The influence of sensitization on mechanisms of organophosphorus pesticide-induced airway hyperreactivity.

We previously demonstrated that antigen sensitization increases vulnerability to airway hyperreactivity induced by the organophosphorus pesticide (OP) parathion. Sensitization also changes the mechanism of parathion-induced airway hyperreactivity to one that is dependent on IL-5. To determine whether this effect can be generalized to other OPs, and to other classes of pesticides, we measured airway responsiveness to vagal stimulation or intravenous acetylcholine in nonsensitized and ovalbumin-sensitized guinea pigs 24 hours after a single subcutaneous injection of the OPs diazinon or chlorpyrifos, or the pyrethroid permethrin. Sensitization exacerbated the effects of chlorpyrifos on bronchoconstriction in response to vagal stimulation or intravenous acetylcholine. Pretreatment with function-blocking IL-5 antibody prevented chlorpyrifos-induced airway hyperreactivity in sensitized, but not in nonsensitized, guinea pigs. In sensitized guinea pigs, blocking IL-5 decreased eosinophil activation, as measured by decreased eosinophil major basic protein in the trachea. In contrast, sensitization did not alter diazinon-induced airway hyperreactivity, and permethrin did not cause airway hyperreactivity in either nonsensitized or sensitized guinea pigs. None of the pesticides affected inflammatory cells in the bronchoalveolar lavage fluid or blood. We have previously shown that three different OPs cause airway hyperreactivity via loss of neuronal M2 muscarinic receptor function. Similar to parathion, but unlike diazinon, the mechanism of chlorpyrifos-induced airway hyperreactivity is changed by sensitization. Thus, OP-induced airway hyperreactivity is dependent on sensitization status and on the OP used, which may influence therapeutic approaches.

Mitral Transcatheter Edge-to-Edge Repair: Advancing Treatment Options for Degenerative Mitral Regurgitation.

Degenerative mitral regurgitation (DMR) has earned great interest because of modern and innovative technologies emerging in its treatment. MR affects roughly one-tenth of those older adults over the age of 75. MR if untreated leads to adverse heart remodeling, resulting in left ventricular dysfunction, pulmonary hypertension, and heart failure syndrome. Despite surgical valve repair/replacement treatment being the standard of care, a significant proportion of severe MR patients face unmet clinical needs because of high or prohibitive surgical risks. This has led to the emergence of transcatheter therapies for high- and prohibitive-risk surgical patients, most notably mitral transcatheter edge-to-edge repair devices.

Finerenone: Efficacy of a New Nonsteroidal Mineralocorticoid Receptor Antagonist in Treatment of Patients With Chronic Kidney Disease and Type 2 Diabetes.

Mineralocorticoid receptor stimulation by aldosterone can cause various cardiovascular and renal disease complications. Finerenone is a new oral nonsteroidal mineralocorticoid receptor antagonist that has been approved for clinical use by the Federal Drug Aministration, and has been shown in clinical trials to reduce the risk of sustained estimated glomerular filtration rate decline, end-stage renal disease, nonfatal myocardial infarction, hospitalization for heart failure and cardiovascular death in adult patients with chronic kidney disease associated with type 2 diabetes. The drug has also been shown to have fewer side effects than the steroidal mineralocorticoid receptor antagonists like spironolactone and eplerenone. In this review article, the authors will discuss the clinical pharmacology of finerenone, its clinical application and the additional studies that are now underway to further assess the efficacy of the drug in diabetic patients having cardiac and renal disease.

Intravenous Iron Therapy in Heart Failure Patients With Iron Deficiency: Benefits, Safety, and Guidelines.

Iron deficiency is a common comorbidity in heart failure (HF) patients, with up to 50% of ambulatory patients with HF affected. Intravenous (IV) iron therapy has emerged as a promising treatment approach for HF patients with concomitant iron deficiency. This review summarizes the current literature on the use of IV iron therapy in HF patients, focusing on its benefits in improving quality of life, and exercise capacity, and reducing HF hospitalizations. However, concerns about the long-term cardiotoxic effects of IV iron, including the risk of iron overload, are also addressed. The review highlights the importance of a balanced approach to iron replacement and provides an overview of the 2022 American College of Cardiology/American Heart Association guidelines, which recommend IV iron therapy for eligible patients. Additionally, the review underscores the need for further research, particularly in HF patients with preserved ejection fraction and acute HF. While IV iron therapy shows promise, questions about its safety and specific formulations remain to be fully addressed.

Alternative Access for TAVR: Choosing the Right Pathway.

Transcatheter aortic valve replacement (TAVR) has emerged as an alternative treatment option for patients with severe aortic stenosis regardless of surgical risk, particularly in those with a high and prohibitive risk. Since the advent of TAVR, transfemoral access has been the standard of care. However, given comorbidities and anatomical limitations, a proportion of patients are not good candidates for a transfemoral approach. Alternative access, including transapical, transaortic, transaxillary, transsubclavian, transcarotid, and transcaval, can be considered. Each alternative access has advantages and disadvantages, so the vascular route should be tailored to the patient's characteristics. However, there is no standardized algorithm when choosing the optimal alternative vascular access. In this review, we analyzed the evolution and current evidence for the most common alternative access for TAVR and proposed an algorithm for choosing the optimal vascular access in this patient population.

AVACOPAN: A New Adjunctive Therapy for Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Avacopan is a small-molecule complement 5a receptor (CD88) antagonist recently approved by the United States Food and Drug Administration as an adjunct therapy in combination with immunosuppressants and corticosteroids for treatment of ANCA-vasculitis. The selective ability of avacopan to inhibit the C5a receptor blocks neutrophil chemoattraction, activation, and adhesion while maintaining other beneficial complement pathways. Therefore, avacopan's unique selective property provides a breakthrough treatment for ANCA- vasculitis given that current therapies of corticosteroid treatment often lead to a decreased quality of life and a possible relapse. Clinical trials prove that avacopan is an excellent adjunctive treatment option, although it is not approved for the primary treatment of ANCA-vasculitis at this time. Initial clinical trials show substantial promise for avacopan, but additional studies with a longer duration will be needed to test for its durability and safety.

An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafish.

Truncating mutations in the giant sarcomeric protein Titin result in dilated cardiomyopathy and skeletal myopathy. The most severely affected dilated cardiomyopathy patients harbor Titin truncations in the C-terminal two-thirds of the protein, suggesting that mutation position might influence disease mechanism. Using CRISPR/Cas9 technology, we generated six zebrafish lines with Titin truncations in the N-terminal and C-terminal regions. Although all exons were constitutive, C-terminal mutations caused severe myopathy whereas N-terminal mutations demonstrated mild phenotypes. Surprisingly, neither mutation type acted as a dominant negative. Instead, we found a conserved internal promoter at the precise position where divergence in disease severity occurs, with the resulting protein product partially rescuing N-terminal truncations. In addition to its clinical implications, our work may shed light on a long-standing mystery regarding the architecture of the sarcomere.