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.

Cardiovascular Disease Burden and Outcomes Among American Indian and Alaska Native Medicare Beneficiaries.

Importance: American Indian and Alaska Native persons face significant health disparities; however, data regarding the burden of cardiovascular disease in the current era is limited. Objective: To determine the incidence and prevalence of cardiovascular disease, the burden of comorbid conditions, including cardiovascular disease risk factors, and associated mortality among American Indian and Alaska Native patients with Medicare insurance. Design, Setting, and Participants: This was a population-based cohort study conducted from January 2015 to December 2019 using Medicare administrative data. Participants included American Indian and Alaska Native Medicare beneficiaries 65 years and older enrolled in both Medicare part A and B fee-for-service Medicare. Statistical analyses were performed from November 2022 to April 2023. Main Outcomes and Measures: The annual incidence, prevalence, and mortality associated with coronary artery disease (CAD), heart failure (HF), atrial fibrillation/flutter (AF), and cerebrovascular disease (stroke or transient ischemic attack [TIA]). Results: Among 220 598 American Indian and Alaska Native Medicare beneficiaries, the median (IQR) age was 72.5 (68.5-79.0) years, 127 402 were female (57.8%), 78 438 (38.8%) came from communities in the most economically distressed quintile in the Distressed Communities Index. In the cohort, 44.8% of patients (98 833) were diagnosed with diabetes, 61.3% (135 124) were diagnosed with hyperlipidemia, and 72.2% (159 365) were diagnosed with hypertension during the study period. The prevalence of CAD was 38.6% (61 125 patients) in 2015 and 36.7% (68 130 patients) in 2019 (P < .001). The incidence of acute myocardial infarction increased from 6.9 per 1000 person-years in 2015 to 7.7 per 1000 patient-years in 2019 (percentage change, 4.79%; P < .001). The prevalence of HF was 22.9% (36 288 patients) in 2015 and 21.4% (39 857 patients) in 2019 (P < .001). The incidence of HF increased from 26.1 per 1000 person-years in 2015 to 27.0 per 1000 person-years in 2019 (percentage change, 4.08%; P < .001). AF had a stable prevalence of 9% during the study period (2015: 9.4% [14 899 patients] vs 2019: 9.3% [25 175 patients]). The incidence of stroke or TIA decreased slightly throughout the study period (12.7 per 1000 person-years in 2015 and 12.1 per 1000 person-years in 2019; percentage change, 5.08; P = .004). Fifty percent of patients (110 244) had at least 1 severe cardiovascular condition (CAD, HF, AF, or cerebrovascular disease), and the overall mortality rate for the cohort was 19.8% (43 589 patients). Conclusions and Relevance: In this large cohort study of American Indian and Alaska Native patients with Medicare insurance in the US, results suggest a significant burden of cardiovascular disease and cardiometabolic risk factors. These results highlight the critical need for future efforts to prioritize the cardiovascular health of this population.

Primary care and survival among American Indian patients with diabetes in the Southwest United States: Evaluation of a cohort study at Gallup Indian Medical Center, 2009-2016.

OBJECTIVES: To evaluate the role of primary care healthcare delivery on survival for American Indian patients with diabetes in the southwest United States. METHODS: Data from patients with diabetes admitted to Gallup Indian Medical Center between 2009 and 2016 were analyzed using a log-rank test and Cox Proportional Hazards analyses. RESULTS: Of the 2661 patients included in analysis, 286 patients died during the study period. Having visited a primary care provider in the year prior to first admission of the study period was protective against all-cause mortality in unadjusted analysis (HR (95% CI)=0.47 (0.31, 0.73)), and after adjustment. The log-rank test indicated there is a significant difference in overall survival by primary care engagement history prior to admission (p<0.001). The median survival time for patients who had seen a primary care provider was 2322days versus 2158days for those who had not seen a primary care provider. CONCLUSIONS: Compared with those who did not see a primary care provider in the year prior to admission, having seen a primary care provider was associated with improved survival after admission.

EFFECTIVENESS OF INPATIENT INSULIN ORDER SETS USING HUMAN INSULINS IN NONCRITICALLY ILL PATIENTS IN A RURAL HOSPITAL.

OBJECTIVE: Recent guidelines recommend a physiologic approach to non-intensive care unit (ICU) inpatient glucose management utilizing basal-bolus with correctional (BBC) insulin over traditional sliding-scale insulin monotherapy. Unfortunately, few studies exist using a BBC approach restricted to human insulins (regular and neutral protamine Hagedorn [NPH]). This study evaluated changes in provider prescribing patterns, effects on blood glucose, and safety with implementation of hospital order sets for BBC using human insulins. METHODS: Order sets were developed for non-ICU inpatients, consisting of basal, prandial, and correctional insulin using NPH and regular human insulins. Evaluation compared a 4-month period before (admissions, n = 274) with a 4-month period after order set availability (n = 302). Primary outcome was change in insulin prescribing patterns. Secondary outcomes included use of nonpreferred diabetes treatments, hemoglobin A1c testing, mean daily blood glucose, and incidence of hypoglycemia. RESULTS: Use of BBC insulin regimen increased from 10.6 to 27.5% after order set implementation (P<.001). Use of oral antihyperglycemic agents decreased from 24.1 to 14.9% after implementation (P = .006). Hemoglobin A1c testing rose from 50.0 to 62.3% after (P = .003). Mean daily blood glucose improved, with an estimated mean difference of 14.4 mg/dL (95% confidence interval, 2.2 to 26.5 mg/dL) over hospital days 3 through 9 (P = .02). There was no significant change in the incidence of moderate or severe hypoglycemia. CONCLUSION: Implementation of hospital-wide human insulin order sets led to improvements in prescribing practices and blood glucose control, without increasing the incidence of hypoglycemia. These order sets may be useful for facilities limited by formulary and cost considerations to the use of older human insulins.

Na+,K+-ATPase activity and subunit protein expression: ontogeny and effects of exogenous and endogenous steroids on the cerebral cortex and renal cortex of sheep.

We examined the effects of development, exogenous, and endogenous glucocorticoids on Na(+),K(+)-ATPase activity and subunit protein expression in ovine cerebral cortices and renal cortices. Ewes at 60%, 80%, and 90% gestation, newborns, and adults received 4 dexamethasone or placebo injections. Cerebral cortex Na(+),K(+)-ATPase activity was higher (P < .05) in placebo-treated newborns than fetuses of placebo-treated ewes and adults, α(1)-expression was higher at 90% gestation than the other ages; α(2)-expression was higher in newborns than fetuses; α(3)-expression was higher in newborns than 60% gestation; ß(1)-expression was higher in newborns than the other ages, and ß(2)-expression higher at 60% than 80% and 90% gestation, and in adults. Renal cortex Na(+),K(+)-ATPase activity was higher in placebo-treated adults and newborns than fetuses. Cerebral cortex Na(+),K(+)-ATPase activity was higher in dexamethasone- than placebo-treated adults, and α(1)-expression higher in fetuses of dexamethasone- than placebo-treated ewes at 60% and 80% gestation. Renal cortex Na(+),K(+)-ATPase activity and α(1)-expression were higher in fetuses of dexamethasone- than placebo-treated ewes at each gestational age, and ß(1)-expression was higher in fetuses of dexamethasone- than placebo-treated ewes at 90% gestation and in dexamethasone- than placebo-treated adults. Cerebral cortex Na(+),K(+)-ATPase activity, α(1)-expression, ß(1)-expression, and renal cortex α(1)-expression correlated directly with increases in fetal cortisol. In conclusion, Na(+),K(+)-ATPase activity and subunit expression exhibit specific developmental patterns in brain and kidney; exogenous glucocorticoids regulate activity and subunit expression in brain and kidney at some ages; endogenous increases in fetal cortisol regulate cerebral Na(+),K(+)-ATPase, but exogenous glucocorticoids have a greater effect on renal than cerebral Na(+),K(+)-ATPase.

Cortisol is necessary for seawater tolerance in larvae of a marine teleost the summer flounder.

Larval-stage summer flounder (Paralichthys dentatus) were immersed in the corticosteroid-receptor blocker RU486 to test the effects of cortisol deficiency on salinity tolerance. Premetamorphic larvae held at 10 (near isosmotic) or 30 (hyperosmotic) parts per thousand ( per thousand) seawater survived well over 5d in 0, 0.012, or 0.12 microM RU486. However, at concentrations of 1.2 or 3.6 microM RU486, mortality was significantly greater for larvae in 30 per thousand compared to larvae in 10 per thousand. In a separate experiment, the ability of RU486 to inhibit tolerance to hyperosmotic medium (30 per thousand) was confirmed; immersion at 1.2 microM RU486 induced mortality of larvae in the metamorphic climax stage held at 30 per thousand, but not 0 or 10 per thousand. Mortality due to RU486 in pre- or prometamorphic stage larvae was prevented by concurrent immersion in cortisol at concentrations approximately 10-200 times greater than RU486, indicating that the action of RU486 was specific to antagonism of cortisol. The efficacy of 1.2 microM RU486 in reducing survival in 30 per thousand was found to be stage-dependent and exhibited the following hierarchy for fastest time to 50% mortality: prometamorphosis>metamorphic climax>premetamorphosis. In a 5-d pretreatment of pre- or prometamorphic larvae by immersion in 20 microM cortisol and/or 0.12 microM RU486 at 30 per thousand, only RU486 had a limited effect on decreasing survival when larvae were challenged with abrupt exposure to 50 per thousand. In total, the results evidence for the first time a necessary role for cortisol in seawater tolerance of a larval marine teleost.

Effects of postnatal steroids on Na+/K+-ATPase activity and alpha1- and beta1-subunit protein expression in the cerebral cortex and renal cortex of newborn lambs.

Na(+)/K(+)-ATPase is a membrane-bound enzyme responsible for Na(+)/K(+) translocation across cell membranes. It is essential for the generation of electrochemical gradients, which control the ionic environment necessary for electrical activity and water and electrolyte balance. Newborn infants who are at risk of developing bronchopulmonary dysplasia (BPD) are frequently treated with corticosteroids. Although these infants are at risk for neurological, water and electrolyte abnormalities, there is little information regarding the effects of clinically relevant doses of corticosteroids on Na(+)/K(+)-ATPase activity and protein isoform expression in the brain and kidney of newborns. In the present study, we examined the effects of dexamethasone on cerebral cortical and renal cortical Na(+)/K(+)-ATPase activity and alpha1- and beta1-protein isoform expression in newborn lambs. Lambs were given four injections of a placebo (n = 11) or one of three different doses of dexamethasone (0.01 mg kg(-1), n = 9; 0.25 mg kg(-1), n = 11; or 0.50 mg kg(-1), n = 9) 12 h apart on Postnatal Days 3 and 4 up to 18 h before harvest of the cerebral cortex and renal cortex. We selected doses in a range to approximate those used to treat infants with BPD. Na(+)/K(+)-ATPase activity was measured in membrane preparations as ouabain-sensitive inorganic phosphate liberation from ATP and alpha1- and beta1-subunit abundance by Western immunoblot. Postnatal treatment of lambs with dexamethasone resulted in a 21.4% increase in Na(+)/K(+)-ATPase activity and a 30.4% increase in catalytic alpha1-protein expression in the cerebral cortex at a dose of 0.50 mg kg(-1) dexamethasone, but not at the lower doses. Dexamethasone treatment was not associated with changes in beta1-isoform expression in the cerebral cortex. In the kidney, dexamethasone treatment was not associated with significant changes in Na(+)/K(+)-ATPase activity or alpha1- or beta1-isoform expression for the doses we examined. Therefore, clinically relevant corticosteroid treatment exerts dose-related, differential organ-specific effects on Na(+)/K(+)-ATPase activity and protein isoform expression in newborn lambs.

Localized accumulation of angiotensin II and production of angiotensin-(1-7) in rat luteal cells and effects on steroidogenesis.

These studies aim to investigate subcellular distribution of angiotensin II (ANG II) in rat luteal cells, identify other bioactive angiotensin peptides, and investigate a role for angiotensin peptides in luteal steroidogenesis. Confocal microscopy showed ANG II distributed within the cytoplasm and nuclei of luteal cells. HPLC analysis showed peaks that eluted with the same retention times as ANG-(1-7), ANG II, and ANG III. Their relative concentrations were ANG II >or= ANG-(1-7) > ANG III, and accumulation was modulated by quinapril, an inhibitor of angiotensin-converting enzyme (ACE), Z-proprolinal (ZPP), an inhibitor of prolyl endopeptidase (PEP), and parachloromercurylsulfonic acid (PCMS), an inhibitor of sulfhydryl protease. Phenylmethylsulfonyl fluoride (PMSF), a serine protease inhibitor, did not affect peptide accumulation. Quinapril, ZPP, PCMS, and PMSF, as well as losartan and PD-123319, the angiotensin receptor type 1 (AT1) and type 2 (AT2) receptor antagonists, were used in progesterone production studies. ZPP significantly reduced luteinizing hormone (LH)-dependent progesterone production (P < 0.05). Quinapril plus ZPP had a greater inhibitory effect on LH-stimulated progesterone than either inhibitor alone, but this was not reversed by exogenous ANG II or ANG-(1-7). Both PCMS and PMSF acutely blocked LH-stimulated progesterone, and PCMS blocked LH-sensitive cAMP accumulation. Losartan inhibited progesterone production in permeabilized but not intact luteal cells and was reversed by ANG II. PD-123319 had no significant effect on luteal progesterone production in either intact or permeabilized cells. These data suggest that steroidogenesis may be modulated by angiotensin peptides that act in part through intracellular AT1 receptors.