Dropout in a clinical trial for comorbid PTSD and MDD among US service members: Are pretreatment characteristics predictive?

OBJECTIVE: Despite effective treatment options for posttraumatic stress disorder (PTSD), many patients do not complete therapy. This includes U.S. active duty service members, yet factors linked to attendance in this population remain understudied and dropout remains difficult to predict. Additionally, most studies have not examined samples with PTSD and co-occurring major depressive disorder (MDD) despite high rates of comorbidity. METHOD: The current study explored predictors of dropout among service members with comorbid PTSD and MDD (N = 94) randomized to cognitive processing therapy enhanced with behavioral activation (BA + CPT) or CPT as part of a clinical trial. RESULTS: Using the Fournier approach, only two predictors were associated with lower dropout risk among over 20 examined: shorter duration between pretreatment assessment and Session 1 (p = .041) and past 3-month PTSD treatment engagement (p = .036). CONCLUSION: Results suggest the possible utility of early momentum in starting therapy and leveraging recent treatment to improve attendance. However, this study also highlights the possible limitations of commonly assessed pretreatment factors in predicting attendance and current challenges in measuring dropout risk. Strategies to improve prediction, such as shifting focus to assess modifiable factors and processes more proximal to dropout during treatment, may be needed.Trial registration: ClinicalTrials.gov identifier: NCT02874131.

PTSD, depression, and treatment outcomes: A latent profile analysis among active duty personnel in a residential PTSD program.

Depression frequently co-occurs with posttraumatic stress disorder (PTSD), including among active duty service members. However, symptom heterogeneity of this comorbidity is complex and its association with treatment outcomes is poorly understood, particularly among active duty service members in residential treatment. This study used latent profile analysis (LPA) to identify symptom-based subgroups of PTSD and depression among 282 male service members in a 10-week, residential PTSD treatment program with evidence-based PTSD psychotherapies and adjunctive interventions. The PTSD Checklist-Military Version and Patient Health Questionnaire-8 were completed by service members at pre- and posttreatment and weekly during treatment. Multilevel models compared subgroups on PTSD and depression symptom change across treatment. LPA indicated four subgroups provided optimal fit: Depressive (high depression severity, low PTSD avoidance; n = 33, 11.7%), Avoidant (high PTSD avoidance, moderate depression severity; n = 89, 31.6%), Moderate (moderate PTSD and depression severity; n = 27, 9.6%), and Distressed (high PTSD and depression severity; n = 133, 47.2%). Treatment response differed across classes for both PTSD and depression outcomes (time × LPA class interaction ps < 0.001). In PTSD models, post-hoc comparisons indicated the Moderate class was associated with less PTSD symptom improvement relative to the other classes (ps < 0.006). In depression models, symptom reduction was greatest for the Distressed and Depressive subgroups relative to the other two classes (ps < 0.009). Study results provide an initial model for two prevalent, impairing disorders among service members and show how these symptom-based subgroups may differentially respond to residential PTSD treatment.

Gender Differences in Psychological Outcomes Following Surf versus Hike Therapy among U.S. Service Members.

BACKGROUND: Surf and hike therapies have demonstrated effectiveness as adjunct interventions for service members with major depressive disorder (MDD). This study explores gender differences in intervention outcomes following a pragmatic, randomized controlled trial of Surf and Hike Therapy for service members with MDD (N = 96; men, n = 46; women, n = 50). METHODS: Clinician-administered and self-report measures (depression, anxiety, positive affect, negative affect, resilience, and pain) were completed at preprogram, postprogram, and 3-month follow-up; brief measures (depression/anxiety and positive affect) were completed before and after each session. RESULTS: Multilevel modeling results showed that anxiety decreased from pre- to postprogram and significantly differed by gender (B = -2.26, p = 0.029), with women reporting greater reductions. The remaining outcomes from pre- to postprogram demonstrated significant improvements that did not differ by gender (ps = 0.218-0.733). There were no gender differences through follow-up (ps = 0.119-0.780). However, within sessions, women reported greater improvements in depression/anxiety (B = -0.93, p = 0.005) and positive affect (B = 3.73, p = 0.001). The change in positive affect scores within sessions was greater for women in Hike Therapy compared to men (p = 0.016). CONCLUSIONS: Overall, results demonstrate that both genders benefit from adjunctive Surf and Hike Therapies, but women exhibit a better response in terms of longer-term anxiety and immediate psychological outcomes.

The effectiveness of the National Veterans Summer Sports Clinic for veterans with probable posttraumatic stress disorder.

Introduction: Recreational and adaptive sports programs may be beneficial therapeutic interventions for improving psychological outcomes among veterans and service members with posttraumatic stress disorder (PTSD) because they provide opportunities for exercise, socialization, respite, and time outdoors. Although there are an increasing number of sports programs for veterans and service members with PTSD, data evaluating the outcomes of such programs are limited. Materials and methods: The sample included 74 U.S. veterans who participated in the National Veterans Summer Sports Clinic (NVSSC), an annual, week-long adaptive sports program in San Diego, California. Participants were categorized into two subgroups: those who met criteria for probable PTSD using the PTSD Checklist for DSM-5 (n = 20) and those who did not (n = 54). Participants completed self-report assessments before and after each daily activity, before and after the program, and 3 months following program completion. Results: Over the course of NVSSC program participation, the diagnostic subgroups (probable PTSD vs. no PTSD) did not significantly differ on changes in depression, positive affect, negative affect, or insomnia. Compared to those without PTSD, veterans with PTSD experienced greater reduction in generalized anxiety during the program (MD = -3.07, p = 0.034). Veterans with PTSD also experienced significant improvements in PTSD symptoms at postprogram (MD = -23.76, p < 0.001). For both groups, significant benefits were shown during the program but rebounded by the 3-month follow-up. Over the course of each daily activity, positive affect (MD = 2.71, p < 0.001) and depression/anxiety scores significantly decreased (MD = -0.75, p < 0.001), with no differences between PTSD diagnostic groups across time (ps = 0.714 and 0.961, respectively). Conclusion: Veterans with and without PTSD benefited from participation in the NVSSC. Participants with probable PTSD experienced greater improvements in generalized anxiety at postprogram only; there were no other significant differences between the two groups at postprogram or at 3-month follow-up. In line with prior research, benefits for those with PTSD were lost by 3-month follow-up, suggesting that regular engagement in recreational and adaptive sports may be necessary to sustain psychological health improvements.

Comparison of behavioral activation-enhanced cognitive processing therapy and cognitive processing therapy among U.S. service members: A randomized clinical trial.

Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) frequently co-occur and can cause significant impairment. Data are lacking as to whether interventions targeting both PTSD and MDD may improve treatment outcomes among individuals with this comorbidity compared with existing evidence-based PTSD treatments alone. This randomized trial compared the effectiveness of cognitive processing therapy (CPT) enhanced with behavioral activation (BA+CPT) versus CPT among 94 service members (52 women and 42 men; age M = 28.5 years) with comorbid PTSD and MDD. The primary outcome was clinician-administered depression symptom severity on the Montgomery-Åsberg Depression Rating Scale (MADRS) from pretreatment through 3-month follow-up. Intent-to-treat analyses using multilevel models showed statistically and clinically significant decreases in MADRS scores for both conditions over time, with no significant differences between BA+CPT and CPT. Secondary depression and PTSD symptom outcomes followed a similar pattern of results. For diagnostic MDD and PTSD outcomes using available data, no statistically significant differences between treatments emerged at posttreatment or 3-month follow-up. Sessions attended, dropout rate, and treatment satisfaction did not significantly differ between treatments. Outcomes were comparable for both treatments, suggesting that BA+CPT and CPT were similarly effective psychotherapy options for comorbid PTSD and MDD.

Psychological and functional outcomes following a randomized controlled trial of surf and hike therapy for U.S. service members.

Introduction: Exercise-based interventions have established benefits for the treatment of depression and other psychological outcomes; however, limited data exist evaluating psychological, social, and functional outcomes for exercise outdoors. Methods: The current study sought to expand knowledge about the breadth of effects following outdoor exercise interventions by using data from a randomized control trial comparing Surf and Hike Therapy among 96 U.S. active duty service members with major depressive disorder (MDD). Assessments examining psychological symptoms and functioning were completed before and after the 6-week programs, and 3 months following program completion. Participants also completed assessments before and after each exercise session. Multilevel modeling was used to determine whether psychological and functional outcomes (anxiety, positive and negative affect, resilience, pain, and physical and social functioning) improved for service members receiving Surf or Hike Therapy, and whether improvements differed by intervention. Results: Study findings showed improved anxiety (p < 0.001), negative affect (p < 0.001), psychological resilience (p = 0.013), and social functioning (p < 0.001) following program participation, with no differences by intervention. Positive affect, pain, and physical functioning did not significantly improve after the program. Within sessions, positive affect (p < 0.001) and pain (p = 0.036) changed, and to a greater extent for those in the Surf Therapy condition. Conclusion: Study results suggest that both Surf Therapy and Hike Therapy can improve psychological symptoms and social functioning impairments that commonly co-occur among service members with MDD, but Surf Therapy may provide enhanced immediate effects on positive affect and pain. Clinical trial registration: ClinicalTrials.gov, NCT03302611.

A randomized controlled trial of surf and hike therapy for U.S. active duty service members with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is the most prevalent mental health disorder worldwide, including among U.S. service members. In addition to evidence-based treatments, activity-based approaches have been shown to effectively treat depressive symptoms, particularly when they occur in the natural environment. METHODS: This study compared two activity-based interventions, Surf Therapy and Hike Therapy, on depression outcomes among 96 active duty service members with MDD. Participants were randomized to 6 weeks of Surf or Hike Therapy. Clinician-administered and self-report measures were completed at preprogram, postprogram, and 3-month follow-up. A brief depression/anxiety measure was completed before and after each activity session. RESULTS: Multilevel modeling results showed that continuous depression outcomes changed significantly over time (ps < .001). Although service members in Hike Therapy reported higher average depression scores than those in Surf Therapy, the trajectory of symptom improvement did not significantly differ between groups. Regarding MDD diagnostic status, there were no significant differences between the groups at postprogram (p = .401), but Surf Therapy participants were more likely to remit from MDD than were those in Hike Therapy at the 3-month follow-up (p = .015). LIMITATIONS: The sample consisted of service members, so results may not generalize to other populations. Most participants received concurrent psychotherapy or pharmacotherapy, and, although statistically accounted for, results should be interpreted in this context. CONCLUSIONS: Both Surf and Hike Therapies appear to be effective adjunctive interventions for service members with MDD. Research is needed to examine the effectiveness of these therapies as standalone interventions. TRIAL REGISTRATION: Clinical trials registration number NCT03302611; First registered on 05/10/2017.

Bivalent hemagglutinin and neuraminidase influenza replicon particle vaccines protect pigs against influenza a virus without causing vaccine associated enhanced respiratory disease.

Alphavirus-derived RNA replicon particle (RP) vaccines represent the next generation of swine influenza A virus (IAV) vaccines, as they were shown to be safe, effective, and offer advantages over traditional vaccine platforms. IAV is a significant respiratory pathogen of swine and there is a critical need to improve current commercial swine IAV vaccine platforms. Adjuvanted whole inactivated virus (WIV) IAV swine vaccines provide limited heterologous protection and may lead to vaccine-associated enhanced respiratory disease (VAERD). This study investigated the ability of RP IAV hemagglutinin (HA) vaccines to avoid VAERD and evaluated experimental multivalent HA and neuraminidase (NA) RP vaccines. RP vaccines were formulated with HA or NA heterologous or homologous to the challenge virus in monovalent HA or HA and NA bivalent combinations (HA/NA bivalent). Pigs were vaccinated with an HA RP, HA/NA bivalent RP, or heterologous HA WIV, followed by IAV challenge and necropsy 5 days post infection. RP vaccines provided homologous protection from challenge and induced robust peripheral and local antibody responses. The RP vaccine did not induce VAERD after challenge with a virus containing the heterologous HA, in contrast to the traditional WIV vaccine. The HA monovalent and HA/NA bivalent RP vaccines showed superior protection compared to traditional WIV. Additionally, the RP platform allows greater flexibility to adjust HA and NA content to reflect circulating IAV in swine antigenic diversity.

Rural-urban disparities in the nutritional status of younger adolescents in Tanzania.

Research on geographic differences in health focuses largely on children less than five years; little is known about adolescents-and even less regarding younger adolescents-a vulnerable group at a critical stage of the life course. Africa's rapid population growth and urbanization rates, coupled with stagnant rates of undernutrition, further indicate the need for country-specific data on rural-urban health disparities to inform development policies. This study examined rural-urban disparities in body mass index-for-age-and-sex (BAZ) and height-for-age-and-sex z-scores (HAZ) among younger adolescents in Tanzania. Participants were randomly selected adolescents aged 10-14 years (N = 1,125) residing in Kilosa (rural) and Moshi (urban) districts of Tanzania. Individual and household-level data were collected using surveys and anthropometric data was collected on all adolescents. Age, sex, household living conditions, and assets were self-reported. BAZ and HAZ were calculated using the WHO reference guide. The prevalence of undernutrition was 10.9% among rural and 5.1% among urban adolescents (p<0.001). Similarly, stunting prevalence was greater in rural (64.5%) than urban (3.1%) adolescents (p<0.001). After adjusting for covariates, rural residence was significantly and inversely associated with BAZ (B = -0.29, 95% CI: -0.52, -0.70, p = 0.01), as well as with HAZ (B = -1.79, 95% CI: -2.03, -1.54, p<0.001). Self-identified males had lower BAZ (B = -0.23, 95% CI: -0.34, -0.11, p<0.001) and HAZ (B = -0.22, 95% CI: -0.35, -0.09, p = 0.001) than self-identified female adolescents. Rural-urban disparities in nutritional status were significant and gendered. Findings confirm place of residence as a key determinant of BAZ and HAZ among younger adolescents in Tanzania. Targeted gender-sensitive interventions are needed to limit growth faltering and improve health outcomes in rural settings.

Gender Differences in Psychological Outcomes Following Surf Therapy Sessions among U.S. Service Members.

Surf therapy is increasingly being used as an intervention to address various health problems, including psychological symptoms. Although recent research supports the positive impact of surf therapy on psychological outcomes, it is unclear whether these outcomes differ between men and women. This study compared changes in depression/anxiety (Patient Health Questionnaire-4), positive affect (Positive and Negative Affect Schedule), and pain (Numerical Pain Rating Scale) between U.S. service men and women (N = 74) during six weekly surf therapy sessions. Overall, participants reported decreased depression/anxiety (p < 0.001) and increased positive affect (p < 0.001), but no change in pain rating following each session (p = 0.141). Significant gender differences were found in the magnitude of changes in depression/anxiety (B = -1.01, p = 0.008) and positive affect (B = 4.53, p < 0.001) during surf sessions, despite no differences in pre-session scores on either outcome. Women showed greater improvements in depression/anxiety and positive affect compared with men-an important finding, given that surfing and military environments are often socially dominated by men. Future research is needed to replicate these findings in other samples, extend this research to other underrepresented populations, and identify barriers and facilitators of the sustainable implementation of surf therapy across populations.

Toward a science of delivering aid with dignity: Experimental evidence and local forecasts from Kenya.

How can governments and nonprofits design aid programs that afford dignity and facilitate beneficial outcomes for recipients? We conceptualize dignity as a state that manifests when the stigma associated with receiving aid is countered and recipients are empowered, both in culturally resonant ways. Yet materials from the largest cash transfer programs in Africa predominantly characterize recipients as needy and vulnerable. Three studies examined the causal effects of alternative aid narratives on cash transfer recipients and donors. In study 1, residents of low-income settlements in Nairobi, Kenya (N = 565) received cash-based aid accompanied by a randomly assigned narrative: the default deficit-focused "Poverty Alleviation" narrative, an "Individual Empowerment" narrative, or a "Community Empowerment" narrative. They then chose whether to spend time building business skills or watching leisure videos. Both empowerment narratives improved self-efficacy and anticipated social mobility, but only the "Community Empowerment" narrative significantly motivated recipients' choice to build skills and reduced stigma. Given the diverse settings in which aid is delivered, how can organizations quickly identify effective narratives in a context? We asked recipients to predict which narrative would best motivate skill-building in their community. In study 2, this "local forecasting" methodology outperformed participant evaluations and experimental pilots in accurately ranking treatments. Finally, study 3 confirmed that the narrative most effective for recipients did not undermine donors' willingness to contribute to the program. Together these studies show that responding to recipients' psychological and sociocultural realities in the design of aid can afford recipients dignity and help realize aid's potential.

Comparison of surf and hike therapy for active duty service members with major depressive disorder: Study protocol for a randomized controlled trial of novel interventions in a naturalistic setting.

Many active duty service members suffer from major depressive disorder (MDD). Although traditional treatments exist, alternative approaches may also be effective in treating depressive symptoms. Previous research has shown that physical activity has significant positive effects on depression symptoms in individuals with MDD, and that these benefits may be enhanced when physical activity occurs in a natural environment. Even though physical activity (i.e., hiking, walking) in natural environments has been shown to reduce depressive symptoms, water-based activity occurring in a natural environment (e.g., surfing) may produce even greater improvements in depressive symptoms. We detail an ongoing randomized controlled trial (RCT) comparing the efficacy of surf therapy and hike therapy with respect to immediate and longer-term psychological, physical, and functional outcomes in active duty service members with MDD. We describe the methodological development of this RCT evaluating novel treatment approaches and discuss considerations for evaluating physical activity interventions in a naturalistic setting.

Evaluation of an integrated treatment for active duty service members with comorbid posttraumatic stress disorder and major depressive disorder: Study protocol for a randomized controlled trial.

Posttraumatic stress disorder (PTSD) commonly co-occurs with major depressive disorder (MDD) in both civilian and military/veteran populations. Existing, evidence-based PTSD treatments, such as cognitive processing therapy (CPT), often reduce symptoms of both PTSD and depression; however, findings related to the influence of comorbid MDD on PTSD treatment outcomes are mixed, and few studies use samples of individuals with both conditions. Behavioral activation (BA), an approach that relies on behavioral principles, is an effective treatment for depression. We have integrated BA into CPT (BA+CPT), a more cognitive approach, to address depressive symptoms among active duty service members with both PTSD and comorbid MDD. We describe an ongoing randomized controlled trial investigating the efficacy of our innovative, integrated BA+CPT intervention, compared with standard CPT, for active duty service members with PTSD and comorbid MDD. We detail the development of this integrated treatment, as well as the design and implementation of the randomized controlled trial, to evaluate its effect on symptoms.

Porcine reproductive and respiratory disease virus: Evolution and recombination yields distinct ORF5 RFLP 1-7-4 viruses with individual pathogenicity.

Recent cases of porcine reproductive and respiratory syndrome virus (PRRSV) infection in United States swine-herds have been associated with high mortality in piglets and severe morbidity in sows. Analysis of the ORF5 gene from such clinical cases revealed a unique restriction fragment polymorphism (RFLP) of 1-7-4. The genome diversity of seventeen of these viruses (81.4% to 99.8% identical; collected 2013-2015) and the pathogenicity of 4 representative viruses were compared to that of SDSU73, a known moderately virulent strain. Recombination analyses revealed genomic breakpoints in structural and nonstructural regions of the genomes with evidence for recombination events between lineages. Pathogenicity varied between the isolates and the patterns were not consistent. IA/2014/NADC34, IA/2013/ISU-1 and IN/2014/ISU-5 caused more severe disease, and IA/2014/ISU-2 did not cause pyrexia and had little effect on pig growth. ORF5 RFLP genotyping was ineffectual in providing insight into isolate pathogenicity and that other parameters of virulence remain to be identified.

Measuring self-efficacy, executive function, and temporal discounting in Kenya.

Developing countries have low adherence to medical regimens like water chlorination or antenatal and postnatal care, contributing to high infant and child mortality rates. We hypothesize that high levels of stress affect adherence through temporal discounting, self-efficacy, and executive control. Measurement of these constructs in developing countries requires adaptation of existing measures. In the current study, we adapt psychological scales and behavioral tasks, measuring each of these three constructs, for use among adults in Kenya. We translated and back-translated each measure to Kiswahili and conducted cognitive interviewing to establish cultural acceptability, refined existing behavioral tasks, and developed new ones. Then, in a laboratory session lasting 3 h, participants (N=511) completed the adapted psychological inventories and behavioral tasks. We report the psychometric properties of these measures. We find relatively low reliability and poor correlational evidence between psychological scales and behavioral tasks measuring the same construct, highlighting the challenges of adapting measures across cultures, and suggesting that assays within the same domain may tap distinct underlying processes.

Sexual Contact in Childhood, Revictimization, and Lifetime Sexual and Psychological Outcomes.

Using data from the 2010 to 2011 wave of the National Social Life, Health, and Aging Project-a nationally representative probability sample of older U.S. adults-this study queried distinctive linkages of mild and of severe childhood sexual contact with lifetime sexual and psychological outcomes among women and men aged 60-99 years (N = 3283). In addition, we examined stratification of these associations by sexual revictimization (forced sex and/or harassment). Among women, sequelae of childhood contact seemed consistently negative for the mild rather than severe variant-but only in the co-presence of revictimization-a pattern that may have remained obscured in previous analysis of event effects. Men's results suggested lifelong eroticizing but not psychological effects of this early experience-with the co-presence of revictimization potentially enhancing rather than lowering their mental health. Overall, findings appeared to reflect gendered patterns of risk-with mild childhood contact potentially channeling women but not men into revictimization and finally to elevated sexuality and poor mental health in late life. Early sexual experiences should thus be conceptualized not as singular events, but as part of a lifelong career with regularities and rhythms that may influence their pathogenic potential.

Prodeath signaling of G protein-coupled receptor kinase 2 in cardiac myocytes after ischemic stress occurs via extracellular signal-regulated kinase-dependent heat shock protein 90-mediated mitochondrial targeting.

RATIONALE: G protein-coupled receptor kinase 2 (GRK2) is abundantly expressed in the heart, and its expression and activity are increased in injured or stressed myocardium. This upregulation has been shown to be pathological. GRK2 can promote cell death in ischemic myocytes, and its inhibition by a peptide comprising the last 194 amino acids of GRK2 (known as carboxyl-terminus of ß-adrenergic receptor kinase [bARKct]) is cardioprotective. OBJECTIVE: The aim of this study was to elucidate the signaling mechanism that accounts for the prodeath signaling seen in the presence of elevated GRK2 and the cardioprotection afforded by the carboxyl-terminus of ß-adrenergic receptor kinase. METHODS AND RESULTS: Using in vivo mouse models of ischemic injury and also cultured myocytes, we found that GRK2 localizes to mitochondria, providing novel insight into GRK2-dependent pathophysiological signaling mechanisms. Mitochondrial localization of GRK2 in cardiomyocytes was enhanced after ischemic and oxidative stress, events that induced prodeath signaling. Localization of GRK2 to mitochondria was dependent on phosphorylation at residue Ser670 within its extreme carboxyl-terminus by extracellular signal-regulated kinases, resulting in enhanced GRK2 binding to heat shock protein 90, which chaperoned GRK2 to mitochondria. Mechanistic studies in vivo and in vitro showed that extracellular signal-regulated kinase regulation of the C-tail of GRK2 was an absolute requirement for stress-induced, mitochondrial-dependent prodeath signaling, and blocking this led to cardioprotection. Elevated mitochondrial GRK2 also caused increased Ca(2+)-induced opening of the mitochondrial permeability transition pore, a key step in cellular injury. CONCLUSIONS: We identify GRK2 as a prodeath kinase in the heart, acting in a novel manner through mitochondrial localization via extracellular signal-regulated kinase regulation.

G protein-coupled receptor kinase 2 activity impairs cardiac glucose uptake and promotes insulin resistance after myocardial ischemia.

BACKGROUND: Alterations in cardiac energy metabolism downstream of neurohormonal stimulation play a crucial role in the pathogenesis of heart failure. The chronic adrenergic stimulation that accompanies heart failure is a signaling abnormality that leads to the upregulation of G protein-coupled receptor kinase 2 (GRK2), which is pathological in the myocyte during disease progression in part owing to uncoupling of the ß-adrenergic receptor system. In this study, we explored the possibility that enhanced GRK2 expression and activity, as seen during heart failure, can negatively affect cardiac metabolism as part of its pathogenic profile. METHODS AND RESULTS: Positron emission tomography studies revealed in transgenic mice that cardiac-specific overexpression of GRK2 negatively affected cardiac metabolism by inhibiting glucose uptake and desensitization of insulin signaling, which increases after ischemic injury and precedes heart failure development. Mechanistically, GRK2 interacts with and directly phosphorylates insulin receptor substrate-1 in cardiomyocytes, causing insulin-dependent negative signaling feedback, including inhibition of membrane translocation of the glucose transporter GLUT4. This identifies insulin receptor substrate-1 as a novel nonreceptor target for GRK2 and represents a new pathological mechanism for this kinase in the failing heart. Importantly, inhibition of GRK2 activity prevents postischemic defects in myocardial insulin signaling and improves cardiac metabolism via normalized glucose uptake, which appears to participate in GRK2-targeted prevention of heart failure. CONCLUSIONS: Our data provide novel insights into how GRK2 is pathological in the injured heart. Moreover, it appears to be a critical mechanistic link within neurohormonal crosstalk governing cardiac contractile signaling/function through ß-adrenergic receptors and metabolism through the insulin receptor.

Dynamic changes in lymphocyte GRK2 levels in cardiac transplant patients: a biomarker for left ventricular function.

G protein-coupled receptor kinase 2 (GRK2), which is upregulated in the failing human myocardium, appears to have a role in heart failure (HF) pathogenesis. In peripheral lymphocytes, GRK2 expression has been shown to reflect myocardial levels. This study represents an attempt to define the role for GRK2 as a potential biomarker of left ventricular function in HF patients. We obtained blood from 24 HF patients before and after heart transplantation and followed them for up to 1 year, also recording hemodynamic data and histological results from endomyocardial biopsies. We determined blood GRK2 protein by Western blotting and enzyme-linked immunosorbent assay. GRK2 levels were obtained before transplant and at first posttransplant biopsy. GRK2 levels significantly declined after transplant and remained low over the course of the study period. After transplantation, we found that blood GRK2 significantly dropped and remained low consistent with improved cardiac function in the transplanted heart. Blood GRK2 has potential as a biomarker for myocardial function in end-stage HF.