Telephone-Based Guideline-Directed Medical Therapy Optimization in Navajo Nation: The Hózhó Randomized Clinical Trial.

Importance: Underutilization of guideline-directed medical therapy for heart failure with reduced ejection fraction is a major cause of poor outcomes. For many American Indian patients receiving care through the Indian Health Service, access to care, especially cardiology care, is limited, contributing to poor uptake of recommended therapy. Objective: To examine whether a telehealth model in which guideline-directed medical therapy is initiated and titrated over the phone with remote telemonitoring using a home blood pressure cuff improves guideline-directed medical therapy use (eg, drug classes and dosage) in patients with heart failure with reduced ejection fraction in Navajo Nation. Design, Setting, and Participants: The Heart Failure Optimization at Home to Improve Outcomes (Hózhó) randomized clinical trial was a stepped-wedge, pragmatic comparative effectiveness trial conducted from February to August 2023. Patients 18 years and older with a diagnosis of heart failure with reduced ejection fraction receiving care at 2 Indian Health Service facilities in rural Navajo Nation (defined as having primary care physician with 1 clinical visit and 1 prescription filled in the last 12 months) were enrolled. Patients were randomized to the telehealth care model or usual care in a stepped-wedge fashion, with 5 time points (30-day intervals) until all patients crossed over into the intervention. Data analyses were completed in January 2024. Intervention: A phone-based telehealth model in which guideline-directed medical therapy is initiated and titrated at home, using remote telemonitoring with a home blood pressure cuff. Main Outcomes and Measures: The primary outcome was an increase in the number of guideline-directed classes of drugs filled from the pharmacy at 30 days postrandomization. Results: Of 103 enrolled American Indian patients, 42 (40.8%) were female, and the median (IQR) age was 65 (53-77) years. The median (IQR) left ventricular ejection fraction was 32% (24%-36%). The primary outcome occurred significantly more in the intervention group (66.2% vs 13.1%), thus increasing uptake of guideline-directed classes of drugs by 53% (odds ratio, 12.99; 95% CI, 6.87-24.53; P < .001). The number of patients needed to receive the telehealth intervention to result in an increase of guideline-directed drug classes was 1.88. Conclusions and Relevance: In this heart failure trial in Navajo Nation, a telephone-based strategy of remote initiation and titration for outpatients with heart failure with reduced ejection fraction led to improved rates of guideline-directed medical therapy at 30 days compared with usual care. This low-cost strategy could be expanded to other rural settings where access to care is limited. Trial Registration: ClinicalTrials.gov Identifier: NCT05792085.

Location of HIV diagnosis impacts linkage to medical care.

: We evaluated 1359 adults newly diagnosed with HIV in Philadelphia in 2010-2011 to determine if diagnosis site (medical clinic, inpatient setting, counseling and testing center (CTC), and correctional facility) impacted time to linkage to care (difference between date of diagnosis and first CD4/viral load). A total of 1093 patients (80%) linked to care: 86% diagnosed in medical clinics, 75% in inpatient settings, 62% in CTCs, and 44% in correctional facilities. Adjusting for other factors, diagnosis in inpatient settings, CTCs, and correctional facilities resulted in a 33% (adjusted hazard ratio = 0.77; 95% confidence interval: 0.64 to 0.92), 46% (0.56; 0.42-0.72), and 75% (0.25; 0.18-0.35) decrease in the probability of linkage compared with medical clinics, respectively.

Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure.

The exogenous administration of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS), has been shown to reduce left ventricular hypertrophy, fibrosis, and cardiac dysfunction in mice with pre-established heart disease induced by pressure-overload. In this setting, BH4 re-coupled endothelial NOS (eNOS), with subsequent reduction of NOS-dependent oxidative stress and reversal of maladaptive remodeling. However, recent studies suggest the effective BH4 dosing may be narrower than previously thought, potentially due to its oxidation upon oral consumption. Accordingly, we assessed the dose response of daily oral synthetic sapropterin dihydrochloride (6-R-l-erythro-5,6,7,8-tetrahydrobiopterin, 6R-BH4) on pre-established pressure-overload cardiac disease. Mice (n=64) were administered 0-400mg/kg/d BH4 by ingesting small pre-made pellets (consumed over 15-30 min). In a dose range of 36-200mg/kg/d, 6R-BH4 suppressed cardiac chamber remodeling, hypertrophy, fibrosis, and oxidative stress with pressure-overload. However, at both lower and higher doses, BH4 had less or no ameliorative effects. The effective doses correlated with a higher myocardial BH4/BH2 ratio. However, BH2 rose linearly with dose, and at the 400mg/kg/d, this lowered the BH4/BH2 ratio back toward control. These results expose a potential limitation for the clinical use of BH4, as variability of cellular redox and perhaps heart disease could produce a variable therapeutic window among individuals. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.''

Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice.

The heart initially compensates for hypertension-mediated pressure overload by enhancing its contractile force and developing hypertrophy without dilation. Gq protein-coupled receptor pathways become activated and can depress function, leading to cardiac failure. Initial adaptation mechanisms to reduce cardiac damage during such stimulation remain largely unknown. Here we have shown that this initial adaptation requires regulator of G protein signaling 2 (RGS2). Mice lacking RGS2 had a normal basal cardiac phenotype, yet responded rapidly to pressure overload, with increased myocardial Gq signaling, marked cardiac hypertrophy and failure, and early mortality. Swimming exercise, which is not accompanied by Gq activation, induced a normal cardiac response, while Rgs2 deletion in Galphaq-overexpressing hearts exacerbated hypertrophy and dilation. In vascular smooth muscle, RGS2 is activated by cGMP-dependent protein kinase (PKG), suppressing Gq-stimulated vascular contraction. In normal mice, but not Rgs2-/- mice, PKG activation by the chronic inhibition of cGMP-selective phosphodiesterase 5 (PDE5) suppressed maladaptive cardiac hypertrophy, inhibiting Gq-coupled stimuli. Importantly, PKG was similarly activated by PDE5 inhibition in myocardium from both genotypes, but PKG plasma membrane translocation was more transient in Rgs2-/- myocytes than in controls and was unaffected by PDE5 inhibition. Thus, RGS2 is required for early myocardial compensation to pressure overload and mediates the initial antihypertrophic and cardioprotective effects of PDE5 inhibitors.

Reversal of cardiac hypertrophy and fibrosis from pressure overload by tetrahydrobiopterin: efficacy of recoupling nitric oxide synthase as a therapeutic strategy.

BACKGROUND: Sustained pressure overload induces pathological cardiac hypertrophy and dysfunction. Oxidative stress linked to nitric oxide synthase (NOS) uncoupling may play an important role. We tested whether tetrahydrobiopterin (BH4) can recouple NOS and reverse preestablished advanced hypertrophy, fibrosis, and dysfunction. METHODS AND RESULTS: C57/Bl6 mice underwent transverse aortic constriction for 4 weeks, increasing cardiac mass (190%) and diastolic dimension (144%), lowering ejection fraction (-46%), and triggering NOS uncoupling and oxidative stress. Oral BH4 was then administered for 5 more weeks of pressure overload. Without reducing loading, BH4 reversed hypertrophy and fibrosis, recoupled endothelial NOS, lowered oxidant stress, and improved chamber and myocyte function, whereas untreated hearts worsened. If BH4 was started at the onset of pressure overload, it did not suppress hypertrophy over the first week when NOS activity remained preserved even in untreated transverse aortic constriction hearts. However, BH4 stopped subsequent remodeling when NOS activity was otherwise declining. A broad antioxidant, Tempol, also reduced oxidant stress yet did not recouple NOS or reverse worsened hypertrophy/fibrosis from sustained transverse aortic constriction. Microarray analysis revealed very different gene expression profiles for both treatments. BH4 did not enhance net protein kinase G activity. Finally, transgenic mice with enhanced BH4 synthesis confined to endothelial cells were unprotected against pressure overload, indicating that exogenous BH4 targeted myocytes and fibroblasts. CONCLUSIONS: NOS recoupling by exogenous BH4 ameliorates preexisting advanced cardiac hypertrophy/fibrosis and is more effective than a less targeted antioxidant approach (Tempol). These data highlight the importance of myocyte NOS uncoupling in hypertrophic heart disease and support BH4 as a potential new approach to treat this disorder.

Compartmentalization of cardiac beta-adrenergic inotropy modulation by phosphodiesterase type 5.

BACKGROUND: Recent cell-based studies have found that cGMP synthesis and hydrolysis by phosphodiesterase (PDE) appear compartmentalized, with nitric oxide synthase-derived and/or PDE type 5 (PDE-5)-hydrolyzable cGMP undetected at the sarcolemmal membrane in contrast to cGMP stimulated by natriuretic peptide. In the present study, we determine the functional significance of such compartments with a comparison of beta-adrenergic modulation by PDE-5 inhibition to that of natriuretic peptide stimulation in both cardiomyocytes and intact hearts. The potential role of differential cGMP and protein kinase G stimulation by these 2 modulators was also studied. METHODS AND RESULTS: Intact C57/BL6 mouse hearts were studied with pressure-volume analysis, and adult isolated myocytes were studied with fluorescence microscopy. PDE-5 inhibition with 0.1 to 1 micromol/L sildenafil (SIL) suppressed isoproterenol (ISO)-stimulated contractility, whereas 10 micromol/L atrial natriuretic peptide (ANP) had no effect. ISO suppression by SIL was prevented in cells pretreated with a protein kinase G inhibitor. Surprisingly, myocardial cGMP changed little with SIL+ISO yet rose nearly 5-fold with ANP, whereas protein kinase G activation (vasodilator-stimulated protein phosphorylation; ELISA assay) displayed the opposite: increased with SIL+ISO but unaltered by ANP+ISO. PDE-5 and ANP compartments were functionally separated, as inhibition of nitric oxide synthase by N(w)-nitro-L-arginine methyl ester eliminated antiadrenergic effects of SIL, yet this was not restorable by co-stimulation with ANP. CONCLUSIONS: Regulation of cardiac beta-adrenergic response by cGMP is specifically linked to a nitric oxide-synthesis/PDE-5-hydrolyzed pool signaling via protein kinase G. Natriuretic peptide stimulation achieves greater detectable increases in cGMP but not protein kinase G activity and does not modulate beta-adrenergic response. Such disparities likely contribute to differential cardiac regulation by drugs that modulate cGMP synthesis and hydrolysis.

Peroxynitrite and myocardial contractility: in vivo versus in vitro effects.

Generation of peroxynitrite (ONOO-) as a result of altered redox balance has been shown to affect cardiac function; however, inconsistencies in the data exist, particularly for myocardial contractility. The hypothesis that the cardiac impact of ONOO- formation depends on its site of generation, intravascular or intramyocardial, was examined. Cardiac contractility was assessed by pressure-volume analysis to delineate vascular versus cardiac changes on direct infusion of ONOO- into the right atria of conscious dogs both with normal cardiac function and in heart failure. Additionally, ONOO- was administered to isolated murine cardiomyocytes to mimic in situ cardiac generation. When infused in vivo, ONOO- had little impact on inotropy but led to systemic arterial dilation, likely as a result of rapid decomposition to NO2- and NO3-. In contrast, infused ONOO- was long lived enough to abolish beta-adrenergic (dobutamine)-stimulated contractility/relaxation, most likely through catecholamine oxidation to aminochrome. When administered to isolated murine cardiomyocytes, ONOO- induced a rapid reduction in sarcomere shortening and whole cell calcium transients, although neither decomposed ONOO- or NaNO2 had any effect. Thus, systemic generation of ONOO- is unlikely to have primary cardiac effects, but may modulate cardiac contractile reserve, via blunted beta-adrenergic stimulation, and vascular tone, as a result of generation of NO2- and NO3-. However, myocyte generation of ONOO- may impair contractile function by directly altering Ca2+ handling. These data demonstrate that the site of generation within the cardiovascular system largely dictates the ability of ONOO- to directly or indirectly modulate cardiac pump function.

Expression of the adenovirus E4 34k oncoprotein inhibits repair of double strand breaks in the cellular genome of a 293-based inducible cell line.

The human adenovirus E4 ORF 6 34 kDa oncoprotein (E4 34k), in concert with the 55 kDa product of E1b, prevents concatenation of viral genomes in infected cells, inhibits the repair of double strand breaks (DSBs) in the viral genome, and inhibits V(D)J recombination in a plasmid transfection assay. These activities are consistent with a general inhibition by the E4 34k and E1b 55k proteins of DSB repair by non-homologous end joining (NHEJ) on extrachromosomal substrates. To determine whether inhibition of NHEJ extends to repair of DSBs in the cell chromosome, we have examined the effects of E4 34k on repair of chromosomal DSBs induced by ionizing radiation in a cell line in which E4 34k expression and biological activity is inducible and E1b 55k is produced constitutively. We demonstrate that in this cell line, induction of E4 34k inhibits chromosomal DSB repair. Recently, it has been shown that in infected cells, E4 34k and the adenovirus E1b 55k proteins cooperate to destabilize Mre11 and Rad50, components of mammalian NHEJ systems. Consistent with this, induction of expression of E4 34k in the inducible cell line also reduces the steady state level of Mre11 protein.