Treatment Of Systolic Heart Failure Research Articles

Predictors of Higher Frequency of Atrial Fibrillation in Patients with Cardiac Resynchronization Therapy.

Background and Objectives: Cardiac resynchronization therapy (CRT) is one of the effective therapeutic options in the treatment of systolic heart failure (HF) with persistent symptoms. This prospective study was designed to determine whether CRT with biventricular pacing would reduce the risk of development of atrial fibrillation (AF) and to identify predictors for AF occurrence. Materials and Methods: The study population consisted of 126 patients, with a mean age of 63.8 ± 9.1 years, who were eligible for CRT with biventricular pacing. Inclusion criteria were left ventricular ejection fraction (LVEF) ≤ 35%, QRS duration ≥ 130 msec, and persistent HF symptoms of New York Heart Association (NYHA) II or III, despite optimal drug therapy. Patients were followed for a period of 24 months and were evaluated through clinical, electrocardiographic, and echocardiographic examination at baseline (prior to CRT implantation), as well as at 6 and 24 months post-implantation. At the end of follow-up, patients were divided into clinical responders and non-responders based on the following criteria: decrease in NYHA class ≥ I, increase in LVEF ≥ 10%, and reduction in QRS duration ≥ 20 msec. Results: At follow-up, CRT was associated with a significant increase in LVEF (20.6 ± 6.9% pre-implantation, 32.9 ± 9.3% 24 months after implantation; p < 0.001), reduction in left ventricular end-diastolic and end-systolic diameters, and decrease in QRS duration (167.6 ± 14.3 msec pre-implantation, 131.7 ± 11.7 msec 24 months after implantation; p < 0.001), while left atrial (LA) diameter was slightly increased (p = 0.070). The frequency of AF occurrence increased after two years of follow-up (52.4% to 56.9%, p < 0.001). Significant predictors of AF occurrence in our study population were response to CRT-AF more frequent in non-responders (B = 8.134; p < 0.001), LA diameter-AF more frequent with larger LA diameter (B = 0.813; p < 0.001), and coronary sinus (CS) lead position-AF more frequent with posterolateral in comparison with lateral CS lead position (B = 5.159; p = 0.005). Conclusions: The results of our study provide new data on AF predictors in patients with HF subjected to CRT. There remains a permanent need for new predictors, which might help in patient selection and improvement in response rate.

Effect of implantable cardioverter-defibrillator in non-ischaemic systolic heart failure according to the Heart Failure Collaboratory Medical Therapy Score: extended follow-up of the DANISH trial

Abstract Background The Heart Failure Collaboratory (HFC) has developed a medical therapy score which integrates types and doses of guideline-directed pharmacotherapies in patients with systolic heart failure, providing a measure of treatment quality. In clinical trials, this score may help determine the additive effect of new treatments. In the Danish Study to Assess the Efficacy of Implantable Cardioverter Defibrillators (ICDs) in Patients with Non-ischaemic Systolic Heart Failure on Mortality (DANISH) trial, ICD implantation did not provide an overall survival benefit in patients with non-ischaemic systolic heart failure. Purpose Adding four years of additional follow-up to the DANISH trial, we examined the effect of ICD implantation according to baseline modified HFC (mHFC) medical therapy score. Methods In the DANISH trial, 1,116 patients with non-ischaemic systolic heart failure were randomised to receive an ICD (N = 556) or usual clinical care (N = 560, control group). The primary outcome was death from any cause. In the mHFC score, patients were assigned a score for each drug class of the original cornerstones of systolic heart failure treatment (renin-angiotensin-system inhibitor, beta-blocker, and mineralocorticoid receptor antagonist). The maximum score was 100%, corresponding to optimal medical therapy with all three types of medication (=&amp;gt;50% of target dose). Results The median mHFC score at baseline was 67% (25th-75th percentile, 67%-100%; range, 17%-100%). During a median follow-up of 9.5 years, the ICD group did not have significantly lower all-cause mortality compared with the control group (hazard ratio [HR] 0.89 [95% CI, 0.74-1.08]). The results were independent of the mHFC score at baseline (mHFC score = &amp;lt; median: HR 0.91 [95% CI, 0.70-1.19]; mHFC score &amp;gt; median: HR 0.87 [95% CI, 0.66-1.14]; P for interaction, 0.94). Similarly, ICD implantation did not reduce the rate of cardiovascular death overall (HR 0.87 [95% CI, 0.70-1.09]), and this association was not modified by the mHFC score (mHFC score = &amp;lt; median: HR 0.90 [95% CI, 0.65-1.24]; mHFC score &amp;gt; median: HR 0.84 [95% CI, 0.61-1.15]; P for interaction, 0.89). The ICD group had a significantly lower rate of sudden cardiovascular death in the overall population (HR, 0.60 [95% CI, 0.40-0.92]), and this association was not modified by the mHFC score (mHFC score = &amp;lt; median: HR 0.72 [95% CI, 0.40-1.29]; mHFC score &amp;gt; median: HR 0.53 [95% CI, 0.28-0.99]; P for interaction, 0.59). See Figure for results. Conclusions In this extended follow-up study of the DANISH trial, ICD implantation did not provide an overall survival benefit in patients with non-ischaemic systolic heart failure regardless of baseline medical heart failure therapy, assessed by the mHFC score.Modified HFC score in the DANISH trial

Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction.

In the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with HF and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) ≥70 bpm. In this study, we sought to determine the clinical significance of the time durations of HR reduction and the significant treatment effect on outcomes among patients with HFrEF. The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all-cause death after 169 days. Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta-blockers at maximally tolerated doses.

Characterization of Stimulatory Action on Voltage-Gated Na+ Currents Caused by Omecamtiv Mecarbil, Known to Be a Myosin Activator.

Omecamtiv mecarbil (OM, CK-1827452) is recognized as an activator of myosin and has been demonstrated to be beneficial for the treatment of systolic heart failure. However, the mechanisms by which this compound interacts with ionic currents in electrically excitable cells remain largely unknown. The objective of this study was to investigate the effects of OM on ionic currents in GH3 pituitary cells and Neuro-2a neuroblastoma cells. In GH3 cells, whole-cell current recordings showed that the addition of OM had different potencies in stimulating the transient (INa(T)) and late components (INa(L)) of the voltage-gated Na+ current (INa) with different potencies in GH3 cells. The EC50 value required to observe the stimulatory effect of this compound on INa(T) or INa(L) in GH3 cells was found to be 15.8 and 2.3 µM, respectively. Exposure to OM did not affect the current versus voltage relationship of INa(T). However, the steady-state inactivation curve of the current was observed to shift towards a depolarized potential of approximately 11 mV, with no changes in the slope factor of the curve. The addition of OM resulted in an increase in the decaying time constant during the cumulative inhibition of INa(T) in response to pulse-train depolarizing stimuli. Furthermore, the presence of OM led to a shortening of the recovery time constant in the slow inactivation of INa(T). Adding OM also resulted in an augmentation of the strength of the window Na+ current, which was evoked by a short ascending ramp voltage. However, the OM exposure had little to no effect on the magnitude of L-type Ca2+ currents in GH3 cells. On the other hand, the delayed-rectifier K+ currents in GH3 cells were observed to be mildly suppressed in its presence. Neuro-2a cells also showed a susceptibility to the differential stimulation of INa(T) or INa(L) upon the addition of OM. Molecular analysis revealed potential interactions between the OM molecule and hNaV1.7 channels. Overall, the direct stimulation of INa(T) and INa(L) by OM is assumed to not be mediated by an interaction with myosin, and this has potential implications for its pharmacological or therapeutic actions occurring in vivo.

PS-R02-2: HEART FAILURE AS A PRESENTING FEATURE OF CUSHING'S DISEASE: A CASE REPORT

Cushing's disease is an endocrine disorder in which the pituitary gland releases too much adrenocorticotropic hormone, resulting in excess synthesis and secretion of cortisol by the adrenal glands. Cushing's disease associated heart failure is rare in clinic and can be misdiagnosed with initial presentation of heart failure. Symptoms of heart failure are caused by structural and functional alterations in the heart. The disturbances of cardiac structure and function may be recovered by eucortisolaemia. A 30-year-old man with a medical past of hypertension and history of smoking presented to the outpatient department with global heart failure. The left ventricular ejection fraction (LVEF) was estimated as 31% and the blood pressure (BP) was above 180/100 mmHg. After 1 months of optimal pharmacological treatment for systolic heart failure, there was obvious improvement of LVEF of 42%. Clinical features were suspicious for Cushing's disease. Initially, the patient could not have an MRI because of metal sheet in the body. After removal of metal sheet, the pituitary imaging were suggestive of Cushing's disease. The patient was referred to the neurosurgical department and the adenoma was successfully removed. Approximately one year after his initial hospitalization, his cardiac structure and function had nearly returned to normal and there were no high BP and signs of Cushing's syndrome.

Insights into the Mechanism of the Cardiac Drug Omecamtiv Mecarbil─A Computational Study.

Omecamtiv mecarbil (OM) is a positive inotrope that is thought to bind directly to an allosteric site of the β-cardiac myosin. The drug is under investigation for the treatment of systolic heart failure. The drug is classified as a cardiac myosin modulator and has been observed to affect multiple vital steps of the cross-bridge cycle including the recovery stroke and the chemical step. We explored the free-energy surface of the recovery stroke of the human cardiac β-myosin in the presence of OM to determine its influence on this process. We also investigated the effects of OM on the recovery stroke in the presence of genetic cardiomyopathic mutations R712L, F764L, and P710R using metadynamics. We also utilized the method of transition path sampling to generate an unbiased ensemble of reactive trajectories for the ATP hydrolysis step in the presence of OM that were able to provide insight into the differences observed due to OM in the dynamics and mechanism of the decomposition of ATP to ADP and HPO42-, a central part of the power generation in cardiac muscle. We studied chemistry in the presence of the same three mutations to further elucidate the effect of OM, and its use in the treatment of cardiac disease.

Sustained-Release Ivabradine Hemisulfate in Patients With Systolic Heart Failure

BackgroundIvabradine has potent actions in reducing heart rate and improving clinical outcomes of chronic heart failure with reduced ejection fraction (HFrEF). At present, only the short-acting formulation of ivabradine is available that needs to be administered twice daily. ObjectivesThis study sought to evaluate the role of ivabradine hemisulfate sustained release (SR), a novel long-acting formulation of ivabradine dosed once daily, in stable patients with HFrEF. MethodsPatients with stabilized HFrEF in New York Heart Association functional class II-IV were enrolled and randomized to receive placebo or ivabradine SR in addition to standard medications. The primary endpoint was the change of left ventricular (LV) end-systolic volume index from baseline to week 32. ResultsWe randomly assigned 181 patients to placebo and 179 patients to ivabradine SR. After 32 weeks, a significant improvement of LV end-systolic volume index from baseline was observed in both arms with a greater effect in the ivabradine SR arm. Ivabradine SR therapy also exhibited superiority in improving LV end-diastolic volume index, LV ejection fraction, resting heart rate, the Kansas City Cardiomyopathy Questionnaire score, and hospital admission for heart failure worsening and cardiovascular disease in comparison to placebo. Overall adverse events showed no difference between the treatment arms. There were fewer occurrences of worsening heart failure in the ivabradine SR arm. ConclusionsThe present study demonstrates that ivabradine SR once daily in addition to optimum standard therapy improved heart function in patients with HFrEF. (Clinical Trial of Systolic Heart Failure Treatment of IvabRadine Hemisulfate Sustained-release Tablets [FIRST]; NCT02188082)

Small Molecule RPI-194 Stabilizes Activated Troponin to Increase the Calcium Sensitivity of Striated Muscle Contraction.

Small molecule cardiac troponin activators could potentially enhance cardiac muscle contraction in the treatment of systolic heart failure. We designed a small molecule, RPI-194, to bind cardiac/slow skeletal muscle troponin (Cardiac muscle and slow skeletal muscle share a common isoform of the troponin C subunit.) Using solution NMR and stopped flow fluorescence spectroscopy, we determined that RPI-194 binds to cardiac troponin with a dissociation constant KD of 6–24 μM, stabilizing the activated complex between troponin C and the switch region of troponin I. The interaction between RPI-194 and troponin C is weak (KD 311 μM) in the absence of the switch region. RPI-194 acts as a calcium sensitizer, shifting the pCa50 of isometric contraction from 6.28 to 6.99 in mouse slow skeletal muscle fibers and from 5.68 to 5.96 in skinned cardiac trabeculae at 100 μM concentration. There is also some cross-reactivity with fast skeletal muscle fibers (pCa50 increases from 6.27 to 6.52). In the slack test performed on the same skinned skeletal muscle fibers, RPI-194 slowed the velocity of unloaded shortening at saturating calcium concentrations, suggesting that it slows the rate of actin-myosin cross-bridge cycling under these conditions. However, RPI-194 had no effect on the ATPase activity of purified actin-myosin. In isolated unloaded mouse cardiomyocytes, RPI-194 markedly decreased the velocity and amplitude of contractions. In contrast, cardiac function was preserved in mouse isolated perfused working hearts. In summary, the novel troponin activator RPI-194 acts as a calcium sensitizer in all striated muscle types. Surprisingly, it also slows the velocity of unloaded contraction, but the cause and significance of this is uncertain at this time. RPI-194 represents a new class of non-specific troponin activator that could potentially be used either to enhance cardiac muscle contractility in the setting of systolic heart failure or to enhance skeletal muscle contraction in neuromuscular disorders.

Outcome Benefits Seen With 1 Year of Optimized Sacubitril/Valsartan for the Treatment of Systolic Heart Failure Managed by Pharmacists in a Cardiology Practice.

Pharmacists' care in heart failure (HF) management has been shown to better clinical outcomes, including use of guideline-directed medical therapy and hospital readmission, although the impact observed has varied among studies. To investigate the rates of all-cause hospitalization and hospitalization from HF (hHF) and changes in surrogate markers (left-ventricular ejection fraction, New York Heart Association Functional Classification [NYHA FC], diuretic requirements) for patients with HF with reduced ejection fraction (HFrEF) on angiotensin receptor-neprilysin inhibitor (ARNi) therapy optimized within a pharmacist clinic. Retrospective chart review of patients with HFrEF on sacubitril/valsartan from July 7, 2015, through January 1, 2018. For the primary outcome analysis, 70 patients with pre/post hospitalization data had a reduction in the rate of all-cause hospitalization from 45.7% in the 12 months prior to ARNi therapy initiation to 24.3% during the first year on optimized ARNi therapy (P = 0.004). The rate of hHF reduced from 24.3% to 8.6% (P = 0.003). For the secondary outcome analyses at the 6-month assessment point, which included 104 patients, ejection fraction improved from 26% to 34% (P < 0.001), NYHA FC improved or remained unchanged in 86.6% of patients, and weekly loop diuretic dosing requirements were significantly reduced. Real-world use of sacubitril/valsartan optimized within a pharmacist clinic was associated with reduced prevalence of all-cause and hHF during the first year of ARNi therapy. This study corroborates pharmacist involvement in HF management, which could be used to support further research and expanded pharmacist services.

Myosin Modulators: The New Era of Medical Therapy for Systolic Heart Failure and Hypertrophic Cardiomyopathy.

A new uprising pharmacological treatment for systolic heart failure and hypertrophic cardiomyopathy demonstrates very promising results the last years. Myosin modulators have already been tested in numerous studies. Myosin inhibitor (mavacamten) and myosin stimulator, (omecamtiv mecarbil) exhibit their effect by improving clinical outcomes, as well as reducing morbidity and mortality. More studies are however required for further evaluation and particularly effect on sarcomeric level. Side effects of both pharmacological agents have been described and should always be close monitored. Cardiopulmonary exercise test has a pivotal role by means of assessing treatment efficacy.

Cardiac Myosin Activation for the Treatment of Systolic Heart Failure.

Left ventricular systolic dysfunction is the hallmark pathology in heart failure with reduced ejection fraction. Increasing left ventricular contractility with beta-adrenergic receptor agonists, phosphodiesterase-3 inhibitors, or levosimendan has failed to improve clinical outcomes and, in some situations, increased the risk of sudden cardiac death. Beta-adrenergic receptor agonists and phosphodiesterase-3 inhibitors retain an important role in advanced heart failure. Thus, there remains an unmet need for safe and effective therapies to improve left ventricular systolic function. Two novel cardiac myotropes, omecamtiv mecarbil and danicamtiv, target cardiac myosin to increase left ventricular systolic performance. Neither omecamtiv mecarbil nor danicamtiv affects cardiomyocyte calcium handling, the proposed mechanism underlying the life-threatening arrhythmias associated with cardiac calcitropes and calcium sensitizers. Phase 2 clinical trials have demonstrated that these cardiac myosin activators prolong left ventricular systolic ejection time and promote left ventricular and atrial reverse remodeling. At higher plasma concentrations, these agents may be associated with myocardial ischemia and impaired diastolic function. An ongoing phase 3 clinical trial will estimate the clinical efficacy and safety of omecamtiv mecarbil. An additional study of these agents, which have minimal hemodynamic and renal effects, is warranted in patients with advanced heart failure refractory to guideline-directed neurohormonal blockers.

Comparison of DOS and Windows version of the MwPharm - a pharmacokinetic software for PK/PD monitoring of digoxin

Background and objectives: Digoxin is the oldest drug indicated for the treatment of systolic heart failure (HF). It is also useful in controlling excessive ventricular rate in the presence of atrial arrhythmias. Therapeutic drug monitoring (TDM) has become an integral part of its prescription, allowing to optimize therapy and to reduce the incidence of toxicity. Since 1991, the MwPharm software package (Mediware, Groningen, The Netherlands / Prague, Czech Republic) has been used for pharmacokinetic and pharmacodynamic (PK/PD) modelling in TDM, including digoxin. First Windows version with a broader spectrum was released in 2014, as a reaction of worse support of the DOS background on later versions of Windows. After its release, the company had decided to not develop DOS versions anymore, even though they are globally used with success. The aim of this study was to compare the usefulness of DOS and Windows version (WIN) of the MwPharm, and their prediction quality in TDM of digoxin.

Abstract 12877: Magnesium Deficiency Causes Reversible Metabolic Diastolic and Systolic Cardiomyopathies

Introduction: Low circulating magnesium (Mg) level is associated with increased cardiovascular mortality, and conversely, dietary Mg intake is associated with a decreased risk of developing heart failure. Hypothesis: We investigated whether Mg deficiency alone could cause cardiomyopathy. Methods: C57BL/6J mice were fed with a low-Mg diet (low-Mg, 15-30 mg/kg Mg) or a normal diet (nl-Mg, 600 mg/kg Mg) for 6 weeks. To test reversibility, half of the low-Mg mice were fed then with normal diet for another 6 weeks (low→nl-Mg group). Results: Mg deficiency increased mortality, especially in female mice. After 6 weeks of low-Mg diet, surviving mice showed significantly decreased serum Mg (0.9±0.1 vs. 2.8±0.1 mg/dL for nl-Mg) and a reciprocal increase in serum Ca, K, and Na. Low-Mg mice exhibited a decreased cardiac ejection fraction (EF%, 39.8±1.9% vs. 52.0±1.7% of nl-Mg) and impaired relaxation (E/e’: 21.1±1.1 vs. 15.4±0.4 of nl-Mg) in echocardiography. At the cellular level, ATP, Ca transient amplitude, sarcoplasmic reticulum (SR) Ca load, resting sarcomere length, and sarcomere shortening were all decreased significantly in low-Mg hearts and cardiomyocytes. These changes were accompanied by evidence of mitochondrial dysfunction with significantly increased mitochondrial ROS production and mitochondrial membrane depolarization. Mg repletion normalized electrolytes, contraction, relaxation, and cellular changes. The SR Ca pump (SERCA) was decreased, the SR Ca channel RyR2 oxidized, and cardiac myosin binding protein C S-glutathionylated in low-Mg mouse hearts. These changes were normalized with Mg repletion. In vivo , mitoTEMPO treatment during low Mg diet improved the cardiac relaxation and increased cellular ATP levels without improving contraction. Conclusions: Mg deficiency caused a reversible diastolic and systolic cardiomyopathy associated with mitochondrial dysfunction. This cardiomyopathy may explain the relationship of hypomagnesemia and worsening heart failure. Mg intake could reverse these changes, reinforcing the known correlation of increased Mg intake and reduced heart failure symptoms and mortality. In deficiency states, Mg supplementation may represent a novel treatment for systolic and diastolic heart failure.

Prescription bias in the treatment of chronic systolic heart failure impacts outcome

Abstract Background There is evidence that medical therapy with beta-blockers (BB) and renin-angiotensin-system-inhibitors, uptitrated to target dosage (TD) decreases mortality and hospitalizations in HFrEF. However, physicians seemingly do not sufficiently follow the guidelines and a great number of patients do not receive recommended dosages. As humans are visually deceivable, it might be that absolute numerical values of equipotent recommended TD and the “milligram-based” subjective weighting of tolerability by the individual physician influences the maximal prescribed dosage. Purpose We sought to assess whether different numerical TD of equipotent medications affect prescription patterns, potentially biases uptitration and impacts outcome. Methods 3737 HFrEF outpatients were identified from a prospective registry. Maximal achieved dosages of BB, ACEi and ARB after one year of repeated visits for uptitration were assessed. BB, ACEi and ARB with largest numerical differences in TD (10mg/d bisoprolol/nebivolol vs 200mg/d metoprolol; 10mg/d ramipril vs 40mg/d lisinopril/enalapril/fosinopril; and 32mg/d candesartan vs 320mg/d valsartan) were compared using the individually achieved dose as percentage of the defined TD at one year of FUP. The association of maximal achieved TD with HF hospitalization and overall survival were determined. Results Median age was 65 years (IQR: 55–74), 2720 patients (73%) were male. Within the whole study population, 1434 patients (38%) received bisoprolol/nebivolol, 280 (8%) metoprolol. Ramipril was prescribed in 599 (16%) patients, lisinopril/enalapril/fosinopril in 1138 (30%). 409 patients (11%) were on candesartan, 173 (5%) on valsartan. Significant differences at baseline were not clinically meaningful and there were no contraindications for uptitration in all subgroups. After one year aiming for up-titration dosages increased significantly in all medication-groups (p&amp;lt;0.001 for all). However, significantly less patients were treated with the TD when TD was numerically higher (BB: metoprolol (57 (20%)) vs bisoprolol/nebivolol (446 (31%), p&amp;lt;0.001); ACEi: lisinopril/enalapril/fosinopril (231 (20%) vs ramipril (313 (52%), p&amp;lt;0.001); ARB: valsartan (45 (26%) vs candesartan (166 (41%), p&amp;lt;0.001)). At 45 (IQR: 32–68) months of FUP, 859 (23%) of the patients were hospitalized for HF or died. Achievement of TD significantly improved outcome (Fig. 1A-C) and showed association with mortality and HF-hospitalization (BB: adj.HR=0.87, 95% CI: 0.79–0.95, p&amp;lt;0.001; ACEi: adj.HR=0.89, 95% CI: 0.81–0.97, p=0.023; ARB: adj.HR=0.74, 95% CI: 0.69–0.91, p=0.009). Conclusion The present analysis described the influence of the numerical values of recommended TD of equipotent drugs on the prescription behavior of the treating physician and on outcome. This psychological phenomenon was identified a substantial confounder at least partly responsible for the underuse of BB, ACEi and ARB in HF. Moreover, it was never shown that this cognitive illusion based on risk aversion is linked to outcome. Figure 1 Funding Acknowledgement Type of funding source: None

Identification of diphenylalkylisoxazol-5-amine scaffold as novel activator of cardiac myosin

To identify novel potent cardiac myosin activator, a series of diphenylalkylisoxazol-5-amine compounds 4–7 have been synthesized and evaluated for cardiac myosin ATPase activation. Among the 37 compounds, 4a (CMA at 10 µM = 81.6%), 4w (CMA at 10 µM = 71.2%) and 6b (CMA at 10 µM = 67.4%) showed potent cardiac myosin activation at a single concentration of 10 µM. These results suggested that the introduction of the amino-isoxazole ring as a bioisostere for urea group is acceptable for the cardiac myosin activation. Additional structure–activity relationship (SAR) studies were conducted. Para substitution (-Cl, –OCH3, -SO2N(CH3)2) to the phenyl rings or replacement of a phenyl ring with a heterocycle (pyridine, piperidine and tetrahydropyran) appeared to attenuate cardiac myosin activation at 10 µM. Additional hydrogen bonding acceptor next to the amino group of the isoxazoles did not enhance the activity. The potent isoxazole compounds showed selectivity for cardiac myosin activation over skeletal and smooth muscle myosin, and therefore these potent and selective isoxazole compounds could be considered as a new series of cardiac myosin ATPase activators for the treatment of systolic heart failure.

Short-term efficacy and safety of levosimendan in patients with chronic systolic heart failure.

The objective was to investigate and evaluate the short-term efficacy and safety of levosimendan in patients with chronic systolic heart failure. Forty-nine patients with chronic systolic heart failure during acute decompensation were randomly divided into a levosimendan group (26 cases) and a control group (23 cases). The control group received only routine treatment, while the levosimendan group received a levosimendan bolus with a load of 12 µg/kg, in addition to the same routine treatment as the control group. After 48 hours of treatment, N-terminal pro B-type natriuretic peptide (NT-proBNP) levels in the levosimendan group were significantly lower than those in the control group. In addition, the left ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) cardiac function scores of the levosimendan group were significantly higher and more improved than those of the control group seven days after treatment, but there was no significant difference in the left ventricular end-diastolic diameter between the two groups. Furthermore, 48 hours after treatment, there were no significant differences in potassium, haemoglobin, haematocrit and creatinine levels between the levosimendan and control groups. During the whole hospitalisation, there was one case of sudden death in the control group and one case of palpitations in the levosimendan group, and no hypotension or severe hypokalaemia occurred in either group. Levosimendan significantly improved NT-proBNP and LVEF in patients with chronic systolic heart failure, and improved NYHA cardiac function classification without significant cardiovascular events. Levosimendan is therefore effective and safe in the short-term treatment of chronic systolic heart failure.

Abstract 218: Magnesium Deficiency Causes Reversible Diastolic and Systolic Cardiomyopathies by Impairing Mitochondrial Function

Introduction: Hypomagnesemia is common in patients with diabetes, hypertension, and heart failure. A low circulating Mg level is associated with increased cardiovascular mortality, and conversely, dietary magnesium (Mg) intake is associated with a decreased risk of developing heart failure. In this study, we investigated whether Mg deficiency alone contributed to cardiomyopathy. Methods: C57BL/6J mice were fed with a low-Mg diet (low-Mg, 15-30 mg/kg Mg) or a normal Mg diet (nl-Mg, 600 mg/kg Mg) for 6 weeks. To test reversibility, half of the low-Mg mice were fed then with normal diet for another 6 weeks. Results: Mg deficiency increased mortality. The survival rate after 6-week low-Mg diet was 0 for female and 64.6% for male. Surviving male mice showed significantly decreased serum Mg (0.9±0.1 vs. 2.8±0.1 mg/dL for nl-Mg) and a reciprocal increase in serum Ca, K and Na. Mg deficiency was associated with a decreased ejection fraction (EF%, 39.8±1.9% vs. 52.0±1.7% of nl-Mg), diastolic dysfunction (E/e’: 21.1±1.1 vs. 15.4±0.4 of nl-Mg), and prolonged QTc intervals (55.1±0.8 vs. 46.0±1.2 ms of nl-Mg). At the cellular level, ATP, Ca transient amplitude, resting sarcomere length, and sarcomere shortening were all decreased significantly in low-Mg hearts. These changes were accompanied by significantly increased mitochondrial ROS production. Reintroduction of Mg normalized electrolytes, EF% (52.1±1.4%), E/e’ (15.3±0.7), QTc (49.4±1.7 ms) and cellular changes. SERCA2 was decreased, and oxidation of RyR2 and cardiac myosin binding protein C were increased in low-Mg hearts, all of which were reversed by Mg repletion. In vivo mitoTEMPO treatment on low-Mg mice (1 mg/kg/day IP injection for 2 weeks) improved the diastolic function (E/e’=16.7±2.0) and increased cellular ATP levels. Conclusion: Mg deficiency causes reversible diastolic and systolic cardiomyopathy associated with mitochondrial dysfunction. This cardiomyopathy may explain the relationship of hypomagnesemia and worsening heart failure. Mg intake reverses these changes, reinforcing the known correlation of increased Mg intake and reduced heart failure symptoms. In deficiency states, Mg supplementation may represent a novel treatment for both diastolic and systolic heart failure.

The Treatment of Heart Failure with Reduced Ejection Fraction.

Chronic congestive heart failure is a common condition that, if untreated, markedly impairs the quality of life and is associated with a high risk of recurrent hospitalization and death. This review is based on articles retrieved by a selective search in PubMed, as well as on relevant guidelines. Evidence-based treatment options are available only for congestive heart failure with a low ejection fraction. Pharma - cotherapy is based on neurohumoral inhibition of the renin-angiotensin-aldosterone system and the adrenergic system. The prognosis of patients with this condition has been further improved recently through the introduction of combined angiotensin receptor antagonists and neprilysin inhibitors. Modern implantable devices are a further component of treatment. Implantable defibrillators and special pacemakers for cardiac resynchronization are well established; the utility of alternative devices (baroreflex modulation or cardiac contractility modulation) needs to be investigated in further studies. It was recently shown that the catheter-based treatment of secondary mitral regurgitation with a MitraClip improves the outcome of selected patients. The treatment of chronic systolic heart failure as recommended in the relevant guidelines, with drugs and implanted devices if indicated, can significantly improve the clinical outcome.

The β-arrestin-biased β-adrenergic receptor blocker carvedilol enhances skeletal muscle contractility

A decrease in skeletal muscle strength and functional exercise capacity due to aging, frailty, and muscle wasting poses major unmet clinical needs. These conditions are associated with numerous adverse clinical outcomes including falls, fractures, and increased hospitalization. Clenbuterol, a β2-adrenergic receptor (β2AR) agonist enhances skeletal muscle strength and hypertrophy; however, its clinical utility is limited by side effects such as cardiac arrhythmias mediated by G protein signaling. We recently reported that clenbuterol-induced increases in contractility and skeletal muscle hypertrophy were lost in β-arrestin 1 knockout mice, implying that arrestins, multifunctional adapter and signaling proteins, play a vital role in mediating the skeletal muscle effects of β2AR agonists. Carvedilol, classically defined as a βAR antagonist, is widely used for the treatment of chronic systolic heart failure and hypertension, and has been demonstrated to function as a β-arrestin-biased ligand for the β2AR, stimulating β-arrestin-dependent but not G protein-dependent signaling. In this study, we investigated whether treatment with carvedilol could enhance skeletal muscle strength via β-arrestin-dependent pathways. In a murine model, we demonstrate chronic treatment with carvedilol, but not other β-blockers, indeed enhances contractile force in skeletal muscle and this is mediated by β-arrestin 1. Interestingly, carvedilol enhanced skeletal muscle contractility despite a lack of effect on skeletal muscle hypertrophy. Our findings suggest a potential unique clinical role of carvedilol to stimulate skeletal muscle contractility while avoiding the adverse effects with βAR agonists. This distinctive signaling profile could present an innovative approach to treating sarcopenia, frailty, and secondary muscle wasting.

Beneficial effects of ivabradine in patients with heart failure, low ejection fraction, and heart rate above 77 b.p.m.

AimsIvabradine has been approved in heart failure with reduced ejection fraction (HFrEF) and elevated heart rate despite guideline‐directed medical therapy (GDMT) to reduce cardiovascular (CV) death and hospitalization for worsening HF. The median value of 77 b.p.m. is the lower bound selected for the regulatory approval in Canada, South Africa, and Australia. Patient‐reported outcomes (PROs) including symptoms, quality of life, and global assessment are considered of major interest in the global plan of care of patients with HF. However, the specific impact of GDMT, and specifically ivabradine, on PRO remains poorly studied. In the subgroup of patients from the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT) who had heart rate above the median of 77 b.p.m. (pre‐specified analysis) and for whom the potential for improvement was expected to be larger, we aimed (i) to evaluate the effects of ivabradine on PRO (symptoms, quality of life, and global assessment); (ii) to consolidate the effects of ivabradine on the primary composite endpoint of CV death and hospitalization for HF; and (iii) to reassess the effects of ivabradine on left ventricular (LV) remodelling.Methods and resultsComparisons were made according to therapy, and proportional hazards models (adjusted for baseline beta‐blocker therapy) were used to estimate the association between ivabradine and various outcomes. In SHIFT, n = 3357 (51.6%) patients had a baseline heart rate > 77 b.p.m. After a median follow‐up of 22.9 months (inter‐quartile range 18–28 months), ivabradine on top of GDMT improved symptoms (28% vs. 23% improvement in New York Heart Association functional class, P = 0.0003), quality of life (5.3 vs. 2.2 improvement in Kansas City Cardiomyopathy Questionnaire overall summary score, P = 0.005), and global assessment [from both patient (improved in 72.3%) and physician (improved in 61.0%) perspectives] significantly more than did placebo (both P < 0.0001). Ivabradine induced a 25% reduction in the combined endpoint of CV death and hospitalization for HF (hazard ratio 0.75; P < 0.0001), which translates into a number of patients needed to be treated for 1 year of 17. Patients under ivabradine treatment demonstrated a significant reduction in LV dimensions when reassessed at 8 months (P < 0.05).ConclusionsIn patients with chronic HFrEF, sinus rhythm, and a heart rate > 77 b.p.m. while on GDMT, the present analysis brings novel insights into the role of ivabradine in improving the management of HFrEF, particularly with regard to PRO (ISRCTN70429960).