Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure

Felker, G. Michael; Borentain, Maria; Cleland, John G.F.; DeSouza, Mary M.; Kessler, Paul D.; O’Connor, Christopher M.; Seiffert, Dietmar; Teerlink, John R.; Voors, Adriaan A.; McMurray, John J.V.

doi:10.1002/ejhf.1504

Cited by 21 publications

(26 citation statements)

References 28 publications

(41 reference statements)

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“…Furthermore, in the RELAX‐AHF‐EU study, serelaxin showed a reduction of worsening HF and all‐cause death through Day 5 when added to standard of care therapy 308 . Ongoing studies will assess tolerability and efficacy of BMS‐986231, a novel nitroxyl donor with potential benefits on haemodynamics 309 …”

Section: Acute Heart Failurementioning

confidence: 99%

“…308 Ongoing studies will assess tolerability and efficacy of BMS-986231, a novel nitroxyl donor with potential benefits on haemodynamics. 309 Figure 4 Classification based on congestion/hypoperfusion status assessed by clinical examination performed at admission and discharge. Classification at discharge was used in 7448 patients discharged alive.…”

Section: Medical Therapymentioning

confidence: 99%

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Heart failure in the last year: progress and perspective

et al. 2020

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Research about heart failure (HF) has made major progress in the last years. We give here an update on the most recent findings. Landmark trials have established new treatments for HF with reduced ejection fraction. Sacubitril/valsartan was superior to enalapril in PARADIGM‐HF trial, and its initiation during hospitalization for acute HF or early after discharge can now be considered. More recently, new therapeutic pathways have been developed. In the DAPA‐HF and EMPEROR‐Reduced trials, dapagliflozin and empagliflozin reduced the risk of the primary composite endpoint, compared with placebo [hazard ratio (HR) 0.74; 95% confidence interval (CI) 0.65–0.85; P < 0.001 and HR 0.75; 95% CI 0.65–0.86; P < 0.001, respectively]. Second, vericiguat, an oral soluble guanylate cyclase stimulator, reduced the composite endpoint of cardiovascular death or HF hospitalization vs. placebo (HR 0.90; 95% CI 0.82–0.98; P = 0.02). On the other hand, both the diagnosis and treatment of HF with preserved ejection fraction, as well as management of advanced HF and acute HF, remain challenging. A better phenotyping of patients with HF would be helpful for prognostic stratification and treatment selection. Further aspects, such as the use of devices, treatment of arrhythmias, and percutaneous treatment of valvular heart disease in patients with HF, are also discussed and reviewed in this article.

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Section: Acute Heart Failurementioning

confidence: 99%

Section: Medical Therapymentioning

confidence: 99%

Heart failure in the last year: progress and perspective

et al. 2020

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“…247 A major trial is ongoing. 248 Loop diuretics represent the first option for the treatment of congestion in acute HF and diuretic resistance is associated with poorer outcomes. The cause of such diuretic resistance is mostly due to some defects at the level of renal tubules, rather than reduced diuretic delivery.…”

Section: Medical Therapymentioning

confidence: 99%

Highlights in heart failure

et al. 2019

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Heart failure (HF) remains a major cause of mortality, morbidity, and poor quality of life. It is an area of active research. This article is aimed to give an update on recent advances in all aspects of this syndrome. Major changes occurred in drug treatment of HF with reduced ejection fraction (HFrEF). Sacubitril/valsartan is indicated as a substitute to ACEi/ARBs after PARADIGM-HF (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.73 to 0.87 for sacubitril/valsartan vs. enalapril for the primary endpoint and Wei, Lin and Weissfeld HR 0.79, 95% CI 0.71-0.89 for recurrent events). Its initiation was then shown as safe and potentially useful in studies in patients hospitalized for acute HF. More recently, DAPA-HF trial showed the beneficial effects of the sodium-glucose transporter type 2 (SGLT2) inhibitor dapaglifozin vs. placebo, added to optimal standard therapy [HR, 0.74; 95% CI, 0.65 to 0.85;0.74; 95% CI, 0.65 to 0.85 for the primary endpoint]. Trials with other SGLT 2 inhibitors and in other patients, such as those with HF with preserved ejection fraction (HFpEF) or with recent decompensation, are ongoing. Multiple studies showed the unfavourable prognostic significance of abnormalities in serum potassium levels. Potassium lowering agents may allow initiation and titration of mineralocorticoid antagonists in a larger proportion of patients. Meta-analyses suggest better outcomes with ferric carboxymaltose in patients with iron deficiency. Drugs effective in HFrEF may be useful also in HF with mid-range ejection fraction. Better diagnosis and phenotype characterization seem warranted in HF with preserved ejection fraction. These and other burning aspects of HFpEF research are summarized and reviewed in this article.A multiparametric approach is often proposed for risk stratification of HF patients. The prognostic accuracy of the metabolic exercise test data combined with cardiac and kidney indexes risk score was found as superior to the HF Survival Score and Seattle HF model risk scores in a cohort of 6112 1106 D. Tomasoni et al.

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“…The results from this Phase IIa clinical trial also suggest BMS-986231 is safe and in HFrEF patients, exhibits a favorable hemodynamic profile (Tita et al, 2017). The success of these early Phase I and II clinical trials have led to the development of three further clinical trials to determine the effect of BMS-986231 on (1) symptomatic hypotension in HFrEF patients, (2) cardiac systolic and diastolic function in HFrEF patients, and (3) salt and water-handling in patients with HFrEF and HFmrEF (EF < 45%) [clinicaltrials.gov identifier(s) NCT03016325, NCT03357731, and NCT03730961, respectively] (Felker et al, 2019). To date, these studies have completed recruitment and are on-going.…”

Section: Serca2mentioning

confidence: 99%

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

2020

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Diseases of the heart, such as heart failure and cardiac arrhythmias, are a growing socioeconomic burden. Calcium (Ca 2+) dysregulation is key hallmark of the failing myocardium and has long been touted as a potential therapeutic target in the treatment of a variety of cardiovascular diseases (CVD). In the heart, Ca 2+ is essential for maintaining normal cardiac function through the generation of the cardiac action potential and its involvement in excitation contraction coupling. As such, the proteins which regulate Ca 2+ cycling and signaling play a vital role in maintaining Ca 2+ homeostasis. Changes to the expression levels and function of Ca 2+-channels, pumps and associated intracellular handling proteins contribute to altered Ca 2+ homeostasis in CVD. The remodeling of Ca 2+-handling proteins therefore results in impaired Ca 2+ cycling, Ca 2+ leak from the sarcoplasmic reticulum and reduced Ca 2+ clearance, all of which contributes to increased intracellular Ca 2+. Currently, approved treatments for targeting Ca 2+ handling dysfunction in CVD are focused on Ca 2+ channel blockers. However, whilst Ca 2+ channel blockers have been successful in the treatment of some arrhythmic disorders, they are not universally prescribed to heart failure patients owing to their ability to depress cardiac function. Despite the progress in CVD treatments, there remains a clear need for novel therapeutic approaches which are able to reverse pathophysiology associated with heart failure and arrhythmias. Given that heart failure and cardiac arrhythmias are closely associated with altered Ca 2+ homeostasis, this review will address the molecular changes to proteins associated with both Ca 2+handling and-signaling; their potential as novel therapeutic targets will be discussed in the context of pre-clinical and, where available, clinical data.

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Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure

Cited by 21 publications

References 28 publications

Heart failure in the last year: progress and perspective

Heart failure in the last year: progress and perspective

Highlights in heart failure

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

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