Repurposing the ß3-Adrenergic Receptor Agonist Mirabegron in Patients With Structural Cardiac Disease: The Beta3-LVH Phase 2b Randomized Clinical Trial.

Importance: Left ventricular (LV) hypertrophy contributes to the onset and progression of heart failure (HF), particularly for patients with pre-HF (stage B) for whom no treatment has yet proven effective to prevent transition to overt HF (stage C). The ß3-adrenergic receptors (ß3ARs) may represent a new target, as their activation attenuates LV remodeling. Objective: To determine whether activation of ß3ARs by repurposing a ß3AR agonist, mirabegron, is safe and effective in preventing progression of LV hypertrophy and diastolic dysfunction among patients with pre- or mild HF. Design, Setting, and Participants: The Beta3-LVH prospective, triple-blind, placebo-controlled phase 2b randomized clinical trial enrolled patients between September 12, 2016, and February 26, 2021, with a follow-up of 12 months. The trial was conducted at 10 academic hospitals in 8 countries across Europe (Germany, Poland, France, Belgium, Italy, Portugal, Greece, and the UK). Patients aged 18 years or older with or without HF symptoms (maximum New York Heart Association class II) were screened for the presence of LV hypertrophy (increased LV mass index [LVMI] of ≥95 g/m2 for women or ≥115 g/m2 for men) or maximum wall thickness of 13 mm or greater using echocardiography. Data analysis was performed in August 2022. Intervention: Participants were randomly assigned (1:1) to mirabegron (50 mg/d) or placebo, stratified by the presence of atrial fibrillation and/or type 2 diabetes, for 12 months. Main Outcomes and Measures: The primary end points were LVMI determined using cardiac magnetic resonance imaging and LV diastolic function (early diastolic tissue Doppler velocity [E/e'] ratio assessed using Doppler echocardiography) at 12 months. Patients with at least 1 valid measurement of either primary end point were included in the primary analysis. Safety was assessed for all patients who received at least 1 dose of study medication. Results: Of the 380 patients screened, 296 were enrolled in the trial. There were 147 patients randomized to mirabegron (116 men [79%]; mean [SD] age, 64.0 [10.2] years) and 149 to placebo (112 men [75%]; mean [SD] age, 62.2 [10.9] years). All patients were included in the primary intention-to-treat analysis. At 12 months, the baseline and covariate-adjusted differences between groups included a 1.3-g/m2 increase in LVMI (95% CI, -0.15 to 2.74; P = .08) and a -0.15 decrease in E/e' (95% CI, -0.69 to 0.4; P = .60). A total of 213 adverse events (AEs) occurred in 82 mirabegron-treated patients (including 31 serious AEs in 19 patients) and 215 AEs occurred in 88 placebo-treated patients (including 30 serious AEs in 22 patients). No deaths occurred during the trial. Conclusions: In this study, mirabegron therapy had a neutral effect on LV mass or diastolic function over 12 months among patients who had structural heart disease with no or mild HF symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT02599480.

A new approach to ticagrelor-based de-escalation of antiplatelet therapy after acute coronary syndrome. A rationale for a randomized, double-blind, placebo-controlled, investigator-initiated, multicenter clinical study.

The risk of ischemic events gradually decreases after acute coronary syndrome (ACS), reaching a stable level after 1 month, while the risk of bleeding remains steady during the whole period of dual antiplatelet treatment (DAPT). Several de-escalation strategies of antiplatelet treatment aiming to enhance safety of DAPT without depriving it of its efficacy have been evaluated so far. We hypothesized that reduction of the ticagrelor maintenance dose 1 month after ACS and its continuation until 12 months after ACS may improve adherence to antiplatelet treatment due to better tolerability compared with the standard dose of ticagrelor. Moreover, improved safety of treatment and preserved anti-ischemic benefit may also be expected with additional acetylsalicylic acid (ASA) withdrawal. To evaluate these hypotheses, we designed the Evaluating Safety and Efficacy of Two Ticagrelor-based De-escalation Antiplatelet Strategies in Acute Coronary Syndrome - a randomized clinical trial (ELECTRA-SIRIO 2), to assess the influence of ticagrelor dose reduction with or without continuation of ASA versus DAPT with standard dose ticagrelor in reducing clinically relevant bleeding and maintaining anti-ischemic efficacy in ACS patients. The study was designed as a phase III, randomized, multicenter, double-blind, investigator-initiated clinical study with a 12-month follow-up (ClinicalTrials.gov Identifier: NCT04718025; EudraCT number: 2020-005130-15).

Phrenic nerve stimulation in patients with central sleep apnea: a single­center experience from pilot and pivotal trials evaluating the remede System.

BACKGROUND: Patients with central sleep apnea (CSA) have recently been shown to have improved sleep metrics and quality of life (QoL) with phrenic nerve stimulation (PNS). AIMS: The aim of this study was to report the results of a partnership between cardiology, sleep medicine, and electrophysiology in a single clinical center as well as the enrollment, implantation, and follow­up experience demonstrating both the safety and efficacy of PNS. METHODS: This analysis included data from the pilot and pivotal trials investigating the effect of PNS using an implantable transvenous system in patients with CSA. We present our experience and data on the enrollment processes, implantation feasibility and safety, sleep indices, and QoL at 6 and 12 months of follow­up. RESULTS: Between June 2010 and May 2015, cardiology patients were prescreened and 588 of them were sent for in­home sleep test. Ninety­six patients were referred for polysomnographic studies, and 33 were enrolled and had an implant attempt, with 31 successfully receiving an implant. The apnea-hypopnea index was reduced in the pilot trial (mean [SD] of 48.7 [15.5] events/h to 22.5 [13.2] events/h; P <0.001) and in the pivotal trial (mean [SD] of 48.3 [18.8] events/h to 26.0 [21.9] events/h; P <0.001). Improvement in QoL was also observed. CONCLUSIONS: We showed that PNS improved sleep metrics and QoL in patients with CSA, which is a result of multiple factors, including a comprehensive coordination between cardiology, sleep medicine, and electrophysiology. This ensures appropriate patient identification leading to safe implantation and full patient compliance during follow­up visits.

InterAtrial Shunt Device (IASD®) implantation - a novel treatment method for heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a condition with complex pathophysiology and clinical profile. No treatment has been proven to reduce mortality or reduce morbidity in a meaningful way. In the era of percutaneous cardiac interventions, a novel method of reducing left atrial pressure by creating an iatrogenic interatrial shunt has been introduced. We present a report of implantation of InterAtrial Shunt Device (IASD®) in three consecutive patients.

Psychological gender of men with systolic heart failure: a neglected strategy to cope with the disease?

Diminished exercise capacity is a fundamental symptom of heart failure (HF), which is particularly disadvantageous for men for whom exercise capacity contributes significantly to their gender identity, self-esteem, and quality of life. In this study, we aimed to examine whether psychological gender would be different in men with systolic HF as compared with their healthy peers. The authors examined 48 men with systolic HF (age = 64 ± 10 years; body mass index = 28.3 ± 3.4 kg/m(2); NYHA I/II/III [%] = 25/65/10; left ventricular ejection fraction [LVEF] = 32.1 ± 7.8%) and 15 age-matched healthy men. Based on the results of the Polish version of the Bem Sex Role Inventory, the examined men were divided into four types of psychological gender: "masculine" (M), "feminine" (F), "unspecified" (U), and "androgynous" (A). None of the men with HF presented M type of psychological gender, whereas this type was found in 27% of the healthy men (p = .0002). The prevalence of both A (38% vs. 47%) and F (10% vs. 20%, both p > .05) types of psychological gender was similar between men with HF versus without HF. More men with HF fulfilled the criteria of the U type of psychological gender as compared with healthy peers (51% vs. 7%, p = .002). Men with HF and the F type of psychological gender were treated with spironolactone more frequently than those classified with the U and A types (both p < .05). The lack of "psychologically masculine" and the overrepresentation of "psychologically unspecified" gender types in the HF group suggests that psychological gender may be affected among men with HF.

[Intracardiac thrombi in pulmonary embolism of a priori non high risk: therapeutic dilemma]. / Skrzepliny wewnatrzsercowe w zatorowosci plucnej a priori niewysokiego ryzyka: dylematy terapeutyczne.

Pulmonary embolism (PE) of a priori non high risk according to ESC guidelines, but coexisting with intracardiac thrombi is potentially a life threatening disease. The recommendations regarding therapy in such situations are not clear. We report two cases of PE with coexisting intracardiac thrombi. The 74 year-old woman was admitted after previous cardiac arrest in the course of PE with the presence of intracardiac thrombi in right ventricle. Due to lack of clinical improvement during heparin administration she was treated with thrombolysis. The 72 year-old obese woman with hypertension, diabetes and previous stroke with right-sided paresis was admitted after 2 episodes of loss of consciousness, with intracardiac thrombus in both right and left heart. Due to contraindications to both surgery and thrombolysis, she was treated with heparin. Both women recovered successfully. These cases illustrate the importance of individual treatment strategy.

Comparison of invasive and non-invasive measurements of haemodynamic parameters in patients with advanced heart failure.

AIM: Measurement of haemodynamic parameters using a Swan-Ganz catheter is of clinical importance in patients with advanced heart failure; however, its applicability is limited due to its invasiveness. The aim of the study was to estimate the concordance between invasive and non-invasive measurements of haemodynamic parameters in patients with advanced heart failure. METHODS AND RESULTS: We examined 25 patients with advanced heart failure (20 men, age: 64 ± 11 years, New York Heart Association class III/IV: 88/12%, left ventricular ejection fraction: 37 ± 20%), 13 (52%) demonstrated decompensated heart failure. Resting haemodynamic parameters were measured simultaneously using two methods: an invasive Swan-Ganz catheterization and a thermodilution technique; and a non-invasive recording using a device for finger arterial pressure waveform analysis. The following parameters were analysed: stroke volume (SV, ml), cardiac output (CO, l/min) and systemic vascular resistance (SVR, dyne × s/cm5). The concordance between these two methods was assessed using the variability coefficient calculated according to a Bland-Altman method. Comparing the invasive and non-invasive measures, variability coefficients were: 13, 18 and 11% for SV, SVR and CO, respectively. Similar variability coefficients were obtained when invasive and non-invasive measurements were compared in prespecified subgroups of patients, distinguished based on the presence of decompensation, atrial fibrillation and values of SBP. CONCLUSIONS: Evaluation of haemodynamic parameters using a non-invasive method based on a pressure pulse contour model reveals an adequate concordance with the measures obtained using an invasive approach. Our results suggest that a non-invasive method for haemodynamic monitoring could be applied in clinical practice in patients with advanced heart failure.

Chronotropic response during exercise and recovery in men with mild systolic chronic heart failure.

BACKGROUND AND AIM: Pattern of heart rate (HR) changes during exercise and recovery is deranged in patients with cardiovascular disease, being considered as an independent predictor of poor outcome. This issue has been poorly examined in patients with chronic heart failure (CHF), particularly in the early stages of this syndrome. METHODS: Cardiopulmonary exercise testing (CPX) was performed in 54 men with sinus rhythm with mild stable systolic CHF in NYHA class I-II (age 57±12 years, LVEF 31±8%) and in 27 male volunteers without CHF (age 54±8 years, LVEF 67±7%). Apart from peak oxygen consumption (peakVO2), chronotropic response was evaluated using the following parameters: peak heart rate (HR) expressed in absolute values (maxHR) and age-predicted maximal values (%maxHR), HR increase during exercise (ΔHR), chronotropic index (CI=ΔHR/predicted ΔHR) and a regression coefficient of a linear function between HR and time during exercise (HR-time slope). Chronotropic response was also evaluated during recovery based on a regression coefficient of a linear function between HR and time during the first three-min of recovery (HR-time slope) and HR decrease after 90 s (HRR90), 120 s (HRR120) and 180 s (HRR180) from peak exercise. RESULTS: Men with CHF in NYHA II and I class demonstrated impaired chronotropic response to exercise as compared to control peers: NYHA II vs NYHA I vs control: maxHR 122±24 vs 154±25 vs 166±13 bpm, all p<0.05; %maxHR 76±14 vs 91±11 vs 101±7%, all p<0.001; ΔHR 48±20 vs 75±20 vs 91±14 bpm, all p<0.01; HR-time slope during exercise 5.6±2.2 vs 6.5±2.6 vs 8.3±1.2, all p<0.01 (NYHA I vs NYHA II, p>0.2); CI 0.56±0.36 vs 0.85±0.21 vs 1.02±0.13, all p<0.01; HR-time slope during three-min of recovery -14.0±7.0 vs -19.2±5.1 vs -23.5±3.8, p<0.05 (NYHA I vs control p>0.2); HRR90 30±17 vs 44±14 vs 49±9 bpm, p<0.05 (NYHA I vs control p>0.2); HRR120 35±8 vs 51±13 vs 59±9 bpm, all p<0.05; HRR180 41±17 vs 57±15 vs 68±10 bpm, all p<0.01. In CHF men, impaired peakVO2 was related to HR response to exercise (r=0.60, p<0.001) and recovery (r=0.50, p<0.001). Abnormal HR response to recovery correlated also to high NT-proBNP (r=0.33, p<0.05). In 13 men with CHF in whom CPX was performed twice between 17±11 days, variability coefficients for analysed parameters of chronotropic response ranged 8-15%. CONCLUSIONS: Parameters reflecting the chronotropic response to exercise and recovery are characterised by a good reproducibility, hence may be useful in the clinical assessment of patients with CHF. There is a marked reduction of chronotropic response in patients in the early stages of CHF, which may be another mechanism limiting exercise capacity.