Super Responders Research Articles

Why Is the Group of Non-responders to Cardiac Resynchronization Therapy so Large? Some Ethical and Medical Aspects of the Topic

The aim of this single centre study (“St. Ekaterina” Hospital) is to assess the effect of a second successful cardiac resynchronization therapy (CRT) in patients who had already had an unsuccessful implantation of a CRT system at other medical centres in Bulgaria and were defined as “non-responders”. This is a prospective observational study. The patients have previously had an unsuccessful implantation of a left ventricular (LV) lead or the latter has not been placed in the target vessel. After the successful implantation of a new LV lead in another target vessel, the post-procedure criteria for echocardiographic (EchoCG) and clinical response were monitored. Over the period 2017–2019, 18 CRT systems have been implanted in 18 patients with an average age 65±1 years with initial heart failure (HF) according to the Classification of the New York Heart Association (NYHA) class III. The average LV ejection fraction (LVEF) was 28±1%. After the successful implantation of a new LV lead, patients presented with HF class II–III and LVEF 36±1%. In the new “upgrading” procedure, 15 patients (83%) had a good clinical and EchoCG response, and two of those 15 patients were “super responders”. The remaining three patients (17%) were “poor responders”. After the good clinical and echocardiographic response to the therapy with a second successful implantation of a LV lead in another target vessel, an important question arises, whether all “non-responders” to the CRT are actually supposed to be defined as such.

Characterization of Super-Responder Profile in Chronic Plaque Psoriatic Patients under Guselkumab Treatment: A Long-Term Real-Life Experience.

Background: The term "super responder" identifies a group of patients who exhibit a rapid and optimal response to biological treatment compared to the overall treated population. The primary objective of our study is to characterize this subgroup of patients to enable the early identification of those who will respond most effectively to the proposed treatment while also evaluating clinical efficacy. Methods: This retrospective study evaluated 232 patients treated with guselkumab in monotherapy for at least 20 weeks between November 2018 and November 2023. Patients were divided into two groups: those who achieved complete clear skin (PASI = 0) during the first 20 weeks of treatment were defined as super responders (SRe) and non-super responders (nSRe) were the remaining patients. PASI was assessed at weeks 0, 4, and subsequently every eight weeks. Predictors of the SRe status were evaluated by univariate and multivariate logistic regression analyses. Results: The univariate analyses showed that patients with psoriatic arthritis at the baseline, bio-naïve patients, or those who had not received an interleukin (IL) 17 inhibitor as their last therapy before guselkumab administration were more likely to be super responders to the proposed treatment. Multivariate logistic analysis models suggested that the combination of psoriatic arthritis at the baseline and the bio-naïve condition was the strongest predictive model for the SRe status. At week 204, the main difference between the two groups concerned the achievement of PASI100, maintained by 86.8 of SRe compared to 62.8% of nSRe. Conclusions: The efficacy and safety of guselkumab are confirmed in our real-life experience. Identifying the SRe status will undoubtedly play a role in clinical practice and the therapeutic decision-making algorithm.

Noninferiority of 16-Week vs 8-Week Guselkumab Dosing in Super Responders for Maintaining Control of Psoriasis

Psoriasis is a chronic inflammatory skin disease with unmet needs for tailored treatment and therapy de-escalation strategies. To evaluate early intervention with and prolonging the dosing interval for guselkumab, a p19 subunit-targeted interleukin (IL)-23 inhibitor, in patients with moderate to severe psoriasis. The GUIDE clinical trial is an ongoing phase 3b, randomized, double-blinded trial conducted across 80 centers in Germany and France comprising 3 parts evaluating the impact of early disease intervention, prolonged dosing interval, and maintenance of response following treatment withdrawal among adults with moderate to severe plaque psoriasis. In study part 2, reported herein, first and last patient visits were September 2019 and March 2022, respectively. In GUIDE part 1 (week [W]0-W28), patients received guselkumab, 100 mg, at W0, W4, W12, and W20. Those achieving a Psoriasis Area and Severity Index (PASI) of 0 at both W20 and W28 were termed super responders (SRes). In part 2 (W28-W68), SRes were randomized to guselkumab, 100 mg, every 8 weeks or every 16 weeks; non-SRes continued open-label guselkumab every 8 weeks. Primary objective was to demonstrate noninferiority (with a 10% margin) of guselkumab every 16 weeks vs every 8 weeks dosing among SRes for maintenance of disease control (PASI <3 at W68). Biomarker substudies assessed immunologic effects in skin and blood. Overall, 822 patients received guselkumab in part 2 (297 [36.1%] SRes [every 8 weeks/every 16 weeks; n = 148/n = 149] and 525 [63.9%] non-SRes). Among SRes, mean (SD) age was 39.4 (14.1) years, 95 (32.0%) were female, and 202 (68.0%) were male. The primary end point of noninferiority for guselkumab every 16 weeks vs every 8 weeks in SRes was met (P = .001), with 91.9% (137/149; 90% CI, 87.3%-95.3%) of SRes receiving every 16 weeks and 92.6% (137/148; 90% CI, 88.0%-95.8%) of SRes receiving dosing every 8 weeks having PASI lower than 3 at W68. Clinical effects corresponded with immunologic changes; skin CD8-positive tissue-resident memory T (TRM)-cell count decreased quickly from baseline, remaining low in both dosing groups. Similarly, serum IL-17A, IL-17F, IL-22, and β defensin (BD)-2 levels decreased significantly from baseline, remaining low in both dosing groups to W68. Guselkumab was well-tolerated; no new safety signals were identified. Psoriasis treatment guidelines lack or provide inconsistent advice on patient stratification and treatment de-escalation. We present the first randomized trial providing evidence that, in patients with early complete skin clearance at 2 consecutive visits (W20 and W28), extending the guselkumab dosing interval may control disease activity. ClinicalTrials.gov Identifier: NCT03818035.

A predictive model of super response to cardiac resynchronization therapy in short-term period.

The left bundle branch block, nonischemic heart failure (HF) and female gender are the most powerful predictors of a super response to cardiac resynchronization therapy (CRT). It is important to identify super responders who can derive most benefits from CRT. We aimed to establish a predicting model that could be used for prognosis of a super response to CRT in short-term period. Patients with QRS ≥ 130ms, New York Heart Association (NYHA) II-III class of HF, left ventricle ejection fraction (LVEF) ≤ 35% and indications for CRT were included in the study. Before and 6month after CRT the electrocardiography, echocardiography and cardiac scintigraphy were performed. The study's primary endpoint was the NYHA class improvement ≥ 1 and left ventricle end systolic volume decrease > 30% or LVEF improvement > 15% after 6month CRT. Based on collected data, we developed a predictive model regarding a super response to CRT. Of 49 (100.0%) patients, 32 (65.3%) had a super response to CRT. Patients with a super response were likelier to have a lower cardiac index (p = 0.007), higher rates of interventricular delay (IVD) (p = 0.003), phase standard deviation of left ventricle anterior wall (PSD LVAW) (p = 0.009) and ∆QRS (p = 0.02). Only IVD and PSD LVAW were independently associated with a super response to CRT in univariate and multivariate logistic regression. We created a logistic equation and calculated a cut-off value. The resulting ROC curve revealed a discriminative ability with AUC of 0.812 (sensitivity 90.62%; specificity 70.59%). Our predictive model is able to distinguish patients with a super response to CRT.

Nine-Month Continuous Fremanezumab Prophylaxis on the Response to Triptans and Also on the Incidence of Triggers, Hypersensitivity and Prodromal Symptoms of Patients with High-Frequency Episodic Migraine.

Objective: To investigate whether the incidence of triggers, prodromal symptoms, hypersensitivity symptoms accompanying headache and responses to triptans were modified during a continuous 9-month fremanezumab therapy for migraine prophylaxis. Patients and methods: We studied 63 patients with high-frequency episodic migraine (HFEM). Enrolled patients received fremanezumab for nine consecutive months before defining the response rates and being stratified into treatment responders (≥50-74% reduction in monthly headache days (MHDs)), super responders (≥75%), partial non-responders (<50%) and super non-responders (<30%). Through headache diaries, patients provided data in order to document the impact of fremanezumab on the incidence of triggers, associated symptoms followed by headache and response to triptans (the use of the migraine treatment optimization questionnaire-4 (mTOQ-4)) during the 9-month treatment period. Results: Fremanezumab had early (after 3 monthly cycles) beneficial effects on the response to triptans in the majority of responders with relevant increases in mTOQ-4 scoring, but also in half of partial non-responders. A significant reduction in median days with migraine-associated symptoms was seen in responders after 6 months of therapy with fremanezumab, mostly for osmophobia, photophobia, phonophobia and nausea/vomiting, but partial non-responders also benefited. Likewise, the incidence of self-reported prodromal symptoms was significantly reduced in responders and was modestly diminished in partial non-responders. Triggers remained unaffected in both responders and non-responders. Conclusions: Fremanezumab given for at least 6-9 months may exert neuromodulatory effects in the migraine brain. These effects could result both in the inhibition of migraine chronification, but also in the diminishing of the magnitude of migraine-associated symptoms, mostly in responders and in partial non-responders.

Obesity-Resistant Mice on a High-Fat Diet Display a Distinct Phenotype Linked to Enhanced Lipid Metabolism.

Individually, metabolic variations can significantly influence predisposition to obesity in the form of the obesity-prone (super-responders) and obesity-resistant (non-responders) phenotypes in response to modern calorie-dense diets. In this study, C57BL/6J mice (n = 76) were randomly assigned to either a low-fat diet (LFD) or a high-fat diet (HFD) for 6 weeks, followed by selection of the normally obese (HFD), non-responders (NR), super-responders (SR), or super-responders switched back to the low-fat diet (SR-LFD) for an additional 8 weeks. SR mice showed the highest gains in body weight, lean and fat body mass, and total and free water, in part due to increased feed efficiency, despite having a respiratory exchange ratio (RER) similar to that of NR mice. A switch to the LFD was sufficient to revert most of the observed physiological changes in the SR-LFD mice; however, voluntary physical activity and exercise capacity did not return to the basal level. NR mice showed the highest food intake, lowest feed efficiency, increased oxygen consumption during the light (rest) cycle, increased physical activity during the dark (active) cycle, and increased heat production during both cycles. These variations were observed in the absence of changes in food intake and fecal parameters; however, NR fecal lipid content was lower, and the NR fecal microbiome profile was characterized by reduced abundance of Actinobacteria. Taken together, our findings suggest that NR mice showed an increased ability to metabolize excessive dietary fats in skeletal muscle at the expense of reduced exercise capacity that persisted for the duration of the study. These findings underscore the need for further comprehensive investigations into the mechanisms of obesity resistance, as they hold potential implications for weight-loss strategies in human subjects.

Characteristics of 'super responders' and 'super nonresponders' to first biologic monotherapy for psoriasis: a nested case-control study.

It is unknown why some patients with psoriasis experience long-term effectiveness with their first biologic monotherapy. Our aim was to compare the baseline demographic, disease, genotypic, clinical and lifestyle characteristics of patients with psoriasis registered in the British Association of Dermatologists Biologics and Immunomodulators Register and the aligned Biomarkers and Stratification to Optimise outcomes in Psoriasis study who were designated as ‘super responders’ (SRs), defined as patients on their first biologic with more than 5 years continuous biologic monotherapy, or ‘super nonresponders’ (SNRs), defined as patients on their first biologic who had discontinued at least two biologics in their first year of treatment, to biologic therapy. Female sex, shorter study follow-up, higher Dermatology Life Quality Index, high frequency of adalimumab, less frequency of ustekinumab at registration, and higher number of comorbidities were associated with SNRs compared with SRs.

Cardiac resynchronosation and left ventricular ejection fraction improvement with single ventricular conduction pacing system lead

Abstract Background Conduction system pacing is a new modality to obtain physiologic pacing (PP) and normal to near normal cardiac synchrony; they often obtain shorter QRS durations and they could replace the need of Bi-V (CRT) implants if LVEF improves as much with less leads implanted. Methods From our cohort of 340 physiologic pacing attempts (2019-2023), we extracted all patients (pts) with available ultrasounds before and after implants, aiming to describe the variation of Left Ventricular Ejection Fraction (LVEF) over time; all attempts, including failures were analyzed. Results A total of 146 pts completed follow-up LVEF evaluation. Pts were 36,8% females; median age was 79 +/- 8.5 years. Indications were: SSS 25%, AV block 41% (including 11 post TAVR), Pacemaker induced cardiomyopathy (PIMC) 27% and AV node ablation in 7%. Success to achieve cardiac resynchronisation (defined as a QRS shorter than 140ms and a LVAT shorter than 90ms, or 20% reduction in QRS width) was obtained in 82,6% of pts (higher success rate achieved with LBB-P: 88,4% vs 55,5% for His-P). Procedural time (pts in-out) was 88min (+/- 37min). Pts with a QRS larger than 150ms (CRT indication) were 49% of the cohort. Patients with a LVEF less than 50% accounted for 54,8% of the cohort. Mean QRS duration was 141,9ms (+/-36) pre-implant and 129,3ms (+/- 19) post implant. Mean LVEF was 43,6% (+/- 14) before implant and increased to 50,2% (+/-12) post implant for the entire cohort, in pts with CRT indication, variation persisted: mean LVEF improved from 33,2 to 43,8% and QRS duration from 172,9 to 136,8ms. Pts with less than 50% LVEF had a response rate of 75,5% (increase in LVEF from 4-41%), and 33% of patients increase their LEVF between 10-30% (deemed super responders), only one pt decrease 10% her LVEF (a His failure implant). Conclusion Cardiac resynchronisation is feasible with only one ventricular lead, potentially with longer duration of batteries and lesser costs. Response rate is similar to CRT historical controls but super responders are twice to three times higher than historical controls.

Closed-loop stimulation in periods with less epileptiform activity drives improved epilepsy outcomes.

In patients with drug-resistant epilepsy, electrical stimulation of the brain in response to epileptiform activity can make seizures less frequent and debilitating. This therapy, known as closed-loop responsive neurostimulation (RNS), aims to directly halt seizure activity via targeted stimulation of a burgeoning seizure. Rather than immediately stopping seizures as they start, many RNS implants produce slower, long-lasting changes in brain dynamics that better predict clinical outcomes. Here we hypothesize that stimulation during brain states with less epileptiform activity drives long-term changes that restore healthy brain networks. To test this, we quantified stimulation episodes during low- and high-risk brain states-that is, stimulation during periods with a lower or higher risk of generating epileptiform activity-in a cohort of 40 patients treated with RNS. More frequent stimulation in tonic low-risk states and out of rhythmic high-risk states predicted seizure reduction. Additionally, stimulation events were more likely to be phase-locked to prolonged episodes of abnormal activity for intermediate and poor responders when compared to super-responders, consistent with the hypothesis that improved outcomes are driven by stimulation during low-risk states. These results support the hypothesis that stimulation during low-risk periods might underlie the mechanisms of RNS, suggesting a relationship between temporal patterns of neuromodulation and plasticity that facilitates long-term seizure reduction.

Conduction system pacing vs. biventricular pacing for cardiac resynchronization therapy in heart failure with reduced ejection fraction: An updated systematic review and meta-analysis

Conduction system pacing (CSP) is considered an effective and physiological form of pacing in patients requiring cardiac resynchronization therapy (CRT). To compare electrocardiographic (ECG), echocardiographic (ECHO) characteristics and clinical outcomes among patients with heart failure with reduced ejection fraction (HFrEF) undergoing CRT with CSP or biventricular pacing (BVP). This study protocol was registered in the PROSPERO registry (CRD42022375155) and the review was conducted per the PRISMA protocol. Four major databases were searched from inception till October 20, 2022, for relevant studies comparing CSP to BVP for CRT in patients with HFrEF. From a total of 10,072 references identified, 35 full-text were assessed and 18 studies (6 RCTs, 12 observational studies) were included in the review. Following left bundle branch area pacing (LBBAP), on average, paced QRS duration was 28 ms narrower in comparison to BVP (MD -27.69, CI -36.59 to -18.80), and a similar result was obtained with HBP vs. BVP as well. Left ventricular ejection fraction (LVEF) improvement was greater with CSP in comparison to BVP [LBBAP (MD 6.03, CI 4.16-7.91); HBP (MD 3.79, CI 0.46-7.11); HPSP (MD 6.60, CI 4.42-8.78). There were higher odds of being responders (OR 3.82, CI 1.88-7.75)/super responders (OR 2.08, CI 1.53-2.82) (per ECHO findings) in the CSP group, and overall mortality (OR 0.61, CI 0.40-0.93) and hospitalization for HF (HHF) (OR 0.37, CI 0.25-0.55) was lower in CSP group. Our analysis showed better ECG, ECHO, and clinical outcomes in terms of mortality and HHF with CSP compared to BVP.

Long-Term Efficacy of Mepolizumab at 3 Years in Patients with Severe Asthma: Comparison with Clinical Trials and Super Responders.

The efficacy mepolizumab in severe asthmatic patients is proven in the literature. Primarily to study the effect of mepolizumab on exacerbations, steroid dependence, and the continuation of efficacy in the long term. Secondarily to evaluate the effect of the drug on nasal polyps. Analyzing data from SANI (Severe Asthma Network Italy) clinics, we observed severe asthmatic patients treated with mepolizumab 100 mg/4 weeks, for a period of 3 years. 157 patients were observed. Exacerbations were reduced from the first year (-84.6%) and progressively to 90 and 95% in the second and third ones. Steroid-dependent patients decreased from 54% to 21% and subsequently to 11% in the second year and 6% in the third year. Patients with concomitant nasal polyps, assessed by SNOT-22, showed a 49% reduction in value from baseline to the third year. The study demonstrated the long-term efficacy of mepolizumab in a real-life setting.

Real-world experience with cannabidiol as add-on treatment in drug-resistant epilepsy

PurposeTo evaluate the efficacy and safety of cannabidiol (CBD) for the treatment of epilepsy in a real-world setting. MethodsIn this retrospective observational study, we included PwE with epilepsy who received a prescription for CBD between 01.03.2019 and 30.11.2022 and had a follow-up period ≥ 3 months. Participants were evaluated at baseline and after 3, 6, and 12 months. "Responders" were defined as individuals experiencing a reduction in seizure frequency > 30% but < 80% compared to baseline, while "super responders" were those with a reduction ≥ 80%. Adverse events were recorded to assess safety. ResultsForty-two PwE were included (mean age 36.1 ± 10.9 years; 14 females). In 24 patients CBD was prescribed on-label (Lennox-Gastaut syndrome, n = 18; Dravet syndrome, n = 5; tuberous sclerosis, n = 1), while 18 patients were treated off-label (ring chromosome 20 syndrome, n = 1; ring chromosome 17 syndrome, n = 1; Lafora disease, n = 3; Unverricht-Lundborg disease, n = 1; polymicrogyria, n = 2; febrile infection-related epilepsy syndrome, n = 1; non-lesional focal epilepsy, n = 2; developmental and/or epileptic encephalopathy of unknown etiology n = 6). The mean number of concomitant antiseizure medications was 3.4 (≥2 for all patients). At 3 months, 10 subjects (23%) were “responders” and 12 (29%) were “super-responders”. Efficacy was sustained at 6 and 12 months of follow-up. Twenty-two patients (52.3%) developed AEs, with drowsiness (36.5%) and diarrhea (9.8%) being the most common. The retention rate was 85.7%, 78.6%, and 71.4% at 3, 6, and 12 months, respectively. ConclusionsIn this monocentric real-world study, CBD was a safe and effective therapeutic option for highly drug-resistant patients, leading to a dramatic reduction in seizure frequency in over one-fourth of them, including off-label indications.

Parameters associated with improvement of systolic function in patients with heart failure

AimsIdentifying clinical and echocardiographic parameters associated with improvement in systolic function in outpatients with heart failure with reduced ejection fraction (HFrEF) could lead to more targeted treatment improving systolic function...

Real-world Performance of a New Strategy for Off-Label Use of Guselkumab in Moderate to Severe Psoriasis: Super-Responder Patients as the Epitome of Efficacy and Optimisation.

Guselkumab is a drug used to treat moderate to severe plaque psoriasis. However, real-life clinical data on its off-label use are limited, especially regarding the optimal drug dosage regimen for different patient profiles. The main objective of this real-world, single-centre, retrospective study was to identify the off-label guselkumab dosing regimen used in clinical practice. The study also aimed to evaluate the drug's efficacy, safety, and survival, as well as the proportion of super-responders (SR) based on a newly proposed definition. The study included 69 patients who started treatment with guselkumab between March 2019 and July 2021. Patients were followed up until April 2022, during which time their efficacy, safety, persistence, and use of guselkumab were recorded. Patients were aged ≥ 18 years and had moderate to severe plaque psoriasis. The mean disease duration was 18.6 years, and 59% of patients had received at least one biologic treatment before guselkumab with a mean of 1.3 biologics per patient. The initial absolute Psoriasis Area and Severity Index(PASI) was 10.1 and decreased to 2.1 between Week 11-20 without significant changes in the PASI value throughout the 90 weeks of follow-up. The cumulative probability of drug survival was 93.5% at Week 52. No differences were found in terms of efficacy and survival associated with the off-label drug dosage regimens compared to the doses described in the Summary of Product Characteristics (SmPC). The greatest adjustments in the drug administration regimen were achieved in the subgroups of bio-naïve and SR patients, with a reduction in the number of administrations by 40% and 47% compared to the regimen described in the SmPC. Super-response to guselkumab was mainly associated with patients naïve to previous biologic treatment. The study demonstrated that off-label use of guselkumab was safe and effective in real-life clinical practice. The findings suggest that adjustments to the drug administration regimen may be necessary to optimise its use in different patient profiles, especially in SR and bio-naïve patients. Further studies are needed to confirm these findings.

Effectiveness of mepolizumab in patients with severe eosinophilic asthma: In a real life study

We analyzed the effects of mepolizumab treatment on symptoms, asthma attacks, pulmonary function test parameters peripheral blood eosinophil level, and percentage in patients with severe eosinophilic asthma receiving mepolizumab treatment as the baseline, sixth and twelfthmonth data. The medical records of patients diagnosed with severe eosinophilic asthma and treated with mepolizumab at our clinic were retrospectively reviewed for the period between January 2018 and December 2021. Demographic data of the patients, duration of asthma disease, comorbidities such as a nasal polyp, eosinophilic granulomatous polyangiitis, and nonsteroidal anti-inflammatory drug exacerbated respiratory disease were investigated. A comparison was made of various factors before initiating mepolizumab treatment, as well as at the sixth and twelfth month after treatment initiation. These factors include asthma control test scores, frequency of asthma attacks (including emergency admissions, hospitalizations, and intensive care admissions), peripheral blood eosinophil levels and percentages, and pulmonary function test parameters. Clinic and laboratory parameters that provide a prediction of being a responder and super responder were evaluated. A total of 21 patients were included in the study. Their mean age was 50.7 ± 11.9 years, and four (19%) were males. The mean duration of asthma diagnosis was 17.5 ±13.7 years. 14 patients (66.7%) were atopic. 4 patients (19%) had nasal polyps and four patients (19%) had NERD. Before mepolizumab, 13 (61.9%) patients had received omalizumab. The duration of receiving mepolizumab treatment was 29.2 ± 9.9 months. A statistically significant decrease was observed in both the number and percentage of eosinophils at months six and 12 (p<0.01). There was a statistically significant increase in FEV1 values both as a percentage and in milliliters at month 12. There was an increase in both percentage and milliliters in FEF25-75 values, but this increase did not reach statistical significance. There was a decrease in service admissions, intensive care admissions, and emergency admissions due to asthma exacerbations. Out of 21 patients, 11 (52.4%) were classified as responders, while 10 (47.6%) were classified as super responders. Although the number of patients in our study was limited, mepolizumab improved symptom scores in severe eosinophilic asthma, reduced the number of attacks, and improved pulmonary function test values.

The transjugular intrahepatic portosystemic shunt: Smaller stent diameters are required to optimize pressure response

The present treatment goal of the transjugular intrahepatic portosystemic shunt (TIPS) is a portosystemic pressure gradient of ≤12 mmHg or its reduction by >50%. This study relates the stent diameter to the reduction of the pressure gradient and attempts to predict the appropriate stent diameter necessary to reach the treatment goal. Pressure response, super response, and poor response were investigated in 208 de-novo TIPS patients and defined as post-TIPS gradients between >6 and 12 mmHg, ≤6 mmHg, or not reaching the goal (>12 mmHg, reduction <50%), respectively. Pressures were related to the smallest stent diameters measured by planimetry of the radiographic image. Responders (65%), super responders (26%), or poor responders (9%) had comparable stent diameters of 7.2 ± 1.0 mm, but different post-TIPS gradients (9.7 ± 1.9 mmHg, 4.5 ± 1.5 mmHg, and 14.2 ± 1.4 mmHg, p < 0.001), relative reduction of pre-TIPS gradients (51.7 ± 11.4%, 73.6 ± 11.1%, and 34.0 ± 9.1%, p < 0.001), and specific reduction per mm of stent diameter (7.5 ± 2.0%/mm, 10.1 ± 2.0%/mm, and 4.8 ± 1.4%/mm, p < 0.001). Prediction of the stent diameter required to reach response was not possible. Only two super responders had a stent diameter of <6 mm. Super and poor responders differed by the increase in the right atrial pressure (+5.0 mmHg vs. +3.1 mmHg, p = 0.026) and reduction in the portal vein pressure (−8.6 mmHg vs. −4.6 mmHg, p < 0.001). Most patients reached the treatment goal with stent diameters of <8 mm. Overtreatment (super response, gradient ≤6 mmHg) can be prevented by stent diameters as small as 6 mm. The individual response was not related to the stent diameter and not predictable. Cardiac dysfunction may play an important role by its effect on the right atrial (preload) and portal pressure (afterload).

THE NEW PCSK9-INHIBITOR INCLISIRAN: AN EXCEPTIONAL REDUCTION IN LDL CHOLESTEROL FROM THE FIRST PATIENTS OF THE NIGUARDA HOSPITAL

Objective: Dyslipidemia is one of the most prominent risk factors in coronary artery disease. With the new strict target of Low Density Lipoprotein (LDL) cholesterol in secondary prevention in some patients oral medication may not be sufficient. Inclisiran is a small interfiring RNA that inhibits the hepatic PCSK-9 synthesis inducing a reduction in low-density lipoprotein levels up to 50%. Conveniently, it only requires one administration every six months. Design and method: A 53-year-old man, with no previous cardiologic history, presented to our emergency department reporting acute chest pain and left arm paresthesia developed after an emotional stress. Electrocardiogram was normal with a slightly and stable increased of high sensitivity troponin T levels (18 ng/l). The patient had the following cardiovascular risk factors: type 2 diabetes mellitus, dyslipidemia, obstructive sleep apnea syndrome, obesity (body mass index 30), sedentary lifestyle. Taking into consideration his clinical presentation and his cardiovascular risk, a coronary computer tomography was performed showing severe stenosis in Left Anterior Descending (LAD) and right coronary arteries. The subsequent coronary angiography confirms the severe stenosis in the proxymal LAD and the mild stenosis (30%) in the right coronary artery. The LAD was treated with a drug eluting stent. At the time of the event the patient was already on therapy with rosuvastatina/ezetimibe 10/10 mg that we increased to a dosage of 20/10 mg. At the first medical examination after the hospitalization, his blood tests showed uncontrolled LDL cholesterol (70 mg/dl). We therefore decided to try lowering his cholesterol levels with addition of inclisiran. Results: After 3 months of inclisiran therapy, his blood test showed a surprisingly decrease in cholesterol levels (total cholesterol 78 mg/dl and LDL 11 mg/dl) reaching the desirable target. Conclusions: Inclisiran is a valid therapeutic strategy for reaching the desiderable cholesterol target in patient at high cardiovascular risk. In our first patients inclisiran, added to statin and ezetimibe therapy, successfully lowered LDL to the desirable target. Surprinsigly, it lowered LDL up to 85%, much more than expected. Further studies will be needed to identify which patients may be super responders to Inclisiran.

P487 THE NEW PCSK9–INHIBITOR INCLISIRAN: AN EXCEPTIONAL REDUCTION IN LDL CHOLESTEROL FROM THE FIRST PATIENTS OF THE NIGUARDA HOSPITAL

Abstract Background Dyslipidemia is one of the most prominent risk factors in coronary artery disease. With the new strict target of Low Density Lipoprotein (LDL) cholesterol in secondary prevention in some patients oral medication may not be sufficient. Inclisiran is a small interfiring RNA that inhibits the hepatic PCSK–9 synthesis inducing a reduction in low–density lipoprotein levels up to 50%. Conveniently, it only requires one administration every six months. Case description: a 53–year–old man, with no previous cardiologic history, presented to our emergency department reporting acute chest pain and left arm paresthesia developed after an emotional stress. Electrocardiogram was normal with a slightly and stable increased of high sensitivity troponin T levels (18 ng/l). The patient had the following cardiovascular risk factors: type 2 diabetes mellitus, dyslipidemia, obstructive sleep apnea syndrome, obesity (body mass index 30), sedentary lifestyle. Taking into consideration his clinical presentation and his cardiovascular risk, a coronary computer tomography was performed showing severe stenosis in Left Anterior Descending (LAD) and right coronary arteries. The subsequent coronary angiography confirms the severe stenosis in the proxymal LAD and the mild stenosis (30%) in the right coronary artery. The LAD was treated with a drug eluting stent. At the time of the event the patient was already on therapy with rosuvastatina/ezetimibe 10/10 mg that we increased to a dosage of 20/10 mg. At the first medical examination after the hospitalization, his blood tests showed uncontrolled LDL cholesterol (70 mg/dl). We therefore decided to try lowering his cholesterol levels with addition of inclisiran. After 3 months of inclisiran therapy, his blood test showed a surprisingly decrease in cholesterol levels (total cholesterol 78 mg/dl and LDL 11 mg/dl) reaching the desirable target. Conclusion Inclisiran is a valid therapeutic strategy for reaching the desiderable cholesterol target in patient at high cardiovascular risk. In our first patients inclisiran, added to statin and ezetimibe therapy, successfully lowered LDL to the desirable target. Surprinsigly, it lowered LDL up to 85%, much more than expected. Further studies will be needed to identify which patients may be super responders to Inclisiran.

MP-453086-9 CARDIAC RESYNCHRONIZATION THERAPY IN HEART FAILURE WITH REDUCED EJECTION FRACTION: CONDUCTION SYSTEM PACING VERSUS BIVENTRICULAR PACING: A SYSTEMATIC REVIEW AND META-ANALYSIS

Conduction system pacing (CSP) is considered a more physiological form of pacing in patients requiring cardiac resynchronization therapy (CRT). Recently there are studies showing the benefit of CSP over biventricular pacing (BVP) among patients with heart failure with reduced ejection fraction (HFrEF). However, published data were based on small and mostly single-centered studies. To compare ECG, echocardiographic characteristics, and clinical improvement among patients with HFrEF undergoing CRT with CSP versus BVP. This study protocol is registered in the PROSPERO (CRD42022375155), and the review is conducted per PRISMA protocol. Four major databases were searched from inception till October 20, 2022, for relevant publications comparing conduction system pacing with biventricular pacing for cardiac resynchronization therapy indications in the HFrEF population. All relevant data were extracted in an excel spreadsheet. Data analysis was performed using RevMan 5.4 software. Dichotomous data variables were pooled using an odds ratio (OR) with a 95% confidence interval (CI). Continuous variable pooled using mean difference (MD). A total of 10,072 references were found in the database search. 35 studies were assessed for full days eligibility;18 studies (6 RCTs, 12 observational studies) with a total of 1375 patients were included in the review. Following left bundle branch area pacing (LBBAP), the average paced QRS duration was 28 ms narrower in comparison to BVP (MD -27.69, CI -36.59 to -18.80, n = 515), and a similar result was obtained in His bundle pacing (HBP) vs BVP (MD -31.76, CI -48.74 to -14.77; n= 413). LVEF significantly improved in CSP in comparison to BVP [LBBAP (MD 6.03, CI 4.16-7.91; n= 564); HBP (MD 3.79, CI 0.46-7.11; n= 260); His-Purkinje system pacing (HPSP) (MD 6.60, CI 4.42-8.78; n=477) (FIGURE). There were higher odds of being responders (OR 3.82, CI 1.88-7.75; n = 265)/super responders (OR 2.08, CI 1.53-2.82; n= 811) (per ECHO findings) in the CSP group, and overall mortality (OR 0.61, CI 0.40-0.93; n= 908) and hospitalization for heart failure (HHF) (OR 0.37, CI 0.25-0.55; n= 993) was lower in CSP group. Our analysis showed that CSP was superior to BVP with regard to ECG and echocardiographic parameters, as well as clinical outcomes in terms of mortality and HHF.

Considering Diastolic Dyssynchrony as a Predictor of Favorable Response in LV-Only Fusion Pacing Cardiac Resynchronization Therapy

Background: CRT improves systolic and diastolic function, increasing cardiac output. Aim of the study: to assess the outcome of LV diastolic dyssynchrony in a population of fusion pacing CRT. Methods: Diastolic dyssynchrony was measured by offline speckle-tracking-derived TDI timing assessment of the simultaneity of E″ and A″ basal septal and lateral walls. New parameters introduced: E″ and, respectively, A″ time (E″T/A″T) as the time difference between E″ (respectively, A″) peak septal and lateral wall. Patients were divided into super-responders (SR), responders (R), and non-responders (NR). Results: Baseline characteristics: 62 pts (62 ± 11 y.o.) with idiopathic DCM, EF 27 ± 5.2%; 29% type III diastolic dysfunction (DD), 63% type II, 8% type I. Average follow-up 45 ± 19 months: LVEF 37 ± 7.9%, 34%SR, 61%R, 5%NR. The E″T decreased from 90 ± 20 ms to 25 ± 10 ms in SR with significant LV reverse remodeling (LV end-diastolic volume 193.7 ± 81 vs. 243.2 ± 82 mL at baseline, p < 0.0028) and lower LV filling pressures (E/E' 13.2 ± 4.6 vs. 11.4 ± 4.5, p = 0.0295). DD profile improved in 65% of R with a reduction in E/E' ratio (21 ± 9 vs. 14 ± 4 ms, p < 0.0001). Significant cut-off value calculated by ROC curve for LV diastolic dyssynchrony is E″T > 80 ms and A″T > 30 msec. Conclusions: The study identifies the cut-off values of diastolic dyssynchrony parameters as predictors of favorable outcomes in responders and super-responder patients with fusion CRT pacing. These findings may have important implications in patient selection and follow-up.