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Aims: Heart failure with reduced ejection fraction (HFrEF) is a disease with high mortality and morbidity. Recent positive inotropic drug developments focused on cardiac myofilaments, that is, direct activators of the myosin molecule and Ca 2+ sensitizers for patients with advanced HFrEF. Omecamtiv mecarbil (OM) is the first direct myosin activator with promising results in clinical studies. Here, we aimed to elucidate the cellular mechanisms of the positive inotropic effect of OM in a comparative in vitro investigation where Ca 2+ -sensitizing positive inotropic agents with distinct mechanisms of action [EMD 53998 (EMD), which also docks on the myosin molecule, and levosimendan (Levo), which binds to troponin C] were included., Methods: Enzymatically isolated canine cardiomyocytes with intact cell membranes were loaded with Fura-2AM, a Ca 2+ -sensitive, ratiometric, fluorescent dye. Changes in sarcomere length (SL) and intracellular Ca 2+ concentration were recorded in parallel at room temperature, whereas cardiomyocyte contractions were evoked by field stimulation at 0.1 Hz in the presence of different OM, EMD, or Levo concentrations., Results: SL was reduced by about 23% or 9% in the presence of 1 μM OM or 1 μM EMD in the absence of electrical stimulation, whereas 1 μM Levo had no effect on resting SL. Fractional sarcomere shortening was increased by 1 μM EMD or 1 μM Levo to about 152%, but only to about 128% in the presence of 0.03 μM OM. At higher OM concentrations, no significant increase in fractional sarcomere shortening could be recorded. Contraction durations largely increased, whereas the kinetics of contractions and relaxations decreased with increasing OM concentrations. One-micromole EMD or 1 μM Levo had no effects on contraction durations. One-micromole Levo, but not 1 μM EMD, accelerated the kinetics of cardiomyocyte contractions and relaxations. Ca 2+ transient amplitudes were unaffected by all treatments., Conclusions: Our data revealed major distinctions between the cellular effects of myofilament targeted agents (OM, EMD, or Levo) depending on their target proteins and binding sites, although they were compatible with the involvement of Ca 2+ -sensitizing mechanisms for all three drugs. Significant part of the cardiotonic effect of OM relates to the prolongation of systolic contraction in combination with its Ca 2+ -sensitizing effect., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: While sympathetic overactivity in heart failure (HF) with reduced ejection fraction (HFrEF; EF < 40%) is well-documented, it is ill-defined in patients with mildly reduced EF (HFmrEF; EF 40-49%). Furthermore, the significance of ischaemic versus non-ischaemic aetiology in sympathetic activation is also unclear and has yet to be studied in HF. Our goal was to compare muscle sympathetic nerve activity (MSNA) in HFmrEF and HFrEF patients and in healthy subjects, as well as to elucidate the influence of the underlying disease., Methods and Results: Twenty-three HFrEF (age 58 ± 10 years), 33 HFmrEF patients (age 61 ± 10 years), including 11 subjects with non-ischaemic cardiomyopathy in each HF groups and 10 healthy controls (age 55 ± 10 years), were studied. MSNA-detected by peroneal microneurography, continuous arterial pressure, and ECG-was recorded. MSNA frequency (burst/min) and incidence (burst/100 cycles) were calculated. Association with the patients' characteristics were assessed, and aetiology-based comparisons were performed. Burst frequency demonstrated a significant stepwise increase in both HFmrEF (41 ± 11 burst/min) and HFrEF (58 ± 17 burst/min, P < 0.001) patients as compared with controls (27 ± 9; P < 0.001 for both HF groups). Similarly, burst incidences were 66 ± 17, 82 ± 15, and 36 ± 10 burst/100 cycles in HFmrEF, HFrEF patients, and in healthy controls, respectively (P < 0.001 for all). Burst frequencies in HF patients showed significant correlation with NT-proBNP levels, and significant inverse correlations with the subjects' mean RR intervals, stroke volumes, pulse pressures, and EF., Conclusions: Muscle sympathetic nerve activity parameters indicated significant sympathetic activation in both HFmrEF and HFrEF patients as compared with healthy controls with no difference in relation to ischaemic versus non-ischaemic aetiology., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: The current guidelines on pulmonary hypertension (PH) recommend the use of invasive examination for differentiating between left-sided heart disease-related (post-capillary) and pre-capillary PH. However, atrial sizes are considered markers of ventricular filling pressures. Therefore, we aimed to test the clinical applicability of atrial volumes measured by transthoracic three-dimensional echocardiography (3DE) in differentiating between pre-capillary and post-capillary PH., Methods and Results: Seventy-five consecutive patients with PH were prospectively examined with transthoracic 3DE. After less than 24 h, the patients underwent right heart catheterization and 3DE and were classified as pre-capillary or post-capillary PH according to the recommendations of the ESC guidelines. The atrial volumes were measured offline with dedicated commercial software. Thirty-eight patients (13 men, age 65 ± 18 year) had pre-capillary PH, and 37 (23 men, age 62 ± year) had post-capillary PH. The mean pulmonary artery pressures were similar in patients with pre-capillary and post-capillary PH (38 [IQR 26, 54] mmHg vs. 41 [IQR 33, 48] mmHg, respectively, P = 0.49). The left atrial indexed maximum (LAVi max) and minimum (LAVi min) volumes were significantly larger in the post-capillary PH patient group than in the pre-capillary PH patient group (LAVi max: 64 ± 32 mL/m 2 vs. 41 ± 25 mL/m 2 , P = 0.001; LAVi min: 50 ± 22 mL/m 2 vs. 26 ± 24 mL/m 2 , P < 0.0001). The indexed right atrial minimum volume (RAVi min) was also higher in patients with post-capillary PH (51 ± 27 mL/m 2 vs. 38 ± 26 mL/m 2 ; P = 0.02). Both the left atrial (LA) and right atrial (RA) volumes, especially the LA minimum volume, correlated with the pulmonary artery wedge pressure (PAWP) (r = 0.62 (P < 0.0001) for LAV min vs. r = 0.49 (P < 0.0001) for LAV max; r = 0.32 (P = 0.005) for RAV min vs. r = 0.24 (P = 0.04) for RAV max). Multivariate logistic regression analysis showed that LAVi min was an independent predictor of post-capillary PH. In the receiver operating characteristic (ROC) curves of parameters predicting the post-capillary PH, the areas under the curve (AUC) for LAVi min, LAVi max, and RAVi min were 0.86 (95% CI, 0.76-0.95), 0.78 (95% CI, 0.67-0.89), and 0.66 (0.53-0.78), respectively. Concerning the performance of the atrial volume ratio for differentiating post-capillary PH, the AUC of the atrial volume ratio was significantly lower [AUC: 0.66 (95% CI, 0.53-0.78)]. The ROC analysis indicated a possible cutoff value of 27.7 mL/m 2 for LAVi min to predict post-capillary PH (AUC = 0.86; sensitivity = 86%, specificity = 76%)., Conclusions: The BSA-indexed left atrial minimum volume measured by transthoracic 3DE is a useful parameter for differentiating pre-capillary from post-capillary pulmonary hypertension., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)