Heart failure with improved ejection fraction: Beyond diagnosis to trajectory analysis.

Left ventricular (LV) systolic dysfunction represents a highly treatable cause of heart failure (HF). A substantial proportion of patients with HF with reduced ejection fraction (EF;HFrEF) demonstrate improvement in LV systolic function (termed HF with improved EF [HFimpEF]), either spontaneously or when treated with guideline-directed medical therapy (GDMT). Although it is a relatively new HF classification, HFimpEF has emerged in recent years as an important and distinct clinical entity. Improvement in LVEF leads to decreased rates of mortality and adverse HF-related outcomes compared to patients with sustained LV systolic dysfunction (HFrEF). While numerous clinical and imaging factors have been associated with HFimpEF, identification of which patients do and do not improve requires further investigation. In addition, patients improve at different rates, and what determines the trajectory of HFimpEF patients after improvement is incompletely characterized. A proportion of patients maintain improvement in LV systolic function, while others experience a recrudescence of systolic dysfunction, especially with GDMT discontinuation. In this review we discuss the contemporary guideline-recommended classification definition of HFimpEF, the epidemiology of improvement in LV systolic function, and the clinical course of this unique patient population. We also offer evidence-based recommendations for the clinical management of HFimpEF and provide a roadmap for future directions in understanding and improving outcomes in the care of patients with HFimpEF.

Palliative Care for Patients With Heart Failure: Results From a Heart Failure Society of America Survey.

BACKGROUND: Multiple guidelines recommend specialty palliative care (PC) for patients with heart failure (HF), including patients with left ventricular assist devices (LVADs). However, the degree of integration and clinicians' perceptions of PC in HF care remain incompletely characterized. METHODS AND RESULTS: A 36-item survey was sent to 2109 members of the Heart Failure Society of America. Eighty respondents (53% physicians), including 51 respondents from at least 42 medical centers, completed the survey, with the majority practicing in urban (76%) academic medical centers (62%) that implanted LVADs (81%). Among the 42 unique medical centers identified, respondents reported both independent (40%) and integrated (40%) outpatient PC clinic models, whereas 12% reported not having outpatient PC at their institutions. A minority (12%) reported that their institution used triggered PC referrals based on objective clinical data. Of respondents from LVAD sites, the majority reported that a clinician from the PC team was required to see all patients prior to implantation, but there was variability in practices. Among all respondents, the most common reasons for PC referral in HF were poor prognosis, consideration of advanced cardiac therapies or other high-risk procedures and advance-care planning or goals-of-care discussions. The most frequent perceived barriers to PC consultation included lack of PC clinicians, unpredictable HF clinical trajectories and limited understanding of how PC can complement traditional HF care. CONCLUSION: PC integration and clinician perceptions of services vary in HF care. More research and guidance regarding evidence-based models of PC delivery in HF are needed.

Genetically based atrial fibrillation: Current considerations for diagnosis and management.

Atrial fibrillation (AF) is the most common atrial arrhythmia and is subcategorized into numerous clinical phenotypes. Given its heterogeneity, investigations into the genetic mechanisms underlying AF have been pursued in recent decades, with predominant analyses focusing on early onset or lone AF. Linkage analyses, genome-wide association studies (GWAS), and single gene analyses have led to the identification of rare and common genetic variants associated with AF risk. Significant overlap with genetic variants implicated in dilated cardiomyopathy syndromes, including truncating variants of the sarcomere protein titin, have been identified through these analyses, in addition to other genes associated with cardiac structure and function. Despite this, widespread utilization of genetic testing in AF remains hindered by the unclear impact of genetic risk identification on clinical outcomes and the high prevalence of variants of unknown significance (VUS). However, genetic testing is a reasonable option for patients with early onset AF and in those with significant family history of arrhythmia. While many knowledge gaps remain, emerging data support genotyping to inform selection of AF therapeutics. In this review, we highlight the current understanding of the complex genetic basis of AF and explore the overlap of AF with inherited cardiomyopathy syndromes. We propose a set of criteria for clinical genetic testing in AF patients and outline future steps for the integration of genetics into AF care.

Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors.

Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342. We synthesized both truncated and polar 2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes. Although aniline and pyridine derivatives interact with His342, benzonitriles conferred the best rat and human nNOS inhibition. Both introduction of a hydrophobic substituent next to the cyano group and aminoquinoline methylation considerably improved isoform selectivity. Most importantly, these modifications preserved Caco-2 permeability and reduced off-target CNS binding.

Targeting Bacterial Nitric Oxide Synthase with Aminoquinoline-Based Inhibitors.

Nitric oxide is produced in Gram-positive pathogens Bacillus anthracis and Staphylococcus aureus by the bacterial isoform of nitric oxide synthase (NOS). Inhibition of bacterial nitric oxide synthase (bNOS) has been identified as a promising antibacterial strategy for targeting methicillin-resistant S. aureus [Holden, J. K., et al. (2015) Chem. Biol. 22, 785-779]. One class of NOS inhibitors that demonstrates antimicrobial efficacy utilizes an aminoquinoline scaffold. Here we report on a variety of aminoquinolines that target the bacterial NOS active site, in part, by binding to a hydrophobic patch that is unique to bNOS. Through mutagenesis and crystallographic studies, our findings demonstrate that aminoquinolines are an excellent scaffold for further aiding in the development of bNOS specific inhibitors.

Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase.

Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding.