Treatment of Hyperkalemia in Heart Failure

Abstract

Purpose of Review

The aim of this paper is to discuss strategies for prevention and management of hyperkalemia in patients with heart failure, including the role of novel therapies.

Recent Findings

Renin-angiotensin-aldosterone system (RAAS) antagonists, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and mineralocorticoid receptor antagonists (MRA) decrease mortality and morbidity in heart failure but increase the risk of hyperkalemia, especially when used in combination. Prevention of hyperkalemia and its associated complications requires careful patient selection, counseling regarding dietary potassium intake, awareness of drug interactions, and regular laboratory surveillance. Recent data suggests that the risk of hyperkalemia may be further moderated through the use of combined angiotensin-neprilysin inhibitors, novel MRAs, and novel potassium binding agents.

Summary

Clinicians should be mindful of the risk of hyperkalemia when prescribing RAAS inhibitors to patients with heart failure. In patients at highest risk, such as those with diabetes, the elderly, and advanced chronic kidney disease, more intensive laboratory surveillance of potassium and creatinine may be required. Novel therapies hold promise for reducing the risk of hyperkalemia and enhancing the tolerability of RAAS antagonists.

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Targeting Mitochondrial Calcium Handling and Reactive Oxygen Species in Heart Failure

Abstract

Purpose of Review

In highly prevalent cardiac diseases, new therapeutic approaches are needed. Since the first description of oxidative stress in heart failure, reactive oxygen species (ROS) have been considered as attractive drug targets. Though clinical trials evaluating antioxidant vitamins as ROS-scavenging agents yielded neutral results in patients at cardiovascular risk, the knowledge of ROS as pathophysiological factors has considerably advanced in the past few years and led to novel treatment approaches. Here, we review recent new insights and current strategies in targeting mitochondrial calcium handling and ROS in heart failure.

Recent Findings

Mitochondria are an important ROS source, and more recently, drug development focused on targeting mitochondria (e.g. by SS-31 or MitoQ). Important advancement has also been made to decipher how the matching of energy supply and demand through calcium (Ca²⁺) handling impacts on mitochondrial ROS production and elimination. This opens novel opportunities to ameliorate mitochondrial dysfunction in heart failure by targeting cytosolic and mitochondrial ion transporters to improve this matching process. According to this approach, highly specific substances as the preclinical CGP-37157, as well as the clinically used ranolazine and empagliflozin, provide promising results on different levels of evidence. Furthermore, the understanding of redox signalling relays, resembled by catalyst-mediated protein oxidation, is about to change former paradigms of ROS signalling. Novel methods, as redox proteomics, allow to precisely analyse key regulatory thiol switches, which may induce adaptive or maladaptive signalling. Additionally, the generation of genetically encoded probes increased the spatial and temporal resolution of ROS imaging and opened a new methodological window to subtle, formerly obscured processes.

Summary

These novel insights may broaden our understanding of why previous attempts to target oxidative stress have failed, and at the same time provide us with new targets for drug development.

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Neuroendocrine Tumors of the Esophagus: State of the Art in Diagnostic and Therapeutic Management

Abstract

Introduction

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms composed of cells containing dense-core neuroendocrine secretory granules in their cytoplasm. NETs of the esophagus are exceedingly uncommon, with a parallel absence of data published on clinical features, prognosis, and proposed treatment strategies.

Methods

As relevant classification is not well-established, knowledge acquired in NETs of lung and gastrointestinal sites usually guides esophageal NET management. Associated subtypes are divided based upon shared neuroendocrine features into small and large cell NET, typical and atypical carcinoid.

Results

Common presenting symptoms include dysphagia, abdominal discomfort, weight loss, melena, and on occasion, signs of carcinoid syndrome. Endoscopic findings describe a polypoid, nodular elevated lesion with an overlying surface depicted as mostly smooth and glistening. Disease metastasis is assessed using anatomical imaging, including computed tomography (CT), endoscopic ultrasonography (EUS), and positron emission tomography (PET)-CT. Prognosis is influenced by the extent of lymph node metastasis and potential lymphovascular invasion. Furthermore, proliferative activity, estimated using mitotic count or Ki-67 immunostaining, has been suggested as a significant prognostic parameter.

Conclusion

Therapeutic approach depends on clinical staging. Nevertheless, currently, a specific treatment algorithm for esophageal NETs has not been elucidated. Endoscopic resection has been proposed in NETs less than 1 cm in size with absence of regional lymph node metastasis, while surgical excision combined with adjuvant chemotherapy remains the treatment of choice.

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Barcelona Clinic Liver Cancer (BCLC) Staging: Does It Cover All Our Expectation

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Erratum to: Numerical Modelling of Femur Fracture and Experimental Validation Using Bone Simulant

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Electrospun PLGA Nanofiber Scaffolds Release Ibuprofen Faster and Degrade Slower After In Vivo Implantation

Abstract

While delayed delivery of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with improved tendon healing, early delivery has been associated with impaired healing. Therefore, NSAID use is appropriate only if the dose, timing, and mode of delivery relieves pain but does not impede tissue repair. Because delivery parameters can be controlled using drug-eluting nanofibrous scaffolds, our objective was to develop a scaffold for local controlled release of ibuprofen (IBP), and characterize the release profile and degradation both in vitro and in vivo. We found that when incubated in vitro in saline, scaffolds containing IBP had a linear release profile. However, when implanted subcutaneously in vivo or when incubated in vitro in serum, scaffolds showed a rapid burst release. These data demonstrate that scaffold properties are dependent on the environment in which they are placed and the importance of using serum, rather than saline, for initial in vitro evaluation of biofactor release from biodegradable scaffolds.

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Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

Abstract

One of the major challenges in the epilepsy field is identifying disease-modifying drugs in order to prevent or delay spontaneous recurrent seizure onset or to cure already established epilepsy. It has been recently reported that fingolimod, currently approved for the treatment of relapsing–remitting multiple sclerosis, has demonstrated antiepileptogenic effects in 2 different preclinical models of acquired epilepsy. However, to date, no data exist regarding the role of fingolimod against genetic epilepsy. Therefore, we have addressed this issue by studying the effects of fingolimod in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, a well-established genetic model of absence epilepsy, epileptogenesis, and neuropsychiatric comorbidity. Our results have demonstrated that an early long-term treatment with fingolimod (1 mg/kg/day), started before absence seizure onset, has both antiepileptogenic and antidepressant-like effects in WAG/Rij rats. However, these effects were transitory, as 5 months after treatment discontinuation, both absence seizure and depressive like-behavior returned to control levels. Furthermore, a temporary reduction of mTOR signaling pathway activity, indicated by reduced phosphorylated mammalian target of rapamycin and phosphorylated p70S6k levels, and by increased phosphorylated Akt in WAG/Rij rats of 6 months of age accompanied the transitory antiepileptogenic effects of fingolimod. Surprisingly, fingolimod has demonstrated longer-lasting positive effects on cognitive decline in this strain. This effect was accompanied by an increased acetylation of lysine 8 of histone H4 (at both 6 and 10 months of age). In conclusion, our results support the antiepileptogenic effects of fingolimod. However, the antiepileptogenic effects were transitory. Moreover, fingolimod might also have a positive impact on animal behavior and particularly in protecting the development of memory decline.

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