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Background Electric isolation of the pulmonary veins (PVs) can successfully treat patients with atrial fibrillation (AF). Isolation of pulmonary veins can be achieved by several methods: radiofrequency, cryoballoon or laser balloon ablation (LBA). The main procedural challenge with either method is to achieve a continuous circumferential lesion at the left atrium-PVs junction, with the persistence of functional gaps. Purpose A novel endoscopic ablation system equipped with a precise motor control system (MCS) has been evaluated. The balloon is used with an endoscope to directly visualize and ablate tissue at the left atrial-PVs junction with laser energy. This system enables uninterrupted, high-speed, circumferential lesion creation under direct control of the physician. The MCS is intended to reduce procedure time and to ensure continuity of ablation lesions. The feasibility of the motorized ablation in terms of extent of applicability along each PV-left atrium junction and time of use of the manual point-by-point mode has been investigated. Methods 27 consecutive patients (male 70.3%, age 61.2±8.7 years) with paroxysmal or persistent AF who underwent LBA were enrolled in our institution. Exclusion criteria were any contraindication for the procedure including the presence of intracavitary thrombosis and contraindications to general anesthesia or deep sedation. After transseptal puncture, the balloon-based endoscopic ablation system was advanced to each PV ostium, and laser energy were projected onto the target. Results A total of 110 PVs were treated with LBA; in 9 patients there was a redundant right intermediate pulmonary vein; in 4 patients there was a right common ostium and in 2 a left common ostium. MCS was used for 82 PVs (74.5%): in particular, MCS was used continuously between 180° and 325° degrees (50 to 90% of PV circumference) for 35 PVs (31.8%) and between 326° and 359° degrees (91 to 99% of PV circumference) for 25 veins (22.7%). In 13 PVs (12%) MCS was used for the entire circumference. During 8508 (19.6%) seconds out of a total of 43.368 seconds, laser energy delivery occurred in the rapid mode by MCS. No clinical complications, either local or systemic (stroke or TIA, pericardial effusion, pericardial tamponade, pulmonary vein stenosis, esophageal injury, temporary or permanent phrenic nerve palsy), were observed neither during the use of MSC nor during the use of manual point-by-point mode. Of note, a pinhole rupture of the balloon occurred in 3 cases of our series, during the use of MCS, without harm to the patient and requiring only replacement of the LBA. Conclusions In our case series, laser balloon ablation with the help of motor control system appears safe and feasible in most cases for large portions of pulmonary vein circumference, providing considerable time sparing (74.5% of total ablation extent in 19.6% of total ablation time). Funding Acknowledgement Type of funding sources: None.

Funding Acknowledgements Type of funding sources: None. Background Implantable cardioverter defibrillator (ICD) is an effective therapy for sudden cardiac death (SCD). 2015 HRS/EHRA/APHRS/SOLAECE expert consensus document suggests long VT detection, above 185 bpm, as optimal ICD programming to reduce unnecessary therapies in primary prevention (PP). Purpose The aim of our study is to evaluate incidence, safety and efficacy of ICD treatment for VT arrhythmias below 185 bpm, in a contemporary population of PP ICD recipients with long detection intervals (LDI), morphological discrimination algorithm and antitachycardia pacing therapies (ATP) before shock. Methods We conducted a single centre retrospective study enrolling 236 patients implanted with a primary-prevention indication from January 2013 to June 2019. Patients were implanted with single or dual chamber single-lead transvenous ICD. All patients had standard device setting with long (at least 20 s in VT and 7 s in VF) VT/VF detection above 150 bpm and therapies starting from 171 with up to 5 ATP and multiple shocks. PainFREE-like bursts and Schaumann-like ramps ATP were always set in VT zone. Of each patient we collected a detailed report of up to five appropriate events and three inappropriate events. Arrhythmia diagnosis was confirmed from 3 independent expert physicians. Date of the event, cycle length, type of morphology (polymorphic or monomorphic), therapies with their effect were collected. Results During a mean follow-up of 42 months, 47 (20 %) and 18 (8%) patients had at least one appropriate and inappropriate activation, respectively. The detailed-events analysis shows that 16 (7%) patients had 38 (30%) appropriate events with rate Conclusions One third of detected arrhythmias had a rate below 188 bpm and 73% were true VT. In this slow VT zone, ATP had a high success rate with low percentage of acceleration.

Objectives This study sought to investigate the effect of different body mass index (BMI) categories on clinical outcomes in female patients treated with percutaneous coronary intervention (PCI) and drug-eluting stents. Background Patients with higher BMI might, paradoxically, have better long-term clinical outcomes after acute coronary syndrome treated with PCI. Methods We pooled patient-level data for female participants from 26 randomized trials on PCI with drug-eluting stents. Patients were stratified into underweight (BMI, Results Among 11,557 female patients included in the pooled database, 9,420 were treated with a drug-eluting stent and had BMI data available. Patients with higher BMI were significantly younger and with more cardiovascular risk factors. Only 139 patients were underweight and had significantly higher adjusted rates of cardiac mortality and all-cause mortality than the rest of the population (hazard ratio: 2.20 [1.31 to 3.71] compared with normoweight). There was a significantly lower frequency of unadjusted 3-year all-cause mortality in overweight, obese, and severely obese patients compared with normoweight. However, following multivariable analysis, a trend toward increased risk of death in severely obese patients was observed, describing an inverse “J”-shaped relation between BMI and 3-year mortality. Conversely, the relationship between BMI and other outcomes, such as major adverse cardiac events, was flat for normoweight and higher BMI. Conclusions The risk of 3-year adjusted cardiac events did not differ across BMI groups, whereas the risk of all-cause mortality compared with normoweight was significantly higher in underweight patients and lower in overweight patients with a trend toward increased risk in the severely obese population.

Background Available data on the long-term impact of coronary artery calcification (CAC) after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) are limited. Purpose We evaluated the long-term impact of CAC on outcomes after PCI and the respective performance of first- and second-generation DES. Methods We pooled patient-level data from 18 randomized trials evaluating DES categorized according to the presence of angiographic core lab-confirmed moderate or severe CAC in any target lesion. Outcome measures of interest were the patient-oriented composite endpoint (POCE; death, myocardial infarction [MI], or any revascularization), the device-oriented composite endpoint of target lesion failure (TLF; cardiac death, target vessel MI or ischemia-driven target lesion revascularization), and definite or probable stent thrombosis (ST). Multivariable Cox proportional regression with study as a random effect was used to assess 5-year outcomes. Results A total of 19,833 patients were included. Moderate or severe CAC was present in 6211 (31.3%) patients and associated with increased 5-year risk of the POCE (adjHR 1.12, 95% CI 1.05–1.20, p Conclusion In this large-scale study, target lesion moderate or severe CAC was associated with adverse patient- and device-related outcomes at 5 years, risks that were reduced but not eliminated with second-generation DES. Acknowledgement/Funding This investigator-sponsored study was funded by Abbott Vascular.

Background Heart failure with preserved ejection fraction (HFpEF) is a prevalent clinical condition in the aging population. HFpEF lacks specific therapies with a significant impact on survival, different therapeutic approaches have indeed failed, indicating a specific need in understanding the pathophysiology of the disease. Cardiac hypertrophy is one of the main features of HFpEF that contributes to impair diastolic function. Reducing ventricular stiffness associated with cardiomyocyte hypertrophy may indeed result in improved diastolic filling. Growth differentiation factor 11 (Gdf11), a TGF-β family factor, has been identified as a circulating factor able to reduce cardiac hypertrophy. Purpose Similar to myostatin (Gdf8), Gdf11 promotes the activation of atrophy pathways that induce ubiquitination of sarcomeric proteins. Gdf11 and Gdf8 activate both type I and II Tgf-β receptors, specifically by interacting with Acvr2a and Acvr2b (type II) and Alk 4/5/7 (type I), they activate Smad 3/4 pathway. Our data indicate a specific and more potent effect of Gdf11 in reducing cardiomyocytes size that is not recapitulated by Gdf8. Understanding the specific effect of Gdf11 on cardiomyocytes is crucial to develop therapeutic strategies to target the hypertrophic phenotype. Methods To investigate the effects of specific type I receptor KO on Smad signaling cascade we performed our preliminary experiment on HL-1 cells, a cardiac muscle cell line carrying a doxycycline inducible Cas9 transgene. Cell sensitivity of HL-1 to Gdf11 and Gdf8 was tested by performing a dose-response curve using a luciferase reporter for Smad 3/4 pathway activation (CAGA12). Selective Tgf-β type I receptor KO was induced using, for each receptor, two sgRNAs that have been designed to cleave the receptor coding sequence creating INDEL mutations and disrupt proper translation of the protein and confirmed by western blotting. Smad 3/4 activity was measured using a CAGA12-luciferase assay on HL-1-Cas9 transduced cells. Results Our data in HL-1 cells confirm a more potent effect of Gdf11 in activating Smad 3/4 pathway when compared to Gdf8 (Fig. 1A). Selective Alk4 and Alk5 KO induced a similar reduction in Smad 3/4 activation for both Gdf11 and Gdf8. Interestingly, Alk7 KO significantly reduced Gdf11 signaling that was not recapitulated when using Gdf8, suggesting that Alk7 receptor is crucial for Gdf11-dependent Smad 3/4 activation in HL-1 cells (Fig. 1B). Figure 1 Conclusions Our preliminary results indicate that part of Gdf11 cardiac specificity when compared to Gdf8 may reside in the usage of Alk7 for signaling. Alk7 has proposed as a protective factor for pathological cardiac hypertrophy by negatively regulating Mek-Erk1/2 signalling. Our results are now under investigation in vitro using mouse neonatal cardiomyocytes expressing Cas-9 and in vivo using cardiac-specific-Cas9-expressing C57 transgenic mice, in resting condition and after induction of pathological hypertrophy.

Current guidelines recommend high intensity lipid lowering (HILL) for treatment of established coronary artery disease (CAD). Adherence to and predictors of HILL use in usual-care setting remains unknown. We analyzed 8,976 consecutive patients with CAD undergoing PCI from Jan 2010 to May 2016 in

Background: Both Impella and Intra-aortic balloon pump (IABP) are used to provide hemodynamic support in high risk patients undergoing complex percutaneous coronary intervention (PCI). However, patterns of use and selection strategies for these devices in routine clinical practice are unclear

16 Normal Values for Arterial Stiffness in a Large Cohort of Healthy Children and Adolescents

A radioimmunoassay for luteinizing hormone-releasing hormone (LH-RH) is described which is capable of detecting LH-RH in plasma and brain tissues. Fluctuations in plasma and hypothalamic LH-RH as well as plasma LH were measured in immature female rats in which ovulation was induced by a single injection of pregnant mare serum (PMS). High plasma levels of LH-RH were found 47-49 h after the initial injection of PMS, coincident with high plasma LH concentrations. However plasma LH-RH levels were considerably lower at 55-57 h post-PMS, when plasma LH levels were elevated. Hypothalamic LH-RH content could not be correlated with either plasma LH-RH or LH levels.

Immature female rats were induced to ovulate 72 hours after an injection of pregnant mare serum (PMS). Melatonin, a compound synthesized in the pineal gland, was injected by 3 different routes; subcutaneously, intravenously, and intraocularly. 5 experiments were conducted to determine the influence of melatonin on the ovulation in the PMS-treated immature rat when given through the 3 different methods mentioned. In experiment 1, 10 mcg of melatonin, injected at 12, 2, and 4 p.m. on Day 2 after PMS, was ineffective in preventing ovulation, whether injected subcutaneously or into the eyeball. However, 100 mcg of melatonin placed into the eyeball reduced the number of rats ovulating, as well as ovarian weights, relative to controls. Uterine weights of these rats were increased compared to controls. In experiment 2, the intraocular injection of 100 mcg of melatonin inhibited ovulation in the greatest number of rats, compared with the intravenous or subcutaneous routes. Experiment 3 was a repeat of experiment 2, with comparable results. In experiment 4, with a dosage of 75 mcg of melatonin, the intraocular administration appeared to be the most effective route for inhibiting ovulation. In experiment 5, subcutaneous administration of 50 mcg of melatonin was completely ineffective in blocking ovulation or altering ovarian weights. The findings of this study confirm the inhibitory effect of melatonin upon ovulation in the immature PMS-induced ovulating rat and demonstrate that melatonin is more effective in inhibiting ovulation when administered intraocularly than subcutaneously, and more effective subcutaneously than intravenously.

Our initial decision to undertake an investigation of protein synthesis in cardiac muscle as a function of age was prompted by the conviction that the general question of age related changes in protein synthesis might usefully be studied in a tissue obviously essential to the survival of the animal. Heart certainly meets that criterion, and it offers some other advantages, too. The perfused heart system we selected occupies what is (to us at least) a satisfying intermediate position between whole-animal studies and their problems in controlling conditions, and cell-free preparations with their argueable physiological significance. There was one small problem at the start of this research; no one had reported procedures for the perfusion of isolated mouse hearts, but we were reasonably confident that it would be possible to adapt the standard rat system we had been using for some time (Florini and Dankberg, 1970) to studies on the mouse heart. Surprisingly, this turned out to be true.

It has previously been shown that plasma radioimmunoassayable growth hormone (GH) falls following exposure to cold. This response was examined in the normal, adrenalectomized, thyroparathyroidectomized, and adrenalectomized-thyroparathyroid-ectomized rat to determine the effects of the absence of corticosterone (B) and of the thyroid and parathyroid glands on this response. GH decreased from a high prestress level to a low poststress level in both the normal and adrenalectomized animal. The thyropara-thyroidectomized and the adrenalectomized-thyroparathyroidectomized rats had a low prestress GH level, which was not decreased further following cold exposure. The prestress B levels were higher in the thyroparathyroidectomized animals than in the normal. Poststress levels of B were similar in both groups. It appears that an intact thyroid and/or parathyroid gland is necessary to maintain the normal resting plasma levels of GH and B, whereas stress levels do not appear to be affected.

Resting plasma levels of growth hormone (GH) and corticosterone (B) were examined in the thyroid-deficient rat. Plasma GH was found to be lowered in thyroparathyroidectomized (TPTx) and 6-methylthiour