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.

Is depression after an acute coronary syndrome simply a marker of known prognostic factors for mortality?

OBJECTIVE: Controversy remains over whether the association between depression and mortality in patients with acute coronary syndrome (ACS) is confounded by incomplete adjustment for measures of known prognostic markers. We assessed a) whether depression was associated with the most comprehensive empirically derived index of clinical mortality predictors: the Global Registry of Acute Coronary Events (GRACE) risk score for predicting 6-month mortality after discharge for ACS; and b) whether depression remained an independent predictor of all-cause mortality after adjustment for the GRACE score and left ventricular dysfunction. METHODS: We surveyed prospectively 457 patients with ACS (aged 25-92 years; 41% women, 13% black, and 11% Hispanic), hospitalized between May 2003 and June 2005. Depressive symptoms were assessed with the Beck Depression Inventory (BDI) and diagnosis of major depressive disorder (MDD) was made by a structured psychiatric interview, within 1 week of hospitalization. RESULTS: Despite differences in individual components of the GRACE score between depressed and nondepressed participants, neither depression measure was associated with overall GRACE score. For participants with MDD, the mean +/- standard deviation GRACE score was 84 +/- 33, compared with 92 +/- 31 for those without MDD (p = .09). Using Cox proportional hazards regression analysis, MDD and depressive symptom severity each predicted mortality after controlling for GRACE score and left ventricular dysfunction (adjusted hazard ratio for MDD = 2.51; 95% Confidence Interval = 1.45-4.37). CONCLUSION: Depression is not simply a marker of clinical indicators that predict all-cause mortality after ACS. This strengthens the assertion that there is something unique in the association between depression and post-ACS prognosis, independent of known prognostic markers.

Targeting the mitochondria to augment myocardial protection.

The dynamic regulation of the structure, function and turnover of mitochondria is recognized as an immutable control node maintaining cellular integrity and homeostasis. The term 'mitohormesis' has recently been coined to describe the adaptive reprogramming of mitochondrial biology in response to low levels of metabolic substrate deprivation to augment subsequent mitochondrial and cellular tolerance to biological stress. Disruption of these regulatory programs gives rise to cardiovascular and neurodegenerative diseases, and augmentation or fine-tuning of these programs may ameliorate mitochondrial and global cellular stress tolerance. This is in part via the regulation of reactive oxygen species, calcium homeostasis, and in response to caloric restriction, the capacity to augment DNA repair. The objective of this manuscript is to briefly review these regulatory programs and to postulate novel therapeutic approaches with the primary goal of modulating mitochondria to enhance tolerance to cardiac ischemic stress.

A mixed methods study of symptom perception in patients with chronic heart failure.

BACKGROUND: Early heart failure (HF) symptoms are frequently unrecognized for reasons that are unclear. We explored symptom perception in patients with chronic HF. METHODS: We enrolled 36 HF out-patients into a longitudinal sequential explanatory mixed methods study. We used objectively measured thoracic fluid accumulation and daily reports of signs and symptoms to evaluate accuracy of detected changes in fluid retention. Patterns of symptom interpretation and response were explored in telephone interviews conducted every 2 weeks for 3-months. RESULTS: In this sample, 44% had a mismatch between objective and subjective fluid retention; younger persons were more likely to have mismatch. In interviews, two patterns were identified: those able to interpret and respond appropriately to symptoms were higher in decision-making skill and the quality of social support received. CONCLUSION: Many HF patients were poor at interpreting and managing their symptoms. These results suggest a subgroup of patients to target for intervention.

Human resistin in chemotherapy-induced heart failure in humanized male mice and in women treated for breast cancer.

Resistin is a circulating mediator of insulin resistance mainly expressed in human monocytes and responsive to inflammatory stimuli. Recent clinical studies have connected elevated resistin levels with the development and severity of heart failure. To further our understanding of the role of human resistin in heart failure, we studied a humanized mouse model lacking murine resistin but transgenic for the human Retn gene (Hum-Retn mice), which exhibits basal and inflammation-stimulated resistin levels similar to humans. Specifically, we explored whether resistin underlies acute anthracycline-induced cardiotoxicity. Remarkably, doxorubicin (25mg/kg ip) led to a 4-fold induction of serum resistin levels in Hum-Retn mice. Moreover, doxorubicin-induced cardiotoxicity was greater in the Hum-Retn mice than in littermate controls not expressing human resistin (Retn(-/-)). Hum-Retn mice showed increased cardiac mRNA levels of inflammatory and cell adhesion genes compared with Retn(-/-) mice. Macrophages, but not cardiomyocytes, from Hum-Retn mice treated with doxorubicin in vitro showed dramatic induction of hRetn (human resistin) mRNA and protein expression. We also examined resistin levels in anthracycline-treated breast cancer patients with and without cardiotoxicity. Intriguingly, serum resistin levels in women undergoing anthracycline-containing chemotherapy increased significantly at 3 months and remained elevated at 6 months in those with subsequent cardiotoxicity. Further, elevation in resistin correlated with decline in ejection fraction in these women. These results suggest that elevated resistin is a biomarker of anthracycline-induced cardiotoxicity and may contribute in the development of heart failure via its direct effects on macrophages. These results further implicate resistin as a link between inflammation, metabolism, and heart disease.

Human resistin: found in translation from mouse to man.

The discovery of resistin 10 years ago as a fat cell-secreted factor that modulates insulin resistance suggested a link to the current obesity-associated epidemics of diabetes and cardiovascular disease, which are major human health concerns. Although adipocyte-derived resistin is indisputably linked to insulin resistance in rodent models, the relevance of human resistin is complicated because human resistin is secreted by macrophages rather than adipocytes, and because of the descriptive nature of human epidemiology. In this review, we examine the recent and growing evidence that human resistin is an inflammatory biomarker and a potential mediator of diabetes and cardiovascular disease.

PGC-1alpha integrates insulin signaling, mitochondrial regulation, and bioenergetic function in skeletal muscle.

The pathophysiology underlying mitochondrial dysfunction in insulin-resistant skeletal muscle is incompletely characterized. To further delineate this we investigated the interaction between insulin signaling, mitochondrial regulation, and function in C2C12 myotubes and in skeletal muscle. In myotubes elevated insulin and glucose disrupt insulin signaling, mitochondrial biogenesis, and mitochondrial bioenergetics. The insulin-sensitizing thiazolidinedione pioglitazone restores these perturbations in parallel with induction of the mitochondrial biogenesis regulator PGC-1alpha. Overexpression of PGC-1alpha rescues insulin signaling and mitochondrial bioenergetics, and its silencing concordantly disrupts insulin signaling and mitochondrial bioenergetics. In primary skeletal myoblasts pioglitazone also up-regulates PGC-1alpha expression and restores the insulin-resistant mitochondrial bioenergetic profile. In parallel, pioglitazone up-regulates PGC-1alpha in db/db mouse skeletal muscle. Interestingly, the small interfering RNA knockdown of the insulin receptor in C2C12 myotubes down-regulates PGC-1alpha and attenuates mitochondrial bioenergetics. Concordantly, mitochondrial bioenergetics are blunted in insulin receptor knock-out mouse-derived skeletal myoblasts. Taken together these data demonstrate that elevated glucose and insulin impairs and pioglitazone restores skeletal myotube insulin signaling, mitochondrial regulation, and bioenergetics. Pioglitazone functions in part via the induction of PGC-1alpha. Moreover, PGC-1alpha is identified as a bidirectional regulatory link integrating insulin-signaling and mitochondrial homeostasis in skeletal muscle.

A discordance in rosiglitazone mediated insulin sensitization and skeletal muscle mitochondrial content/activity in Type 2 diabetes mellitus.

Skeletal muscle mitochondrial dysfunction is hypothesized to contribute to the pathophysiology of insulin resistance and Type 2 diabetes. Whether thiazolidinedione therapy enhances skeletal muscle mitochondrial function as a component of its insulin-sensitizing effect is unknown. To test this, we evaluated skeletal muscle mitochondria and exercise capacity in Type 2 diabetic subjects with otherwise normal cardiopulmonary function in response to rosiglitazone therapy. Twenty-three subjects were treated for 12 wk and underwent pre- and posttherapy metabolic stress testing and skeletal muscle biopsies. Rosiglitazone significantly ameliorated fasting glucose, insulin, and free fatty acid levels but did not augment the subjects' maximal oxygen consumption (Vo(2max)) or their skeletal muscle mitochondrial copy number. The baseline Vo(2max) correlated strongly with muscle mitochondrial copy number (r = 0.56, P = 0.018, n = 17) and inversely with the duration of diabetes (r = -0.67, P = 0.004, n = 23). Despite the global lack of effect of rosiglitazone-mediated insulin sensitization on skeletal muscle mitochondria, subjects with the most preserved functional capacity demonstrated some plasticity in their mitochondria biology as evidenced by an upregulation of electron transfer chain proteins and in citrate synthase activity. This study demonstrates that the augmentation of skeletal muscle mitochondrial electron transfer chain content and/or bioenergetics is not a prerequisite for rosiglitazone-mediated improved insulin sensitivity. Moreover, in diabetic subjects, Vo(2max) reflects the duration of diabetes and skeletal muscle mitochondrial content. It remains to be determined whether longer-term insulin sensitization therapy with rosiglitazone will augment skeletal muscle mitochondrial bioenergetics in those diabetic subjects with relatively preserved basal aerobic capacity.