The Efficacy and Safety of Sacubitril/Valsartan in Heart Failure Patients: A Review

Heart failure (HF) is one of the leading causes of morbidity and mortality worldwide. Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, has been approved for the treatment of HF. At present, there have been few systematic and detailed reviews discussing the efficacy and safety of sacubitril/valsartan in HF. In this review, we first introduced the pharmacological mechanisms of sacubitril/valsartan, including the reduction in the degradation of natriuretic peptides in the natriuretic peptide system and inhibition of the renin-angiotensin system. Then, we summarized the efficacy of sacubitril/valsartan in HF patients with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF) including the reduction in risks of mortality and hospitalization, reversal of cardiac remodeling, regulation of biomarkers of HF, improvement of the quality of life, antiarrhythmia, improving renal dysfunction and regulation of metabolism. Finally, we discussed the safety and tolerability of sacubitril/valsartan in the treatment of HFrEF or HFpEF. Compared with ACEIs/ARBs or placebo, sacubitril/valsartan showed good safety and tolerability, although the risk of hypotension might be high. In conclusion, the overwhelming majority of studies show that sacubitril/valsartan is effective and safe in the treatment of HFrEF patients but that it has little benefit in HFpEF patients. Sacubitril/valsartan will probably be a promising anti-HF drug in the near future.

Toward a New Paradigm for Targeted Natriuretic Peptide Enhancement in Heart Failure

The natriuretic peptide system (NPS) plays a fundamental role in maintaining cardiorenal homeostasis, and its potent filling pressure-regulated diuretic and vasodilatory effects constitute a beneficial compensatory mechanism in heart failure (HF). Leveraging the NPS for therapeutic benefit in HF has been the subject of intense investigation during the last three decades and has ultimately reached widespread clinical use in the form of angiotensin receptor-neprilysin inhibition (ARNi). NPS enhancement via ARNi confers beneficial effects on mortality and hospitalization in HF, but inhibition of neprilysin leads to the accumulation of a number of other vasoactive peptides in the circulation, often resulting in hypotension and raising potential concerns over long-term adverse effects. Moreover, ARNi is less effective in the large group of HF patients with preserved ejection fraction. Alternative approaches for therapeutic augmentation of the NPS with increased specificity and efficacy are therefore warranted, and are now becoming feasible particularly with recent development of RNA therapeutics. In this review, the current state-of-the-art in terms of experimental and clinical strategies for NPS augmentation and their implementation will be reviewed and discussed.

About Sacubitril/Valsartan: A Clinically-Oriented Primer for Internists

The medical therapy of heart failure (HF) has been traditionally based on inhibiting the main pathophysiologic mechanisms: the adrenergic and renin-angiotensin-aldosterone systems. Introducing the therapeutical triad of beta-blockers, angiotensin converting enzyme inhibitors and mineralocorticoid receptor antagonists in the treatment of HF patients almost 40 years ago marked an important step since they were not only addressing the symptoms of HF, but also the prognosis and life- expectancy of these patients. Although many discoveries have been made in the past years, no other therapeutic class was able to increase survival among HF patients, until recently, when th SA e benefits of modulating the natriuretic peptide system were brought to the attention of the scientific community. Increasing the levels of natriuretic peptides with Sacubitril/ Valsartan (SV) led to several benefits for the reduced ejection fraction HF population, including less long and short term complications, increased survival and a reduced symptom burden. As this article is being written, it is estimated that more than 2.8 million patients are being treated with SV(1). Therefore, SV is an important and validated therapy for HF patients and internists should be aware of its indications, benefits and management in clinical practice.

Modular complement assemblies for mitigating inflammatory conditions

Complement protein C3dg, a key linkage between innate and adaptive immunity, is capable of stimulating both humoral and cell-mediated immune responses, leading to considerable interest in its use as a molecular adjuvant. However, the potential of C3dg as an adjuvant is limited without ways of controllably assembling multiple copies of it into vaccine platforms. Here, we report a strategy to assemble C3dg into supramolecular nanofibers with excellent compositional control, using β-tail fusion tags. These assemblies were investigated as therapeutic active immunotherapies, which may offer advantages over existing biologics, particularly toward chronic inflammatory diseases. Supramolecular assemblies based on the Q11 peptide system containing β-tail–tagged C3dg, B cell epitopes from TNF, and the universal T cell epitope PADRE raised strong antibody responses against both TNF and C3dg, and prophylactic immunization with these materials significantly improved protection in a lethal TNF-mediated inflammation model. Additionally, in a murine model of psoriasis induced by imiquimod, the C3dg-adjuvanted nanofiber vaccine performed as well as anti-TNF monoclonal antibodies. Nanofibers containing only β-tail–C3dg and lacking the TNF B cell epitope also showed improvements in both models, suggesting that supramolecular C3dg, by itself, played an important therapeutic role. We observed that immunization with β-tail–C3dg caused the expansion of an autoreactive C3dg-specific T cell population, which may act to dampen the immune response, preventing excessive inflammation. These findings indicate that molecular assemblies displaying C3dg warrant further development as active immunotherapies.

ACE2 polymorphisms interplay with the apelinergic peptide system: potential tools for COVID-19 diagnosis and treatment

ACE2 polymorphisms have been previously linked to increased susceptibility to multiple diseases and are currently linked to SARS CoV-2 susceptibility and complications. Notably, ACE2 transcribed or regulated proteins include the activity of metaloproteinsase-2 and apelin-13 and 36, might be linked to abnormal immune responses and complications. Furthermore, potential genetic or serological tests might be developed to detect the higher vulnerable groups to SARS CoV-2 complications and/or mortality. Furthermore, we hypothesize that diabetic and obese patients suffer from exhausted and/or abnormally functioning apelinergic peptides that predispose them to a higher severe COVID-19 risk. Moreover, infusion of apelin-13 to treat selected critical cases of COVID-19, especially those complaining of refractory advanced heart failure not responding to other drugs, might be considered for clinical trials.

Surface peptide functionalization of zeolitic imidazolate framework-8 for autonomous homing and enhanced delivery of chemotherapeutic agent to lung tumor cells

This work demonstrates a new one-pot strategy for realizing a surface-functionalized zeolitic imidazolate framework that actively targets cancer cells via an autonomous homing peptide system to deliver a chemotherapeutic payload effectively.