that both proteins are beneficial during MI by influencing apoptosis and inflammation.

Background Extracorporeal life support (ECLS) by veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a valuable treatment option during severe cardiogenic shock and during cardiac arrest unresponsive to conventional management. It is applied to bridge the first critical days until the patient recovers or a destination therapy is established.1 Prolonged episodes without cardiac electrical activity during VA-ECMO are a major problem, as they may cause pulmonary oedema and severe left ventricular (LV) thrombosis.2 Here, we report a case of a 50-year-old man who presented with a 30-h episode of complete absence of electromechanical activity during ECLS and finally recovered with favourable neurological outcome. Case summary A 50-year-old man with out-of-hospital cardiac arrest was transferred to a peripheral hospital after initial successful cardiopulmonary resuscitation (CPR). In the emergency room, he presented with ST-segment elevation myocardial infarction and cardiogenic shock with third-degree atrioventricular block. After immediate insertion of a temporary pacemaker, he received percutaneous coronary intervention of the left anterior descending artery and the circumflex artery. Due to worsening cardiogenic shock, ECLS with VA-ECMO and an Impella® pump was established. Cumulative time of CPR (out of hospital and in hospital) was 41 min. After transfer to our institution’s intensive care unit, both the heart’s mechanical and electrical activity ceased for more than 24 h and recovered slowly thereafter. After showing promising neurological outcome, epicardial pacemaker leads, an implantable cardioverter-defibrillator, and finally, a LV assist device were implanted. He was dismissed into rehabilitation with only minor neurological residua 6 weeks later. Discussion Impella® implantation on top of VA-ECMO may be considered beneficial in the therapy of prolonged cardiac arrest.3 While VA-ECMO ensures oxygenation and organ perfusion, Impella® vents the left ventricle and enhances coronary perfusion. In the presented case, a favourable outcome was reached despite an ‘untreated’ prolonged absence of cardiac electromechanical activity. Under specific circumstances during ECLS with extracorporeal membrane oxygenation and Impella®, waiving of temporary pacing may be considered in absent cardiac electromechanical activity to avoid further complications.

Background Percutaneous mitral valve edge‐to‐edge repair ( pMVR ) with a MitraClip is beneficial for the clinical symptoms of patients irrespective of the ejection fraction ( EF ). Nevertheless, the consequences on hemodynamics are poorly understood. Therefore, we used data from noninvasive pressure‐volume loops to investigate the left ventricular (LV) remodeling of patients after pMVR dependent on their baseline EF. Methods and Results In 130 patients with successful pMVR , the end‐diastolic pressure‐volume relationship (EDPVR) and end‐systolic pressure‐volume relationship were estimated noninvasively from echocardiographic data. We compared EDPVR and end‐systolic pressure‐volume relationship at discharge and follow‐up between patients with a reduced EF (EF (≥40%). Reduced EF was present in 71 patients (54%). Mean follow‐up duration was 277±117 days. We observed a significant reduction in degree of mitral regurgitation and an improvement in functional status at follow‐up irrespective of baseline EF . In patients with a mid‐ranged or preserved EF , the EDPVR and end‐systolic pressure‐volume relationship were shifted leftwards, suggesting an improvement in LV function. In contrast, in patients with a reduced EF , EDPVR and end‐systolic pressure‐volume relationship remained stable, although comparison with the baseline data indicates a rightward shift of the EDPVR . This indicates that there is no improvement in LV function after pMVR in patients with reduced EF. Conclusions The pMVR is associated with improved clinical symptoms in all patient subgroups. However, it leads to different hemodynamic responses. In patients with mid‐ranged or preserved EF , we found reverse remodeling with reduced LV dilatation and increased contractility. In contrast, in patients with reduced EF , we observed no reverse remodeling and no improvement in LV function.

BACKGROUND Aorto-ostial lesions as well as bifurcation lesions still provide challenges in percutaneous coronary intervention (PCI), as meticulous stent placement is needed. The Szabo-technique, which uses a second wire to anchor the stent at the ostium, may be helpful here. In this article, we will provide detailed information on the technique including video material as well as procedural and long-term follow-up data of a cohort of patients treated with this technique. METHODS A retrospective single-centre study was performed in patients undergoing Szabo-PCI from 2014 to 2016 (N.=28). RESULTS Indications for PCI were elective in 53% and urgent/emergent in 47%. Target vessel was the ostial right coronary artery in 43%, the ostial left main artery in 7%, the proximal left anterior descending artery in 29% and the proximal circumflex artery in 21% of the cases. Primary success rate was 86%. In the other 14%, delivery of the stent failed due to a high-grade calcification. There were no periprocedural complications. During the follow-up time (mean 308 days) there was one case of cardiovascular and one case of non-cardiovascular death without any stroke events. In one case target lesions revascularisation was necessary. CONCLUSIONS The Szabo-technique offers a feasible and safe approach for PCI of ostial and bifurcation lesions. Calcified lesions seem to be a challenging aspect.

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine known to play a major role in inflammatory diseases such as myocardial infarction (MI), where its expression increases. Cardio protective functions of MIF during ischemia have been reported. Recently, the structurally related MIF-2 was identified and similar effects are assumed. We wanted to further investigate the role of MIF and MIF-2 on inflammatory processes during MI. Therefore, we subjected mice to experimentally induced MI by coronary occlusion for one and five days. During the acute phase of MI, the gene expression of Mif was upregulated in the infarct zone, whereas Mif-2 was downregulated, suggesting a minor role of MIF-2. Simulating ischemic conditions or mechanical stress in vitro, we demonstrated that Mif expression was induced in resident cardiac cells. To investigate possible auto /paracrine effects, cardiomyocytes and cardiac fibroblasts were individually treated with recombinant murine MIF, which in turn induced Mif expression and the expression of pro-inflammatory genes in cardiac fibroblasts. Cardiomyocytes did not respond to recombinant MIF with pro-inflammatory gene expression. While MIF stimulation alone did not change the expression of pro-fibrotic genes in cardiac fibroblasts, ischemia reduced their expression. Mimicking the increased MIF levels during MI, we exposed cardiac fibroblasts to simulated ischemia in the presence of MIF, which led to further reduced expression of pro-fibrotic genes. The presented data show that MIF was expressed by resident cardiac cells during MI. In vitro, Mif expression was induced by different external stimuli in cardiomyocytes and cardiac fibroblasts. Addition of recombinant MIF protein increased the expression of pro-inflammatory genes in cardiac fibroblasts including Mif expression itself. Thereby, cardiac fibroblasts may amplify Mif expression during ischemia promoting cardiomyocyte survival.

Heart failure (HF) incidence is rising worldwide and HF with preserved ejection fraction (HFpEF) represents nearly half of all cases. Treatment options are still limited in HFpEF in comparison to HF with reduced ejection fraction (HFrEF).We analyzed biomarkers in the general population to characterize HFpEF and HFrEF and defined a biomarker index to differentiate HFpEF from HFrEF. Growth differentiation factor-15 (GDF-15), soluble source of tumorigenicity 2 (sST2), C-reactive protein (CRP) and NT-proBNP were measured in 5000 individuals of the population-based Gutenberg Health Study (GHS). The median follow-up time for all-cause mortality was 7.3years with 213 events.Identification of subjects with HF was improved by GDF-15 (p0.001) in addition to NT-proBNP with an odds ratio (OR) of 1.4 (95% confidence interval [CI]:1.1-1.7). Discrimination of subjects with and without HF was slightly higher for GDF-15 (area under the ROC curve [AUC]:0.79 [95%CI:0.75-0.83]) compared to NT-proBNP (AUC:0.77 [95% CI:0.72-0.82]). For subjects with HF, differentiating HFpEF from HFrEF was feasible with the index ((CRP+GDF-15+sST2)/NT-proBNP) with an OR of 3.7 (95% CI:1.9-8.5) (p0.001). The best biomarkers predicting all-cause mortality were NT-proBNP and GDF-15 with a hazard ratio (HR) of 1.9 (95% CI:1.6-2.2) and 1.7 (95%CI:1.6-1.9) (both p0.001), respectively.GDF-15 was useful to detect prevalent HF in addition to NT-proBNP and was elevated in HFrEF and HFpEF, whereas NT-proBNP was higher in HFrEF than in HFpEF. All biomarkers were useful to predict mortality in the general population. The index of ((CRP+GDF-15s+sST2)/NT-proBNP) was able to discriminate HFpEF from HFrEF.

Objectives:The results from the recent Targeted Temperature Management trial raised the question whether cooling or merely the avoidance of fever mediates better neurologic outcome in resuscitated patients. As temperature per se is a major determinant of cardiac function, we characterized the effect

Die Therapie des akuten Myokardinfark­tes hat in den vergangenen Dekaden durch die Etablierung der Akut-PTCA, der Stents und die Fortentwicklung der medi­kamentosen Therapie (zuletzt die neuen Thrombozytenaggregationshemmer Pra­sugrel und Ticagrelor) grose Fortschritte erzielt. Wahrend die initiale Einfuhrung von Stents zu einer massiven Verbesse­rung des Ergebnisses gegenuber der allei­nigen Ballondilatation gefuhrt hat, waren die weiteren Schritte hin zu einer besse­ren Stentstruktur in Summe sehr nutzlich, jedoch in den einzelnen Schritten nur noch von geringem Zusatznutzen.

Mechanisms underlying atrial remodeling toward atrial fibrillation (AF) are incompletely understood. We induced AF in 16 pigs by 6weeks of rapid atrial pacing (RAP, 600bpm) using a custom-built, telemetrically controlled pacemaker. AF evolution was monitored three times per week telemetrically in unstressed, conscious animals. We established a dose-response relationship between RAP duration and occurrence of sustained AF >60minutes. Left atrial (LA) dilatation was present already at 2weeks of RAP. There was no evidence of left ventricular heart failure after 6weeks of RAP. As a proof-of-principle, arterial hypertension was induced in 5/16 animals by implanting desoxycorticosterone acetate (DOCA, an aldosterone-analog) subcutaneously to accelerate atrial remodeling. RAP+DOCA resulted in increased AF stability with earlier onset of sustained AF and accelerated anatomical atrial remodeling with more pronounced LA dilatation. This novel porcine model can serve to characterize effects of maladaptive stimuli or protective interventions specifically during early AF.

Heart failure with preserved ejection fraction (HFPEF) evolves with the accumulation of risk factors. Relevant animal models to identify potential therapeutic targets and to test novel therapies for HFPEF are missing. We induced hypertension and hyperlipidemia in landrace pigs ( n = 8) by deoxycorticosteroneacetate (DOCA, 100 mg/kg, 90-day-release subcutaneous depot) and a Western diet (WD) containing high amounts of salt, fat, cholesterol, and sugar for 12 wk. Compared with weight-matched controls ( n = 8), DOCA/WD-treated pigs showed left ventricular (LV) concentric hypertrophy and left atrial dilatation in the absence of significant changes in LV ejection fraction or symptoms of heart failure at rest. The LV end-diastolic pressure-volume relationship was markedly shifted leftward. During simultaneous right atrial pacing and dobutamine infusion, cardiac output reserve and LV peak inflow velocities were lower in DOCA/WD-treated pigs at higher LV end-diastolic pressures. In LV biopsies, we observed myocyte hypertrophy, a shift toward the stiffer titin isoform N2B, and reduced total titin phosphorylation. LV superoxide production was increased, in part attributable to nitric oxide synthase (NOS) uncoupling, whereas AKT and NOS isoform expression and phosphorylation were unchanged. In conclusion, we developed a large-animal model in which loss of LV capacitance was associated with a titin isoform shift and dysfunctional NOS, in the presence of preserved LV ejection fraction. Our findings identify potential targets for the treatment of HFPEF in a relevant large-animal model.

OBJECTIVE We tested whether mild hypothermia impacts on circulatory and respiratory dysfunction during experimental endotoxemia. DESIGN Randomized controlled prospective experimental study. SETTING Large animal facility, Medical University of Graz, Austria. SUBJECTS Thirteen anesthetized and mechanically ventilated pigs. INTERVENTIONS Lipopolysaccharide was administered for 4 hours. With the beginning of lipopolysaccharide infusion, animals were assigned to either normothermia (38°C, n = 7) or mild hypothermia (33°C, n = 6, intravascular cooling) and followed for 8 hours in total. MEASUREMENTS AND MAIN RESULTS At the end of the protocol, cardiac output was lower in mild hypothermia than in normothermia (4.5 ± 0.4 L/min vs 6.6 ± 0.4 L/min, p < 0.05), but systemic vascular resistance (885 ± 77 dyn·s/cm vs 531 ± 29 dyn·s/cm, p < 0.05) and (Equation is included in full-text article.)(77% ± 6% vs 54% ± 3%, p < 0.05) were higher. Indices of left ventricular contractility in vivo were not different between groups. The high-frequency band in spectral analysis of heart rate variability indicated a better preserved vagal autonomic modulation of sinuatrial node activity in mild hypothermia versus normothermia (87 ± 5 vs 47 ± 5, normalized units, p < 0.05). Plasma norepinephrine levels were elevated compared with baseline in normothermia (2.13 ± 0.27 log pg/mL vs 0.27 ± 0.17 log pg/mL, p < 0.05) but not in mild hypothermia (1.02 ± 0.31 vs 0.55 ± 0.26, p = not significant). At 38°C in vitro, left ventricular muscle strips isolated from the mild hypothermia group had a higher force response to isoproterenol. SaO2 (100% ± 0% vs 92% ± 3%, p < 0.05) and the oxygenation index (PO2/FIO2, 386 ± 52 mm Hg vs 132 ± 32 mm Hg, p < 0.05) were substantially higher in mild hypothermia versus normothermia. Plasma cytokine levels were not consistently different between groups (interleukin 10) or higher (tumor necrosis factor-α and interleukin 6 and 8) during mild hypothermia versus normothermia. CONCLUSION The induction of mild hypothermia attenuates cardiac and respiratory dysfunction and counteracts sympathetic activation during experimental endotoxemia. This was not associated with lower plasma cytokine levels, indicating a reduction of cytokine responsiveness by mild hypothermia.