Berlin Heart (Germany)

Carbon capture and storage (CCS) is vital to climate change mitigation, and has application across the economy, in addition to facilitating atmospheric carbon dioxide removal resulting in emissions offsets and net negative emissions. This contribution reviews the state-of-the-art and identifies key challenges which must be overcome in order to pave the way for its large-scale deployment.

This paper presents a first–ever empirical examination of the effectiveness of signals that entrepreneurs use to induce (small) investors to commit financial resources in an equity crowdfunding context. We examine the impact of venture quality (human capital, social [alliance] capital, and intellectual capital) and uncertainty on fundraising success. Our data highlight that retaining equity and providing more detailed information about risks can be interpreted as effective signals and can therefore strongly impact the probability of funding success. Social capital and intellectual capital, by contrast, have little or no impact on funding success. We discuss the implications of our results for theory, future research, and practice.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) represents a therapeutic concept for type B aortic dissection. Long-term outcomes and morphology after TEVAR for uncomplicated dissection are unknown. METHODS AND RESULTS: A total of 140 patients with stable type B aortic dissection previously randomized to optimal medical treatment and TEVAR (n=72) versus optimal medical treatment alone (n=68) were analyzed retrospectively for aorta-specific, all-cause outcomes, and disease progression using landmark statistical analysis of years 2 to 5 after index procedure. Cox regression was used to compare outcomes between groups; all analyses are based on intention to treat. The risk of all-cause mortality (11.1% versus 19.3%; P=0.13), aorta-specific mortality (6.9% versus 19.3%; P=0.04), and progression (27.0% versus 46.1%; P=0.04) after 5 years was lower with TEVAR than with optimal medical treatment alone. Landmark analysis suggested a benefit of TEVAR for all end points between 2 and 5 years; for example, for all-cause mortality (0% versus 16.9%; P=0.0003), aorta-specific mortality (0% versus 16.9%; P=0.0005), and for progression (4.1% versus 28.1%; P=0.004); Landmarking at 1 year and 1 month revealed consistent findings. Both improved survival and less progression of disease at 5 years after elective TEVAR were associated with stent graft induced false lumen thrombosis in 90.6% of cases (P<0.0001). CONCLUSIONS: In this study of survivors of type B aortic dissection, TEVAR in addition to optimal medical treatment is associated with improved 5-year aorta-specific survival and delayed disease progression. In stable type B dissection with suitable anatomy, preemptive TEVAR should be considered to improve late outcome. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01415804.

Cardiovascular Magnetic Resonance is increasingly used to differentiate the aetiology of cardiomyopathies. Late Gadolinium Enhancement (LGE) is the reference standard for non-invasive imaging of myocardial scar and focal fibrosis and is valuable in the differential diagnosis of ischaemic versus non-ischaemic cardiomyopathy. Diffuse fibrosis may go undetected on LGE imaging. Tissue characterisation with parametric mapping methods has the potential to detect and quantify both focal and diffuse alterations in myocardial structure not assessable by LGE. Native and post-contrast T1 mapping in particular has shown promise as a novel biomarker to support diagnostic, therapeutic and prognostic decision making in ischaemic and non-ischaemic cardiomyopathies as well as in patients with acute chest pain syndromes. Furthermore, changes in the myocardium over time may be assessed longitudinally with this non-invasive tissue characterisation method.

Immune mechanisms and the renin-angiotensin system are implicated in preeclampsia. We investigated 25 preeclamptic patients and compared them with 12 normotensive pregnant women and 10 pregnant patients with essential hypertension. Antibodies were detected by the chronotropic responses to AT1 receptor-mediated stimulation of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists. Immunoglobulin from all preeclamptic patients stimulated the AT1 receptor, whereas immunoglobulin from controls had no effect. The increased autoimmune activity decreased after delivery. Affinity-column purification and anti-human IgG and IgM antibody exposure implicated an IgG antibody directed at the AT1 receptor. Peptides corresponding to sites on the AT1 receptor's second extracellular loop abolished the stimulatory effect. Western blotting with purified patient IgG and a commercially obtained AT1 receptor antibody produced bands of identical molecular weight. Furthermore, confocal microscopy of vascular smooth muscle cells showed colocalization of purified patient IgG and AT1 receptor antibody. The protein kinase C (PKC) inhibitor calphostin C prevented the stimulatory effect. Our results suggest that preeclamptic patients develop stimulatory autoantibodies against the second extracellular AT1 receptor loop. The effect appears to be PKC-mediated. These novel autoantibodies may participate in the angiotensin II-induced vascular lesions in these patients.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) represents a novel concept for type B aortic dissection. Although life-saving in acute emergencies, outcomes and survival of TEVAR in stable dissection are unknown. METHODS AND RESULTS: One hundred forty patients in stable clinical condition at least 2 weeks after index dissection were randomly subjected to elective stent-graft placement in addition to optimal medical therapy (n=72) or to optimal medical therapy alone (n=68) with surveillance (arterial pressure according to World Health Organization guidelines < or =120/80 mm Hg). The primary end point was all-cause death at 2 years, whereas aorta-related death, progression (with need for conversion or additional endovascular or open surgery), and aortic remodeling were secondary end points. There was no difference in all-cause deaths, with a 2-year cumulative survival rate of 95.6+/-2.5% with optimal medical therapy versus 88.9+/-3.7% with TEVAR (P=0.15); the trial, however, turned out to be underpowered. Moreover, the aorta-related death rate was not different (P=0.44), and the risk for the combined end point of aorta-related death (rupture) and progression (including conversion or additional endovascular or open surgery) was similar (P=0.65). Three neurological adverse events occurred in the TEVAR group (1 paraplegia, 1 stroke, and 1 transient paraparesis), versus 1 case of paraparesis with medical treatment. Finally, aortic remodeling (with true-lumen recovery and thoracic false-lumen thrombosis) occurred in 91.3% of patients with TEVAR versus 19.4% of those who received medical treatment (P<0.001), which suggests ongoing aortic remodeling. CONCLUSIONS: In the first randomized study on elective stent-graft placement in survivors of uncomplicated type B aortic dissection, TEVAR failed to improve 2-year survival and adverse event rates despite favorable aortic remodeling.

Malnutrition in older adults has been recognised as a challenging health concern associated with not only increased mortality and morbidity, but also with physical decline, which has wide ranging acute implications for activities of daily living and quality of life in general. Malnutrition is common and may also contribute to the development of the geriatric syndromes in older adults. Malnutrition in the old is reflected by either involuntary weight loss or low body mass index, but hidden deficiencies such as micronutrient deficiencies are more difficult to assess and therefore frequently overlooked in the community-dwelling old. In developed countries, the most cited cause of malnutrition is disease, as both acute and chronic disorders have the potential to result in or aggravate malnutrition. Therefore, as higher age is one risk factor for developing disease, older adults have the highest risk of being at nutritional risk or becoming malnourished. However, the aetiology of malnutrition is complex and multifactorial, and the development of malnutrition in the old is most likely also facilitated by ageing processes. This comprehensive narrative review summarizes current evidence on the prevalence and determinants of malnutrition in old adults spanning from age-related changes to disease-associated risk factors, and outlines remaining challenges in the understanding, identification as well as treatment of malnutrition, which in some cases may include targeted supplementation of macro- and/or micronutrients, when diet alone is not sufficient to meet age-specific requirements.

BACKGROUND: Serum uric acid (UA) could be a valid prognostic marker and useful for metabolic, hemodynamic, and functional (MFH) staging in chronic heart failure (CHF). METHODS AND RESULTS: For the derivation study, 112 patients with CHF (age 59+/-12 years, peak oxygen consumption [Vo2] 17+/-7 mL/kg per minute) were recruited. In separate studies, we validated the prognostic value of UA (n=182) and investigated the relationship between MFH score and the decision to list patients for heart transplantation (n=120). In the derivation study, the best mortality predicting UA cutoff (at 12 months) was 565 micromol/L (9.50 mg/dL) (independently of age, peak Vo2, left ventricular ejection fraction, diuretic dose, sodium, creatinine, and urea; P<0.0001). In the validation study, UA >or=565 micromol/L predicted mortality (hazard ratio, 7.14; P<0.0001). In 16 patients (from both studies) with UA >or=565 micromol/L, left ventricular ejection fraction <or=25% and peak Vo2 <or=14 mL/kg per min (MFH score 3), 12-month survival was lowest (31%) compared with patients with 2 (64%), 1 (77%), or no (98%, P<0.0001) risk factor. In an independent study, 51% of patients with MFH score 2 and 81% of patients with MFH score 3 were listed for transplantation. The positive predictive value of not being listed for heart transplantation with an MFH score of 0 or 1 was 100%. CONCLUSIONS: High serum UA levels are a strong, independent marker of impaired prognosis in patients with moderate to severe CHF. The relationship between serum UA and survival in CHF is graded. MFH staging of patients with CHF is feasible.

BACKGROUND: Myocardial perfusion reserve can be noninvasively assessed with cardiovascular MR. In this study, the diagnostic accuracy of this technique for the detection of significant coronary artery stenosis was evaluated. METHODS AND RESULTS: In 15 patients with single-vessel coronary artery disease and 5 patients without significant coronary artery disease, the signal intensity-time curves of the first pass of a gadolinium-DTPA bolus injected through a central vein catheter were evaluated before and after dipyridamole infusion to validate the technique. A linear fit was used to determine the upslope, and a cutoff value for the differentiation between the myocardium supplied by stenotic and nonstenotic coronary arteries was defined. The diagnostic accuracy was then examined prospectively in 34 patients with coronary artery disease and was compared with coronary angiography. A significant difference in myocardial perfusion reserve between ischemic and normal myocardial segments (1.08+/-0.23 and 2.33+/-0.41; P<0.001) was found that resulted in a cutoff value of 1.5 (mean minus 2 SD of normal segments). In the prospective analysis, sensitivity, specificity, and diagnostic accuracy for the detection of coronary artery stenosis (> or =75%) were 90%, 83%, and 87%, respectively. Interobserver and intraobserver variabilities for the linear fit were low (r=0.96 and 0.99). CONCLUSIONS: MR first-pass perfusion measurements yielded a high diagnostic accuracy for the detection of coronary artery disease. Myocardial perfusion reserve can be easily and reproducibly determined by a linear fit of the upslope of the signal intensity-time curves.

BACKGROUND: Adenosine stress magnetic resonance perfusion (MRP) and dobutamine stress magnetic resonance (DSMR) wall motion analyses are highly accurate for the detection of myocardial ischemia. However, knowledge about the prognostic value of stress MR examinations is limited. We sought to determine the value of MRP and DSMR, as assessed during a single-session examination, in predicting the outcome of patients with known or suspected coronary artery disease. METHODS AND RESULTS: In 513 patients (with known or suspected coronary disease, prior coronary artery bypass graft, or percutaneous coronary intervention), a combined single-session magnetic resonance stress examination (MRP and DSMR) was performed at 1.5 T. For first-pass perfusion imaging, the standard adenosine stress imaging protocol (140 microg x kg(-1) x min(-1) for 6 minutes, 3-slice turbo field echo-echo-planar imaging or steady-state free precession sequence, 0.05 mmol/kg Gd-DTPA) was applied, and for DSMR, the standard high-dose dobutamine/atropine protocol (steady-state free-precession cine sequence) was applied. Stress testing was classified as pathological if at MRP > or = 1 segment showed an inducible perfusion deficit > 25% transmurality or if at DSMR > or = 1 segment showed an inducible wall motion abnormality. During a median follow-up of 2.3 years (range, 0.06 to 4.55 years), 19 cardiac events occurred (4.1%; 9 cardiac deaths, 10 nonfatal myocardial infarctions). The 3-year event-free survival was 99.2% for patients with normal MRP and DSMR and 83.5% for those with abnormal MRP and DSMR. Univariate analysis showed ischemia identified by MRP and DSMR to be predictive of cardiac events (hazard ratio, 12.51; 95% confidence interval, 3.64 to 43.03; and hazard ratio, 5.42; 95% confidence interval, 2.18 to 13.50; P<0.001, respectively); other predictors were diabetes mellitus, known coronary artery disease, and the presence of resting wall motion abnormality. By multivariate analysis, ischemia on magnetic resonance stress testing (MRP or DSMR) was an independent predictor of cardiac events. In a stepwise multivariate model (Cox regression), an abnormal magnetic resonance stress test result had significant incremental value over clinical risk factors and resting wall motion abnormality (P<0.001). CONCLUSIONS: In patients with known or suspected coronary artery disease, myocardial ischemia detected by MRP and DSMR can be used to identify patients at high risk for subsequent cardiac death or nonfatal myocardial infarction. For patients with normal MRP and DSMR, the 3-year event-free survival was 99.2%. MR stress testing provides important incremental information over clinical risk factors and resting wall motion abnormalities.

Vascular smooth muscle cell (VSMC) proliferation and migration are responses to arterial injury that are highly important to the processes of restenosis and atherosclerosis. In the arterial balloon injury model in the rat, platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) are induced in the vessel wall and regulate these VSMC activities. Novel insulin sensitizing agents, thiazolidinediones, have been demonstrated to inhibit insulin and epidermal growth factor-induced growth of VSMCs. We hypothesized that these agents might also inhibit the effect of PDGF and bFGF on cultured VSMCs and intimal hyperplasia in vivo. Troglitazone (1 microM), a member of the thiazolidinedione class, produced a near complete inhibition of both bFGF-induced DNA synthesis as measured by bromodeoxyuridine incorporation (6.5+/-3.9 vs. 17.6+/-4.3% cells labeled, P < 0.05) and c-fos induction. This effect was associated with an inhibition (by 73+/-4%, P < 0.01) by troglitazone of the transactivation of the serum response element, which regulates c-fos expression. Inhibition of c-fos induction by troglitazone appeared to occur via a blockade of the MAP kinase pathway at a point downstream of MAP kinase activation by MAP kinase kinase. At this dose, troglitazone also inhibited PDGF-BB-directed migration of VSMC (by 70+/-6%, P < 0.01). These in vitro effects were operative in vivo. Quantitative image analysis revealed that troglitazone-treated rats had 62% (P < 0.001) less neointima/media area ratio 14 d after balloon injury of the aorta compared with injured rats that received no troglitazone. These results suggest troglitazone is a potent inhibitor of VSMC proliferation and migration and, thus, may be a useful agent to prevent restenosis and possibly atherosclerosis.

BACKGROUND: Options for mechanical circulatory support as a bridge to heart transplantation in children with severe heart failure are limited. METHODS: We conducted a prospective, single-group trial of a ventricular assist device designed specifically for children as a bridge to heart transplantation. Patients 16 years of age or younger were divided into two cohorts according to body-surface area (cohort 1, <0.7 m(2); cohort 2, 0.7 to <1.5 m(2)), with 24 patients in each group. Survival in the two cohorts receiving mechanical support (with data censored at the time of transplantation or weaning from the device owing to recovery) was compared with survival in two propensity-score-matched historical control groups (one for each cohort) undergoing extracorporeal membrane oxygenation (ECMO). RESULTS: For participants in cohort 1, the median survival time had not been reached at 174 days, whereas in the matched ECMO group, the median survival was 13 days (P<0.001 by the log-rank test). For participants in cohort 2 and the matched ECMO group, the median survival was 144 days and 10 days, respectively (P<0.001 by the log-rank test). Serious adverse events in cohort 1 and cohort 2 included major bleeding (in 42% and 50% of patients, respectively), infection (in 63% and 50%), and stroke (in 29% and 29%). CONCLUSIONS: Our trial showed that survival rates were significantly higher with the ventricular assist device than with ECMO. Serious adverse events, including infection, stroke, and bleeding, occurred in a majority of study participants. (Funded by Berlin Heart and the Food and Drug Administration Office of Orphan Product Development; ClinicalTrials.gov number, NCT00583661.).

OBJECTIVE: To determine the contribution of maternal glucose and lipids to intrauterine metabolic environment and fetal growth in pregnancies with gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: In 150 pregnancies, serum triglycerides (TGs), cholesterol, free fatty acids (FFAs), glycerol, insulin, and glucose were determined in maternal serum and cord blood during the 3rd trimester. Maternal glucose values came from oral glucose tolerance testing and glucose profiles. Measurements of fetal abdominal circumference (AC) were performed simultaneously with maternal blood sampling and birth weight, and BMI and neonatal fat mass were obtained following delivery. RESULTS: Maternal TGs and FFAs correlated with fetal AC size (at 28 weeks: triglycerides, P = 0.001; FFAs, P = 0.02), and at delivery they correlated with all neonatal anthropometric measures (FFA: birth weight, P = 0.002; BMI, P = 0.001; fat mass, P = 0.01). After adjustment for confounding variables, maternal FFAs and TGs at delivery remained the only parameters independently related to newborns large for gestational age (LGA) (P = 0.008 and P = 0.04, respectively). Maternal FFA levels were higher in mothers with LGA newborns than in those with appropriate for gestational age (AGA) newborns (362.8 +/- 101.7 vs. 252.4 +/- 10.1, P = 0.002). Maternal levels of TGs, FFAs, and glycerol at delivery correlated with those in cord blood (P = 0.003, P = 0.004, and P = 0.005, respectively). Fetal triglyceride and cholesterol levels were negatively correlated with newborn birth weight (P = 0.001), BMI (P = 0.004), and fat mass (P = 0.001). TGs were significantly higher in small for gestational age (SGA) newborns compared with AGA or LGA newborns, while insulin-to-glucose ratio and FFAs were the highest in LGA newborns. CONCLUSIONS: In well-controlled GDM pregnancies, maternal lipids are strong predictors for fetal lipids and fetal growth. Infants with abnormal growth seem to be exposed to a distinct intrauterine environment compared with those with appropriate growth.

Engraftment of mesenchymal stem cells (MSCs) derived from adult bone marrow has been proposed as a potential therapeutic approach for postinfarction left ventricular dysfunction. However, limited cell viability after transplantation into the myocardium has restricted its regenerative capacity. In this study, we genetically modified MSCs with an antiapoptotic Bcl-2 gene and evaluated cell survival, engraftment, revascularization, and functional improvement in a rat left anterior descending ligation model via intracardiac injection. Rat MSCs were manipulated to overexpress the Bcl-2 gene. In vitro, the antiapoptotic and paracrine effects were assessed under hypoxic conditions. In vivo, the Bcl-2 gene-modified MSCs (Bcl-2-MSCs) were injected after myocardial infarction. The surviving cells were tracked after transplantation. Capillary density was quantified after 3 weeks. The left ventricular function was evaluated by pressure-volume loops. The Bcl-2 gene protected MSCs against apoptosis. In vitro, Bcl-2 overexpression reduced MSC apoptosis by 32% and enhanced vascular endothelial growth factor secretion by more than 60% under hypoxic conditions. Transplantation with Bcl-2-MSCs increased 2.2-fold, 1.9-fold, and 1.2-fold of the cellular survival at 4 days, 3 weeks, and 6 weeks, respectively, compared with the vector-MSC group. Capillary density in the infarct border zone was 15% higher in Bcl-2-MSC transplanted animals than in vector-MSC treated animals. Furthermore, Bcl-2-MSC transplanted animals had 17% smaller infarct size than vector-MSC treated animals and exhibited functional recovery remarkably. Our current findings support the premise that transplantation of antiapoptotic gene-modified MSCs may have values for mediating substantial functional recovery after acute myocardial infarction.

We present a publicly available dataset of 227 healthy participants comprising a young (N=153, 25.1±3.1 years, range 20-35 years, 45 female) and an elderly group (N=74, 67.6±4.7 years, range 59-77 years, 37 female) acquired cross-sectionally in Leipzig, Germany, between 2013 and 2015 to study mind-body-emotion interactions. During a two-day assessment, participants completed MRI at 3 Tesla (resting-state fMRI, quantitative T1 (MP2RAGE), T2-weighted, FLAIR, SWI/QSM, DWI) and a 62-channel EEG experiment at rest. During task-free resting-state fMRI, cardiovascular measures (blood pressure, heart rate, pulse, respiration) were continuously acquired. Anthropometrics, blood samples, and urine drug tests were obtained. Psychiatric symptoms were identified with Standardized Clinical Interview for DSM IV (SCID-I), Hamilton Depression Scale, and Borderline Symptoms List. Psychological assessment comprised 6 cognitive tests as well as 21 questionnaires related to emotional behavior, personality traits and tendencies, eating behavior, and addictive behavior. We provide information on study design, methods, and details of the data. This dataset is part of the larger MPI Leipzig Mind-Brain-Body database.

The number of cardiac implantable electronic device (CIED) implantations has increased over recent years1,2 as a result of population growth, increasing life expectancy, adoption of guidelines, and better access to healthcare. Transvenous lead extraction (TLE), as a part of an overall lead management strategy, has also been increasing, not only as a consequence of this growth, but also because of increasing rates of infection,3 lead failure, awareness of indications for lead management, and development of extraction tools. Clinical research is essential for understanding efficacy and risks of TLE, which has important implications regarding decision-making and therapeutic strategies in patients who are candidates for this procedure. Data on TLE have mainly come from retrospective series, with variable reporting of endpoints. Recently, the ELECTRa registry conducted by the European Heart Rhythm Association (EHRA), has reported the largest prospective experience on lead extraction published to date in 3555 patients recruited from 19 European countries.4 There remain unresolved issues, which is a strong incentive for conducting further specifically-designed clinical trials to answer important questions in this area. In addition to clinical studies, national registries are potentially useful for evaluating epidemiology of TLE as well as for quality control and understanding resource implications. Standardization of definitions and reporting of parameters are paramount in order to analyse, compare, and pool data for scientific purposes. Expert consensus statements on lead extraction have been published by the Heart Rhythm Society (HRS) in 20095 and 2017,6 and by EHRA in 2012.7 Experience from the ELECTRa registry has been valuable for identifying challenges faced with conducting scientific studies in this field, and provides a framework for future endeavours. This writing group has been commissioned by EHRA to provide recommendations for designing scientific studies, reports and registries relating to lead extraction. In order to clarify the indications for lead extraction the following definitions are proposed (see Table 1). CIED-related infection types CIED, cardiac implantable electronic device. This was the most frequent indication for TLE in the ELECTRa registry amounting to 52.8% (of which approximately two-thirds were local infections).4 Several entities exist, which should be specified. This is defined as an infection limited to the generator pocket or along the lead course. It is clinically associated with local signs of inflammation, including erythema, warmth, fluctuance, wound dehiscence, tenderness, or purulent drainage, with negative blood cultures.8–10 This entity should be differentiated from superficial incisional Infection, which involves only skin and subcutaneous tissue without communication with the pocket (and may not require lead extraction). This is a chronic process whereby the device and/or lead(s) are exposed through the skin, with or without local signs of infection (the device should however be considered infected, whatever the mechanism for erosion). Very often the erosion is preceded by the adherence of the skin on the device with a concomitant browning and thinning of the skin. Erosion is usually indicative of infection. Blood cultures are negative, and some of these patients are asymptomatic, while others complain of local pain. In presence of positive blood cultures with or without systemic infection symptoms and signs. Local signs of pocket infection and positive blood cultures and lead or valvular vegetation(s). The 2015 European Society of Cardiology (ESC) modified Duke Criteria8 have been used to define endocarditis. It should be noted that these criteria are used to define valvular endocarditis. For CIED-related endocarditis, additional criteria might be considered, such as positive cultures of the extracted lead in case of negative blood cultures, presence of lead vegetations, and abnormal metabolic activity around the CIED generator and/or leads detected by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) or radiolabelled leucocytes single-photon-emission computed tomography/CT. Local signs of pocket infection and positive blood cultures, without lead or valvular vegetation(s). Bacteraemia with or without lead or valvular vegetation(s), and without local signs of pocket infection. Bacteraemia without an obvious source other than the CIED. After extraction, disappearance of bacteraemia is expected. In case of lead dysfunction, there is the option of abandoning the lead or extracting it (e.g. to reduce intravascular lead burden or regain access in the presence of venous occlusion). Lead dysfunction was the second most frequent reason for lead extraction in the ELECTRa registry, amounting to 38.1% of cases.4 Causes for lead dysfunction may be lead fracture or insulation failure resulting in issues with lead impedance, sensing or capture. In some cases, the electrical parameters may still be normal, but the integrity of the lead is clearly compromised (e.g. inside out cable externalization of Riata leads, radiological evidence of subclavian crush etc.). There are a variety of situations where a functional lead may no longer be required, with the option of either abandoning or extracting the lead. Examples are upgrades from a pacemaker to an implantable cardioverter-defibrillator (ICD), downgrading from dual- to single-chamber systems, lead recall with prophylactic revision, system relocation for radiotherapy, lack of device indication etc. These abandoned leads may be extracted to reduce the intravascular lead burden in order to avoid future issues (see Table 2). Definitions of terms for non-infected leads CIED, cardiac implantable electronic device. Leads may be functional but cause complications for which extraction may be indicated (e.g. thromboembolic events, superior vena cava syndrome, arrhythmias, perforation, lead-lead interaction etc.). If stenting is planned for treating stenosis in a vein with a transvenous lead, extraction is usually performed to avoid entrapment of the lead. Up to 25% of patients with transvenous leads develop some degree of stenosis,11 which may later hinder additional lead implantation (e.g. in case of upgrades). There are a number of different management strategies,12 which include tunnelling a contra-lateral lead across the chest, venoplasty, or lead extraction to provide a channel through which new leads can be implanted. There is evidence that magnetic resonance imaging (MRI) can be safely performed in patients implanted with non-conditional CIEDs, but abandoned or dysfunctional leads are considered to be contra-indications (even if an MRI-conditional device is implanted).13 Therefore, extraction of these leads may be performed in selected cases, with appropriate assessment of the risk and benefits of the lead extraction procedure, in order to allow access to MRI, when no other diagnostic alternatives to MRI are available. Some patients may have severe chronic pain attributed to lead insertion (e.g. due to a periosteal reaction), for which lead extraction may be performed. It is important to recognize that chronic pain may be a sign of an infection. A number of other rare indications for lead extraction exist, such as prophylactic extraction of leads that due to their design or their failure pose a potential future threat to the patient if left in place e.g. Accufix leads (Telectronics). Lead removal often includes a wide spectrum of tools and techniques, ranging from simple manual traction to multiple procedures and combined approaches (see Table 3). Definition of LE approaches, techniques and tools LE, lead extraction; RFA, radiofrequency ablation. Most lead extractions are performed using a percutaneous approach as it is less invasive. In specific situations (e.g. high-risk procedures or in case of very large vegetations), an open extraction with sternotomy and cardiopulmonary bypass may be preferred. Some centres perform hybrid approaches that combine percutaneous extraction with minimally invasive surgery or thoracoscopy. The various approaches for percutaneous TLE are detailed below. Most lead extraction procedures begin via the identical route of lead implantation, also known as venous entry or implant vein approaches. If the venous entry approach fails, or in the presence of free-floating leads, an internal jugular venous approach can be used, combining superior and femoral accesses.14 Extraction may be performed with femoral venous access as a primary strategy or as a bailout procedure, using specialized tools.15 When reporting data for lead extraction procedures, it is important to be specific regarding the tools and techniques used, as these will have a direct impact on outcome and also on costs. Often, a ‘stepwise’ approach is used whereby the operator transitions from simple to more complex strategies. Therefore, different tools and techniques may be used during a procedure, even for the same lead. In case of a stepwise approach, it is useful to report the sequence of techniques, which were employed for a given lead. Applying mild pulling force without the use of specialized tools (other than a standard stylet) was used in 27% of patients in the ELECTRa registry,4 and may be effective for leads with a short dwell time (i.e. time since implant <1–2 years). These are designed to improve tensile strength to facilitate traction and to stabilize leads. They may be used alone or in combination with other tools such as sheaths. These sheaths are designed for blunt dissection of fibrotic binding sites, using simple manual pushing/rotational force. They are most often composed of polypropylene, but metallic or Teflon (PTFE) sheaths are also available. They may be used alone or with handles that facilitate rotation, and most often with a locking stylet. When reporting use of powered sheaths, it is important to specify which type of tool was used, as their mechanism, efficacy and risk profiles may differ. They are used in conjunction with a locking stylet inserted into the lead, which builds a rail upon which the device is advanced. Rotational mechanical sheaths are currently hand powered and have a threaded tip which dissects adherent tissue.16,Electrosurgical sheaths use radiofrequency energy to dissect fibrous tissue but are now seldom used. Laser sheaths use laser energy delivered circumferentially along the tip of the sheath.17 As additional tools become available this list should be expanded accordingly. These are most often deployed via a femoral approach, and may consist of a single or double15 loop, which can be used for grasping free-floating lead extremities or the lead body (double loop design). These devices are usually introduced via a femoral approach to grasp free-floating lead extremities, but are seldom used today. These wires are used for grasping conductor cables or lumenless leads in order to be able to use an extraction sheath. These tools allow secure binding of locking stylets and the proximal components of the lead to facilitate extraction.18 In case of a vascular tear, these highly compliant balloons are filled with diluted contrast agents to stem bleeding while awaiting surgical bailout.19 Tools that are dedicated to other procedures may sometimes be used for lead extraction (e.g. for grasping leads), such as pigtail catheters, deflectable wires, deflectable catheters, bioptomes, deflectable sheaths etc. It is recommended to report the size of the tools used, as these may impact complications (e.g. bleeding at the venous entry site, collateral damage, etc.). However, it is important to realize that tool size may be labelled differently (e.g. mechanical sheath size usually refers to internal diameters, whereas laser sheath size refers to external diameter), and that use of outer sheaths will also impact tool size. To interpret studies, whether prospective randomized trials or retrospective studies, there must be clear and consistent definitions. Since many complications may occur after the patient leaves the procedural venue, appropriate follow-up should be performed. In addition, true informed consent requires each operator to know their own volumes and outcomes. This requires and able to report in a Definitions of a lead extraction, procedural and complications have been well in the and consensus on and used in the ELECTRa It will be the of this to with to the of A of the that the of lead extraction has which reporting of the and efficacy of lead extraction procedures to The removal of a lead is clearly different from a lead. To the clear definitions for and is not a lead extraction procedure, which have been in the and also in this When a the following definitions should be of a lead or lead using This entity includes removal of subcutaneous leads. A lead removal using simple traction techniques locking sheaths, or femoral extraction and leads were implanted with removal of at lead that has been implanted for more than or a lead of of implant the of specialized that is not as part of the implant and/or removal of a lead from a route other than the implant removal of may be considered as extraction For scientific it is important to of the as a as well as to data on of extraction of leads (e.g. in order to for leads, and for The of will very upon and can only be in case the follow-up is In case of leads, a CIED removal is even if a may be to consensus of In case of non-infected leads, clinical may be of lead tip on A list of definitions regarding and outcome is reported in Table Definitions for extraction procedures and implantable of leads and with the of or where there is by the number of of a of a lead that not impact the outcome of the procedure. This may be the tip or a part of the lead or the when the part not the risk of perforation, events, of or cause of or where there is clinical by the number of to either procedural or clinical or the development of or Extraction procedures that by the number of Lead or extraction with removal of lead Lead or extraction where part of the lead in the body or of complications is more complex as patients may also be additional procedures at the time of extraction, such as (e.g. was the pocket due to the extraction or the In addition, can impact (e.g. the patient as a of the extraction or due to the that was the indication for the It is important that be reported as as to avoid The of the is less important to the patient than the the complications must be and list of complications is in Table clear definitions to and allow for a understanding of the risks of the procedure. As the and complications are defined by their time in to the and their from to the of a that or from the time patient the the patient leaves the This includes complications to the of the the of and and the to the that or following the to the that or after following the and during the are into or with on and must be and This reporting and the to quality and outcomes. increased in a specific must be and a performed. complications can be only if are of the to the procedure, which is or in or In addition, that or requires or of or that requires surgical to of the to the that requires or procedural to and not or the it life or cause are as standard reported for a This complications and to the procedure, and should be the follow-up should be for a longer (e.g. This allow for a better understanding of the to the indication for extraction (e.g. of and if an extraction approach has For patients extraction for a device infection have to a 25% extraction. In addition, data extraction for infection The quality of scientific or registry is by the quality of the As with there is a of to be and for the to the data will should be to with and and avoid are available. such is Data at and by a This is a secure that can be used to of this is that it and data can be A list of parameters are detailed (the of parameters will upon the of the and an of a case report is available on the etc.). and (e.g. open left Heart Association presence of as these may procedural for the CIED. for extraction. should be and leads of leads. of device and leads. The lead of the and each of these components can the of the It is important that these data are available for The of an extracted lead may be if the is in the using to avoid in data for and each lead to the specific As an the (e.g. leads, subcutaneous leads, leads, or may be for each lead. The and for the device and leads should be of implant of procedural and complications are to this of leads etc.). of of leads including leads, lead etc. at extraction (and the of leads, presence of vegetations, contrast lead etc. Blood etc. these parameters may and in order to with of blood cultures infection is and of procedure. or procedure. or hybrid or whether a cardiac is in or operator imaging of and and their of etc.). tools used in which order for each of tools in the superior vena cava etc.). performed during the (e.g. pocket venoplasty, lead with or without of the lead etc.). of extraction for each in failure in access site, type of device this may and complications bleeding and their If the of vascular or cardiac should be as have an impact on performed. Blood management (e.g. etc.). type of access of complications date and and of There are in evidence in the of lead extraction. Some of the are below. in case of devices a removal is the following have to be the of additional diagnostic tools in patients with Clinical of different strategies of and of and their a system to the risk of complications associated with percutaneous removal that will a of patients for an open surgical approach for CIED extraction is the of device with or device as management in local and systemic infection. of of whether open surgery is in patients with a and endocarditis, but without an or other indication for open surgery (e.g. is a size to be extracted by TLE, open surgical or pacemaker and leads a decision-making process when extraction. The issues are around clearly the risk associated with lead and whether the potential of lead extraction the risk of the procedure. In an of the Data patients removal of an or lead complications and than with a lead There are data on the lead burden that in venous access issues and superior vena cava syndrome, and consensus are on as to the of abandoned leads that extraction of more than leads on or leads through the issues with abandoned leads, such as are also not well of on leads are abandoned (e.g. of the lead is important since this has a on future follow-up and extraction For leads or and data is essential to with clinical to the and a recall is an to a with a device that are by the to the degree of by the The provides but are by national and use a different recall system to the the This is an by a to reduce a risk of or in the of associated with the use of a device that is on the whether associated with direct or should be reported and should be via a the of clinical registries for device and lead in with and such as the and Experience This will of lead and patient in Standardization of and data is important for this require such as the system proposed by the tools for prospective of CIED may improve the a registry to This will require and of from multiple as proposed by the and other the or provides a from which lead (and data can be It is well that the presence of a wide variety of extraction tools is of to patient as well as procedural of and efficacy of the different tools is as some devices (e.g. may be used as for studies are for with the of new tools for which data (e.g. There are a number of risk associated with lead extraction research may for which may with management There to be a lack of consensus regarding should be to become in lead extraction. There are that extracting a of leads in at procedures as a for with of procedures at each to However, it is to for the multiple available tools in a limited number of It has been in a with that of locking stylets and laser can provide an and may improve types of are also available using and which allow of parameters such as traction force at different may also provide a to for who have a research is however to that can improve and impact procedural number of that an operator is to provide and effective lead extraction, and there are no true to may provide that can of extraction tools and but their will be by the with which the There is some evidence that the of complications and are to the of a TLE and the experience of the This is by data of the where the for and centres was procedures The was different and centres with in centres However, there was no in The differentiated and centres on case over a and data are to that are associated with better patient which may have future implications. The of different or hybrid on procedural is a of potential scientific In a large retrospective TLE procedures on the of surgical or management of procedural it was that was if surgical or was performed in the than in an A European Heart Rhythm Association published in that most TLE procedures at that time were performed in a hybrid In the ELECTRa of the procedures were performed in an hybrid This might a in the of TLE centres or might be to the different centres in the data studies the of management in TLE should the for such procedures on endpoints. A further with lack of evidence is the impact of type local with or without on during Data from the ELECTRa registry an even types the centres with a use of local on TLE procedures not clearly specific but require in case the is not performed data to be and to clarify this There a strong to a scientific for lead extraction recommendations in patient patient consist but are not to very and patients potentially open extraction procedures (e.g. lead than or leads into or to these patient is the that the of such patients in single series, even in are to It is of to perform future studies on a data of multiple either in the of studies or a lead extraction registry pool but this is to in the In this a of data should be to allow for data multiple As lead extraction is a for a randomized clinical but questions the should and provide appropriate have published clinical on TLE and large which are to improve understanding in this However, many questions still remain regarding TLE, not only the limited number of randomized trials but also the lack of in reporting procedures and These unresolved issues have given a strong incentive for this consensus The recommendations are to and and are to clinical scientific guidelines, quality and The also in evidence lead extraction, with the to in scientific trials and is available at of The EHRA

IMPORTANCE: Worsening chronic heart failure (HF) is a major public health problem. OBJECTIVE: To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF). DESIGN, SETTING, AND PARTICIPANTS: Dose-finding phase 2 study that randomized 456 patients across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic. INTERVENTIONS: Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was change from baseline to week 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point. RESULTS: Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, -0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, -0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, -0.122; 90% CI, -0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73-1.08; P = .15). The exploratory secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P < .02). Rates of any adverse event were 77.2% and 71.4% among the placebo and 10-mg vericiguat groups, respectively. CONCLUSIONS AND RELEVANCE: Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01951625.

There is an unmet need for effective treatment strategies to reduce morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Until recently, attention in patients with HFpEF was almost exclusively focused on the left side. However, it is now increasingly recognized that right heart dysfunction is common and contributes importantly to poor prognosis in HFpEF. More insights into the development of right heart dysfunction in HFpEF may aid to our knowledge about this complex disease and may eventually lead to better treatments to improve outcomes in these patients. In this position paper from the Heart Failure Association of the European Society of Cardiology, the Committee on Heart Failure with Preserved Ejection Fraction reviews the prevalence, diagnosis, and pathophysiology of right heart dysfunction and failure in patients with HFpEF. Finally, potential treatment strategies, important knowledge gaps and future directions regarding the right side in HFpEF are discussed.

Impairment of health after overcoming the acute phase of COVID-19 is being observed more and more frequently. Here different symptoms of neurological and/or cardiological origin have been reported. With symptoms, which are very similar to the ones reported but are not caused by SARS-CoV-2, the occurrence of functionally active autoantibodies (fAABs) targeting G-protein coupled receptors (GPCR-fAABs) has been discussed to be involved. We, therefore investigated, whether GPCR-fAABs are detectable in 31 patients suffering from different Long-COVID-19 symptoms after recovery from the acute phase of the disease. The spectrum of symptoms was mostly of neurological origin (29/31 patients), including post-COVID-19 fatigue, alopecia, attention deficit, tremor and others. Combined neurological and cardiovascular disorders were reported in 17 of the 31 patients. Two recovered COVID-19 patients were free of follow-up symptoms. All 31 former COVID-19 patients had between 2 and 7 different GPCR-fAABs that acted as receptor agonists. Some of those GPCR-fAABs activate their target receptors which cause a positive chronotropic effect in neonatal rat cardiomyocytes, the read-out in the test system for their detection (bioassay for GPCR-fAAB detection). Other GPCR-fAABs, in opposite, cause a negative chronotropic effect on those cells. The positive chronotropic GPCR-fAABs identified in the blood of Long-COVID patients targeted the β2-adrenoceptor (β2-fAAB), the α1-adrenoceptor (α1-fAAB), the angiotensin II AT1-receptor (AT1-fAAB), and the nociceptin—like opioid receptor (NOC-fAAB). The negative chronotropic GPCR-fAABs identified targeted the muscarinic M2-receptor (M2-fAAB), the MAS-receptor (MAS-fAAB), and the ETA-receptor (ETA-fAAB). It was analysed which of the extracellular receptor loops was targeted by the autoantibodies.

BACKGROUND: Implantation of mechanical cardiac support systems (MCSS) in patients with idiopathic dilated cardiomyopathy (IDC) may improve cardiac function and allow explantation of the device. We report of long-term effects of ventricular unloading on cardiac function, humoral anti-beta1-adrenoceptor autoantibodies (A-beta1-AABs), and myocardial fibrosis. METHODS AND RESULTS: Seventeen patients in New York Heart Association functional class IV with nonischemic IDC received MCSS. All had a cardiac index of < 1.6 L x min(-1) x m(-2) of body surface area, a left ventricular ejection fraction (LVEF) of <16%, and a left ventricular internal diameter in diastole (LVIDd) of >68 mm and tested positive for A-beta1-AABs. Echocardiographic evaluation, serum tests for A-beta1-AABs, and histological assessment of myocardial fibrosis were performed before and after MCSS implantation. The mean support duration was 230+/-201 days. Six patients died, four were transplanted, and two are still on MCSS. Five patients with significant cardiac recovery (mean LVIDd, 54+/-2.3 mm; LVEF, 47+/-3.7%) were weaned after 160 to 794 days and are now device free for 51 to 592 days. A-beta1-AABs disappeared gradually during MCSS without increase after weaning; cardiac function and volume density of fibrosis remained normal. Nine patients' cardiac function hardly improved during ventricular unloading. CONCLUSIONS: Cardiac function can be normalized in selected patients with end-stage IDC by MCSS. The degree of preoperative myocardial fibrosis may be an indicator for outcome; A-beta1-AABs can be used to monitor myocyte recovery. Weaning from MCSS offers an alternative to cardiac transplantation in certain patients.