Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Combined gas electron diffraction and mass spectrometric experimental setup at Bielefeld University

Vishnevskiy Y, Blomeyer S, Reuter C, Pimenov OA, Shlykov SA. Combined gas electron diffraction and mass spectrometric experimental setup at Bielefeld University. REVIEW OF SCIENTIFIC INSTRUMENTS. 2020;91(7).We have designed and constructed a combined experimental setup for synchronous measurements of electron diffraction patterns and mass-spectra of gas samples. Test measurements have been performed for acetic acid at two temperatures, 296 K and 457 K. Electron diffraction data have been analyzed taking into account mass spectra measured in the same experiments. From the diffraction intensities, molecular structures and mole fractions of the acetic acid monomer and dimer have been refined. The obtained results demonstrate the importance of measuring mass spectra in gas electron diffraction experiments. In particular, it is possible to detect the sample decomposition, which can be used for the optimization of experimental conditions and for the data interpretation. The length of the hydrogen bond in the acetic acid dimer determined in this work, r(e)(OH) = 1.657(9) angstrom, is in good agreement with modern theoretical predictions. We recommend measuring the diffraction patterns of acetic acid for the calibration of the sample pressure in the diffraction volume

Combined Gas Electron Diffraction and Mass Spectrometric Experimental Setup at Bielefeld University

We have designed and constructed a combined experimental setup for synchronous measurements of electron diffraction patterns and mass-spectra of gas samples. Test measurements have been performed for acetic acid at two temperatures, 296 and 457 K, respectively. Electron diffraction data have been analysed taking into account mass spectra measured in the same experiments. From the diffraction intensities molecular structures and mole fractions of the acetic acid monomer and dimer have been refined. The obtained results demonstrate the importance of measuring mass spectra in gas electron diffraction experiments. In particular, it is possible to detect the sample decomposition, which can be used for the optimization of experimental conditions and for the data interpretation. The determined in this work length of the hydrogen bond in the acetic acid dimer, re(O...H) = 1.657(9) Å, is in good agreement with modern theoretical predictions. We recommend to measure diffraction patterns of acetic acid for the calibration of the sample pressure in the diffraction point.<br /

Gas-phase structure and conformations of copper(II) 2,9,16,23-tetra-tert-butyl phthalocyanine

Pimenov OA, Giricheva NI, Blomeyer S, Mayzlish VE, Mitzel NW, Girichev GV. Gas-phase structure and conformations of copper(II) 2,9,16,23-tetra-tert-butyl phthalocyanine. Structural Chemistry. 2015;26(5-6):1531-1541.The molecular structure of copper(II) 2,9,16,23-tetra-tert-butyl phthalocyanine (Cu(pc (t) )) was investigated by gas-phase electron diffraction with mass spectrometric control of vapor composition. Two conformers of C (4h) symmetry and three conformers of C (s) symmetry are predicted by quantum chemical calculations using the hybrid DFT method UB3LYP with 6-31G* and cc-pVTZ basis sets. According to the relative energies at the temperature of GED experiments (436 A degrees C), the two C (4h) symmetric conformers occur in 1.1 and 2.3 % abundance in the gas phase. The highest mole fraction (66.6 %) and lowest R-factor (4.25 %) correspond to one of the C (s) symmetric conformers; however, the two C (4h) symmetric models cannot be disproved by the Hamilton R-factor ratio test. The GED structural data of the three models mentioned reliably confirm approximate local D (4h) symmetry of the phthalocyanine ligand core

Photocontrol of Voltage-Gated Ion Channel Activity by Azobenzene Trimethylammonium Bromide in Neonatal Rat Cardiomyocytes

<div><p>The ability of azobenzene trimethylammonium bromide (azoTAB) to sensitize cardiac tissue excitability to light was recently reported. The dark, thermally relaxed <i>trans</i>- isomer of azoTAB suppressed spontaneous activity and excitation propagation speed, whereas the <i>cis</i>- isomer had no detectable effect on the electrical properties of cardiomyocyte monolayers. As the membrane potential of cardiac cells is mainly controlled by activity of voltage-gated ion channels, this study examined whether the sensitization effect of azoTAB was exerted primarily via the modulation of voltage-gated ion channel activity. The effects of <i>trans</i>- and <i>cis</i>- isomers of azoTAB on voltage-dependent sodium (INav), calcium (ICav), and potassium (IKv) currents in isolated neonatal rat cardiomyocytes were investigated using the whole-cell patch-clamp technique. The experiments showed that azoTAB modulated ion currents, causing suppression of sodium (Na⁺) and calcium (Ca²⁺) currents and potentiation of net potassium (K⁺) currents. This finding confirms that azoTAB-effect on cardiac tissue excitability do indeed result from modulation of voltage-gated ion channels responsible for action potential.</p></div

Effect of azoTAB on voltage-dependent Ca²⁺ currents in neonatal rat ventricular cardiomyocytes.

<p>(A) L-type Ca²⁺ currents obtained in the absence (control) and presence of 100 μM <i>trans</i>- azoTAB and after ~365 nm near-UV irradiation. Inset: original current trace in response to a voltage step from -40 to 0 mV for 300 ms. Inactivation of INav was achieved by a prestep from a holding potential HP of -80 mV to -40 mV for 100 ms. Similar results were obtained in three other cells. (B) ICavpeak recorded before and after incubation with 100 μM azoTAB, as well as after near-UV irradiation, and expressed as a percentage of that of the peak currents before the treatment. Each cardiomyocyte was incubated in the presence of azoTAB at room temperature for ~3 min in a measuring chamber. The currents were inhibited by approximately 60% relative to the control. Near-UV was applied for 90 s. The data are the means ± SEM from three cardiomyocytes, *<i>p</i>< 0.05. (C) Averaged I/V relations of the L-type Ca²⁺ currents elicited by the voltage-clamp protocol illustrated in the inset (HP = -80 mV) and plotted before (filled circles) and after (open circles) the application of azoTAB. The values are expressed as the mean ± SEM, <i>n</i> = 4. The current density is plotted as a function of the voltage.</p

Effect of azobenzene trimethylammonium bromide (azoTAB) on ramp currents in neonatal rat ventricular myocytes.

<p>(A) A representative TTX-sensitive current that was evoked when the voltage was increased smoothly from -120 to +50 mV for 200 ms. The cell was prepulsed to -120 mV for 100 ms from a HP of -80mV. The voltage protocol is shown above the current trace. The inset shows scaled current traces for comparison before and after the addition of 10 μM TTX. Similar results were obtained in three other cells. (B) Scaled ramp-evoked currents recorded in response to the same ramp protocol (from -120 to +50 mV, 200 ms) in the control and after the addition of 100 μM <i>trans</i>- azoTAB. Currents were recorded every 15 s after the application of the photoreactive substance. Three minutes after the application, the current was inhibited by approximately 83% relative to that of the control. Similar results were obtained in three other cells. (C) Ion currents recorded before and after incubation with 100 μM <i>trans</i>-azoTAB, as well as after near-ultraviolet (near-UV) irradiation and expressed as percentage. Each cardiomyocyte was incubated in the presence of azoTAB at room temperature for at least 3 min in a measuring chamber. Near-UV was applied for 90 s. The data represent the means ± SEM from four cardiomyocytes, *<i>p<</i> 0.05.</p

Effect of azoTAB on voltage-dependent Na⁺ currents in neonatal rat ventricular myocytes.

<p>(A) Current-voltage relationships recorded from single neonatal ventricular cardiomyocytes under control conditions (filled circles) and after exposure to 100 μM <i>trans</i>-azoTAB (open circles). Inset: the shape of the current-voltage stimulation protocol. The current density was calculated as the Na⁺ peak current divided by the membrane capacitance of each cell (<i>n</i> = 4). (B) Concentration dependency for <i>trans</i>- azoTAB-induced inhibition of INav in neonatal rat ventricular cardiomyocytes. Mean ± SEM, <i>n</i> = 3–4 for each point.</p